Doctor of Philosophy Doctor of Philosophy

PhD Thesis entitled

“Design, Development and Optimization of Controlled Release Gastroretentive Drug Delivery Systems of Hypoglycemic Drug(s)” Submitted To

Maharshi Dayanand University, Rohtak For the Award of Degree of

Doctor of Philosophy (Pharmaceutical Sciences) Submitted by: Mr Lalit Singh Registration No. : 08/PH.D./PHARMACEUTICAL SCIENCES-6

Supervisors: Dr. Arun Nanda Professor & Dean Faculty of Pharmaceutical Sciences Maharshi Dayanand University Rohtak

Dr. Bhupinder Singh Bhoop Professor & Dean, Faculty of Pharma Sciences Coordinator, UGC Centre of Advanced Studies University Institute of Pharmaceutical Sciences Panjab University, Chandigarh

Department of Pharmaceutical Sciences Maharshi Dayanand University, Rohtak 2014

Index Chapter

Section

1 1.1. 2 2.1. 2.1.1. 2.1.2. 2.1.2.1. 2.1.2.2. 2.1.2.3. 2.1.2.3.1. 2.1.2.3.2. 2.1.2.4. 2.1.2.4.1. 2.1.2.4.2.

2.1.3. 2.1.4. 2.1.5.

2.1.6.

2.1.7.

2.1.8.

Title

Page No

Certificates Acknowledgements List of tables List of figures List of abbreviations

I-II III-IV V-VIII IX-XI XII-XIII

AIMS AND OBJECTIVES Aims and objectives of the investigation

1-2

INTRODUCTION Dosage Forms Modified Release Oral Drug Delivery Systems Approaches to Gastroretention Co-administration of Pharmacological Agents that Slow Gastric Motility Bioadhesive Systems Size-Increasing Systems Expanding Swellable Systems A) Super porous hydrogel systems Unfolding and Modified-Shape Systems Density-Controlled Systems High Density Systems Floating Systems • Non-Effervescent Floating Drug Delivery Systems A) Colloidal gel barrier systems B) Hollow microspheres • Effervescent Floating Drug Delivery Systems A) Gas-generating systems B) Volatile liquid containing systems Basic Anatomy of Stomach and Gastrointestinal Tract Physiology Factors Affecting Gastric Retention Formulation of Stomach Specific Dosage Forms A) Hydrocolloids B) Inert fatty materials C) Buoyancy increasing agents D) Miscellaneous Evaluation of Stomach Specific Systems A) Bioadhesive systems B) Magnetic systems C) Swelling and expanding systems D) Floating drug delivery systems Types of Floating Dosage Forms A) Floating bilayer compressed matrices B) Multiple-unit oral floating dosage forms C) Floatable asymmetric configuration drug delivery systems D) Floating non compressed sustained release tablets E) Microballoons Advantages of Gastroretentive Drug Delivery

3-76 3 3-5 5-6 6 7-8 8 8 9 9 9 10 10 10-11

11-12

12-14 14-15 15-16

16-18

18-19

19-20

2.1.9. 2.1.10. 2.1.11. 2.1.12.

Limitations of Gastroretentive Drug Delivery Application of Gastroretentive Drug Delivery Future Prospects and Potential Potential Drug Candidates for Gastroretentive Drug Delivery Drugs Unsuitable for Gastroretentive Drug Delivery Stability Studies Diabetes Mellitus Insulin Dependent Diabetes Mellitus (IDDM) Non-Insulin Dependent Diabetes Mellitus (NIDDM) Histopathology of Type II Diabetes Approaches to Management of Hyperglycemia in NIDDM Glipizide Sodium Alginate Controlled Drug Delivery from Alginate Matrices Application of Alginates in Oral Dosage Forms Chitosan Pharmaceutical Applications of Chitosan Hydroxypropylmethylcellulose (HPMC) Pharmaceutical Applications of HPMC Carbopol Applications of Carbopol Formulation by Design (FbD): Traditional Vs Systematic Approach Optimization: Fundamental Precepts Objective Response Experimental Domain Experimental Design Central Composite Design Mathematical Model Graphic Representation of Optimization Results Optimization Methodology Search for an Optimum Search Methods Mathematical Optimization Method Graphical Optimization • Location of the stationary point • Search method • Overlay Plot Optimization Strategy Computer Use in Optimization References

20 20-21 21 21- 22

74-123 74-105 105-106

3.2.1. 3.2.2. 3.3.

LITERATURE REVIEW Literature Review of Earlier Work An Updated Review on Systematic Design and Optimization of Oral Drug Delivery System Oral Controlled Release Matrices Gastroretentive Systems References

4.1. 4.2. 4.2.1. 4.2.2.

EXPERIMENTAL SETUP Idea and Hypothesis Experimental Setup Materials Used in Investigation Instruments Used in Investigation

124-145 124-125

2.1.13. 2.1.14. 2.2. 2.2.1. 2.2.2. 2.2.3. 2.2.4. 2.3. 2.4. 2.4.1. 2.4.2. 2.5. 2.5.1. 2.6. 2.6.1. 2.7. 2.7.1. 2.8. 2.8.1. 2.8.1.1. 2.8.1.2. 2.8.1.3. 2.8.1.4. 2.8.1.5. 2.8.1.6. 2.8.1.7. 2.8.2. 2.8.2.1. 2.8.2.1.1. 2.8.2.1.2. 2.8.2.1.3.

2.8.3. 2.8.4. 2.9. 3 3.1. 3.2.

4

22 23 23-25 25-26 26-27 28 28 29-31 31-33 33-34 34-35 36-37 37 38-39 39-40 40-42 42 42-47 48 49-50 50 50-53 53-55 55-58 58 58-60 60 60 60-61 61-62 62-63

64-65 65 66-73

106-107 107-109 110-123

126 126-127

4.2.3. 4.3. 4.3.1. 4.3.2. 4.3.3. 4.3.3.1. 4.3.3.2. 4.3.3.3. 4.3.3.4. 4.3.3.5. 4.3.3.6. 4.3.3.7. 4.3.3.7.1. 4.3.3.7.2. 4.3.3.8. 4.3.3.9. 4.3.3.10. 4.3.4.11. 4.4. 4.4.1. 4.4.2. 4.4.3. 4.4.3.1. 4.4.3.2. 4.4.3.3. 4.4.3.4. 4.4.3.5. 4.4.3.6. 4.4.3.7. 4.4.3.8. 4.4.3.9. 4.4.3.9.1. 4.4.3.9.2. 4.4.3.10. 4.4.3.11. 4.4.3.12. 4.4.3.13. 4.5. 5 5.1. 5.2. 5.3. 5.4. 5.5. 5.5.1. 5.5.2. 5.5.3. 5.5.4.

Standard Curve, of Glipizide Formulation, Optimization and Evaluation of Glipizide Floating-Bioadhesive Tablets Preliminary Studies Formulation of Floating-Bioadhesive Tablets as Per CCD Evaluation of Floating-Bioadhesive Tablets Drug Excipient Compatibility and Physical Evaluation Drug Content Tablet Swelling Ability In Vitro Buoyancy Studies In Vitro Drug Release Studies Ex Vivo bioadhesion Studies In Vivo Imaging Studies X-ray Photographic Studies in Rabbits In Vivo γ-Scintigraphic Studies in Man Data Analysis FbD Data Analysis and Validation of FbD Methodology Comparison with Marketed Formulation Accelerated Stability Studies Formulation, Optimization and Evaluation of Glipizide Floating-Bioadhesive Beads Preliminary Studies Formulation of Floating-Bioadhesive Beads as per CCD Evaluation of Floating-Bioadhesive Beads Drug Excipient Compatibility, External Appearance and Size Uniformity Studies Swelling Index Studies Scanning Electron Microscopy Studies Estimation of Glipizide Entrapment Efficiency Studies In Vitro Buoyancy Study Ex Vivo Bioadhesion Study In Vitro Glipizide Release Studies In Vivo imaging Studies X-ray Photographic Studies in Rabbits In Vivo γ-Scintigraphic Studies in Man Data Analysis Optimization Data Analysis and Validation of FbD Methodology Comparison of Drug Release of Optimized with Marketed Formulation Accelerated Stability Studies References

127 127-134

RESULTS AND DISCUSSION Selection of Drug Selection of Drug Delivery System Standard Curve of Glipizide Initial pre-Optimization Studies: Selection of Suitable Polymers, Excipients and their Levels Studies on glipizide tablets Selection of Suitable Design of Experiment Drug Excipient Compatibility, Physical Evaluation and Assay of Tablet Formulations Drug Release Studies Bioadhesion Studies

146-230 146 146-147 147-148 148-149

127-128 128-129 130 130 130 130 130 130 131 131 131 131-132 132 133 133 134 135-142 135 135-136 136 136 137 137 137-138 138 138 138-139 139 139-140 139 140 140-141 141 141 142 143-145

149-153 153 153-154 155-170 171

171-172 172-173 174-179 180-184 185-189 189-192

5.7.

Buoyancy Time Swelling Index Studies Response Surface Analysis Search for Optimum Formulations Validation of FbD Studies In Vivo Imaging Studies X-ray Photographic Studies in Rabbits In Vivo γ-scintigraphic Studies in Man Comparison of Drug Release of Optimized Formulation with Marketed Formulation Stability Studies on Optimized Formulation Studies on Floating-Bioadhesive Glipizide Beads Selection of Design of Experiment (DoE) for Preparation of Floating-Bioadhesive Glipizide Beads Drug Excipient Compatibility Studies, Physical Evaluation and Assay of Floating-Bioadhesive Beads Swelling Studies on Floating-Bioadhesive Beads Scanning Electron Microscopy Entrapment Efficiency In Vitro Buoyancy of Beads In Vitro Glipizide Release Studies Data Analysis and Drug Release Kinetics Search for Optimum Formulation Validation of Optimum Formulation In Vivo Imaging Studies for Beads X-ray Photographic Studies in Rabbits In Vivo γ-Scintigraphic Studies in Man Accelerated Stability Studies of Optimized Formulation Comparison of Drug Release of Optimized with Marketed Formulation References

6.1. 6.1.1. 6.1.2. 6.2.

SUMMARY AND CONCLUSIONS Floating-Bioadhesive Tablets Floating-Bioadhesive Beads Future Potential

231-234 232-233 233-234 234

APPENDICES Approval Letter for Human Studies Volunteer Consent Form Indian Veterinary Research Institute (IVRI) Approval for Animal Studies Gastroretention Studies Certificate from IVRI QUALICAPS Capsule Analysis Certificate

A1-A7 A1 A2-A3 A4

5.5.5. 5.5.6. 5.4.7. 5.5.8. 5.5.9. 5.5.10. 5.5.10.1. 5.5.10.2. 5.5.11. 5.5.12. 5.6. 5.6.1. 5.6.2. 5.6.3. 5.6.4. 5.6.5. 5.6.6. 5.6.7. 5.6.8. 5.6.9. 5.6.10. 5.6.11. 5.6.11.1. 5.6.11.2. 5.6.12. 5.6.13.

6

7 7.1. 7.2. 7.3. 7.4. 7.5. 8

PAPERS PUBLISHED

193-194 194 195 195-196 196-197 197 197-199 200 200-202 202-203 203-210 211-218 218-219 219-224 221 221 225 225-226 227-230

A5 A6-A7

DEPARTMENT OF PHARMACEUTICAL SCIENCES MAHARSHI DAYANAND UNIVERSITY, ROHTAK-124001 (HARYANA)

Certificate This is to certify that the contents of this thesis entitled “Design, Development and Optimization of Controlled Release Gastroretentive Drug Delivery Systems of Hypoglycemic Drug(s)” for the award of Degree of Doctor of Philosophy in “Pharmaceutical Sciences” in Faculty of Pharmaceutical Sciences, were carried out in the laboratories of Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, by Mr. Lalit Singh under our direct guidance and supervision.

The research work has not been submitted either partly or wholly for any degree to Maharshi Dayanand University, Rohtak, or any other University.

Dr. Arun Nanda Professor & Dean Faculty of Pharmaceutical Sciences Maharshi Dayanand University Rohtak (Supervisor)

Dr. Bhupinder Singh Bhoop Professor & Dean, Faculty of Pharma Sciences Coordinator, UGC Centre of Advanced Studies University Institute of Pharmaceutical Sciences Panjab University, Chandigarh (Supervisor)

Forwarded by:

Dr. B. Narasimhan

Dr. Arun Nanda

Head Department of Pharmaceutical Sciences Maharshi Dayanand University Rohtak

Dean Faculty of Pharmaceutical Sciences Maharshi Dayanand University Rohtak

I

DEPARTMENT OF PHARMACEUTICAL SCIENCES MAHARSHI DAYANAND UNIVERSITY, ROHTAK-124001 (HARYANA)

Candidate’s Declaration This is to certify that the material embodied in the present work entitled “Design, Development and Optimization of Controlled Release Gastroretentive Drug Delivery Systems of Hypoglycemic Drug(s)” is an independent investigation carried out by me under the guidance and supervision of Prof Arun Nanda and Prof Bhupinder Singh. In the thesis, references of the work done by others which have been used are cited at appropriate places. I hereby declare that the work incorporated in the present thesis is original and has not been submitted to any other university or body in quest of a degree, diploma or any other kind of academic award. My indebtness to other workers has been duly acknowledged at the relevant places.

Lalit Singh (08/PH.D./PHARMACEUTICAL SCIENCES-6)

II

Acknowledgements God a great refuge and strength of everyone is also the same for me where help is always present, when we need it most, I thank him for guiding and helping me in all rough and torn paths for always being less than a whisper away…..I thank the almighty God, for it is under His grace that we live, learn and flourish!! God’s hand is there, always guiding me and leading me to greater heights. As no research is ever the outcome of single individual’s talent or efforts. I also have seen and experienced the countless blessings showered on me by my parents, all family members, teachers, friends and all my well-wishers knowing me. It provides me pleasure to convey my sincere gratitude to all those who have directly or indirectly contributed to make this work a success. I must make special mention of some of the personalities and acknowledge my sincere indebtedness to them. This thesis is the result of six years of work during which I have been accompanied and supported by many people. First and foremost, I wish to express my deepest gratitude to my supervisors, for whom I find it difficult to get appropriate words to express the feelings fully. Speech fails me and I fumble for words to express my heartfelt gratitude and sincere thanks to my worthy guides, Prof Arun Nanda and Prof Bhupinder Singh Bhoop for their unceasing encouragement, professional guidance, helpful advices, constructive criticism, precious suggestions, crucial help and benevolent attention, enabled me to execute this project successfully. I am very grateful for their scientific support and for providing me such an interesting topic. I want to give special thanks to Prof Bhoop for providing, precious and erudite suggestions and directions, constant and untiring guidance specially in optimization studies using FbD technology where he is the most eminent personality in the country. To work under the guidance of such an eminent person has been a great and inexplicable experience, which will go a long way down my memory lane in my life. My heartily thanks go to him. Furthermore, I am very thankful to both of my guide for the opportunity to support their editorial role in various papers published. I also express my sincere gratitude to Prof M. Hoque, Department of Surgery of Indian Veterinary Research Institute (IVRI), Bareilly, for his valuable support in the in-vivo floating mucoadhesive and anti-diabetic studies at IVRI.

III

My sincere thanks are also due to Prof Y P Singla for his unconditional help and support in conducting the human studies. With great pleasure and reverence, I express my debt of profound gratitude to Dr Mrs. Sanju Nanda for her advice from the very early stage of this research as well as giving me extraordinary experiences throughout the work. Her conceptual and technical insights into my thesis work have been invaluable. Words are an inadequate medium to express my deep sense of gratitude to Ms Babita and Mr Sarwar Beg Research scholar, UIPS, Chandigarh, for their keen interest, propelling inspiration, informative and critical discussions, valuable suggestions and directions, selfless support and persistent encouragement throughout this investigation. I would also like to record my sincerest gratitude to Dr B. Narasimhan, Head, department of pharmaceutical sciences and other teachers of the department for providing the most congenial working atmosphere and excellent laboratory facility in the centre. Dr B. Narasimhan provided unflinching encouragement and support in various ways. It gives me immense pleasure to express my sincere thanks to other non- teaching and office staff of the department for their benevolent help and genuine concern. I wish to thank my friend Mr Saurabh Sharma for his kind help and support during the period of all six years of the project. I wish to thank all the staff members of my college for their involvement and friendly attitude during my work specially Mr Vijay Sharma and Mr Pratiush Saxena for their support. Gift samples of Glipizide by Cadila Pharmaceuticals Limited, Ahmedabad, HPMC by Colorcon India, HPMC capsule Shell by Qualicaps, Japan, are gratefully acknowledged. Most importantly, with my deep gratitude, I wish to thank my family for their love, constant encouragement and never-ending support over the years. Last but not the least my special thanks to Shri. Devmurti Ji Chairman SRMS Trust, Lucknow-Bareilly for his kind support in providing all necessary facilities required.

(Lalit Singh)

IV

List of Tables Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12

Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26

Table 27 Table 28 Table 28a

Different possible theoretical mechanisms of bioadhesion Some marketed products of GRDDS Comparative study of type I and type II diabeties Important pharmacokinetic parameters of glipizide Method of preparation of alginate beads Cross-linking agents used for preparation of alginate particulates Various uses of alginates in pharmaceuticals Various uses of HPMC in pharmaceuticals Various uses of Carbopol in pharmaceuticals Merits and demerits of various experimental designs Recent literature reports on gastroretentive drug delivery systems FbD formulation optimization reports on compressed oral sustained release matrices formulated using natural or semisynthetic polymers FbD formulation optimization reports on oral sustained release matrices formulated using synthetic polymers FbD formulation optimization reports on floating drug delivery systems List of materials used List of instruments used General composition of glipizide matrices during initial studies Different Ratio of Polymer taken during Initial Studies for tablet Factor combination as per central composite design for tablets Quantities of Ingredients per tablet and their percentage General composition of glipizide floating-bioadhesive beads during initial studies FbD design matrix of floating-bioadhesive beads as per CCD Various parameters of the floating bioadhesive tablets of glipizide with different polymers in 1:2 ratio Various parameters of the floating bioadhesive tablets of glipizide with different polymers in 1:5 ratio Various parameters of the floating bioadhesive tablets of glipizide with different polymers in 1:10 ratio Dissolution parameter of various floating bioadhesive glipizide formulations with different ratio of CP 934P and HPMC K4M in pre-optimization studies Physical evaluation of all the formulations prepared as per the experimental design Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT1 Regression Parameters for the batch FT1 V

Table 29 Table 29a Table 30 Table 30a Table 31 Table 31a Table 32 Table 32a Table 33 Table 33a Table 34 Table 34a Table 35 Table 35a Table 36 Table 36a Table 37 Table 37a Table 38 Table 38a Table 39 Table 39a Table 40 Table 40a Table 41 Table 42 Table 43 Table 44

Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT2 Regression Parameters for the batch FT2 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT3 Regression parameters for the batch FT3 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT4 Regression parameters for the batch FT4 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT5 Regression parameters for the batch FT5 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT6 Regression parameters for the batch FT6 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT7 Regression parameters for the batch FT7 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT8 Regression parameters for the batch FT8 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT9 Regression parameters for the batch FT9 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT10 Regression parameters for the batch FT10 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT11 Regression parameters for the batch FT11 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT12 Regression parameters for the batch FT12 Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT13 Regression parameters for the batch FT13 Overall Dissolution Parameters as per Central Composite Design for different formulations Swelling Index of all the formulations prepared as per the experimental design Values of the coefficients for the polynomial equations and R for various response variables of the glipizide tablet formulations Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Release in 16 h (Q16) VI

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52 Table 53 Table 54 Table 55 Tablet 56

Table 57 Table 58 Table 59 Table 60

Table 61

Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for 60 % Release (T60) Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Total Floating Time (Tb) Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Bioadhesive strength (BS) Intensive Grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Release in 16 h (Q16) Intensive Grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for 60 % Release (T60) Intensive Grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Total Floating Time (Tb) Intensive Grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Bioadhesive strength (BS) Physical evaluation of validation check points and optimized product Drug Release and Regression Parameters for Validation Check Points and optimized tablet Checkpoint Composition, their Results and Percentage error Drug release profile of the optimized and marketed formulation of glipizide Various parameters of the optimized formulation (TOPT) analyzed at different time points during accelerated stability studies Physicochemical Properties of floating-bioadhesive beads Entrapment efficiency and floating properties of floatingbioadhesive beads Various Kinetic Rates of floating-bioadhesive beads Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Release in 10 h (Q10) Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Entrapment efficiency (EE) VII

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70 Table 71 Table 72 Table 73

Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Floating lag time (Tlag) Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Total buoyancy (Tb) Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bead size (BSI) Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Release in 10 h (Q10) Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Entrapment efficiency (EE) Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Floating lag time (Tlag) Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Total buoyancy (Tb) Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bead size (Bsize) Physical evaluation of validation check points Various checkpoint composition and their results Stability study data for floating-bioadhesive beads Drug release profile of the BOPT and marketed brand of glipizide

VIII

List of Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Figure 7 Figure 8 Figure 9

Figure 10 Figure Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23

Intra-gastric residence positions of floating and non-floating units Anatomy of Stomach Motility patterns of the GIT in fasted state Symptoms of diabetes Mechanism of action of sulphonyl ureas Schematic representation of ‘‘Egg Box’’ model showing mechanism of reaction between calcium ions and sodium alginate leading to gelation System with controlled input variable(s) X, uncontrolled input variable(s) U, transfer function T, and output variable(s) Y Five steps strategy of formulating DDS using FbD Illustration of quantitative factors and the factor space. The axes for the natural variables, compression time and force are labeled U1, U2 and the axes of the corresponding coded variables are labeled as X1 and X2 Inter-relationship between knowledge, design and control spaces Standard curve of glipizide in 0.1 N HCl Position of the design points in (I) 22 factorial design; and (II) star design Representation of CCD (I) rectangular domain with α=1; (II) spherical domain with α = 1.414 Representation of (I) a face centered CCD; (II) a circumscribed rotatable CCD; (III) an inscribed rotatable CCD Contour lines (a) maximum; (b) saddle point; (c) ridge; and (d) rising ridge A typical response surface plotted between two factors X1 and X2 and a response variable Y Overlay plot showing the design space demarcating the optimized formulation A bird’s eye view of the overall strategy for optimization of drug formulations Bioadhesion strength of the prepared formulation using texture analyzer Standard curve of Glipizide in 0.1 N HCl Drug release profile of glipizide for various formulations employing different types of polymers with ratio of 1: 2 Drug release profile of glipizide for various formulations employing different types of polymers with ratio of 1: 5 Drug release profile of glipizide for various formulations employing different types of polymers with ratio of 1: 10 Dissolution profile of various floating-bioadhesive glipizide tablets (A, B, C) in pre-optimization studies

IX


Figure 27 Figure 28 Figure 29 Figure 30 Figure 31 Figure 32 Figure 33 Figure 34 Figure 35 Figure 36 Figure 37 Figure 38 Figure 39 Figure 40 Figure 41

Figure 42

Figure 43

Figure 44 Figure 45 Figure 46 Figure 47

IR Spectra of glipizide pure drug and tablet In vitro drug release profiles of the various batches formulated (A), and corresponding rates of drug release (B). Bar diagram showing bioadhesive strength determined as force of detachment of all the formulations prepared as per the experimental design Bar diagram showing buoyancy time determined of all the formulations prepared as per the experimental design Plot between Swelling Index and Time for various formulations prepared as per the experimental design Response Surface plot showing effect of HPMC K4M and CP 934P on drug release Corresponding contour Plots showing effect of HPMC K4M and CP 934P on drug release Response Surface plot showing effect of HPMC K4M and CP 934P on buoyancy Time Corresponding contour plot showing effect of HPMC K4M and CP 934P on buoyancy time Response Surface plot showing effect of HPMC K4M and CP 934P on bioadhesive strength Corresponding contour Plots showing effect of HPMC K4M and CP 934P on bioadhesive strength Response Surface plot showing effect of HPMC K4M and CP 934P on T60 Corresponding contour Plots showing effect of HPMC K4M and CP 934P on T60 Linear correlation and residual plots between different anticipated and experimental response variables Overlay plot showing the area for optimized formulation X-ray imaging of rabbit stomach without formulation X- ray imaging of rabbit stomach with formulation at 0h, 4h and 8h Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled tablet at different time interval Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Saurabh Sharma stomach following oral administration of 99mTc-labelled tablet at different time interval In-vitro drug release profiles of the optimized tablet and marketed formulations (A) and corresponding rates of drug release (B) IR spectra of glipizide pure drug and Beads Scanning electron micrograph of glipizide beads without chitosan Scanning electron micrograph of glipizide beads with chitosan Scanning electron micrograph of glipizide beads with chitosan enlarged view X


Figure 51 Figure 52

Figure 53 Figure 54 Figure 55 Figure 56 Figure 57 Figure 58 Figure 59 Figure 60 Figure 61 Figure 62 Figure 63 Figure 64 Figure 65 Figure 66

Figure 67

Figure 68

Scanning electron micrograph of glipizide beads with larger concentration of light liquid paraffin showing tailing Tlag of different glipizide beads batch as per experimental design Drug release (Q10) profile from various glipizide beads batch (the point GF9 represents a mean of 5 replicate runs i.e. GF9, GF10, GF11, GF12 and GF13) Response surface plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads Corresponding contour plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads Response surface plot showing the effect of polymer and light liquid paraffin concentration on total buoyancy of beads Corresponding contour plot showing the effect of polymer and light liquid paraffin concentration on total buoyancy of beads Response surface plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads Corresponding contour plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads Response surface plot showing the effect of polymer and light liquid paraffin concentration on bead size Corresponding contour plot showing the effect of polymer and light liquid paraffin concentration on bead size Response surface plot showing the effect of polymer and light liquid paraffin concentration on drug release Corresponding contour plot showing the effect of polymer and light liquid paraffin concentration on drug release from beads Overlay plot showing the design space demarcating the optimized formulation Linear correlation and residual plots between different anticipated and experimental response variables Scanning electron micrograph of optimized bead X- ray imaging of rabbit stomach without formulation X- ray imaging of rabbit stomach with formulation after 0h, 4h and 8h Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled beads at different time interval Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled beads at different time interval In-vitro drug release profiles of the optimized tablet and marketed formulations

XI

List of Abbreviations AUC BP BS Bsize CCD Cmax CP 934P CR CRDDS DDS DoE EE FDA FDDS Tlag GI GIT GRDDS GRT HBS HPMC HPMC K15M HPMC K4M IAA ICA ICH IDDM LLP MC MLRA MMC MCC NIDDM PEG Q16 Q10 Q8 RH RSM

Area under curve British Pharmacopoeia Bioadhesive strength Bead size Central Composite Design Maximum concentration of drug in blood Carbopol 934P Controlled release Controlled release drug delivery system Drug delivery system Design of Experiments Entrapment efficiency Food and Drug Administration Floating drug delivery system Floating/ buoyancy lag time Gastrointestinal Gastrointestinal tract Gastroretentive drug delivery system Gastric residence time Hydro-dynamically balanced system Hydroxypropyl methyl cellulose Hydroxypropyl methyl cellulose K15M Hydroxypropyl methyl cellulose K4M Insulin auto-antibodies Islet cell antibodies International Conference on Harmonisation Insulin-Dependent Diabetes Mellitus Light liquid paraffin Methyl cellulose Multiple linear regression analysis Migrating myloelectric cycle Microcrystalline cellulose Non-Insulin Dependent Diabetes Mellitus Polyethylene glycol Cumulative amount of drug released in 16 h Cumulative amount of drug released in 10 h Cumulative amount of drug released in 8 h Relative humidity Response surface methodology

XII

SA SEM SGF Sodium CMC T50 T60 T75 Tb UDCA USP WHO

Sodium alginate Scanning electron micrograph Simulated gastric fluid Sodium carboxy methyl cellulose Time required for 50 % drug release Time required for 60 % drug release Time required for 75 % drug release Total buocancy/Total floating time Ursodeoxycholic acid United States Pharmacopeia World Health Organization

XIII

1. Aims Aims & Objectives

“A fact is a simple statement that everyone believes. It is innocent, unless found guilty. A hypothesis is a novel suggestion that no one wants to believe. It is guilty, until found effective” ........Edward Teller

2. Introduction

“I seem like a boy playing on the sea shore & diverting myself in now and then finding a smoother pebble or prettier shell than the ordinary, whilst the great ocean of truth lay all undiscovered before me” … Issac Newton

3. Literature review

“The important thing in science science is not so much to obtain new facts as to discover new ways of thinking about them” .......William Lawrence Bragg

4. Experimental setup

“Research is to see what everybody else has seen and to think what nobody else has thought” Szent--Gyorgyi ...... Albert Szent

5. Results & Discussion

“Every great advance in science has issued from a

new audacity of imagination” .........John Dewey

6. Summary & Conclusions Conclusions

“The present contains contains nothing more than the

past & what is found in the effect was already in the cause” ...... Henri Bergson

7. Appendices

8. Papers Published

Aims and objectives

1.1. AIMS AND OBJECTIVES OF THE INVESTIGATION Easiest and predominant route of drug delivery is oral since long time. Since it is the most studied route since last decade, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate. An ideal sustained and controlled release delivery system should release the content continuously in an amount sufficient to maintain constant plasma levels once the steady state is reached. More often, drug absorption is unsatisfactory and highly variable among and between individuals, despite excellent in vitro release patterns. The reasons for this are essentially physiological and usually affected by the gastrointestinal (GI) transit of the form, especially its GRT, which appears to be one of the major causes of the overall transit time variability. Over the past three decades, the pursuit and exploration of devices designed to be retained in the upper part of the GI tract has advanced consistently in terms of technology and diversity, encompassing a variety of systems and devices such as floating systems, raft systems, expanding systems, bioadhesive systems and low-density systems. Stomach specific (gastric-retention) will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region. Also, longer residence time in the stomach could be advantageous for local action in the upper part of the small intestine, as in treatment of peptic ulcer disease. Furthermore, improved bioavailability is expected for drugs that are absorbed readily upon release in the GI tract. These drugs can be delivered ideally by slow release from the stomach. Thus various objectives were• • •

• • •

Selection of a suitable drug for making gastro retentive systems Selection of suitable dosage form(s) for gastroretention. Design development and evaluation of gastro retentive systems using Formulation by Design Formulation, optimization and evaluation of floating bioadhesive tablets Formulation, optimization and evaluation of floating beads Validation of optimized products Comparison of optimized products with marketed formulation Stability studies of optimized products

Above said aims and objectives of the present work were chased by using Central Composite Design (CCD), where as per the Design of Experiment the polymers composition (tablet) and polymer and oil composition (beads) were changed for

[Department of Pharm Sci., MDU, Rohtak]

Page 1

Aims and objectives

getting the product with appropriate properties. In vivo retention of the products was ascertained using X-ray imaging technique. Optimized products were also compared with marketed samples. The products were tested for stability by doing accelerated stability studies in zone II conditions (40 ± 2 0C/ 75 ± 5 % RH), as per ICH Q1 guidelines.

[Department of Pharm Sci., MDU, Rohtak]

Page 2

Introduction

2.1. DOSAGE FORM Illness and diseases may be treated by various methods for treating, but chemotherapy (treatment with drugs) is the most frequently used technique, as it has the broad range of applications for variety of disease states and is frequently the preferred treatment method (Gilbert, 1990). Since long time, acute disease or a chronic illness has been mostly treated by delivery of drugs to patients using various pharmaceutical dosage forms including tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectables as drug (Yie, 1992) but of course, the most favoured route - oral delivery. Oral administration is adopted wherever and whenever possible. It is safest, easiest, and most economical route of drug administration (Rawlins et al., 1992). Amongst drugs that are administered orally solid oral dosage forms, i.e., tablets and capsules, represent the preferred class of products, which have number of advantages like tamper proof, low cost, and speed of manufacturing (direct compression, flexibility in formulation for tablet), ease of administration, patient compliance etc (Garg and Shringi, 2003). The goal of any DDS is to provide a therapeutic amount of drug to the proper site of the body, to achieve minimum effective concentration promptly then to maintain, the desired therapeutic drug concentration that elicits the desired pharmacological action(s) and also to minimize the incidence and the severity of unwanted adverse effects. This goal may be achieved more conveniently by reducing a dosing frequency to once, or at most, a twice-daily regimen. An appropriately designed extended/controlled/sustained/modified release dosage form can be a major advance to achieve this goal compared to conventional immediate release dosage forms (Darshana et al., 2000). The development of improved method of drug delivery has received a lot of attention in the last two decades (Kumar et al., 1999). 2.1.1. MODIFIED RELEASE ORAL DRUG DELIVERY SYSTEMS The oral route represents nowadays the predominant and most preferable route for drug delivery. Unlike the majority of parenteral dosage forms, it allows ease of administration by the patient and it’s the natural, and therefore a highly convenient way for substances to be introduced into the human body. Oral DDS are divided into immediate release and modified release systems. Immediate

[Dept of Pharmaceutical Sciences, MDU, Rohtak]

Page 3

Introduction

release DDS are intended to disintegrate rapidly, and exhibit instant drug release. They are associated with a fast increase and decrease, and hence fluctuations in drug plasma levels, which leads to reduction or loss in drug effectiveness or increased incidence of side effects. Administration of the DDS several times per day is therefore necessary to compensate the decrease in drug plasma concentration due to metabolism and excretion. Modified release systems, on the other hand, have been developed to improve the pharmacokinetic profiles of active pharmaceutical ingredients and patient compliance, as well as reducing side effects (Eisen et al., 1990; Sansom, 1999; Getsios et al., 2004). Oral modified release DDS are most commonly used for Delayed release (e.g., by using an enteric coating); Extended release (e.g., zero-order, first-order, biphasic release, etc.); Programmed release (e.g., pulsatile, triggered, etc.) and Site specific or timed release (e.g., for colonic delivery or gastric retention). Extended, sustained or prolonged release delivery systems are terms used alternatively to describe this group of controlled drug delivery devices, with predictability and reproducibility in the drug release kinetics (Longer and Robinson, 1990). Delayed release dosage forms are distinguished from the ones mentioned above as they exhibit a pronounced lag time before the drug is released. Oral extended release dosage forms offer the opportunity to provide constant or nearly constant drug plasma levels over an extended period of time following administration (Hoffman, 1998). Extended release DDS include singleunit, such as tablets or capsules, and multiple-unit dosage forms, such as minitablets, pellets, beads or granules, either as coated or matrix devices (Kumar and Kumar, 2001). The design of oral control DDS should be primarily aimed to achieve more predictable and increased bioavailability (Bullock, 1989). Nowadays most of the pharmaceutical scientists are involved in developing the ideal DDS. This ideal system should have advantage of single dose for the whole duration of treatment and it should deliver the active drug directly at the specific site. Controlled release implies the predictability and reproducibility to control the drug release, drug concentration in target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose (Rathbone et al., 1989; Montoro, 1989). Modified extended release DDS offer


Page 4

Introduction

several advantages over conventional: i.

Avoiding drug level fluctuations by maintenance of optimal therapeutic plasma and tissue concentrations over prolonged time periods, avoiding sub-therapeutic as well as toxic concentrations, thus minimizing the risk of failure of the medical treatment and undesirable side effects;

ii.

Reducing the administered dose while achieving comparable effects;

iii.

Reduced frequency of administration leading to improved patients’ compliance and subsequently improved efficacy of the therapy and cost effectiveness;

iv.

Targeting or timing of the drug action. Hence, it is highly desirable to develop sustained DDS releasing the drug at predetermined rates to achieve optimal drug levels at the site of action.

On the other hand, drugs administered as sustained or extended release oral dosage form should comply with the following parameters: Maintain a constant plasma level over prolonged time periods; Have a broad therapeutic window to avoid health hazard to the patient in case of undesirable burst release of the nominal dose. 2.1.2. APPROACHES TO GASTRORETENTION Under certain circumstances prolonging the gastric retention of a delivery system is desirable for achieving greater therapeutic benefit of the drug substances. For example, drugs that are absorbed in the proximal part of the GI tract (Shea et al., 1990), and the drugs that are less soluble or are degraded by the alkaline pH may benefit from prolong gastric retention (Echizen and Ishizaki, 1991). In addition, for local and sustained drug delivery to the stomach and the proximal small intestine to treat certain conditions, prolonging gastric retention of the therapeutic moiety may offer numerous advantages including improved bioavailability, therapeutic efficacy and possible reduction of the dose size (Langtry, 1989; James and Raynold, 1996). It has been suggested that prolong local availability of antibacterial agents may augment their effectiveness in treating H. pylori related peptic ulcers. GRDDS however are not suitable for drugs that may cause gastric lesions, e.g., Non-steroidal anti-inflammatory agents (Gladziwa, 1988; Inotsume, 1989; Sailma, 1990; Foster and Polsker, 2000; Menger et al., 2002). Various approaches have been pursued over the last three decades, to [Dept of Pharmaceutical Sciences, MDU, Rohtak]

Page 5

Introduction

increase the retention of oral dosage forms in the stomach as depicted in Figure 1.

Figure 1: Approaches of gastroretentive systems 2.1.2.1. Co-Administration of Pharmacological Agents that slow Gastric Motility Co-administration of Pharmacological Agents includes the ingestion of Indigestible polymers (Leung et al., 1993; Russel and Bass,1985) Fatty acid salts (Keinke and Ehrlein, 1983; Malbert, 1999) It changes the motility pattern of the stomach to a fed state, thereby decreasing the gastric emptying rate and accordingly permitting prolongation of drug release (Moes, 1993; Deshpande et al., 1996; Reddy and Murthy, 2002; Klausner et al., 2003a). A number of these techniques were reported to be successful in various in vitro tests (Talukder and Fassisi, 2004; Umamaheshwari et al., 2003) and in preclinical investigations, particularly demonstrating prolonged retention in a dog model (Fix et al., 1993; Chen and Park, 2000; Davis, 2005).


Page 6

Introduction

2.1.2.2.

Bioadhesive Systems

This approach is used to localize a delivery device within the lumen and cavity of the body to enhance the drug absorption process in a site-specific manner (Itoh et al., 1986). A bioadhesive can be defined as a substance with the ability to interact with biological materials and is capable of being retained on the biological substrate for a period of time. Bioadhesion always occurs in the presence of water (Andrews et al., 2009; Park and Robinson, 1985). Table 1: Different possible theoretical mechanisms of bioadhesion S No

Theory

Bioadhesion Mechanism

Comments

1

Electronic theory

Attractive electrostatic forces Electron transfer occurs between glycoprotein mucin between the two forming a and the bioadhesive material double layer of electric charge at the interface.

2

Adsorption Surface forces resulting in Strong pri. forces: covalent chemical bonding. bonds, Weak sec. forces: ionic theory bonds, H2 bonds & Vander Waal’s forces.

3

Wetting theory

Ability of bioadhesive polymers to spread and develop intimate contact with the mucus membranes.

4

Diffusion theory

Physical entanglement of For maximum diffusion and mucin strands and the best bioadhesive strength: flexible polymer chains. solubility parameters of the Interpenetration of mucin polymer and the mucus must be strands into the porous glycol-proteins similar. structure of the polymer.

5

Fracture theory

Analyses the maximum tensile stress developed during detachment of the buccal DDS from the mucosal surfaces.

Spreading coefficients of polymers must be positive.The contact angle between polymer and cells must be near to zero

Does not require physical entanglement of bioadhesive polymer chains and mucin strands.

It involves the use of bioadhesive polymers that can adhere to the epithelial surface of the GIT. These are usually macromolecular, hydrophilic gelling substances with numerous hydrogen-bond forming groups, such as carboxyl, hydroxyl, amide and sulfate groups (e.g., crosslinked polyacrylic acids, sodium


Page 7

Introduction

carboxymethyl cellulose, sodium alginate and carrageenan). Lehr studied a broad spectrum of polymers for their bioadhesive properties and it was concluded that anionic polymers have better binding capacity than neutral or cationic polymers (Lehr, 1994). Several types of dosage forms have been proposed to allow prolonged gastric residence based on bioadhesive polymers and different mechanisms they adopt for bioadhesion are given in Table 1. 2.1.2.3.

Size-Increasing Systems

This approach involves retaining the dosage form in the stomach by increasing its size above that of the pyloric sphincter. Due to significant inter-individual variations, the cutoff size cannot be given exactly, but its diameter was reported to be 12.8 ± 7.0 mm. Streubel et al., estimated, that dosage forms should exhibit a minimum size of 13 mm for being retained in the stomach, however, even bigger units have been reported to be emptied through the pylorus (Streubel et al., 2006). In order to facilitate swallowing, the dosage form should have an initially small size. Once in the stomach, the dosage forms should quickly increase in size, to prevent premature emptying through the pylorus. In order to avoid accumulation following multiple administrations, the system should be cleared from the stomach after a predetermined time interval. In addition, the dosage form should have no effect on gastric motility or emptying process and be inexpensive for industrial manufacture (Klausner et al., 2003b). The increase in the system’s size can be based on several principles, including expansion due to swellable excipients or unfolding and/ or shape modification (to complex geometric shapes) in the stomach. 2.1.2.3.1. Expanding Swellable Systems The expansion of this type of DDS is generally due to the presence of specific hydrogel formers, which after swallowing, drastically increase in size upon contact with aqueous media. This increase in size prevents their exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be referred to as the “plug type systems” since they exhibit a tendency to remain lodged at the pyloric sphincter.


Page 8

Introduction

A) Super porous hydrogel systems These are the swellable systems where super porous hydrogels of average pore size >100 micrometer, swell to equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous open pores which are interconnected. They swell to a large size (swelling ratio: 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction (Jimenez-Castellanos et al., 1993). 2.1.2.3.2. Unfolding and Modified-Shape Systems These are non disintegrating geometric shapes moulded from silastic elastomer or extruded from polyethylene blends, which extend the GRT depending on size, shape and flexural modulus of the drug delivery device (Cargill et al., 1988; Fix et al., 1993; Kedzierewicz et al., 1999). Devices with different geometrical shapes such as continuous solid stick, tetrahedron, ring, cloverleaf, planer disk, string and pellet/sphere had been investigated (Klausner et al., 2003b). These systems consist of at least one erodible polymer (e.g., Eudragit® E, hydroxypropyl cellulose), one non-erodible polymer (e.g., polyamides, polyolefins, polyurethanes), and a drug dispersed within the polymer matrix. Cloverleaf, disk, string and pellet shapes were moulded from silastic elastomer, while tetrahedron and rigid-ring shapes were fabricated from blends of low-density polyethylene and ethylene: vinyl acetate copolymer. The devices are compressible to a size suitable for swallowing within a capsule, and are self-expandable to a size, which prevents their passage through the pylorus. Furthermore, they are sufficiently resistant to forces of the stomach to prevent rapid passage through the pylorus for a pre-determined period of time, and erode in the presence of gastric juices. In vivo studies in beagle dogs have been performed to study the systems physical characteristics, such as size, shape and flexibility on the gastric emptying (Cargill et al., 1988), after they were folded and placed in a gelatin capsule. The tetrahedron-shaped devices remained in the stomach for longer periods of time than the other shapes, while strings and pellets were eliminated fairly rapidly. 2.1.2.4.

Density-Controlled Systems

2.1.2.4.1. High Density Systems These devices use their weight as a retention mechanism. When the density of the system is larger than that of the gastric juice (~1.004 g/cm³), the device settles down to the bottom of the stomach, and remains located below the pylorus. This


Page 9

Introduction

could be accomplished by including a heavy inert material such as zinc oxide, titanium dioxide, iron powder or barium sulphate (Clarke et al., 1995; Rouge et al.,1998) into the drug containing core pellets or coating drug containing pellets with it. These materials increase density by up to 1.5–2.4 g/cm3. However, it has been reported that such devices did not significantly extend the GRT (Gupta and Robinson, 1995). 2.1.2.4.2. Floating Systems The concept of floating DDS was first described in the literature in 1968 (Davis, 1968), when Davis developed a method for overcoming the difficulty experienced by persons of gagging or choking while swallowing medicinal pills. He suggested that such difficulty could be overcome by providing pills with a density of less than 1 g/cm³, so that the pill will float on water surface. Since then several approaches have been used to develop an ideal floating system. Floating DDS or hydro-dynamically balanced systems (HBS) have a bulk density lower than the gastric fluids ( or = 6.5. They measured the activity in 12 healthy subjects, using a specific enzyme immunoassay, the serum levels of UDCA after a single oral dose of 450 mg of UDCA in three different formulations; enteric coated sinking tablet,

[Department of Pharm. Sci., MDU, Rohtak]

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Literature review

stomach-floating

enteric

coated

hard

gelatin capsule and

conventional

gelatin capsule. The effect following oral administration of enteric-coated, sinking UDCA was significantly higher than that obtained after both conventional UDCA and floating enteric coated UDCA. Atyabi et al., (1996a, 1996b) used the ion exchange resin Dowex for developing a floating tablet. The resin beads were loaded with bicarbonate and theophylline which were bound to the resin. Drug loaded resin beads were coated with a semi-permeable membrane to overcome rapid loss of CO2. After exposure to gastric media, exchange of bicarbonate and chloride ions took place and lead to the formation of CO2, which was trapped within the membrane, causing the particles to float. GRT was substantially prolonged, compared with a control, when the system was given after a light, mainly liquid meal. Furthermore, the system was capable of sustaining the drug release. Chun (1996) developed alginate microspheres of Ampicillin sodium (AMPNa) by

the emulsification

process,

acetone was used as hardening agent.

Different parameters such as the concentration of calcium chloride, the stirring time and the amount of AMP-Na were investigated. The preparation parameters had no

significant effect on

the

release of

AMP-Na from

the alginate

microspheres, although they had some effects on the physical properties and morphology of the microspheres had some effects on the physical properties and morphology of the microspheres. Deshpande et al., (1997) prepared a controlled-release gastric retention system composed of a swellable core, consisting of the drug, chlorphenramine maleate or riboflavin 5′ phosphate, and the expanding agents polyvinyl pyrolidone (PVP), Carbopol 934P and calcium carbonate. The tablet core was coated with a permeable coating, consisting of blends of Eudragit RL® 30 D and NE 30 D in different ratios. The prepared tablets swelled to 2- 4 times their original volume, and releasing the drug in a controlled manner. The optimal ratio of Eudragit® RL 30 D: NE 30 D was reported to be 70: 30, which was optimum for sufficient elasticity to withstand the pressure of expansion during the initial swelling phase, and allowing the breakdown of the tablet following release of the drug. Bhagwat et al., (1997) reported a novel solid matrix controlled release, oral dosage form where the dosage form contains a therapeutically effective amount of a sulfonylurea or a salt or derivative thereof in the matrix. Further, the use of an [Department of Pharm. Sci., MDU, Rohtak]

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Literature review

aqueous alkalizing medium afforded substantially complete bioavailability of the drug from the matrix of the tablet. The core tablets could optionally be coated with a coating material in the range of 2 % to 10 % with an enteric material or with a water insoluble material like ethyl cellulose. Ahuja et al., (1997) reported that muco-adhesion in DDS had gained interest among pharmaceutical scientists as a means of promoting dosage form residence time as well as improving intimacy of contact with various absorptive membranes of the biological system. Besides acting as platforms for sustainedrelease dosage forms, bioadhesive polymers could themselves exert some control over the rate and amount of drug release, and thus contribute to the therapeutic advantage of such systems. Ponchel and Irache (1998) reported that the concept of bio-adhesion beside its increasing popularity in alternative routes of administration (e.g., , nasal, buccal, ocular, vaginal and rectal), the systems do not seem to be a very feasible solution as this bond formation is prevented by the acidic environment and thick mucous present in the stomach. High turnover rate of the gastric mucous leads to difficulties in retaining a mucoadhesive system at the desired site. Whitehead et al., (1998) formulated multiple unit floating calcium alginate beads by freeze drying. These beads maintained a positive floating force for over 12 h, and the density measurement was done by using a helium pycnometer, found to be less than 1 g/cm3. The in-vivo behavior of this system compared to nonfloating multiple-unit dosage forms manufactured from identical material was done using γ-scintigraphy in the fed state. Prolonged GRTs of over 5.5 h were achieved for the floating formulations, while the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. Nagahara et al., (1998) augmented the anti- H. pylori effect of amoxicillin, by making mucoadhesive microspheres, which had the ability to reside in the GI tract for an extended period. The microspheres contained the antimicrobial agent and an adhesive polymer (carboxyvinyl polymer) powder dispersed in waxy hydrogenated castor oil. The percentage of amoxicillin remaining in the stomach both 2 and 4 h after oral administration of the mucoadhesive microspheres to Mongolian gerbils under fed conditions was about three times higher than that after administration in the form of a 0.5% methylcellulose suspension.


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Literature review

Rouge and Allemann (1998) studied the factors which improves the in-vitro buoyancy and drug release profile of floating minitablets containing either Piretinide or Atenolol as the model drug. The buoyancy of the minitablets was achieved either by the swelling of the excipients or by incorporating gas generating agent, sodium bicarbonate. The study concluded that it was possible to produce minitablets containing either Piretinide or Atenolol, which have a positive resultant weight during more than 6 hr and satisfactory release profile. Iannuccelli et al., (1998a) and Iannuccelli et al., (1998b) developed a multiple-unit gastroretentive DDS which contained air compartments. The units forming the system were composed of a calcium alginate core separated by an air compartment from a membrane of calcium alginate or calcium alginate/ polyvinyl acetate. Floating in-vitro and in-vivo of drug-free systems was observed. (Iannuccelli et al., 1998a; Iannuccelli et al., 1998b) Krogel and Bodmeier (1999) formulated a floating device consisting of two drugloaded HPMC matrix tablets, placed within an open impermeable, hollow polypropylene cylinder. Each matrix tablet closed one of the ends of the cylinder so that an air-filled space was created between them, which in turn provided a low, overall density of the system. The device was expected to remain floating until at least one of the tablets has dissolved. Kulkarni et al., (1999) developed and optimized, controlled release SA beads containing Diclofenac sodium by precipitation of SA in alcohol followed by crosslinking with glutaraldehyde in acidic medium. Beads were optimized by considering the percentage entrapment efficiency, swelling capacity of beads in water and their release data. The beads produced at higher temperatures and longer times of exposure to the crosslinking agent had shown the lower entrapment efficiency, but extended release of DS from the beads. Yohko and Nagahara (1999) formulated muco-adhesive microspheres containing drug and Carbopol 934P, which were dispersed within a waxy matrix of polyglycerol esters of fatty acids. The microspheres were reported to prolong the GI residence of the drug after oral administration, by adhering to the stomach mucosa in rats and Mongolian gerbils, which was due to the hydration and swelling of the Carbopol in the microspheres on contact with water. Chen et al., (2000) described superporous hydrogels, having gastroretentive


Page 79

Literature review

properties due to rapid swelling and superabsorbent properties. Equilibrium swelling was reached in less than 1 m. Improved mechanical strength was achieved by adding a composite material, such as croscarmellose sodium. In-vivo experiments in dogs, even under fasting conditions showed gastric retention for 2 – 3 h, after which they emptied into the intestine. On the other hand, in the fed state, the superporous hydrogel composites stayed in the stomach for > 24 h. Lynne et al., (2000) prepared floating alginate beads from alginate solutions containing either dissolved or suspended Amoxicillin. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. The beads retained their buoyancy when amylose and Amoxicillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy. Foster et al., (2000) reported that glipizide extended release produced better cost outcomes than metformin and acarbose in a model of 3 years' treatment of type-2 diabetes mellitus.

Glipizide extended release had pharmacoeconomic and

quality of life was advantageous, but more clinically relevant comparisons with other antidiabetic agents were needed. There were limitations to the present data, but the available pharmacoeconomic data have been favourable for glipizide extended release. Giunchedi et al., (2000) have prepared matrix

tablets of

Ketoprofen for

prolonged release by employing direct compression method using polymers like Sodium alginate, Calcium gluconate and Hydroxypropyl methyl cellulose. In-vitro release tests and erosion studies of the matrix tablets were carried out in USP phosphate buffer pH 7.4. Matrices consisting of SA alone or in combination and HPMC gave a prolonged drug release at a fairly constant rate. Only the matrices containing the highest quantity of HPMC maintained their capacity to release ketoprofen for a prolonged period of time. Jackson et al., (2000) reported extended GRTs of the positively charged ionexchange resin cholestyramine, an anionic resin, due to adhering to and coating of the gastric mucosa. On the other hand, the oppositely charged cationicexchange resin Amberlite IRP-69 did not possess the same characteristics. Such [Department of Pharm. Sci., MDU, Rohtak]

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Literature review

behaviors lead to concluding that the surface charge of the resin might play a significant role in mucoadhesion and subsequent retention. Shoufeng et al., (2001) developed an optimized gastric floating DDS for oral controlled delivery of calcium. A central composite Box-Wilson design for the controlled release of calcium was used with three formulation variables; HPMC loading, citric acid loading and magnesium stearate loading. All three formulation variables were found to significantly affect release properties. Only HPMC loading was found to be significant for floating properties. Takeuchi (2001) reported that mucoadhesive drug delivery devices offer several advantages over traditional dosage forms including the ability to optimize the therapeutic effects of a drug by controlling its release into the body. It has been shown that various types of poly (acrylic acid) (PAA) hydrogels were able to inhibit the hydrolytic activity of GI enzymes, such as trypsin, resulting in an increase of the bioavailability of the drug. Acrylic-based polymers could be used for the attachment of mucoadhesive delivery systems to the mucosa. Polymer hydrogels modified by grafting mucophilic copolymers such as poly (ethylene glycol) (PEG) onto the back-bone chains of the polymer can promote the adhesive process. Mucoadhesive nanoparticles have been used by Takeuchi for the oral administration of peptide drugs, and have been shown to be more effective with a more prolonged action as compared to non-coated system. Streubel et al., (2002) developed floating microparticles based on low-density foam powder. Oil-in-water solvent extraction/evaporation method was adopted for formulation of the floating microparticles which were composed of polypropylene foam powder. verapamil HCl as the model drug and a controlled release polymer, Eudragit® RS, EC or polymethyl methacrylate (PMMA). The microparticles were found irregular in shape and highly porous. Good in-vitro floating behavior was observed. The increase in drug release was proportional to the drug loading and inversely proportional to the amount of polymer and the release profile varied with varying the polymer type. Shoufeng, et al., (2002) studied and evaluated the contribution of formulation variables on the floating properties of gastric floating drug delivery using a continuous floating monitoring system and statistical design. several formulation variable such as different types of HPMC, varying HPMC/carbopol ratio, and addition of magnesium stearate, were evaluated using Taguchi design, and the [Department of Pharm. Sci., MDU, Rohtak]

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Literature review

effect of these variables are subjected to statistical analysis. Chung et al., (2002) evaluated and compared the pharmacokinetics and pharmaco-dynamics of immediate-release glipizide and the glipizide extended release formulation in a short-term, 5-day study. Five days of treatment with either glipizide extended release or immediate release glipizide produced similar reductions in glucose and increases in insulin and C-peptide levels. However, the pharmacokinetic profile of the glipizide extended release tablet was significantly different from that of the immediate-release glipizide tablet in that the extended release formulation resulted in lower glipizide Cmax and AUC

0-24

values. Thus, with short-term treatment, the delivery of a low steady-state concentration of the drug provided similar efficacy to that seen with higher concentrations obtained with twice-daily dosing of the immediate release formulation. Klausner et al., (2002) developed an unfolding system which was composed of multilayer, polymeric films based on a drug-containing shellac matrix as the inner layer, with outer shielding layers on both sides composed of hydrolysed gelatin/ Eudragit S/ glycerine/ glutaraldehyde. This system was optionally framed with rigid polymeric strips composed of L-poly(lactic acid)/ ethyl cellulose. Such type of dosage forms were administered to beagle dogs, after encapsulation in gelatin capsules shell. The dimensions and the mechanical properties of the films influenced the in-vivo gastric retention behavior. Prolonged residence times and improved absorption properties could be achieved with the model drug riboflavin using a ≥ 2.5 × 2.5 cm large device. Tonnesen and Karlsen (2002) studied alginate and their use in DDS and reported that naturally occurring alginate polymers have a wide potential in drug formulation due to their extensive application as food additives and their recognized lack of toxicity. Alginate can be tailor-made to suit the demands of applicants in both the pharmaceutical and biomedical areas. This group of polymers possesses a number of characteristics that make them useful as pharmaceutical aid both as a conventional excipient and more specifically as a tool in polymeric-controlled drug delivery. Chan and Heng (2002) studied cross-linking mechanisms of calcium and zinc in production of alginate microspheres prepared by emulsion cross-linking method. The microspheres cross-linked by a combination of these two salts showed [Department of Pharm. Sci., MDU, Rohtak]

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Literature review

different morphology and slower drug release compared with those crosslinked by the calcium salt alone. It was found that alginate microspheres could be successfully produced by the emulsification method using calcium chloride, but not zinc sulphate as the sole cross-linking agent. Chan et al., (2002) also studied the effect of aldehydes and methods of crosslinking

on

properties

of

calcium

alginate

microspheres

prepared

by

emulsification. Aldehydes produced varying effects on the properties of calcium alginate microspheres loaded with sulphaguanidine. Chowdary and Rao (2003) worked on mucoadhesive microspheres of glipizide for oral controlled release. Microspheres containing glipizide were prepared by orifice ionic gelation process using SA in combination with four mucoadhesive polymers such as sodium CMC, Mehylcellulose, Carbopol and HPMC. The microspheres so prepared exhibited good mucoadhesive property, slow release of drug and followed zero order kinetics after a lag period of 1 h. Garg and Sharma (2003) described a number of gastroretentive systems which were in use like FDDS, gas-generating (effervescent) systems, non-effervescent systems, bio-adhesive systems, high - density systems, large single - unit dosage forms, co - administration of gastric - emptying delaying drugs (Garg S et al., 2003). CT/alginate microcapsules were prepared by Tian, et al., (2003) by continuous air extrusion method. The influences on loading efficiency and release, such as air flow-rate, chitosan molecular weight and concentration, alginate concentration, pH of chitosan solution, ethyl cellulose, and freezing drying the capsules were studied. Adikwu et al., (2003) worked on development of bioadhesive delivery of Metformin using Prosopis Gum. The bioadhesive value of the gum was commensurate with those of Carbopol 974-P and sodium carboxymethyl cellulose.

The release of the drug was higher from prosopis gum based

bioadhesive formulations than from sodium carboxymethyl cellulose and Carbopol 974-P products. This was shown by the shorter time required to reach t50 (the time required for 50 % of the drug to be released) or t20 (time required for 20 % of the drug to be released) for the release of metformin. Qurrat-ul-Ain (2003) developed oral sustained delivery alginate microparticles [Department of Pharm. Sci., MDU, Rohtak]

Page 83

Literature review

for antitubercular drugs in order to improve patient compliance. In the study, pharmacokinetics microparticulate

and

therapeutic

antitubercular

effects

drugs,

i.e.,

of

alginate

isoniazid,

encapsulated

rifampicin

and

pyrazinamide were examined in guinea pigs. Alginate microparticles containing antitubercular drugs were evaluated for in-vitro and in-vivo

release profiles.

These microparticles exhibited sustained release of isoniazid, rifampicin and pyrazinamide for 3–5 days in plasma and up to 9 days in organs. Streubel et al., (2003) developed floating controlled DDS consisting of polypropylene foam powder. The highly porous foam powder provided low density and, thus, excellent in-vitro floating behavior of the tablets. Polymer studied in formulation of different types of matrix were, hydroxypropyl methylcellulose (HPMC), polyacrylates, SA, corn starch, carrageenan, gum guar and gum arabic. The tablets eroded upon contact with the release medium, and the relative importance of drug diffusion, polymer swelling and tablet erosion for the resulting release patterns varied significantly with the type of matrix former. Variation in the matrix-forming polymer/ foam powder ratio may effectively modify the release rate. Shoufeng et al., (2003) worked on the effect of formulation variables on drug release and floating properties of the delivery system. Hydroxypropyl methylcellulose (HPMC) of different viscosity grades and Carbopol 934P (CP934) were used to formulate the Gastric Floating Drug Delivery System (GFDDS) employing 2 ×3 full factorial design. Main effects and interaction terms of the formulation variables were evaluated quantitatively by a mathematical model. The research concluded that both HPMC viscosity and the presence of carbopol and their interaction had significant effect on the release and floating properties of the delivery system. It was observed that release rate decreases with increase in the viscosity of the polymeric system. Holte et al., (2003) worked on the sustained release of water soluble drug from directly compressed alginate tablets. In different formulations, the effect of the amount and type of alginate (Protanal LF 120 L, Protanal LF 120M, Protanal LV 120D, Protanal SF 120) on the drug release rate was evaluated. The in-vitro release studies were done in dissolution medium 0.1M HCl for 2 h followed by phosphate buffer pH 6.8.

Among the grades of alginate investigated, no

signiﬁcant difference in the resulting drug release proﬁles from the tablets was


Page 84

Literature review

found. Sustained drug release up to 16 h was achieved using SA in combination with dibasic calcium phosphate. Kubo et al., (2003) developed oral sustained delivery of paracetamol from in-situ gelling gellan and SA formulations. The potential for the oral sustained delivery of paracetamol of two formulations with in-situ gelling properties was evaluated. In-vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of six h. The bioavailability of paracetamol from the gels formed in-situ in the stomachs of rabbits following oral administration of the liquid formulations was similar to that of a commercially available suspension containing an identical dose of Paracetamol. Pandey and Khuller (2004) evaluated chemotherapeutic potential of alginate–CT microspheres as anti-tubercular drug carriers and found that administration of a single dose of alginate-CT microspheres to guinea pigs resulted in sustained drug level in plasma for 7 days and in organs for 9 days. The half life and mean residence time of the drugs were increased 13-15 fold by microspheres encapsulation, along with an enhanced relative/absolute bioavailability. Sustained release and increase in bioavailability were also observed with a sub therapeutic dose of the microspheres (Pandey R et al., 2004). Chowdary and Rao (2004) worked on mucoadhesive microspheres and reported a unique carrier system for many pharmaceuticals, which could be tailored to adhere to any mucosal tissue, including those found in eyes, oral cavity and throughout

the

respiratory,

urinary

and

GI

tract.

The

mucoadhesive

microspheres could be used not only for controlled release but also for enhancing bioavailability, for targeted delivery of the drugs to specific sites in the body. Drug delivery through mucoadhesive microspheres was a promising area for continued research with the aim of achieving controlled release with enhanced bioavailability over longer periods of time, and for drug targeting to various sites in the body. Dorozynski et al., (2004) evaluated the macromolecular polymers used as excipients for the preparation of HBS. Capsule shells were filled with various polymers such as CT, HPMC, and SA are investigated for density, hydration, erosion, and floating force. They reported that the size of the HBS influenced the floating force value. The mechanism of erosion and swelling of polymers played a dominant role in floating. [Department of Pharm. Sci., MDU, Rohtak]

Page 85

Literature review

Verma and Garg (2004) formulated and evaluated extended release formulation of glipizide based on osmotic technology. The effect of different formulation variables, namely, level of solubility modifier in the core, membrane weight gain, and level of pore former in the membrane, were studied. Drug release was found to be affected by the level of solubility modifier in the core formulation. Glipizide release was inversely proportional to the membrane weight but directly related to the initial level of pore former (PVP) in the membrane. Burst strength of the exhausted shells increased with the weight gain of the membrane. On the other hand, burst strength decreased with an increase in the level of pore former in the membrane. Drug release from the developed formulations was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Results of SEM studies showed the formation of pores in the membrane from where the drug release occurred. The numbers of pores were directly proportional to the initial level of pore former in the membrane. The manufacturing procedure was found to be reproducible and formulations were stable after 3 months of accelerated stability studies. Chaumeila et al., (2004) controlled the drug release rate of Indomethacin, through reduction of diffusion rate of the drug within the particle by impregnation of calcium alginate inside the porous microspheres.

Studied parameters were

alginate concentration, alginate diffusion time and calcium concentration. Indomethacin was loaded into the microspheres by eluting an aqueous indomethacin solution through a chromatographic column packed with impregnated microspheres. Indomethacin loading was reduced by alginate. Higo et al., (2004) developed Tetracycline–sucralfate complex under acidic conditions its mucoadhesive properties both in-vitro and in-vivo were evaluated. The complex showed excellent mucoadhesive properties, where higher amounts of the complex were retained on the gastric mucosa compared with the physical mixtures of tetracycline and sucralfate. Sinha et al., (2004) reported the great potential of a biodegradable natural polymer CT for pharmaceutical applications due to its biocompatibility, high charge density, non-toxicity and mucoadhesion. It had been shown that it not only improved the dissolution of poorly soluble drugs but also exerted a significant effect on fat metabolism in the body. Various techniques used for preparing CT microspheres and evaluations of these microspheres had also been reviewed. [Department of Pharm. Sci., MDU, Rohtak]

Page 86

Literature review

Dave et al., (2004) developed a GRDDS of ranitidine with guar gum, xanthan gum and hydroxypropyl methylcellulose K4M. Sodium bicarbonate was incorporated as a gas-generating agent. The effects of citric acid and stearic acid on drug release profile and floating properties were investigated. Results indicate that the addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile. The amounts of citric acid anhydrous (X1) and stearic acid (X2) were selected as independent variables. The time required for 50 % (t50) and 80 % drug dissolution (t80), and the similarity factor were selected as dependent variables. The results of the full factorial design showed that a less amount of citric acid and a more amount of stearic acid favors sustained release of ranitidine hydrochloride from a gastroretentive formulation. Dawan and Singhal (2004) in US Pattents. No. 6,703,045 described a composition useful for reducing serum glucose levels by an oral controlled release system and a method for treating diabetes in a human being by controlling the blood glucose level

(BGL)

and

reducing

the

complications

associated

with

diabetic

hyperglycemia and also the long term management of Non-Insulin Dependent Diabetes Mellitus (NIDDM) by avoiding the problems associated with the tight control of BGL, i.e., hypoglycemia tolerance and seizures. The composition was directed to a solid, hydrophilic matrix controlled release oral dosage form where the dosage form contains a therapeutically effective amount of antidiabetic drug in the matrix ensuring complete bioavailability of the drug from the matrix of the tablet. The formulation undergoes substantially or approaches zero order release of active drug and the concentration of the excipients and the water swellable polymers was chosen in such a way that the erosion or dissolution rate of the polymer was equal to the swelling rate of the polymer to get a constant release. Dhawan et al., (2004) studied the mucoadhesive properties of CT microspheres prepared by different methods and evaluated by studying the interaction between mucin and microspheres in aqueous solution. The interaction was determined by the measurement of mucin adsorbed on the microspheres. A strong interaction between CT microspheres and mucin was detected. The intensity of the interaction was dependent upon the method of preparation of CT microspheres and the amount of mucin added. The extent of mucus adsorption was proportional to the absolute values of the positive zeta potential of CT microspheres.


Page 87

Literature review

Hejazi and Amiji (2004) developed intra-gastric floating DDS by using HPMC K4M, CT and found that the developed delivery system has potential to increase the efficacy of the therapy and improve patient compliance. Bosch and Ryde (2005) invented nano-particulate compositions comprising glipizide. The glipizide particles of the composition preferably have an effective average particle size of less than about 2 µ. Patel et al., (2005) prepared, glipizide microspheres containing CT by simple emulsification phase separation technique using glutaraldehyde as a crosslinking agent. Results of preliminary trials indicated that volume of cross-linking agent, time for cross-linking, polymer-to-drug ratio, and speed of rotation affected characteristics of microspheres. Microspheres were discrete, spherical, and free flowing. The microspheres exhibited good mucoadhesive property in the in-vitro wash-off test and also showed a high percentage drug entrapment efficiency. Mutalik et al., (2006) prepared glipizide matrix transdermal systems using the combinations of ethyl cellulose/polyvinyl pyrrolidone and Eudragit RL100/Eudragit RS-100. The systems were evaluated for various in-vitro (drug content, drug permeation, scanning electron microscopy and drug–polymer interactions) and in-vivo (acute and long-term hypoglycemic activity, biochemical and histo-pathological studies, skin irritation and pharmacokinetic studies in mice) parameters. Drug content of the patches was found to be more than 98 %. Variations in drug permeation profiles were observed among various formulations. The in-vivo results revealed that the patches successfully prevented the severe hypoglycemia in the initial hours and they were also effective on chronic application. The transdermal route exhibited negligible skin irritation and produced better improvement with all the tested in-vivo parameters compared to oral administration. Tadakazu and Yoshiharu (2006) formulated an intra-gastric buoyant sustainedrelease tablet (IGB-T) containing Amoxicillin (AMX) to eradicate gastric H. pylori. Tablets were prepared by compressing the mixture of Hydroxypropyl celluloseH, citric acid, sodium hydrogen carbonate and AMX was employed as the basic system for preparing IGB-T. IGB-T containing AMX and HPC-H was buoyant. This system showed a sustained-release pattern in water. However, this was confirmed to be buoyant for 24 h while maintaining a tablet shape and showed a [Department of Pharm. Sci., MDU, Rohtak]

Page 88

Literature review

sustained-release pattern in water and buffer solutions of pH 1.2 and 6.8. Bhagwat et al., (2005) had taken a patent on once a day controlled release sulfonylurea anti-diabetic formulation suitable for 24 hour administration and was formulated in to solid sustained release matrix that included an alkalizing or an acidifying medium affording substantially complete bioavailability from the sustained release matrix. This method gave an improved and more economical method for stable and convenient treatment of diabetes of the type that is responsive to control by sulfonylurea anti-diabetic agents, here glipizide controlled release 24 hours formulation was developed. Ammar, et al., (2006) developed a transdermal delivery system for glipizide as a potential for convenient, safe and effective antidiabetic therapy. For this purpose, inclusion complexes of the drug in β-cyclodextrin (β- CyD), dimethyl-β-cyclodextrin (DMβ-CyD), hydroxypropyl-β-cyclodextrin (HP-β-CyD), and hydroxypropyl-γcyclodextrin (HP-γ-CyD) were prepared. And according to authors transdermal delivery system might be used for treatment of type-2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease. Fan et al., (2005) in U S Pat. 6,972,284 described about CT and method of preparing CT. Choudhury and Kar (2005) worked on a new emulsion gelation method to prepare gel beads for a highly water-soluble drug metformin hydrochloride using SA as the polymer. The gel beads containing oil was prepared by gently mixing or homogenizing oil and water phase containing SA which was then extruded into calcium chloride solution to produce gel beads. The effects of factors like type of oil and percentage of oil on the morphology and release characteristics were investigated. A variety of oils were used to study the effect on the sustaining property of the formed beads.

The oil entrapped calcium

alginate gel beads showed good sustained release. Bardonnet et al., (2006) suggested that gas-generating system inevitably have a lag time before floating on the stomach contents, during which the dosage form may undergo premature evacuation through the pyloric sphincter. Low-density system (35 g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10 h in rabbit's stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40 °C temperature 75 ± 5% relative humidity for 3 months. Brahmandam et al., (2014) investigated to formulate a novel gastro retentive system, floating tablets of Sitagliptin Phosphate, an anti diabetic agent by direct compression technique using lactose as diluent. The drug-excipients interaction was ruled out through FTIR studies. Nine formulations of Sitagliptin Phosphate tablets were prepared using HPMC K100 and HPMC K4M as release retarding agents in different concentrations of 10, 15 and 20% w/w. The prepared batches were evaluated for organoleptic properties, hardness, friability, weight variation and in vitro drug release. All the formulations showed low weight variation with rapid dispersion time and rapid in vitro dissolution. One amongst nine promising formulations, the formulation prepared by using 15% of HPMC K100 emerged as overall the best formulation. This optimized formulation showed good release profile with complete drug release within 24 hours. It was concluded that floating tablets of Sitagliptin John et al., (2014) developed floating tablets of ciprofloxacin to increase the gastric residence time. Tablets were prepared by dry granulation technique. Different grades of hydroxypropyl methylcellulose (HPMC K4M, HPMC K15M), sodium alginate and sodium bicarbonate were used for the formulation. Tablets were evaluated for their physical characteristics, viz., hardness, thickness, friability, and weight variation, drug content and floating properties. Further tablets were studied for in vitro drug release pattern over the dissolution medium. Non-Fickian diffusion was confirmed as the drug release mechanism from these tablets, indicating that water diffusion and polymer rearrangement proved as the essential role in drug release. The ideal formulation was selected based on in vitro characteristics and was preceded with in-vivo radiographic studies by incorporating barium sulphate. The in-vivo x-ray studies revealed that the tablets were in floating stage in the rabbit stomach up to 8 hours. Thus it was concluded that the sustained release formulation containing Ciprofloxacin hydrochloride was found to improve patient compliance, minimize the side effect and decrease the frequency of administration. Table 11 shows a consolidated literature report on gastroretentive drug delivery systems. [Department of Pharm. Sci., MDU, Rohtak]

Page 100

Literature review

Table 11: Recent literature reports on gastroretentive drug delivery systems Drug(s)

Dosage form(s)

Constituent(s)

1. FLOATING DDS A. HYDRODYNAMICALLY BALANCED SYSTEMS HPMC K4M, Pioglitazone Tablet HPMCK15M Trimetazidin Chitosan, SLS Microspheres Dihydrochloride L-dopa

HPMC, carrageenan

Tablet

Propanolol hydrochloride

Sodium alginate, sodium CMC, magnesium alumino metasilicate HPMC K4M CR, HPMC K15M CR, Poloxamer Sodium alginate, sodium CMC, Eudragit HPMC, HPC, xanthan gum, sodium alginate

Clarithromycin

HPMC K4M

Tablet

L-dopa

HPMC 2208

Capsule

Metformin

HPMC K4M, cellulose

Cimetidine

HPMC, ethyl cellulose

Metroprolol succinate Labetalol hydrochloride Metformin

Sodium Chitosan B. EFFERVESCENT DDS _

Lamivudine Zolpidem tartarate Cefuroxime Axetil Tizanidine hydrochloride

ethyl

Tablet

Tablet Tablet Tablet

Capsule

Reference(s)

(Raju and Narayan 2013) (El-Nahas and Hosny 2012) (Dorozynski 2011) (Boldhane and Kuchekar 2010) (Garse et al. 2010) (Boldhane and Kuchekar 2009) (Jagdale et al. 2009) (Nama et al. 2008) (Dorozynski et al. 2007) (Ali 2007)

(Srivastava et al. 2005) alginate, Hard gelatin (Dorozynski et capsule al. 2004)

HPMC, Carbopol

Microspheres

Tablet

(Singh 2012)

et

al.

Sodium bicarbonate, Layered Eudragit NE 30D pellets

(Amrutkar et al. 2012)

HPMC K4M and HPMC Tablet K100M

(Bomma and Veerabrahma 2012)

HPMC K4M, K15M and Tablet K100M

(Someshwar al. 2011)


et

Page 101

Literature review

Drug(s) Metronidazole

Liquorice

Ciprofloxacin

DA-6034

Theophylline Ranitidine hydrochloride Phenylproponol amine Atenolol

Constituent(s) Carrageenan (CG) and Eudragit E, Na bicarbonate HPMC K100M, liquorice extract, sod. bicarbonate, talc, and magnesium stearate HPMC K15M, sodium alginate, sodium bicarbonate or calcium carbonate HPMC, CP 934P, Kollidon CL, sodium bicarbonate HPMC, sodium bicarbonate, Eudragit® RL 30D HPMC, sodium bicarbonate HPMC K4M, CP 971P, sodium bicarbonate HPMC K15M & K4M, Guargum, Sod. CMC

Dosage form(s) Tablet

(Bani-Jaber et al. 2011)

Tablet

(Ram et al. 2010)

Tablet

(Tadros 2010)

Tablet

(Jang et al. 2008)

Tablet

(Sungthongjeen et al. 2008)

Tablet

(Hassan 2007)

Tablet

(Xu et al. 2006)

Tablet

Coated pellets C. FLOATING BEADS AND MICROPARTICLES Metformin Ethyl cellulose Microparticles hydrochloride Ginger extract Calcium carbonate and (Zingiber Beads sodium alginate officinale) Calcium carbonate Nevirapine sodium alginate, HPMC, Beads calcium chloride Verapamil

Amoxicillin Riboflavin-5′phosphate 5-Fluorouracil Orlistat

PMMA

Chitosan

Beads

Sodium alginate, anhydrous citric acid, Beads calcium chloride HPMC K15M, Sod. Beads Alginate Eudragit S, calcium Microspheres silicate


Reference(s)

(Srivastava 2005) (Sawicki and Glod 2004) (Patel et al. 2013) (Kumar Singh and Pal Kaur 2011) (Vedha 2010)

et

al.

(Sahasathian al. 2010)

et

(Stops 2008)

et

al.

(Shishu 2007)

et

al.

(Jain et al. 2007)

Page 102

Literature review

Drug(s)

Constituent(s)

Dosage form(s)

Metronidazole

Calcium pectinate

Beads

Cimetidine

HPMC, EC

Microspheres

Repaglinide

Calcium Silicate, Eudragit S

Microspheres

-

Calcium pectinate

Beads

Reference(s) (Sriamornsak et al. 2005) (Srivastava 2005) (Jain 2005) (Sriamornsak 2005) (El-Gibaly et al. 2003)

Chitosan, SLS, Microcapsules DOS Polypropylene foam Verapamil powder, Eudragit RS, Microparticles hydrochloride EC, PMMA D. HOLLOW MICROSPHERES

(Streubel 2002)

Ranitidine hydrochloride

Eudragit RLPO

Microspheres

(Singh and Chaudhary 2011)

Nifedipine

Polyvinyl pyrrolidone, Microspheres ethyl cellulose

(Zhao et al. 2010)

Famotidine

Eudragit L-100, PEG

Microspheres

(Ramachandran et al. 2010)

Rosiglitazone maleate

HPMC, EC

Microspheres

(Rao et al. 2009)

Eudragit S 100

Microspheres

(Junyaprasert and Pornsuwannaph a 2008)

Enteric acrylic polymers

Microspheres

(Sato et al. 2004)

Dichloromethane Ethanol.

Microspheres

(Sato et al. 2003)

Melatonin

Acyclovir Aspirin, Salicylic acid, Ethoxybenzamid e, Indomethacin and Riboflavin Riboflavin, Aspirin Acetohydroxami c acid Piroxicam

and

Polycarbonates

Microspheres

Polycarbonate resin

Microspheres

2. MUCOADHESIVE DDS A. TABLET FORMULATIONS Sodium alginate, Nebivolol sodium CMC, Carbopol Tablet 974P, EC


(Umamaheshwa ri et al. 2003) (Joseph et al. 2002)

(Shirsand et al. 2013)

Page 103

Literature review

Drug(s) Carvedilol

Zolmitriptan

Captopril

Cephalexin Diltiazem Propranolol Hydrochloride Lercanidipine hydrochloride

Dosage form(s)

Constituent(s) Carbopol, chitosan HPMC, chitosan and sodium carboxy methyl cellulose HPMC E5, HPMC E50, sodium salt of carboxy methyl cellulose (NaCMC) HPMC, HPC, chitosan, carbopol, sodium carboxymethylcellulose HPMC K4M, Carbopol 934 Locust bean gum and chitosan PEO, HPMC

Tablet

(Bayrak 2011)

et

al.

Tablet

(Mandal 2011)

et

al.

Tablet

(Sonani 2010)

et

al.

Tablet Tablet

Carvedilol

HPMC K4M, K15M, CP 934

Chlorhexidine

CP 940P, HPMC

Tablet

Atenolol

CP, Na CMC

Tablet

Ofloxacin

Psyllium husk, HPMC, Tablet Crosspovidone

Low molecular weight Heparin Polycarbophil, HEC (LMWH) Piroxicam

HPMC, CP 940, HP β-CD

-

Thiolated derivatives

Diltiazem

Sod. CMC, HPMC, EC

B. MICROSPHERES FORMULATIONS Trimethylchitosa Eudragit L100 n chloride Carbopol, Ketorolac polycarbophil, chitosan


Tablet

Mini-tablet

Tablet chitosan

(Yedurkar et al. 2012)

Tablet

Tablet HPMC

Reference(s)

Tablet Tablet

Microspheres Microspheres

(Shayeda et al. 2009) (Vijayaraghavan et al. 2008) (Charde et al. 2008) (Yamsani et al. 2007) (Carlo Ceschel et al. 2006) (Singh et al. 2006) (Chavanpatil et al. 2006) (Schmitz et al. 2005) (Jug and Becirevic-Lacan 2004) (Roldo et al. 2004) (Chowdary et al. 2003) (Marais 2013) (Nagda 2011)

et

al.

et

al.

Page 104

Literature review

Drug(s)

Constituent(s)

Dosage form(s)

Tramadol HCl

HPMC E15

Microspheres

Linseed mucilage

Microspheres

Venlafaxine Amoxicillin

Ethyl cellulose, Microspheres Carbopol-934P

Cyclosporine- A

Chitosan

Microspheres

Reference(s) (Belgamwar et al. 2011) (Nerkar and Gattani 2011) (Patel and Chavda 2009) (MalaekehNikouei et al. 2008)

[CA: Citric acid; CMC: Carboxymethylcellulose; CP: Carbopol; DOS: Sodium dioctylsulfosuccinate; EC: Ethylcellulose; HP-ß-CD: Hydroxypropyl- ß-Cyclodextrin; HPC: Hydroxypropylcellulose; HPMC: Hydroxypropylmethylcellulose; MC: Methylcellulose; Paa: Polyacrylic acid; PEG: Polyethyleneglycol; PMA: Polymethylacrylic acid; PMMA: Polymethyl methacrylate; PVP: Polyvinylpyrollidine; SLS: Sodium lauryl sulphate]

3.2. AN UPDATED REVIEW ON SYSTEMATIC DESIGN AND OPTIMIZATION OF ORAL DRUG DELIVERY SYSTEM A product development scientist has to handle a heterogeneous group of formulations. These dosage forms may vary markedly from oral to topical, transdermal, parenetral, ophthalmic, pulmonary, nasal, rectal formulations with diverse rates of release and site specificity. An exhaustive literature inquest carried out by me in pharmaceutical journals and texts till date, reveals that the DoE optimization techniques have been employed for almost all of these dosage forms, ranging from the simple conventional ones to that of the most intricate novel DDS. The updated literature reports unequivocally point out the increasing application of DoE (Design of Experiment) techniques, with a significant shift in the focus of the formulator from optimization of the conventional formulations to that of the modern drug delivery devices (Singh 2006). Recently this approach together with the federal philosophy of quality by design (QbD) has been assigned a new acronym by us as “FbD” (Singh et al. 2011) However, the work on DoE optimization of various DDS started relatively lately. Albeit the initial studies on drug delivery optimization were reported in early eighties, the major work has only been undertaken in the last decade. Since oral route is the most preferred and complied route of drug administration, most DDS explored for the purpose are the oral CR matrices, micro- and macroparticulate systems, floating systems, solid dispersions, osmotic pumps, etc. Besides, considerable work has also been carried out on transdermal therapeutic systems (patches, gels, ionotophoresis and electroporation) and mucoadhesive dosage forms (gels, patches and tablets). Verily, DoE optimization techniques have


Page 105

Literature review

become an integral and regular phenomenon globally in rational drug delivery and dosage form design in pharmaceutical drug industry (Singh 2005) Amongst the conventional dosage forms, tablets have predominantly been investigated, whereas, amongst various DDS, macroparticulates and CR matrices have majorly been studied followed by microparticulates, fast release (FR) dosage forms, transdermal drug delivery systems (TDDS) and vesicular systems. Here in below we reproduce the extensive search carried out by us on the use of optimization techniques in developing diverse types of solid oral CR DDS, GRDDS. 3.2.1. ORAL CONTROLLED RELEASE MATRICES The FbD optimization on oral CR matrix delivery devices started since early eighties (Harris et al., 1989). Such devices encompass, the inert matrices like hydrophilic (Joly and Brossard 1987; Gohel and Patel 1997), hydrocolloid (Waaler et al. 1992), silicone elastomer (Li and Peck 1991) and the lipid matrices (Singh et al. 1998). Table 12: FbD formulation optimization reports on compressed oral sustained release matrices formulated using natural or semisynthetic polymers Drug(s)

Factor(s) /Polymer(s)

Design

Reference

Lamivudine

CP 971P and HPMC

CCD

(Singh et al., 2012)

Rivastigmine

CP 974P and HPMC K15M

CCD

(Kapil et al., 2012)

Pravastatin Sodium

HPMC K4M and CP 934P

FD

(Maurya et al., 2012)

Mesalazine

CP 940, Eudragit

BBD

(Elbary et al., 2011)

Acyclovir

Polycarbophil, pluronic F68

FD

(Bhosale et al., 2011)

Tramadol HCl

HPMC, CP 971P

CCD


Hydralazine HCl

HPMC, carbomer

CCD


Metformin HCl

HPMC K15M, PVP K30

CCD

(Mandal et al., 2007)

Losartan potasium

HPMC K15M, K100M, Na CMC

BBD

(Chopra et al., 2007)

HPMC

Salt of a weakly HPMC, amount of water, FD alkaline drug tablet hardness Metformin HCl

HPMC of various viscosity grades, adhesive type, RSM lubricant, preparation method

(Huang et al., 2003)

(Li et al., 2003)

(EC: Ethylcellulose; HCl: hydrochloride; HPMC: Hydroxypropylmethylcellulose; Na CMC: Sodium carboxymethylcellulose; BBD: Box-Behnken design; CCD; FD: Factorial design)


Page 106

Literature review

The other response variables that have been optimized include, disintegration time, BA, bioequivalence, etc (Dincer and Ozdurmus 1977) Tables 12 & 13 depicts the use of statistical experimental design in optimization of oral sustained release (SR) matrices, categorized on the basis of various types of polymers (natural, semisynthetic, synthetic) and the type of dosage form (matrices, dispersions, coated tablets). FbD optimization reports on SR matrices formulated using synthetic polymers like acrylates, polymethacrylates, silicone elastomers, polyethylene glycols, etc. are shown in Table 13 (Singh, Kumar and Ahuja 2005). Table 13: FbD formulation optimization reports on oral sustained release matrices formulated Drug(s) Salbutamol sulphate Venlafaxine

using synthetic polymers

Factor(s) /Polymer(s) Design investigated Methocel(®) K100M, xanthan RSM gum, Carbopol(®) 974P HPMC K15M, Etylcellulose RSM

Serratiopeptidase Eudragit S 100

FFD

Polyherbal gels

CP 934P, CP 974P, Polycarbophil

BBD

Protein

Chitosan, Tri poly phosphate

FD

Paracetamol

CP 971 P, CP 71 G, tablet size

FD

Bumetanide

Polymer, pH modifiers, solubility modifiers Eudragit L 100, compression force PEG 6000, lactose, stearic acid

D-OD, CCD CCD

Aspirin Theophylline Aspirin

RSM

Eudragit RS PO, compression CCD force

Reference (Chaibva and Walker 2011) (Madgulkar et al., 2009) (Rawat and Saraf 2009) (Chopra et al., 2007) (Asghar and Chandran 2006) (Parojcic et al., 2004) (Sakr and Tillotson 2004) (Ibric et al. 2003) (Grassi et al. 2003) (Ibric et al. 2002)

(CP: Carbopol; D-OD: D-Optimal design; EC: Ethylcellulose; HPMC: Hydroxypropylmethylcellulose; MCC: Microcrystallinecellulose; MS: Magnesium stearate; PEG: Polyethyleneglycol; BBD: Box Behnken design; CCD; FD: Factorial design; FFD: Fractional factorial design)

3.2.2. GASTRORETENTIVE SYSTEMS GR delivery systems have evolved with the overall objective of localized delivery to the GIT, using the concept of floating-buoyancy or bioadhesion (Hou et al.


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2003). The most commonly studied variables in the optimization of floatingbioadhesive CR systems include the polymer-to-drug ratio, different polymer grades, and ratio of polymers and ratio of diluents. If these variables are not addressed during the system design, the duration of buoyancy, dissolution time, BS, compression force, and tablet density will be greatly affected, which in turn affect the drug’s overall performance (Kannan et al. 2003). Mucoadhesive gels and tablets have also been optimized separately for bioadhesion strength and drug release profile. Limited reports on optimization of hydrodynamically balanced DDS are available in literature. The input variables vary from 2 to 4 and the response variables from 1 to 5. The commonly employed designs are CCD, SMD and FD. Table 14 enlists various optimization reports on floating DDS (Singh 2005). Table 14: FbD formulation optimization reports on floating drug delivery systems Drug

Polymer(s)/Factor(s)

Design

Reference

Acyclovir

Ethylcellulose

FFD

Acyclovir

Ranitidine HCl

Psyllium husk (X1), HPMC FFD K4M Eudragit S100, Eudragit CCD L100-55 Compritol, Gelucire 50/13 FD and 43/01

(Vinodbhai et al., 2011) (Kharia et al. 2010)

Metoprolol

HPMC K4M

Famotidine

FD

Cefruoxime HPMC k4M, HPMC k100LV axetil

FD

Ranitidine

FD

Calcium

Citric acid, stearic acid

(Gupta and Pathak 2008) (Patel et al. 2007) (Narendra et al., 2006) (Patel and Patel 2006)

(Dave, Amin Patel 2004) HPMC of various grades, Taguchi (Li et al. 2002) HPMC:CP ratio, MS

and

(CP: Carbopol; EC: Ethylcellulose; HPMC: Hydroxypropyl methylcellulose; MS: Magnesium stearate; CCD: Central Composite Design; FD: Factorial design)

Literature review shows that controlling/sustaining/prolonging/targeting of drug/dosage form comes in existence in early eighties and since then it becomes one of the specific area of research; it reflects that it is a promising area to work on, for getting much better, practically possible dosage form. [Department of Pharm. Sci., MDU, Rohtak]

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To achieve different aims of modified release, various technologies have been investigated, e.g. sustained, delayed, pulsatile, targeted, and programmed release delivery systems. In all the delivery types, the main mechanisms associated with drug transport in these systems include diffusion, swelling, erosion, ion exchange, and osmotic effect which have been investigated in several studies. Out of different types used for making controlled release, hydrophilic matrix type delivery systems are popular because of their ease of manufacture. It excludes complex production procedure such as coating and pelletization, and drug release from the dosage form is controlled mainly by the type and proportion of the polymers used in the preparation, while multi-particulate system further decreases the irritation by distributing the drug concentration in subdivided unit. During development of new delivery systems, systematic FbD methodology with RSM efficiently surmounts the hiccup of balancing floatation and bioadhesion employing optimized polymer. It is well-documented to develop “the best possible” formulation under a given set of conditions circumventing unnecessary experimentation and thus, save, time, money and effort. The site of absorption of glipizide lies in the stomach. Dosage forms that are retained in the stomach would increase the absorption, improve drug efficiency and decrease dose requirements.


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4.1. IDEA AND HYPOTHESIS “Patients don’t take drugs, they take dosage forms”. “All drugs are toxins”. The above two sentences together means that we give toxins to patients using dosage forms. Sixty years ago, although many scientists agreed that all drugs (toxins) are useful in curing diseases, yet many of them do not realized that the dosage forms can offer distinct advantages such as reducing toxicity, extending therapeutic efficiency of drugs etc. In last fifty to sixty years, scientists have developed many types of delivery systems each with unique advantages. One of the oldest DDS is oral DDS. Oral DDS are popular far more than a century due to many distinct advantages such as ease of administration, palatability, ease of manufacturing, high patient compliance compared to parentral administration, reduced or no need for hospitalization etc. Oral systems include tablets, capsules, and moulded pills. Since most of the drugs are available as solids and the stability of drugs is high at solid state, solid oral DDS are the most popular category of oral DDS among pharmaceutical scientists who explore use of different delivery systems for patient use. However, oral DDS are not “cure for all” technique. Modifications in the design of delivery system may be required based on needs. Needs may be different for each case. One of the most profound needs is to maintain drug concentration in systemic circulation for longer period of time. This is one of the most desirable properties of an ideal DDS. Oral sustained-release technology provides oral delivery for 24 hr; however, in substances that cannot be well absorbed throughout the whole GI tract, it may be disadvantageous (Baumgartner et al., 2000). Prolonged/extended-release dosage forms with extended residence times in the stomach are highly desirable for drugs with narrow absorption windows, stability problems in the intestinal or colonic environments, locally acting in the stomach, and poor solubility in the intestine (Streubel et al., 2003). Glipizide is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from the pancreas and is typically prescribed to treat type II diabetes (non-insulin-dependent diabetes mellitus). Its short biological half-life (3.4 ± 0.7 hr) necessitates that it be administered in 2 or 3 doses of 2.5 to 10 mg per day (Foster and Plosker, 2000).


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Glipizide is available in a GI Therapeutic System (GITS) extended-release formulation. Glipizide GITS provides more stable plasma drug concentrations than the immediate-release formulation and the once-daily regimen may optimize patient compliance. In patients with type II diabetes mellitus, glipizide GITS is at least as effective as the immediate-release formulation of glipizide in providing glycaemic control, and may have a greater effect on fasting plasma glucose levels. Any therapeutic advantage over other antidiabetic agents remains to be established, but in a preliminary report (n = 40) Glipizide GITS provided better glycaemic control and produced less fasting insulinaemia than glibenclamide (glyburide) (Foster and Plosker, 2000). Menger et al., compared the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide given with that of immediate-release glipizide in patients with type II diabetes mellitus (Menger, et al., 2002). At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects. Thus, the development of controlled/extended release dosage forms of glipizide would clearly be advantageous. The hypothesis for this research work is that if glipizide can be delivered in a controlled/ sustained manner to the duodenum at a rate that does not exceed the maximum rate of its absorption, then the oral bioavailability of glipizide will be more uniform therefore more consistent management of sugar level will be possible as well as it could result in more bioavailability. Based on this hypothesis, the gastric floating and bioadhesive tablets were designed in such a way that they should be retained in the stomach for a prolonged period of time. Again as the glipizide, a potent oral hypoglycaemic agent, is one among those with narrow therapeutic index (Krishna et al., 2004) as well as in some it may also produce application site irritation (Sarode et al., 2011). So the glipizide is required to be presented in various sub units which will decrease the chances of accidental toxicity of the drug, and also it will decrease the chances of application site irritation associated with the drug.


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4.2.

EXPERIMENTAL SETUP

4.2.1. MATERIALS USED IN INVESTIGATION Various materials used during investigation are shown in Table 15. Table 15: List of materials used Chemicals

Source

Acetic acid

SD Fine Chemicals Ltd., Mumbai, India.

Calcium chloride


Carbopol-934P

Noveon, Mumbai, India.

Chitosan

Sigma Aldrich, Germany.

Glipizide (powder)

USV Ltd., Daman, India.

Hydrochloride acid

E merck India Ltd., Mumbai, India.

Hydroxypropyl Methylcllulose-K4M/ K15M

Zydus Cadila, Ahmedabad, India.

Light Liquid Paraffin

Loba Chemie Pvt. Ltd., Mumbai.

Magnesium stearate


Micro crystalline cellulose


Sodium Alginate


Sodium bicarbonate

Merck, Germany.

Sodium citrate

Sigma Chemicals Ltd, New Delhi, India.

Sodium hydroxide


Talc


All other materials and chemicals employed in the present work were of fine quality and analytical grades. 4.2.2. INSTRUMENTS USED IN INVESTIGATION Table 16 enlist various instrument used during study. Table 16: List of instruments used Instrument Automatic tablet compression machine Digital balance (0.1 mg) Dissolution test apparatus Environment chamber FTIR Hardness tester Homogeniser

Source Rimek Minipress-I, 16 station, Karnawati, India. Shimadzu Electronics, Japan. TDT-06T Electrolab, Mumbai, India. Jindal Instrument, India IR Affinity 1, Shimadzu Electronics, Japan Monsento hardness tester Remi-Motors, RQ- 122, Vasai, India


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Instrument pH meter Roche friabilator Scanning electron microscope Software

Stirrer : Mechanical stirrer Texture profile analyzer

Tray dryer UV Spectrophotometer Vernier Calliper

Source Systronic, 335 pH Meter, Ahemdabad, India Campbell electronics, Mumbai Phillips 1500, Scanning Electron Microscope (Birbal Sahani Institute of Paleobotany, Lucknow) Zorel 21, Graph 2, Design Expert® 8.7.0.1, PCP DISSO, EndNote X5, MS-Windows 2007, MSWord 2007 and MS-Excel 2007. Remi motors, Mumbai, India. Tax Tee 32; M/S Stable Microsystems, Godalming, Surrey, UK (UIPS, Punjab University) J K industries, Gandhinagar, Gujrat India. Shimadzu UV-1800, UV/Vis Double Beam Spectrophotometer (Kyoto, Japan). Mitutoyo, Japan.

4.2.3. STANDARD CURVE, OF GLIPIZIDE Accurately weighed (10 mg) of glipizide was dissolved in minimum amount of methanol and volume was made up to 100 mL with 0.1 N HCl in volumetric flask. It gave 0.1 mg / mL or 100 µg / mL drug solution. Further dilutions of 5, 10, 15, 20, 25, 30 and 35 µg / mL were done and absorbance was taken at 276 nm (Indian Pharmacopoeia, 2007).

4.3. FORMULATION, OPTIMIZATION AND EVALUATION OF GLIPIZIDE FLOATING-BIOADHESIVE TABLETS 4.3.1. PRELIMINARY STUDIES During pre-optimization three polymers like CP 934P, HPMC K4M and HPMC K15M were investigated for formulating oral CR floating bioadhesive matrices of glipizide. Tablets were prepared using these polymers in combination. In preliminary studies glipizide and polymers were used in the ratio of 1:2 to 1:10 for 200 mg tablet and using micro crystalline cellulose as diluents. Later polymers blend with two polymers CP 934P and HPMC K4M were selected for further investigation. Formula for the study after selecting the polymers is given in Table 17. During preliminary studies, various formulations were prepared using different ratios of the two polymers and it was done to aid in choosing the limits for polymers for further study. Four formulations employed for pre-optimization


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study with different ratio of CP 934P and HPMC K4M keeping total tablet weight constant, i.e., 200 mg and glipizide 10 mg (Table 18). Table 17: General Composition of Glipizide Matrices during Initial Studies S. No.

Ingredient

Percentage (W/W)

1

Glipizide

5.00

2

CP 934P

10.00-25.00

3

HPMC K4M

25-52

4

Magnesium stearate

1.00

5

Talc

2.00

6

Sodium bicarbonate

10

7

Microcrystalline cellulose (MCC)

qs

Table 18: Different Ratio of Polymer taken during Initial Studies Formulation Glipizide

:

CP 934P

:

HPMC K4M

A

1

:

2

:

B

1

:

3

:

7.5

C

1

:

4

:

5

After studying release characteristic, floating and bioadhesive properties of formulations A, B and C the limits for further detailed studies using 32 CCD with α=1 were chosen. 4.3.2. FORMULATION OF FLOATING-BIOADHESIVE TABLETS AS PER CCD CCD with α=1 using three level of two factors CP 934P and HPMC K4M, was adopted for further investigation. The central point (0, 0) was studied in quintuplicate (batch FT5, FT10, FT11, FT12, FT13 and mean results of the five batches were used in the investigation). Various formulation batch prepared are indicated in the Table 19. Amount of magnesium stearate and talc was kept constant and MCC was taken in sufficient quantity for maintaining the tablet weight 200 mg. Quantities of all ingredients per tablet are given in Table 20. Tablets were prepared by direct compression method for all experimental runs (50 tablets per batch). All product variables (except concentration of two polymers) and process variables like mixing time, compression force and punch size were kept constant. Glipizide was mixed with the required quantities of HPMC K4M, CP 934P and sodium bicarbonate by geometric mixing for 10


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minutes. After that the mixture was blended with microcrystalline cellulose, lubricated with magnesium stearate and talc for additional 2-3 minutes. Table 19: Factor combination as per CCD S. no.

Formulation code

Coded values Factor X1 (HPMC K4M)

1 2 3 4 5 6 7 8 9 10 11 12 13

Factor X2 (CP 934P)

FT1 -1 FT2 -1 FT3 -1 FT4 0 FT5 0 FT6 0 FT7 +1 FT8 +1 FT9 +1 FT10 0 FT11 0 FT12 0 FT13 0 Translation of coded levels in actual units

-1 0 +1 -1 0 +1 -1 0 +1 0 0 0 0

Coded Level

−1

0

1

Factor X1 (HPMC K4M)

64

82

100

Factor X2 (CP 934P)

12

20

28

TABLE 20: Quantities of Ingredients per tablet and their percentage S. no.

Ingredients

Quantity/tablet (mg)

Percentage

10

5%

1

Glipizide

2

Hydroxypropyl methyl cellulose K4M (HPMC K4M)

64-100

32-50%

3

Carbopol 934P (CP 934P)

12-28

6-14%

4

Microcrystalline cellulose (MCC)

36-88

18-44%

5

Magnesium stearate

4

2%

6

Talc

2

1%

7

Sodium bicarbonate

20

10%

All powders were sieved through sieve of mesh size 60. Then 200 mg tablets containing 10 mg glipizide were prepared by direct compression on tablet punch machine (M/s Rimek, Minipress-I, 16 station rotatory, Karnawati, India) using 8mm diameter flat face punch. Compression force of the machine was adjusted to obtain the hardness in the range of 3.5-4 kg/cm2. [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

4.3.3. EVALUATION OF FLOATING-BIOADHESIVE TABLETS 4.3.3.1.

Drug

excipients

compatibility

study

and

physical

evaluation IR spectra of glipizide in KBr pellets at moderate scanning speed between 4000400 cm-1 was carried out using FTIR (IR Affinity 1, Shimadzu Electronics, Japan). The peak values (Wave number (cm-1) and the possibility of functional group present were interpreted, and it was compared with the IR spectra of the tablet. The tablets were evaluated for diameter, thickness, hardness (Monsanto hardness tester), friability (Roche friabilator, Campbell Electronics, Mumbai), and weight variation (Shimadzu electronics, Japan) (Mallikarjun et al., 2009). 4.3.3.2.

Drug content

For determination of drug content, ten tablets were taken and powdered (Ponchel and Irache, 1998). The powder equivalent to 10 mg of glipizide was accurately weighted and transferred to 100 mL volumetric flask and the volume was made up to 100 mL with 0.1N HCl, 1mL of the aliquot was further diluted to 100 ml with 0.1N HCl. The absorbance was measured at 276 nm (Shimadzu 1800, Japan) (IP, 2007). 4.3.3.3.

Tablet swelling ability

Briefly, a tablet was weighed (W1) and placed in a glass beaker containing 200 mL of 0.1 N HCl maintained in a water bath at 37.0 ± 0.50C. At regular time intervals, the tablets were removed and the excess surface liquid was carefully soaked on by a filter paper. The swollen tablet was then reweighed (W2) (Dorozynski et al., 2004). The swelling index (SI) was calculated using the eqn. 10. = 4.3.3.4.

× 100

(10)

In vitro buoyancy studies

The floating behavior of the tablets was determined visually in triplicate by placing the tablet in a glass beaker, containing 200 mL of 0.1 N HCl, maintained in a water bath at 37.0 ± 0.50C. The Tlag (the time between tablet introduction and its buoyancy) and Tb (total buoyancy time) were recorded (Jimenez et al., 1994). 4.3.3.5.

In vitro drug release studies

The release rate of glipizide floating tablets were determined by using a USP XXIV Type-II apparatus (Electrolab, TDT-06T, India) at 37.0 ± 0.50C and 50 rpm using 900 mL of 0.1N HCl (n = 6) (Prabhakara et al., 2008). Aliquot sample (5 mL) [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

was withdrawn at periodically and filtered through a 0.45 micrometer membrane filter, diluted suitably, and analyzed UV spectrophotometrically against 0.1N HCl as a blank at λmax 276 nm. An equal amount of fresh dissolution medium was replenished immediately, following the withdrawal of the test sample to maintain the sink conditions. 4.3.3.6.

Ex vivo bioadhesive studies

Goat gastric mucosa was used as the model membrane for ex vivo determination of the BS of the various formulations. Goat gastric mucosal membrane was excised by removing the underlying connective tissue and it was placed on the base of a Texture Profile Analyzer (TAX TEE 32; M/s Stable Microsystems, Godalming, Surrey, UK). A single tablet was attached to the stainless-steel probe fixed to the mobile arm of the texture analyser. The area of contact of mucosa was moistened with 50 µL of SGF. The mobile arm was lowered at a rate of 0.5 mm/s until a contact with the membrane was made. A contact force of 10 g was maintained for 300 s, after which the probe was withdrawn from the membrane. The peak attachment force, determined in triplicate was recorded, as reported in literature (Ch'ng et al., 1985).

Figure 18: Bioadhesion strength of the prepared formulation using texture analyzer 4.3.3.7.

In vivo Imaging studies

4.3.3.7.1.

X-ray Photographic studies in rabbits

The preclinical study protocol was approved by Institutional Animal Ethical Committee, (Proposal No. IAEC/SRMS/2012/03) SRMSCET, Bareilly, Uttar Pradesh, India. Experiments were conducted according to the guidelines of committee for the “Purpose of Control and Supervision of Experiment on Animals” (CPCSEA) approval no. 715/2/CPCSEA. Healthy rabbit weighing


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Experimental

approximately 1.5 - 2 Kg were used to assess in vivo floating and bioadhesive behavior. Rabbit were fasted overnight (approximately 12 h) with free access to water ad libitum and X-ray photograph was taken to ensure absence of radio opaque material in the stomach. Barium sulphate loaded tablet formulation was administered in the morning with a 3.5 mL / kg water rinse via oral gavages to mimic clinical dosing conditions. During the experiment rabbit were not allowed to eat but water was provided. At predetermined time intervals the radiograph of abdomen was taken to locate the formulation. 4.3.3.7.2. In vivo γ-scintigraphic studies in man The scintigraphic study was performed at the Department of Nuclear Medicine at the Institute of Medicine and Allied Sciences (INMAS), Delhi, India. The investigation followed the tenets of the Declaration of Helsinki (WMA, 2008) duly approved by the Institutional Ethics Committee, Lord Shiva College of Pharmacy, Sirsa (Approval letter no. LSCP/IEC/11/01). Prior informed consent was obtained from each participating volunteer. The control and optimized formulation were labelled with 500–700 mCi (18.5–25.9 MBq) of 99mTc sulfur colloid, by incorporating a volume of 100 ml of the colloid solution into the granular mix and then compressing it in the centre of the tablets. The tablets were administered orally to each individual with 200 ml of potable water. Following oral administration of the radiolabelled preparation, anterior static images (2 min/image) were acquired under the dual-head Ecam gamma camera (M/s Siemens, Erlangan, Germany) at time intervals of 0, 75, 150, 240, 300 and 360 min for the test formulation and 0, 30, 60, 80 and 110 min for the control formulation. The study subjects were instructed to keep medically mobile and had free access to water until the completion of the radiographic acquisition. The scintigraphic images obtained with the control and the optimized formulations were subjected to analysis (Singh et al., 2012; Kapil et al., 2012; Wang et al., 2008) [volunteer consent form: appendix-A1]. 4.3.3.8.

Data analysis

Drug release data obtained during in vitro drug dissolution studies were analyzed using ZOREL software (Singh and Singh, 1997) which have in-built provisions for applying the correction factor for volume and drug losses during sampling (Singh et al., 1998). The value of T60% was calculated using Stineman interpolation option of the GRAPH 2.0 software (M/s Micromath Inc., Saint [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

Louis, USA). Further, drug release data were applied to release models like Higuchi model, which indicates that the drug release mechanism deviates from Fick’s laws and shows anomalous behavior (Higuchi, 1997). Based on the phenomenological analysis, the type of release, i.e., whether Fickian, non-Fickian (anomalous) or zero-order, was predicted. This is demonstrated by the equation 11. /

=K

(11)

Where, Q is the amount of drug release at time t, and KH is the Higuchi rate constant. The dissolution data was also fitted to the well-known Koresmeyer equation (eqn. 12 and 13), which is often used to describe the drug release behavior from polymer systems (Korsmeyer et al., 1983). ∝

= . ∝

(12) = log ! + # log

(13)

Where Mt is amount of the drug release at time t, Mα is the amount of drug release after infinite time and K is release rate constant incorporating structural and geometric characteristic of the tablet and n is the diffusion exponent indicating the mechanism of drug release. 4.3.3.9.

Optimization

data

analysis

and

validation

of

FbD

methodology The response variables which were considered for optimization included Q16 (release in 16 hours), BS (Bioadhesive strength), Tb (total buoyency) and T60% (time required for 60% release). For the studied design, the multiple linear regression analysis (MLRA) method was applied using Design expert 8.0.7.1 (M/s Stat-Ease, Minneapolis, USA) software to fit full second-order polynomial equation (Eqn. 14) with added interaction terms to correlate the studied responses with the examined variables. Y = B0 + B1X1 + B2X2 + B3X1X2 + B4X12 + B5X22 + B6X1X22 + B7X12X2

(14)

The polynomial regression results were demonstrated for the studied responses. Finally, the prognosis of optimum formulation was conducted in two-stages [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

using brute force technique with the help of in-house developed MS-Excel spreadsheet software. First, a feasible space was located and second, an exhaustive grid search was conducted to predict the possible solutions. The region of optimality was ratified using overlay plots, drawn using the Design Expert® software. Four formulations were selected as the confirmatory checkpoints and these were validated by RSM. The observed and predicted responses were critically compared. Linear correlation plots were constructed for the chosen check point formulations. The residual graphs between predicted and observed responses were also constructed separately and the percent bias (% prediction error) was calculated with respect to the observed responses. After studying the responses surfaces for all properties feasibility and grid searches through MS-excel utility and overlay plot generation method through Design expert were used for finding the optimized product. Optimized product was validated taking total six formulations selected as check points. The tablet formulation using the chosen formulation composition from grid search were formulated and tested for various evaluation parameters. Further linear correlation plots were made between the observed and predicted responses with line pass through the origin. Plots between predicted and observed responses were compared. 4.3.3.10.

Comparison with marketed formulation

The drug release profile of optimized formulation was compared with marketed formulation (Glynase XL, USV limited) containing 10 mg of glipizide. 4.3.3.11.

Accelerated stability studies

Accelerated stability studies of optimized formulation were carried out as per the ICH guidelines. Environment chamber (Jindal Instrument, India) was used for maintaining the storage conditions. The samples were withdrawn periodically and evaluated (Abdelbary et al., 2010). The tablets were packed in screw capped HDPE bottles and were stored at 40 ± 20C and 75 % RH for 6 months. After storage for 6 months, the products were tested for drug content floating characteristics and drug release rate as per the methods described earlier.


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4.4. FORMULATION, OPTIMIZATION AND EVALUATION OF GLIPIZIDE FLOATING-BIOADHESIVE BEADS 4.4.1. PRELIMINARY STUDIES During pre-optimization, polymer like HPMC K4M, CP 934P and CT along with SA and light liquid paraffin (LLP) were investigated for formulating oral CR floating-bioadhesive beads of glipizide. In the preliminary studies glipizide and SA were used in the ratio of 1:2 to 1:10 while this SA solution with drug was emulsified with 10-20% LLP and coated with, HPMC K4M, CP 934P or CT. SA and LLP were selected for further investigation, where as CT concentration for coating was fixed, i.e., 1 %. Formula for the study after selecting the polymers is shown in Table 21. Table 21: General composition of glipizide floating-bioadhesive beads during initial studies S. No.

Ingredient

Percentage (w/w)

1

Glipizide

500

2

Drug: polymer

1:5-1:9

3

LLP

10-15 (w/v)

4

Tween 80

0.5

5

Chitosan

1 % (w/v)

During preliminary studies, various formulations were prepared using different ratios of the SA and LLP for choosing the limits of SA and LLP for further study. 4.4.2. FORMULATION OF FLOATING-BIOADHESIVE BEADS AS PER CCD CCD with α=1 using three level of two factors SA and LLP, was adopted for further investigation. The center point (0, 0) was studied in quintuplicate (batch FB9, FB10, FB11, FB12, FB13 and mean results of the five batches were used in the investigation). Various formulation batch prepared along with their translational actual values are indicated in the Table 22. Beads were prepared by emulsion-gelation technique (Gonzalez-rodriguze et al., 2002; Sriamornsak et al., 2004). The required amount of SA (w/v) was added in distilled water to make polymer solution. LLP in the required concentration (v/v) was then added to the polymer solution. The mixtures were homogenized at 10,000 rpm using a homogenizer (Remi-motors, RQ- 122, Vasai, India) for 20 m with the addition of emulsifier tween 80 to ensure stabilization of emulsion. [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

Glipizide (500 mg) was then dispersed in the formed emulsion. The bubble free drug loaded emulsion was extruded, using a 20 gauge needle into 100 mL 0.45 mol L–1 calcium chloride solution with 1% CT in 1% acetic acid, maintained under gentle agitation at room temperature. The beads were allowed to stand in the solution for 15 min before being separated and washed with distilled water. Further beads were dried at 400C temperature and stored. The time of drying was optimized by weighing the beads repeatedly, until they obtained a constant weight. Table 22: FbD design matrix of floating-bioadhesive beads as per CCD Coded values S. no.

1 2 3 4 5 6 7 8 9 10 11 12 13

Batch code

Factor A (drug: polymer)

Factor B (LLP)

FB1 -1 FB2 +1 FB3 -1 FB4 +1 FB5 -1 FB6 +1 FB7 0 FB8 0 FB9 0 FB10 0 FB11 0 FB12 0 FB13 0 Translation of coded levels in actual units

-1 -1 +1 +1 0 0 -1 +1 0 0 0 0 0

Coded Level

−1

0

1

Factor A (drug: polymer)

1:5

1:7

1:9

Factor B (LLP)

10

12.5

15

4.4.3. EVALUATION OF FLOATING-BIOADHESIVE BEADS 4.4.3.1.

Drug excipients compatibility, external appearance and size uniformity studies

IR spectra of glipizide in KBr pellets at moderate scanning speed between 4000400 cm-1 was carried out using FTIR (IR Affinity 1, Shimadzu Electronics, Japan). The peak values (Wave number (cm-1) and the possibility of functional group present were interpreted, and it was compared with the IR spectra of the floatingbioadhesive beads.


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Experimental

All the formulated batches of buoyant beads were visually analyzed for oil leakage, shape and color. External surface of gel beads were studied with a scanning electron microscope. Particle size of the prepared beads was determined using a digital vernier (Mitutoyo, Japan). Twenty dried beads were measured for calculating the mean diameter. The result was expressed as the mean diameter (mm) ± standard deviation. 4.4.3.2.

Swelling Index studies

The swelling properties of the beads were carried out using 0.1 N HCl. The microcapsules of known weight were placed in 50 mL of 0.1 N HCl for 24 h. At the time intervals of 15 m for first one hour, 30 m for next two hours and one hour for next four hours, the beads were removed and excess surface liquid was removed by soaking on a tissue paper and their weight was recorded (Wagner, 1969). The percentage swelling (S) was determined by the following equation (Eqn. 10). S=

× 100

(10)

Where- W1= weight of dry beads W2= weight of swollen beads

4.4.3.3.

Scanning electron microscopy studies

Surface morphology of beads was studied by scanning electron microscopy of floating-bioadhesive beads (Phillips 1500, scanning electron microscope). The beads were previously fixed on a brass stub using double sided adhesive tape and then were made electrically conductive by coating in vacuums, with a thin layer of gold (approximately 300 Å), for 30s and at 30 W. The pictures were taken at an excitation voltage of 15 Kv and at magnification of 65 and 610X. SEM studies were carried out at Birbal Sahni Institute of Paleobotany, Lucknow. 4.4.3.4.

Estimation of Glipizide

Glipizide was estimated spectrophotometrically using double beam UV-Vis spectrophotometer

(Shimadzu

UV-1800,

UV/Vis

Double

Beam

Spectrophotometer (Kyoto, Japan). Accurately weighed amount of floatingbioadhesive beads (100 mg) were dissolved in 100 mL of phosphate buffer (pH 7.4) and absorbance was measured on UV/Vis spectrophotometer at 276 nm (IP, 2007).


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Experimental

4.4.3.5.

Entrapment efficiency (EE) studies

Approximately 50 mg beads were crushed in a glass mortar-pestle and the powde was suspended in 10 mL ethanol in 100 mL volumetric flask and volume was made up with 0.1 N HCl. After suitable dilution the analysis was carried out spectrophotometrically at 276 nm, for the drug content. The EE was calculated by Eqn. 15 (Sato et al., 2003). EE =

&'()*+ ,-). '/0(10(

231/-1(4'*+ ,-). '/0(10(

4.4.3.6.

5 100

(15)

In vitro buoyancy studies

In vitro buoyancy of the prepared floating-bioadhesive beads was determined using USP dissolution apparatus type II. Fifty beads were kept in the vessel and the paddles were rotated at 50 rpm in 500 mL of 0.1 N HCl maintained at 37 ± 0.50C for 18 hours. The floating and the settled portion of beads were collected separately after test. Percentage buoyancy was calculated as the ratio of the number of beads that remained floating from the total number of beads taken for the study (Eqn. 16). The floating ability of the beads was measured by visual observation, percentage of floating were taken as the average of three determinations. The preparations were considered to have buoyancy, only when all beads floated on the test solution immediately or within a lag time which did not exceed 2 min (Elmowafy et al., 2009). Percentage buoyancy =

67 6

(16)

Where total beads=89 and beads remain floating= 8:

4.4.3.7.

Ex vivo bioadhesion studies

Goat gastric mucosa was used as the model membrane for ex vivo determination of the BS of the various formulations. Goat gastric mucosal membrane was excised by removing the underlying connective tissue and it was placed on the base of a Texture Profile Analyzer (TAX TEE 32; M/s Stable Microsystems, Godalming, Surrey, UK). Before testing, it was kept in SGF for 12 h, the weighed microspheres were spread on the membrane fixed to the bottom and other part of membrane was attached to the mobile arm of the texture analyzer (Figure 18). The area of contact of mucosa was moistened with 50 µL of SGF. The mobile arm was lowered at a rate of 0.5 mm/s until a contact with the membrane was made. [Department of Pharm. Sci., MDU, Rohtak]

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Experimental

A contact force of 10 g was maintained for 300 s, after which the probe was withdrawn from the membrane. The peak attachment force was determined in triplicate (Ch'ng et al., 1985). 4.4.3.8.

In vitro glipizide release studies

In vitro release studies were carried out on glipizide loaded buoyant beads using USP XXIV dissolution test apparatus-I. Weighed quantity of beads equivalent to 10 mg of glipizide were introduced into dissolution basket and the basket was placed in 900 mL. simulated gastric fluid (0.1 N HCl) maintained at 37 ± 0.5 0 C and 50 rpm (Prabhakara, et al., 2008). Aliquots of 5 mL solution were withdrawn at predetermined time intervals and replaced with fresh dissolution medium. The

withdrawn

samples

were

analyzed

for

glipizide

content

spectrophotometrically (Schimadzu 1800, Japan) at 276 nm (IP, 2007). The results of in vitro release data were fitted into various release equations and to following kinetic models like zero-order, first order, Higuchi, Korsemeyer and Peppas models. 4.4.3.9.

In vivo imaging studies

4.4.3.9.1. X-ray Photographic Studies in Rabbits The preclinical study protocol was approved by Institutional Animal Ethical Committee, (Proposal No. IAEC/SRMS/2012/03) SRMSCET, Bareilly, Uttar Pradesh, India. Experiments were conducted according to the guidelines of committee for the “Purpose of Control and Supervision of Experiment on Animals” (CPCSEA) approval no. 715/2/CPCSEA. Healthy rabbit weighing approximately 1.5-2.0 Kg was used to assess in vivo floating/mucoadhesiv behaviour. Rabbit allocated to a study was fasted overnight (approximately 12 h) with access to water ad libitum

and X-ray photograph was taken to ensure

absence of radio opaque material in the stomach. Barium sulphate loaded floating-bioadhesive beads were administered in the morning with a 3.5 mL / kg water rinse via oral gavages to mimic clinical dosing conditions. During the experiment rabbit was not allowed to eat but water was provided. At predetermined time intervals the radiograph of abdomen was taken to locate the formulation.


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4.4.3.9.2. In vivo γ-scintigraphic studies in man The scintigraphic study was performed at the Department of NuclearMedicine at the Institute of Medicine and Allied Sciences (INMAS), Delhi, India. The investigation followed the tenets of the Declaration of Helsinki (WMA, 2008) duly approved by the Institutional Ethics Committee, Lord Shiva College of Pharmacy, Sirsa (Approval letter no. LSCP/IEC/11/01). Prior informed consent was obtained from each participating volunteer. The control and optimized formulation were labelled with 500–700 mCi (18.5–25.9 MBq) of 99mTc sulfur colloid, by incorporating a volume of 100 ml of the colloid solution into the beads and then the radiolabelled beads were placed in hard gelatin capsule shells (Quallicaps, Japan) and each capsule contained an equivalent of 10 mg of glipizide. The capsule was administered orally to each individual with 200 ml of potable water. Following oral administration of the radiolabelled preparation, anterior static images (2 min/image) were acquired under the dual-head Ecam gamma camera (M/s Siemens, Erlangan, Germany) at time intervals of 0, 75, 150, 240, 300 and 360 min for the test formulation and 0, 30, 60, 80 and 110 min for the control formulation. The study subjects were instructed to keep medically mobile and had free access to water until the completion of the radiographic acquisition. The scintigraphic images obtained with the control and the optimized formulations were subjected to analysis (Singh et al., 2012; Kapil et al., 2012; Wang et al., 2008) [volunteer consent form: appendix-A2]. 4.4.3.10.

Data analysis

Drug release data obtained during in vitro drug dissolution studies were analyzed using ZOREL software (Singh et al., 1998) which have in-built provisions for applying the correction factor for volume and drug losses during sampling (Singh et al., 1997). Based on the phenomenological analysis, the type of release, i.e., whether Fickian, non-Fickian (anomalous) or zero-order, was predicted. The value of T60% was calculated using Stineman interpolation option of the GRAPH 2.0 software (M/s Micromath Inc., Saint Louis, USA). Further, drug release data were applied to release models, Higuchi model which indicates that the drug release mechanism deviates from Fick’s laws and shows anomalous behavior (Higuchi, 1997). This is demonstrated by the Eqn. 11


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Experimental

= !;

(11)

Where, Q is the amount of drug release at time t, and KH is the Higuchi constant. The dissolution data was also fitted to the well-known Koresmeyer equation (eq. 12 and 13), which is often used to describe the drug release behavior from polymer systems (Korsmeyer et al., 1983). ∝

= . ∝

(12) = log ! + # log

(13)

Where ‘Mt’ is the amount of the drug release at time ‘t’, ‘Mα’ is the amount of drug release after infinite time and ‘K’ is a release rate constant incorporating structural and geometric characteristic of the tablet and ‘n’ is the diffusion exponent indications of the mechanism of drug release. 4.4.3.11.

Optimization

Data

Analysis

and

validation

of

FbD

methodology The response variables which were considered for optimization included Q16, BS, Tb and T60 (time required for 60 % release). For the studied design, the multiple linear regression analysis (MLRA) method was applied using Design expert 8.0.7.1 (Stat-Ease, Minneapolis, USA) software to fit full second-order polynomial equation (Eqn. 17) with added interaction terms to correlate the studied responses with the examined variables. Y = B0 + B1X1 + B2X2 + B3X1X2 + B4X12 + B5X22 + B6X1X22 + B7X12X2

(17)

The polynomial regression results were demonstrated for the studied responses. Finally, the prognosis of optimum formulation was conducted using a two-stage brute force technique using MS-Excel spreadsheet software. First, a feasible region was located followed by an exhaustive grid search to predict the possible solutions. The region of optimality was ratified using overlay plots, drawn using the Design Expert software. Total six formulations were selected as the confirmatory check-points for validated of FbD. The observed and predicted responses were critically compared. Linear correlation plots were constructed for the chosen check point formulations. The residual graphs between predicted and observed responses were also constructed separately and the percent bias (% prediction error) was calculated with respect to the observed responses.


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Experimental

4.4.3.12. Comparison of drug release of optimized with marketed formulation The drug release profile of optimized formulation was compared with marketed formulation (Glynase XL, USV limited) containing 10 mg of glipizide. The conditions used for drug release studies studies were identical as per the procedure described earlier. 4.4.3.13.

Accelerated Stability studies

Optimized formulation apart from other requirements, should be stable with regard to its properties especially drug release characteristics. The stability of selected floating-bioadhesive beads formulations was evaluated as per ICH guidelines for accelerated and long term testing. Environment chamber (Jindal Instrument, India) was used for maintaining the storage conditions. The samples were withdrawn periodically and evaluated (Abdelbary et al., 2010). The beads were packed in screw capped HDPE bottles and were stored at 40 ± 20C and 75 % RH for 6 months. After storage for 6 months, the products were tested for drug content floating characteristics and drug release rate as per the methods described earlier.


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Experimental

4.5. 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

REFERENCE Abdelbary A, El-Gazayerly ON, El-Gendy NA, Ali AA. Floating Tablet of Trimetazidine Dihydrochloride: An Approach for Extended Release with Zero-Order Kinetics. AAPS PharmSciTech. 2010; 11(3): 1058-67. Baumgartner S, Kristl J, Vrecer F, Vodopivec P, Zorko B. Optimisation of Floating Matrix Tablets and Evaluation of Their Gastric Residence Time. Int J Pharm. 2000; 195: 125-35. Ch'ng H, Park H, Kelly P, Robinson JR. Bioadhesive Polymers as Platforms for Oral Controlled Drug Delivery, II: Synthesis and Evaluation of Some Swelling Water Insoluble Bioadhesive Polymers. J Pharm Sci. 1985; 74: 399-405. Cho B and Shin S. Quality Improvement and Robust Design Methods to a Pharmaceut Res and Development. Math Probl Eng. 2012; Article ID 193246:1-14. Chowdary K and Rao YS. Design and in vitro and in-Vivo Evaluation of Mucoadhesive Microcapsules of Glipizide for Oral Controlled Release: A Technical Note. AAPSPharmSciTech. 2003; 4: E39-E44. Doornbos D and Haan P. Optimization Techniques in Formulation and Processing. Encyclopedia of Pharm Technol. Boylan JS, J, editor. New York: Marcel Dekker; 1995. Elmowafy M, Awad GAS, Mansour SA, El-Shamy AE. Ionotropically Emulsion Gelled Polysaccharides Beads: Preparation, in vitro and in vivo Evaluation. Carbohydr Polym. 2009; 75: 135-42. Foster R and Plosker G. Glipizide: A Review of the Pharmacoeconomic Implications of the Extended-Release Formulation in Type 2 Diabetes Mellitus. PharmacoEconomics. 2000; 18(3): 289-306. Fursule R, Patra CHN, Patil GB, Kosalge SB, Patil PO, Deshmukh PK. Study of Multiparticulate Floating Drug Delivery System Prepared by Emulsion Gelation Technique. Int J Chem Tech Res. 2009; 1(2): 162-8. Gonzalez-rodriguze M, Holgado M, Sanchez L. Alginate / Chitosan Particulate System for Sodium Diclofenac Release. Int J Pharm. 2002; 232: 225-34. Higuchi T. Mechanism of Sustained-Action Medication: Theoretical Analysis of Rate of Release of Solid Drugs Dispersed in Solid Matrices. J Pharm Sci. 1963; 52: 1145-9. Indian Pharmacopoeia. The Indian Pharmacopoeia Commission, Central Indian Pharmacopoeia Laboratory, Ministry of Health & Family Welfare, Govt. of India, Sector 23, Raj Nagar, Ghaziabad 201 002, India. (2007): 1167-1168. Jimenez C, Zia H, Rhodes CT. Design and Testing in Vitro of a Bioadhesive and Floating Drug Delivery System for Oral Application. Int J Pharm. 1994; 105: 65-70. Kapil R, Dhawan S, Singh B, Garg B, Singh B. Systematic formulation development of once-a-day gastroretentive controlled release tablets of rivastigmine using optimized polymer blends. J Drug Del Sci Tech. 2012; 22 (6): 511-521.


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Experimental

15. Korsmeyer R, Gurny R, Peppas N. Mechanisms of Solute Release from Porous Hydrophilic Polymers. Int J Pharm. 1983; 15: 25-35. 16. Krishna B, Vimala DM, Hima SK. In Vitro Evaluation of Commercial Modified Release Glipizide Tablets. Ind Pharm. 2004; 3(21): 65-9. 17. Mallikarjun V, Ravi P, Rajesh BV, Kiran G, Shiva KM. Design and Evaluation of Glipizide Floating Tablets. J Pharmacy Research. 2009; 2(4): 691-3. 18. Menger C, Lone K, William C, Tamara S, Michael M, Rochelle H. Pharmacokinetics and Pharmacodynamics of Extended-Release Glipizide Gits Compared with Immediate-Release Glipizide in Patients with Type II Diabetes Mellitus. J Clin Pharmacol. 2002; 42(6): 651-7. 19. Ponchel G, Irache JM. Specific and Non-Specific Bioadhesive Particulate System for Oral Delivery to the Gastrointestinal Tract. Adv Drug Deliver Rev. 1998; 34: 191-219. 20. Prabhakara P, Harish NM, Gulzar AM, Brijesh Y, Narayana CR, Satyanarayana D, Subrahmanayam EVS. Formulation and in Vitro Evaluation of Gastric Oral Floating Tablets of Glipizide. Indian J Pharm Educ. 2008; 42(2): 173-83. 21. Sarode S, Mitta M, Magar RM, Shelke AD, Shrivastava B, Vidyasagar G. Formulation and Evaluation of Floating Microspheres of Glipizide. J Chem Pharm Res. 2011; 3(3): 775-83. 22. Sato Y, Kawashima Y Tekuchi N. Physicochemical Properties to Determine the Buyoncy of Hollow Microsphere (Microballon) Prepared by Emulsion Solvent Diffusion Method. Eur J Pharm Biopharm. 2003; 55: 297-304. 23. Singh B and Singh S. A Comprehensive Computer Program for Study of Drug Release Kinetics from Compressed Matrices. Indian J Pharm Sci. 1998; 60: 358-62. 24. Singh B, Chakkal SK, Ahuja N. Formulation and Optimization of Controlled Release Mucoadhesive Tablets of Atenolol Using Response Surface Methodology. AAPS PharmSciTech. 2006; 7: E1-E10. 25. Singh B, Garg B, Chaturvedi SC, Arora S, Mandsaurwale R, Kapil R, Singh B. Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends. J Pharm Pharmacol. 2012; 64: 654–669. 26. Singh B, Kaur T, Singh S. Correction of Raw Disolution Data for Loss of Drug During Sampling. Indian J Pharm Sci. 1997; 59: 196-9. 27. Sriamornsak P, Thirawong N, Putkhachorn S. Morphology and Buoyancy of Oil-Entrapped Calcium Pectinate Gel Beads. AAPS Journal. 2004; 6(3): 65-71. 28. Streubel A, Siepmann J, Bodmeier R. Floating Matrix Tablets Based on Low-Density Foam Powder: Effects of Formulation and Processing Parameters on Drug Release. Eur J Pharm Sci. 2003; 18(1): 37-45. 29. Thombre A, Denoto AR, Gibbes DC. Delivery of Glipizide from Asymmetric Membrane Capsules Using Encapsulated Excipients. J Control Release. 1999; 60: 333-41.


Page 144

Experimental

30. Wagner J. Interpretation of Percent Dissolved-Time Plots Derived from in vitro Testing of Conventional Tablets and Capsules. J Pharm Sci. 1969; 58: 1253-7. 31. Wang J, Cui F, Shi K, Yang L, Wang S, Zhang L. In vivo evaluation of a sustained-release multiple-unit floating system containing nitrendipine. Asian J Pharmaceut Sci. 2008; 3 (4): 151-57. 32. WMA. Ethical principles for medical research involving human subjects: World Medical Association, Declaration of Helsinki. 59th WMA General Assembly, Seoul 2008.


Page 145

Results and Discussion

The current studies were undertaken for FbD based development, optimization and evaluation of the oral GRDDS of glipizide by rationally integrating the principles of drug release regulation with floating and bioadhesion.

5.1. SELECTION OF DRUG Oral CRDDS with clinical efficacy more than 12 h are primarily developed for short half life drugs, having high frequency of their administration (Robinson et al., 1987). While some drugs with longer half lives or with very less frequency of administration (two or even one) also may be tried for CRDDS, especially when reduction in fluctuation of drug blood concentration at steady state is desired (Ritschel, 1989). Glipizide was chosen as drug candidate for CR formulations owing to its potential as anti-diabetic drug. Further high frequency of administration (twice daily), short half life (3.5 h) low dose (5-20 mg) and physico-chemical stability at stomach pH are the properties associated with the drug which make it a suitable candidate for CRDDS (Berelowitz et al., 1994). Glipizide extended-release tablets results in less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide.

5.2. SELECTION OF DRUG DELIVERY SYSTEM Gastric emptying and intestinal peristalsis can displace the conventional CR system from its absorption site before the drug is completely released from the system, and it causes inadequate drug absorption while the drug released from devices that prolong gastric retention would be emptied with the gastric contents for an extended period. Thus prolonged gastric retention would improve bioavailability and reduce drug wastage (Fell et al., 2000). Scintigraphic studies involving measurements of gastric-emptying rates in healthy human subjects have revealed that an orally administered CR dosage form is mainly subjected to two physiological adversities, the short GRT and the variable gastric emptying time (GET) (Falkén et al. 2013). Overall, the relatively brief GI transit time of most drug products, (approximately 8 to 12 h), impedes their formulation as a once-daily dosage form. These problems can be exacerbated by alteration in gastric emptying that occurs due to factors, such as age, race, sex, and disease states, as they may seriously affect the release of a drug from its DDS. It is, therefore, highly desirable to have a once-a-day CR


Page 146


product exhibiting an extended GI residence and a drugdrug-release profile, independent of patient-related related variables. The floating bioadhesive tablets can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the GI tract. These systems help in continuously releasing sing the drug before it reaches the absorption window, thus ensuring optimal bioavailability (Klausner Klausner et al., 2003). Floating DDS or hydro-dynamically dynamically balanced systems (HBS) have a bulk density lower than the gastric fluids (0.45), the levels of two

polymers in their blend were chosen, as indicated in Table 26. MCC was chosen as the diluents. Drug release, as discerned from t75% values, was found to be better extended with increase in the levels of either polymer. However, rel8 h was found to be less than 92 % in all the cases, buoyancy time was found to decrease with increase in CP 934P content, while reverse is the case with increasing HPMC [Department of Pharm. Sci., MDU, Rohtak]

Page 152


K4M content. Hence, for further investigation HPMC K4M (50-100 mg) and CP 934P (14-28 mg) in combination, different from the ranges studied during preoptimization studies, i.e., 50-100 mg for HPMC K4M and 20-40 mg for CP 934P, were chosen. 100

% Drug Release

75

50

25

A

B

C

0 0

4

8

12

16

Time (h)

Figure 23: Dissolution profile of various floating-bioadhesive glipizide tablets (A, B, C) in pre-optimization studies (n=3) 5.5.1.

SELECTION OF SUITABLE DESIGN OF EXPERIMENTAL (DOE)

A CCD is considered as most efficient in estimating the influence of individual variables (main effects) and their interactions, using minimum experimentation (Doornbos and Haan, 1995; Schwartz and Connor, 1996; Lewis et al., 1999). In a CCD, all the factors are studied at all the possible combinations. The design also determines the quadratic response, which are not estimable using a factorial design (FD) at two levels. In the present study, fitting a cubic model is considered to be better as the values of the response surfaces are not known from the previous findings. Hence, a CCD for two factors at three levels with α= 1, which in turn is equivalent to a 32 FD, was chosen for the current formulation optimization study. The central point (0, 0) was studied in quintuplicate. 5.5.2.

DRUG

EXCIPIENT

COMPATIBILITY

STUDY,

PHYSICAL

EVALUATION AND ASSAY OF TABLET FORMULATIONS Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and various excipients (Tablet) was studied. The characteristic absorption peaks of glipizide were obtained at [Department of Pharm. Sci., MDU, Rohtak]

Page 153


3554 cm-1 - NH stretching of NH2 2943 cm-1 - C-H2 aliphatic group 1689 cm-1 - C=O stretching 1651 cm-1 - C=N aliphatic group 1529 cm-1 - CH aliphatic group These peaks obtained in the spectrum of tablet were correlated with the peaks of pure drug. The parent peaks of the drug did not show any deviation, which indicate that drug was compatible with these formulation component (Figure 24).

Figure 24: IR Spectra of glipizide drug and tablet All the tablet preparations were evaluated for various physical parameters and assay before proceeding further. Table 27 includes the values (mean ± SD) of weights, hardness, diameter and thickness of 13 tablet batches prepared using the polymer combinations along with the values of their assay and friability. Tablet weights in all the 13 batches of polymer blends varied between 198.7 mg and 200.8 mg, diameter was 8.0 mm, tablet hardness between 3.5 to 4.7 kg / cm2 and tablet friability between 0.54 % to 0.76 %. The assay of content of glipizide varied between 97.5 % to 101.5 %. Thus, all the physical parameters of the tablets were quite within the limit.


Page 154


TABLE 27: Physical evaluation of all the formulation prepared as per the experimental design Formulation

Wt. Variation

Hardness

Friability

Assay

Code

Test (mg)

(kg/cm2)

(%)

(%)

FT1

200.3±1.0

4.3±0.2

0.57±0.03

99.7±1.0

FT2

199.7±1.5

4.1±0.5

0.55±0.1

99.6±1.1

FT3

200.8±1.4

4.2±0.4

0.64±0.05

99.6±1.0

FT4

200.5±0.5

4.0±0.2

0.75±0.1

99.8±1.5

FT5

199.4±0.9

4.1±0.2

0.72±0.1

99.9±1.0

FT6

200.7±0.6

4.0±0.2

0.68±0.1

99.6±2.1

FT7

199.8±1.3

4.1±0.2

0.70±0.2

99.7±1.3

FT8

199.9±0.2

4.2±0.1

0.61±0.1

101.0±0.5

FT9

198.7±0.6

4.0±0.2

0.65±0.1

100.7±0.3

FT10

200.1±0.4

4.0±0.2

0.70±0.1

100.5±0.1

FT11

200.0±0.5

4.1±0.5

0.66±0.1

100.5±0.1

FT12

200.2±0.9

4.0±0.3

0.65±0.1

99.8±1.0

FT13

199.9±0.9

4.0±0.5

0.71±0.2

99.6±1.1

5.5.3.

DRUG RELEASE STUDIES

Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms, for formulations prepared using the polymer blend of CP 934P and HPMC K4M (FT-1 to FT-13) are listed in Tables 28 to 40, while the overall dissolution and statistical parameters for each dosage form unit are listed in Tables 28a to 40a. Summary of the dissolution parameter is indicated in Table 41 and Figure 25 (A) and (B).


Page 155


100

% Drug release

75

F1 F2 50

F3 F4 F5 F6

25 F7 F8 F9 0 0

1

2

3

4

5

6

7

8

9

10

12

16

20

Time (h) (A)

3.5 F1

F2

F3

F4

F6

F7

F8

F9

F5

Mean rate of drug release (mg/h)

3 2.5 2 1.5 1 0.5 0 0

5

10

15

20

Mid point of time interval (h)

(B) Figure 25: In vitro drug release profiles of the various batches formulated (A), and corresponding rates of drug release (B). [Department of Pharm. Sci., MDU, Rohtak]

Page 156


Table 28: Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT1 Amount of Drug Released (mg) Time (h)

Percent Drug Release Mean± S.D.

1

Log (Time)

Time Interval (h)

Mid Point of Time Interval (h)

Rate of Drug Release (mg/h) Mean± S.D.

Fickian Diffusion

Polymer Rlaxation

Total

28.18

2.66

0.15

2.81

0.000

0.0-1.0

0.5

2.81

2

31.58

2.93

0.23

3.16

0.693

1.0-2.0

1.5

0.34

3

44.32

4.03

0.40

4.43

1.099

2.0-3.0

2.5

1.27

4

48.41

4.36

0.48

4.84

1.386

3.0-4.0

3.5

0.41

5

54.96

4.87

0.62

5.49

1.609

4.0-5.0

4.5

0.65

6

59.72

5.22

0.75

5.97

1.792

5.0-6.0

5.5

0.48

7

65.72

5.6

0.97

6.57

1.946

6.0-7.0

6.5

0.6

8

71.76

7.06

0.11

7.17

2.079

7.0-8.0

7.5

0.58

9

77.82

7.65

0.13

7.78

2.197

8.0-9.0

8.5

0.61

10

82.7

8.13

0.14

8.27

2.303

9.0-10.0

9.5

0.49

12

87.81

8.62

0.16

8.78

2.485

10.0-12.0

11.0

0.51

16

95.17

9.32

0.20

9.52

2.773

12.0-16.0

14.0

0.74

Table 28a: Regression Parameters for the batch FT1 Parameter

Values

k

n

R²

SEOE

AOEV

p value

0.2600

0.4739

0.9786

0.0617

0.9766

≤.001

0.2533

0.4951

0.9770

0.0605

0.9744

≤.001

0.2540

0.4926

0.9728

0.0640

0.9695

≤.001


Page 157




1

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

Log (Time)

27.56

2.74

0.02

2.75

0.000

0.0-1.0

0.5

2.76

2

30.96

3.07

0.03

3.09

0.693

1.0-2.0

1.5

0.34

3

43.5

4.3

0.05

4.35

1.099

2.0-3.0

2.5

1.25

4

47.79

4.72

0.063

4.78

1.386

3.0-4.0

3.5

0.43

5

54.13

5.33

0.078

5.41

1.609

4.0-5.0

4.5

0.63

6

60.71

5.98

0.095

6.07

1.792

5.0-6.0

5.5

0.66

7

64.69

6.36

0.109

6.47

1.946

6.0-7.0

6.5

0.40

8

71.33

7.00

0.127

7.13

2.079

7.0-8.0

7.5

0.66

9

76.89

7.54

0.144

7.69

2.197

8.0-9.0

8.5

0.56

10

81.86

8.02

0.161

8.19

2.303

9.0-10.0

9.5

0.50

12

86.35

8.45

0.184

8.63

2.485

10.0-12.0

11.0

0.45

16

93.1

9.08

0.225

9.31

2.773

12.0-16.0

14.0

0.67

Table 29a: Regression Parameters for the batch FT2

Parameter

k

n

R²

SEOE

AOEV

p value

0.2549

0.4783

0.9793

0.0612

0.9774

≤.001

0.2511

0.4904

0.9792

0.0596

0.9771

≤.001

0.2511

0.4954

0.9793

0.0610

0.9773

≤.001

Values


Page 158


Table 30: Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms of batch FT3

Log (Time)

Time Interval (h)


Amount of Drug Released (mg) Time (h)

Percent Drug Release Mean± S.D. Fickian Diffusion

Polymer Rlaxation

Total


1

27.36

2.71

0.02

2.74

0.000

0.0-1.0

0.5

2.73

2

30.55

3.02

0.031

3.05

0.693

1.0-2.0

1.5

0.32

3

43.09

4.25

0.052

4.31

1.099

2.0-3.0

2.5

1.25

4

47.58

4.69

0.066

4.76

1.386

3.0-4.0

3.5

0.45

5

53.52

5.27

0.082

5.35

1.609

4.0-5.0

4.5

0.59

6

59.49

5.85

0.098

5.95

1.792

5.0-6.0

5.5

0.59

7

64.27

6.31

0.114

6.42

1.946

6.0-7.0

6.5

0.47

8

70.70

6.93

0.133

7.07

2.079

7.0-8.0

7.5

0.64

9

76.35

7.48

0.151

7.63

2.197

8.0-9.0

8.5

0.56

10

81.43

7.97

0.169

8.14

2.303

9.0-10.0

9.5

0.50

12

85.72

8.38

0.192

8.57

2.485

10.0-12.0

11.0

0.42

16

92.46

9.01

0.235

9.24

2.773

12.0-16.0

14.0

0.67


k

n

R²

SEOE

AOEV

p value

0.2521

0.4797

0.9789

0.0620

0.9770

≤.001

0.2518

0.4796

0.9786

0.0616

0.9769

≤.001

0.2484

0.4913

0.9784

0.0609

0.9768

≤.001

Values


Page 159





Polymer Rlaxation

Total

Log (Time)

Time Interval (h)



1

27.16

2.69

0.021

2.71

0.000

0.0-1.0

0.5

2.71

2

30.55

3.02

0.032

3.05

0.693

1.0-2.0

1.5

0.33

3

42.68

4.21

0.054

4.26

1.099

2.0-3.0

2.5

1.21

4

47.17

4.64

0.068

4.71

1.386

3.0-4.0

3.5

0.44

5

53.11

5.22

0.084

5.31

1.609

4.0-5.0

4.5

0.59

6

58.87

5.78

0.101

5.88

1.792

5.0-6.0

5.5

0.57

7

63.65

6.24

0.117

6.36

1.946

6.0-7.0

6.5

0.47

8

70.08

6.87

0.137

7.00

2.079

7.0-8.0

7.5

0.64

9

75.52

7.39

0.155

7.55

2.197

8.0-9.0

8.5

0.54

10

79.99

7.82

0.172

7.99

2.303

9.0-10.0

9.5

0.44

12

85.48

8.34

0.199

8.54

2.485

10.0-12.0

11.0

0.54

16

92.63

9.01

0.245

9.26

2.773

12.0-16.0

14.0

0.71


Values

k

n

R²

SEOE

AOEV

p value

0.2484

0.4911

0.9806

0.0582

0.9786

≤.001

0.2479

0.4990

0.9784

0.0591

0.9785

≤.001

0.2500

0.4803

0.9811

0.0586

0.9794

≤.001


Page 160





Polymer Rlaxation

Total

Log (Time)

Time Interval (h)



1

27.16

2.69

0.022

2.71

0.000

0.0-1.0

0.5

2.71

2

30.15

2.98

0.032

3.01

0.693

1.0-2.0

1.5

0.29

3

42.07

4.15

0.054

4.20

1.099

2.0-3.0

2.5

1.19

4

46.76

4.60

0.069

4.67

1.386

3.0-4.0

3.5

0.46

5

52.29

5.14

0.085

5.23

1.609

4.0-5.0

4.5

0.55

6

58.45

5.74

0.102

5.84

1.792

5.0-6.0

5.5

0.61

7

63.03

6.18

0.118

6.30

1.946

6.0-7.0

6.5

0.45

8

69.05

6.76

0.137

6.90

2.079

7.0-8.0

7.5

0.60

9

74.49

7.29

0.156

7.44

2.197

8.0-9.0

8.5

0.54

10

78.34

7.66

0.172

7.83

2.303

9.0-10.0

9.5

0.38

12

84.84

8.28

0.202

8.48

2.485

10.0-12.0

11.0

0.65

16

92.18

8.92

0.295

9.21

2.773

12.0-16.0

14.0

0.73


Values

k

n

R²

0.2449

0.4884

0.9799

0.2475

0.4801

0.2447

0.4892


SEOE

AOEV

p value

0.0589

0.9779

≤.001

0.9812

0.0586

0.9794

≤.001

0.9797

0.0588

0.9776

≤.001

Page 161




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.75

2.65

0.025

2.67

0.000

0.0-1.0

0.5

2.67

2

29.54

2.91

0.037

2.95

0.693

1.0-2.0

1.5

0.27

3

41.25

4.06

0.062

4.12

1.099

2.0-3.0

2.5

1.17

4

46.14

4.53

0.078

4.61

1.386

3.0-4.0

3.5

0.48

5

52.07

5.11

0.097

5.20

1.609

4.0-5.0

4.5

0.59

6

57.63

5.64

0.117

5.76

1.792

5.0-6.0

5.5

0.55

7

62.20

6.08

0.135

6.22

1.946

6.0-7.0

6.5

0.45

8

68.41

6.68

0.157

6.84

2.079

7.0-8.0

7.5

0.62

9

74.68

7.28

0.179

7.46

2.197

8.0-9.0

8.5

0.62

10

77.68

7.57

0.194

7.76

2.303

9.0-10.0

9.5

0.30

12

84.60

8.22

0.232

8.46

2.485

10.0-12.0

11.0

0.69

16

91.74

8.88

0.285

9.17

2.773

12.0-16.0

14.0

0.71


k

n

R²

0.2421

0.4867

0.9801

SEOE

AOEV

p value

0.0599

0.9791

≤.001

Values 0.2400

0.4936

0.9792

0.0601

0.9771

≤.001

0.2426

0.4851

0.9810

0.0594

0.9793

≤.001


Page 162




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.35

2.60

0.028

2.63

0.000

0.0-1.0

0.5

2.63

2

28.39

2.79

0.041

2.84

0.693

1.0-2.0

1.5

0.20

3

40.84

4.01

0.07

4.08

1.099

2.0-3.0

2.5

1.24

4

45.53

4.46

0.088

4.55

1.386

3.0-4.0

3.5

0.46

5

51.25

5.87

0.11

5.12

1.609

4.0-5.0

4.5

0.57

6

57.43

5.61

0.133

5.74

1.792

5.0-6.0

5.5

0.61

7

61.98

6.04

0.154

6.19

1.946

6.0-7.0

6.5

0.45

8

67.99

6.62

0.179

6.79

2.079

7.0-8.0

7.5

0.60

9

73.43

7.14

0.203

7.34

2.197

8.0-9.0

8.5

0.54

10

77.47

7.52

0.225

7.74

2.303

9.0-10.0

9.5

0.40

12

83.97

8.13

0.264

8.39

2.485

10.0-12.0

11.0

0.65

16

91.31

8.80

0.325

9.13

2.773

12.0-16.0

14.0

0.73


k

n

R²

0.2383

0.4919

0.9799

SEOE

AOEV

p value

0.0621

0.9778

≤.001

Values 0.2354

0.5002

0.9777

0.0630

0.9755

≤.001

0.2381

0.4910

0.9796

0.0624

0.9777

≤.001


Page 163




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.14

2.59

0.018

2.61

0.000

0.0-1.0

0.5

2.61

2

28.72

2.84

0.027

2.87

0.693

1.0-2.0

1.5

0.25

3

40.43

3.99

0.046

4.04

1.099

2.0-3.0

2.5

1.17

4

44.91

4.43

0.058

4.49

1.386

3.0-4.0

3.5

0.44

5

50.84

5.01

0.072

5.08

1.609

4.0-5.0

4.5

0.59

6

56.79

5.59

0.087

5.68

1.792

5.0-6.0

5.5

0.59

7

60.95

5.99

0.1

6.09

1.946

6.0-7.0

6.5

0.41

8

67.16

6.59

0.117

6.71

2.079

7.0-8.0

7.5

0.62

9

72.8

7.14

0.133

7.28

2.197

8.0-9.0

8.5

0.56

10

77.04

7.55

0.148

7.70

2.303

9.0-10.0

9.5

0.42

12

83.33

8.16

0.173

8.33

2.485

10.0-12.0

11.0

0.62

16

90.47

8.83

0.214

9.04

2.773

12.0-16.0

14.0

0.71


Parameter

k

n

R²

0.2392

0.4801

0.9799

SEOE

AOEV

p value

0.0638

0.9780

≤.001

Values 0.2361

0.4900

0.9790

0.0631

0.9771

≤.001

0.2390

0.4808

0.9796

0.0636

0.9779

≤.001


Page 164




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

25.94

2.57

0.019

2.59

0.000

0.0-1.0

0.5

2.59

2

28.72

2.84

0.029

2.87

0.693

1.0-2.0

1.5

0.27

3

40.03

3.95

0.049

4.00

1.099

2.0-3.0

2.5

1.13

4

44.30

4.36

0.061

4.43

1.386

3.0-4.0

3.5

0.42

5

50.02

4.92

0.076

5.00

1.609

4.0-5.0

4.5

0.57

6

56.17

5.52

0.093

5.62

1.792

5.0-6.0

5.5

0.61

7

59.92

5.88

0.106

5.99

1.946

6.0-7.0

6.5

0.37

8

66.94

6.56

0.125

6.69

2.079

7.0-8.0

7.5

0.70

9

70.95

6.95

0.14

7.09

2.197

8.0-9.0

8.5

0.40

10

76.20

7.46

0.157

7.62

2.303

9.0-10.0

9.5

0.52

12

82.69

8.08

0.185

8.27

2.485

10.0-12.0

11.0

0.64

16

89.62

8.73

0.227

8.96

2.773

12.0-16.0

14.0

0.69


Parameter

k

n

R²

SEOE

AOEV

p value

0.2341

0.4839

0.9810

0.0604

0.9795

≤.001

0.2339

0.4895

0.9806

0.0607

0.9788

≤.001

0.2362

0.4820

0.9817

0.0603

0.9802

≤.001

Values


Page 165




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

27.36

2.71

0.021

2.74

0.000

0.0-1.0

0.5

2.73

2

29.54

2.92

0.031

2.95

0.693

1.0-2.0

1.5

0.21

3

41.66

4.11

0.052

4.16

1.099

2.0-3.0

2.5

1.21

4

46.15

4.55

0.065

4.61

1.386

3.0-4.0

3.5

0.44

5

52.48

5.16

0.082

5.25

1.609

4.0-5.0

4.5

0.63

6

58.65

5.76

0.1

5.86

1.792

5.0-6.0

5.5

0.61

7

62.62

6.14

0.114

6.26

1.946

6.0-7.0

6.5

0.39

8

69.24

6.79

0.133

6.92

2.079

7.0-8.0

7.5

0.66

9

74.08

7.25

0.15

7.41

2.197

8.0-9.0

8.5

0.48

10

77.92

7.62

0.166

7.79

2.303

9.0-10.0

9.5

0.38

12

84.42

8.24

0.194

8.44

2.485

10.0-12.0

11.0

0.65

16

91.56

8.91

0.239

9.15

2.773

12.0-16.0

14.0

0.71


k

n

R²

0.2466

0.4796

0.9817

SEOE

AOEV

p value

0.0644

0.9752

≤.001

Values 0.2436

0.4892

0.9753

0.0649

0.9729

≤.001

0.2446

0.4862

0.9773

0.0645

0.9737

≤.001


Page 166




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.95

2.67

0.023

2.69

0.000

0.0-1.0

0.5

2.69

2

29.74

2.94

0.034

2.97

0.693

1.0-2.0

1.5

0.27

3

41.86

4.12

0.057

4.18

1.099

2.0-3.0

2.5

1.21

4

46.15

4.54

0.071

4.61

1.386

3.0-4.0

3.5

0.42

5

52.08

5.11

0.089

5.21

1.609

4.0-5.0

4.5

0.59

6

57.84

5.67

0.107

5.78

1.792

5.0-6.0

5.5

0.57

7

62.81

6.15

0.124

6.28

1.946

6.0-7.0

6.5

0.49

8

68.63

6.71

0.144

6.86

2.079

7.0-8.0

7.5

0.58

9

73.86

7.22

0.163

7.38

2.197

8.0-9.0

8.5

0.52

10

78.52

7.67

0.182

7.85

2.303

9.0-10.0

9.5

0.46

12

84.82

8.27

0.212

8.48

2.485

10.0-12.0

11.0

0.63

16

91.36

8.87

0.259

9.13

2.773

12.0-16.0

14.0

0.65


Parameter

k

n

R²

SEOE

AOEV

p value

0.2422

0.4916

0.9780

0.0615

0.9758

≤.001

0.2450

0.4822

0.9796

0.0612

0.9778

≤.001

0.2446

0.4862

0.9790

0.0614

0.9769

≤.001

Values


Page 167




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.95

2.67

0.024

2.69

0.000

0.0-1.0

0.5

2.69

2

29.54

2.91

0.035

2.95

0.693

1.0-2.0

1.5

0.25

3

41.25

4.06

0.059

4.12

1.099

2.0-3.0

2.5

1.17

4

46.35

4.56

0.075

4.63

1.386

3.0-4.0

3.5

0.50

5

52.28

5.13

0.093

5.23

1.609

4.0-5.0

4.5

0.59

6

58.24

5.71

0.112

5.82

1.792

5.0-6.0

5.5

0.59

7

63

6.17

0.13

6.30

1.946

6.0-7.0

6.5

0.45

8

69.14

6.76

0.151

6.91

2.079

7.0-8.0

7.5

0.63

9

73.66

7.19

0.17

7.36

2.197

8.0-9.0

8.5

0.45

10

78.72

7.68

0.19

7.87

2.303

9.0-10.0

9.5

0.50

12

84.62

8.24

0.221

8.46

2.485

10.0-12.0

11.0

0.59

16

91.56

8.88

0.271

9.15

2.773

12.0-16.0

14.0

0.69


k

n

R²

0.2440

0.4829

0.9780

SEOE

AOEV

p value

0.0627

0.9763

≤.001

Values 0.2442

0.4840

0.9788

0.0627

0.9769

≤.001

0.2411

0.4943

0.9775

0.0626

0.9752

≤.001


Page 168




1

Log (Time)

Time Interval (h)



Fickian Diffusion

Polymer Rlaxation

Total

26.95

2.67

0.024

2.69

0.000

0.0-1.0

0.5

2.69

2

29.74

2.93

0.035

2.97

0.693

1.0-2.0

1.5

0.27

3

41.66

4.10

0.059

4.17

1.099

2.0-3.0

2.5

1.19

4

46.35

4.55

0.076

4.63

1.386

3.0-4.0

3.5

0.46

5

52.28

5.13

0.093

5.23

1.609

4.0-5.0

4.5

0.59

6

58.65

5.75

0.109

5.86

1.792

5.0-6.0

5.5

0.63

7

63

6.17

0.129

6.3

1.946

6.0-7.0

6.5

0.45

8

68.84

6.69

0.152

6.88

2.079

7.0-8.0

7.5

0.56

9

74.08

7.23

0.169

7.41

2.197

8.0-9.0

8.5

0.52

10

78.73

7.68

0.191

7.87

2.303

9.0-10.0

9.5

0.46

12

84.63

8.24

0.22

8.46

2.485

10.0-12.0

11.0

0.59

16

91.56

8.88

0.272

9.15

2.773

12.0-16.0

14.0

0.69


k

n

R²

0.2446

0.4830

0.9757

SEOE

AOEV

p value

0.0628

0.9730

≤.001

Values 0.2409

0.4974

0.9714

0.0663

0.9678

≤.001

0.2448

0.4825

0.9761

0.0624

0.9738

≤.001


Page 169


Table 41: Overall Dissolution Parameters as per CCD for different formulations T60%

Drug release rate (mg/h)

(h)

(Mean± S.D.)

95.170

6.04

0.815 ± 0.845

0.0076

93.105

6.06

0.808 ± 0.825

1.2820

0.0080

92.465

6.09

0.804 ± 0.817

0.2500

1.2786

0.0083

92.636

6.22

0.796 ± 0.805

0.4801

0.2475

1.2747

0.0085

92.189

6.32

0.787 ± 0.805

FT6

0.4851

0.2426

1.2672

0.0097

91.744

6.51

0.778 ± 0.794

FT7

0.4910

0.2381

1.2605

0.0111

91.316

6.57

0.779 ± 0.781

FT8

0.4808

0.2390

1.2669

0.0073

90.473

6.78

0.726 ± 0.765

FT9

0.4820

0.2362

1.2622

0.0079

89.623

7.01

0.723 ± 0.755

FT10

0.4796

0.2466

1.2740

0.0082

91.568

6.32

0.782 ± 0.821

FT11

0.4822

0.2450

1.2713

0.0089

91.360

6.43

0.786 ± 0.801

FT12

0.4840

0.2442

1.2702

0.0093

91.565

6.37

0.786 ± 0.799

FT13

0.4830

0.2446

1.2708

0.0091

91.456

6.28

0.785 ± 0.810

Batch

n

K

k1

k2

Q16

FT1

0.4739

0.2600

1.2931

0.0067

FT2

0.4783

0.2549

1.2862

FT3

0.4797

0.2521

FT4

0.4803

FT5


Page 170


5.5.4. BIOADHESION STUDIES The study shows an increasing trend in the BS with an increase in amount of either polymer (CP 934P and HPMC K4M), which is in consonance with the literature (Duchene et al., 1988; Gupta et al., 2002; Prudat-Christiaens et al., 1996; Singh and Ahuja, 2002). Hydrogels gets swell readily when in contact with the hydrated mucous membrane, it provides a large adhesive surface of hydrogels for maximum contact with mucin and polymer chain flexibility for more interpenetration with mucin. The water sorption reduces the glass transition temperature below the ambient conditions and hydrogels become progressively rubbery due to uncoiling of polymer chains and subsequent increased mobility of the polymer chains (Singh and Ahuja, 2002). This glass-rubbery transition provides hydrogel plasticization resulting in large adhesive surface for maximum contact with mucin and flexibility to the polymer chains for interpenetration with mucin. Increase in the polymer concentration may give more adhesive sites and polymer chains for more interpenetration with mucin and results in increment of BS. Although the BS is increasing with increasing levels of both polymers, the effect of CP 934P was found to be distinctly more pronounced than that of HPMC K4M. The bar diagram (Figure 26) clearly depicts the linear increasing trend in BS with polymer level. Force of detachment (g)

20 15 10 5 0 FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8

FT9 FT10 FT11 FT12 FT13

Figure 26: Bar diagram showing BS determined as force of detachment of all the formulation prepared as per the experimental design 5.5.5

BUOYANCY TIME

Swelling of the tablet plays a vital part in floatation of tablet (Timmermans and Moes, 1990). Kinetics of swelling is important because the gel barrier is formed with water permeation. Swelling is also a vital factor to ensure floating. To obtain floating the balance between swelling and water acceptance must be restored (Baumgartner et al., 2000). It was proved earlier that swelling is a vital factor to ensure floatation. Buoyancy time of the tablets increased in a linear fashion with [Department of Pharm. Sci., MDU, Rohtak]

Page 171


increase in HPMC K4M content (Table 27, Figure 27), owing ostensibly to swelling (hydration) of the hydrocolloid particles on the tablet surface, which in turn, results in an increase in the bulk volume. The air entrapped in the swollen polymer maintains a density less than unity and confers buoyancy to these dosage forms, as is vivid from the data in the table. With increase in CP 934P content, buoyancy time decreases following a linear trend, due to higher density of CP (1.76 g/cc) than HPMC (1.28 g/cc). The bar diagram (Figure 28) corroborates the significant positive and negative influence of HPMC K4M and CP 934P on floatation, respectively. Hence, increasing concentration of CP 934P has a distinct negative effect on the floating behaviour of the delivery system. But, it is of interest to mention that, the presence of CP 934P because of its mucoadhesive nature could possibly assist in the adhesion of the dosage form on the gastric wall and aid in retaining the tablet following oral ingestion within the stomach, which in turn, may aid in increasing the tablet gastric retention time (Singh et al., 2010; Nur and Zhang, 2000). Initial (dry state) bulk density of the dosage form and change in the floating strength with time should be characterised. Tablet density of all the formulations was found to be lower than the density of gastric contents (1.004 g / cc), which satisfies the major criterion for a dosage form to float. 25

Buoyancy Time (h)

20 15 10 5 0 FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8


Figure 27: Bar diagram showing buoyancy time determined for all the formulations prepared as per the experimental design 5.5.6

SWELLING INDEX STUDIES

The swelling index of glipizide tablets for a period for 6h is shown in Table 42 and Figure 28. The hygroscopic nature of the polymer affects the onset of swelling. Faster swelling has been observed for tablets containing higher amount of HPMC K4M. Maximum swelling was attained in 6 h, after which polymer started eroding slowly. High amount of water uptake may be due to quick [Department of Pharm. Sci., MDU, Rohtak]

Page 172


hydration of HPMC K4M and swelling rate of the tablets increases with increase in the concentration of HPMC K4M in tablets. Table 42: Swelling Index of all the formulations prepared as per the experimental design Swelling Index

Formulation code

1h

2h

3h

4h

5h

6h

FT1

0.30

0.34

0.37

0.40

0.42

0.43

FT2

0.32

0.37

0.41

0.43

0.44

0.45

FT3

0.33

0.40

0.43

0.45

0.47

0.48

FT4

0.35

0.41

0.47

0.54

0.58

0.60

FT5

0.36

0.43

0.49

0.56

0.61

0.63

FT6

0.38

0.46

0.54

0.61

0.65

0.66

FT7

0.40

0.51

0.60

0.66

0.73

0.74

FT8

0.41

0.52

0.61

0.68

0.75

0.76

FT9

0.43

0.53

0.65

0.71

0.79

0.80

FT10

0.35

0.43

0.49

0.55

0.60

0.62

FT11

0.35

0.42

0.49

0.56

0.61

0.63

FT12

0.36

0.44

0.48

0.55

0.61

0.63

FT13

0.36

0.43

0.50

0.57

0.62

0.64

FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8

FT9

Swelling index

0.8

0.6

0.4

0.2

0 1

2

3

4

5

6

Time (h)

Figure 28: Plot between Swelling Index and Time for various formulations prepared as per the experimental design


Page 173


5.5.7. RESPONSE SURFACE ANALYSIS Coefficients and calculation: Mathematical relationships were generated using multiple linear regression analysis (MLRA) for the number of response variables. High values of R2 of the MLRA coefficients for all four responses, ranging between 0.9403 and 0.9963, vouch high prognostic ability of the RSM polynomials. Seven coefficients (B1 to B7) were calculated with B0 representing the intercept, and B3 to B7, representing the various quadratic and interaction terms as shown in the Eqn. 18. Y = B0 + B1X1 + B2X2 + B3X1X2 + B4X12 + B5X22 + B6X1X22 + B7X12X2

(18)

Various response surfaces plotted for the studied response show the effect of polymers in combination on the properties and they are known to facilitate an understanding of contribution of the variables and their interaction (Table 43). Figure 29 and 30 reveals a sharp decline in the value of Q16 with an increase in the amount of each of the polymers, i.e., HPMC K4M and CP 934P, the influence of HPMC K4M being much more pronounced. Nonlinear descending contour lines in figure further showed that the variation in Q16 is a complex function of the polymer levels. Figure 31 and 32 portrays a linear increase or decrease relationship of Tb with increasing and decreasing amounts of HPMC K4M and CP 934P, respectively. Nearly linear lines in contour plot nullify the presence of any interaction between the polymers. Figure 33 and 34 shows a nearly linear ascending pattern for the values of BS, as the content of either polymer is increased, the effect being much more prominent with CP 934P. Maximum BS is observable at the highest levels of both polymers, viz., CP 934P and HPMC K4M. Nearly vertical contour lines corroborate the markedly significant influence of CP 934P on r values vis-à-vis HPMC K4M. T60 increases as both the polymers viz. CP 934P and HPMC K4M increase but the effect is more pronounced for CP as depicted in Figure 35 and 36.


Page 174


Table 43: Values of the coefficients for the polynomial equations and R for various response variables of the glipizide tablet formulations Coefficient code

Polynomial coefficient values for studied response variables Q16

Tb

BS

T60%

B0

+91.32

+13.26

+9.47

+6.33

B1

-1.316

+4.57

+2.75

+0.45

B2

-0.5495

-1.32

+0.65

+0.145

B3

+0.2545

-0.0075

+0.075

+0.097

B4

+0.301

+1.418

+1.63

+0.022

B5

+0.598

+1.168

-0.23

+0.057

B6

-0.548

+0.227

-0.175

-0.022

B7

-0.359

+0.007

+0.025

-0.087

R2

0.9403

0.9938

0.9963

0.9488

P value

0.001

0.001

0.001

0.001


Page 175


93.00-95.00

91.00-93.00

89.00-91.00

95.00

Q16

93.00 91.00 1.00 89.00 -1.00

0.00 CP 934P

0.00 -1.00

HPMC K4M 1.00

Figure 29:: Response Surface plot showing effect of HPMC K4M and CP 934P on drug release

Q16

1.00

90

B : CP

0.50

0.00

5

91

0.00

0.50

92

93

-0.50

94 -1.00 -1.00

-0.50

1.00

A: HPMC

Figure 30: Corresponding contour contour Plots showing effect of HPMC K4M and CP 934P on drug release [Department of Pharm. Sci., MDU, Rohtak]

Page 176


17.00-21.00

13.00-17.00

9.00-13.00

21.00

Tb

17.00 13.00 1.00 9.00 -1.00

0.00 CP 934P

0.00 HPMC K4M

-1.00 1.00

Figure 31:: Response Surface plot showing effect of HPMC K4M and CP 934P on buoyancy Time

Tb

1.00

10

B: CP

0.50

0.00

12

5

14

16

18

-0.50

20 -1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 32: Corresponding contour plot showing effect of HPMC K4M and CP 934P on buoyancy time [Department of Pharm. Sci., MDU, Rohtak]

Page 177


Figure 33:: Response Surface plot showing effect of HPMC K4M and CP 934P on bioadhesive strength

BS

1.00

14 0.50

B : CP

9

10

5

0.00

11

12

13

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 34: Corresponding contour contour Plots showing effect of HPMC K4M and CP 934P on bioadhesive strength [Department of Pharm. Sci., MDU, Rohtak]

Page 178


5.80 5.80-6.20

6.20-6.60

6.60-7.00

T60%

7.00

6.60

6.20

1.00

5.80

0.00

-1.00

CP 934P 0.00 HPMC K4M

-1.00 1.00

Figure 35:: Response Surface plot showing effect of HPMC K4M and CP 934P on T60

T60

1.00

0.50

6.8

B : CP

6

0.00

6.2

5

6.4

6.6

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 36: Corresponding contour c Plots showing effect ct of HPMC K4M and CP 934P on T60


Page 179


5.5.8. SEARCH FOR OPTIMUM FORMULATIONS Feasibility and grid searches method through MS-excel utility and overlay plot generation method through Design expert were used for finding the optimized product. The results for the feasibility search to find the suitable region for further location of optimum formulations are presented in Table 44, 45, 46 and 47. The criteria for selection of suitable feasible region (shown with thicker borders) were primarily based upon the highest possible values of Q16, T60%, Tb and BS. The selected regions were based on the following criteria. For selected region: Q16>92%; T60% > 6.1 h; Tb >12 and BS>8.1 The results of the exhaustive grid searches performed subsequent to feasibility searches are presented in Tables 48, 49, 50 and 51.


Page 180


Table 44: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Q16 HPMC CP

-1.00

-1.00

95.43 94.81 94.24 93.72 93.25 92.84 92.48 92.17 91.92 91.72 91.58

-0.80

94.89 94.33 93.83 93.37 92.95 92.58 92.25 91.97 91.73 91.54 91.39

-0.60

94.40 93.92 93.47 93.06 92.69 92.35 92.05 91.78 91.55 91.36 91.20

-0.40

93.97 93.56 93.17 92.80 92.47 92.16 91.88 91.62 91.40 91.20 91.02

-0.20

93.61 93.25 92.91 92.59 92.28 92.00 91.73 91.48 91.25 91.04 90.85

0.00

93.31 93.00 92.70 92.42 92.14 91.87 91.61 91.36 91.12 90.90 90.68

0.20

93.07 92.81 92.55 92.29 92.03 91.78 91.52 91.27 91.01 90.76 90.51

0.40

92.89 92.67 92.44 92.21 91.97 91.72 91.46 91.19 90.92 90.64 90.35

0.60

92.78 92.59 92.39 92.17 91.94 91.69 91.42 91.14 90.84 90.52 90.19

0.80

92.72 92.57 92.39 92.18 91.95 91.69 91.41 91.11 90.78 90.42 90.04

1.00

92.73 92.60 92.43 92.23 92.00 91.73 91.43 91.10 90.73 90.33 89.89

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

Table 45: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for T60% HPMC CP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

6.03

6.06

6.10

6.15

6.19

6.25

6.30

6.36

6.42

6.49

6.56

-0.80

5.98

6.03

6.08

6.13

6.19

6.25

6.32

6.39

6.46

6.53

6.61

-0.60

5.94

6.00

6.06

6.13

6.20

6.27

6.34

6.42

6.50

6.58

6.66

-0.40

5.92

5.99

6.06

6.13

6.21

6.28

6.36

6.45

6.53

6.62

6.71

-0.20

5.91

5.98

6.06

6.14

6.22

6.31

6.39

6.48

6.57

6.67

6.76

0.00

5.91

5.99

6.07

6.16

6.24

6.33

6.42

6.52

6.61

6.71

6.81

0.20

5.92

6.00

6.09

6.18

6.27

6.36

6.46

6.55

6.65

6.75

6.85

0.40

5.94

6.03

6.12

6.21

6.31

6.40

6.50

6.59

6.69

6.79

6.89

0.60

5.97

6.07

6.16

6.25

6.35

6.44

6.54

6.63

6.73

6.83

6.93

0.80

6.02

6.11

6.21

6.30

6.39

6.49

6.58

6.68

6.77

6.87

6.96

1.00

6.08

6.17

6.26

6.35

6.44

6.54

6.63

6.72

6.81

6.90

7.00


Page 181


Table 46: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Tb HPMC CP

-1.00

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

11.37 11.85 12.43 13.11 13.88 14.75 15.71 16.77 17.92 19.17 20.51

-0.80 11.09 11.56 12.13 12.79 13.56 14.42 15.39 16.45 17.61 18.87 20.23 -0.60

10.82 11.28 11.83 12.49 13.25 14.11 15.08 16.15 17.32 18.59 19.97

-0.40

10.57 11.01 11.55 12.20 12.95 13.81 14.78 15.86 17.04 18.32 19.71

-0.20

10.33 10.75 11.28 11.92 12.67 13.53 14.50 15.58 16.77 18.07 19.47

0.00

10.11 10.51 11.03 11.66 12.40 13.26 14.23 15.31 16.51 17.82 19.25

0.20

9.90

10.28 10.79 11.41 12.15 13.00 13.97 15.06 16.27 17.59 19.03

0.40

9.70

10.07 10.56 11.17 11.91 12.76 13.73 14.83 16.04 17.38 18.83

0.60

9.52

9.87

10.35 10.95 11.68 12.53 13.50 14.60 15.83 17.17 18.65

0.80

9.35

9.69

10.15 10.74 11.46 12.31 13.29 14.39 15.62 16.98 18.47

1.00

9.20

9.52

9.97

10.55 11.26 12.11 13.09 14.19 15.43 16.81 18.31

Table 47: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for BS HPMC CP

-1.00 -0.80 -0.60 -0.40 -0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

8.17

8.06

8.09

8.27

8.59

9.06

9.67

10.43

11.33

12.38

13.57

-0.80

8.17

8.08

8.12

8.31

8.63

9.10

9.72

10.47

11.37

12.40

13.58

-0.60

8.19

8.11

8.17

8.36

8.70

9.17

9.78

10.53

11.42

12.45

13.62

-0.40

8.23

8.16

8.23

8.44

8.78

9.25

9.87

10.61

11.50

12.52

13.68

-0.20

8.29

8.23

8.31

8.53

8.87

9.35

9.97

10.72

11.60

12.61

13.76

0.00

8.36

8.32

8.41

8.64

8.99

9.48

10.09

10.84

11.71

12.72

13.86

0.20

8.45

8.42

8.53

8.76

9.13

9.61

10.23

10.98

11.85

12.85

13.98

0.40

8.55

8.55

8.67

8.91

9.28

9.77

10.39

11.14

12.01

13.00

14.12

0.60

8.67

8.68

8.82

9.07

9.45

9.95

10.57

11.32

12.18

13.17

14.28

0.80

8.81

8.84

8.99

9.25

9.64

10.14

10.77

11.51

12.38

13.36

14.46

1.00

8.97

9.01

9.17

9.45

9.85

10.36

10.99

11.73

12.59

13.57

14.67

The highlighted portions indicate the area investigated for feasibility


Page 182


Table 48: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Q16 HPMC CP

-0.40

-1.00

93.72 93.57 93.43 93.30 93.16 93.04 92.92 92.80 92.69 92.58 92.48

-0.96

93.64 93.50 93.36 93.23 93.10 92.98 92.86 92.75 92.64 92.53 92.43

-0.92

93.57 93.43 93.30 93.17 93.04 92.92 92.81 92.69 92.59 92.48 92.39

-0.88

93.50 93.37 93.23 93.11 92.98 92.87 92.75 92.64 92.54 92.44 92.34

-0.84

93.43 93.30 93.17 93.05 92.93 92.81 92.70 92.59 92.49 92.39 92.29

-0.80

93.37 93.24 93.11 92.99 92.87 92.76 92.65 92.54 92.44 92.34 92.25

-0.76

93.30 93.18 93.05 92.93 92.82 92.71 92.60 92.50 92.40 92.30 92.21

-0.72

93.24 93.12 93.00 92.88 92.77 92.66 92.55 92.45 92.35 92.26 92.17

-0.68

93.18 93.06 92.94 92.83 92.72 92.61 92.51 92.41 92.31 92.22 92.13

-0.64

93.12 93.00 92.89 92.77 92.67 92.56 92.46 92.36 92.27 92.18 92.09

-0.60

93.06 92.95 92.83 92.72 92.62 92.52 92.42 92.32 92.23 92.14 92.05

-0.34

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

Table 49: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for T60% HPMC CP

-0.40 -0.34 -0.28 -0.22 -0.16 -0.10 -0.04

0.02

0.08

0.14

0.20

-1.00

6.15

6.16

6.18

6.19

6.20

6.22

6.24

6.25

6.27

6.28

6.30

-0.96

6.14

6.16

6.17

6.19

6.20

6.22

6.24

6.25

6.27

6.29

6.30

-0.92

6.14

6.16

6.17

6.19

6.20

6.22

6.24

6.25

6.27

6.29

6.31

-0.88

6.14

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.27

6.29

6.31

-0.84

6.14

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.28

6.30

6.32

-0.80

6.13

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.28

6.30

6.32

-0.76

6.13

6.15

6.17

6.19

6.21

6.22

6.24

6.26

6.28

6.30

6.32

-0.72

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.33

-0.68

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.33

-0.64

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.34

-0.60

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.30

6.32

6.34


Page 183


Table 50: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Tb HPMC CP

-0.34

-0.40

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

-1.00 13.11 13.33 13.56 13.80 14.05 14.30 14.57 14.84 15.12 15.41 15.71 -0.96 13.05 13.27 13.50 13.73 13.98 14.24 14.50 14.77 15.06 15.35 15.64 -0.92 12.98 13.20 13.43 13.67 13.92 14.17 14.44 14.71 14.99 15.28 15.58 -0.88 12.92 13.14 13.37 13.61 13.85 14.11 14.37 14.64 14.93 15.22 15.51 -0.84 12.86 13.08 13.30 13.54 13.79 14.04 14.31 14.58 14.86 15.15 15.45 -0.80 12.79 13.01 13.24 13.48 13.72 13.98 14.24 14.52 14.80 15.09 15.39 -0.76 12.73 12.95 13.18 13.41 13.66 13.92 14.18 14.45 14.73 15.02 15.32 -0.72 12.67 12.89 13.12 13.35 13.60 13.85 14.12 14.39 14.67 14.96 15.26 -0.68 12.61 12.83 13.05 13.29 13.54 13.79 14.05 14.33 14.61 14.90 15.20 -0.64 12.55 12.77 12.99 13.23 13.47 13.73 13.99 14.27 14.55 14.84 15.14 -0.60 12.49 12.71 12.93 13.17 13.41 13.67 13.93 14.20 14.49 14.78 15.08

Table 51: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for BS HPMC CP

-0.40

-0.34

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

-1.00

8.27

8.35

8.44

8.55

8.67

8.81

8.95

9.11

9.29

9.47

9.67

-0.96

8.27

8.36

8.45

8.56

8.68

8.81

8.96

9.12

9.29

9.48

9.68

-0.92

8.28

8.36

8.46

8.57

8.69

8.82

8.97

9.13

9.30

9.49

9.69

-0.88

8.29

8.37

8.47

8.58

8.70

8.83

8.98

9.14

9.31

9.50

9.70

-0.84

8.30

8.38

8.48

8.59

8.71

8.84

8.99

9.15

9.32

9.51

9.71

-0.80

8.31

8.39

8.49

8.60

8.72

8.85

9.00

9.16

9.33

9.52

9.72

-0.76

8.32

8.40

8.50

8.61

8.73

8.86

9.01

9.17

9.34

9.53

9.73

-0.72

8.33

8.41

8.51

8.62

8.74

8.88

9.02

9.18

9.36

9.54

9.74

-0.68

8.34

8.42

8.52

8.63

8.75

8.89

9.04

9.20

9.37

9.56

9.75

-0.64

8.35

8.43

8.53

8.64

8.77

8.90

9.05

9.21

9.38

9.57

9.77

-0.60

8.36

8.45

8.55

8.66

8.78

8.92

9.06

9.22

9.40

9.58

9.78

Highlighted area shows optimized formulation (Italic) and validation check points (Non-italic) [Department of Pharm. Sci., MDU, Rohtak]

Page 184


5.5.9. VALIDATION OF FbD STUDIES Physical evaluation results of the tablets and assay of the optimized formulations and various validation check points (VCT) are listed in Table 52. All the values were found within limits and their release behaviour are shown in Table 53. Table 52: Physical evaluations of validation check points and optimized product Batch Code

Wt. Variation Test (mg)

Hardness Friability (kg/cm2) (%)

Assay (%)

BS (Dyne/cm2)

Tb (h)

VCT1

200.8±1.1

4.1±0.5

0.72±0.1

99.7±1.3

8.2±0.2

13.1±0.3

VCT2

200.5±0.5

4.0±0.3

0.67±0.2

99.8±1.5

8.5±0.2

13.5±0.3

VCT3

199.9±0.9

4.0±0.2

0.59±0.1

100.5±1.2

8.3±0.1

12.5±0.3

VCT4

200.1±0.7

4.0±0.5

0.71±0.05

99.6±1.4

8.35±0.2

13.8±0.2

VCT5

200.1±0.7

4.0±0.2

0.68±0.1

99.9±1.3

9.3±0.1

14.7±0.2

VCT6

200.1±0.7

4.0±0.5

0.67±0.1

99.8±1.1

9.7±0.2

15.7±0.2

TOPT

200.2±0.5

4.0±0.2

0.65±0.1

99.9±1.1

8.55±0.1

12.9±0.2

Upon comparison of the observed responses with those of the anticipated ones (Table 54), the prediction error varied between -1.121 % and 0.862 % (mean ± SD = 0.32 ± 1.8 %). Linear correlation plots drawn between the predicted and observed responses after forcing the line through the origin, also demonstrated high values of R (0. 9403 to 0.9963) (Figure 37), indicating excellent goodness of fit (p < 0.001). The corresponding residual plots show nearly uniform and random scatter around the mean values of response variables. The optimum formulation was selected by trading off various response variables and adopting the following maximizing criteria: Q16>92%; T60% > 6.1 h; Tb >12 and BS>8.1. Upon comprehensive evaluation of grid searches, the formulation (X1= -0.28 and X2= -0.60 i.e. HPMC K4M=78.96 mg and CP 934P= 15.2 mg) fulfilled the optimal criteria of best regulation of the release rate Q16=92.85%; T60% = 6.18 h; Tb=12.9h and BS=8.6, this formulation was taken as optimized formulation. The release behaviour is distinctly zero order throughout. Further, high BS and high floatation times associated with these formulations are very likely to increase GRT, eventually improving the In-vivo extension in drug and the extent of absorption.


Page 185


Table 53: Drug release and regression parameters for validation check points and optimized tablet Batch code VCT1

Q16 (%)

k

n

R²

SEOE

AOEV

93.5

0.2605

0.4746

0.9770

0.0627

0.9763

VCT2

93.3

0.2539

0.4950

0.9771

0.0606

0.9743

VCT3

92.5

0.2448

0.4825

0.9761

0.0624

0.9738

VCT4

93.1

0.2513

0.4900

0.9793

0.0610

0.9771

VCT5

92.4

0.2479

0.4990

0.9784

0.0591

0.9785

VCT6

92.2

0.2500

0.4803

0.9811

0.0586

0.9794

TOPT

92.8

0.2442

0.4826

0.9763

0.0625

0.9731

Overlay plot obtained from design expert also conform the results of optimized formulation selection (Figure 38).


Page 186


Table 54: Checkpoint composition, their results and percentage error Validation X1 HPMC batch K4M mg

VCT1

VCT2

VCT3

VCT4

VCT5

VCT6

TOPT

74.8

78.96

85.20

74.8

91.44

95.0

78.96

X2 CP 934P mg

12.32

12.96

13.92

15.2

13.6

12.0

15.2

Response variables

Prediction values

Observed values

Percentage error

Q16 (%)

93.64

93.5

0.1495

T60% (h)

6.14

6.13

0.1628

Tb (h)

13.05

13.1

-0.3831

BS (d/cm2)

8.27

8.2

0.8464

Q16 (%)

93.23

93.3

-0.0750

T60% (h)

6.17

6.2

-0.4862

Tb (h)

13.37

13.52

-1.1219

BS (d/cm2)

8.47

8.5

-0.3541

Q16 (%)

92.71

92.5

0.2265

T60% (h)

6.22

6.21

0.1607

Tb (h)

13.92

13.8

0.8620

BS (d/cm2)

8.86

8.85

0.1128

Q16 (%)

93.06

93.1

-0.042

T60% (h)

6.13

6.12

0.1631

Tb (h)

12.49

12.5

-0.0800

BS (d/cm2)

8.36

8.35

0.1196

Q16 (%)

92.44

92.4

0.0432

T60% (h)

6.28

6.29

-0.1592

Tb (h)

14.8

14.7

0.6756

BS (d/cm2)

9.33

9.3

0.3215

Q16 (%)

92.48

92.2

0.3027

T60% (h)

6.3

6.29

0.1587

Tb (h)

15.71

15.7

0.0636

BS (d/cm2)

9.67

9.7

-0.3102

Q16 (%)

92.83

92.85

-0.02154

T60% (h)

6.17

6.18

-0.16207

Tb (h)

12.93

12.9

0.232019

BS (d/cm2)

8.55

8.6

-0.5848


Page 187


94

0.2 0.1 Residuals

Observed Q16

R² = 0.9403

93

0 -0.1 92

93

94

-0.2 -0.3 -0.4

92 92

93

-0.5

94

Predicted Q16

Observed Q16

0.6 R² = 0.9488

0.4 Residuals

Observed T60

6.3

6.2

0.2 0 6.1

6.1 6.1

6.2

6.3

6.3

-0.2

Predicted T60

observed T60 (h)

1.5 Residuals

17 Observed Tb

6.2

R² = 0.9938

14.5

1 0.5 0 12

12 12

14.5

17

17

-1

Predicted Tb

Observed Tb (h)

Residuals

10 Observed BS

14.5

-0.5

R² = 0.9963

9

8 8

9

Predicted BS

10

0.6 0.4 0.2 0 -0.2 8 -0.4 -0.6 -0.8 -1

9

10

Observed BS

Figure 37: Linear correlation and residual plots between different anticipated and experimental response variables [Department of Pharm. Sci., MDU, Rohtak]

Page 188


Figure 38: Overlay plot showing the design space demarcating the optimized formulation 5.5.10. IN VIVO IMAGING STUDIES 5.5.10.1. X-ray photographic studies in rabbits In vivo floatability/mucoadhesion studies conducted for optimized formulation showed that the tablets did not escape from stomach up to 8 h and floated in the gastric fluid then adhered up to 8 h. This was evident by X-ray photographs taken at 0 h, 4 h & 8 h in rabbit (Figure 39, 40). 5.5.10.2. In vivo γ-scintigraphic studies in man Figure 41 and 42 portray the γ-Scintigraphic images corresponding to the test formulation (TOPT). TOPT was found to be retained for 6 h or more (Singh et al. 2012), significantly higher vis-à-vis conventional formulation, which got retained for only 30-60 mins (Richardson et al. 1996). All the subjects ingesting test formulation (TOPT), showed gastroretention (Fig. 41 and 42) for around 360 min, for which imaging of all the volunteers was conducted. Use of γ-scintigraphy in evaluating the gastroretentive potential has already been successfully demonstrated by several scientists (Singh 2012, Richardson 1996, Ibekwe 2006). In a nutshell, the study is therefore, construe that the test formulation, TOPT posseses the desirable GR characteristics contributed by optimized blend of HPMC K4M and CP 934P, through the ostensible interplay of floatational and bioadhesional mechanism. [Department of Pharm. Sci., MDU, Rohtak]

Page 189


Figure 39: X-ray ray imaging of rabbit abbit stomach without formulation

At 0 h

After 4h

After 8 h Figure 40: X- ray imaging of rabbit stomach with formulation at 0h, 4h and 8h


Page 190


(0 Min)

(150 Min)

(300 Min)

(75 Min)

(240 Min)

(360 Min)

Figure 41: Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled tablet at different time interval


Page 191


(0 m)

(150 m)

(300 m)

(75 m)

(240 m)

(360 m)

Figure 42: Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Saurabh Sharma stomach following oral administration of

99mTc-

labelled tablet at different time interval [Department of Pharm. Sci., MDU, Rohtak]

Page 192


5.5.11. COMPARISON OF DRUG RELEASE OF OPTIMIZED FORMULATION WITH MARKETED PRODUCT Drug release data shown in Table 55 give details of marketed Glynase XL 10 mg extended release glipizide tablet and its comparison with optimized formulation.

Table 55: Drug release profile of the optimized and marketed formulation of glipizide Formulation

T60%(h)

Q12%

Q16%

n

K

Glynase XL

6.13

89.70

94.09

0.6161

0.1964

Optimized formulation

6.12

84.5

93.5

0.4802

0.2505

100

Similarity Factor (f2) 67

Marketed Optmtimized

90 % Drug Release

80 70 60 50 40 30 20 10 0 0

5

10 Time (h)

15

20

Mean drug release (mg/h)

(A) 3.5 3 2.5 2

Optimized

1.5

Marketed

1 0.5 0 0

5

10

15

20


(B) Figure 43: In-vitro drug release profiles of the optimized tablet and marketed formulations (A) and corresponding rates of drug release (B) [Department of Pharm. Sci., MDU, Rohtak]

Page 193


Drug release from the optimized formulation at 12 h (84.51%) was found to be closer to that of Glynase XL (89.30%) (Table 55). Similarly, the release parameters like T60%, Rel16h were quite close to each other. These values unambiguously corroborate the sameness of the release profiles. Figure 43 portrays the respective release profiles of the marketed formulations and optimized formulation superimposed over each other also indicating almost analogy of release performance with each other. Thus, the studies conclude successful development of gastroretentive CR formulation of glipizide capable of maintaining similar drug release profiles as observed with the marketed CR products and delivering the drug at its preferred site of absorption in the GI tract. Similarity factor (f2) between optimized and marketed formulation was

67 and difference factor (f1) was 6. 5.5.12. STABILITY STUDIES ON OPTIMIZED FORMULATION All the parameters viz., content, Tb, BS and drug release remained quite well within the desirable limits, showing negligible and random variation over six months of storage under accelerated conditions and normal long term storage conditions. Various dissolution parameters (viz. T60% and Q16), obtained during various time points of stability studies carried out at 40 ± 2 0 C and 75 ± 5% RH as well as 25 ± 2 0 C and 80 ± 5% RH, remained almost unaffected during the studies, suggesting the robustness of the optimized formulation with respect to dissolution characteristics (Table 56).

Table 56: Various parameters of the optimized formulation (TOPT) analyzed at different time points during accelerated stability studies Drug release

Accelerated Conditions

Drug content

Tb

BS

1 month

99.5±1.2

12.2

3 month

99.4±1.4

6 month

99.5±1.5

T60%

Q16

8.2

6.14

91.9


12.2

8.1

6.15

91.75

99

12.1

8.2

6.2

90.85

97

Similarity factor (f2) between optimized formulation at zero time and during stability studies for 1,3 and 6 month, reflects very minute change in the formulation release characteristics as it was found 99 while difference factor (f1) was 0, which shows that the optimized product was stable in the prevailing atmospheric conditions. [Department of Pharm. Sci., MDU, Rohtak]

Page 194


5.6. STUDIES BEADS

ON

FLOATING-BIOADHESIVE

GLIPIZIDE

Polymers like HPMC K4M, CP 934P and Chitosan (CT) were selected for preliminary pre-optimization studies for beads formulation (alginate beads), because of their excellent bioadhesion strength, release rate controlling ability, nontoxicity, stability at GI pH and compatibility with drug. CT was selected for use in further studies as per its good bioadhesive properties. The successful use of the polymer combination of SA and CT has already been documented in literature reports for attaining CR (Choudhary and Ali, 2013). Therefore the combination was chosen for formulating CR formulation of glipizide, owing to their high sustained, bioadhesive potential. Hence the aim of the current study was fulfilled with the use of polymer combination.

5.6.1. SELECTION OF DESIGN OF EXPERIMENT (DoE) FOR PREPARATION OF FLOATING-BIOADHESIVE GLIPIZIDE BEADS A CCD is considered as most efficient in estimating the influence of individual variables (main effects) and their interactions, using minimum experimentation (Doornbos and Haan, 1995; Schwartz and Connor, 1996; Lewis et al., 1999). In a CCD, all the factors are studied at all the possible combinations. The design also determining the quadratic response surfaces, which are not estimable, using a FD at two levels (Singh et al., 2004). In the present study, fitting a cubic model is considered to be better as the values of the response surfaces are not known from the previous findings. Hence, a CCD for two factors at three levels with α= 1, which in turn is equivalent to a 32 FD, was chosen for the current formulation optimization study. The central point (0, 0, i.e., FB9, FB10, FB11, FB12 and FB13) was studied in quintuplicate. Preliminary trial batches of beads were prepared by using SA, the stirring speed was varied from 50, 75 and 100 rpm and cross linking time 5, 10 and 15 minutes was also varied. From these batches, 50 rpm and 15 minutes cross-linking time was the optimum revolution and time used for the preparation of floating beads. The crosslinking time did not have a significant effect on the percentage EE. Concentration of calcium chloride and hardening time had a negative effect on the Bsize. High calcium chloride concentration and hardening time caused shrinkage of [Department of Pharm. Sci., MDU, Rohtak]

Page 195


beads and smaller particles are formed because of a high degree of cross linking. This negative effect of calcium chloride concentration and cross linking time was of less magnitude, calcium chloride and cross linking time are much effecting the morphology of the beads, and the surface became rougher with some, very small pores, which is in accordance with the earlier findings (Moghadam et al., 2009)

5.6.2. DRUG EXCIPIENT COMPATIBILITY STUDIES, PHYSICAL EVALUATION AND ASSAY OF FLOATING-BIOADHESIVE BEADS Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and various excipients (Tablet) was studied. The characteristic absorption peaks of glipizide were obtained at 3554 cm-1 - NH stretching of NH2 2943 cm-1 - C-H2 aliphatic group 1689 cm-1 - C=O stretching 1651 cm-1 - C=N aliphatic group 1529 cm-1 - CH aliphatic group These peaks obtained in the spectrum of beads were correlated with the peaks of pure drug. The parent peaks of the drug did not show any deviation, which indicate that drug was compatible with these formulation component (Figure 44).

Figure 44: IR spectra of glipizide pure drug and Beads [Department of Pharm. Sci., MDU, Rohtak]

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The glipizide floating beads were prepared by simple emulsion-gelation technique using SA a natural polymer.

Polymer concentration (drug: polymer) was an

important factor as viscosity of polymer solution effects the size of beads. Three different polymer concentrations 2.5, 3.5 and 4.5 % w/v were selected, 2.5 % concentration [1:5 (drug: polymer)] showed a maximum sphericity, least size and no oil leakage, with increase in concentration and hence, the viscosity of SA solutions, beads with larger surface area and less surface porosity were obtained, which releases drug slowly. Uniform beads (i.e., of the same size and density) were prepared by maintaining conditions such as viscosity, rate of falling of drops, stirring rate and distance between syringe and gelation media, constant during the course of preparation. Variation in any of these parameters during the microcarrier formation process may result in the production of non-homogenous and nonuniform beads, affecting the overall results to an appreciable extent (Fursule et al., 2009). Size of bead is also influenced by the opening through which the SA solution is allowed to pass (which was kept constant). Increased viscosity at a higher concentration of SA resulted in larger particles (2.210 - 2.251; Table 57). Beads, with more light liquid paraffin (LLP) concentration, show oil leakage and flowability decreases. When a standard drug solution was analyzed repeatedly (n = 3), the mean error (accuracy) and relative standard deviation (precision) were found to be 0.8% and 1.2%, respectively.

5.6.3. SWELLING STUDIES ON FLOATING-BIOADHESIVE BEADS Swelling index of beads was based on concentration of SA as more SA was resulting in more swelling index of beads, it is also dependent on the concentration of LLP present in the beads, as beads with more LLP were having less swelling percent as compared to beads with less LLP (Table 57).

5.6.4. SCANNING ELECTRON MICROSCOPY (SURFACE TOPOGRAPHY) Surface topography of prepared beads was studied by scanning electron microscopy and it is shown in

Figure 45-48. Floating beads of glipizide were well-rounded

spheres with rough surface because of sudden cross linking of SA with calcium (Figure 45). When beads were prepared with coating of CT (CT dissolved in calcium chloride solution) SEM shows that the beads surface becomes smoother (Figure 46). LLP entrapped beads had an “orange peel” surface with corrugations (Figure 47). [Department of Pharm. Sci., MDU, Rohtak]

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The drug-loaded beads were spherical and tailing begins with increase in LLP concentration (Figure 48) in emulsion. Pores or small channels distributed throughout the surface. Beads were found to be free flowing and of monolithic matrix type. The beads of each batch were uniform in size.

Figure 45: Scanning electron micrograph of glipizide beads without chitosan

Figure 46: Scanning electron micrograph of glipizide beads with chitosan


Page 198


Figure 47: Scanning electron micrograph of glipizide beads with CT enlarged view

Figure 48: Scanning electron micrograph of glipizide beads with larger concentration of light liquid paraffin showing tailing [Department of Pharm. Sci., MDU, Rohtak]

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Table 57: Physicochemical Properties of floating-bioadhesive beads Batch

Size (mm)

Mean swelling (%)

Oil leakage

Shape and color

Flowability

FB 1

2.02±0.02

5.44

NO

SOW

Free flowing

FB 2

2.13±0.01

5.23

NO

SOWT

Flowing

FB 3

2.13±0.01

3.13

NO

SLY

Free flowing

FB 4

2.24±0.01

3.21

YES

SLYT

Sticky with oil

FB 5

2.14±0.02

4.16

NO

SOW

Free flowing

FB 6

2.15±0.02

4.24

NO

SOWT

Flowing

FB 7

2.05±0.01

4.87

NO

SOW

Free flowing

FB 8

2.16±0.01

3.84

YES

ASLY

Free flowing

FB 9

2.06±0.02

4.36

NO

ASLY

Free flowing

FB 10

2.09±0.03

4.78

NO

ASOW

Free flowing

FB 11

2.06±0.02

4.35

NO

ASOW

Free flowing

FB 12

2.06±0.02

3.78

NO

ASOW

Free flowing

FB 13

2.04±0.02

3.43

NO

ASOW

Free flowing

(Spherical off White=SOW, Spherical off White with Tailing=SOWT, Spherical Light Yellow=SLY, Spherical Light Yellow with Tailing =SLYT, almost spherical off white=ASOW)

5.6.5. ENTRAPMENT EFFICIENCY It is an important variable for assessing the drug loading capacity of beads and their drug release profile, thus suggesting the amount of drug availability at site. EE ranged from 75 % to 87 % depending on the composition of the thirteen batches of alginate beads of glipizide (Table 58). The curing time were kept to 15 minutes since drug is insoluble in water. EE of the beads was found correlated with proportion of LLP present in beads, with increase in LLP concentration the drug entrapped increased due to partitioning of the drug in the LLP phase. Moreover, an increase in the amount of SA increases EE due to increased space for drug molecules to be retained throughout a larger cross linked network of calcium alginate.

5.6.6. IN VITRO BUOYANCY OF BEADS Table 58 shows how the LLP loadings affect the buoyancy of the alginate beads. All samples with LLP stayed afloat for >12 h in a 18h test cycle except FB6 which float [Department of Pharm. Sci., MDU, Rohtak]

Page 200


for 2.5 h. Table also lists the Tlag of the drug loaded beads. The results show that the Tlag decreased for the beads with more oil inclusion but at the same time the concentration of polymer is also governing the Tlag, i.e., low polymer concentration was resulting in easy floating and with increase in polymer concentration Tlag was increased (Figure 49). It may be due to the increased density of dried beads and as the volume of beads increases with adsorption of water its density decreases and it begins to float.

Table 58: Entrapment efficiency and floating properties of floating-bioadhesive beads Batch

EE (%)

Mean Density (gm/cm3)

Tlag (s)

Tb (h)

FB 1

75.0±2.4

0.87

0

>12

FB 2

81.5±2.4

0.99

121

2.5

FB 3

81.0±2.1

0.67

0

>18

FB 4

87.0±4.2

0.97

50

>12

FB 5

79.5±3.2

0.74

0

>12

FB 6

84.3±1.8

0.98

110

>12

FB 7

78.5±1.2

0.89

32

>12

FB 8

83.1±3.2

0.88

18

>12

FB 9

80.5±1.5

0.90

27

>12

FB 10

80.6±1.8

0.90

27

>12

FB 11

80.5±1.2

0.89

27

>12

FB 12

80.9±1.7

0.90

26

>12

FB 13

80.7±1.1

0.90

25

>12


Page 201


140 120

Time (s)

100 80 60 40 20 0 FB 1

FB 2

FB 3

FB 4

FB 5

FB 6

FB 7

FB 8

FB 9 FB 10 FB 11 FB 12 FB 13

Figure 49: Tlag of various glipizide beads batches prepared as per the experimental design 5.6.7. IN VITRO GLIPIZIDE RELEASE STUDIES In-vitro drug release study of glipizide alginate beads was carried out in the simulated fasted state, pH 1.2 for a period of 14 h. In the fasted state, gel beads exhibited a biphasic release profile as an initial rapid drug release phase (burst effect) was followed by a slower, gradually decreasing drug release phase after one hour extending up to 14 h (Figure 50). FB1 released 32.29 ± 2.0 % glipizide within one hour, followed by a tailing off sustained release profile for 14 h. The initial faster release may be due to drug dissolution from the surface of beads. The drug release was found to be slower in formulations with higher oil concentration. The slow release of the drug from the beads may be due to the formation of drug- LLP dispersion system in the oil pockets of the beads. Where, the drug has to firstly diffuse from the oil pockets into the polymeric matrix and followed by transportation of drug out of the polymeric matrix into the dissolution medium.


Page 202


GF1

GF2

GF3

GF4

GF5

GF6

GF7

GF8

GF9

100 90

% Drug release

80 70 60 50 40 30 20 10 0 0

1

2

3

4

5 Time (h)

6

7

8

9

10

Figure 50: Drug release (Q10) profile from various glipizide beads batch (the point GF9 represents a mean of 5 replicate runs i.e. GF9, GF10, GF11, GF12 and GF13) 5.6.8. DATA ANALYSIS AND DRUG RELEASE KINETICS The mechanism of drug release was investigated by fitting to models representing zero-order, first order, Higuchi’s square root of time model and Korsmeyer-Peppas model. First order gave r2 value 0.9263-0.9911 (Table 59) describing the drug release rate relationship with concentration of drug. The best linearity was found in Higuchi’s equation plot, r2 is between 0.9912-0.9950 indicating the release of drug from matrix as a square root of time dependent process. The diffusion exponent (n) value, as calculated from Korsmeyer- Peppas model, for glipizide loaded beads ranged from 0.4470 to 0.5170 (Table 59), showing anomalous (non-Fickian) diffusion involving a combination of swelling, diffusion and/or erosion of matrices, in most of batch except FB9, as 0.45 < n < 0.89 for non-Fickian diffusion. Results of ANOVA for Response Surface Quadratic Model for various dependent [Department of Pharm. Sci., MDU, Rohtak]

Page 203


parameters are like Eqn. 19, 20, 21, 22 and 23. Entrapment Efficiency (EE) EE= +80.72 + 2.4*A + 2.3*B-0.13*A*B +0.84*A2 - 0.26*B2+0.58*A2*B+0.73*A*B2

(19)

Total buoyency (Tb) Tb =+24.83-0.00*A+0.00*B+6.00*A*B-2.90*A2-2.90*B2+6.00*A2*B-6.00*A*B2

(20)

Floating Lag Time (Tlag) Tlag =17.14+55.0*A-17.0*B-115.0*A*B+63.52*41.52A2+*B2-98.0*A2*B+80.0*A*B2

(21)

Bead Size (Bsize)

Bsize=+2.12+0.060*A+0.030*B+5.000E-003*A*B-4.138E-003*A2+5.862E-003*B2+1.000E002*A2*B+1.000E-002*A*B2

(22)

Drug Release (DR) DR=+91.22-6.95*A-3.35*B-1.67*A*B-2.01*A2+0.49*B2-0.38*A2*B+1.72*A*B2

(23)

Table 59: Various kinetic rates of floating-bioadhesive beads Zero order R2

First order R2

Higuchi R2

FB1

0.9000

0.9263

FB2

0.9244

FB3

Batch

Korsmeyer R2

n

0.9912

0.9752

0.4681

0.9795

0.9930

0.9863

0.5154

0.8874

0.9713

0.9944

0.9827

0.4568

FB4

0.9132

0.9911

0.9950

0.9913

0.5061

FB5

0.8971

0.9476

0.9916

0.9760

0.4596

FB6

0.9135

0.9887

0.9944

0.9898

0.5011

FB7

0.8940

0.9615

0.9940

0.9815

0.4632

FB8

0.9204

0.9874

0.9946

0.9899

0.5170

FB9

0.8848

0.9427

0.9721

0.9424

0.4470

FB10

0.8914

0.9694

0.9938

0.9819

0.4584

FB11

0.8951

0.9688

0.9937

0.9820

0.4638

FB12

0.8923

0.9708

0.9933

0.9818

0.4598

FB13

0.8906

0.9729

0.9935

0.9814

0.4568


Page 204


Various response surfaces plotted for the studied response using these equations shows the effect of polymer and light liquid paraffin in combination on the properties and they are known to facilitate an understanding of contribution of the variables and their interactions as shown in figures Figure 51 and corresponding contour lines (Figure 52) shows a nearly linear ascending pattern for the values of entrapment efficiency, as the content of LLP increased, while the entrapment efficiency decreases with increasing SA. Maximum entrapment efficiency is observable at the highest levels of LLP and lowest SA. Contour lines corroborate markedly significant influence of LLP and SA on entrapment efficiency. Figure 53 and corresponding contour lines (Figure 54) portrays a nonlinear increase or decrease relationship of TFT with increasing and decreasing amounts of SA and LLP. Nonlinear lines in contour plot shows the presence of any interaction between the polymer and LLP for TFT as it increases with increasing LLP and at high LLP concentration with low SA it is maximum while with high SA it again decreases. Figure 55 and contour plot (Figure 56) shows that the FLT is almost zero at all concentration of LLP with Lowest SA while the increasing concentration of SA increases Tlag. Maximum Tlag was found at highest SA and lowest LLP combination. Bead size according to Figure 57 and contour plot (Figure 58) shows a nearly linear ascending pattern for the values, as the content of either SA or LLP is increased, the effect being much more prominent with SA. Maximum bead size is observable at the highest levels of both SA and LLP. Figure 59 and their relative contour plot (Figure 60) for Q10, reveals a sharp decline in the value of Q10 with an increase in the amount of the polymers, i.e., SA while with increase in LLP it decreases, the influence of SA is more pronounced. Nonlinear contour lines in figure further show that the variation in Q10 is a complex function of the polymer SA and entrapped LLP levels.


Page 205


75.00-80.00

80.00-85.00

85.00-90.00

Entrapment Efficiency

90.00 85.00 80.00 1.00 75.00 -1.00 0.00 ALGINATE

-1.00

0.00 LIQUID PARAFFIN

1.00

Figure 51:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads

ENTRAPPMENT EFFICIENCY

1.00

86

84

B: LIQUID PARAFFIN

0.50

82

5

0.00

80

-0.50

78 76

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 52: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads


Page 206


14.00 10.00 10.00-14.00 10.00 Tb

6.00 6.00-10.00 6.00

2.00 2.00-6.00

1.00 0.00

1.00

0.00

-1.00

2.00

Liquid Paraffin

-1.00

Figure 53:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on o total buoyancy of beads

Tb

1.00

12

B : LIQ UID P A RA FF IN

0.50

12

5

0.00

12

-0.50

10 8 6 4

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 54: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on total buoyancy of beads [Department of Pharm. Sci., MDU, Rohtak]

Page 207


0.00-40.00 40.00

40.00-80.00

80.00-120.00

120.00-125.00 125.00

FLT

120.00 80.00 40.00 1.00 0.00 0.00

-1.00 0.00 LIQUID PARAFFIN

-…

ALGINATE

1.00

Figure 55:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads

Tlag

1.00

B : LIQ U ID P A R A F F IN

0.50

40

20 0

0.00

60

5

80 100

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 56: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads


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2.00-2.08

2.08-2.17

2.17-2.25

2.25-2.25

2.25

BSI

2.17

2.08 2.00 1.00

-1.00 0.00


ALGINATE 1.00 -1.00

Figure 57:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on bead size

BEAD SIZE

1.00

2.2

B: LIQUID PARAFFIN

0.50

2.15 2.1

0.00

5

2.05

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 58: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on bead size [Department of Pharm. Sci., MDU, Rohtak]

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92.00-98.00

86.00-92.00

80.00-86.00

Q10

98.00 92.00 86.00 80.00 -1.00

1.00 ALGINATE 0.00

0.00 LIQUID PARAFFIN -1.00 1.00

Figure 59:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on drug release

DRUG RELEASE

1.00

B: LIQUID P A RAFFIN

0.50

85

0.00

95

5

90

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 60: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on drug release from beads [Department of Pharm. Sci., MDU, Rohtak]

Page 210


5.6.9. SEARCH FOR OPTIMUM FORMULATIONS Feasibility and grid searches method through MS-excel utility and overlay plot generation method through Design expert were used for finding the optimized product. The results for the feasibility search to find the suitable region for further location of optimum formulations are presented in Table 60, 61, 62, 63 and 64 and area for optimized product are shown in Figure 62. The criteria for selection of suitable feasible region (shown with thicker borders) were primarily based upon the highest possible values of Q10; EE; Tlag; Tb and Bsize. The selected regions were based on the following criteria. For selected region: Q10≥91%; EE > 80%; Tlag ≤45s; Tb ≥11.5h and Bsize ≤ 2.15 mm The results of the exhaustive grid searches performed subsequent to feasibility searches are presented in Tables 65, 66, 67, 68 and 69. The optimum formulation was selected by trading off various response variables and adopting the following maximizing criteria: Q10≥91%; EE > 80%; Tlag ≤45s; Tb ≥11.5h and Bsize ≤ 2.15 mm. Upon comprehensive evaluation of grid searches, the formulation (X1=-0.36 and X2=0.16 i.e. SA= 3.14g and LLP= 12.9 ml) fulfilled the optimal criteria of best regulation of the, Q10=93.1%; EE=82.0%; Tlag =39.5s; Tb=12.3h and Bsize =2.09mm, this formulation was taken as optimized formulation (BOPT).


Page 211


Table 60: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Q10 SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

97.92

98.09

98.12

98.02

97.80

97.44

96.96

96.34

95.60

94.73

93.72

-0.80

97.93

97.93

97.84

97.63

97.33

96.92

96.41

95.80

95.09

94.27

93.35

-0.60

97.78

97.62

97.38

97.07

96.68

96.22

95.68

95.06

94.37

93.60

92.76

-0.40

97.46

97.13

96.75

96.32

95.84

95.32

94.74

94.11

93.44

92.72

91.94

-0.20

96.98

96.48

95.95

95.39

94.82

94.22

93.60

92.96

92.30

91.61

90.90

0.00

96.34

95.65

94.97

94.29

93.61

92.94

92.27

91.61

90.95

90.29

89.64

0.20

95.54

94.66

93.82

93.00

92.22

91.50

90.74

90.05

89.39

88.76

88.16

0.40

94.58

93.51

92.49

91.54

90.64

89.80

89.01

88.29

87.62

87.01

86.45

0.60

93.46

92.18

90.99

89.89

88.87

87.94

87.09

86.32

85.64

85.04

84.53

0.80

92.17

90.69

89.32

88.07

86.92

85.88

84.96

84.15

83.45

82.86

82.38

1.00

90.72

89.03

87.48

86.06

84.78

83.64

82.64

81.77

81.04

80.45

80.00

Table 61: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for EE SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

79.97

79.56

79.18

78.81

78.47

78.15

77.85

77.57

77.32

77.08

76.87

-0.80

80.92

80.42

79.94

79.50

79.08

78.70

78.35

78.03

77.74

77.48

77.25

-0.60

81.80

81.20

80.65

80.14

79.66

79.23

78.84

78.48

78.17

77.90

77.67

-0.40

82.59

81.92

81.30

80.73

80.21

79.74

79.32

78.94

78.62

78.35

78.12

-0.20

83.31

82.58

81.90

81.29

80.73

80.23

79.79

79.41

79.09

78.82

78.62

0.00

83.95

83.16

82.45

81.80

81.21

80.70

80.25

79.88

79.57

79.32

79.15

0.20

84.51

83.68

82.93

82.26

81.67

81.15

80.71

80.35

80.06

79.85

79.72

0.40

84.99

84.14

83.37

82.69

82.09

81.58

81.16

80.82

80.57

80.41

80.33

0.60

85.40

84.52

83.75

83.07

82.48

81.99

81.60

81.30

81.10

80.99

80.98

0.80

85.72

84.84

84.07

83.40

82.84

82.38

82.03

81.78

81.64

81.60

81.67

1.00

85.97

85.10

84.34

83.69

83.17

82.75

82.45

82.26

82.19

82.23

82.39


Page 212


Table 62: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tlag SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

1.87

-0.15

-1.72

-2.84

-3.52

-3.74

-3.52

-2.84

-1.72

-0.15

1.87

-0.80

1.69

0.62

-0.20

-0.77

-1.09

-1.15

-0.96

-0.52

0.18

1.13

2.33

-0.60

4.24

3.94

3.70

3.51

3.38

3.31

3.29

3.34

3.43

3.59

3.80

-0.40

9.52

9.82

9.98

10.01

9.89

9.64

9.24

8.71

8.04

7.23

6.28

-0.20

17.52

18.26

18.65

18.72

18.44

17.83

16.89 15.61 14.00 12.05

9.76

0.00

28.26

29.25

29.71

29.64

29.03

27.90

26.23 24.04 21.31 18.05 14.26

0.20

41.72

42.80

43.15

42.77

41.67

39.83

37.27 33.99 29.97 25.23 19.76

0.40

57.92

58.91

58.98

58.12

56.34

53.64

50.01 45.46 39.99 33.60 26.28

0.60

76.84

77.57

77.19

75.68

73.05

69.31

64.45 58.46 51.36 43.14 33.80

0.80

98.49

98.79

97.78

95.45

91.81

86.85

80.58 72.99 64.08 53.86 42.33

1.00

122.8

122.5

120.7

117.4

112.6

106.2

98.40 89.04 78.16 65.77 51.87

Table 63: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tb SA -1.00 LLP

-0.80

-0.60

-0.40

-0.20

-1.00

12.42 11.98

11.63

11.38 11.23 11.18 11.23 11.37 11.62 11.96 12.40

-0.80

12.74 12.39

12.10

11.87 11.70 11.59 11.55 11.56 11.63 11.77 11.96

-0.60

12.77 12.55

12.36

12.19 12.04 11.92 11.81 11.73 11.67 11.63 11.62

-0.40

12.52 12.48

12.42

12.34 12.25 12.15 12.02 11.89 11.73 11.56 11.38

-0.20

11.99 12.16

12.27

12.33 12.33 12.28 12.18 12.02 11.81 11.55 11.23

0.00

11.18 11.59

11.92

12.15 12.28 12.33 12.28 12.15 11.92 11.59 11.18

0.20

10.09 10.79

11.36

11.80 12.10 12.28 12.33 12.25 12.04 11.70 11.23

0.40

8.71

9.74

10.59

11.28 11.80 12.15 12.33 12.34 12.19 11.87 11.38

0.60

7.06

8.44

9.62

10.59 11.36 11.92 12.27 12.42 12.36 12.09 11.62

0.80

5.12

6.90

8.44

9.74

10.79 11.59 12.16 12.47 12.55 12.38 11.96

1.00

2.90

5.12

7.06

8.72

10.09 11.18 11.99 12.52 12.76 12.72 12.40


0.00

0.20

0.40

0.60

0.80

1.00

Page 213


Table 64: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bsize SA

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

2.01

2.03

2.04

2.06

2.07

2.08

2.10

2.11

2.12

2.13

2.14

-0.80

2.03

2.04

2.05

2.07

2.08

2.09

2.10

2.12

2.13

2.14

2.15

-0.60

2.04

2.05

2.06

2.08

2.09

2.10

2.11

2.12

2.14

2.15

2.16

-0.40

2.05

2.06

2.07

2.08

2.10

2.11

2.12

2.13

2.14

2.15

2.17

-0.20

2.06

2.07

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.16

2.18

0.00

2.06

2.07

2.09

2.10

2.11

2.12

2.13

2.14

2.16

2.17

2.18

0.20

2.07

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.16

2.18

2.19

0.40

2.08

2.09

2.10

2.11

2.12

2.13

2.14

2.16

2.17

2.19

2.20

0.60

2.08

2.09

2.10

2.11

2.12

2.14

2.15

2.16

2.18

2.20

2.21

0.80

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.17

2.19

2.20

2.22

1.00

2.08

2.09

2.10

2.12

2.13

2.14

2.16

2.18

2.19

2.21

2.23

LLP


Page 214


Table 65: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Q10 SA LLP

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

95.39

95.28

95.17

95.05

94.94

94.82

94.70

94.58

94.47

94.35

94.22

-0.16

95.19

95.07

94.95

94.83

94.71

94.59

94.47

94.35

94.23

94.11

93.98

-0.12

94.97

94.85

94.73

94.61

94.48

94.36

94.24

94.11

93.99

93.86

93.73

-0.08

94.75

94.63

94.50

94.37

94.25

94.12

93.99

93.86

93.73

93.61

93.48

-0.04

94.52

94.39

94.26

94.13

94.00

93.87

93.74

93.61

93.47

93.34

93.21

0.00

94.29

94.15

94.02

93.88

93.75

93.61

93.48

93.34

93.21

93.07

92.94

0.04

94.05

93.91

93.77

93.63

93.49

93.35

93.21

93.07

92.93

92.80

92.66

0.08

93.80

93.65

93.51

93.36

93.22

93.08

92.93

92.79

92.65

92.51

92.37

0.12

93.54

93.39

93.24

93.09

92.94

92.80

92.65

92.51

92.36

92.22

92.08

0.16

93.27

93.12

92.97

92.81

92.66

92.51

92.36

92.21

92.07

91.92

92.7

0.20

93.00

92.84

92.68

92.53

92.37

92.22

92.06

91.91

91.76

91.61

91.5

Table 66: Grid Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for EE SA LLP

-0.40

-0.36

-0.32

-0.28

-0.20

81.29 81.17

81.06

80.94 80.84 80.73 80.62 80.52 80.42 80.33 80.23

-0.16

81.39 81.27

81.16

81.05 80.94 80.83 80.72 80.62 80.52 80.42 80.33

-0.12

81.50 81.38

81.26

81.15 81.04 80.93 80.82 80.72 80.62 80.52 80.42

-0.08

81.60 81.48

81.36

81.25 81.13 81.02 80.92 80.81 80.71 80.61 80.51

-0.04

81.70 81.58

81.46

81.34 81.23 81.12 81.01 80.91 80.80 80.70 80.61

0.00

81.80 81.67

81.56

81.44 81.32 81.21 81.11 81.00 80.90 80.80 80.70

0.04

81.89 81.77

81.65

81.53 81.42 81.31 81.20 81.09 80.99 80.89 80.79

0.08

81.99 81.86

81.74

81.63 81.51 81.40 81.29 81.18 81.08 80.98 80.88

0.12

82.08 81.96

81.84

81.72 81.60 81.49 81.38 81.27 81.17 81.07 80.97

0.16

82.17 82.05

81.93

81.81 81.69 81.58 81.47 81.36 81.26 81.16 81.06

0.20

82.26 82.14

82.02

81.90 81.78 81.67 81.56 81.45 81.35 81.25 81.15

-0.24


-0.20

-0.16

-0.12

-0.08

-0.04

0.00

Page 215


Table 67: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tlag SA LLP

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

18.72

18.69

18.65

18.59

18.52

18.44

18.35

18.24

18.12

17.98

17.83

-0.16

20.72

20.69

20.64

20.57

20.49

20.40

20.29

20.16

20.02

19.87

19.70

-0.12

22.82

22.78

22.71

22.64

22.54

22.43

22.31

22.16

22.01

21.83

21.64

-0.08

25.00

24.95

24.88

24.79

24.68

24.55

24.41

24.25

24.07

23.87

23.65

-0.04

27.28

27.21

27.13

27.02

26.90

26.75

26.59

26.41

26.20

25.98

25.74

0.00

29.64

29.56

29.46

29.34

29.20

29.03

28.85

28.64

28.42

28.17

27.90

0.04

32.09

32.00

31.88

31.74

31.58

31.40

31.19

30.96

30.71

30.44

30.14

0.08

34.63

34.52

34.39

34.23

34.05

33.84

33.61

33.36

33.08

32.78

32.45

0.12

37.25

37.13

36.98

36.80

36.60

36.37

36.11

35.83

35.53

35.19

34.84

0.16

39.97

39.82

39.65

39.46

39.23

38.98

38.70

38.39

38.05

37.69

37.30

0.20

42.77

42.61

42.42

42.20

41.95

41.67

41.36

41.02

40.65

40.26

39.83

Table 68: Grid Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tb SA LLP

-0.40

-0.36

-0.32

-0.28

-0.20

12.00 12.02

12.03

12.07 12.11 12.14 12.18 12.21 12.23 12.26 12.28

-0.16

12.01 12.04

12.08

12.12 12.15 12.18 12.21 12.24 12.26 12.28 12.30

-0.12

12.05 12.09

12.12

12.16 12.19 12.21 12.24 12.26 12.28 12.30 12.31

-0.08

12.09 12.12

12.16

12.19 12.22 12.24 12.27 12.28 12.30 12.31 12.32

-0.04

12.12 12.16

12.19

12.22 12.24 12.27 12.29 12.30 12.31 12.32 12.33

0.00

12.15 12.18

12.21

12.24 12.26 12.28 12.30 12.31 12.32 12.33 12.33

0.04

12.17 12.20

12.23

12.26 12.28 12.30 12.31 12.32 12.33 12.33 12.33

0.08

12.18 12.21

12.24

12.27 12.29 12.30 12.32 12.32 12.33 12.33 12.32

0.12

12.18 12.22

12.25

12.27 12.29 12.31 12.32 12.32 12.32 12.32 12.31

0.16

12.18 12.22

12.25

12.27 12.29 12.30 12.31 12.32 12.32 12.31 12.30

0.20

12.18 12.21

12.24

12.26 12.28 12.30 12.30 12.31 12.30 12.30 12.28

-0.24


-0.20

-0.16

-0.12

-0.08

-0.04

0.00

Page 216


Table 69: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bsize SA

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

2.09

2.09

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

-0.16

2.09

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

-0.12

2.09

2.10

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

-0.08

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

-0.04

2.10

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

0.00

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

0.04

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

0.08

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

0.12

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

0.16

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

2.12

0.20

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

2.13

LLP

Highlighted (non-italic) rectangle show validation check points and Highlighted (italic) rectangle show optimized batch


Page 217


Figure 61: Overlay plot showing the design space demarcating the optimized formulation 5.6.10. VALIDATION OF OPTIMIZED FORMULATIONS Physical evaluation results of the beads and assay of the optimised formulations and various validation check point are listed in Table 70. All the values were found within limits, topographic studies done by scanning electron micrograph (Figure 63) show a well rounded smooth surface bead. Table 70: Physical evaluation parameters of validation check points Mean Bsize Tlag Batch Oil Shape Swelling code leakage and color (mm) (s) (%) VCB1 2.09 4.36 NO SOW 20.5 2.11 4.3 NO SOW 26.5 VCB2 2.1 4.35 NO SOW 36.7 VCB3 VCB4 2.1 4.4 NO SOW 42.5 2.11 4.3 NO SOW 22.5 VCB5 VCB6 2.14 4.4 NO SOW 39.5 BOPT 2.1 4.3 NO SOW 39.8

Tb (h) 12.05 12.25 12.3 12.2 12.3 12.3 12.2

(Spherical off White=SOW)


Page 218


Table 71: Various checkpoint composition and their results Batch

VDB1

VDB2

VDB3

VDB4

VDB5

VDB6

BOPT

X1 (SA) Mg

3.14

3.3

3.18

3.1

3.42

3.5

X2 (LLP) mL

12.1

12.4

12.8

13

12.2

13

Response variables

Prediction values

Observed values

Percentage error

Q10 (%)

95.07

95.1

-0.0315

EE (%)

81.27

81.3

-0.0369

Tlag (s)

20.69

20.5

0.9183

Tb (h)

12.04

12.05

-0.0830

Bsize (mm)

2.09

2.09

0

Q10 (%)

93.87

93.6

0.2876

EE (%)

81.12

81.1

Tlag (s)

26.75

26.5

0.0246 0.9345

Tb (h)

12.27

12.25

0.1629

Bsize (mm)

2.11

2.12

-0.4739

Q10 (%)

93.24

93.1

0.1501

EE (%)

81.84

81.75

Tlag (s)

36.98

36.7

0.1099 0.7571

Tb (h)

12.25

12.3

-0.4081

Bsize (mm)

2.1

2.1

0

Q10 (%)

93

92.5

0.5376

EE (%)

82.26

82.2

0.0729

Tlag (s)

42.77

42.5

0.6312

Tb (h)

12.18

12.2

-0.1642

Bsize (mm)

2.1

2.1

0

Q10 (%)

93.99

93.5

0.5213

EE (%)

80.62

80.5

0.1488

Tlag (s)

22.01

22.5

-2.2261

Tb (h)

12.28

12.3

-0.1628

Bsize (mm)

2.11

2.11

0

Q10 (%)

91.5

91.75

-0.2732

EE (%)

81.15

81.2

-0.0616

Tlag (s)

39.83

39.5

0.8285

Tb (h)

12.28

12.3

-0.1628

Bsize (mm) Q10 (%)

2.13 93.12

2.14 93.1

-0.4694 0.0214

EE (%)

82.05

82

0.0609

Tlag (s)

39.8

39.5

0.7537

Tb (h)

12.2

12.3

-0.8196

Bsize (mm)

2.1

2.09

0.4761S


Page 219


Observed Q10

95

0.4 Residuals

R² = 0.9392

93

0.2 0 -0.2

91

93

-0.4

91 91

93

-0.6

95

Observed Q10%

Predicted Q10

0.1

82

0.05

Residuals

Observed EE

83 R² = 0.9867

81

0 -0.05

80

81

82

83

-0.1

80 80

81

82

83

-0.15

Predicted EE

Observed EE%

3

44 R² = 0.9739

2

Residuals

Observed Tlag

95

32

1 0 -1

20 20

32

20

32

44

-2

44

Predicted Tlag

Observed Tlag (s)

12.3

0.6 Residuals

Observed Tb

R² = 0.9478

12.15

0.4 0.2 0

12

12 12

12.15

12.3

12.15

12.3

-0.2 Observed Tb (h)

Predicted Tb

2.14

1 Residuals

Observed Bsize

R² = 0.9643

2.11

0.5 0 2.08

2.08 2.08

2.11

2.14

Predicted Bsize

2.11

2.14

-0.5 Observed BSIZE (mm)


Page 220


Figure 63: Scanning electron micrograph of optimized bead Upon comparison of the observed responses with those of the anticipated ones (Table 71), the prediction error varied between 0.93 and -2.22 %. The linear correlation plots drawn between the predicted and observed responses, forcing the line through the origin, demonstrated high values of R (0.9392 to 0.9867) (Figure 62), indicating excellent goodness of fit (p < 0.001). The corresponding residual plots show nearly uniform and random scatter around the mean values of response variables. 5.6.11. IN VIVO IMAGING STUDIES FOR BEADS 5.6.11.1. X-ray Photographic Studies in Rabbits In vivo floatability and mucoadhesion studies conducted for optimized formulation showed that beads did not escape from stomach up to 6 h and floated in the gastric fluid and then adhered up to 6 h and more. This was evident by the X-ray photographs taken at 2 h & 6 h (Figure 64, 65).

5.6.11.2. In Vivo γ-scintigraphic Studies in Man Figure 66 and 67 portray the γ-Scintigraphic images corresponding to the test formulation (BOPT). BOPT was found to be retained for 6 h or more (Singh et al. 2012), significantly higher vis-à-vis conventional formulation, which got retained for only 30-60 m (Richardson et al. 1996). All the subjects ingesting test formulation (BOPT), showed gastroretention (Fig. 66 and 67) for around 360 m, for which imaging of all the volunteers was conducted. Use of γ-scintigraphy in evaluating the gastroretentive potential has already been successfully demonstrated by several scientists (Singh 2012, Richardson 1996, Ibekwe 2006). In a nutshell, the study is therefore, construe that the test formulation, BOPT posseses the desirable GR characteristics contributed by optimized blend of SA and LLP along with CT, through the ostensible interplay of floatational and [Department of Pharm. Sci., MDU, Rohtak]

Page 221


bioadhesional mechanism.

Figure 64: X- ray imaging of rabbit stomach without formulation

At 0 h

After 4 h

After 6 h Figure 65: X- ray imaging of rabbit stomach with formulation after 0h, 4h and 8h [Department of Pharm. Sci., MDU, Rohtak]

Page 222


(0 Min)

(75 Min)

(150 Min)

(240 Min)

(300 Min)

(360 Min)

Figure 66: Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled beads at different time interval [Department of Pharm. Sci., MDU, Rohtak]

Page 223


(0 m)

(75 m)

(150 m)

(240 m)

(300 m)

(360 m)


99mTc-

labelled beads at different time interval


Page 224


5.5.12

Accelerated stability studies on optimized formulation

All the parameters viz., content, Tb, Tlag, Bsize and drug release remained quite well within the desirable limits, showing negligible and random variation over six months of storage under accelerated conditions. Dissolution parameter (viz. Q10), obtained during various time points of stability studies carried out at 40 ± 2 °C and 75 ± 5% RH, remained almost unaffected during the studies, suggesting the robustness of the optimized formulation with respect to dissolution characteristics (Figure 68, Table 72). Table 72: Stability study data

Accelerated

5.5.13

Similarity

Tb (h)

Bsize (mm)

Q10%

1 month

12.3

2.09

93.1

95

3 month

12.3

2.08

93.0

93

6 month

12.2

2.08

93.0

93

Conditions

factor (f2)

Comparison of Optimized Formulation with Marketed Product

Tablet 73 shows all the drug release data of marketed Glynase XL 10 mg extended release glipizide tablet and its comparison with optimized formulation. Table 73: Drug release profile of the BOPT and marketed brand of glipizide Formulation

Q10 (%)

Q14 (%)

n

Glynase XL

82.10

90.14

0.6161

BOPT

93.1

95.10

0.4598

As the results shows the release of optimized batch for a prolonged duration, the studies conclude successful development of gastroretentive CR formulation of glipizide capable of maintaining the drug release profiles for a prolonged duration as observed with the marketed CR products while eliminating the disadvantages of single unit and delivering the drug at its preferred site of absorption in the GI tract.


Page 225


100

% Drug release

75

50 Marketed BOPT 25

0 0

5

10 Time (h)

15

20

Figure 68: In-vitro drug release profiles of the optimized tablet and marketed formulations


Page 226


5.7. REFERENCE 1.

Baumgartner S, Julijana K, Franc V, Polona V, Bojan Z. Optimisation of Floating Matrix Tablets and Evaluation of Their Gastric Residence Time. Int J Pharm. 2000; 195(1-2): 125-35.

2.

Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA. Comparative Efficacy of a Once-Daily Controlled-Release Formulation of Glipizide and Immediate-Release Glipizide in Patients with NIDDM. Diabetes Care. 1994; 17(12): 1460-4.

3.

Chitnis V, Malshe VS, Lalla JK.

Bioadhesive Polymers - Synthesis,

Evaluation and Application in Controlled Release Tablets. Drug Dev Ind Pharm. 1991; 17(6): 879-92.

4.

Chowdary K and Ali SM.

Recent Research on Mucoadhesive Drug

Delivery Systems - A Review. World J Pharm Res. 2013; 2(2): 319-30. 5.

Chueh H, Zia H, Rhodes CT. Optimization of Sotalol and Bioadhesive Extended-Release Tablet Formulations. Drug Dev Ind Pharm. 1995; 21(15): 1725-47.

6.

Deshpande A, Rhodes CT, Shah NH, Malick W. Development of a Noval Controlled-Release for Gastric Retention. Pharmaceut Res. 1997; 14: 815-9.

7.

Doornbos C and Haan PD. Optimization Techniques in Formulation and Processing Encyclopedia of Pharmaceutical Technology. Boylan J, Swarbrick, J, editor. New York: Marcel Dekker Inc; 1995.

8.

Duchene D, Touchard F, Peppas NA. Pharmaceutical and Medical Aspect of Bioadhesive Systems for Administration. Drug Dev Ind Pharm. 1998; 14: 283-318.

9.

Falkén Y, Webb DL, Abraham-Nordling M, Kressner U, Hellström PM, Näslund E. Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans. Neurogastroent Motil. 2013; 25(6): 474-80.

10.

Fell J, Whitehead L, Colletts JH. Prolonged Gastric Retention Using Floating Dosage Forms. Pharmaceut Tecnol. 2000: 82-90.

11.

Gohel M and Amin AF. Formulation Optimization of Controlled Release Diclofenac Sodium Beads Using Factorial Design. J Control Release. 1998;


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51: 115-22. 12.

Gupta P, Vermani K, Garg S. Hydrogels: From Controlled Release to pHResponsive Drug Delivery. Drug Discov Today. 2002; 7(10): 569-79.

13.

Hilton A and Deasy PB. In-vitro and In-vivo Evaluation of Oral Sustained Release Floating Dosage Form of Amoxicillin Trihydrate. Int J Pharm. 1992; 86: 79-88.

14.

Klausner E, Lavy E, Friedman M, Hoffman A. Expandable Gastro Retentive Dosage Form. J Control Release. 2003; 90(2): 143-62.

15.

Kohri N. Improving the Oral Bioavailability of Sulpride by GastricRetained from in Rabbits. J Pharm Pharmacol. 1996; 48: 371-4.

16.

Krishna, BPSS, Vimala, DM, Hima, SK. In-vitro Evaluation of Commercial Modified Release Glipizide Tablets. Ind Pharm. 2004; 3(21):65-9.

17.

Krogel I and Bodmeier R. Development of a Multinational Matrix Drug Delivery System Surrounded by an Impermeable Cylinder. J Control Release. 1999; 61: 43-50.

18.

Lehr C, Bouwstra JA, Schacht EH, Junginger HE. In-vitro Evaluation of Mucoadhesive Properties of Chitosan and Some Other Natural Polymers.Int J Pharm. 1992; 78: 43-8.

19.

Lewis G, Mathieu D, Phan-Tan-Luu R. Pharmaceutical Experimental Design. 1 ed. New York: Marcel Dekker Inc; 1999.

20.

Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. Effect of Hpmc and Carbopol on the Release and Floating Properties of Gastric Floating Drug Delivery System Using Factorial Design. Int J Pharm. 2003; 253(1-2): 13-22.

21.

Moghadam H, Samimi M, Samimi A, Khorram M. Study of Parameters Affecting Size Distribution of Beads Produced from Electro-Spray of High Viscous Liquids. Iran J Chem Eng. 2009; 6(3): 88-98.

22.

Moore JW and Flanner HH. Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm Technol. 1996; 20(6): 64-74.

23.

Mortazavi S and Smart JO. An Investigation of Some Factors Influencing the In-vitro Assessment of Mucoadhesion. Int J Pharm. 1995; 116: 223-30.

24.

Nur A and Zhang JS. Captopril Floating and/or Bioadhesive Tablets:


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Design and Release Kinetics. Drug Dev Ind Pharm. 2000b; 26(9): 965-9. 25.

Nur A and Zhang JS. Recent Progress in Sustained/Controlled Oral Delivery of Captopril: An Overview. Int J Pharm. 2000a; 194(2): 139-46.

26.

Park K and Robinson JK. Bloadhesive Polymer: A Platforms for Oral Controlled Drug Delivery: Method to Study Bioadhesion. Int J Pharm. 1984; 19: 107-27.

27.

Prudat-Christiaens C, Amaud P, Allain P, Chaumeil JC. Aminophylline Bioadhesive Tablets Attempted by Wet Granulation. Int J Pharm. 1996; 141: 109-16.

28.

Rao SB, Sharma CP. Use of Chitosan as Biomaterial: Studies on Its Safety

and Hemostatic Potential. J Biomed Mater Res. 1997; 34: 21-8. 29.

Schwartz J and Connor RE. Optimization Techniques in Pharmaceutical Formulation and Processing. 3 ed. Rhodes C, Banker, GS, editor. New York: Marcel Dekker Inc; 1996.

30.

Singh B and Ahuja N. Development of Controlled-Release Buccoadhesive Hydrophilic Matrices of Diltiazem Hydrochloride: Optimization of Bioadhesion, Dissolution, and Diffusion Parameters. Drug Dev Ind Pharm. 2002; 28(4): 431-42.

31.

Singh B, Chakkal SK, Ahuja N.

Formulation and Optimization of

Controlled Release Mucoadhesive Tablets of Atenolol Using Response Surface Methodology. AAPS PharmSciTech. 2006; 7(1): E3. 32.

Singh B, Garg B, Chaturvedi SC, Arora S, Mandsaurwale R, Kapil R. Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends. J Pharm Pharmacol. 2012; 64(5):654-69.

33.

Singh B, Pahuja S, Kapil R, Ahuja N. Formulation Development of Oral Controlled Release Tablets of Hydralazine: Optimization of Drug Release and Bioadhesive Characteristics. Acta Pharm. 2009; 59: 1-13.

34.

Singh B, Rani A, Babita, Ahuja N, Kapil R. Formulation Optimization of Hydrodynamically Balanced Oral Controlled Release Bioadhesive Tablets of Tramadol Hydrochloride. Sci Pharm. 2010; 78: 303-23.


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35.

Smart J, Kellaway IW, Worthington HEC. An In-vitro Investigation of Mucosa-Adhesive Materials for Use in Controlled Drug Delivery. J Pharm Pharmacol. 1984; 36: 295-9.

36.

Streubel A, Sieprnarin J, Bodmeier FL. Floating Matrix Tablets Based on Low Density Foam Powder: Effects of Formulation and Processing Parameters on Drug Release. Eur J Pharm Sci. 2003; 18(1): 37-48.

37.

Timmermans J and Moes AJ. How Well Do Floating Dosage Forms Float? Int J Pharm. 1990; 62: 207-16.

38.

Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating Dosage Forms: An In-vivo Study Demonstrating Prolonged Gastric Retention. J Control Release. 1998; 55: 3-12.

39.

Woo B, Jiang G, Jo YW, DeLuca PP. Preparation and Characterization of a Composite Plga and Poly (Acryloyl Hydroxymethyl Starch) Microsphere System for Protein Delivery. Pharmaceut Res. 2001; 18: 1600-6.


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The current studies were undertaken for FbD based development, optimization and evaluation of the oral GRDDS of glipizide by rationally integrating the principles of drug release regulation with floating and bioadhesion.

5.1. SELECTION OF DRUG Oral CRDDS with clinical efficacy more than 12 h are primarily developed for short half life drugs, having high frequency of their administration (Robinson et al., 1987). While some drugs with longer half lives or with very less frequency of administration (two or even one) also may be tried for CRDDS, especially when reduction in fluctuation of drug blood concentration at steady state is desired (Ritschel, 1989). Glipizide was chosen as drug candidate for CR formulations owing to its potential as anti-diabetic drug. Further high frequency of administration (twice daily), short half life (3.5 h) low dose (5-20 mg) and physico-chemical stability at stomach pH are the properties associated with the drug which make it a suitable candidate for CRDDS (Berelowitz et al., 1994). Glipizide extended-release tablets results in less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide.

5.2. SELECTION OF DRUG DELIVERY SYSTEM Gastric emptying and intestinal peristalsis can displace the conventional CR system from its absorption site before the drug is completely released from the system, and it causes inadequate drug absorption while the drug released from devices that prolong gastric retention would be emptied with the gastric contents for an extended period. Thus prolonged gastric retention would improve bioavailability and reduce drug wastage (Fell et al., 2000). Scintigraphic studies involving measurements of gastric-emptying rates in healthy human subjects have revealed that an orally administered CR dosage form is mainly subjected to two physiological adversities, the short GRT and the variable gastric emptying time (GET) (Falkén et al. 2013). Overall, the relatively brief GI transit time of most drug products, (approximately 8 to 12 h), impedes their formulation as a once-daily dosage form. These problems can be exacerbated by alteration in gastric emptying that occurs due to factors, such as age, race, sex, and disease states, as they may seriously affect the release of a drug from its DDS. It is, therefore, highly desirable to have a once-a-day CR


Page 146


product exhibiting an extended GI residence and a drugdrug-release profile, independent of patient-related related variables. The floating bioadhesive tablets can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the GI tract. These systems help in continuously releasing sing the drug before it reaches the absorption window, thus ensuring optimal bioavailability (Klausner Klausner et al., 2003). Floating DDS or hydro-dynamically dynamically balanced systems (HBS) have a bulk density lower than the gastric fluids (0.45), the levels of two

polymers in their blend were chosen, as indicated in Table 26. MCC was chosen as the diluents. Drug release, as discerned from t75% values, was found to be better extended with increase in the levels of either polymer. However, rel8 h was found to be less than 92 % in all the cases, buoyancy time was found to decrease with increase in CP 934P content, while reverse is the case with increasing HPMC [Department of Pharm. Sci., MDU, Rohtak]

Page 152


K4M content. Hence, for further investigation HPMC K4M (50-100 mg) and CP 934P (14-28 mg) in combination, different from the ranges studied during preoptimization studies, i.e., 50-100 mg for HPMC K4M and 20-40 mg for CP 934P, were chosen. 100

% Drug Release

75

50

25

A

B

C

0 0

4

8

12

16

Time (h)

Figure 23: Dissolution profile of various floating-bioadhesive glipizide tablets (A, B, C) in pre-optimization studies (n=3) 5.5.1.

SELECTION OF SUITABLE DESIGN OF EXPERIMENTAL (DOE)

A CCD is considered as most efficient in estimating the influence of individual variables (main effects) and their interactions, using minimum experimentation (Doornbos and Haan, 1995; Schwartz and Connor, 1996; Lewis et al., 1999). In a CCD, all the factors are studied at all the possible combinations. The design also determines the quadratic response, which are not estimable using a factorial design (FD) at two levels. In the present study, fitting a cubic model is considered to be better as the values of the response surfaces are not known from the previous findings. Hence, a CCD for two factors at three levels with α= 1, which in turn is equivalent to a 32 FD, was chosen for the current formulation optimization study. The central point (0, 0) was studied in quintuplicate. 5.5.2.

DRUG

EXCIPIENT

COMPATIBILITY

STUDY,

PHYSICAL

EVALUATION AND ASSAY OF TABLET FORMULATIONS Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and various excipients (Tablet) was studied. The characteristic absorption peaks of glipizide were obtained at [Department of Pharm. Sci., MDU, Rohtak]

Page 153


3554 cm-1 - NH stretching of NH2 2943 cm-1 - C-H2 aliphatic group 1689 cm-1 - C=O stretching 1651 cm-1 - C=N aliphatic group 1529 cm-1 - CH aliphatic group These peaks obtained in the spectrum of tablet were correlated with the peaks of pure drug. The parent peaks of the drug did not show any deviation, which indicate that drug was compatible with these formulation component (Figure 24).

Figure 24: IR Spectra of glipizide drug and tablet All the tablet preparations were evaluated for various physical parameters and assay before proceeding further. Table 27 includes the values (mean ± SD) of weights, hardness, diameter and thickness of 13 tablet batches prepared using the polymer combinations along with the values of their assay and friability. Tablet weights in all the 13 batches of polymer blends varied between 198.7 mg and 200.8 mg, diameter was 8.0 mm, tablet hardness between 3.5 to 4.7 kg / cm2 and tablet friability between 0.54 % to 0.76 %. The assay of content of glipizide varied between 97.5 % to 101.5 %. Thus, all the physical parameters of the tablets were quite within the limit.


Page 154


TABLE 27: Physical evaluation of all the formulation prepared as per the experimental design Formulation

Wt. Variation

Hardness

Friability

Assay

Code

Test (mg)

(kg/cm2)

(%)

(%)

FT1

200.3±1.0

4.3±0.2

0.57±0.03

99.7±1.0

FT2

199.7±1.5

4.1±0.5

0.55±0.1

99.6±1.1

FT3

200.8±1.4

4.2±0.4

0.64±0.05

99.6±1.0

FT4

200.5±0.5

4.0±0.2

0.75±0.1

99.8±1.5

FT5

199.4±0.9

4.1±0.2

0.72±0.1

99.9±1.0

FT6

200.7±0.6

4.0±0.2

0.68±0.1

99.6±2.1

FT7

199.8±1.3

4.1±0.2

0.70±0.2

99.7±1.3

FT8

199.9±0.2

4.2±0.1

0.61±0.1

101.0±0.5

FT9

198.7±0.6

4.0±0.2

0.65±0.1

100.7±0.3

FT10

200.1±0.4

4.0±0.2

0.70±0.1

100.5±0.1

FT11

200.0±0.5

4.1±0.5

0.66±0.1

100.5±0.1

FT12

200.2±0.9

4.0±0.3

0.65±0.1

99.8±1.0

FT13

199.9±0.9

4.0±0.5

0.71±0.2

99.6±1.1

5.5.3.

DRUG RELEASE STUDIES

Mean values of the release parameters, with contribution from Fickian and relaxation mechanisms, for formulations prepared using the polymer blend of CP 934P and HPMC K4M (FT-1 to FT-13) are listed in Tables 28 to 40, while the overall dissolution and statistical parameters for each dosage form unit are listed in Tables 28a to 40a. Summary of the dissolution parameter is indicated in Table 41 and Figure 25 (A) and (B).


Page 155


100

% Drug release

75

F1 F2 50

F3 F4 F5 F6

25 F7 F8 F9 0 0

1

2

3

4

5

6

7

8

9

10

12

16

20

Time (h) (A)

3.5 F1

F2

F3

F4

F6

F7

F8

F9

F5

Mean rate of drug release (mg/h)

3 2.5 2 1.5 1 0.5 0 0

5

10

15

20


(B) Figure 25: In vitro drug release profiles of the various batches formulated (A), and corresponding rates of drug release (B). [Department of Pharm. Sci., MDU, Rohtak]

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Page 169



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5.5.4. BIOADHESION STUDIES The study shows an increasing trend in the BS with an increase in amount of either polymer (CP 934P and HPMC K4M), which is in consonance with the literature (Duchene et al., 1988; Gupta et al., 2002; Prudat-Christiaens et al., 1996; Singh and Ahuja, 2002). Hydrogels gets swell readily when in contact with the hydrated mucous membrane, it provides a large adhesive surface of hydrogels for maximum contact with mucin and polymer chain flexibility for more interpenetration with mucin. The water sorption reduces the glass transition temperature below the ambient conditions and hydrogels become progressively rubbery due to uncoiling of polymer chains and subsequent increased mobility of the polymer chains (Singh and Ahuja, 2002). This glass-rubbery transition provides hydrogel plasticization resulting in large adhesive surface for maximum contact with mucin and flexibility to the polymer chains for interpenetration with mucin. Increase in the polymer concentration may give more adhesive sites and polymer chains for more interpenetration with mucin and results in increment of BS. Although the BS is increasing with increasing levels of both polymers, the effect of CP 934P was found to be distinctly more pronounced than that of HPMC K4M. The bar diagram (Figure 26) clearly depicts the linear increasing trend in BS with polymer level. Force of detachment (g)

20 15 10 5 0 FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8


Figure 26: Bar diagram showing BS determined as force of detachment of all the formulation prepared as per the experimental design 5.5.5

BUOYANCY TIME

Swelling of the tablet plays a vital part in floatation of tablet (Timmermans and Moes, 1990). Kinetics of swelling is important because the gel barrier is formed with water permeation. Swelling is also a vital factor to ensure floating. To obtain floating the balance between swelling and water acceptance must be restored (Baumgartner et al., 2000). It was proved earlier that swelling is a vital factor to ensure floatation. Buoyancy time of the tablets increased in a linear fashion with [Department of Pharm. Sci., MDU, Rohtak]

Page 171


increase in HPMC K4M content (Table 27, Figure 27), owing ostensibly to swelling (hydration) of the hydrocolloid particles on the tablet surface, which in turn, results in an increase in the bulk volume. The air entrapped in the swollen polymer maintains a density less than unity and confers buoyancy to these dosage forms, as is vivid from the data in the table. With increase in CP 934P content, buoyancy time decreases following a linear trend, due to higher density of CP (1.76 g/cc) than HPMC (1.28 g/cc). The bar diagram (Figure 28) corroborates the significant positive and negative influence of HPMC K4M and CP 934P on floatation, respectively. Hence, increasing concentration of CP 934P has a distinct negative effect on the floating behaviour of the delivery system. But, it is of interest to mention that, the presence of CP 934P because of its mucoadhesive nature could possibly assist in the adhesion of the dosage form on the gastric wall and aid in retaining the tablet following oral ingestion within the stomach, which in turn, may aid in increasing the tablet gastric retention time (Singh et al., 2010; Nur and Zhang, 2000). Initial (dry state) bulk density of the dosage form and change in the floating strength with time should be characterised. Tablet density of all the formulations was found to be lower than the density of gastric contents (1.004 g / cc), which satisfies the major criterion for a dosage form to float. 25

Buoyancy Time (h)

20 15 10 5 0 FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8


Figure 27: Bar diagram showing buoyancy time determined for all the formulations prepared as per the experimental design 5.5.6

SWELLING INDEX STUDIES

The swelling index of glipizide tablets for a period for 6h is shown in Table 42 and Figure 28. The hygroscopic nature of the polymer affects the onset of swelling. Faster swelling has been observed for tablets containing higher amount of HPMC K4M. Maximum swelling was attained in 6 h, after which polymer started eroding slowly. High amount of water uptake may be due to quick [Department of Pharm. Sci., MDU, Rohtak]

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hydration of HPMC K4M and swelling rate of the tablets increases with increase in the concentration of HPMC K4M in tablets. Table 42: Swelling Index of all the formulations prepared as per the experimental design Swelling Index

Formulation code

1h

2h

3h

4h

5h

6h

FT1

0.30

0.34

0.37

0.40

0.42

0.43

FT2

0.32

0.37

0.41

0.43

0.44

0.45

FT3

0.33

0.40

0.43

0.45

0.47

0.48

FT4

0.35

0.41

0.47

0.54

0.58

0.60

FT5

0.36

0.43

0.49

0.56

0.61

0.63

FT6

0.38

0.46

0.54

0.61

0.65

0.66

FT7

0.40

0.51

0.60

0.66

0.73

0.74

FT8

0.41

0.52

0.61

0.68

0.75

0.76

FT9

0.43

0.53

0.65

0.71

0.79

0.80

FT10

0.35

0.43

0.49

0.55

0.60

0.62

FT11

0.35

0.42

0.49

0.56

0.61

0.63

FT12

0.36

0.44

0.48

0.55

0.61

0.63

FT13

0.36

0.43

0.50

0.57

0.62

0.64

FT1

FT2

FT3

FT4

FT5

FT6

FT7

FT8

FT9

Swelling index

0.8

0.6

0.4

0.2

0 1

2

3

4

5

6

Time (h)

Figure 28: Plot between Swelling Index and Time for various formulations prepared as per the experimental design


Page 173


5.5.7. RESPONSE SURFACE ANALYSIS Coefficients and calculation: Mathematical relationships were generated using multiple linear regression analysis (MLRA) for the number of response variables. High values of R2 of the MLRA coefficients for all four responses, ranging between 0.9403 and 0.9963, vouch high prognostic ability of the RSM polynomials. Seven coefficients (B1 to B7) were calculated with B0 representing the intercept, and B3 to B7, representing the various quadratic and interaction terms as shown in the Eqn. 18. Y = B0 + B1X1 + B2X2 + B3X1X2 + B4X12 + B5X22 + B6X1X22 + B7X12X2

(18)

Various response surfaces plotted for the studied response show the effect of polymers in combination on the properties and they are known to facilitate an understanding of contribution of the variables and their interaction (Table 43). Figure 29 and 30 reveals a sharp decline in the value of Q16 with an increase in the amount of each of the polymers, i.e., HPMC K4M and CP 934P, the influence of HPMC K4M being much more pronounced. Nonlinear descending contour lines in figure further showed that the variation in Q16 is a complex function of the polymer levels. Figure 31 and 32 portrays a linear increase or decrease relationship of Tb with increasing and decreasing amounts of HPMC K4M and CP 934P, respectively. Nearly linear lines in contour plot nullify the presence of any interaction between the polymers. Figure 33 and 34 shows a nearly linear ascending pattern for the values of BS, as the content of either polymer is increased, the effect being much more prominent with CP 934P. Maximum BS is observable at the highest levels of both polymers, viz., CP 934P and HPMC K4M. Nearly vertical contour lines corroborate the markedly significant influence of CP 934P on r values vis-à-vis HPMC K4M. T60 increases as both the polymers viz. CP 934P and HPMC K4M increase but the effect is more pronounced for CP as depicted in Figure 35 and 36.


Page 174


Table 43: Values of the coefficients for the polynomial equations and R for various response variables of the glipizide tablet formulations Coefficient code

Polynomial coefficient values for studied response variables Q16

Tb

BS

T60%

B0

+91.32

+13.26

+9.47

+6.33

B1

-1.316

+4.57

+2.75

+0.45

B2

-0.5495

-1.32

+0.65

+0.145

B3

+0.2545

-0.0075

+0.075

+0.097

B4

+0.301

+1.418

+1.63

+0.022

B5

+0.598

+1.168

-0.23

+0.057

B6

-0.548

+0.227

-0.175

-0.022

B7

-0.359

+0.007

+0.025

-0.087

R2

0.9403

0.9938

0.9963

0.9488

P value

0.001

0.001

0.001

0.001


Page 175


93.00-95.00

91.00-93.00

89.00-91.00

95.00

Q16

93.00 91.00 1.00 89.00 -1.00

0.00 CP 934P

0.00 -1.00

HPMC K4M 1.00

Figure 29:: Response Surface plot showing effect of HPMC K4M and CP 934P on drug release

Q16

1.00

90

B : CP

0.50

0.00

5

91

0.00

0.50

92

93

-0.50

94 -1.00 -1.00

-0.50

1.00

A: HPMC

Figure 30: Corresponding contour contour Plots showing effect of HPMC K4M and CP 934P on drug release [Department of Pharm. Sci., MDU, Rohtak]

Page 176


17.00-21.00

13.00-17.00

9.00-13.00

21.00

Tb

17.00 13.00 1.00 9.00 -1.00

0.00 CP 934P

0.00 HPMC K4M

-1.00 1.00

Figure 31:: Response Surface plot showing effect of HPMC K4M and CP 934P on buoyancy Time

Tb

1.00

10

B: CP

0.50

0.00

12

5

14

16

18

-0.50

20 -1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 32: Corresponding contour plot showing effect of HPMC K4M and CP 934P on buoyancy time [Department of Pharm. Sci., MDU, Rohtak]

Page 177


Figure 33:: Response Surface plot showing effect of HPMC K4M and CP 934P on bioadhesive strength

BS

1.00

14 0.50

B : CP

9

10

5

0.00

11

12

13

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 34: Corresponding contour contour Plots showing effect of HPMC K4M and CP 934P on bioadhesive strength [Department of Pharm. Sci., MDU, Rohtak]

Page 178


5.80 5.80-6.20

6.20-6.60

6.60-7.00

T60%

7.00

6.60

6.20

1.00

5.80

0.00

-1.00

CP 934P 0.00 HPMC K4M

-1.00 1.00

Figure 35:: Response Surface plot showing effect of HPMC K4M and CP 934P on T60

T60

1.00

0.50

6.8

B : CP

6

0.00

6.2

5

6.4

6.6

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: HPMC

Figure 36: Corresponding contour c Plots showing effect ct of HPMC K4M and CP 934P on T60


Page 179


5.5.8. SEARCH FOR OPTIMUM FORMULATIONS Feasibility and grid searches method through MS-excel utility and overlay plot generation method through Design expert were used for finding the optimized product. The results for the feasibility search to find the suitable region for further location of optimum formulations are presented in Table 44, 45, 46 and 47. The criteria for selection of suitable feasible region (shown with thicker borders) were primarily based upon the highest possible values of Q16, T60%, Tb and BS. The selected regions were based on the following criteria. For selected region: Q16>92%; T60% > 6.1 h; Tb >12 and BS>8.1 The results of the exhaustive grid searches performed subsequent to feasibility searches are presented in Tables 48, 49, 50 and 51.


Page 180


Table 44: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Q16 HPMC CP

-1.00

-1.00

95.43 94.81 94.24 93.72 93.25 92.84 92.48 92.17 91.92 91.72 91.58

-0.80

94.89 94.33 93.83 93.37 92.95 92.58 92.25 91.97 91.73 91.54 91.39

-0.60

94.40 93.92 93.47 93.06 92.69 92.35 92.05 91.78 91.55 91.36 91.20

-0.40

93.97 93.56 93.17 92.80 92.47 92.16 91.88 91.62 91.40 91.20 91.02

-0.20

93.61 93.25 92.91 92.59 92.28 92.00 91.73 91.48 91.25 91.04 90.85

0.00

93.31 93.00 92.70 92.42 92.14 91.87 91.61 91.36 91.12 90.90 90.68

0.20

93.07 92.81 92.55 92.29 92.03 91.78 91.52 91.27 91.01 90.76 90.51

0.40

92.89 92.67 92.44 92.21 91.97 91.72 91.46 91.19 90.92 90.64 90.35

0.60

92.78 92.59 92.39 92.17 91.94 91.69 91.42 91.14 90.84 90.52 90.19

0.80

92.72 92.57 92.39 92.18 91.95 91.69 91.41 91.11 90.78 90.42 90.04

1.00

92.73 92.60 92.43 92.23 92.00 91.73 91.43 91.10 90.73 90.33 89.89

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

Table 45: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for T60% HPMC CP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

6.03

6.06

6.10

6.15

6.19

6.25

6.30

6.36

6.42

6.49

6.56

-0.80

5.98

6.03

6.08

6.13

6.19

6.25

6.32

6.39

6.46

6.53

6.61

-0.60

5.94

6.00

6.06

6.13

6.20

6.27

6.34

6.42

6.50

6.58

6.66

-0.40

5.92

5.99

6.06

6.13

6.21

6.28

6.36

6.45

6.53

6.62

6.71

-0.20

5.91

5.98

6.06

6.14

6.22

6.31

6.39

6.48

6.57

6.67

6.76

0.00

5.91

5.99

6.07

6.16

6.24

6.33

6.42

6.52

6.61

6.71

6.81

0.20

5.92

6.00

6.09

6.18

6.27

6.36

6.46

6.55

6.65

6.75

6.85

0.40

5.94

6.03

6.12

6.21

6.31

6.40

6.50

6.59

6.69

6.79

6.89

0.60

5.97

6.07

6.16

6.25

6.35

6.44

6.54

6.63

6.73

6.83

6.93

0.80

6.02

6.11

6.21

6.30

6.39

6.49

6.58

6.68

6.77

6.87

6.96

1.00

6.08

6.17

6.26

6.35

6.44

6.54

6.63

6.72

6.81

6.90

7.00


Page 181


Table 46: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Tb HPMC CP

-1.00

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

11.37 11.85 12.43 13.11 13.88 14.75 15.71 16.77 17.92 19.17 20.51

-0.80 11.09 11.56 12.13 12.79 13.56 14.42 15.39 16.45 17.61 18.87 20.23 -0.60

10.82 11.28 11.83 12.49 13.25 14.11 15.08 16.15 17.32 18.59 19.97

-0.40

10.57 11.01 11.55 12.20 12.95 13.81 14.78 15.86 17.04 18.32 19.71

-0.20

10.33 10.75 11.28 11.92 12.67 13.53 14.50 15.58 16.77 18.07 19.47

0.00

10.11 10.51 11.03 11.66 12.40 13.26 14.23 15.31 16.51 17.82 19.25

0.20

9.90

10.28 10.79 11.41 12.15 13.00 13.97 15.06 16.27 17.59 19.03

0.40

9.70

10.07 10.56 11.17 11.91 12.76 13.73 14.83 16.04 17.38 18.83

0.60

9.52

9.87

10.35 10.95 11.68 12.53 13.50 14.60 15.83 17.17 18.65

0.80

9.35

9.69

10.15 10.74 11.46 12.31 13.29 14.39 15.62 16.98 18.47

1.00

9.20

9.52

9.97

10.55 11.26 12.11 13.09 14.19 15.43 16.81 18.31

Table 47: Feasibility search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for BS HPMC CP

-1.00 -0.80 -0.60 -0.40 -0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

8.17

8.06

8.09

8.27

8.59

9.06

9.67

10.43

11.33

12.38

13.57

-0.80

8.17

8.08

8.12

8.31

8.63

9.10

9.72

10.47

11.37

12.40

13.58

-0.60

8.19

8.11

8.17

8.36

8.70

9.17

9.78

10.53

11.42

12.45

13.62

-0.40

8.23

8.16

8.23

8.44

8.78

9.25

9.87

10.61

11.50

12.52

13.68

-0.20

8.29

8.23

8.31

8.53

8.87

9.35

9.97

10.72

11.60

12.61

13.76

0.00

8.36

8.32

8.41

8.64

8.99

9.48

10.09

10.84

11.71

12.72

13.86

0.20

8.45

8.42

8.53

8.76

9.13

9.61

10.23

10.98

11.85

12.85

13.98

0.40

8.55

8.55

8.67

8.91

9.28

9.77

10.39

11.14

12.01

13.00

14.12

0.60

8.67

8.68

8.82

9.07

9.45

9.95

10.57

11.32

12.18

13.17

14.28

0.80

8.81

8.84

8.99

9.25

9.64

10.14

10.77

11.51

12.38

13.36

14.46

1.00

8.97

9.01

9.17

9.45

9.85

10.36

10.99

11.73

12.59

13.57

14.67

The highlighted portions indicate the area investigated for feasibility


Page 182


Table 48: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Q16 HPMC CP

-0.40

-1.00

93.72 93.57 93.43 93.30 93.16 93.04 92.92 92.80 92.69 92.58 92.48

-0.96

93.64 93.50 93.36 93.23 93.10 92.98 92.86 92.75 92.64 92.53 92.43

-0.92

93.57 93.43 93.30 93.17 93.04 92.92 92.81 92.69 92.59 92.48 92.39

-0.88

93.50 93.37 93.23 93.11 92.98 92.87 92.75 92.64 92.54 92.44 92.34

-0.84

93.43 93.30 93.17 93.05 92.93 92.81 92.70 92.59 92.49 92.39 92.29

-0.80

93.37 93.24 93.11 92.99 92.87 92.76 92.65 92.54 92.44 92.34 92.25

-0.76

93.30 93.18 93.05 92.93 92.82 92.71 92.60 92.50 92.40 92.30 92.21

-0.72

93.24 93.12 93.00 92.88 92.77 92.66 92.55 92.45 92.35 92.26 92.17

-0.68

93.18 93.06 92.94 92.83 92.72 92.61 92.51 92.41 92.31 92.22 92.13

-0.64

93.12 93.00 92.89 92.77 92.67 92.56 92.46 92.36 92.27 92.18 92.09

-0.60

93.06 92.95 92.83 92.72 92.62 92.52 92.42 92.32 92.23 92.14 92.05

-0.34

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

Table 49: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for T60% HPMC CP

-0.40 -0.34 -0.28 -0.22 -0.16 -0.10 -0.04

0.02

0.08

0.14

0.20

-1.00

6.15

6.16

6.18

6.19

6.20

6.22

6.24

6.25

6.27

6.28

6.30

-0.96

6.14

6.16

6.17

6.19

6.20

6.22

6.24

6.25

6.27

6.29

6.30

-0.92

6.14

6.16

6.17

6.19

6.20

6.22

6.24

6.25

6.27

6.29

6.31

-0.88

6.14

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.27

6.29

6.31

-0.84

6.14

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.28

6.30

6.32

-0.80

6.13

6.15

6.17

6.19

6.20

6.22

6.24

6.26

6.28

6.30

6.32

-0.76

6.13

6.15

6.17

6.19

6.21

6.22

6.24

6.26

6.28

6.30

6.32

-0.72

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.33

-0.68

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.33

-0.64

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.29

6.31

6.34

-0.60

6.13

6.15

6.17

6.19

6.21

6.23

6.25

6.27

6.30

6.32

6.34


Page 183


Table 50: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for Tb HPMC CP

-0.34

-0.40

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

-1.00 13.11 13.33 13.56 13.80 14.05 14.30 14.57 14.84 15.12 15.41 15.71 -0.96 13.05 13.27 13.50 13.73 13.98 14.24 14.50 14.77 15.06 15.35 15.64 -0.92 12.98 13.20 13.43 13.67 13.92 14.17 14.44 14.71 14.99 15.28 15.58 -0.88 12.92 13.14 13.37 13.61 13.85 14.11 14.37 14.64 14.93 15.22 15.51 -0.84 12.86 13.08 13.30 13.54 13.79 14.04 14.31 14.58 14.86 15.15 15.45 -0.80 12.79 13.01 13.24 13.48 13.72 13.98 14.24 14.52 14.80 15.09 15.39 -0.76 12.73 12.95 13.18 13.41 13.66 13.92 14.18 14.45 14.73 15.02 15.32 -0.72 12.67 12.89 13.12 13.35 13.60 13.85 14.12 14.39 14.67 14.96 15.26 -0.68 12.61 12.83 13.05 13.29 13.54 13.79 14.05 14.33 14.61 14.90 15.20 -0.64 12.55 12.77 12.99 13.23 13.47 13.73 13.99 14.27 14.55 14.84 15.14 -0.60 12.49 12.71 12.93 13.17 13.41 13.67 13.93 14.20 14.49 14.78 15.08

Table 51: Intensive grid search for locating a region of glipizide for polymer blend employing HPMC K4M and CP 934P from various floating bioadhesive tablet formulation of glipizide for BS HPMC CP

-0.40

-0.34

-0.28

-0.22

-0.16

-0.10

-0.04

0.02

0.08

0.14

0.20

-1.00

8.27

8.35

8.44

8.55

8.67

8.81

8.95

9.11

9.29

9.47

9.67

-0.96

8.27

8.36

8.45

8.56

8.68

8.81

8.96

9.12

9.29

9.48

9.68

-0.92

8.28

8.36

8.46

8.57

8.69

8.82

8.97

9.13

9.30

9.49

9.69

-0.88

8.29

8.37

8.47

8.58

8.70

8.83

8.98

9.14

9.31

9.50

9.70

-0.84

8.30

8.38

8.48

8.59

8.71

8.84

8.99

9.15

9.32

9.51

9.71

-0.80

8.31

8.39

8.49

8.60

8.72

8.85

9.00

9.16

9.33

9.52

9.72

-0.76

8.32

8.40

8.50

8.61

8.73

8.86

9.01

9.17

9.34

9.53

9.73

-0.72

8.33

8.41

8.51

8.62

8.74

8.88

9.02

9.18

9.36

9.54

9.74

-0.68

8.34

8.42

8.52

8.63

8.75

8.89

9.04

9.20

9.37

9.56

9.75

-0.64

8.35

8.43

8.53

8.64

8.77

8.90

9.05

9.21

9.38

9.57

9.77

-0.60

8.36

8.45

8.55

8.66

8.78

8.92

9.06

9.22

9.40

9.58

9.78

Highlighted area shows optimized formulation (Italic) and validation check points (Non-italic) [Department of Pharm. Sci., MDU, Rohtak]

Page 184


5.5.9. VALIDATION OF FbD STUDIES Physical evaluation results of the tablets and assay of the optimized formulations and various validation check points (VCT) are listed in Table 52. All the values were found within limits and their release behaviour are shown in Table 53. Table 52: Physical evaluations of validation check points and optimized product Batch Code

Wt. Variation Test (mg)

Hardness Friability (kg/cm2) (%)

Assay (%)

BS (Dyne/cm2)

Tb (h)

VCT1

200.8±1.1

4.1±0.5

0.72±0.1

99.7±1.3

8.2±0.2

13.1±0.3

VCT2

200.5±0.5

4.0±0.3

0.67±0.2

99.8±1.5

8.5±0.2

13.5±0.3

VCT3

199.9±0.9

4.0±0.2

0.59±0.1

100.5±1.2

8.3±0.1

12.5±0.3

VCT4

200.1±0.7

4.0±0.5

0.71±0.05

99.6±1.4

8.35±0.2

13.8±0.2

VCT5

200.1±0.7

4.0±0.2

0.68±0.1

99.9±1.3

9.3±0.1

14.7±0.2

VCT6

200.1±0.7

4.0±0.5

0.67±0.1

99.8±1.1

9.7±0.2

15.7±0.2

TOPT

200.2±0.5

4.0±0.2

0.65±0.1

99.9±1.1

8.55±0.1

12.9±0.2

Upon comparison of the observed responses with those of the anticipated ones (Table 54), the prediction error varied between -1.121 % and 0.862 % (mean ± SD = 0.32 ± 1.8 %). Linear correlation plots drawn between the predicted and observed responses after forcing the line through the origin, also demonstrated high values of R (0. 9403 to 0.9963) (Figure 37), indicating excellent goodness of fit (p < 0.001). The corresponding residual plots show nearly uniform and random scatter around the mean values of response variables. The optimum formulation was selected by trading off various response variables and adopting the following maximizing criteria: Q16>92%; T60% > 6.1 h; Tb >12 and BS>8.1. Upon comprehensive evaluation of grid searches, the formulation (X1= -0.28 and X2= -0.60 i.e. HPMC K4M=78.96 mg and CP 934P= 15.2 mg) fulfilled the optimal criteria of best regulation of the release rate Q16=92.85%; T60% = 6.18 h; Tb=12.9h and BS=8.6, this formulation was taken as optimized formulation. The release behaviour is distinctly zero order throughout. Further, high BS and high floatation times associated with these formulations are very likely to increase GRT, eventually improving the In-vivo extension in drug and the extent of absorption.


Page 185


Table 53: Drug release and regression parameters for validation check points and optimized tablet Batch code VCT1

Q16 (%)

k

n

R²

SEOE

AOEV

93.5

0.2605

0.4746

0.9770

0.0627

0.9763

VCT2

93.3

0.2539

0.4950

0.9771

0.0606

0.9743

VCT3

92.5

0.2448

0.4825

0.9761

0.0624

0.9738

VCT4

93.1

0.2513

0.4900

0.9793

0.0610

0.9771

VCT5

92.4

0.2479

0.4990

0.9784

0.0591

0.9785

VCT6

92.2

0.2500

0.4803

0.9811

0.0586

0.9794

TOPT

92.8

0.2442

0.4826

0.9763

0.0625

0.9731

Overlay plot obtained from design expert also conform the results of optimized formulation selection (Figure 38).


Page 186


Table 54: Checkpoint composition, their results and percentage error Validation X1 HPMC batch K4M mg

VCT1

VCT2

VCT3

VCT4

VCT5

VCT6

TOPT

74.8

78.96

85.20

74.8

91.44

95.0

78.96

X2 CP 934P mg

12.32

12.96

13.92

15.2

13.6

12.0

15.2

Response variables

Prediction values

Observed values

Percentage error

Q16 (%)

93.64

93.5

0.1495

T60% (h)

6.14

6.13

0.1628

Tb (h)

13.05

13.1

-0.3831

BS (d/cm2)

8.27

8.2

0.8464

Q16 (%)

93.23

93.3

-0.0750

T60% (h)

6.17

6.2

-0.4862

Tb (h)

13.37

13.52

-1.1219

BS (d/cm2)

8.47

8.5

-0.3541

Q16 (%)

92.71

92.5

0.2265

T60% (h)

6.22

6.21

0.1607

Tb (h)

13.92

13.8

0.8620

BS (d/cm2)

8.86

8.85

0.1128

Q16 (%)

93.06

93.1

-0.042

T60% (h)

6.13

6.12

0.1631

Tb (h)

12.49

12.5

-0.0800

BS (d/cm2)

8.36

8.35

0.1196

Q16 (%)

92.44

92.4

0.0432

T60% (h)

6.28

6.29

-0.1592

Tb (h)

14.8

14.7

0.6756

BS (d/cm2)

9.33

9.3

0.3215

Q16 (%)

92.48

92.2

0.3027

T60% (h)

6.3

6.29

0.1587

Tb (h)

15.71

15.7

0.0636

BS (d/cm2)

9.67

9.7

-0.3102

Q16 (%)

92.83

92.85

-0.02154

T60% (h)

6.17

6.18

-0.16207

Tb (h)

12.93

12.9

0.232019

BS (d/cm2)

8.55

8.6

-0.5848


Page 187


94

0.2 0.1 Residuals

Observed Q16

R² = 0.9403

93

0 -0.1 92

93

94

-0.2 -0.3 -0.4

92 92

93

-0.5

94

Predicted Q16

Observed Q16

0.6 R² = 0.9488

0.4 Residuals

Observed T60

6.3

6.2

0.2 0 6.1

6.1 6.1

6.2

6.3

6.3

-0.2

Predicted T60

observed T60 (h)

1.5 Residuals

17 Observed Tb

6.2

R² = 0.9938

14.5

1 0.5 0 12

12 12

14.5

17

17

-1

Predicted Tb

Observed Tb (h)

Residuals

10 Observed BS

14.5

-0.5

R² = 0.9963

9

8 8

9

Predicted BS

10

0.6 0.4 0.2 0 -0.2 8 -0.4 -0.6 -0.8 -1

9

10

Observed BS


Page 188


Figure 38: Overlay plot showing the design space demarcating the optimized formulation 5.5.10. IN VIVO IMAGING STUDIES 5.5.10.1. X-ray photographic studies in rabbits In vivo floatability/mucoadhesion studies conducted for optimized formulation showed that the tablets did not escape from stomach up to 8 h and floated in the gastric fluid then adhered up to 8 h. This was evident by X-ray photographs taken at 0 h, 4 h & 8 h in rabbit (Figure 39, 40). 5.5.10.2. In vivo γ-scintigraphic studies in man Figure 41 and 42 portray the γ-Scintigraphic images corresponding to the test formulation (TOPT). TOPT was found to be retained for 6 h or more (Singh et al. 2012), significantly higher vis-à-vis conventional formulation, which got retained for only 30-60 mins (Richardson et al. 1996). All the subjects ingesting test formulation (TOPT), showed gastroretention (Fig. 41 and 42) for around 360 min, for which imaging of all the volunteers was conducted. Use of γ-scintigraphy in evaluating the gastroretentive potential has already been successfully demonstrated by several scientists (Singh 2012, Richardson 1996, Ibekwe 2006). In a nutshell, the study is therefore, construe that the test formulation, TOPT posseses the desirable GR characteristics contributed by optimized blend of HPMC K4M and CP 934P, through the ostensible interplay of floatational and bioadhesional mechanism. [Department of Pharm. Sci., MDU, Rohtak]

Page 189


Figure 39: X-ray ray imaging of rabbit abbit stomach without formulation

At 0 h

After 4h

After 8 h Figure 40: X- ray imaging of rabbit stomach with formulation at 0h, 4h and 8h


Page 190


(0 Min)

(150 Min)

(300 Min)

(75 Min)

(240 Min)

(360 Min)

Figure 41: Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled tablet at different time interval


Page 191


(0 m)

(150 m)

(300 m)

(75 m)

(240 m)

(360 m)


99mTc-

labelled tablet at different time interval [Department of Pharm. Sci., MDU, Rohtak]

Page 192


5.5.11. COMPARISON OF DRUG RELEASE OF OPTIMIZED FORMULATION WITH MARKETED PRODUCT Drug release data shown in Table 55 give details of marketed Glynase XL 10 mg extended release glipizide tablet and its comparison with optimized formulation.

Table 55: Drug release profile of the optimized and marketed formulation of glipizide Formulation

T60%(h)

Q12%

Q16%

n

K

Glynase XL

6.13

89.70

94.09

0.6161

0.1964

Optimized formulation

6.12

84.5

93.5

0.4802

0.2505

100


Marketed Optmtimized

90 % Drug Release

80 70 60 50 40 30 20 10 0 0

5

10 Time (h)

15

20

Mean drug release (mg/h)

(A) 3.5 3 2.5 2

Optimized

1.5

Marketed

1 0.5 0 0

5

10

15

20


(B) Figure 43: In-vitro drug release profiles of the optimized tablet and marketed formulations (A) and corresponding rates of drug release (B) [Department of Pharm. Sci., MDU, Rohtak]

Page 193


Drug release from the optimized formulation at 12 h (84.51%) was found to be closer to that of Glynase XL (89.30%) (Table 55). Similarly, the release parameters like T60%, Rel16h were quite close to each other. These values unambiguously corroborate the sameness of the release profiles. Figure 43 portrays the respective release profiles of the marketed formulations and optimized formulation superimposed over each other also indicating almost analogy of release performance with each other. Thus, the studies conclude successful development of gastroretentive CR formulation of glipizide capable of maintaining similar drug release profiles as observed with the marketed CR products and delivering the drug at its preferred site of absorption in the GI tract. Similarity factor (f2) between optimized and marketed formulation was

67 and difference factor (f1) was 6. 5.5.12. STABILITY STUDIES ON OPTIMIZED FORMULATION All the parameters viz., content, Tb, BS and drug release remained quite well within the desirable limits, showing negligible and random variation over six months of storage under accelerated conditions and normal long term storage conditions. Various dissolution parameters (viz. T60% and Q16), obtained during various time points of stability studies carried out at 40 ± 2 0 C and 75 ± 5% RH as well as 25 ± 2 0 C and 80 ± 5% RH, remained almost unaffected during the studies, suggesting the robustness of the optimized formulation with respect to dissolution characteristics (Table 56).

Table 56: Various parameters of the optimized formulation (TOPT) analyzed at different time points during accelerated stability studies Drug release

Accelerated Conditions

Drug content

Tb

BS

1 month

99.5±1.2

12.2

3 month

99.4±1.4

6 month

99.5±1.5

T60%

Q16

8.2

6.14

91.9


12.2

8.1

6.15

91.75

99

12.1

8.2

6.2

90.85

97

Similarity factor (f2) between optimized formulation at zero time and during stability studies for 1,3 and 6 month, reflects very minute change in the formulation release characteristics as it was found 99 while difference factor (f1) was 0, which shows that the optimized product was stable in the prevailing atmospheric conditions. [Department of Pharm. Sci., MDU, Rohtak]

Page 194


5.6. STUDIES BEADS

ON

FLOATING-BIOADHESIVE

GLIPIZIDE

Polymers like HPMC K4M, CP 934P and Chitosan (CT) were selected for preliminary pre-optimization studies for beads formulation (alginate beads), because of their excellent bioadhesion strength, release rate controlling ability, nontoxicity, stability at GI pH and compatibility with drug. CT was selected for use in further studies as per its good bioadhesive properties. The successful use of the polymer combination of SA and CT has already been documented in literature reports for attaining CR (Choudhary and Ali, 2013). Therefore the combination was chosen for formulating CR formulation of glipizide, owing to their high sustained, bioadhesive potential. Hence the aim of the current study was fulfilled with the use of polymer combination.

5.6.1. SELECTION OF DESIGN OF EXPERIMENT (DoE) FOR PREPARATION OF FLOATING-BIOADHESIVE GLIPIZIDE BEADS A CCD is considered as most efficient in estimating the influence of individual variables (main effects) and their interactions, using minimum experimentation (Doornbos and Haan, 1995; Schwartz and Connor, 1996; Lewis et al., 1999). In a CCD, all the factors are studied at all the possible combinations. The design also determining the quadratic response surfaces, which are not estimable, using a FD at two levels (Singh et al., 2004). In the present study, fitting a cubic model is considered to be better as the values of the response surfaces are not known from the previous findings. Hence, a CCD for two factors at three levels with α= 1, which in turn is equivalent to a 32 FD, was chosen for the current formulation optimization study. The central point (0, 0, i.e., FB9, FB10, FB11, FB12 and FB13) was studied in quintuplicate. Preliminary trial batches of beads were prepared by using SA, the stirring speed was varied from 50, 75 and 100 rpm and cross linking time 5, 10 and 15 minutes was also varied. From these batches, 50 rpm and 15 minutes cross-linking time was the optimum revolution and time used for the preparation of floating beads. The crosslinking time did not have a significant effect on the percentage EE. Concentration of calcium chloride and hardening time had a negative effect on the Bsize. High calcium chloride concentration and hardening time caused shrinkage of [Department of Pharm. Sci., MDU, Rohtak]

Page 195


beads and smaller particles are formed because of a high degree of cross linking. This negative effect of calcium chloride concentration and cross linking time was of less magnitude, calcium chloride and cross linking time are much effecting the morphology of the beads, and the surface became rougher with some, very small pores, which is in accordance with the earlier findings (Moghadam et al., 2009)

5.6.2. DRUG EXCIPIENT COMPATIBILITY STUDIES, PHYSICAL EVALUATION AND ASSAY OF FLOATING-BIOADHESIVE BEADS Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and various excipients (Tablet) was studied. The characteristic absorption peaks of glipizide were obtained at 3554 cm-1 - NH stretching of NH2 2943 cm-1 - C-H2 aliphatic group 1689 cm-1 - C=O stretching 1651 cm-1 - C=N aliphatic group 1529 cm-1 - CH aliphatic group These peaks obtained in the spectrum of beads were correlated with the peaks of pure drug. The parent peaks of the drug did not show any deviation, which indicate that drug was compatible with these formulation component (Figure 44).

Figure 44: IR spectra of glipizide pure drug and Beads [Department of Pharm. Sci., MDU, Rohtak]

Page 196


The glipizide floating beads were prepared by simple emulsion-gelation technique using SA a natural polymer.

Polymer concentration (drug: polymer) was an

important factor as viscosity of polymer solution effects the size of beads. Three different polymer concentrations 2.5, 3.5 and 4.5 % w/v were selected, 2.5 % concentration [1:5 (drug: polymer)] showed a maximum sphericity, least size and no oil leakage, with increase in concentration and hence, the viscosity of SA solutions, beads with larger surface area and less surface porosity were obtained, which releases drug slowly. Uniform beads (i.e., of the same size and density) were prepared by maintaining conditions such as viscosity, rate of falling of drops, stirring rate and distance between syringe and gelation media, constant during the course of preparation. Variation in any of these parameters during the microcarrier formation process may result in the production of non-homogenous and nonuniform beads, affecting the overall results to an appreciable extent (Fursule et al., 2009). Size of bead is also influenced by the opening through which the SA solution is allowed to pass (which was kept constant). Increased viscosity at a higher concentration of SA resulted in larger particles (2.210 - 2.251; Table 57). Beads, with more light liquid paraffin (LLP) concentration, show oil leakage and flowability decreases. When a standard drug solution was analyzed repeatedly (n = 3), the mean error (accuracy) and relative standard deviation (precision) were found to be 0.8% and 1.2%, respectively.

5.6.3. SWELLING STUDIES ON FLOATING-BIOADHESIVE BEADS Swelling index of beads was based on concentration of SA as more SA was resulting in more swelling index of beads, it is also dependent on the concentration of LLP present in the beads, as beads with more LLP were having less swelling percent as compared to beads with less LLP (Table 57).

5.6.4. SCANNING ELECTRON MICROSCOPY (SURFACE TOPOGRAPHY) Surface topography of prepared beads was studied by scanning electron microscopy and it is shown in

Figure 45-48. Floating beads of glipizide were well-rounded

spheres with rough surface because of sudden cross linking of SA with calcium (Figure 45). When beads were prepared with coating of CT (CT dissolved in calcium chloride solution) SEM shows that the beads surface becomes smoother (Figure 46). LLP entrapped beads had an “orange peel” surface with corrugations (Figure 47). [Department of Pharm. Sci., MDU, Rohtak]

Page 197


The drug-loaded beads were spherical and tailing begins with increase in LLP concentration (Figure 48) in emulsion. Pores or small channels distributed throughout the surface. Beads were found to be free flowing and of monolithic matrix type. The beads of each batch were uniform in size.

Figure 45: Scanning electron micrograph of glipizide beads without chitosan

Figure 46: Scanning electron micrograph of glipizide beads with chitosan


Page 198


Figure 47: Scanning electron micrograph of glipizide beads with CT enlarged view

Figure 48: Scanning electron micrograph of glipizide beads with larger concentration of light liquid paraffin showing tailing [Department of Pharm. Sci., MDU, Rohtak]

Page 199


Table 57: Physicochemical Properties of floating-bioadhesive beads Batch

Size (mm)

Mean swelling (%)

Oil leakage

Shape and color

Flowability

FB 1

2.02±0.02

5.44

NO

SOW

Free flowing

FB 2

2.13±0.01

5.23

NO

SOWT

Flowing

FB 3

2.13±0.01

3.13

NO

SLY

Free flowing

FB 4

2.24±0.01

3.21

YES

SLYT

Sticky with oil

FB 5

2.14±0.02

4.16

NO

SOW

Free flowing

FB 6

2.15±0.02

4.24

NO

SOWT

Flowing

FB 7

2.05±0.01

4.87

NO

SOW

Free flowing

FB 8

2.16±0.01

3.84

YES

ASLY

Free flowing

FB 9

2.06±0.02

4.36

NO

ASLY

Free flowing

FB 10

2.09±0.03

4.78

NO

ASOW

Free flowing

FB 11

2.06±0.02

4.35

NO

ASOW

Free flowing

FB 12

2.06±0.02

3.78

NO

ASOW

Free flowing

FB 13

2.04±0.02

3.43

NO

ASOW

Free flowing

(Spherical off White=SOW, Spherical off White with Tailing=SOWT, Spherical Light Yellow=SLY, Spherical Light Yellow with Tailing =SLYT, almost spherical off white=ASOW)

5.6.5. ENTRAPMENT EFFICIENCY It is an important variable for assessing the drug loading capacity of beads and their drug release profile, thus suggesting the amount of drug availability at site. EE ranged from 75 % to 87 % depending on the composition of the thirteen batches of alginate beads of glipizide (Table 58). The curing time were kept to 15 minutes since drug is insoluble in water. EE of the beads was found correlated with proportion of LLP present in beads, with increase in LLP concentration the drug entrapped increased due to partitioning of the drug in the LLP phase. Moreover, an increase in the amount of SA increases EE due to increased space for drug molecules to be retained throughout a larger cross linked network of calcium alginate.

5.6.6. IN VITRO BUOYANCY OF BEADS Table 58 shows how the LLP loadings affect the buoyancy of the alginate beads. All samples with LLP stayed afloat for >12 h in a 18h test cycle except FB6 which float [Department of Pharm. Sci., MDU, Rohtak]

Page 200


for 2.5 h. Table also lists the Tlag of the drug loaded beads. The results show that the Tlag decreased for the beads with more oil inclusion but at the same time the concentration of polymer is also governing the Tlag, i.e., low polymer concentration was resulting in easy floating and with increase in polymer concentration Tlag was increased (Figure 49). It may be due to the increased density of dried beads and as the volume of beads increases with adsorption of water its density decreases and it begins to float.

Table 58: Entrapment efficiency and floating properties of floating-bioadhesive beads Batch

EE (%)

Mean Density (gm/cm3)

Tlag (s)

Tb (h)

FB 1

75.0±2.4

0.87

0

>12

FB 2

81.5±2.4

0.99

121

2.5

FB 3

81.0±2.1

0.67

0

>18

FB 4

87.0±4.2

0.97

50

>12

FB 5

79.5±3.2

0.74

0

>12

FB 6

84.3±1.8

0.98

110

>12

FB 7

78.5±1.2

0.89

32

>12

FB 8

83.1±3.2

0.88

18

>12

FB 9

80.5±1.5

0.90

27

>12

FB 10

80.6±1.8

0.90

27

>12

FB 11

80.5±1.2

0.89

27

>12

FB 12

80.9±1.7

0.90

26

>12

FB 13

80.7±1.1

0.90

25

>12


Page 201


140 120

Time (s)

100 80 60 40 20 0 FB 1

FB 2

FB 3

FB 4

FB 5

FB 6

FB 7

FB 8

FB 9 FB 10 FB 11 FB 12 FB 13

Figure 49: Tlag of various glipizide beads batches prepared as per the experimental design 5.6.7. IN VITRO GLIPIZIDE RELEASE STUDIES In-vitro drug release study of glipizide alginate beads was carried out in the simulated fasted state, pH 1.2 for a period of 14 h. In the fasted state, gel beads exhibited a biphasic release profile as an initial rapid drug release phase (burst effect) was followed by a slower, gradually decreasing drug release phase after one hour extending up to 14 h (Figure 50). FB1 released 32.29 ± 2.0 % glipizide within one hour, followed by a tailing off sustained release profile for 14 h. The initial faster release may be due to drug dissolution from the surface of beads. The drug release was found to be slower in formulations with higher oil concentration. The slow release of the drug from the beads may be due to the formation of drug- LLP dispersion system in the oil pockets of the beads. Where, the drug has to firstly diffuse from the oil pockets into the polymeric matrix and followed by transportation of drug out of the polymeric matrix into the dissolution medium.


Page 202


GF1

GF2

GF3

GF4

GF5

GF6

GF7

GF8

GF9

100 90

% Drug release

80 70 60 50 40 30 20 10 0 0

1

2

3

4

5 Time (h)

6

7

8

9

10

Figure 50: Drug release (Q10) profile from various glipizide beads batch (the point GF9 represents a mean of 5 replicate runs i.e. GF9, GF10, GF11, GF12 and GF13) 5.6.8. DATA ANALYSIS AND DRUG RELEASE KINETICS The mechanism of drug release was investigated by fitting to models representing zero-order, first order, Higuchi’s square root of time model and Korsmeyer-Peppas model. First order gave r2 value 0.9263-0.9911 (Table 59) describing the drug release rate relationship with concentration of drug. The best linearity was found in Higuchi’s equation plot, r2 is between 0.9912-0.9950 indicating the release of drug from matrix as a square root of time dependent process. The diffusion exponent (n) value, as calculated from Korsmeyer- Peppas model, for glipizide loaded beads ranged from 0.4470 to 0.5170 (Table 59), showing anomalous (non-Fickian) diffusion involving a combination of swelling, diffusion and/or erosion of matrices, in most of batch except FB9, as 0.45 < n < 0.89 for non-Fickian diffusion. Results of ANOVA for Response Surface Quadratic Model for various dependent [Department of Pharm. Sci., MDU, Rohtak]

Page 203


parameters are like Eqn. 19, 20, 21, 22 and 23. Entrapment Efficiency (EE) EE= +80.72 + 2.4*A + 2.3*B-0.13*A*B +0.84*A2 - 0.26*B2+0.58*A2*B+0.73*A*B2

(19)

Total buoyency (Tb) Tb =+24.83-0.00*A+0.00*B+6.00*A*B-2.90*A2-2.90*B2+6.00*A2*B-6.00*A*B2

(20)

Floating Lag Time (Tlag) Tlag =17.14+55.0*A-17.0*B-115.0*A*B+63.52*41.52A2+*B2-98.0*A2*B+80.0*A*B2

(21)

Bead Size (Bsize)

Bsize=+2.12+0.060*A+0.030*B+5.000E-003*A*B-4.138E-003*A2+5.862E-003*B2+1.000E002*A2*B+1.000E-002*A*B2

(22)

Drug Release (DR) DR=+91.22-6.95*A-3.35*B-1.67*A*B-2.01*A2+0.49*B2-0.38*A2*B+1.72*A*B2

(23)

Table 59: Various kinetic rates of floating-bioadhesive beads Zero order R2

First order R2

Higuchi R2

FB1

0.9000

0.9263

FB2

0.9244

FB3

Batch

Korsmeyer R2

n

0.9912

0.9752

0.4681

0.9795

0.9930

0.9863

0.5154

0.8874

0.9713

0.9944

0.9827

0.4568

FB4

0.9132

0.9911

0.9950

0.9913

0.5061

FB5

0.8971

0.9476

0.9916

0.9760

0.4596

FB6

0.9135

0.9887

0.9944

0.9898

0.5011

FB7

0.8940

0.9615

0.9940

0.9815

0.4632

FB8

0.9204

0.9874

0.9946

0.9899

0.5170

FB9

0.8848

0.9427

0.9721

0.9424

0.4470

FB10

0.8914

0.9694

0.9938

0.9819

0.4584

FB11

0.8951

0.9688

0.9937

0.9820

0.4638

FB12

0.8923

0.9708

0.9933

0.9818

0.4598

FB13

0.8906

0.9729

0.9935

0.9814

0.4568


Page 204


Various response surfaces plotted for the studied response using these equations shows the effect of polymer and light liquid paraffin in combination on the properties and they are known to facilitate an understanding of contribution of the variables and their interactions as shown in figures Figure 51 and corresponding contour lines (Figure 52) shows a nearly linear ascending pattern for the values of entrapment efficiency, as the content of LLP increased, while the entrapment efficiency decreases with increasing SA. Maximum entrapment efficiency is observable at the highest levels of LLP and lowest SA. Contour lines corroborate markedly significant influence of LLP and SA on entrapment efficiency. Figure 53 and corresponding contour lines (Figure 54) portrays a nonlinear increase or decrease relationship of TFT with increasing and decreasing amounts of SA and LLP. Nonlinear lines in contour plot shows the presence of any interaction between the polymer and LLP for TFT as it increases with increasing LLP and at high LLP concentration with low SA it is maximum while with high SA it again decreases. Figure 55 and contour plot (Figure 56) shows that the FLT is almost zero at all concentration of LLP with Lowest SA while the increasing concentration of SA increases Tlag. Maximum Tlag was found at highest SA and lowest LLP combination. Bead size according to Figure 57 and contour plot (Figure 58) shows a nearly linear ascending pattern for the values, as the content of either SA or LLP is increased, the effect being much more prominent with SA. Maximum bead size is observable at the highest levels of both SA and LLP. Figure 59 and their relative contour plot (Figure 60) for Q10, reveals a sharp decline in the value of Q10 with an increase in the amount of the polymers, i.e., SA while with increase in LLP it decreases, the influence of SA is more pronounced. Nonlinear contour lines in figure further show that the variation in Q10 is a complex function of the polymer SA and entrapped LLP levels.


Page 205


75.00-80.00

80.00-85.00

85.00-90.00

Entrapment Efficiency

90.00 85.00 80.00 1.00 75.00 -1.00 0.00 ALGINATE

-1.00


1.00

Figure 51:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads

ENTRAPPMENT EFFICIENCY

1.00

86

84

B: LIQUID PARAFFIN

0.50

82

5

0.00

80

-0.50

78 76

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 52: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on entrapment efficiency of beads


Page 206


14.00 10.00 10.00-14.00 10.00 Tb

6.00 6.00-10.00 6.00

2.00 2.00-6.00

1.00 0.00

1.00

0.00

-1.00

2.00

Liquid Paraffin

-1.00

Figure 53:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on o total buoyancy of beads

Tb

1.00

12

B : LIQ UID P A RA FF IN

0.50

12

5

0.00

12

-0.50

10 8 6 4

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 54: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on total buoyancy of beads [Department of Pharm. Sci., MDU, Rohtak]

Page 207


0.00-40.00 40.00

40.00-80.00

80.00-120.00

120.00-125.00 125.00

FLT

120.00 80.00 40.00 1.00 0.00 0.00

-1.00 0.00 LIQUID PARAFFIN

-…

ALGINATE

1.00

Figure 55:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads

Tlag

1.00

B : LIQ U ID P A R A F F IN

0.50

40

20 0

0.00

60

5

80 100

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 56: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on floating lag time of beads


Page 208


2.00-2.08

2.08-2.17

2.17-2.25

2.25-2.25

2.25

BSI

2.17

2.08 2.00 1.00

-1.00 0.00


ALGINATE 1.00 -1.00

Figure 57:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on bead size

BEAD SIZE

1.00

2.2

B: LIQUID PARAFFIN

0.50

2.15 2.1

0.00

5

2.05

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 58: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on bead size [Department of Pharm. Sci., MDU, Rohtak]

Page 209


92.00-98.00

86.00-92.00

80.00-86.00

Q10

98.00 92.00 86.00 80.00 -1.00

1.00 ALGINATE 0.00

0.00 LIQUID PARAFFIN -1.00 1.00

Figure 59:: Response surface plot showing the effect of polymer and light liquid paraffin concentration on drug release

DRUG RELEASE

1.00

B: LIQUID P A RAFFIN

0.50

85

0.00

95

5

90

-0.50

-1.00 -1.00

-0.50

0.00

0.50

1.00

A: ALGINATE

Figure 60: Corresponding contour ontour plot showing the effect of polymer and light liquid paraffin concentration on drug release from beads [Department of Pharm. Sci., MDU, Rohtak]

Page 210


5.6.9. SEARCH FOR OPTIMUM FORMULATIONS Feasibility and grid searches method through MS-excel utility and overlay plot generation method through Design expert were used for finding the optimized product. The results for the feasibility search to find the suitable region for further location of optimum formulations are presented in Table 60, 61, 62, 63 and 64 and area for optimized product are shown in Figure 62. The criteria for selection of suitable feasible region (shown with thicker borders) were primarily based upon the highest possible values of Q10; EE; Tlag; Tb and Bsize. The selected regions were based on the following criteria. For selected region: Q10≥91%; EE > 80%; Tlag ≤45s; Tb ≥11.5h and Bsize ≤ 2.15 mm The results of the exhaustive grid searches performed subsequent to feasibility searches are presented in Tables 65, 66, 67, 68 and 69. The optimum formulation was selected by trading off various response variables and adopting the following maximizing criteria: Q10≥91%; EE > 80%; Tlag ≤45s; Tb ≥11.5h and Bsize ≤ 2.15 mm. Upon comprehensive evaluation of grid searches, the formulation (X1=-0.36 and X2=0.16 i.e. SA= 3.14g and LLP= 12.9 ml) fulfilled the optimal criteria of best regulation of the, Q10=93.1%; EE=82.0%; Tlag =39.5s; Tb=12.3h and Bsize =2.09mm, this formulation was taken as optimized formulation (BOPT).


Page 211


Table 60: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Q10 SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

97.92

98.09

98.12

98.02

97.80

97.44

96.96

96.34

95.60

94.73

93.72

-0.80

97.93

97.93

97.84

97.63

97.33

96.92

96.41

95.80

95.09

94.27

93.35

-0.60

97.78

97.62

97.38

97.07

96.68

96.22

95.68

95.06

94.37

93.60

92.76

-0.40

97.46

97.13

96.75

96.32

95.84

95.32

94.74

94.11

93.44

92.72

91.94

-0.20

96.98

96.48

95.95

95.39

94.82

94.22

93.60

92.96

92.30

91.61

90.90

0.00

96.34

95.65

94.97

94.29

93.61

92.94

92.27

91.61

90.95

90.29

89.64

0.20

95.54

94.66

93.82

93.00

92.22

91.50

90.74

90.05

89.39

88.76

88.16

0.40

94.58

93.51

92.49

91.54

90.64

89.80

89.01

88.29

87.62

87.01

86.45

0.60

93.46

92.18

90.99

89.89

88.87

87.94

87.09

86.32

85.64

85.04

84.53

0.80

92.17

90.69

89.32

88.07

86.92

85.88

84.96

84.15

83.45

82.86

82.38

1.00

90.72

89.03

87.48

86.06

84.78

83.64

82.64

81.77

81.04

80.45

80.00

Table 61: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for EE SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

79.97

79.56

79.18

78.81

78.47

78.15

77.85

77.57

77.32

77.08

76.87

-0.80

80.92

80.42

79.94

79.50

79.08

78.70

78.35

78.03

77.74

77.48

77.25

-0.60

81.80

81.20

80.65

80.14

79.66

79.23

78.84

78.48

78.17

77.90

77.67

-0.40

82.59

81.92

81.30

80.73

80.21

79.74

79.32

78.94

78.62

78.35

78.12

-0.20

83.31

82.58

81.90

81.29

80.73

80.23

79.79

79.41

79.09

78.82

78.62

0.00

83.95

83.16

82.45

81.80

81.21

80.70

80.25

79.88

79.57

79.32

79.15

0.20

84.51

83.68

82.93

82.26

81.67

81.15

80.71

80.35

80.06

79.85

79.72

0.40

84.99

84.14

83.37

82.69

82.09

81.58

81.16

80.82

80.57

80.41

80.33

0.60

85.40

84.52

83.75

83.07

82.48

81.99

81.60

81.30

81.10

80.99

80.98

0.80

85.72

84.84

84.07

83.40

82.84

82.38

82.03

81.78

81.64

81.60

81.67

1.00

85.97

85.10

84.34

83.69

83.17

82.75

82.45

82.26

82.19

82.23

82.39


Page 212


Table 62: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tlag SA LLP

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

1.87

-0.15

-1.72

-2.84

-3.52

-3.74

-3.52

-2.84

-1.72

-0.15

1.87

-0.80

1.69

0.62

-0.20

-0.77

-1.09

-1.15

-0.96

-0.52

0.18

1.13

2.33

-0.60

4.24

3.94

3.70

3.51

3.38

3.31

3.29

3.34

3.43

3.59

3.80

-0.40

9.52

9.82

9.98

10.01

9.89

9.64

9.24

8.71

8.04

7.23

6.28

-0.20

17.52

18.26

18.65

18.72

18.44

17.83

16.89 15.61 14.00 12.05

9.76

0.00

28.26

29.25

29.71

29.64

29.03

27.90

26.23 24.04 21.31 18.05 14.26

0.20

41.72

42.80

43.15

42.77

41.67

39.83

37.27 33.99 29.97 25.23 19.76

0.40

57.92

58.91

58.98

58.12

56.34

53.64

50.01 45.46 39.99 33.60 26.28

0.60

76.84

77.57

77.19

75.68

73.05

69.31

64.45 58.46 51.36 43.14 33.80

0.80

98.49

98.79

97.78

95.45

91.81

86.85

80.58 72.99 64.08 53.86 42.33

1.00

122.8

122.5

120.7

117.4

112.6

106.2

98.40 89.04 78.16 65.77 51.87

Table 63: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tb SA -1.00 LLP

-0.80

-0.60

-0.40

-0.20

-1.00

12.42 11.98

11.63

11.38 11.23 11.18 11.23 11.37 11.62 11.96 12.40

-0.80

12.74 12.39

12.10

11.87 11.70 11.59 11.55 11.56 11.63 11.77 11.96

-0.60

12.77 12.55

12.36

12.19 12.04 11.92 11.81 11.73 11.67 11.63 11.62

-0.40

12.52 12.48

12.42

12.34 12.25 12.15 12.02 11.89 11.73 11.56 11.38

-0.20

11.99 12.16

12.27

12.33 12.33 12.28 12.18 12.02 11.81 11.55 11.23

0.00

11.18 11.59

11.92

12.15 12.28 12.33 12.28 12.15 11.92 11.59 11.18

0.20

10.09 10.79

11.36

11.80 12.10 12.28 12.33 12.25 12.04 11.70 11.23

0.40

8.71

9.74

10.59

11.28 11.80 12.15 12.33 12.34 12.19 11.87 11.38

0.60

7.06

8.44

9.62

10.59 11.36 11.92 12.27 12.42 12.36 12.09 11.62

0.80

5.12

6.90

8.44

9.74

10.79 11.59 12.16 12.47 12.55 12.38 11.96

1.00

2.90

5.12

7.06

8.72

10.09 11.18 11.99 12.52 12.76 12.72 12.40


0.00

0.20

0.40

0.60

0.80

1.00

Page 213


Table 64: Feasibility search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bsize SA

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0.40

0.60

0.80

1.00

-1.00

2.01

2.03

2.04

2.06

2.07

2.08

2.10

2.11

2.12

2.13

2.14

-0.80

2.03

2.04

2.05

2.07

2.08

2.09

2.10

2.12

2.13

2.14

2.15

-0.60

2.04

2.05

2.06

2.08

2.09

2.10

2.11

2.12

2.14

2.15

2.16

-0.40

2.05

2.06

2.07

2.08

2.10

2.11

2.12

2.13

2.14

2.15

2.17

-0.20

2.06

2.07

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.16

2.18

0.00

2.06

2.07

2.09

2.10

2.11

2.12

2.13

2.14

2.16

2.17

2.18

0.20

2.07

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.16

2.18

2.19

0.40

2.08

2.09

2.10

2.11

2.12

2.13

2.14

2.16

2.17

2.19

2.20

0.60

2.08

2.09

2.10

2.11

2.12

2.14

2.15

2.16

2.18

2.20

2.21

0.80

2.08

2.09

2.10

2.11

2.13

2.14

2.15

2.17

2.19

2.20

2.22

1.00

2.08

2.09

2.10

2.12

2.13

2.14

2.16

2.18

2.19

2.21

2.23

LLP


Page 214


Table 65: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Q10 SA LLP

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

95.39

95.28

95.17

95.05

94.94

94.82

94.70

94.58

94.47

94.35

94.22

-0.16

95.19

95.07

94.95

94.83

94.71

94.59

94.47

94.35

94.23

94.11

93.98

-0.12

94.97

94.85

94.73

94.61

94.48

94.36

94.24

94.11

93.99

93.86

93.73

-0.08

94.75

94.63

94.50

94.37

94.25

94.12

93.99

93.86

93.73

93.61

93.48

-0.04

94.52

94.39

94.26

94.13

94.00

93.87

93.74

93.61

93.47

93.34

93.21

0.00

94.29

94.15

94.02

93.88

93.75

93.61

93.48

93.34

93.21

93.07

92.94

0.04

94.05

93.91

93.77

93.63

93.49

93.35

93.21

93.07

92.93

92.80

92.66

0.08

93.80

93.65

93.51

93.36

93.22

93.08

92.93

92.79

92.65

92.51

92.37

0.12

93.54

93.39

93.24

93.09

92.94

92.80

92.65

92.51

92.36

92.22

92.08

0.16

93.27

93.12

92.97

92.81

92.66

92.51

92.36

92.21

92.07

91.92

92.7

0.20

93.00

92.84

92.68

92.53

92.37

92.22

92.06

91.91

91.76

91.61

91.5

Table 66: Grid Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for EE SA LLP

-0.40

-0.36

-0.32

-0.28

-0.20

81.29 81.17

81.06

80.94 80.84 80.73 80.62 80.52 80.42 80.33 80.23

-0.16

81.39 81.27

81.16

81.05 80.94 80.83 80.72 80.62 80.52 80.42 80.33

-0.12

81.50 81.38

81.26

81.15 81.04 80.93 80.82 80.72 80.62 80.52 80.42

-0.08

81.60 81.48

81.36

81.25 81.13 81.02 80.92 80.81 80.71 80.61 80.51

-0.04

81.70 81.58

81.46

81.34 81.23 81.12 81.01 80.91 80.80 80.70 80.61

0.00

81.80 81.67

81.56

81.44 81.32 81.21 81.11 81.00 80.90 80.80 80.70

0.04

81.89 81.77

81.65

81.53 81.42 81.31 81.20 81.09 80.99 80.89 80.79

0.08

81.99 81.86

81.74

81.63 81.51 81.40 81.29 81.18 81.08 80.98 80.88

0.12

82.08 81.96

81.84

81.72 81.60 81.49 81.38 81.27 81.17 81.07 80.97

0.16

82.17 82.05

81.93

81.81 81.69 81.58 81.47 81.36 81.26 81.16 81.06

0.20

82.26 82.14

82.02

81.90 81.78 81.67 81.56 81.45 81.35 81.25 81.15

-0.24


-0.20

-0.16

-0.12

-0.08

-0.04

0.00

Page 215


Table 67: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tlag SA LLP

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

18.72

18.69

18.65

18.59

18.52

18.44

18.35

18.24

18.12

17.98

17.83

-0.16

20.72

20.69

20.64

20.57

20.49

20.40

20.29

20.16

20.02

19.87

19.70

-0.12

22.82

22.78

22.71

22.64

22.54

22.43

22.31

22.16

22.01

21.83

21.64

-0.08

25.00

24.95

24.88

24.79

24.68

24.55

24.41

24.25

24.07

23.87

23.65

-0.04

27.28

27.21

27.13

27.02

26.90

26.75

26.59

26.41

26.20

25.98

25.74

0.00

29.64

29.56

29.46

29.34

29.20

29.03

28.85

28.64

28.42

28.17

27.90

0.04

32.09

32.00

31.88

31.74

31.58

31.40

31.19

30.96

30.71

30.44

30.14

0.08

34.63

34.52

34.39

34.23

34.05

33.84

33.61

33.36

33.08

32.78

32.45

0.12

37.25

37.13

36.98

36.80

36.60

36.37

36.11

35.83

35.53

35.19

34.84

0.16

39.97

39.82

39.65

39.46

39.23

38.98

38.70

38.39

38.05

37.69

37.30

0.20

42.77

42.61

42.42

42.20

41.95

41.67

41.36

41.02

40.65

40.26

39.83

Table 68: Grid Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Tb SA LLP

-0.40

-0.36

-0.32

-0.28

-0.20

12.00 12.02

12.03

12.07 12.11 12.14 12.18 12.21 12.23 12.26 12.28

-0.16

12.01 12.04

12.08

12.12 12.15 12.18 12.21 12.24 12.26 12.28 12.30

-0.12

12.05 12.09

12.12

12.16 12.19 12.21 12.24 12.26 12.28 12.30 12.31

-0.08

12.09 12.12

12.16

12.19 12.22 12.24 12.27 12.28 12.30 12.31 12.32

-0.04

12.12 12.16

12.19

12.22 12.24 12.27 12.29 12.30 12.31 12.32 12.33

0.00

12.15 12.18

12.21

12.24 12.26 12.28 12.30 12.31 12.32 12.33 12.33

0.04

12.17 12.20

12.23

12.26 12.28 12.30 12.31 12.32 12.33 12.33 12.33

0.08

12.18 12.21

12.24

12.27 12.29 12.30 12.32 12.32 12.33 12.33 12.32

0.12

12.18 12.22

12.25

12.27 12.29 12.31 12.32 12.32 12.32 12.32 12.31

0.16

12.18 12.22

12.25

12.27 12.29 12.30 12.31 12.32 12.32 12.31 12.30

0.20

12.18 12.21

12.24

12.26 12.28 12.30 12.30 12.31 12.30 12.30 12.28

-0.24


-0.20

-0.16

-0.12

-0.08

-0.04

0.00

Page 216


Table 69: Intensive grid search for locating a region of glipizide for SA and LLP blend from various floating bioadhesive beads formulation of glipizide for Bsize SA

-0.40

-0.36

-0.32

-0.28

-0.24

-0.20

-0.16

-0.12

-0.08

-0.04

0.00

-0.20

2.09

2.09

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

-0.16

2.09

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

-0.12

2.09

2.10

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

-0.08

2.09

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

-0.04

2.10

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

0.00

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

0.04

2.10

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

0.08

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

0.12

2.10

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

0.16

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

2.12

0.20

2.10

2.10

2.11

2.11

2.11

2.11

2.12

2.12

2.12

2.12

2.13

LLP

Highlighted (non-italic) rectangle show validation check points and Highlighted (italic) rectangle show optimized batch


Page 217


Figure 61: Overlay plot showing the design space demarcating the optimized formulation 5.6.10. VALIDATION OF OPTIMIZED FORMULATIONS Physical evaluation results of the beads and assay of the optimised formulations and various validation check point are listed in Table 70. All the values were found within limits, topographic studies done by scanning electron micrograph (Figure 63) show a well rounded smooth surface bead. Table 70: Physical evaluation parameters of validation check points Mean Bsize Tlag Batch Oil Shape Swelling code leakage and color (mm) (s) (%) VCB1 2.09 4.36 NO SOW 20.5 2.11 4.3 NO SOW 26.5 VCB2 2.1 4.35 NO SOW 36.7 VCB3 VCB4 2.1 4.4 NO SOW 42.5 2.11 4.3 NO SOW 22.5 VCB5 VCB6 2.14 4.4 NO SOW 39.5 BOPT 2.1 4.3 NO SOW 39.8

Tb (h) 12.05 12.25 12.3 12.2 12.3 12.3 12.2

(Spherical off White=SOW)


Page 218


Table 71: Various checkpoint composition and their results Batch

VDB1

VDB2

VDB3

VDB4

VDB5

VDB6

BOPT

X1 (SA) Mg

3.14

3.3

3.18

3.1

3.42

3.5

X2 (LLP) mL

12.1

12.4

12.8

13

12.2

13

Response variables

Prediction values

Observed values

Percentage error

Q10 (%)

95.07

95.1

-0.0315

EE (%)

81.27

81.3

-0.0369

Tlag (s)

20.69

20.5

0.9183

Tb (h)

12.04

12.05

-0.0830

Bsize (mm)

2.09

2.09

0

Q10 (%)

93.87

93.6

0.2876

EE (%)

81.12

81.1

Tlag (s)

26.75

26.5

0.0246 0.9345

Tb (h)

12.27

12.25

0.1629

Bsize (mm)

2.11

2.12

-0.4739

Q10 (%)

93.24

93.1

0.1501

EE (%)

81.84

81.75

Tlag (s)

36.98

36.7

0.1099 0.7571

Tb (h)

12.25

12.3

-0.4081

Bsize (mm)

2.1

2.1

0

Q10 (%)

93

92.5

0.5376

EE (%)

82.26

82.2

0.0729

Tlag (s)

42.77

42.5

0.6312

Tb (h)

12.18

12.2

-0.1642

Bsize (mm)

2.1

2.1

0

Q10 (%)

93.99

93.5

0.5213

EE (%)

80.62

80.5

0.1488

Tlag (s)

22.01

22.5

-2.2261

Tb (h)

12.28

12.3

-0.1628

Bsize (mm)

2.11

2.11

0

Q10 (%)

91.5

91.75

-0.2732

EE (%)

81.15

81.2

-0.0616

Tlag (s)

39.83

39.5

0.8285

Tb (h)

12.28

12.3

-0.1628

Bsize (mm) Q10 (%)

2.13 93.12

2.14 93.1

-0.4694 0.0214

EE (%)

82.05

82

0.0609

Tlag (s)

39.8

39.5

0.7537

Tb (h)

12.2

12.3

-0.8196

Bsize (mm)

2.1

2.09

0.4761S


Page 219


Observed Q10

95

0.4 Residuals

R² = 0.9392

93

0.2 0 -0.2

91

93

-0.4

91 91

93

-0.6

95

Observed Q10%

Predicted Q10

0.1

82

0.05

Residuals

Observed EE

83 R² = 0.9867

81

0 -0.05

80

81

82

83

-0.1

80 80

81

82

83

-0.15

Predicted EE

Observed EE%

3

44 R² = 0.9739

2

Residuals

Observed Tlag

95

32

1 0 -1

20 20

32

20

32

44

-2

44

Predicted Tlag

Observed Tlag (s)

12.3

0.6 Residuals

Observed Tb

R² = 0.9478

12.15

0.4 0.2 0

12

12 12

12.15

12.3

12.15

12.3

-0.2 Observed Tb (h)

Predicted Tb

2.14

1 Residuals

Observed Bsize

R² = 0.9643

2.11

0.5 0 2.08

2.08 2.08

2.11

2.14

Predicted Bsize

2.11

2.14

-0.5 Observed BSIZE (mm)


Page 220


Figure 63: Scanning electron micrograph of optimized bead Upon comparison of the observed responses with those of the anticipated ones (Table 71), the prediction error varied between 0.93 and -2.22 %. The linear correlation plots drawn between the predicted and observed responses, forcing the line through the origin, demonstrated high values of R (0.9392 to 0.9867) (Figure 62), indicating excellent goodness of fit (p < 0.001). The corresponding residual plots show nearly uniform and random scatter around the mean values of response variables. 5.6.11. IN VIVO IMAGING STUDIES FOR BEADS 5.6.11.1. X-ray Photographic Studies in Rabbits In vivo floatability and mucoadhesion studies conducted for optimized formulation showed that beads did not escape from stomach up to 6 h and floated in the gastric fluid and then adhered up to 6 h and more. This was evident by the X-ray photographs taken at 2 h & 6 h (Figure 64, 65).

5.6.11.2. In Vivo γ-scintigraphic Studies in Man Figure 66 and 67 portray the γ-Scintigraphic images corresponding to the test formulation (BOPT). BOPT was found to be retained for 6 h or more (Singh et al. 2012), significantly higher vis-à-vis conventional formulation, which got retained for only 30-60 m (Richardson et al. 1996). All the subjects ingesting test formulation (BOPT), showed gastroretention (Fig. 66 and 67) for around 360 m, for which imaging of all the volunteers was conducted. Use of γ-scintigraphy in evaluating the gastroretentive potential has already been successfully demonstrated by several scientists (Singh 2012, Richardson 1996, Ibekwe 2006). In a nutshell, the study is therefore, construe that the test formulation, BOPT posseses the desirable GR characteristics contributed by optimized blend of SA and LLP along with CT, through the ostensible interplay of floatational and [Department of Pharm. Sci., MDU, Rohtak]

Page 221


bioadhesional mechanism.

Figure 64: X- ray imaging of rabbit stomach without formulation

At 0 h

After 4 h

After 6 h Figure 65: X- ray imaging of rabbit stomach with formulation after 0h, 4h and 8h [Department of Pharm. Sci., MDU, Rohtak]

Page 222


(0 Min)

(75 Min)

(150 Min)

(240 Min)

(300 Min)

(360 Min)

Figure 66: Anterior static scintigraphic images of the stomach of healthy volunteer Mr. Lalit Singh stomach following oral administration of 99mTc-labelled beads at different time interval [Department of Pharm. Sci., MDU, Rohtak]

Page 223


(0 m)

(75 m)

(150 m)

(240 m)

(300 m)

(360 m)


99mTc-

labelled beads at different time interval


Page 224


5.5.12

Accelerated stability studies on optimized formulation

All the parameters viz., content, Tb, Tlag, Bsize and drug release remained quite well within the desirable limits, showing negligible and random variation over six months of storage under accelerated conditions. Dissolution parameter (viz. Q10), obtained during various time points of stability studies carried out at 40 ± 2 °C and 75 ± 5% RH, remained almost unaffected during the studies, suggesting the robustness of the optimized formulation with respect to dissolution characteristics (Figure 68, Table 72). Table 72: Stability study data

Accelerated

5.5.13

Similarity

Tb (h)

Bsize (mm)

Q10%

1 month

12.3

2.09

93.1

95

3 month

12.3

2.08

93.0

93

6 month

12.2

2.08

93.0

93

Conditions

factor (f2)

Comparison of Optimized Formulation with Marketed Product

Tablet 73 shows all the drug release data of marketed Glynase XL 10 mg extended release glipizide tablet and its comparison with optimized formulation. Table 73: Drug release profile of the BOPT and marketed brand of glipizide Formulation

Q10 (%)

Q14 (%)

n

Glynase XL

82.10

90.14

0.6161

BOPT

93.1

95.10

0.4598

As the results shows the release of optimized batch for a prolonged duration, the studies conclude successful development of gastroretentive CR formulation of glipizide capable of maintaining the drug release profiles for a prolonged duration as observed with the marketed CR products while eliminating the disadvantages of single unit and delivering the drug at its preferred site of absorption in the GI tract.


Page 225


100

% Drug release

75

50 Marketed BOPT 25

0 0

5

10 Time (h)

15

20

Figure 68: In-vitro drug release profiles of the optimized tablet and marketed formulations


Page 226


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Summary and Conclusions

6.1. SUMMARY AND CONCLUSIONS Oral intake has been the most sought after route of drug administration owing to the wide acceptability of this “natural” route, improved patient compliance, low cost of therapy and ease of administration. For highly soluble and permeable BCS class I drugs, oral drug therapy for improving chronic disorders invariably calls for the development of controlled release (CR) products. Conventional CR formulations, however, suffer from the limitation of limited stay in the stomach and the upper GI tract, the preferred site of absorption for most of the drugs. Gastroretentive (GR) formulations, in this regard, offer a viable solution by providing a sustained release of drug at the desired location. Amongst the various GR systems, the floating DDS (FDDS) with bioadhesion constitute one of the most popular approaches for prolonging gastric retention. With a bulk density less than that of gastric fluids, a FDDS remains buoyant in the stomach for a prolonged period of time without affecting the gastric emptying rate. Nevertheless, an FDDS is effective only when the fluid level in the stomach is sufficiently high. As the stomach empties and the tablet is at the pylorus, the buoyancy of the dosage form may be impeded. This serious limitation can largely be overcome by enabling the FDDS to adhere to the mucous lining of stomach wall. Floating and bioadhesive DDS, therefore, greatly improve the possibility of increasing the residence time of DDS in the stomach, resulting in more effective absorption and increased bioavailability of drugs. Glipizide is an anti-diabetic drug which maintains sugar level in type- II diabetes. Its short half-life (3.5 hrs.), low dose (5-20 mg), narrow absorption window, i.e., stomach and, high physicochemical stability, etc. make it an ideal drug for floating bioadhesive formulations. Matrix type delivery systems are popular because of their ease of manufacture. It excludes complex production procedure such as coating and pelletization, and drug release from the dosage form is controlled mainly by the type and proportion of the polymers used in the preparation, both single and multiparticulate system may be developed for this, while multi-particulate system further decreases the irritation by distributing the drug concentration in subdivided unit. FbD methodology with RSM efficiently surmounts the hiccup of balancing floatation and bioadhesion, employing variation in independent variables. It is well-documented to develop “the best possible” formulation under a given set of conditions circumventing unnecessary experimentation and thus, save, time, money and effort. [Department of Pharm. Sci., MDU, Rohtak]

Page 231


Thus objectives of the investigations were to develop and systematically optimize the effervescent floating-bioadhesive formulations of glipizide, single unit (tablet) and multiple units (beads), employing FbD approach. The various conclusions drawn for Tablets and beads are listed below 6.1.1. FLOATING-BIOADHESIVE TABLET FORMULATIONS Preliminary studies, carried out with several polymers viz. CP 934P, CP 971P, HPMC K4M, HPMC K15M, indicated that the combination of CP 934P and HPMC K4M along with effervescent producing agent showed excellent promise

for

drug

release

prolongation,

bioadhesion,

and

buoyant

characteristics, respectively. All

the

controlled

release

floating-bioadhesive

hydrophilic

matrix

formulations of glipizide, containing polymer blend of CP 934P and HPMC K4M, showed zero order drug release behaviour. Significant increase in T60% was observed with increase in either CP 934P or HPMC K4M the influence of CP 934P being more pronounced. A descending, almost linear trend was observed in QI6 with an increase either in CP 934P or HPMC K4M fraction. For all the formulations prepared using polymer blend of CP 934P and HPMC K4M, the values of Q16 ranged between 89.65-95.17%, indicating the plausibility of the major amount of the drug release before the device is finally eliminated from the G.I. tract. BS increases linearly with increase in content of either polymer, the contribution of CP 934P being much greater than HPMC K4M. Buoyancy time tends to show nearly linear increasing and decreasing trends with increase in the levels of HPMC K4M and CP 934P levels, respectively. Exhaustive feasibility and grid searches as well as overlay plot were used to locate the optimized formulation (TOPT= HPMC K4M=78.96 mg and CP 934P= 15.2 mg) which fulfilled maximum requisites because of better regulation of release rate, higher BS and more floatation time, it was also validated by six validation check points. The pharmacokinetic performance of the optimized formulations was promising vis-à-vis the marketed formulation. The formulations are likely to perform even better in the light of higher gastro-retentivity imparted by bioadhesive and buoyant characteristics of the polymers. An appropriate balancing between the levels of the two polymers (HPMC K4M and CP 934P) is imperative to acquire maximum extension in drug release, adequate bioadhesion and floatation time. The increased CP levels were instrumental in attaining maximal prolongation of drug release and


Page 232


bioadhesion, while the role of HPMC was stellar in governing the buoyant characteristics of the formulation. An appropriate use of optimization methodology helped to predict the best possible formulation, as percent error in prognosis was only between –1.12 and 0.86 %. The design chosen, i.e., CCD, mathematical model for generation of polynomial, i.e., MLRA, and method for locating the optimum, i.e., grid search, were successfully utilized for embarking upon the optimal formulation(s). Accelerated stability studies of the optimized formulation carried out for three months showed no significant loss in drug assay and controlled drug release characteristics. On comparison with a marketed brand, the overall drug release performance of the optimized formulation was found to be comparable. The in vivo studies, carried out in rabbits and healthy human volunteers, corroborated significant improvement in the gastric retention time of the optimized formulation to 6-7 hours without disintegration. Conclusively, the current study attained the successful design, development and optimization of once-a-day tablet formulation of glipizide. 6.1.2. FLOATING-BIOADHESIVE BEADS FORMULATION Preliminary studies, based on literature available on alginate beads carried out with several polymers viz. CT, CP 934P, HPMC K4M indicated that the combination of CT with calcium chloride in formulation of calcium alginate liquid paraffin beads showed excellent promise for drug release prolongation and, bio-adhesion, respectively in floating beads. Extensive literature search indicates that the optimization of the oral drug delivery devices has become a regular phenomenon round the globe. All the controlled release beads formulations of glipizide, containing blend of polymer SA and CT, and low density liquid paraffin, showed non-fickian drug release behaviour. A descending, almost linear trend was observed in Q10 with an increase in LLP fraction as well as alginate. For all the formulations prepared using polymer blend of SA, CT with calcium chloride, and LLP the values of Q10 ranged between 80-98%, indicating the plausibility of the major amount of the drug release before the device is finally eliminated from the GI tract. Evaluation of seven formulations, chosen as optimal from grid searches, indicated that the formulation BOPT (SA= 3.14g and LP= 12.9 ml) fulfilled maximum requisites because of better regulation of release rate, higher EE and better floating properties. [Department of Pharm. Sci., MDU, Rohtak]

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An appropriate balancing between the levels of the alginate and LLP is imperative to acquire maximum extension in drug release and adequate floating along with better EE. The increased alginate and LLP were instrumental in attaining prolongation of drug release and floating at the same time increase in alginate results in release prolongation and decrease floating. An appropriate use of optimization methodology helped to predict the best possible formulation, as percent error in prognosis was only between –2.22 and 0.93 %. The design chosen, i.e., CCD, mathematical model for generation of polynomial, i.e., MLRA, and method for locating the optimum, i.e., grid search, were successfully utilized for embarking upon the optimal formulation(s). In vivo performance of the optimized formulations may further improve in the light of higher gastroretentivity imparted by floating characteristics of the LLP. in vivo studies confirm the retention of the dosage form in the stomach, and drug release characteristics are found to be similar with marketed brand. Stability at accelerated stability studies further strengthen the acceptance of formulation. Conclusively, the current study attained the successful design, development and optimization of once-a-day multi-particulate formulation of glipizide.

6.2 FUTURE POTENTIAL The techniques used in the present work for preparation of tablets and beads may be easily transferred in to high scale manufacturing facility. Both technology considerations, i.e. risk involved and high scale manufacturing facilities availability as well as commercial consideration, i.e. potential commercial application and abundant availability of potential market for the products are satisfied by drug and dosage form. Hence, the studies can be safely regarded as a platform technology in the manufacture of floating bioadhesive CR formulations.


Page 234