Current Clinical Pharmacology

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Current Clinical Pharmacology

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RESEARCH ARTICLE ISSN: 1574-8847 eISSN: 2212-3938

Formulation of Herbal Fast Disintegrating Tablets and its Ex-vivo Study for Anti-histaminic Activity in Guinea Pig Ileum BENTHAM SCIENCE

Dinesh Puri1,*, Anil Bhandari2, Praveen Kumar Gaur1, Mohammad Yasir3, S. Sadish Kumar1, Deepak Choudhary4 and Prasoon Kumar Saxena1 1

I.T.S College of Pharmacy, Murad Nagar, Ghaziabad (U.P.), India; 2Faluty of Pharmacy, Jai Narayan Vyas University, Jodhpur, Rajathan; 3Department of Pharmacy, College of Health and Science, Arsi University, Asella, Ethiopia; 4Department of Pharmaceutical Sciences, Mohan Lal Sukhadia University, Udaipur, Rajasthan, India Abstract: Objective: The aim of present research work was to develop a herbal fast disintegrating tablet containing Fagonia schweinfurthii Hadidi dried extract and determining its antihistaminic activity using guinea pig ileum.

A R T I C L E H I S T O R Y Received: June 08, 2017 Revised: February 28, 2018 Accepted: March 06, 2018 DOI: 10.2174/1574884713666180309153942

Method: The tablets were formulated by wet granulation technique using three different superdisintegrants (croscarmillose, crospovidone and sodium starch glycolate) at three different levels. The tablets were evaluated for various physical properties like hardness, friability weight variation etc. and various mechanical properties like disintegration time, wetting time to select the best superdisintegrant. The selected superdisintegrant was further used as intra as well as extra granulating agent to develop fast disintegrating tablets of Fagonia schweinfurthii Hadidi dried extract. The optimized formulation was subjected to stability study as per the ICH guidelines. Finally, Ex-vivo antihistaminic study was conducted on guinea pig ileum for optimized formulation and compared with marketed tablet containing cetrizine HCl as API (Stanhist-10, Ranbaxy, Pvt. Ltd). Results: Physical properties of all tablet batches were found to be acceptable and comply with various official specifications. The disintegration time and wetting time of optimized formulation (F’3) were found to be 1.15±0.08 and 0.56±0.04 min respectively. Results of Ex-vivo study showed a comparable histamine inhibition between optimized tablet (15%) and marketed tablet formulation (18.8%) in a dose of 5 μg/ml. Conclusion: On the basis of in-vitro and Ex-vivo studies, it was concluded that prepared herbal fast disintegrating tablets were stable and had potent antihistaminic activity.

Keywords: Antihistaminic activity, croscarmillose, fast disintegrating tablets, herbal formulation, Fagonia species, friability weight variation. 1. INTRODUCTION Histamine is one of the most important mediator for broncho constriction and inflammation. It is released from degranulated mast cells. In antihistaminic therapy, histamine can be targeted by either prevention of its release from mast cells or use of histamine receptors antagonists [1, 2]. Herbal treatment to target the histamine is important to reduce the side effect like drying up of secretions, increased coughing and wheezing of conventional antihistamines drugs [3]. Several plant extracts have been studied for the treatment of bronchial asthma and allergic disorders like Clitoria ternatea [4], Bauhinia racemosa [5], Acalypha canescana [6], Fagonia bruguieri [7], Fagonia schweinfurthii [8] etc.

*Address correspondence to this author at the I.T.S College of Pharmacy, Murad Nagar, Ghaziabad (UP), India; Tel: +91-9045413689; E-mail: [email protected] 2212-3938/18 $58.00+.00

Fagonia species are traditionally well known for the treatment of antimicrobial activity [9], cytotoxic and antitumor activity [10], anti-allergic property [7], hemorrhoids, inflammation, sores, leprosy, open wounds and fever in the form of internal and external conventional formulation [11]. Fagonia schweinfurthii Hadidi (Family-Zygophylaceae) and its closely related species are widely distributed in deserts and dry areas of India, Pakistan to tropical Africa [12, 13]. Fagonia schweinfurthii Hadidi was claimed for the treatment of antioxidant and hepatoprotective activity [14], antiinflammatory and wound healing effects [15], allergies and other skin diseases [16], anti-fungal [17] and anti-histaminic activity in guinea pig ileum [8]. Fast disintegrating tablets (FDTs) are beneficial for patients such as paediatric, geriatric, bedridden, or other disabled persons, who may face difficulties in swallowing conventional tablets or capsule and liquid oral syrup [18].

© 2018 Bentham Science Publishers

Ex-vivo Study of Herbal Fast Disintegrating Tablets in Guinea Pig Ileum

In the present work, fast disintegrating tablets containing dried extract of Fagonia schweinfurthii Hadidi were prepared and evaluated for anti-histaminic activity in comparison to marketed tablet containing cerizine HCl (Stanhist-10, manufactured by Ranbaxy Pvt. Ltd). 2. MATERIAL AND METHODS 2.1. Plant Material The plant material was collected from Jodhpur region of Rajasthan, India and was authenticated by Botanical Survey of India, Jodhpur, Rajasthan (India). A voucher specimen (No. JNU/PH/2013/Fs/F3) and herbarium sheet were kept in the institute for further references.

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granulated through sieve no. 22. Various concentrations of superdisintegrant (croscarmillose, crospovidone and sodium starch glycolate) were used in blends along with magnesium stearate, menthol and aspartame. The sized granules, superdisintegrant, magnesium stearate, menthol and aspartame were mixed properly for sufficient time (approximate 20 min.). Mixed blend was compressed in tablet using 12 mm punches on 8 station rotary tablet compression machine (Hardik Engineers, Ahmadabad). 2.4. Characterization of Fast Disintegrating Tablets Prepared tablets were evaluated for certain physical and mechanical parameters like disintegration time, wetting time etc. as follows: 2.4.1. Physical Parameters

2.2. Preparation of Aqueous Extract Fresh plant of Fagonia schweinfurthii Hadidi was shade dried and ground to prepare a coarse powder. The material was extracted by decoction method with water at 40°C for 5 hrs. The extract was filtered through a membrane filter (45 μm), and the filtrate was concentrated to dryness by vacuum evaporator (Jindal Pvt. Ltd.). Crude extract was stored in a desiccator. 2.3. Preparation of Tablets 200 mg dose of extract in tablet was selected on the basis of the previous study done by Puri et al. [8]. Tablet weight was maintained at 500 mg. At initial stage total nine tablet formulations were prepared by wet granulation technique using three superdisintegrating agents at three different levels of concentrations. Tablets were prepared according to the composition given in Table 1. Lactose and starch pasteswere used as a diluent and binding agent respectively. Granules were prepared and semi-dried. Then the wetted mass was sized using sieve no. 10 and dried in hot air oven (Jindal Pvt. Ltd.) for one hour at 30°C. After drying the granules were reTable 1.

Current Clinical Pharmacology, 2018, Vol. 13, No. 2

Tablets were evaluated for hardness (Monsanto Hardness Tester), friability (Roche Friabilator) and weight variation [19, 20]. 2.4.1.1. Disintegration Time Test was carried out on 6 tablets using the apparatus specified in I.P.2007 [20]. 900 ml of water was taken in a 1000 ml beaker at 37±2°C and tablets were placed in six glass tubes. Time required for complete disintegration of the tablet was recorded as disintegration time. 2.4.1.2. Wetting Time Wetting time of dosage form is related to the contact angle. It needs to be assessed to give an insight into the disintegration properties of the tablets; a lower wetting time implies a quicker disintegration of the tablet [21]. A petri dish containing 6 ml of distilled water was used as wetting medium. A tissue paper folded twice was kept in the petri dish and a tablet was placed on it. A small quantity of amaranth red colour was put on the upper surface of the tablet. Time required for the upper surface of the tablet to become red was noted as the wetting time of the tablet.

Composition of fast disintegrating tablets.

Ingredient (in mg)

Formulation Code F1

F2

F3

F4

F5

F6

F7

F8

F9

Drug (Extract)

200

200

200

200

200

200

200

200

200

Sodium starch glycolate

10

25

40

-

-

-

-

-

-

Crospovidone

-

-

-

10

25

40

-

-

-

Croscarmillose

-

-

-

-

-

-

10

25

40

Mag. Stearate

5

5

5

5

5

5

5

5

5

Aspartame

20

20

20

20

20

20

20

20

20

Menthol

1

1

1

1

1

1

1

1

1

Lactose

264

249

234

264

249

234

264

249

234

Starch paste (5%w/w)

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

Total (in mg)

500

500

500

500

500

500

500

500

500

130 Current Clinical Pharmacology, 2018, Vol. 13, No. 2

Puri et al.

2.4.1.3. Stability Study Stability studies for the optimized formulations were carried out to determine the effect of formulation additives on the stability of drug and also to determine the physical stability of the formulation under accelerated storage conditions. Tablets were stored in an aluminium foil pouch and subjected to elevated temperature and humidity conditions of 40 ± 2oC/ 75 ± 5% RH. Samples were withdrawn at the end of 0, 2, 4 and 6 months and evaluated for disintegration time and hardness [22].

of the formulated tablet were prepared. A standard dose response curve of histamine was recorded by addition of 0.05ml, 0.1ml, 0.4ml, 0.8ml, 1.6ml histamine solution. 0.1ml dose of antihistaminic preparations was given to tissue. Again responses of histamine in the presence of different antihistaminic preparations like cetirizine solution and formulated tablet solutions were recorded [23, 24]. 3. RESULT AND DISCUSSION

2.5. Antihistaminic Activity by Using Guinea Pig Ileum

3.1. Formulation of Fast Disintegrating Tablets by Using Super-disintegrating Agents

Guinea pig ileum preparations are very commonly used for isolated tissue works. 100µg/ml histamine stock solutions, 50µg/ml stock solution of a marketed tablet containing cetirizine HCl drug and 1000µg/ml stock solution

Nine formulations of tablets were prepared by using three levels of three superdisintegrating agents. The blends and tablets were evaluated for various parameters as the prescribed method.

Table 2.

Evaluation of physical properties of tablet blends.

Formulation Code

Bulk Density (gm/ml)±SD

Tapped Density (gm/ml)±SD

Hausner’s Ratio

Compressibility Index

Angle of repose±SD(ino)

F1

0.517±0.003

0.555±0.001

1.07

6.84

27.96±0.31

F2

0.517±0.002

0.553±0.002

1.08

6.50

29.35±0.44

F3

0.533±0.004

0.576±0.001

1.08

7.46

29.89±0.91

F4

0.517±0.001

0.557±0.002

1.07

7.18

28.59±0.36

F5

0.519±0.002

0.581±0.003

1.09

10.67

29.16±0.25

F6

0.531±0.002

0.557±0.001

1.07

4.66

28.59±0.54

F7

0.517±0.003

0.559±0.004

1.08

7.51

26.56±0.16

F8

0.519±0.004

0.553±0.001

1.06

6.14

28.59±0.27

F9

0.526±0.002

0.559±0.005

1.06

5.90

28.59±0.3

Broad range

0.517-0.533

0.553-0.81

1.06-1.09

4.66-10.67

26.56-29.89

n=3.

Table 3.

n= 3.

Physical evaluation of tablet formulations.

Formulation Code

Wt. Variation ±SD (mg)

Hardness ± SD (kg/cm2)

Diameter (mm)

Thickness ±SD (mm)

F1

499±3

3.3±0.57

12

6.0±0.11

F2

500±3

3.0±1

12

6.1±0.05

F3

501±2

3.3±1.1

12

6.1±0.11

F4

498±3

3.6±0.57

12

6.0±0.05

F5

501±1

3.6±0.57

12

6.1±0.05

F6

502±3

4±1

12

6.1±0.11

F7

501±2

4±0

12

6.0±0.05

F8

501±1

3.6±0.57

12

6.0±0.05

F9

499±2

3.6±0.57

12

6.0±0.11

Broad range

498-502

3-4

12

6.0-6.1

Ex-vivo Study of Herbal Fast Disintegrating Tablets in Guinea Pig Ileum

Table 4.

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131

Evaluation of various parameters of tablets.

Formulation Code

Disintegration Time (Min) ±SD

Wetting Time (Min) ±SD

Friability %±SD

F1

5.47±0.10

4.13±0.13

0.49±0.01

F2

4.56±0.13

3.59±0.12

0.23±0.02

F3

3.28±0.09

3.10±0.10

0.14±0.13

F4

5.14±0.05

3.29±0.12

0.44±0.05

F5

3.46±0.07

2.55±0.08

0.45±0.06

F6

3.38±0.08

2.06±0.05

0.39±0.07

F7

3.51±0.06

3.03±0.06

0.49±0.10

F8

2.15±0.05

1.45±0.07

0.34±0.05

F9

2.05±0.06

1.06±0.06

0.53±0.06

Broad range

2.05-5.47

1.06-4.13

0.39-0.53

n=3.

3.1.1. Evaluation of Physical Properties of Tablet Blends Prepared batches were evaluated for various micromeritic parameters including flow properties and results are shown in Table 2. Values of compressibility index were less than 30. The Hausner’s ratio was between 1.06 and 1.09. The angle of repose was less than 30°. The outcomes of these parameters indicated the excellent flow properties and suitability of blends for compression. 3.1.2. Evaluation of Tablets Prepared tables were evaluated for various parameters like weight variation, hardness, thickness, disintegration time, wetting time and friability and the results are shown in Tables 3 and 4. All the tablets were within limits of weight variation allowed by I.P. 2007 [20]. Hardness of the tablets was within 3-4 kg/cm2 which indicated good mechanical strength. Diameter of the tablets was close to 12 mm. Thickness varied from 6.0-6.1 mm. 3.1.2.1. Friability Friability of all the formulation was found to be less than 1.0%. The results indicated resistance to loss of weight and ability to withstand abrasion in handling, packaging and shipment.

formulation for further study. All the results of optimized formulation are given in Table 5. 3.1.3. IR Spectroscopy Compatibility Study

of

Extract

and

Excipient

ATR (Attenuated total reflection) is a sampling technique used in conjunction with infrared spectroscopy which enables samples to be examined directly in the solid or liquid state without further preparation. Compatibility between plant extract and excipient was observed by Infrared spectroscopy (Bruker –α-T). IR spectra of plant extract, croscarmillose and granules were recorded and comparedto check the interaction In the spectrum of granules, all the characteristic peaks of croscarmillose were present indicating no interaction between croscarmillose and plant extract. Spectra of croscarmillose, plant extract and granules are shown in Figs. 1, 2 and 3 respectively. Table 5.

S. No.

Various parameters for optimized tablet formulation (F8).

Parameters

Values for Optimized Formulation (F8)

3.1.2.2. Wetting Time

1.

Hardness± SD (kg/cm2)

3.6±0.57

Wetting time for tablet formulations was found to vary in the range 1.06-4.13 minutes. It was observed that disintegration process was started by wetting of the tablets.

2.

Diameter (mm)

12

3.

Thickness± SD (mm)

6.0±0.05

4.

Weight variation ± SD (mg)

501±1

5.

Disintegration time (Min) ±SD

2.15±0.05

6.

Wetting time(Min) ±SD

1.45±0.07

7.

Friability %± SD

0.39±0.07

3.1.2.3. Disintegration Time Among all the batches, low disintegration time was observed in case F8 (2.15 min) and F9 (2.05 min) formulation. But low concentration of croscarmillose was used in the case of F8 formulation (5%) as compared to F9 (8%). So, F8 formulation was selected as an optimized

Puri et al.

99 98

3500

3000

2500

2000

1500

1018.19

1317.94

1457.35 1416.44

1574.92

2319.73

2859.30

3210.49

3744.22

97

Transmittance [%]

100

101

132 Current Clinical Pharmacology, 2018, Vol. 13, No. 2

1000

Wavenumber cm-1

3500

3000

2500

2000

1500

640.03

1066.61

1418.54

1570.35

3858.40

99.0

Transmittance [%] 99.2 99.4 99.6

99.8

Fig. (1). IR Spectra of croscarmillose.

1000

Wavenumber cm-1

Fig. (2). IR Spectra of plant extract.

3.2. Formulation of Tablets by Using Croscarmillose Sodium as Intra-granular and Extra-granular and Evaluation Low disintegration time is desired for disintegrating tablets as per the literature. Quality related to disintegration time can be improved by using super-disintegrating agent as intra-granular or extra-granular. Croscarmillose sodium was selected on the basis of previous part of study. Tablets were prepared by using croscarmillose sodium as intra-granular as well as extra-granular formulation of tablets are given in Table 6. Tablet blends and prepared tablets were evaluated for various parameters (results are shown in Table 7).

Wet granulation method was used for the preparation of tablets in which three different percentage 2% (10 mg), 3.5% (17.5 mg) and 5% (25 mg) of croscarmillose sodium was used as extra-granular while 2% was used as intragranular. Results (on the basic of Table 8) reveal that desired disintegration time and wetting time was obtained by using croscarmillose as intragranular and extragranular. So F’3 was selected as optimizedformulation for Ex-vivo and stability studies.

Current Clinical Pharmacology, 2018, Vol. 13, No. 2

133

98 97

3500

3000

2500

2000

1500

757.34

873.45

1070.53 1027.01

1257.42 1204.85

1422.48 1376.65

1549.90

1656.05

2898.34

3331.25 3261.79

95

96

Transmittance [%]

99

Ex-vivo Study of Herbal Fast Disintegrating Tablets in Guinea Pig Ileum

1000

Wavenumber cm-1

Fig. (3). IR Spectra of granules.

Table 6.

Formulation of tablets (F’1,F’2,F’3). Ingredient (in mg)

Table 7.

Formulation Code F’1

F’2

F’3

Drug (Extract)

200

200

200

Croscarmillose (Intragranular)

10

10

10

Lactose

254

246.5

239

Croscarmillose (Extragranular)

10

17.5

25

Mag. stearate

5

5

5

Aspartame

20

20

20

Menthol

1

1

1

Starch paste (5%w/w)

q.s.

q.s.

q.s.

Total (in mg)

500

500

500

Evaluation of physical properties of tablet blends (F’1,F’2,F’3).

Formulation Code

Bulk Density (gm/ml)±SD

Tapped Density (gm/ml)±SD

Hausner’s Ratio

Compressi-bility Index

Angle of Repose±SD (in o)

F’1

0.515±0.003

0.557±0.002

1.08

7.53

28.81±0.43

F’2

0.517±0.002

0.551±0.002

1.06

6.17

29.24±0.29

F’3

0.513±0.002

0.553±0.001

1.07

7.23

29.24±0.32

n=3.

3.3. Ex-Vivo Antihistaminic Activity of Tablet (F’3) by Using Guinea Pig Intestine 50 μg/ml stock solution of marketed cetirizine HCl tablet (Stanhist-10) manufactured by Ranbaxy Pvt. Ltd. was used in the study. Students’t test was used to compare the

antihistaminic activity produced by developed formulation and standard drug. Antihistaminic activity of formulated tablet showed that percentage inhibition (1000 μg/ml solution) was nearly equal to inhibition produced by 50 μg/ml of standard drug (p ≤ 0.05). The data for concentration

134 Current Clinical Pharmacology, 2018, Vol. 13, No. 2

Table 8.

Puri et al.

Evaluation parameters of tablet formulation (F’1,F’2,F’3). Formulation Code

S. No.

Parameters 2

F’1

F’2

F’3

1.

Hardness± SD (kg/cm )

3.6±0.57

3.3±0.52

3.6±1.1

2.

Diameter (mm)

12

12

12

3.

Thickness± SD (mm)

6.1±0.05

6.0±0.05

6.0±0.05

4.

Wt. Variation± SD (mg)

501±1

500±2

500±1

5.

Disintegration time (Min.) ±SD

2.05±0.05

1.35±0.07

1.15±0.08

6.

Wetting time (Min.) ±SD

1.45±0.06

1.05±0.07

0.56±0.04

7.

Friability %± SD

0.33±0.05

0.24±0.07

0.32±0.04

n=3.

Table 9.

Results of concentration response curve(F’3).

S. No.

Dose of Histamine (μg/ml)

% Max. Response of Histamine

% Max. Response of Histamine in Presence of Tablet Formulation

% Max. Response of Histamine in Presence of Marketed Tablet

1.

5

45± 2.59

30±2.33

26.2± 1.42

2.

10

68± 2.37

40±1.23

40± 2.87

3.

20

79± 1.83

50±1.65

64± 2.95

4.

40

90±1.94

70±2.02

75± 2.56

5.

80

100±2.45

78±1.42

80± 1.73

The value were expressed as Mean ±SEM (n = 6).

response curve in the presence of marketed tablet and prepared optimized tablet are shown in Table 9. Ex-vivo antihistaminic activity of tablet showed that preparation has antihistaminic property and no interference was produced by excipients. 3.4. Stability Study Tablets were stored in an aluminium foil and subjected to elevated temperature and humidity conditions of 40 ± 2oC/ 75 ± 5% RH. Samples were withdrawn at the end of 0, 2, 4 and 6 months and evaluated for disintegration time and hardness. Results of stability studies revealed that no significant change was observed in the disintegration time Table 10. Stability study on optimized formula F’3. Time

Disintegrating Time (Min.)

Hardness (kg/cm2)

Initial

1.15±0.08

3.6±1.1

2 month

1.10±0.06

3.6±0.57

4 month

1.14±0.05

3.4±1.0

6 month

1.12±0.05

3.3±0.57

Values are given as mean±SD, n=3.

and hardness after 6 months study at different temperature and humidity conditions. Results of stability studied are given in Table 10. CONCLUSION Fast disintegrating tablets containing dried extract of Fagonia schweinfurthii Hadidi was prepared successfully by using croscarmillose as superdisintegrating agent. Tablets were evaluated for various evaluation parameters like hardness (3.6±1.1 kg/cm2), weight variation (500±1mg), % friability (0.32±0.04), disintegration time (1.15±0.08 min.) and wetting time (0.56±0.04 min.). It was found that disintegration time can be reduced by using superdisintegrating as extra granular as well as intra granular. FTIR study showed that there was no interaction between croscarmillose and plant extract, so it was suitable for the preparation of tablets. Stability study revealed that prepared formulation was stable. Ex-vivo antihistaminic activity of tablet showed that preparation had potent antihistaminic activity and it was comparable to the marketed tablet. ETHICS APPROVAL PARTICIPATE

AND

CONSENT

TO

The study received ethics committee approval of I.T.S College of Pharmacy, Murad Nagar, Ghaziabad (No. JNU/ PH/2013/Fs/F3).

Ex-vivo Study of Herbal Fast Disintegrating Tablets in Guinea Pig Ileum

Current Clinical Pharmacology, 2018, Vol. 13, No. 2

HUMAN AND ANIMAL RIGHTS

[9]

No humans were used in this research. All animal research procedures followed were in accordance with the standards set forth in the eighth edition of Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences, The National Academies Press, Washington, D.C.).

[10]

CONSENT FOR PUBLICATION

[13]

Not Applicable.

[11]

[12]

[14]

CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS

[15]

[16]

Declared none. [17]

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