Natural And Synthetic Drug Polymers

Natural And Synthetic Drug Polymers 978-3-330-97430-2 NOOR PUBLISHING

Firyal Mohammed Ali Alsalami Sanaa Hatour List of Contents No.

Page 4 6 8 9

4

Subject Preface Abbreviations -Introduction -Polymers in the pharmaceutical applications -Polymers with the pharmacological effects and polymeric blood substitutes - Bioactive Polymers

5 6

-Natural polymers - Natural biodegradable polymers

15 16

7 8

-Classification of natural Polymers 16 -The modification of natural 18 polymers -Starch 19

1 2 3

9

1

9

12

10

21

11 13 14 15 16 16 a

-Starch in the pharmaceutical industry -Co-polymerized starch(S1) -Gelatin - Casein -Albumin -Synthetic Polymers -Poly Acrylic Acid

17 `19

-Melamine -Pharmaceutical polymers:-

55 61

20 21

-Super absorbance polymers:-Mechanisms of Swelling in Super Absorbent Polymers - Nanoparticles Biomaterial -Advantages of polymeric Nanoparticles

63 65

24

-Macromolecular prodrugs

71

25 26

72 72

27 28 29

- Controlled drug release -Requirements for selecting polymers as -Chitosan -Pullulan -Controlled drug release

30

-Bioavailability

81

22 23

2

22 27 41 44 46 50

68 71

73 76 79

31 32 33

-Factors that influence 81 bioavailability - Biodegradable polymers 82 - Nadic Anhydride 84

34 35 36 37 38 39 40 41 42 43 44

-Maleic Anhydride (MAN -Polyimides -Poly(Amic Acids - EDTA in Medicine Field -Polyvinylpyrrolidinone(PVP) -Antibiotics -Penicillins Types of Penicillins -Ampicillin -. Amoxillin -Salbutamol

84 88 88 93 95 99 101 101 103 105 170

45 46

-Mefenamic acid -Procaine

107 108

47 48 49 50

- 4-AminoAntipyrine - Captopril - Eugenol . -Thermal Properties of drug polymers - Swelling percentage -Drug release -Diffusion-Controlled Systems

109 110 111 114

51 52 53

3

115 142 159

54 55

-Synthetic polymers -Medical Applications of Syntheti

161 162

56

-Synthetic polymers in dentistry

163

57

-Preparation(MMA)

165

References

107878

preface Some drugs suffer from different problems such as low poor solubility and stability, short circulation time, and non-specific toxicity limiting their therapeutic efficacy. Biopharmaceuticals such as nucleic acids, peptides, and proteins are often limited by poor stability and rapid clearance from the body. the materials and methods of drug delivery are not widely available to those outside the polymer synthesis field. The objective of effective drug delivery is improving the pharmacokinetics and therapeutic to enable drug delivery to the right place . Drug polymers techniques such as encapsulation, compression, spray and immerse coating, have been used in the pharmaceutical industry as bioactive agents with polymers These confronts, coupled with the complexity and diversity of new 4

pharmaceuticals, novel drug delivery systems that overcome bioavailability and delivery obstacles .Both synthetic and natural polymers are available but the use of natural polymers. For pharmaceutical applications have attractive because they are non-toxic. They are capable of chemical modifications, economical, readily available and potentially biodegradable and biocompatible .In field of drug discovery led to target-specific site, the growing importance of polymer drug delivery methodologies.

5

Abbreviations DMF, Dimethyl formamide; DMSO, Dimethylsulfoxide; TMS, Tetramethyl silane; FTIR, Fourier Transform Infra red; M.P. ,Melting points; µ,Ionic strength; λmax,Wave length at which maximum absorbance occur; PVP,Polyvinylpyrrolidinon;; PCL ,polycaprolactone diol ; PLGA ,DL-lactide/glycolide copolymer ; PLA, poly(lactic acid) ; PEG, poly(ethylene glycol) ; PD ,prodrug; D, drug; NIAMDD ,National Institute of Arthritic. Metabolic and Digestive Diseases; SEVA-C, starch/ethylene-co-vinyl alcohol copolymer blend;; LCST,lower critical solution temperature; AAP ,aminoantipyrine; PEI ,polyetherimide ; AC, acryloyl chloride ; PAC, poly (acryloyl chloride); PAMP-L, poly (N-acryloyl-N-methyl piperazine; NCAs, N-carboxyanhydrides; UV, Ultra 6

Violet; THF, Tetrahydrofurane; NMA, Nadic methyl anhydride; rel ,relative viscosity; sp ,specific viscosity; red ,reduced viscosity; in , intrinsic viscosity; FT-IR, Fourier Transform Infrared ; 1H-NMR Proton Nuclear Magnetic Resonance; TGA, thermogravtimetric analysis; DT ,Decomposition temperature; DSC, differential scanning calorimetric; PAAm, polyacrylamide; Temp., Temperature; EO, Ethylene oxide; 6-APA,6aminpenicillanic acid;; FDA, food and drug administration; APS Ammonium per sulphat ;MA,Maleicanhydride. ,

7

1-Introduction Biopolymers, synthetic polymers and their derivatives are commonly used in medicine and pharmacy. Recently, particular interest of scientists has been focused on biomedical polymers, the main objective of this work is to discuss various polymers recommended for the pharmaceutical applications and then to describe natural compounds used and the synthesis of biodegradable and bioresorbable polyesters and their substituted ,especially those used for drug delivery systems, therapeutic systems and macromolecular prodrugs. The applications have opened new exciting prospects for medicine, because specially designed polymers are capable of delivering medicinal substances to the target diseased tissues and cells together with dosing those drugs according to controlled specified pharmacodynamics. Particular attention has recently been paid to chemistry of biocompatiable and biodegradable polymers, because they have an advantage of being readily hydrolyzed into removable and non-toxic products, which can be subsequently eliminated by metabolic pathways. Also the biomedical polymers have to be synthesized now 8

using friendly for the environment and safe for human health. 2. Polymers in the pharmaceutical applications Macromolecules are applied in pharmacy as the pharmacological substances, blood substitutes, drug delivery and therapeutic systems, in the synthesis of macromolecular prodrugs and in the technology of prolonged release drug formulations.. in Biotechnology. 3- Polymers with the pharmacological effects and polymeric blood substitutes One of the most interesting polymers used in pharmacy, are those exerting a pharmacological effect. DIVEMA, copolymer of divinyl ether-maleic anhydride is an example of such compound with antitumoral and antiviral properties. Its action probably includes the stimulation of the glycoprotein production, which suppresses viral RNA translocation in cells and division of cancer cells. Furthermore, the polymers are often applied as swelling, relaxation and sliding agents. Methylcellulose taken orally is not absorbed from the alimentary tract. However, it detains water on swelling

9

and in consequence causes relaxation of the stercorous mass. A copolymer of ethylene and propylene glycols has found an application in the therapy of constipations This non-ionic, surfaceactive polymer is unable to penetrate through the gut walls because of large average molecular weight. However, it causes relaxation and hydration of the stercorous mass by the reduction of the surface tension. A linear polymer of uronic acids - alginic acid (mannuronic acid conjugated 1,4 and Lguluronoic acid glycosidically conjugated -1,4) is mainly obtained from the Laminaria algae. This polymer neutralizes hydrochloric acid. Its action relies on detaining of water in stomach followed by reduction of irritations and pain. A polyvinylpyrrolidone has found an application as anti-diarrhoeal drug Its amphoteric properties normalize pH in stomach and intestines through acids or bases adsorption, which are usually raised as result of fermentation or putrefaction.

10

The synthetic hormones with the protein structure play an important role in the modern pharmacology synthetic analogues of Gonadoliberin (the hormone of hypothalamus). These oligopeptides are obtained by exchanging of some amino acids in Gonadoliberin molecule and then are used to treat prostate and breast cancers or endometriosis. Another example is synthetic analogue of Somatoliberin used for treating children with some forms of GH deficiency. The synthetic analogue of Somatostatin -Octreotide is applied to treat the alimentary tract Corticotrophins are examples of synthetic hormones of the anteriorpituitary, often applied in the therapy of rheumatoid diseases and severe asthma. Thus, Oxitocin, the group of hormones of posterior lobe of the hypophysis First of them causes uterine contractions, second can contract the smooth muscles of the blood vessels while Ornipressin is often added to the anaesthetics. Moreover causes the vessels contraction. The peptide antibiotics are the relatively numerous group of the natural oligomers. They are composed of peptide-bounded amino acids to form cyclic, linear or cyclic-linear structures.They may act the 11

Gram-negative (Polymyxin) and Gram-positive (Gramicidin, Prostinamycin) bacteria as well as fungi and protozoa. 4- Bioactive Polymers Initiators and Catalysts in the Synthesis of Biodegradable and Bioresorbable Polyesters and Polycarbonates. A cyclosporine A – branched and cyclic oligopeptide composed of 11 amino acids is an important macromolecular immunosuppressive drug Cyclosporine A selectively inhibits lymphocytes T function, thus is widely used as an immune barrier tolerance agent in the transplantology. Macromolecular inhibitors that absorb the cholesterol from the intestines are also known; form them insoluble in water polymers, which produce complexes with the bile acids. To this polymer group belongs: copolymer of divinylbenzene and styrene substituted with quaternary trimethylammonium group and copolymer of diethyltriamine and epichlorohydrin. A heparin, obtained from the animal tissues (mainly livers and lungs) 12

example of the natural polysaccharide used as the therapeutic agent. The heparin effects on the all blood clotting phases. Usually is used to treat arterial embolism and thrombosis, heart failure and before surgical operations. A very important group of the biomedical polymers is macromolecular blood substitutes. They are accountable for the regular osmotic pressure and viscosity, closed to the osmotic pressure and blood viscosity; usually used in the anaphylactic shock, heart failure, intoxication, burns, toxic diarrhoea, embolicthrombotic complications as well as microcirculation impairment. A polyvinylpyrrolidone was the first synthetic polymer used as the blood substitutes. Its solutions were mainly used to treat the shock after the burns and, in the case when the blood transfusion was not indicated Likewise, the solutions of polyvinyl alcohol have found the applications as the blood substitutes. However, they were withdrawn from the list of the blood substitutes as result of their undesirable side effects.

13

The blood susbstitutes with the therapeutic action has also been elaborated as result of incorporation of some therapeutic agents (e.g. penicillin, pelentanic acid, paminosalicylic chloride) into polyvinyl alcohol Currently, the solutions of polysaccharides (e.g. dextran), modified starch derivatives and modified gelatin products (polygeline, oksopolygelin, liquid gelatin) are commonly used as the blood substititues The dextran with the average molecular weight ranged from 40 000 to 70 000 Da is used as 6 or 10% solution. This polysaccharide is produced by fermentation of the sucrose solutions in the presence of the Leuconostoc mesenteroides bacteria. Obtained glucose is polymerized to dextran in the presence of enzymes. A hydroksyethyl starch is obtained by hydrolysis of high-amylopectine starch in acidic environment The reaction products are neutralized followed by the reaction with ethylene oxide. The starch substituted with hydroxyethyl group is then produced in this reaction. A polygeline is obtained from the reaction of diisocyanate with the gelatin. As result, linked urea 14

groups are produced, whereas liquid gelatin is produced in the reaction with succinic Anhydride. 5-Natural polymers:- Today, the whole world is increasingly interested in natural drugs Natural materials have advantages over synthetic materials because they are nontoxic, less expensive and freely available. Furthermore, they can be modified to tailor made materials for drug delivery systems allowing them to compete with the synthetic products that are commercially available . Polymers play a vital role in the drug delivery. So, the selection of polymer plays an important role in drug manufacturing. But, while selecting polymers care has to be taken regarding its toxicity, drug Compatibility and degradation pattern. By this review, we can say that natural polymers can be good substitute for the synthetic polymers and many of the side effects of the synthetic polymers can be overcome by using natural polymers Natural polymers can be good substitute for the synthetic polymers and many of the side effects of 15

the synthetic polymers can be overcome by using natural polymers. 6- Natural biodegradable polymers Natural biodegradable polymers have received much more attention in the last decades due to their applications in the fields related to environmental protection and the maintenance of physical health. To improve the properties of them, a number of methods have been developed, such as random and block copolymerization or grafting. These improve both the biodegradation rate and the mechanical properties of the final products. To provide added value to biodegradable polymers . 7-Classification of natural Polymers:a-Plant origin Glucomannan,

-

Cellulose,

Hemicellulose,

Agar, Starch, Pectin, Inulin, Rosin, Guar gum, Locust bean 16

Gum, Gum Acacia, Karaya gum, Gum Tragacanth, Aloe Vera gel. b- Animal origin - Chitin, Alginates, Carageenans, Psyllium, Xanthum gum. The specific application of plant-derived polymers in pharmaceutical formulations include their use in the manufacture of solid monolithic matrix systems, implants, films, beads, micro-particles, nanoparticles, inhalable and injectable systems as well as viscous liquid formulations . Within these dosage forms, polymeric materials have fulfilled different roles such as binders, matrix formers or drug release modifiers, film coating formers, thickeners or viscosity enhancers, stabilizers, disintegrates, solubilizes, emulsifiers, suspending agents, gelling agents and Bio-adhesives /

17

8-The modification of natural polymers The modification of natural polymers is a promising method for the preparation of new materials. An efficient approach to modify natural polymers in order to synthesis natural-based superabsorbent polymers.Grafted copolymerization of unsaturated monomer on to natural polymers to add new properties and more attention tissue engineering and tissues adhere.Natural polymers are modified as a means to overcome their setbacks such as drop in viscosity, microbial degradation, and partial or low solubility. In addition, modification of natural polymers enhances their drug delivery properties and versatility. Modification should be undertaken such that the natural polymers do not lose their biological properties. Methods of modification include grafting, crosslinking, derivative formation and polymer-polymer blending. 18

Chemical modification of natural polymers by grafting serves the twofold purpose of utilizing renewable, naturally derived products, such as polysaccharides and proteins, as replacements for petroleum-based polymers and as biodegradable compositions which can be tailored for the slower or faster rates of degradation, 9-Starch Starch is a natural, cheap, available, renewable, and biodegradable polymer produced by many plants as a source of stored energy. The most readily available natural polymer besides cellulose is starch. It is a polysaccharide which consists of repeating Dglucopyranose units, linked together by -1, 4 and -1, 6 glycosidic bonds

Starch is an extremely abundant edible polysaccharide present in a wide variety of tubers and 19

cereal grains. In most of its manifestations, it is composed of two macromolecules bearing the same structural units, 1,4- D -glucopyranose, in linear and highly branched architectures, present in different proportions according to the species that produces it .

Figure (1) The two macromolecular components of starch: (a) amylose and (b) amylopectin. The employment of starch or its derivatives for the productionof adhesives, or as wet-end additives in papermaking, constitute traditional applications to 20

which a variety of novel materials, including plasticized starch, blends and composites, have been recently added. this biopolymer finds application in other industries including medicine and Pharmacy. From serving as food for man, starch has been found to be effective in drying up skin lesions (dermatitis), especially where there are watery exudates. Consequently, starch is a major component of dusting powders, pastes and ointments meant to provide protective and healing effect on skins. Starch mucilage has also performed well as emollient and major base in enemas. Because of its ability to form complex with iodine, starch has been used in treating iodine poisoning. Acute diarrhea has also been effectively prevented or treated with starch based solutions due to the excellent ability of starch to take up water. In Pharmacy, starch appears indispensable; It is used as excipients in several medicines. Its traditional role as a disintegrant or diluent is giving way to the more modern role as drug carrier; the therapeutic effect of the starch-adsorbed or starch-encapsulated or starch-conjugated drug largely depends on the type of starch . 21

10-Starch in the pharmaceutical industry During recent years, starch has been taken as a new potential biomaterial for pharmaceutical applications because of the unique physicochemical and functional characteristics , 1.as pharmaceutical excipient, 2. as tablet disintegrant, 3. as controlled/sustained release polymer for drugs and hormones, 4. as plasma volume expander, 6. in artificial red cells 5 Starch in bone tissue engineering, 2.Starch in nanotechnology(microparticles, microcapsules, nanoparticles). 11-Co-polymerized starch(S1) Graft copolymerization of monomers onto natural polymers was reported by various researchers for the synthesis of polymeric materials . Starch grafting usually entails etherification, acetylation, or esterification of the starch with vinyl monomers to introduce a reaction site for further formation of a copolymeric chain. Such a chain would typically consist of either identical or different vinyl

22

monomers (block polymers), or it may be grafted onto another polymer altogether. Graft copolymers find application in the design of various stimuli-responsive controlled release systems such as transdermal films, buccal tablets, matrix tablets, microsphers/hydrogel bead system and nano particulate system .. Starch can be plasticized to some degree, by blending it with i.e. glycerine or with other synthetic polymers. This approach is applied already, e.g. for packaging materials. However, such mixtures still have shortcomings like poor strength associated with the poor mixing of the hydrophilic starch and the (often) hydrophobic synthetic polymer. These disadvantages can be overcome when the co-feed is chemically attached to starch by covalent bonds, like in grafted copolymers. polysaccharide polymers specifically starch has poor hydrophilicity, and it cannot form stable hydrogel alone, thus an effective method has been suggested to form stable hydrogels made by blending natural and synthetic polymers to meet the advantages of each other. Limited studies on synthetic polymer/starch 23

blend hydrogels have been reported previously in literatures Alfrey and Bandel were the first to synthesize graft copolymer in 1951. In the recent years, the grafting of acryl amide , methacrylamide, acrylonitrile, acrylic acid on the starch was studied in the presence of initiators. The synthesized starch-g-poly (vinyl alcohol) copolymer was used for food packing, biomedical fields, coating and adhesives, drag reduction, textile industry and preparing biodegradable hydrogels . The starch based superabsorbent polymers were developed by grafting with vinyl monomer which are used for the removal of metal ions and dyes from water system . Various researchers have studied the synthesis, characterization and control drug delivery of the polymer hydrogels. Grafted methacrylic acid onto gelatinized potato starch The grafted sample was utilized for the removal of organic dye and metal ions from water system. The grafted starch sample removes metal ions by adsorption on COO groups of methacrylic and also by sorption in the bulk of grafted hydrogel. Therefore, the structure of a polymeric hydrogel affects the level of 24

polymer interaction with water and the provision of active sites to absorb or coordinate metal ions.

Figure(2) (a) SEM of pure starch and (b) starch-gpoly(MAA) The application of hydrogels based on starch-graftacrylic acid has been reviewed specifically . The capacity of the product to absorb water, the controlled release of the absorbed water along with the water-soluble substances e.g. drugs or fertilizers as well as their rubbery consistency, these properties generate many potential applications. Among others these include personal care products, water control during 25

the construction of buildings, food preservative, medical applications and agricultural applications.

Figure (3) The grafting reaction of acrylic acid with starch. Table(1). Application potentials of natural polymerbased copolymers.

26

13-Gelatin (gelatine) is a translucent, colorless, brittle (when dry), flavorless solid substance, derived from the collagen inside animals skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar way are called gelatinous. Gelatin is an irreversibly hydrolysed form of collagen, and is classified as a foodstuff. Gelatine is now classed as a food in its own right and not now subject to the food additives legislation in Europe. Gelatin has its 27

own E number: 441. It is found in some gummy candies as well as other products such as marshmallows, gelatin dessert, and some low-fat yogurt. Household gelatin comes in the form of sheets, granules, or powder. Instant types can be added to the food as they are; others need to be soaked in water beforehand.

Scheme (1) Gelatin graft Acrylic Acid

28

Gelatin-g- acryloyl chloride reacts with amine to form an amide, as explained below :-

Scheme(2) Gelatin graf Acryl Amide The hydrophilic monomers which grafted on surface of polymers are biodegradable and sensitive to stimuli. (pH and temperature) . The important design criterion is to achieve maximum therapeutic efficacy of encapsulated drugs with minimum toxicity .These 29

parameters effected on consideration polymers for controlled drug delivery:

grafted

(1)Chemical and physical properties of the drugs and the polymer (2) Interactions between the drugs and the polymers (3) Biological environment and delivery sites of the drugs (4) Routes of delivery, such as oral, ocular, intravenous, intranasal, intravascular, intra peritoneal, intramuscular, and subcutaneous administration. The main advantages of biodegradable polymers are the products of degradation are not toxic or completely eliminated from the body by natural metabolic pathways, with minimal side effects.. Natural polymer gels are useful for pharmaceutical fields such as controlled delivery devices because of their nontoxic nature, low cost, ready availability, biocompatibility, and biodegradability. Drug delivery systems based on natural hydro gels have been extensively explored to achieve higher concentrations of drugs in a specific region or tissue and a controlled release profile for extended time periods . 30

Gelatin is a high molecular weight polypeptide obtained by controlled hydrolysis of collagen derived from the skin, white connective tissues, and bones of animals.

Figure(3) Chemical structure of Gelatin The most interesting feature of gelatin is that it can be used for the production of practical biocompatible materials .Gelatin hydro gels can be used as biodegradable materials in the pharmaceutical and medical field

31

Equation (1) Gelatin grafted Methyl Metha Acrylate Hydrogel It consists of 19 amino acids. It is water soluble. Gelatin has good film forming abilities. The mechanical and barrier properties of these films depend on the physical and chemical characteristics of the Gelatin.

Figure(4) Amino acid composition of 32

The mechanical and barrier properties of these films depend on the physical and chemical characteristics of the gelatin, especially the amino acid composition and the molecular weight distribution. Combining gelatin with other biopolymers as soy protein, oils and fatty acids or certain . Polysaccharides may improve the physical properties of gelatin films.

Scheme (3) Gelatin graft Metha Acrylate The RGD domains are illustrated as red segments along the Gel MA chains, gelatin grafted methacrylate hydrogels more resemble some properties of native extracellular matrix (ECM) due to the presence of cell 33

attaching and matrix metalloproteinase responsive peptide motifs, which allow cells to proliferate and spread in Gel MA-based scaffolds. Composition of the graft copolymer depends on the temperature used in the process. Cross linked gelatin biomaterials have found application in many ocular tissues: as a bioadhesive to secure and stabilize retinal tissue as a cellsheet carrier for corneal endothelial cells, and as cellularised scaffolds for repair and regeneration of the corneal stoma .

34

Scheme(4)Cross-linked of gelatin Two types of Gelatin products could be used in biosurgery: Gel film, an absorbable film marketed for use in thoracic, ophthalmic and neuron- surgery and Gel foam, a compressed Gelatin sponge, marketed as a haemostatic device. Gelatin-based biomaterials for regenerative medicine applications in ophthalmology are reported herein.

Figure(5) Gelatin –based material repair the ocular Components 14-Chitosan :-

35

Figure(6) Chemical structure of Chitosan Chitosan is a de acetylated derivative of Chitin, biopolymer second in abundance to cellulose; it is biodegradable, nontoxic, and biocompatible . Chitosan has been subjected to chemical modifications to produce advanced functional materials . In dentistry it is used because it prevents the formation of plaque and tooth decay. Since Chitosan can regenerate the connective tissue that covers the teeth near the gums, it offers possibilities for treating periodontal diseases such as gingivitis and periodontitis . It has prospective applications in many fields such as biomedicine, waste water treatment, functional membranes and flocculation. Chitosan bears two types of reactive groups that can be grafted. First, the free amino groups on deacetylated units and secondly, the hydroxyl groups on the C3 and C6 carbons on acetylated or deacetylated units. Grafting of Chitosan allows the formation of functional derivatives by covalent binding of a molecule, the graft onto the Chitosan backbone.. Grafting Chitosan is a common way to improve Chitosan properties such as increasing chelating. 36

Equation (2)Chitosan grafted Meth Acrylic Acid on Hydroxy Propyl Chitosan The reaction of Chitosan in aqueous Acetic Acid solution with aniline in the presence of APS enables the introduction of polyaniline side chains at the amino groups. Chitosan-grafted-polyaniline was fabricated into films and fibers, but the properties varied according to the ratio of the amino groups to aniline in the grafting reaction .

37

Equation (3) Chitosan grafted Poly Aniline

Ethylene di amine tetra Acetic acid (EDTA) grafted onto Chitosan increases the antibacterial activity of Chitosan by complexing magnesium that under normal circumstances stabilizes the outer membrane of gramnegative bacteria .

Figure(7) Chitosan grafted EDTA

38

Chitosan- poly(hydroxyethyl methacrylate) copolymer was study demonstrated the feasibility of using chitosan in electrochemical biosensor fabrication.

Scheme(5)Chitosan graft Phenol and Tyrosin by using Enzymtic There are two types of Chitosan with reactive groups such as free amino groups and hydroxyl groups that can be grafted . Two major types of grafting may be considered: 1. Grafting with single monomer. 39

2. Grafting with two monomers. For example grafting of Chitosan through hydroxyl group.

Equation (4) Chitosan graft phenol and Tyrosin by using enzymtic Or Grafting through the amino group of Chitosan

40

Scheme (6) Chitosan Glycol Metacrylat

-g- Methacrylate-g-Ethylene

14- Casein:Casein is the major of milk protein ,It is inexpensive ,readily available ,non-toxic and high stable .many structural and physicochemical properties of casein facilitate their functionality in drug delivery system .Caseins are the predominant components in milk and they are a family of phosphorylated proteins. Casein is a drug carrier mainly for the sustained delivery of cytotoxic drugs. Casein appears to be a 41

promising carrier for the sustained release of many orally as well as parenteral administered drugs . Casein has great potential for producing protein-based edible films . Edible Casein films can form a good barrier to oxygen and other non polar molecules, because casein provides lots of polar functional groups, such as hydroxyl and amino groups, to the film matrix . This property allows casein films to be used in combination with other packaging materials to protect products prone to oxidation. casein/glycerol films possess good tensile strength and moderate elasticity under normal conditions , but the presence of glycerol affects the barrier properties of casein films . Procaine was first synthesize shortly after Amylocaine, and is the oldest man-made local anesthetic still in clinical use Procaine is a local anesthetic drug .

42

Scheme (7) Structures of Casein-Dextran Curd-like Casein powder is easily molded but it can be hardened by adding formaldehyde in a condensation polymerization. The resulting polymer is rigid and does not melt after heating. This can be used to remove silver when silver solution is passed through the polymer .

43

Equation (5) Reaction of Casein with Formaldehyde 15-Albumin:-

Figure(8) Chemical structure of Albumin Albumin is the most abundant protein in plasma, accounting for more than half of human plasma protein. Albumin has been widely studied as a protein carrier for drug delivery. Albumin is a robust protein. It is stable over a wide pH range (4-9), could be heated at 44

60°C for up to 10 h without deleterious effect, is unaltered by denaturing agents and solvents at moderate concentrations . Albumin –drug conjugated used for treating cancer, to overcome the lack of specificity with regard to the inflamed tissue as well as increasing the half life. Albumin microcapsules were developed for delivering anti-inflammatory drugs. Albumin nanoparticles have been extensively researched for cancer treatment. Aspirin loaded Albumin nanoparticles were prepared by co acervation method. The particle size ranged from (47-191) nm with an aspirin/albumin ratio of 0.06-1.0 . Aspirin released from the nanoparticle at a sustained rate for prolonged duration with 50% total cumulative release at the end of 20 hours. .

.

45

Equation(6) Thiol-ene reaction, with radical (AIBN) addition of O-9-tert-Butylcarbamoyl Qunine 16-Synthetic Polymers :Synthetic polymers are resistant to biological attack because of hard structure, low moisture absorption, soft surface, and lack of susceptibility to enzymatic systems. Synthetic degradable polymer, with good biocompatible properties, poly-L-lactic (PLLA) is widely used in tissue engineering. PLLA has excellent mechanical character; it is used in the fixation of fractured bones in orthopedic and oral surgeries in the form of plates.

46

Equation (7)Chemical structure of poly(lactic-co-glycolic acid) (PLA) is both bio-based and biocompatible, and several favorable properties such as high strength and stiffness at room temperature, PLA is hydrophobic polyester whereas natural materials, such as celluloses, starch, protein, lignin and inorganic fillers, are generally hydrophilic . Blends of PLA with natural additives usually exhibit coarse morphology and poor mechanical performances, due to the lack of affinity .The affinity improved by using a compatibilizer or by the functionalization of PLA chains such as grafting . Maleic anhydride (MA), amide glycidyl methacrylate ,N-vinyl pyrrolidone , PEG and chitosan were grafted onto PLA. MA is popular among 47

these grafting pendants due to its difficulty in homo polymerization and the benefit of cell attachment and proliferation .

Equation (8) Grafting reactions of MA onto PLA chains in the presence of Dicumyl peroxide Poly(vinyl alcohol) is almost completely resistant to fungi and bacteria in dry state. Aqueous solutions are susceptible to microbial degradation .

48

Figure(9) Chemical structure of PVA Polymers have been used as a main tool to control the drug release rate from the formulations. Extensive applications of polymers in drug delivery have been realized because polymers offer unique properties which so far have not been attained by any other materials. Advances in polymer science have led to the development of several novel drug-delivery systems. These newer technological developments include drug modification by chemical means, carrier based drug delivery and drug entrapment in polymeric matrices or within pumps that are placed in desired bodily compartments [58]. Biodegradable polymers have been widely used in biomedical applications because of their known biocompatibility and biodegradability. In general 49

Natural polymers offer fewer advantages than synthetic polymers. 16-a-Poly Acrylic Acid:Poly Acrylic Ascid can be prepared through various techniques such as radical, cationic and anionic polymerization. The functionalization of bioactive molecules can be carried out due to presence of carboxylic groups in poly acrylic acid. Poly (acrylic acid) (PAA) is a water-soluble Polyelectrolyte (PE) .It is important not only in industrial applications, e.g. flocculants or super absorbers, Because of its relatively simple chemical repeat unit, Poly Acrylic Acid (PAA) in the form of hydrogel has been extensively studied for controlled drug delivery applications. Some of the cross linkers that have been used for the formulation of PAA hydrogel are N,N′-Methylene-bis-acrylamide ,4,4′divinylazobenzene, ethylene glycol di Methacrylat and Sucrose. Photo cross linked ,electron beam cross linked of PAA hydrogels have been fabricated , glycerol cross linked PAA hydrogel . Glycerol cross linked PAA is expected to generate the PAA network to encapsulate drugs without compromising the hydrophilicity of the polymer. 50

Equation (9) Synthesis of Glycerol-crosslinked Poly Acrylic Acid There has been a growing interest in PAA as a basis for obtaining various physiologically active polymeric substances capable of separating from the carrier molecule at definite site of the living organism and producing a targeted physiological action. Both PAA and the related compounds are more widely used as polymeric carriers for proteins, enzymes, drugs and other biologic ally active substances .The general reaction of poly Acrylic Acid as reaction bellow :-

51

Equation acid

(10) Chemical modification of polyacrylic

poly Acrylic acid reaction with ethanol amine was prepared as shown below.

52

Equation (11)Poly Acrylic Acid with Ethanol Amin This polymer was a substitution of different drugs [67].

Scheme(8) Substitution of Poly Acrylic Acid with different Drug NH2 Other drug polymers were prepared in by the reaction of poly Acryloyl chloride with different drugs containing amine. Acid chloride reacts with hydroxyl to form an

53

ester, as explained below:-

Equation (12) Reaction of Poly Acrylic Acid with Propionic Acid

These grafted polymer then substitution with amino drug such as reaction bellow:-

54

Equation (13) Substitution of Poly Acrylic Acid –gPropionic Acid with Amino Drug These biological activity of these drug polymer was found very biological activity. toward different bacteria . 17-Melamine:-

55

Figure(10) Chemical structure of melamine Melamine can be produced from three different starting materials: urea, dicyandiamide or hydrogen cyanide. Commercially produced melamine is manufactured using urea as a starting material. .There are differences in the literature regarding the manufacture of melamine from dicyandiamide]. Melamine can be metabolized by at least two strains of bacteria (Pseudomonas strain A and Klebsiellaterragena) into carbon dioxide and ammonia via the pathway shown bellow:-

56

Scheme(9) Metabolism of Melamine CH2

CH NH3Cl

NH (CH 2)3 N

N

CON H

N

NH 3Cl

Figure(11) Melamine condensation with PVP

Other reaction of Melamin with Acrylamide bellow :57

explain

CH 2

CH CO N H

HH C CO CH 3

H N

N

H 2N

N N

NH 2

Figure(12)Melamine grafted Acryl Amide 18-Side Chain for Drug Delivery Systems:Block copolymers have been studied use of polymeric materials for structural purposes, such as in drug delivery systems . Biocompatible coatings and as matrices for reconstitution of biomolecules, there has been little attention paid to self-assembling polymeric membranes that incorporate functionality as an integral part of the membrane during recent years . Synthetic polymers are internalized by cells by pinocytosisand they can be tailor-made to include peptide side-chains degradable intra cellular by specific lysosomal enzymes. Thus they provide the opportunity of achieve controlled intracellular delivery of anticancer agents .Natural macromolecules such human serum albumin and tumor-specific antibodies have all been evaluated as carriers of anti tumor agents. 58

Figure (13) Structure of HPMA Co Polymer –drug Conjugate Amphiphlic copolymers had an important role in material science due to their self-assembly properties in selective solvents and their potential application in life sciences, for example in drug delivery . Biocompatible amphiphilic poly(ethyleneoxide) (PEO) and poly(propylene oxide) (PPO) block structures are in focus for biomedical applications doxorubicin was conjugated to a water-soluble synthetic polymer, N-(2hydroxypropyl) methacrylamide (HMPA) methacylic acid copolymers through a tetrapeptide linker (Gly-PheLeu-Gly) . The tetrapeptide linker allowed selective release of the active drug in the tumors through the action of Lysosomal enzymes.

59

Figure(14)Drugs in nano conjugates

Figure(15) Synthesis of nano conjugates

60

Figure(16) Structures of acid sensitive linkers `19-Pharmaceutical polymers:Several polymeric drug delivery systems such as nanoparticles, micelles, hydrogels, or matrices are being studied worldwide .Polymers are extensively used for the delivery of an active pharmaceutical ingredient. They can form a matrix or membrane that can control release of a drug over prolonged period, thus avoiding repetitive dosing. They can also be used to form (nano) carriers to deliver drugs, in particular poorly soluble drugs or biotechnology-based drugs .Both systems can protect the drug from degradation. Encapsulated drug 61

may be selectively released inside or near a specific tissue or organ. Polymeric delivery systems can modify the pharmacokinetics of a drug, leading to a higher therapeutic index by decreasing the side effects and/or increasing efficacy. These systems are composed of a biocompatible polymer, degradable or not, and of an active pharmaceutical ingredient dispersed or covalently bound to the polymer. The release of the drug usually occurs by diffusion through the polymer, by degradation of the polymer, or by disorganization of the supramolecular structure of the efficacy of many drugs is often limited by their potential to reach the site of therapeutic action. In most cases only a small amount of administered dose reaches the target site, while the majority of the drug distributes through out the rest of the body in accordance with its physicochemical and biological properties. Therefore developing a drug delivery system that optimizes[8384] the pharmaceutical action of drug while reducing its toxic side effects invivo is a challenging risk. Polymers used to form nano particles can be both synthetic and natural polymers. Most of the polymers prepared from water insoluble polymers are involved heat, organic solvent or high shear force that can be harmful to the 62

drug stability. These kinds of polymer constructs called polymer therapeutics.

Figure(17)polymer therapeutics They can be released from a drug core through a porous or nonporous membrane.While drug release through a nonporous membrane is essentially driven by diffusion, porous membrane generates an extra path for the drug release, status of drug release from membrane systems can generally be modified via membrane thickness. Membrane systems have found applications in drug stability, enteric release, taste masking, and sustained release. 20-Super absorbance polymers:The hydrogel can be defined as a crosslinked polymeric network which has the capacity to hold 2 63

water within its porous structure [89].The water holding capacity of the hydrogels arise mainly due to the presence of hydrophilic groups, viz. amino, carboxyl, and hydroxyl groups, in the polymer chains such as sodium Poly Aacrylic Acid:-

Figure (18) Structure of Sodium poly Acrylic Acid as Super Absorbent Polymer Higher the number of the hydrophilic groups, higher is the water holding capacity while with an increase in the cross linking density there is a decrease in the equilibrium swelling due to the decrease in the hydrophilic groups. As the cross linking density increases, there is a subsequent increase in the hydrophobicity and a corresponding decrease in the stretch ability of the polymer network[90-91]. Hydro 64

gels can be classified into two groups depending on the nature of the cross linking reaction. If the cross linking reaction involves formation of covalent bonds, then the hydro gels are termed as permanent hydro gel [92]. The examples of permanent hydrogels include PMMA and PHEMA. superabsorbent polymer can absorb water up to several thousand times of its own weight and keep this water under pressure. The absorbed water can be released slowly when the SAP is put in dry air to maintain the moisture of the environment. Most SAPs are in principle cross linked hydrophilic polymers . Hydrogels are biocompatible and nonirritant in nature [93]. The biocompatibility of the hydrogels is generally associated with the hydrophilic nature of the same, which helps in washing off the toxic and un-reacted chemicals during synthesis. 21-Mechanisms of Swelling in Super Absorbent Polymers :Several mechanisms to the process of swelling all of which contribute to the final swelling capacity or centrifuge retention capacity CRC – which is the amount of 0.9 wt% saline solution that a SAP can retain under free swelling conditions when surface water has been removed in a centrifuge)[94]. Polymer 65

backbone in SAP is hydrophilic i.e. ‘water loving’ because it contains water loving carboxylic acid groups (–COOH). When water is added to SAP there is a polymer/solvent interaction; hydration and the formation of hydrogen bonds are two of these interactions.

.

Figure (19) swelling in superabsorbent polymers

Hydration is the interaction of ions of a solute with -

+

molecules of a solvent i.e. COO and Na ions attract the polar water molecules:

66

Figure(20) Hydration of super absorbent polymer Hydrogen Bonds Hydrogen bonds are electrostatic interactions between molecules, occurring in molecules that have hydrogen atoms attached to small electronegative atoms such as N, F and O. The hydrogen atoms are attracted to the non-bonding electron pairs (lone pairs) on other neighboring electronegative atoms.

Figure(21) Cross-linking in Super Absorbent Polymers:67

There are two main types of cross-linking in mostsuperabsorbent polymers. 1- Bulk or core cross-linking – Which normally takes place during the polymerization stage of superabsorbent production. 2- Surface cross-linking – Which is a newer process that improves the absorption against pressure profile of the polymer.

Figure22)Core cross-linking in superabsorbent polymer 22- Nanoparticles Biomaterial:There has been a great interest in application of nanoparticles as biomaterials for delivery of 68

therapeutic molecules such as drugs and genes and for tissue engineering[98]. Biopolymers are suitable materials as nanoparticles for clinical application due to their versatile traits, including biocompatibility, biodegradability and low immunogenicity such as protein (silk, collagen, gelatin, β-casein, zein and albumin), protein-mimicked polypeptides and polysaccharides (chitosan, alginate, pullulan, starch and heparin) . It is important to control particle size, charge, morphology of surface and release rate of loaded molecules to use biopolymer-based nanoparticles as drug/gene delivery carriers. To obtain a nano-carrier for therapeutic[100]. Polymeric nanoparticles can be fabricated in a wide range of sizes and varieties and can sustain localized drug therapeutic agentfor weeks. Number of polymeric drug/geneloaded nanoparticles have been developed as drug delivery carriers and their mechanism of circulation in human bodies has been extensively investigated].When drugs- or genes-loaded nanoparticles are injected into bodies, they cross epithelial barriers and circulate in the blood vessels before reaching the target site. 23- a- Advantages of polymeric Nanoparticles:69

1-Increases the stability of any volatile pharmaceutical agents, easily and cheaply fabricated inlarge quantities by a multitude of methods. 2- They offer a significant improvement over traditional oral and intravenous methods of administration in terms of efficiency and effectiveness. 3- Delivers a higher concentration of pharmaceutical agent to a desired location. 4- The choice of polymer and the ability to modify drug release from polymeric nanoparticles have made them ideal candidates for cancer therapy, delivery of vaccines, contraceptives and delivery of targeted antibiotics 5- Polymeric nano particles can be easily incorporated into other activities related to drug delivery, such as tissue engineering 24-Macromolecular prodrugs:Prodrug is a Macromolecular prodrugs which are mainly used in the cancer therapy. For example, 5fluorouracil can be applied locally or orally in the therapy of the alimentary tract, urinary bladder, and 70

prostate gland cancers[104]. Which is metabolized into active precursor inhuman body. Conjugations of this therapeutic agent as a pendant group to polyethylene glycol or to vinyl polymer chain as substituent form examples of its macromolecular prodrugs.

Figure(23) Structure of macromolecular prodrugs

25-Advantages of Polymeric Prodrugs: The duration of action of the drug is determined by its plasma concentration which is usually measured as area under curve . The duration of action can be prolonged by linking a drug to a polymer in order to obtain a conjugate. This 71

conjugation results in a slower renal excretion, longer blood circulation and an endocytotic cell uptake]. 26- Controlled drug release: The therapeutic effect is achieved only when the macromolecular drug from the polymeric prodrug is released intracellularly in the lysosomes or tumor tissue which are slightly acidic in comparison to the healthy tissues . PH :-This relatively low pH has been exploited to design pH sensitive spacers such as N-cis-aconityl spacer used to form polymeric prodrug of daunorubicin-linked Amino Ethyl Poly AcrylAmide beads and poly(d-lysine) and Hydrazon linkage used to form cytotoxic adriamycin immunoconjugates which showed highest in vitro and in vivo anti-tumor activity. Enzymes for drug release: When the polymeric prodrug is up taken intra cellularly, it enters the Lysosomes which are present in normal as well as tumor tissues . 26-Requirements for selecting polymers as

candidate drug carriers 72

1- Availability of suitable functional groups -COOH, -OH, -SH or -NH2 for covalent coupling with drugs; 2- Biocompatibility: immunogenic;

preferably

nontoxic,

non

3- Biodegradability or a molecular weight below the renal excretion limit; 4- Availability: reproducibly manufactured conveniently administered to patients;

and

5- Water solubility: hydrophilic to ensure water solubility; 6- Low polydispersity, to ensure an acceptable homogeneity of the final conjugates Natural polymers as prodrug polymer:

Figure(24) Dextran 27-Chitosan:73

Figure(25) Proteins: Includes serum albumin which has been used extensively for preparing polymeric prodrugs with anti-viral drugs . 28-Pullulan:-

Figure(26)

74

Figure(27)Antibody Spacer Drug Conjugated Albert was the first one to suggest the concept of prodrug approach for increasing the efficiency of drug. He described prodrugs as pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness or to decrease associated toxicity .Thus prodrug can be defined as a drug derivative that undergoes biotransformation enzymatically or non enzymatically, inside the body before exhibiting its therapeutic effect. The prodrug is converted to the original drug as soon as the derivative reaches the site of action, followed by the rapid elimination of the released derivatizing group without causing side effects in the process.

enzyme

+

Pro Drug (released at the site of action)

Drug + Pro = PD (synthesis in the lab.)

75

Equation (32)Chemical transformation of inactive prodrug (PD)to active drug(D) at the site of action Ushakov and Panarin 1968 studied derivatives of Penicillin bound to copolymer of vinyl alcohol and vinyl amine (2%) units that shows an activity which is 30-40 times longer lasting than that of the free penicillin. .

CH2

CH2

CH

CH

m

. n

OH

NH

O

C

C

O N H3C

CH NH

H3C

COR

S

Fig(28) Penicillin co Polymer PVA There is a series of further examples of the in vitro activity of polymeric antibacterial, since such preparations are also applied as protection of polymeric materials against bacterial attack or as pesticides . 29-Controlled drug release:Development of novel technologies in the area of drug discovery such as genetic engineering, 76

combinatorial chemistry, and high-throughput screening leads to numbers of drug or a short biological half-life . The emerging of these complex active ingredients has drawn considerable attention on development of novel techniques to deliver them in an effective and efficient way. Parenteral controlled release of drugs represents one of such approach. After one administration, these systems can maintain the drug in the desired therapeutic range for days, weeks, months, and for some products, even years [116]. Compared to conventional oral dosage forms they offer several advantages including: Increase of bioavailability: Parenteral drug administration overcomes the absorption barrier and enzymatic barrier imposed by gastrointestinal tract. Long release period: The drugs are released over extended period and hence improve the patient’s compliance and reduce the need for follow-up care. Constant drug plasma concentration: The drug levels are maintained within a desired range and total dose can be reduced.

77

Localized delivery of drug: The product can be administrated directly at the site where drug action is needed and hence systemic exposure of the drug can be reduced.

Figure(29)Plasma drug concentration versus time profile of a drug when administered orally as compared to a parenteral controlled release drug delivery system The drug release can be diffusion, swelling, and/or erosion controlled, nature and they are also safer since a mechanical defect of the reservoir device rather than matrix device may cause dose dumping. if polymer matrix is non-degradable, the constant release profile is difficult to be achieved with matrix system. 30-Bioavailability:78

Bioavailability is the fraction of administered drug that reaches the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent when the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug. Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for injection. 31-Factors that influence bioavailability:1. First-pass hepatic metabolism: When a drug is absorbed across the body, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. 2. Solubility of the drug:

79

Hydrophilic drugs are poorly absorbed because of their difficulty to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. drug to be readily absorbed, it must be largely hydrophobic .Therefore they have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipidsoluble. 3. Chemical instability: Drugs, such as penicillin G, are unstable in the pH of the gastric contents. such as insulin, are destroyed by degradative enzymes. 4. Nature of the drug formulation: Drug absorption depend of many factors unrelated to the chemistry of the drug. Such as particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 80

32- Biodegradable polymers:Biodegradable polymers commonly contain chemical linkages such as anhydride, ester, or amide bonds .These polymers degrade in vivo either enzymatically or non-enzymatically to biocompatible and non-toxic byproducts. Its can be metabolized or excreted via normal physiological pathways Biodegradable polymer not only have been extensively used in controlled delivery systems, but also extended to medical devices. biodegradable polymers have many advantages including thermoplasticity, high mechanical strength, controlled degradation rate.Biodegradable polymers are formed in nature or synthetic. The investigation of natural biodegradable polymer as drug carrier has been concentrated on proteins and polysaccharides . Natural biodegradable polymers are attractive because they are natural products of living organisms, readily available, relatively inexpensive, and capable of multitude of chemical modifications. Table(2) Nature biodegradable polymers

81

Synthetic biodegradable polymers have gained more popularity than natural biodegradable polymers. Many advantages of synthetic polymers are the high purity of the product, more predictable, and they are free of concerns of immunogenicity. Most of biodegradable polymers are synthesized. these polymers contain linkages in backbone for example esters, , anhydrides, carbonates, amides, urethanes. These polymers are listed in table (2). Table (2) some Synthetic Polymer

82

33- Nadic Anhydride:Nadic Anhydride is an important chemical raw materials of electronic information, synthetic resins and plastics, pesticide and pharmacy, and so on; and can be prepared with low material costs. O O +

O O O O

Equation (14) Synthesis of Nadic anhydride Resins synthesized have better air-drying property, higher thermal resistance, better surface finish, and improved electricity property, erosion resistance and mechanical intensity than resins synthesized by hexa hydro phthalic anhydride and tetrahydrophthalic anhydride. The hexahydro-3,6-Methanophthalic anhydride is a product after hydrogenation of Nadic Anhydride. Comparing with Nadic anhydride, 83

hexahydra-3,6-methanophthalic anhydride has a more stabilized chemical structure and physical/chemical property and lower viscosity, and the product thereof has a lighter solid color and is more weather resistant. Its Preparation of N- Cephalexin Methyl Nadic Acid as a monomers. O H3C

O

+R

O C NH R NH2

H3C

+

HC C OH 3 O (major product)

O

O C OH C NH R O (minor product)

R NH2 = Cephalexine , Ampicillin ,Amoxillin ,4 - Aminoantipyrine , Procaine

Equation (15)Substitution of Methyl Nadic Anhydride with Amino drugs 34-Maleic Anhydride (MAN):Maleic anhydride is a versatile chemical intermediate used to make unsaturated polyester resins, lube oil additives, alkyd resins, and a variety of other products. In 1995,global production of Maleic Anhydride was estimated at 1.8 billion pounds Maleic anhydride (MAN) is an excellent monomer which can provide reactive anhydride or carboxylic groups with nucleophilic 84

molecules.

2C6H6+ 9 O2

. V2O5

2C4H2O3+ H2O +4CO2

MeO3

Maleic anhydrid

Equation (16) Preparation of Maleic Anhydride The anhydride groups, in the polymer chain, make the MAN polymer very reactive, and therefore, it is commonly used in various fields[133].One can modify the polymer via addition of low molecular weight compounds such as water, alcohols, or amines because of the high reactivity of the anhydride group.

85

Scheme(9)Mechanism of grafting of maleic anhydride MA grafted PE is importance for application as a copolymer precursor in polymer blends. The graft of MA onto linear PE poly(PE-g-MA) initiated by dicumyl peroxide. Major MA monomers were attracted onto PE chains as branched graft at higher MA content.

86

Scheme(10)Maleic Anhydride grafted PolyPropylene Blends of anhydride functional polymers and starch could lead to products with useful end properties.

Equation (17(Maleic anhydride grafted polyethylene and cellulose Maleic Anhydride reaction compounds .

87

with

hydroxyl antibiotic

O O O

C

+

R OH C OH O

O

Equation (18) Reaction Hydroxy drug

of Maleic Anhydride with

H

-

O

O C

+ R OH

C O

O +

O

C O

R

O

R

C C O

O

O +

O C

H O R

C

-

C

O

O

OH

O

Scheme (11) Mechanism Ring opening of Maleic Anhydride by drug- OH. 35-Polyimides:Polyimides are thermally stable polymers that are often based on stiff aromatic backbones. The chemistry of polyimides is a large variety of monomers available 88

R

and several methodologies available for synthesis. There has been considerable debate on the various reaction mechanisms involved in different synthesis methods. polyimide synthesis including two step:-

Scheme(12) Preparation of Polyimide

36-Poly(Amic Acids):Poly(amic acid) formation due to the nucleophilic attack of the amino group on the carbonyl carbon of the anhydride groupm a reversible reaction leading to opening of the anhydride ring to form an amic acid group the forward rate constant for the reaction is several orders of magnitude larger than the reverse 89

reaction and thus the reaction often irreversible if pure reagents are utilized.

appears

Equation (19)General reaction mechanism of aromatic imid formation It is also important to note that the poly(amic acid) formation is exothermic and the equilibrium is favored at lower temperatures. The above-discussed factors have lead to some widely practiced methods during the synthesis, namely 1) Higher concentrations of the monomers are favored in the poly(amic acid) synthesis. 2) The amine is added first and the dianhydride second (the dianhydride that isadded second reacts faster with the diamine than with the existing water).

90

3) Sometimes a slight excess of di anhydride is found to be useful in attaining higher molecular weights . at room temperature is also reported. O NH2

+

O NH C

O

O C

OH

O

Equation (20) Prepared N-(P-dimethyl amino phenyl) Maleamic acid by reaction of equimolar amount of the anhydride and amine. Bis maleamic acids were prepared by the reaction of two moles of Maleic Anhydride and one mole of different diamine. The mechanism of the reaction involves nuclophilic attack on the carbonyl followed by ring opening. The mechanism is illustrated in scheme bellow:-

91

O

O

O

+

H2N

+

O

2

-

H2N

R

NH2

O

-

+

H2N

R

O

O

O

O

O

O

O

O NH

C

NH

R

+

C C

C

O

C

HO

OH

H2N

R

C O

-

-

C

C

O

O

H2N

+

O

O

Scheme(13)Mechanism for the preparation of N,Nsubstituted Bis maleamic acid O

O

C

C

O

.

NH

-

C O

+

H2N

R

O

+

H2N

C

NH2

C

C

C

O

O

O

O

R

+

O NH

R

O

NH

NH C

R

C

HO

O

O

C

C

H2N

O

NH

NH

.

O

C

NH

R

n

O

.

.

O

+

R H2N

-

+

H2N O

C

C

O

O

-

R

NH

. n

. n

OH C

C

O

O

Scheme(14)Mechanism for the preparation of Poly Amic Acid 92

37- EDTA in Medicine Field :Amino carboxylic acid molecules, such as ethylene diamine tetra acetic acid (EDTA), is used in medicine and analytical chemistry . Many polymers bearing such groups have been stable complexes with heavy metal ions . Many polymers reaction with linear structures bearing amino acetic acid groups along the polymer chain by ring-opening poly addition reaction of EDTA di anhydride (A-EDTA) . Many studies were reported the preparation, characterization copper (II) complexing capacity of polyesters, derived from some polyethylene glycols with A-EDTA published the synthesis of a water soluble sugar copolymer, with pendant carboxyl groups that were biodegradable and metal complexion .

93

Scheme(15) Poly addition reactions of AEDTA with PEG1000 and HMDA Different diamin reaction with EDTA and CDTA were studied .

Scheme(16 ) General mechanism of EDTA or CDTA with diamines Chitosan-EDTA conjugates examined of cross-linked Chitosan-EDTA polymer could produce stabilized particles with efficient release of the payload in the cytoplasm to result in improved transfect ion.

94

Figure(360) Chemical structures of Chitosan-EDTA Conjugate 38-Polyvinylpyrrolidinone(PVP):Poly(N-vinyl-2-pyrrolidinone) is a white or slightly yellow hygroscope powder, forming hard clear films. Physical properties are determined on films or powder. The polymer strongly interacts through dipole-dipol attraction; the melt viscosity of the polymer is therefore too high for typical thermoplastic-forming operation . Polyvinylpyrrolidinone consists of hydrophobic methylene groups and a strongly hydrophilic imide group. PVP is chemically inert the dry polymer can be stored under normal conditions without decomposition, degradation, or structural change. Heat sensitivity is low, and it is stable at 1300C . 95

However, at 1500C in air, solubility is reduced and color increased. They prepared copolymers of Nmethacryloyl-4-amino benzene sulfonamide with Nvinyl pyrrolidinone as shown in Figure(31 ) CH3 .

CH2

CH

CH2 n

N C

O

C

.

m

C O NH

SO 2NH 2

Figure(31)Copolymers of N-Methacryloyl-4-amino Benzene Sulfonamide with PVP The therapeutic importance of such preparations is based on the selective intentional therapeutics, which above all finds increasing application in the veterinary medicine, since it can be taken for granted that in this case no active substances are able to enter into the body, and thus, into the tissue and flesh. Ring opening of polyvinylpyrrolidinone with amino and hydroxy antibiotic compounds as shown bellow .

96

.

CH2 CH N

.

+R

n

NH2

Dioxane:DMF

Drug

.

.

CH2 CH

Reflux

n

NH (CH2)3 C O

C O

NH R

(PVP) R NH2 = Cephalexine , Ampicillin , Amoxillin , 4 - Aminoantipyrine , Procaine

Equation (21) Ring opening of PVP with amino drugs The mechanism of the reaction involves a nucleophilic attack on the carbonyl as shown below . .

CH2

CH

.

+R

NH2

Dioxane:DMF

N C

CH2

.

Reflux

n

.

CH n

N

O

O

C +

HN

H .

CH2

CH NH (CH2 )3

. n C O

NH

R

Scheme(17) Mechanism of ring opening of PVP with amino drug

97

-

R

.

CH2

CH N

+R

.

OH

Dioxane:DMF

CH2

.

CH

Reflux

n

HN

C O

. n

O

(CH2 )3 C

O

R

OH = Paracetamol or Eugenol

R

OH

OH

O CH3 Paracetamol =

Eugenol = NH

C

CH3 H2C

O

Scheme(18) Mechanism Ring opening drugs

of

Hydroxy

N-substituted heterocyclic or amino acid polymers were prepared from modification of PVP with different amines [149] as shown below:.

CH N

CH2 O

. m

+

HCl dil. H2O

.

CH2 CH NH

. m

(CH2)3 COOH

Equation (22)Ring opening of PVP

98

.

.

CH2 CH

+

RNH 2

Dioxane, DMF

.

reflux, heat

NH m (CH2)3

.

CH2 CH NH m (CH2)3

COOH

CONHR

CH3

.

. . N R=

H3C

Equation amines

O

N N

, CH3 CH3 CH3

CH3 , CH3

N N

N N

(23) N-Substitution

. ,

.

, N

PVP with different

PVP has been widely used in the biomedical fields, the cosmetic and food industrial sectors which are closely . N-Vinyl Pyrrollidone was graft copolymerized onto various natural-based polymers such as sodium carboxymethyl cellulose ,guar gum chitosan ,carrageenan and starch ,Gelatin, one of the most versatile, naturally occurring biopolymers, is widely used in food products and pharmaceutical dosage forms. 39-Antibiotics:-

99

CH3

Antibiotics were natural drugs produced by several fungi or bacteria .Bacterial resistance to antibiotics increasingly hinders treatment of life-threatening illnesses. Misuse and overuse of antibiotics play a critical role in development of resistance and there is evidence that agricultural use of antibiotics is a contributor to the aggregation of resistance in the environment. Bacterial enzymes that are affected by beta-lactams are called penicilin-binding proteins (PBPs). There are various PBPs differing in their detail function, quantity, and affinity for beta-lactams. Betalactams is mostly expressed against multiplying bacteria that are building their cell wall intensively. On the other hand, beta-lactams could not be effective against microbes without the peptodoglycan-containing cell wall (chlamydiae, mycoplasmata, rickettsiae, mycobacteria). Majority of beta-lactams are excreted through the kidneys but exceptions do exist (oxacillin, cefoperazone, ceftriaxone). The half-life of betalactams is rather short and varies from a half an hour(penicillin, oxacillin, cephalotin) to 2-2,5 hours. Antibiotics can be categorized based on their mechanisms for killing or slowing down the growth of bacteria. Six major classes have been indentified and 100

include:. β-lactam, macrolide, quinolones, tetracyclines, aminoglycosides, and glycopeptides. Common uses of antibiotics include the treatment of pneumonia, meningitis, urinary tract infections, bronchitis, intestinal infections, skin infections, and tuberculosis . β-lactam ring and include penicillins and cephalosporins, which together account for the majority of antibiotic use. susceptible to β-Lactam, its half-life at pH 6.5 and 25 0C is 39 days . 40-Penicillins

Figure(32)Structure of Penicillin

41-The Penicillins groups It can be divided in four subgroups: 101

41a-Natural penicillins:They have narrow spectrum containing gram-positive and –negative cocci (streptococci, pneumococci, enterococci, meningococci), gram-positive bands (corynebacteria, L.monocytogenes), spirochetes (Leptospira., Treponema., Borrelia.), and most of anaerobes (peptostreptococci, clostridial species, Actinomyces) ,penicillin or benzyl penicillin (unstable in gastric acid juice, suitable only for intravenous administration) penicillin or phenoxy metyl penicillin (acid-stable form, for oral administration) procainpenicillin . 41b-Anti-staphylococcal penicillins:They are resistant to staphylococcal beta-lactamase but not to other beta-lactamas produced by gram-negative microbes. The drugs have a very narrow spectrum because the effect against gram-positive bacteria other than staphylococci is weaker comparing to penicillin G. 41c-Amino penicillins[. The drugs owe spectrum similar to natural penicillin with extension against common gram-negative bacteria like Escherichia coli, Salmonella enteric. They are more 102

effective than natural penicillin against enterococci and listeriae. 41d- Penicillins:- effective against pseudomonads (and other problematic gram-negative pathogens owing natural resistance) .These drugs are given in intensive care infections, according to the cultivation results. There are important points to get intracellular accumulation of β-Lactam:The esterification of carboxylate function The presence of a protonable amino group in the antibiotic O

O R

C

S

NH C

1

CH3

R C

S NH

CH3

N

O

C O

COOH

1

R =

NH2

CH . (Ampicillin) NH2

CH3 COOH

Cephalosporin

Pencillin NH2 R=

N

CH .

,

(Amoxillin)

HO

CH . (Cephalexin)

Figure(33) Type of Pincilline 42-Ampicillin:103

O H2N

CH C

S

NH C O

N

CH3 CH3

COOH

Figure(34) Structure of Ampicilline Ampicillin is a semi synthetic antibiotic, a member of the pencillin family of antibiotics, it is synthesized for the first time in 1961 , to extent the usefulness of the pencillin to the treatment of infection caused by gramnegative . It is very hydrophilic and does not easily diffuse across the gastrointestinal epithelium, following oral administration and is absorbed from the intestinal tract to produce peak blood level concentrations in about 2 hours . The possession of acyl amino side chain prevents hydrolysis of the β-Lactam ring which kills the bacteria. Two successive steps are usually involved in the interaction of a cationic amphiphilic drug with bi layers, namely]:An electrostatic interaction between the positively charged amino group of the drug and the negatively charged phosphor groups in the phospholipids. 104

A hydrophobic interaction of the lipophilic moieties of the drug with the hydrocarbon chains of the fatty acids. 43-. Amoxillin:-

O H 2N

CH

C

S

NH C

N

CH3 CH3

O

COOH OH

Figure(35) Structure of Amoxillin Amoxicillin, an acid stable, semi‐synthetic drug belongs to a class of antibiotics called the Penicillins (‐lactam antibiotics). effective against a wide range of infections caused by wide range of Gram ‐positive and Gram‐ negative bacteria in both human and Animals. It is a congener of Ampicillin (a semi‐synthetic Aminopenicillin)differing from the parent drug only by hydroxylation of the phenyl side chain. It has found a niche in the treatment of Ampicillin‐responsive infections after oral administration[165]. amoxicillin maintained the broad‐spectrum activity of Ampicillin, 105

but with increased bioavailability. In 1998 under the trade names of amoxicillin, amoxil, and trimox. Amoxicillin is a broad spectrum antibacterial agent, but it exert a short half life values . Amoxicillin has been reported to be successfully used in various infections. Its used to treat the upper and lower tract infections, skin, soft tissue and GI tract infections. Amoxicillin is one of the most important commercial antibiotics due to its high bacterial resistance and large spectrum against a wide variety of microorganisms. 44-Salbutamol:Salbutamol is one of the -agonist bronchodilators, the largest group among the various classes of inhaled asthma drugs. The recent evolution of -agonists can be traced back to adrenal extracts that were used to treat asthma. Asthma is a chronic respiratory disease characterized by inflammation and narrowing of airways in the lungs,scheme (19) explain synthesis of Salbutamol.

106

Scheme(19) Synthesis of Salbutamol 45-Mefenamic acid:-

Figure(36) Structure of Mefenamic

Mefenamic acid belongs to the family of drugs called fenamates, which are aspirin-like drugs that are derivatives of N-phenylanthranilic acid. In tests of anti107

inflammatory activity, mefenamic acid is about half as potent as phenyl butazone.[168] Mefenamic acid has antipyretic and analgesic properties and displays a central as well as a peripheral action. Mefenamic acid is a non-steriodal anti-inflammatory drug used to treat pain, including menstrpain . The side effects of the mefenamic acid include headache, nervousness, vomiting, diarrhea, blood urine, skin rash and swelling.

46-Procaine:O N O

Figure(37) Procaine is a local anesthetic drug of the amino ester group. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it was also used in dentistry. Owing to the ubiquity of the trade name Novocain, in some regions procaine is referred to generically as Novocain. It acts mainly by being a sodium channel blocker .Procaine was first synthesized in 1905, In procaine, the lipophilic portion 108

is a phenyl radical, the hydrophilic portion is an amine, the intermediate chain is an ester, and there are two N atoms and two atoms. lipophilic portion consists at least of one phenyl radical, the hydrophilic portion is a secondary or tertiary amine, and/or the intermediate chain has an ester linkage. This improves the quality of the classification for those anaesthetics similar to procaine. Procaine, an ester anesthetic, is metabolized in the plasma by the enzyme pseudocholinesterase through hydrolysis into para-amino benzoic acid (PABA), which is then excreted by the kidneys into the urine]. 47- 4-AminoAntipyrine:-

Figure(39)Structures of 4-AminoAntipyrine Antipyrine and its derivatives possess interesting pharmacological properties . But, comparatively little is known about complexes of antipyrine derivatives with 109

3d-metal ions ,especially their thermal studies .In view of this, and as part of our continuing interest on thermal aspects of antipyrine derivatives, we present a report regarding the thermal studies of a new series of cobalt(II) complexes of a Schiff base antipyrine ligand containing a variety of counter ions such as nitrate, chloride, bromide and iodide[174]4-aminoantipyrine is a biologically active compound and its analogues and other pyrazole derivatives have shown antiinflammatory, analgesic, antiviral, and antipyretic Properties .It was reported that compounds possessing pyrazole nuclei showed significant anthelmintic as well as antimicrobial activities .Recently, 4-methylantipyrine was found to correlate with the analgesic effect of dipyrone .A study demonstrated for the first time that dipyrone and some 4-Aminoantipyrine derivatives have a high potential to attenuate or prevent the antiplatelet effects of aspirin . 48- Captopril:-

110

Figure(40)Structures of Captopril Captopril is used therapeutically as an antihypertensive agent. Captopril is widely used for the arterial hypertension. It acts as a potent and specific inhibitor of angiotensin converting enzyme. It is used in the management of hypertension, in heart failure, following myocardial infarction and in diabetic nephropathy. Captopril is freely water-soluble and has an elimination half-life of 1.7 h after an oral dose. It is usually prescribed to patients who are chronically ill and require long-term use for therapeutic benefit. Development of a once daily captopril oral formulation would be a significant advantage for patient compliance accompanied by minimization of the drug side effects as a result of reduction in the drug blood concentration fluctuations, especially in long-term therapy .Captopril is stable at pH 1.2, and as the pH increase, the drug becomes unstable and undergoes a degradation reaction. 49- Eugenol:-

111

CH3 O HO

H2C

Figure(41)Structures of Eugenol Clove oil is an essential oil from the dried flower buds, leaves and stems of the tree Syzygium aromatic or Eugenia caryophyllata and Eugenia aromatic [179]. There are only small differences between these species and many consider them to be essentially the same. When applied to growing plants in sufficient quantities, clove oil rapidly desiccates green tissue by removing the waxy cuticle of the plant and disrupting the cell membrane. This results in electrolyte leakage from plant cells, causing tissue death. Clove oil is not trans located in treated plants and provides no residual weed control . It is only effective as a post-emergent herbicide and provides burn down of both annual and perennial broadleaf and grass weeds. It is also used as an insecticide and as a scent attractant in traps for Japanese beetles, wasps, and other insects. Clove oil is a naturally occurring food flavor and is extensively used 112

in fragrance and flavor formulations for its spicy aroma .Clove oil and it’s primary ingredient eugenol have been in widespread use as flavoring and fragrance agents in the United States since before 1900. The soap and detergent industry is a major user of both materials, and eugenol is typically used in such products at concentrations in the range of 0.05–0.1% (v/v)..

Figure(42)Primary Chemical components of Clove Oil.

Indomethacin is a non-steroidal anti-inflammatory drug discovered in 1963. 113

Indomethacin is a non-selective inhibitor of cyclooxygenase enzymes that participate in biosynthesis of prostaglandins. Prostaglandins are hormone-like molecules which have a wide variety of effects, some of which lead to pain, fever, and inflammation. Since indomethacinis an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues Indomethacin has been shown to be an effective antiinflammatory agent, appropriate for long-term use in rheumatoid arthritis,ankylosing spondylitis, and osteoarthritis Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease [185]. scheme bellow explain the synthesis of Indomethacine :-[186-187].

114

Scheme (20

)Synthesis of Indomethocin

50- Cephalexin:-

O S H 2N

CH C NH C

N

O

Figure(43)Structure of Cephalexin 115

CH 3 COOH

Cephalexin is the most widely used cephalosporin antibiotic with an annual use of 3,000 tons and annual sales revenue of $850,000,000 [188-189]. Respiratory tract infections, skin infections, bone infections, urinary tract infections, and otitis media are aliments that are commonly treated with Cephalexin. Industrial production of Cephalexin can be completed by either chemical or enzymatic synthesis . The present review deals with the techniques employed for the modification of developments in designing novel drug delivery systems. Natural poly peptide and polysaccharides and their derivatives represent a group of polymers widely used in the pharmaceutical and biomedical fields for the controlled release of drugs could prepared new natural and synthetic drug polymers, Modification of natural poly peptides such as Gelatine,Casiene Albumine or polysaccharide such as chitosane gave new with improved and developed various properties . The advantages of controlled drug delivery systems are mainly the achievement of an optimum concentration, usually for prolonged times, the enhancement of the activity of labile drugs, due to their protection against hostile environments, and the diminishing of side 116

effects due to the reduction of high initial blood concentrations1. The Natural polymers do hold advantages over the synthetic polymers, generally because they are nontoxic, less expensive, biodegradable, and freely available, compared to their synthetic counterparts. Natural polymers can also be modified to have tailor-made materials for drug delivery systems. drug delivery formulations and the polymers used in these systems have become much more useful, with the ability to do more than simply extend the effective release period for particular drug. For example, intelligent or smart polymers play important role in drug delivery graft copolymerization and substitution which designed primarily for different medical applications. to add new properties to a natural polymers can be interesting starting materials for the synthesis of graft copolymers. Most of the copolymers are prepared through graft polymerization of vinyl monomers onto the biopolymers onto the polysaccharides are mainly achieved by radical polymerization. Graft copolymers are prepared by first generating free radicals on the biopolymers backbone and are employed to graft different drugs and spacers also the synthetic drug polymers such as Substitution of 117

(Melamin –AEDTA condensed polymer with amino drug , and ring opening of PVP by ethylene diamin,ethanol amin ,with amino drugs. were designed as new derivatives .using different methods for another industrial applications. Graft co-polymerization of anhydride with different natural polymer for example of the natural polymer we using in this research take gelatin :Graft-co-polymerization of maleic anhydride with gelatin. Maleic anhydride (MA)was grafted onto gelatin backbones in a homogeneous medium using APS as a radical initiator. A general reaction mechanism for poly gelatin-g-maleic anhydride is shown in Scheme 1. At the first step, the thermally dissociating initiator, i.e. APS, is decomposed under heating to produce sulfate anion-radical Then, the anion-radical abstracts hydrogen from one of the functional groups in side chains (i.e. COOH, NH2) of the substrate to form corresponding radical these macroradicals initiated monomers grafting onto gelatin backbones led to a graft copolymer. Five new drug polymers were 118

prepared by the reaction anhydride in reaction below:O

.

O H N

C

O +

O

(SO4)-.

C

of gelatin with maleic

H N

another Maleic anhydrid chain

o

c

70C0 O R n Maleic anhydride Gelatine backbon Macroradicals R:Diffrent Amino acids n

R

O O

gelatin backbone

O

gelatine-g-maleic anhydride + drug-NH2 0 1hrt 70C reflexe DMF anoither maleic anhydrid

O C

H N

gelatin back bon

COOH

CO-NH-drug

gelatin N-drug maliamic acid

Scheme ( 21 ) reaction of gelatin with maleic anhydride and NH2-drug presence of –NH2 group in the antibiotic, which is a strong nucleophile, which attack the C=Ogroup in the cyclic of maleic anhydride . The mechanism of the reaction this reaction was described as a nucleophilic attack of NH2 group on C=O 119

group, which explained as in scheme (3.2)[146,165] RNH2:- Amoxillin,Ampicillin,Mefenamic acid ,or R-OH Salbutamol

H

-

O

O C

+

HN

C O

+ R NH2

O R

C C

C

O

O

+

O

C

H HN R

C C

-

O

OH

O

O

O

NH R

Scheme ( 22 ) ring opening reaction of acid anhydride by nucleophilic reaction[]. The reaction of cyclic anhydrides with hydroxyl groups present in drugs using , Solvents such as dioxane, dimethyl formamide, at room temperature , the mechanism of the reaction involves nucleophilic attack on the carbonyl followed by ring opening is, as in scheme below:

H

-

O

O C

+

O

C O

C O

+ R OH

O

H

O +

R

C

O C

C

O

O

120

O R

C

-

C

O

O

O

OH

R

Scheme ( 23 ) ring opening reaction of acid anhydride by hydroxyl group of salbutamol drug . Graft co-polymerization Methyl Nadic Anhydride with Grafted copolymerization of un saturated monomer on gelatin back bone carries out could added new properties and more attention production with high stiffness material, gelatin- g-methyl anhydride was modified with amino drug which acted as ring opening of nadic anhydride as illustrated in scheme (24 ).

121

Scheme (24 ) reaction of methyl nadic anhydride with amino drug

O

O

+

HN

C H3C

H

-

O R

C O

C O

+ R NH2

O H3C

C O

122

H3C

O

H +

C

HN R -

C O H3C O

C NH C OH O

R

Scheme (25) ring opening reaction of acid anhydride by nucleophilic reaction. Preparation of graft co-polymerization Acrylate with Albumin backbones:-(SA39)

Glycidyl

This part including grafting natural polymer with Glycidyl Acrylate and ring opening of epoxy with amino drug and hydroxyl drug . In this part the modification of natural polymer with glycidyl acrylat was carried out through grafted copolymerization using potassium per sulfate as an initiator produced functional polymer as epoxy ring which could acted as ring opening through amino group and its nucleophilic attack as illustrated in the following sheme(3.6). drug copolymer was prepared as delivery of drug at a sustained rate ,target delivery of drug at specific sites to minimize toxicity and enhanced selectivity with desirable properties

123

O O

C

H N

C

O

+

H N

APS 60C0

COCH=CH2

CH2-CH2-CO

n O

Scheme (26) reaction of natural polymer with Glycidyl Acrylate O O

H N

C H N

C

+

O

APS 60C0

COCH=CH2

+ drug-NH2

CH2-CH2-CO

n

O

60C0 ref luxe half hr O C

O

H N

C

H N

n CH2-CH-CO -NH drug CH2-CH2CO n CH2-CH-N+H-drug

CH2-CH2 OH

O-

124

H

Scheme (27) ring opening reaction of epoxy nucleophilic reaction..

by

Preparation of graft co-polymerization acrylic acide with gelatin backbones:The acrylic acid was simultaneously grafted onto Gelatin backbones in a homogeneous medium using ammonium per-sulfate as a radical initiator. The first step, Ammonium-per sulfate, is decomposed under heating to produce sulfate anion-radical.Then, the anion-radical removed hydrogen from one of the functional groups in side chains (R) ofthesubstrate to form corresponding radical. So, this initiated monomer grafting onto Gelatin backbones led to macro-radicals a graft copolymer.

125

Scheme ( 28 ) reaction of gelatin acide

with poly acrylic

Substitution of gelatin-graft-poly acrylic acid with amino drug . drug polymers were synthesized from reaction of Gelatin-g-poly acrylic acid(S21)with different aminodrugs.Gelatin-g-poly acrylic acidconverted to Gelatin-g-Poly acryloylchloride, as shown below]. 126

Scheme ( 29) Gelatin-g-poly acrylic acid reaction with thionyl chloride Step (1) and (2) conversion of the OH group into agood leaving group, step (3) and (4) substitution of the leaving group by Cl. Gelatin-g-Poly acryloylchloride reacts with amine to form an amide, as explained below:-

127

O Gelatin backbone

H N

C

CH 2 CH C

Drug

+

another poly acrylic chain

NH2

Cl

O

dioxane DMF

Ref lux -mHCl

O Gelatin backbone

H N

C

another poly acrylic chain

CH2 CH C

NH

Drug

O

Scheme (30) reaction of Gelatin-g-Poly acryloylchloride reacts with amino drug

The mechanism of the reaction involves a nucleophilic attack on the carbonyl group of acid chloride as shown below[146]:-

128

Scheme (31): Mechanism of Gelatin-g-Poly acryloylchloride substituted amino drug The EDTA reacted with acetic anhydride to obtain AEDTA and then it reacted with chitosan backbone to obtain chitosan –g- A-EDTA these reaction showon in schemebelow:-

129

Scheme (32 ) Grafted of AEDTA to Chitosan backbon the reaction mechanism goes by two steps as shown in the scheme(33) below:O

n

O

N C

O

O

O C

H2 H2 C C N

C O

O C

n NH2-Chitosan backbon

O

N C

C

C O C

O

O

H2 H2 C C N

H N

R

OH

Chitosan backbon

Chitosan backbon

n CONH

NHCO

drugNHCO

130

N

N CONHdrug

Scheme ( 33 ) Mechanism of ring opening of AEDTA by Chitosan backbon Graft co-polymerization of A- EDTA with Melamine backbones and Substitution of amine drug with Melamine G- A-EDTA:The Melamine reacted with A-EDTA to obtain melamine –g-A-EDTA and then it could condense with some selected amino drug to obtain polyamide. The reaction is show in schemebelow:NH2

N

N

O

N

N

ref luxe 4hr

DMF

COOH

NH -CO N

N

CO-NH drug

HOOC N

drug NH-CO

N

COOH N

COOH

O

NH2

N

NH2

+

N

N

NH-CO

CHO-NH

COOH N

HOOC

N

CO-NH drug

Scheme ( 34) Grafted of Melamin with AEDTA and substituted with amino drugs 131

Ring opening of poly vinyl pyrrolidinone with ethylene di amin and substitution with carboxylic drug :In this part modification of PVP with ethylene di amine .In this work the first amine group in the ethylene di amin could reacts with polyvinylpyrrolidinone with ring opening and the second amin group reacts with carboxylic drug as shown in the following reaction:H2C

CH2 CH

+

NH2-R-NH2

NH

Dioxan,DMF ref lux

N

CH2 3 HN R HN

C=O

CH

O C

C O

Drug

Scheme(35) reaction ethanol amine

of

polyvinypyrolydien

with

Polyvinypyrrolidinon connected with ethylene di amin and then reacted with carboxylic drug affords both protection than and specific transport properties with longer acting with lesgastic irritation parent drug. The presence of(–NH) group in ethylene di amin acts as a ring openner of polyvinypyrrolidinon as nucleophilic attack as shown in above scheme.The following 132

mechanism shows the modification of PVP with ethylene di amin and substitution with carboxylic drug as shown below . CH2

CH

+

Dioxan,DMF ref lux

NH 2-R-NH 2

CH2

CH n

N

N C=O

O-

C

H ring openning

N+-R-NH2 H

CH

H 2C

NH n (CH 2) 3

NH 2

R

HN

C O

SOCl

RCOOH-drug

H2C

NH

R

HN

CH n NH (CH 2) 3 C O

O

C drug

drug=Mef enamic acid ,Ciprof laxin,Ibuprof en, Captopril

Scheme (36): Mechanism polyvinylpyrrolidinone with compounds .

of

ring opening of carboxylic antibiotic

Ring opening of poly vinyl pyrrolidinone with ethanol amine . 133

drug polymers were prepared by modification of PVP with ethanol amine . .In this work the amine group in the ethanol amine could reacts with poly vinylpyrrolidinone with ring opening and then the hydroxyl group reacted with carboxylic drug by ester bond as shown in the following reaction:H2C

CH2 CH N

+

NH2-R-OH

CH NH

Dioxan,DMF ref lux

n

CH2 3

n O R

C=O O

HN

C

C O

Drug

Scheme(37) reaction ethanol amine

of

134

polyvinypyrolydien

with

CH2 CH

+

Dioxan,DMF ref lux

NH 2-R-OH

CH2

CH n

N

N C=O

O-

C

H ring openning

H 2C

N+-R-OH H

CH NH n (CH 2) 3

OH

R

HN

C O

SOCl

RCOOH-drug

H2C

O

R

HN

CH n NH (CH 2) 3 C O

O

C drug

drug=Mef enamic acid ,Ciprof laxin,Ibuprof en, Captopril

Scheme (38): Mechanism of ring opening of poly vinylpyrrolidinone with carboxylic antibiotic compounds. Ring opening of poly vinylpyrrolidinone with amino drugs . new drug polymers were prepared by the reaction of poly vinylpyrrolidinone with different drugs containing primary amine . as shown in scheme below [121,122]:-

135

CH2 CH

+

N

R-NH2

Dioxan,DMF reflux

C=O

R

H2C CH NH n (CH2) 3 HN C O

drug=Amoxilline,Ampicilline,Allopurinoll,Sulphamethazol

Scheme ( 39) Ring opening of Poly Vinyl Pyrolidione with amino Drugs The mechanism of the reaction involves a nucleophilic attack on the carbonyl as shown below :-

136

CH2 CH

Dioxan,DMF ref lux

R-NH2

+

CH2

CH n

N

N C=O

O-

C

H

N+-R H

H2C CH NH n (CH2) R

3

HN C O

drug=Amoxilline,Ampicilline,Allopurinoll,Sulphamethazol

Scheme (40) Mechanism of Ring opening of PolyViny Pyroledion with amino Drugs as shown below:-

CH

H2C

n

NH O F N

O

C

N

HN

137

CH2 O-R-NH-CO

3

CH

H 2C

n

NH CH 2 HN

CH 2

CH O C

3

C O

O

O SH

N

H 2C

CH

n

NH CH 3 HN

CH 2

CH

3

C

CH3

O

O

CH 3

CO CH 3

H2C

CH NH CH2

n 3

CO-NH

O CH

C

S

NH O

OH

138

N

CH3 CH3

COOH

H2C

CH NH CH2

n 3

O

O

CO- NH

S

CH3

NH N

O

Chitosan backbon

n O CH3

CH2

O-CO

CH3 CH3 CH3

50-Thermal Properties of drug polymers:-

139

Thermal stability of some selective compounds were investigated by thermo gravtimetric analysis (TGA). This technique is based on measuring the weight loss as a function of time at constant temperature or as a function of temperature at constant rate of heating, the thermal stability of the prepared compounds was tested by thermogravemetric technique by measuring the sample weight change at a programmed rate of heating. The change in weight was measured as a function of temperature which gave valuable information about the thermal stability of the prepared compounds. Thermograms were analyzed. Several thermal stability parameters were determined from TGA and DSC curves as following :1-Decomposition temperature (DT). Two type of DT were determined i.e. initial decomposition temperature (Tendo) and the optimum decomposition temperature (Texo). 2-Weight loss temperature (Ts), which was determined from the TG curve, which represents the temperature at which the sample lost of its total weight

140

In this study 10-20 mg. was taken from the prepared polymers under a programmed heating rate of 10 0C /min. under inert atmosphere (N2 gas 50ml/min). Thus the weight-loss vs. temperature thermo grams were recorded and analyzed.

51-Swelling Percentage:Some of the polymer drug with a mass of 1.5 gm were placed into a petridish; which was filled with water and placed in a hood at room temperature. Petri dish lids were placed on the petridishes when they were in the hood to prevent evaporation .

Scanning electron polymer drugs

microscopy

(SEM)of

Some

Microstructure obtained by SEM for the gelatin showed that fracture surface of gelatin exhibits a smooth laminated structure. Comparatively, the fracture surface of grafting seems

141

coarse,indicating

and

improved

the

grafting

Figure(45)SEM of Gelatine. Studying of Ultra Violet Spectra (UV) of some prepared drug polymer:some of prepared drug polymer are studying by UV spectrum . The spectra revealed a high absorption band at (200-355 nm) ,these absorptions were due to n-π* and π-π* transition. 52-Drug release:Responsive Systems Based on pH

142

Physiological pH varies systematically in the body, particularly along the GI tract, where harsh pH and enzymatic conditions in the stomach (pH ~ 2) degrade macromolecules. The small intestine is substantially more alkaline, with pH ~ 6.2--7.5. Physiological pH profiles will also change among cellular compartments. For example, endosomes typically exhibit pH values of 5.0--6.8 and lysosomes 4.5--5.5 . Also, it is well known that diseased or inflamed tissues and exhibit different pH profiles than normal tissue . Tumors have been widely reported to produce acidic conditions (pH ~ 6.5) in the extracellular milieu . Thus, it is no surprise that scientists and engineers have devoted considerable effort toward the rational design of polymers capable of exploiting these pH variations to selectively deliver valuable therapeutics to specific intracellular or extracellular sites of action. By judicious materials selection and careful engineering of molecular architecture, pH-responsive polymer delivery systems can be developed to give well-controlled pH response and drug release. Many synthesized polycationic nanomatrices capable of well-defined hydrophilic-hydrophobic transitions near physiological pH . Relatively uniform particles of poly[2143

(diethylamino)ethyl methacrylate-co-t-butyl methacrylate-g-PEG] (PDBP) measuring 51 nm were synthesized using a novel photoemulsion polymerization technique . Relevant properties of the system, such as swelling ratio, critical swelling pH, surface charge, and biocompatibility, were tailored by tuning polymer composition, crosslinking density, and the incorporation of hydrophobic moieties into the hydrogel core. Ongoing work aims to optimize these systems for intracellular small interfering RNA delivery. Promising work by Hu et al. describes the development of pH-responsive core-shell hydrogels for intracellular delivery of ovalbumin to dendritic cells, a class of cells intimately involved with adaptive immunity. Emulsion polymerization was used to create crosslinked poly(2(diethylamino)ethyl methacrylate) (PDEAEMA) core-poly(2-aminoethyl methacrylate) (PAEMA) shell nanoparticles measuring 205 nm in diameter. The authors hypothesized that PDEAEMA would exhibit pHresponsive behavior whereas PAEMA would remain constitutively ionized throughout the physiological pH range. Interestingly, the authors used the cationic PAEMA shell to adsorb and protect a model ovalbumin 144

protein rather than the archetypal practice of loading therapeutics into the hydrogel core. Subsequent studies demonstrated the versatility of this approach through intracellular delivery of siRNA and influenza A particles . This strategy of using a charged, pH-insensitive shell distinct from the pH-responsive domain represents an intriguing departure from the current paradigm of using a neutral, hydrophilic shell, such as PEG, to shield surface charges. However, several drawbacks may limit the feasibility of this design in vivo. First, charged particles have a much higher opsonization rate than neutral particles , and the cationic PAEMA shell may attract opsonin proteins or promote adsorption of anionic serum proteins, resulting in rapid clearance by the reticuloendothelial system. Secondly, the slow dissociation of electrostatically bound cargo from a polymer shell may provide a kinetic barrier to therapeutic efficacy. Bae and colleagues have recently reported polymer micelles possessing dynamic, multifunctional behavior for drug delivery. Self-assembling amphoteric polyamine-based block copolymers were functionalized with folate , biotin), and HIV peptide trans-activating transcriptional activator (TAT) ligands , thus 145

demonstrating robust applicability in targeted delivery. Folate or biotin ligands enhance cellular uptake via receptor-mediated endocytosis , and TAT is a wellknown peptide transduction domain . By conjugating the cell-penetrating peptide TAT, particles of up to 200 nm gain direct access to the cell , effectively circumventing the intracellular trafficking pathway. The polymer system, a mixture of two block copolymers, poly(L-histidine)-b-PEG (polyHis-b-PEG) and poly(Llactic acid)-b-PEG-b-polyHis-ligand (pLLA-b-PEG-bpolyHisligand), self-assembled into mixed micelles capable of ligand exposure, micelle destabilization, and endosomal disruption in response to pH . A short polyHis block preceding the ligand serves to anchor the ligand at the core-shell interface, which effectively shields its presentation on the micelle surface at neutral pH. Upon exposure to a slightly acidic (6.5 < pH < 7.0) environment, the short polyHis anchor ionizes and PEG-b-polyHis arm unfurls, exposing the ligand on the micellar surface. This response is expected to confer tumor specificity to the micelle carrier, as the ligand will be unavailable to promote receptormediated endocytosis or cellular transduction in normal (pH 7.4) tissue. Further acidification (pH < 6.5) induced 146

micelle dissociation by ionization of the His residues in the micelle core. Breast adenocarcinoma cells exposed to doxorubicin (Dox)-loaded mixed micelles displayed prominent intracellular distribution and nuclear localization of Dox after 30 minutes and experienced ~60% reduction in cell viability after 48 hours. Responsive Systems Based on Redox Potential Polymers containing labile linkages present an attractive opportunity to develop biodegradable or bioerodible delivery devices. Much of the early work in this field focused on acid labile linkages of polyanhydrides , poly(lactic/glycolic acid) ), and more recently poly(β-amino esters) . However, intracellular cues are now being investigated as a means to trigger cytoplasmic degradation of polymer carriers incorporating advanced therapeutics such as siRNA and anticancer drugs. Disulfide linkages are well known to be unstable in a reductive environment as the disulfide bond is readily cleaved in favor of corresponding thiol groups. Polymers with disulfide cross-links have been synthesized as polymersomes , nanogels , and corecross-linked polyplexes and degrade when exposed to cysteine or glutathione, reductive amino-acid based 147

molecules present at intracellular concentrations 50– 1000 fold greater than those of the extracellular milieu). The Hubbell group ) has used amphiphilic copolymers of PEG and poly(propylene sulfide) (PPS) to form vesicular compartments. Rather than relying on hydrolytic linkages, which may respond too slowly to avoid nonproductive lysosomal accumulation of the polymer carrier, they have incorporated a disulfide linkage between the hydrophilic PEG and hydrophobic PPS portions of the polymer, which imparts a high degree of reductive sensitivity to the polymersomes. In another study, glutathione-degradable nanogels were prepared by inverse emulsion atom transfer radical polymerization (ATRP) . Upon exposure to 10 wt% glutathione, half of the polymer degraded in nearly 6 hours. Exposing polymers to 20 wt% glutathione resulted in 85% degradation within 1 hour. Dox was efficiently incorporated into the polymer matrix at 16 wt% of the polymer with more than 50% loading efficiency, and the authors demonstrated in vitro release of fluorescent dye Rhodamine G6 and Dox. Doxloaded nanogels displayed negligible toxicity toward 148

HeLa cells in the absence of glutathione while causing approximately 40% reduction in cell viability following introduction of exogenous glutathione to the cellular media. It remains to be determined if this polymer system is capable of degrading and releasing drug upon exposure to intracellular glutathione concentrations or if the timescale for degradation in the presence of endogenous glutathione will allow efficient cytoplasmic delivery of incorporated therapeutics. In a more recent investigation, Kataoka and colleagues synthesized and thoroughly characterized a core-crosslinked polyplex composed of iminothiolane-modified PEG-block-poly(L-lysine), or [PEG-b-(PLL-IM)], for intracellular siRNA delivery. The use of a block copolymer affords modular functionality; the polycationic poly(L-lysine) segment serves to bind siRNA and provide endosomal buffering capacity whereas the hydrophilic PEG segment prolongs circulation time, prevents aggregation, and reduces opsonization . Lysine groups of the PEG-b-PLL copolymer were reacted with 2-iminothiolane and subsequently oxidized to form disulfide cross-links. Introducing crosslinks to the micelle core confers stability to the system, as crosslinked polymers 149

maintained micellar structure in physiological salt conditions whereas their noncrosslinked counterparts could not. The resulting polyion complex micelles were approximately 60 nm in diameter, a particle size well within the accepted limits (20–100 nm) for avoiding uptake by the RES and renal exclusion . Not surprisingly, micellar stability strongly influenced the ultimate siRNA transfection efficiency. The authors observed a narrowly defined N/P ratio at which stable micellization occurred. Interestingly, this optimum N/P ratio shifted to higher values with increased crosslinking. Highly efficient (more than 80%) knockdown of a reporter gene was detected at the optimum N/P ratio; however, a considerable decrease in transfection efficiency was observed upon slight departure from this critical value.

.Mechanism of these polymer drug were illustrated in the following Figures bellow:-

150

In acidic medium O

O NH-Drug

poly gelatin-Maleic

H

H

poly gelatin-Maleic OH 2

O

H

O

H

OH

Drug-NH2 + poly gelatin-Maleic

H

O

N HDr ug

poly gelatin-Maleic

NH-Drug protonation

O

poly gelatin-Maleic

H

H

NH-Drug OH H

proton transfer O O

Drug-NH 3

+

CH

C

S

NH N

poly gelatin-Maleic

O

OH

OH

CH 3

C H3 COOH

drug -NH2 Amoxilline O

O H N

C

O

n R

O

gelatin Maleic anhydrid

Mechanism (41) illustrated the hydrolysis of drug polymer in acidic medium

151

In basic medium O

O nucleophilic addition poly gelatin-Maleic anhydride

N Drug H

poly gelatin-Maleic anhydride

N Drug H OH

N_Drug -maliamic acid OH (alkaline)

lossNH-Drug

O

O poly gelatin-Maleic anhydride

drug-NH2

O+

poly gelatin-Maleic anhydride

O H

+ drug- NH

O CH

S

C NH O

OH

CH3 CH3

N

COOH

drug -NH2 Amoxilline

O

O H N

C R

O n

O

gelatin

Maleic anhydrid

Mechanism (42) illustrated the hydrolysis of drug polymer in basic medium 152

In acidic medium O O

poly C-M

NH-Drug

H protonation

OH2

NH-Drug O

H

H

O

H

poly C-M

+

H

NH-Drug

poly C-M

OH

H

poly C-M

NH-Drug

C-M

O

Drug-NH2

O

H

OH H

proton transfer O

Drug-NH3

OH

poly C-M

+

,

,

O

O N

NH

NH O

CaSein

,

OH

NH

nO

O

O

, O

Maleic anhydride ,

153

O

N

, R-NH2=Procaein

Scheme (43) hydrolysis of drug polymer medium

in acidic

In basic mediu m

O

O

poly C-M

N H

Drug

nucleophilic addition

polyC-M

OH

N H

Drug

N_Drug -maliamic acid OH

lossNH-Drug

(alkaline)

O O +

O

polyC-M

Drug

poly C-M

NH 2

H

+

Drug

NH

O

O N

O

NH

NH O

CaSein

OH

NH

n O

O

O

, O

Maleic anhydride ,

O

N

R-NH2=Procaein

Scheme ( 44 ) hydrolysis of drug polymerin basic medium

154

In acidic medium O

H

O O

NH-drug

protonation

drug-NH2

+ poly

H

OH2

O

O

H

OH

Albu-Gly

NH-drug

poly Albu-Gly

poly Albu-Gly

H

NH-Drug

poly Albu-Gly

H

poly Albu-Gly

O

H

H

NH-drug OH H

proton transfer O

O drug-NH3

+

OH

poly Albu-Gly

NH2

O S

CH3 NH N

O

drug-NH2 , Salphamethazol O

O NH

NH O

,

NH

CH2=CH-CO

n

O

Glycidyl acrylat

Albumin

Mechanism (45) illustrated the hydrolysis of drug polymer in acidic medium

155

In basic medium O

O N Drug H

poly Albu-Gly

nucleophilic addition poly Albu-Gly

N Drug H OH

N_Drug -maliamic acid OH lossNH-Drug

(alkaline)

O

O poly Albu-Gly

O+

O O NH NH NH n O

drug-NH2

CH2=CH-CO

H2N

H

+ drug- NH

O

O S

NH

CH3

N Salphamethozol

O Albumin

O

poly Albu-Gly

Glycidyl Acrylate

O

Drug NH2

Mechanism (46) illustrated the hydrolysis of drug polymer in basic medium

156

In acidic medium O

O

O H NH-Drug

poly C-M

H

OH2

O

Drug-NH2

+

poly C-M

NH-Drug

C-M

protonation

NH-Drug O

H

H

O

H

poly C-M

H

NH-Drug

poly C-M

OH

H

OH H

proton transfer O

Drug-NH 3

poly C-M

+

OH

O

NH2

N

, H3C

, M=Methyl Nadic Ahydrid o

C= Chitosan

,

H3C

o

N CH3

,

Drug NH2 (4-amino anti pyrin)

o

Mechanism (47) illustrated the hydrolysis of drug polymer in acidic medium

157

In basic medium

O

O

poly C-M

N H

Drug

nucleophilic addit ion

polyC-M

OH

N H

Drug

N_ Drug -maliamic acid OH

lossNH-Dru g

(alkaline)

O

O

polyC-M

O

+

Drug

poly C-M

NH2

O

H

+

Drug

NH O

NH 2 , M=Meth yl Nadic Ahyd rid o

C= Chito san ,

H3 C

o

N H 3C

N CH 3

Drug NH2

o

Mechanism (48) illustrated the hydrolysis of drug polymer in basic medium. Polymers have largely included cellulose derivatives, poly(ethylene glycol) PEG, and poly(N-vinyl pyrrolidone) . From a drug delivery perspective, polymer devices can be categorized as diffusion-controlled (monolithic devices), solvent-activated (swelling- or osmoticallycontrolled devices , chemically controlled (biodegradable), or externally-triggered systems (e.g., pH, temperature) . 53-Diffusion-Controlled Systems

158

Most diffusion-controlled carriers are simple and monolithic in nature. In these systems, a drug is dissolved (or dispersed if the concentration exceeds the polymer's solubility limit) in a non swellable or fully swollen matrix that does not degrade during its therapeutic life. In dissolved systems (C0 < CS), C0 is the initial loading concentration and CS is the saturation concentration. Fick's second law, for slab geometry, ∂Ci∂t=Di∂2Ci∂x2, can be solved under the appropriate boundary conditions to obtain an expression for concentration Ci(x,t). Diis the diffusivity of the solute in the polymer matrix, and Ci is the concentration of species i. Equations for calculating Di for porous, microporous, and nonporous hydrogels have been tabulated . Differentiating Ci(x,t) with respect to x allows for substitution of this result into Fick's first law: 1AdMidt=Ji=DidCidx. This expression can then be integrated under the appropriate boundary conditions at the interface, x, to

159

develop an equation for Mt, where Mt is the cumulative mass or moles released from the system : MtA=∫t0dMtAdtdt=∫t0D∂Ci∂xdt. With dispersed systems (C0 > CS), the situation is more complex as the precipitated regions are considered nondiffusing and disappear as a function of drug release to create a moving boundary problem. The wellknown Higuchi equation (for planar geometry), Mt=S(2C0−Cs)Cs−−−−−−−−−−−√Dt, provides a simple model for release by treating the problem as a pseudosteady state. In this expression, Srepresents the surface area available for drug release. Expansions to this model have produced expressions for spherical geometries and to account for drug concentrations near the solubility limit for the polymer . Solvent-Activated Systems In traditional swellable systems, drugs are loaded into dehydrated hydrophilic polymers or hydrogels by simply packing the two substances together. In the absence of a plasticizing aqueous solvent, these 160

systems are usually well below their glass transition temperature, Tg, and have very low diffusivities. Once exposed to an aqueous environment, the hydrogels imbibe water and swell. If the polymer is not chemically crosslinked (or crystalline), then dissolution creates an erosion front. Drug delivery devices that operate as swelling-controlled systems undergo a transition from the glassy to rubbery state during solvent swelling, which relaxes polymer chains and dissolves dispersed drug deposits. This process creates two simultaneously moving fronts, diffusion and swelling, in addition to the erosion front, if present. This has been shown dramatically using cylindrical hydroxypropyl methylcellulose (HPMC) sections loaded with buflomedil pyridoxal phosphate . Natural polymers:Today, the whole world is increasingly interested in natural drugs Natural materials have advantages over synthetic materials because they are nontoxic, less expensive and freely available. Furthermore, they can be modified to obtain tailor made materials for drug delivery systems allowing them to compete with the synthetic products that are commercially available . Polymers play a vital role in the drug delivery. So, the selection of polymer plays an important role in drug 161

manufacturing. But, while selecting polymers care has to be taken regarding its toxicity, drug Compatibility and degradation pattern. By this review, we can say that natural polymers can be good substitute for the synthetic polymers and many of the side effects of the synthetic polymers can be overcome by using natural polymers .Natural polymers can be good substitute for the synthetic polymers and many of the side effects of the synthetic polymers can be overcome by using natural polymers.

54-Synthetic polymers Synthetic polymers are produced commercially on a very large scale and have a wide range of properties and uses. The materials commonly called plastics are all synthetic polymers as shown belqw:-

162

55-Medical Applications of Synthetic Polymersp Polymers which, due to their fairly good intrinsic haemo compatibility properties, have been largely employed in endo corporeal permanent applications of prosthetic type include polyurethanes, silicone rubbers, hydrogels, teflon and some vinyl polymers or copolymers. (C25).

163

56-Synthetic polymers in dentistry has a hardness similar to that of natural teeth., this material is less expensive than most of the inorganic fillers in use today. Synthetic polymers 1- Methyl methacrylate (MMA) polymers: It is used in dentistry because of it can be easily adopted to individual purposes (fillings, prostheses) and can be in contact with human body and • Suitable manipulation/processing properties (easy to mix, shapable, simple to process and cure), • Good mechanical properties (rigidity, strength, wear resistance), Biocompatible (tasteless, odourless, nontoxic or non-irritating, resistance to microbial colonization), • Aesthetic properties translucency and transparency (colour and optical properties of tooth tissues) • Chemical resistance in oral environment, to disinfectants etc. • Acceptable cost of both material and processing method. 57-Preparation(MMA) • Initiation – Decomposition of dibenzoyl peroxide (DBP) during heating 164

•Propagation

•Chain termination

165

•Chain transfer to MMA monomer

•Chain transfer to phenolic inhibitors

Hydroquinone (HQ) The acrylates and, to a lesser extent, methacrylates (2hydroxyethyl methacrylate (2-HEMA), triethyleneglycol dimethacrylate (TREGDMA), and 2,2- bis[4-(2-hydroxy3-methacryloxypropoxy) phenyl]propane (bis-GMA) are strong irritants,but they are also notorious allergens. These compounds were found at concentrations of 50 to 90% in unhardened dental adhesives and cements.(C28) : Modifications of PMMA for dental applications

166

Example: MMA cross-linked with ethylene glycol dimethacrylate (EGDMA)(C1)

(EGDMA0 )

References 1. Langer R, Peppas NA. Advances in biomaterials, drug delivery, and bionanotechnology. AIChE J.2003;49(12):2990–3006. 2. Rowe RC, Sheskey PJ, Owen SC. Handbook of Pharmaceutical Excipients. 5th ed Pharmaceutical Press; American Pharmacists Association; Grayslake, IL: Washington, D.C.: 2005. p. 850. 167

3. Langer RS, Peppas NA. Present and future applications of biomaterials in controlled drug delivery systems. Biomaterials. 1981;2(4):201–14. 4. Peppas NA. Drug delivery using smart polymers: recent advances. In: Galaev IM, Mattiasson B, editors.Smart Polymers: Applications in Biotechnology and Biomedicine. 2nd ed CRC Press; Boca Raton, FL: 2008. 5 Crank J. The Mathematics of Diffusion. 2nd ed Oxford Univ. Press; New York: 1975. p. 414. 6. 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(12):114–49. Pioneering paper in pharmaceutical delivery that established design conditions for new pharmaceutical formulations 7 Koizumi T, Panomsuk SP. Release of medicaments from spherical matrices containing drug in suspension: theoretical aspects. Int. J. Pharm. 1995;116(1):45–49. 8. Cohen DS, Erneux T. Controlled drug release asymptotics. Siam J. Appl. Math. 1998;58(4):1193–204. 168

9. Colombo P, Bettini R, Santi P, Peppas NA. Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance. Pharm. Sci. Technol. Today. 2000;3(6):198–204 ,10. Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983;15(1):25–35.

11.Zohuriaan . M.J., Pourjavadi A., Kurdtabar M., Salimi H., Polysaccharide-based superabsorbent hydrogels: A Review, Carbohydr Polym, submitted,( 2008) 12.JanaS., Gandhi A., Sen K.K., and Basu S.K.,(Natural polymers and their application in drug delivery and biomedical field), J. of Pharma.Sci. Tech, 1(1) : 16-27, (2011). `13. Saunders G., and Creath B., (Biodegradable polymers analysis of biodegradable polymers Agilent Technologies Inc., Santa Clara, CA, USA, (2010). 14. .Mishra S., Rani G.U. and Sen G., "Microwave initiated synthesis and application of polyacrylic acid 169

grafted carboxymethyl cellulose", Polymers87, 3, : 255-262 (2012).

Carbohydrate

1 5.Jiraprasertkul W., Nuisin R., Jinsart W., and Kiatkamjornwong S., Synthesis and characterization of cassava starch graft poly(acrylic acid) and poly[(acrylic acid)-co-acrylamide] and polymer flocculants for wastewater treatment. JAppl Polymer Sci 102: 2915 – 28(2006).242,(1996). 16.Zentner GM, Rathi R, Shih C, McRea JC, Seo MH, Oh H, Rhee BG, Mestecky J, Moldoveanu Z, Morgan M, Weitman S Biodegradable block copolymers for delivery of proteins andwater-insoluble drugs. JControl Release 72:203–215(2001). 17. Puisieux F., Barratt G., Couarraze G., Couvreur P., Devissaguet J.P., Dubernet C., Fattal E., Fessi H., Vauthier C. , Polymeric Biomaterials, Marcel Dekker Inc., : 749–794(1994). 18. Pekarek KJ, Jacob JS, Mathiowitz E, Double-walled polymer microspheres for controlled drug release, Nature, 367258-260 ,(1994). 19.Mi FL, Lin YM, Wu YB, Shyu SS, Tsai YH, Chitin/PLGA blend microspheres as a biodegradable drug-delivery 170

system: phase-separation, degradation and release behavior, Biomaterials, 3257-3267,(2002) .

20.Jones, R.T. Gelatin: Manufacture and PhysioChemical Properties. In Pharmaceutical Capsules; Podczeck, F., Jones, B.E., Eds.; Pharmaceutical Press: London, UK, 23–60,2004;

21. Bergo, R. A. Carvalho, A. C. , Vadala, V. C. , and Guevara P. J. ,. “Physical properties of gelatin films plasticized with glycerol, Studied Spectroscopic Methods,” Materials Science Forum, 637 , : 753-758, (2010). 22. P. J. A. Sobral, F. C. Menegalli, M. D. Hubinger and M. A. Roques, “Mechanical, Water Vapor Barrier and Thermal Properties of Gelatin Based Edible Films,” Food Hy-drocolloids, Vol. 15, No. 4-6, pp. 423-432. (2001). 23. Ali .P., Mohammad .S., Mohammad M. H., Hossein H., (Synthesis and absorbency of gelatin-graft-poly “sodium acrylate-co-acrylamide” superabsorbent

171

hydrogel with saltand pH-responsiveness properties), J. of Polymers, 57, 1618-7229, (2006). 24. R. A. Carvalho and C. R. F. Grosso, “Characterization of Gelatin Based Films Modified with Trans glutaminase, Glyoxal and Formaldehyde,” Food Hydrocolloids, Vol. 18, No. 5, pp. 717-726. (2004). 25. Ali .P., Mohammad .S., Mohammad M. H., Hossein H., (Synthesis and absorbency of gelatin-graft-poly “sodium acrylate-co-acrylamide” superabsorbent hydrogel with saltand pH-responsiveness properties), J. of Polymers, 57, 1618-7229, (2006). 26. Kopecek J., Smart and genetically engineered biomaterials and drug delivery ystems. European Journal of pharmaceticeutical sciences, 20,.1,: 1116(2003). 27. Jeong B, Bae YH, Lee DS, Kim SW, Biodegradable block copolymers as injectable drug delivery systems, Nature, 388: 860-862, (1997) . 28. Rossi S., Marciello M,, Bonferoni M.C., Ferrari F., Sandri G., DacarroC., Grisoli P., Carmella C.. Thermally sensitive gels based on chitosan derivatives for the 172

treatment of oral mucositis. Eur JPharm Biopharm; 74: 248–254(2010). 29. Lee J.E. , Effects of a chitosan scaffold containing TGF-beta 1encapsulated chitosan microspheres on in vitro chondrocyte culture. Artificialorgans 28 (9), :829839,(2004). 30. Tsai G.I., Wu Z.Y., and Su W.H., Antibactirel activity of chitosan oligosaccharide mixture prepared by cellulose digestion of shrimp Chitosan and its application to milk. J. Food Prot., 63: 747-752, (2000). 31. Lakshmanan, V. K. , Snima , K. , Bumgardner , J. , Nair , S. and Jayakumar , R. Chitosan- based nanoparticles in cancer therapy . In: Jayakumar , R. , Prabaharan , M. and Muzzarelli , R. A., Chitosan for Biomaterials I , Berlin, Heidelberg , Spring ( 2011 ). 32. .Chen C., Liau W., and Tsai G., Antibacterial effects of N-Sulfonated and N-Sulfobenzoyl Chitosan and application to oyster preservation J.Food Prot.,61:11241128, (1998). 33. Cui, Z., Mumper, R.J., Chitosan-based nanoparticles for topical genetic immunization. J. Control. Release, 75,:409–419 , (2001). 173

34. Haque P., Mustafa A. I., and Khan M. A., “Effect of cross- linking monomers on the physico-mechanical and degradation properties of photografted chitosan film,” Car-bohydrate Polymers, 68, 1, : 109-115, (2007). 35. Hejazi R., Amiji M., Chitosan-based gastrointestinal delivery systems, J Control Release, 89:151-165. (2003). 36. Rajam, M., Pulavendran, S., Rose, C.. Mandal, A.B. ,Chitosan nanoparticles as a dual growth factor delivery system for tissue engineering applications. Int. J. Pharm., 410,: 145–152,(2011). 37. Li, N.; Zhuang, C.; Wang, M.; Sun, X.; Nie, S.; Pan, W. Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery. Int. J. Pharm1, 131-138 ,(2009). 38. Paul W., Sharma C.P., Chitosan, a drug carrier for the 21st century: Pharma Sciences; 10(1): 5–22,(2000). 39. P. Haque, A. I. Mustafa and M. A. Khan, “Effect of Cross- Linking Monomers on the Physico-Mechanical and Deg-radation Properties of Photografted Chitosan Film,” Car-bohydrate Polymers, Vol. 68, No. 1, 2007, pp. 109-115. 174

40. Arora N.,Carg T.,Biland A., Review of Casein production and Casein based nano- formulation , International Research J.,of Pharmacy IRJP 3,1(2012). 41. Prabhu S. Poulose, E.K., Silver nanoparticles, Mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects. Int. Nano Lett. 32,:2– 10. (2012). 42. Lund, M. Casein association and micelle formation,Electrostatic chameleons in biological systems. Journal of the American Chemical Society., 111-14.( 2010). 43. Mu, M., X. Pan, P. Yao, and M. Yiang.. Acidic solution properties of β-casein-graft-dextran copolymer prepared through Maillard reaction. J. Colloid Interface Sci.. 301:98– 106(2006). 44. O’Regan, J., and D. M. Mulvihill. Preparation, characterisation and selected functional properties of sodium caseinate–maltodextrin conjugates. Food Chem. 115:1257–1267(2009). 175

45. Zhao, J., D. Shanyi and T. Guishan,. Surface modification of acrylic fiber by grafting of casein. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry.. 44(3): 299-304.( 2007). 46.Elzoghby OA .Casein based formation as promising controlled drug delivery system ,J.of controlled release 2011,1-3. 47. Kohori, F.; Yokoyama, M.; Sakai, K.; Okano, The casein micelle and milk coagulation. T. J Controlled Release 2002, 78, 155–16 48. Sanchez, C.; Renard, D The biological function of casein:. Int J Pharm 2002, 242, 319–324 49. Morimoto Y and Fujimoto, S. “Albumin microspheres as drug carrier” CRC Critical Reviews in Therapeutic Drug Carrier Systems... 1, 2, ,. 19-63(1985). 50. Kratz F. Albumi,n as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J. Control Release 132: 171-183, (2008).

176

51. Morimoto Y., and Fujimoto, S., “Albumin microspheres as drug carrier” Critical Reviews in Therapeutic Drug Carrier Systems.. 1, 2, :19-63,(1985). 52. Kratz F., Elsadek B., .Clinical impact of serum albumin on drug delivery. J.Control Release 161: 429445, (20123. Gonen-Wadmany, M.; Oss-Ronen, L.; Seliktar, D. Biomaterials 8, 3876–3886(2007). 54. K. Eisele, R. A. Gropeanu, C. R. Zehendner, A. Rouhanipour, A. Ramanathan, G. Mihov, K. Koynov, C. R. W. Kuhlmann, S. Vasudevan, H. J. Luhmann, T. Weil, Biomaterials 31, 33, 8789-8801,( 2010). 55 Kulicke W.M,, Nottelmann H., Structure and swelling of some synthetic, semi synthetic, and biopolymer hydrogels, Adv Chem Ser, 223, :15-44,( 1989). 56. Reed A.M., Gilding D.K., Biodegradable polymers for use in surgery – polyglycolic/poly(lactic acid) homo and copolymers: 2 In vitro degradation. Polymer 22:494– 498(1982). 57. Avérous L., (Polylactic Acid; synthesis; properties and applications), CH. 21, India. 435, (2011). 177

58. Liu H., Slamovich E.B., Webster T.J., Less harmful acidic degradation of poly(lacticco-glycolic acid) bone tissue engineering scaffolds through titania nanoparticle addition. Int J Nanomedicine.;1:541– 545,(2006).

59. Choi H.. ,Doya T.. , Sasaki S., Nakai T.,Preparation acharacterization of poly pseudorotaxanes based on biodegeradable poly(L-lactide)/poly(ethylene glycol) triblock copolymers, Macromolecules 36,:9313-8 (2003). 60. Choi, K.M.; Choi, M.C.; Han, D.H.; Park, T.S.; Ha, C.S. Plasticization of poly(lactic acid)(PLA) through chemical grafting of poly(ethylene glycol) (PEG) via in situ reactive blending. Eur. Polym. J., 49, 2356–2364(2013) 51. Zare, A.; Morshed, M.; Bagheri, R.; Karimi, K. Effect of various parameters on the chemical grafting of amide monomers to poly (lactic acid). Fibers Polym., 14, 1783–1793(2013) 52. Taniguchi, J. & Ohkita, K. Testing paper for measuring poly(vinyl alcohol) concentration. 178

Japanese Patent 7765,495, 30 May, to Shikishima Spinning Co., Ltd Chem. Abstr., 88, 54762k, (1977). 53. Pohle, D.; Damm, C.; Neuhof, J.; Rosch, A.; MuPolym Compos 15, 357, (2007) 54. Qiu, K.; Netravali, A.N. Fabrication and characterization of biodegradable composites based on micro fibrillated cellulose and polyvinyl alcohol. Compos. Sci. Technol., 72, 1588–1594. (2012) 55. Chiellini, E.; Corti, A.; D’Antone, S.; Solaro, R. Biodegradation of poly (vinyl alcohol) based materials Prog. Polym. Sci., 28, 963–1014. (2003). 56. Baker, M.I.; Walsh, S.P.; Schwartz, Z.; Boyan, B.D. A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications. J. Biomed. Mater. Res. B Appl. Biomater., 100, 1451–1457, (2012). 57. Kenawy, E.R.; Kamoun, E.A.; Eldin, M.S.; El-Meligya, M.A. Physically crosslinked poly (vinyl alcohol)-hydroxyethyl starch blend hydrogel membranes: Synthesis and characterization for biomedical applications. Arab. J. Chem., 7, 372–380, (2014). 179

rd

58. Icsham A., 3 Edition, Acrylic Acid background Information, Basic Acrylic Monomer Manufacturers),a Summary of Safety and Handling, April (2006). 59. Guo X., Shao H.,Hu, W., Gao W. and Chen X., "Tannin and polyacrylic acid polarity and structure influence on the performance of polyvinylchloride ultrafiltration membrane", Desalination, 250,. 2, : 740744 (2010). 60. Athawale V..D, Lele V., Recent trends in hydrogels based on starch-graft-acrylic acid: A review, Starch/Starke, 3, :7-13,( 2001). 61. Angela S., Gayzen A., Ordonez,and Soma C., (Novel glycerol cross-linked poly, acrylic acid hydrogel for encapsulation and release of benzocaine), Department of Chemistry, school of Science and Engineering, Ateneo de Manila University, Loyola Heights, Quezon City 1108 Philippines, 4, 2:89-100 (2011). 62. Thamizharasi S., and Reddy B.S., (Synthesis and characterization of thermally stable naphthyl acrylate polymers), European Polymer J., Vol.36 (5), :993-1000, (2000). 180

63. Hiramath R.D., Chandrashakhar M.N., Sompur CK , Shattari AFAH, Maske AP, et al. Synthesis, In-Vitro And Bio-Availability Studies Of Acyclovir Prodrug. AJPSR 1: 38-48(2011). 64. Park, H.; Robinson, J.R. ,Mechanisms of mucoadhesion of poly(acrylic acid) hydrogels. Pharm. Res., 4,: 457–464 ,( 1987). 65. Firyal M.A ,Abbas N.M. and Khudyer G.K.(Synthesis of poly paracetamol Acrylate and Study of drug Release ).fifth Scientific Conference –College of ScienceUniversity of Babylon. ..5,: 230-236 ,.Iraq. (2010). 66.Firyal M.A.,TaghreedH.Al-Noor and SaifM.Synthesis and Characterization of Gelatin-G-Poly (AcryloylAmide) Proflavine and Controlled Release Study Chemical and Process Engineering Research . 32: 53-61.( 2015). 67. Firyal M.A., and Jassem M.S., (Substituted poly itaconic acid with different amines as biodegradable polymers), J. College of Education, 6, : 366-377, (2011). 68. Firyal M.A. (Modification of acryloylchlorides polymers ) Um-Salama Science Journal .Vol.2(4)(2005),

181

69. Arduini M et al. A novel type of hydrogen-bonded assemblies based on the melamine–cyanuric acid motif. Journal of Organic Chemistry, 68: 1097–1106. (2003). 70. Brown CA et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. Journal of Veterinary Diagnostic Investigation, 19: 525–531. (2007). 71. Reimschuessel R et al. Evaluation of the renal effects of experimental feeding of melamine and cyanuric acid to fish and pigs. American Journal of Veterinary Research, 69: 1217–1228. (2008). 72. Abeer R. Synthesis and polymerization of monomers containing heterocyclic groups Al-Mustansiriya University MSc. Thesis (2010). 73. Firyal M. A. and Shatha M.A. (Poly condensation of some heterocyclic compounds with acid anhydrides) J. of College of education .3 :58-79(2008). 74. El-Sherbiny I.M., Smyth H.D., Controlled release pulmonary administration of curcumin using swellable biocompatible microparticles. Mol Pharm.;9:269– 280,(2012). 182

75. Lubrizol, (Polymers for Pharmaceutical Applications, Pharmaceutical), Bulletin1, Lubrizol, Wickliffe, OH, USA, 11 August (2010). 76. Ulbrich K.,and Subr V.,(Structural and chemical aspects of HPMA copolymers as drug carriers), Adv. Drug. Del. Rev., Vol. 62, : 150-166, (2010). 77. Carrillo-Conde, B.; Schiltz, E.; Yu, J.; Chris Minion, F.; Phillips, G. J.; Wannemuehler, M. J.; Narasimhan, B. Acta Biomater. 6,: 3110-3119, (2010) 78. 34Thomas T.P., Goonewardena SN, Majoros IJ, Kotlyar A, Cao Z, et al. Folate-targeted nanoparticles show efficacy in the treatment of inflammatory arthritis. Arthritis Rheum 63: 2671-2680,(2011). 79. Piskin E., Kaitian X. and Denkbas, E.B. Novel PDLLA/PEG copolymer micelles as drug carriers. J. Biomater. Sci. Polymer Ed. 7, 359. (1995). 80. Rao J. P., and Geckeler K. E., Polymer nanoparticles: Preparation techniques and sizecontrol.parameters. 183

Progress in Polymer Science, 36, 7, July, : 887–913. (2011). 81. YunY.H., Goetz D.J.. Yellen P.,and Chen W.. Hyaluronan microspheres for sustained gene delivery and site specific targeting, Biomaterials, 25,: 147 – 157 (2004). 82. Singer J.W., Shaffer S.,and Besman M., (An Intracellularly Targeted Taxane), Anti-cancer Drugs,. 16, : 243-254, (2005). 83. Ankita R., Polymers In Drug Delivery: A Review, IJPRD, 2(8), : 9‐20, (2010) 84. Sandip G., Maru, Sapra B., Prakash, Savaliya B., Dharmesh, Sameer A., Agham, Nikunj J., and Aghera, (Natural polymer; gums and mucilage as good pharmaceutical excipients),Ph. Tech. Med., 1, : 22781099, Issue 2,March-April (2012). 85. Shah S.S., Wertheim J., Wang C.T., Pitt C.G., Polymer-drug conjugates: manipulating drug delivery kinetics using model LCST systems. J Control Release. 45: 95–101(1997).

184

86. Harris J. M., Chess R.B., Effect of pegylation on pharmaceuticals. Nature Rev Drug Discov 2:214– 221(2003). 87. Poddar R. K., Rakha P., Singh S.K., Mishra D.N., Bio adhesive polymers as a platform for drug delivery: possibilities and future trends, research J. Phamacetical Dosage Form and Technology, 2,1, 40‐54,(2010). 88. Dutkiewicz J.K., Superabsorbent materials from shellfish waste-A review, J Biomed Mater Res (Appl Biomater), 63, :373-381, (2002). 89. Chunhui L. Bin Z., Zhibo L. Dual stimuli-responsive polymers derived from α-amino acids: Effects of molecular structure, molecular weight and end-group ScienceDirect 53, 8 :1725–1732;(2012). 90. Nnadi, F.,& BraveC.. Environmentally friendly superabsorbent polymers for water conservation in agricultural lands. J. Soil Sci. Environ. Managem., 2(7),: 206–211(2011). 91. Chatterjee P.K.,, Gupta B..,S (Eds), AbsorbentTechnology, Elsevier, Amsterdam, 1-2, (2002). 185

92. Phattanarudee S., Foungfung D., and Kiatkamjornwong S., Effect of mica on water absorption of acrylamide–itaconic acid superabsorbent nano composites. EuropPolymer J., submitted(2007). 93. Buchholz F..,L (Editor) & Graham, A.T., - Modern Superabsorbent Polymer Technology ,John Wiley & Sons, November (1997). 94. Ju H. K., Kim S Y and Lee Y. M. “pH/temperatureresponsive behaviors of semi-IPN and comb-type graft hydrogels composed of alginate and poly(Nisopropylacrylamide)” Polymer. 42, : 6851-6857,( 2001). 95. Mathur A.M,, Moorjani S.K,, Scranton A.B., Methods for synthesis of hydrogel networks, J .Macromol SciRev Macromol Chem Phys, C36,: 405-430, (1999). 96. Rao J. P., and Geckeler K. E., Polymer nanoparticles: Preparation techniques and sizecontrol.parameters. Progress in Polymer Science, 36, 7, July, : 887–913. (2011). 97. Masayuki Y. Drug targeting with nano-sized carrier systems. J. Artif Organs 8:77–84(2005).

186

98. Ulrich P., Tobias W., Michael G., David A G. Nanomedicine for respiratory diseases. European ,Journal of Pharmacology 533: 341–350(2006): 99. Piao L., Zhang M.. DattaJ., Xie X., Su T., Li H., Teknos T.N., Pan Q., Lipid-based nanoparticle delivery of PremiR-107 inhibits the tumorigenicity of head and neck squamous cell carcinoma. Mol. Ther., 20,: 1261–1269. (2012). 101. Heidel J.D., Yu, Z., Liu, J.Y., Rele S.M., Liang Y., Zeidan R.K., Kornbrust D.J.,Davis M.E.,Administration in non-human primates of escalating intravenous doses of targeted nanoparticles.containing ribonucleotide reductase subunit M2 siRNA. Proc. Natl. Acad. Sci. USA, 104, :5715–5721(2007). 102. Hiramath R.D., Chandrashakhar M.N., Sompur CK , Shattari AFAH, Maske AP, et al. Synthesis, In-Vitro And Bio-Availability Studies Of Acyclovir Prodrug. AJPSR 1: 38-48(2011). 103. Piskin E., Kaitian X. and Denkbas, E.B. Novel PDLLA/PEG copolymer micelles as drug carriers. J. Biomater. Sci. Polymer Ed. 7, 359. (1995).

187

104. Kumar, V.,Jolivalt, C., Pulpytel, J., Jafari, R., ArefiKhonsari, F., Development of silver nanoparticle loaded antibacterial polymer mesh using plasma polymerization process. J. Biomed. Mater. Res. A 101, :1121–1132,(2013), 105. Prabhu S. Poulose, E.K., Silver nanoparticles, Mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects. Int. Nano Lett. 32,:2– 10. (2012). 106. Stella VJ.,(Prodrugs, some thoughts and current issues), J. Pharm Sci.,.99 : 4755–4765, (2010). 107. Ravindran Girija, A., Balasubramanian, S., Dhandayudhapani, B., Takahiro, F., Yasuhiko, Y., Toru, M., Kumar, D.S., Biocompatible fluorescent zein nanoparticles for simultaneous bioimaging and drug delivery application. Adv. Nat. Sci, 3,: 25-06. (2012). 108. Johnson M., Koman L. and Neuse E.''Polymeric drug carriers functionalized with pairwise arranged'' J. of Appli. Poly. Sci. 96,.1, : 10-19(2005). 109. Macewan S.R., Callahan D.J., Chilkoti A., Stimulusresponsive macromulecules and nanoparticules for cancer drug delivery. 188

Nanomedicine UK.; 5(5):793-806(2010). 110. Wang, D., Cathepsin K inhibitor‐polymer conjugates: potential drugs for the treatment of osteoporosis and rheumatoid arthritis, Int. J. Pharm., 277(1–2), 73,(2004). 111. Sandip G., Maru, Sapra B., Prakash, Savaliya B., Dharmesh, Sameer A., Agham, Nikunj J., and Aghera, (Natural polymer; gums and mucilage as good pharmaceutical excipients),Ph. Tech. Med., 1, : 22781099, Issue 2,March-April (2012). 112. Khandare J., Minko T., Polymer-drug conjugates: Progress in polymeric prodrugs. Prog Polym Sci 31:. 359-397. (2006). 113. Harris J. M., Chess R.B., Effect of pegylation on pharmaceuticals. Nature Rev Drug Discov 2:214– 221(2003). 114. 78.Ankita R., Polymers In Drug Delivery: A Review, IJPRD, 2(8), : 9‐20, (2010) 115. YunY.H., Goetz D.J.. Yellen P.,and Chen W.. Hyaluronan microspheres for sustained gene delivery

189

and site specific targeting, Biomaterials, 25,: 147 – 157 (2004). 116. Maeda H . Polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 46: 169-185(2001). 117. 73. Voglo., and DonarumaL. G., Polymeric Drugs, Academic Press, New York, NY,(1978). 118. El-Sherbiny I.M., Smyth H.D., Controlled release pulmonary administration of curcumin using swellable biocompatible microparticles. Mol Pharm.;9:269– 280,(2012). 119. Kopecek J.,Synthesis of tailor-made soluble polymeric drug carriers. In: Anderson JM, Recent advances in drug delivery systems, Plenum Press, New York, NY, :41-62(1984). 120. Pekarek K.J., Jacob J.S., Mathiowitz E., Doublewalled polymer microspheres for controlled drug release, Nature, 367:258-260. (1994). 121. Ahmed,M. L., Rao Y. M.,Formulation & characterizationOf matrix & triplelayermatrix tablets for

190

orally controlled drug delivery. Int J. PharmPharmaceut Sci; 2:137-143 (2010). 122. Oettinger C.W., Souza M.J., Microencapsulated drug delivery: a new approach to pro-inflammatory cytokine inhibition. J Microencapsul 29: 455-462, (2012). 123. El-Sherbiny I.M., Smyth H.D., Controlled release pulmonary administration of curcumin using swellable biocompatible microparticles. Mol Pharm.;9:269– 280,(2012). 124. Godin B., Sakamoto J.H., Serda R.E., Grattoni A., Bouamrani A., Ferrari M., Emerging applications of nanomedicine for the diagnosis and treatment of cardiovascular diseases. Trends Pharmacol Sci.;31:199– 205,(2010). 125. Grammer L. C. Shaughnessy M. A., Hogan M. B.,, Berggruen S. M., Watkins D. M., and Yarnold P. R., Value of antibody level in diagnosing anhydrideinduced immunologic respiratory disease. J Lab Clin Med 125 :650-653.( 2005).

191

126. The Industrial Health Foundation, Inc. Cyclic Anhydrides Committee. Revised Robust Summary and Test Plan for the Cyclic Anhydrides Category, December 16,( 2003). 127. Firyal M.A.Al-salami, Abbas N.M.AlSharify, Khudheyer J.Kadem. Preparation of poly(N-4antipyrinyl amic acids) and studying their controlled release drug polymers. Iraqi National Journal of Chemistry (NJC). Vol.43. P(336-346),2011. 128. W. Han, Z. Li, Wang Z.-Q., Yang H.-Q., Preparation and mechanical properties of polypropylene/ maleic anhydride compatibilized polypropylene/ organovermiculite nanocomposites, Polym.-Plast. Technol . Eng. 48 :374-378. (2009). 129 Nieuwhof R., Koudijs A., Marcelis A., Sudholter E. Modification of sidechain liquid-crystalline poly(maleic anhydride-co-alt-1-alkene)s with mesogen-containing alcohols. Macromol 32:6499–6506 , (1999). 130. Zhang, Y. P., Huang, K. C., Mai, Crystallization and dynamic mechanical properties of polypropylene/ polystyrene blends modified with maleic anhydride and styrene, J. Appl. Polym. Sci. 96 :203-204, (2005). 192

131. Bruch M, Mader D., Bauers F., Loontjens T., Mulhaupt R. Melt-modification of poly(styrene-comaleic anhydride) with .alcohols in the presence of 1,3oxazolines. J Polym Sci Part A: Polym Chem 38:1222– 1231(2000) . 132. Firyal M.A ,Abbas N.M. and Khudyer G.K.(Synthesis of poly paracetamol Acrylate and Study of drug Release ).fifth Scientific Conference –College of ScienceUniversity of Babylon.2010 .Vol.5,p(230-236) ,.Iraq. 133. Takekoshi, T., Polyimides- Fundamentals and Applications, Ed. Ghosh, M.K. and Mittal, K.L., Marcel Dekker, New York, 1996, Chapter 2. 134. Bessonov, M.I., Koton, M.M., Kudryavtsev, V.V. and Laius, L.A. Polyimides: Thermally Stable Polymers, 2nd edition, Plenum, New York, 1987. 135. Khalil F., Meisam S. and Maryam F. Synthesis and characterization of new copoly(amide-imide)s Based on N,N’- (4,4’-diphenylsulfone) bistrimellitimide with Different diacids and diamines Bull. Chem. Soc. Ethiop., 24(2), 289-294, (2010). 136. Firyal M.A Abbas N.M.AlSharify Khudheyer J.Kadem Synthesis of N-Ampicilline Amic acids as Drug 193

Polymers. . Iraqi National Journal of Chemistry (NJC). Vol.44. P(590-601),2011. 137. Kahovec J., Matejka Z., and Stamberg J., EDTA ester of bead cellulose a fast-kinetics chelating sorbent, Polym.Bull. 3,: 13-17, (1980). 138. Khalil F., Meisam S. and Maryam F. Synthesis and characterization of new copoly(amide-imide)s Based on N,N’- (4,4’-diphenylsulfone) bistrimellitimide with Different diacids and diamines Bull. Chem. Soc. Ethiop., 24(2), 289-294, (2010). 139. Taghreed Hashim Al-Noor ,Lekaa Khalid Abdul Karim & Firyal Mohammad Ali. Schiff Base And Ligand Metal Complexes of Some Amino Acids and Drug ,Lambert Academic publishing , Number: 137726 ,ISBN: 978-3-659-88556-3 (2016). 140. Wienki M. , Meulemane E., Borneman Z., Vanden B. , and Smolders C.A., Chemical Treatment of Membranes of a Polymer Blend:Mechanism of the Reaction of Hypochlorite with Poly(viny1 pyrrolidone) ,Journal of Polymer Science: Part A Polymer Chemistry, Vol. 33, P.49-54 (1995).

194

141. Srivastava A., Behari K. .Synthesis and characterization of graft copolymer (Guar gum–g–NVinyl-2-pyrrolidone) and Investigation of metal Ion sorption and swelling behavior. J. Appl. Polym. Sci., 100: 2480-2489(2006). 142. Firyal M.A., Abeer A.M, , and Wassal M.Kh., (Sulfonation and substitution of poly vinyl alcohol with amino antibiotics), J. Babylon University, 1, 22: 401-407, (2012). 143. Firyal M.A., Luma A.M. and Amany S.Y., (Modification of poly vinyl pyrrolidinone, Chitosan with paracetamal as drug carrier polymer), (AJPS) acceptance, :11-12-(2015). 144. Firyal M.A., and Abeer A. Modification of polyvinylpyrrolidinone with heterocyclic or amino acids to their corresponding derivative polymers. J.College of Education Al-Mustansiriya University 1:142,(2010). 145. De Queiroz Vargas R. R., Higa, O. Z. Ribeiro R. R., Vıtolo M.,. Copolymerization of N-vinyl pyrrolidone with methylmetha acrylate, Journal of Applied Polymer Science, 84, 767-777,(2002).

195

146. Park D.G ,Decker,, SCopolymerization of N-Vinyl pyrrolidone with methyl methacrylate by Ti(III)-DMG redox initiator. Journal of Physical Chemistry, . 100, 12142-12153,(1996). 147. Srinivas S. , Aparna V. , Rajkamal B. , Saikiran G. , “Synthesis and antimicrobial evaluation of some novel quinolone incorporated azetidinones, Thiazolidinones”, JPSI, 1(2):41-43(2012). 149. Jignesh P. , Hemul V. , Pradip S. , Nilesh H. , and Kishor R. , “A rapid, convenient microwave assisted and conventional synthesis of novel azetidin-2-one derivatives as potent antimicrobial agents", Asian J. Res. Chem., 2(2):171-177(2009). 150. Burton H. , and Abraham E. , “Isolation of antibiotics from a species of cephalosporium: cephalosporins P1, P2, P3, P4 and P5”, Biochem. J., 50(3): 68-71(1951). 151. Asnagar N. ,Gharib N. , “Analysis of three penicillin antibiotics (Ampicillin, Amoxicillin and Cloxacillin) of

196

Several Iranian Pharmaceutical Companies by HPLC”, EJ.Chem., 4(4):36-545 (2007). 152. Nussbaum, F. Brands, M. Hinzen, B. Weigand, S. Häbich, D."Antibacterial natural products in medicinal chemistry-exodus or revival", Angew. Chem. Int. Ed. Engl., 45 (31): 5072–129 (2006). 153. Tong DC, and Rothwell BR., (Antibiotic prophylaxis in dentistry, a review and practice recommendations),J. Am Dent Assoc.,Vol. 131,: 366‐374, (2000). 154. Bush K. β‐lactam antibiotics: Penicillin, and other β‐lactam antibiotics. In: Finch RG, Greenwood D, Norrby SR., and Whitley RJ. Antibiotic and chemotherapy: anti‐infective agents and their use in therapy. 8th ed. Philadelphia (USA): Churchill Livingstone, an imprint of Elsevier Science Limited;:224‐278. (2003). 155. Julio A., Juan J. , and José B. , “The Modern heterocyclic chemistry. Chemistry of 2-Azetidinones (βLactams)”, Wiley-VCH Verlag GmbH and Co. KGaA.Ch24(2011).

197

156. Abhilash, M. “A Short review on β-lactam and Two novel semisynthetic β-lactam antibiotics-garcicillin and garcinosporin”, 5(2):1-3(2014). 157. Essack, S. Y. “The Development of β-Lactam Antibiotics in Response to the Evolution of βLactamases”, Pharm.Res., 18(10):1391-1399(2001). 158. Souza, JC., (Manual of antibacterial antibiotics),Fernando Pessoa University,Oporto,Portugal,: 219-221, (2005). 159. Bruggink, A., E. C. Roos, and E. de Vroom. Penicillin acylase in the industrial production of β-lactam antibiotics. Org. Process Res. Dev. 2: 128–133. (1998). 160. Thomas M. Wooster T. J., Johanson K. M., Fraser K. J., MacFarlane D. R., J. Antonietti, Adv. Mater. L22, 87 (2010). 161. Jignesh P. , Hemul V. , Pradip S. , Nilesh H. , and Kishor R. , “A rapid, convenient microwave assisted and conventional synthesis of novel azetidin-2-one derivatives as potent antimicrobial agents", Asian J. Res. Chem., 2(2):171-177(2009).

198

162.Simar P.K.,Kaura R., andSanju N., (Amoxicillin,a Broad Spectrum Antibiotic), International Journal of Pharmacy and Pharmaceutical Sciences,. 3, Issue 3,(2011). 163 Eppes S.C., Childs J.A., Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease. Pediatrics; 109(6): 1173‐1177. 2002. 164. Firyal M.A., Abbas N.M. and KhudheyerJ.K., (Poly condensation of glycine with amoxicillin), The First Scientific National Conference for Women Researchers, :. 30-37, (2012). 165. Firyal M.A., Abbas N.M. and KhudheyerJ.K., (Synthesis of poly amoxicillinmaleamic acid), The First Scientific National Conference for Women Researchers, : 38-56, (2012). 166. Lemire, J.A., Harrison, J.J., Turner, R.J., Antimicrobial activity of metals: Mechanisms, molecular targets and applications. Nat. Rev. Microbiol., 11,: 371–384(2013).

199

167. Satyajit V E, Cindy B F and Asif M, J Pharm Biomed Anal.40(4), 864-874. 2006) 168. Firyal M.A., Firas A., Aseel Q., and Huda M., (In vitro study of Mefenamic acid starch as drug delivery), 10 ,3, :954-964, (2013). 169. Tayebeh M., Abbas A.,and Masoumeh M.,(Second order advantage of excitation emission matrix for simultaneous spectrofluorimetric determination of paracetamol and mefenamic acid in urine samples),Anal. Chim. Acta, 645, : 25-29, (2009). 170. Sakhare R.S., Roge A.B., Jadhav S.B., Ingole P.G., and Jameel A., (Jadhav A.B.Two wavelength method for estimation of protaverine hydrochloride and mefenamic acidin their combined tablet dosage form), International Journal of Pharm.Tech. Research, 4, 3 : 1288-1293, (2012). 171. Firyal M.A.,Firas A.R. and Ahmed Y.E. Synhesis of prodrug ciprofloxapen procaein maleamide polymer , Iraqi National J.of Chemistry 56:416-425, (2014). 172. DrugBank - Showing drug card for Procaine (DB00721) Update Date23 -06- (2009). 200

173. Harkins J.D., Mundy G.D., and Stanley S., (Determination of highest no effect dose (HNED) for local anaesthetic responses to procaine, cocaine, bupivacaine and benzocaine), Equine. Vet. J., 28, : 3037, (1996). . 174. YuanyuanYi Li, Liu, Haowei Wang, Xiaohui Xiong, Ping Wei, and Fangshi Li, (Synthesis, crystal structure, vibration spectral, andDFT studies of 4-Aminoantipyrine and Its derivatives), Molecules, 18, : 877-893, (2013) 175. Firyal M.A., Abbas N.M. and KhudheyerJ.K Modification of Polyvinylpyrrolidinon With 4Aminoantipyrine As Drug Poly J.College of Education Vol.6.p(531-542).(2011). 176. Alma MH., Ertas M. ,and Nitz S.,. Chemical composition of content of essential oil from the bud of cultivated Turkish Clove. BioRes 2(2):P. 265–269. (2007) 177. USPTO. Eugenol enhancement of transdermal drug delivery. US Patent 4888362. . (1989). 178. Chaieb K, Hajlaoui H, Zmantar T., The chemical composition and biological activity of clove essential oil, 201

Eugenia caryophyllata (Syzigium aromaticum L. Myrtaceae): A short review. Phytotherapy Res 21:P. 501–506. (2007). 179. US FDA. Guidance for Industry: Concerns Related to the Use of Clove Oil as an Anesthetic for Fish, Guideline No. 150. US Food and Drug Administration Center for Veterninary Medicine. April 24, (2007). 180. Francis A. Carey, Organic Chemistry , 4th .p792793,796.(2000). 181. Ayres L., Adams H. M., Lowik D. M.,van Hest, J. beta-sheet side chain polymers synthesized by atomtransfer radical polymerization Biomacromolecules, 6, P.825-831(2005). 182. Meyer M.. Schlaad H. , Poly(2-isopropyl-2oxazoline)-poly(L-glutamate) block copolymers through ammonium-mediated NCA polymerization Macromolecules, 39, P.3967-3970. (2006). 183. Silverstein R. ,and Bassler G. ,Spectrometric identification of organic compound , 2nd ed. John Wiley and sons ltd(1976).

202

184. Billmyer F, Text book of polymers Science, 3rd. John Willey and sons(1984). 185. Lindon J.C., Tranter G.E., Holmes J.L.. Encyclopedia of Spectroscopy and spectrometry . part 1, Canada,(2000). 186. Chini, M. Croti, P.; Favero, L. Macchia, M. Pineschi, M. Tetrahedron Lett., 35, 433-436; 1994

187. Swamy, N. R.; Goud, T. V.; Reddy, S. M.; Krishnaiah, P.; Venkateswarlu, Y. Synth. Commun. 34, 727-734(2004). 188. Silverstein R.M., Webster F.X., Kiemle D.J. , Spectrometric identification of organic compounds. 7 th ed. John Wiley and Sons Inc.(2005). 189. Donald L.Pavia, Gary M. Lampman and George S. Kriz , Introduction to spectroscopy. 3rd ed.( 2006 ). 190. Herbert, M. Jacob, S. Howard, N. George, J. "Organic Chemistry Schaum’s outlines" 4th ed. McGrawHill Companies, Inc. USA (2010).

203

191. Ralph, L. Christine, K. Hermann, T. Morrill, D. Curtin, R. "The systematic identification of organic compounds" 8th ed. John Wiley & Sons, Inc. USA (2004). 192. Cubbon, R. C. P. “Discloses the anionic polymerization of some n-substituted malei mides with butyl lithium”, J. Polymer Sci, 6(1):419-426(1965). 193. Crew P., Rodringuez J. and Jaspars M., Organic structure analysis. Oxford University Press,New York (1998). 194. Manners, I.; Riding, G.H.; Dodge, J.A.; Allcock, H.R. Role of ring strain and steric hindrance in a new method of the synthesis of macrocycles and high polymer phosphazenes. J. Am. Chem. Soc., 111, 3067– 3069. 1989 195. Saha A, Manna S, Nandi AK A mechanistic approach on the self-organization of the twocomponentthermoreversible hydrogel of riboflavin and melamine. Langmuir, 23: 13126–13135. (2007). 196. Allcock, H.R. Ring-Opening Polymerization in Phosphazene Chemistry. In Ring-Opening Polymerization; Brunelle, D.J., Ed.; Hanser Publishers: Munich, Germany,; pp. 217–237(1993). 204

197. Odian , G. Ring – opening polymerization , in Principles of Polymerization , 4th edn , John Wiley &Sons, Inc. , Hoboken, New Jersey , Chapter 7, pp. 544 – 618( 2004 ). 198. Brunelle , D.J. (ed.) ( 1993 ) Ring – Opening Polymerization. Mechanisms, Catalysis, Structure, Utility , Hanser Publishers , Munich, Vienna, New York, Barcelona . 199. John Mc Murry . Organic Chemistry. 7th ed.(2008).

200.Xing R., Bing T. and Shu Z., A simple and practical solvent-free preparation of poly maleimide. J. Molecules ,19,P.1981-1986,(2011). 201. Penczek , S. and Kubisa , P. Cationic ring - opening polymerization , in Ring - Opening Polymerization. Mechanisms, Catalysis, Structure, Utility (ed. D.J. Brunelle ), Hanser Publishers , Munich, Vienna, New York, Barcelona , Ch. 2. ( 1993 )

205

202. Slomkowski , S. and Duda , A. Anionic Ring Opening Polymerization , inRing - Opening Polymerization. Mechanisms, Catalysis, Structure, Utility (ed. D.J. Brunelle ), Hanser Publishers , Munich, Vienna, New York, Barcelona , Ch. 3. ( 1993 ). 203. Field L.D. ,Sternhell S., Kalman J.R. ,Organic Structures from Spectra. 4th ed.(2008). 204. Crew P., Rodringuez J. and Jaspars M., Organic Structure Analysis. Oxford University Press,New York (1998). 205. H. O. Demir.."A novel poly phenol: Synthesis, characterization and investigation of it thermal and electrochemical properties". Polym. J.,44, 699 . (2012). 206. R. Abdul kider. "Study into thermal and mechanical properties of novolac and its composites". M. Sc. Thesis, Applied Science Department, University of Technology. (2001) 207. Lee, S.B.; Koepsel, R.R.; Morley, S.W.; Matyjaszewski, K.; Sun, Y.; Russell, A.J. Permanent, nonleaching antibacterial surfaces, 1. Synthesis by atom 206

transfer radical polymerization. Biomacromolecules, 5, 877–882(2004).

207