ROLE OF ADDITIVES IN FORMULATION

DEVELOPMENT & PROCESSING

ByASHISH KUMAR PAL

Reg. No. 1702-10-885-010Pharmaceutical Analysis and Quality Assurance

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Pharmaceutical additives are defined as secondary ingredients present in both prescription and over-the-counter drug formulations and contributing in one or more of the following ways:

• improving consumption ease of the dosage form

• enabling or enhancing the delivery of the drug or medicine

• increasing the stability of active ingredients

• acting as a filler or diluents so that an adequate amount of material is available to properly fill a dosage form

• acting as an antimicrobial or antioxidant to extend the shelf life of the active ingredient

Definition of Additives

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INTRODUCTION • Despite tremendous advancement in the drug delivery system,

oral route remains the preferred route because of low cost therapy and ease of administration leads to higher levels of patient compliance

• An incomplete release of the drug and shorter residence time of the dosage forms in the upper GIT, which is a prominent site for the absorption of many drugs, leads to decreased bioavailability. Metformin HCI, which is an antihyperglycaemic agent widely used in the management of N IDDM.

• Stepensky et all concluded that absolute oral bioavailability of Metformin HCl is 50-60%.It is safe drug and it has a half-life of 1.5-3 hrs. It is not absorbed completely and gives low bioavailability problem. Almost 80-100% of the drug is excreted unchanged. The total daily requirement of Metformin HCI is 1.5-3g/day

• However, bioavailability of the drug has been found to be reduced further with controlled release dosage forms, probably due to the fact that

1. passage of the controlled release single unit dosage forms from absorption region of the drug is faster than its release and

2. most of the drug released at the colon where metformin hydrochloride is poorly absorbed

PREPARATION AND IN VITRO EVALUATION OF GASTRIC FLOATING MICROCAPSULES OF

METFORMIN HCL

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APPROACHES

• Controlled release formulation suitable for metformin hydrochloride, therefore, should be a gastro-retentive dosage form, which releases the drug slowly in the stomach for gradual absorption in the intestines.

• Among the different approaches that have been developed, low density system holds promise. Floating DDS systems are low density systems that have sufficient buoyancy to float over gastric contents, and the drug is released slowly at the desired rate, which results in increased gastro-retention and reduces fluctuations in plasma drug concentration

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OBJECTIVE

• To design a SR floating microspheres of Metformin HCI using two polymers Cellulose Acetate Butyrate and Eudragit RLI 00, in order to achieve an extended retention in the upper GlT, which may result in enhanced absorption and thereby improved bioavailability.

• The prepared rnicrospheres were also studied for drug release behavior in simulated gastric fluid at pH 1.2 and phosphate buffer at pH 6.8 respectively, and optimize the drug release to match the target release profile and possible release mechanism proposed.

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MATERIALS

• Metformin HCI • Cellulose Acetate Butyrate (Mol.

Wt 16,000) • Eudragit RLIOO (Mol. Wt 150,000) • Acetone, • liquid Paraffin (Light), • Span 80 AR, • Magnesium stearate

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Preparation of floating microspheres

• non- aqueous emulsion solvent evaporation method.

• Eudragit RLI 00 (10% w/w) and Cellulose acetate butyrate (10% w/w) were used separately, and mixed together to form microspheres.

• In case of microsphere made of combination polymers, firstly weighed quantity of eudragit RLlOO and CAB was completely dissolved in acetone at the polymer ratio 1:1, 5% w/w of magnesium stearate (to the total polymer conc. used) and weighed quantity of Metformin HCI (50%w/w) were dispersed to the above slurry and stirred in a magnetic stirrer.

• The drug polymer dispersions were pressurized under CO2 gas, which upon release of the pressure form cavities on the polymeric surface.

• The porous drug polymer dispersions were then slowly introduced into 70 ml liquid paraffin previously emulsified with 1 % Span 80, while stirring at 1000 rpm.

• The whole system was stirred for 3 hour to allow the complete evaporation of acetone. The oil layer was decanted and microspheres were washed several times with petroleum ether (40-60°) The washed micro spheres were dried in an oven at room temperature not exceeding 25°C. 7

Detail composition of each formulation

Formulation Code

Drug Polymer

ratio

Polymerconcentration

10%w/w

Quantity of%w/w

magnesium stearate

Stirring Speed (rpm)

A11:2 RLI00 5 1000

Bl a1:2 CAB 5 1000

AlBIa1:2 RLlOO,CAB

(1:1) _5 1000

B11:2 CAB 5 1500

A1B11:2 RLlOO,CAB

(1:1)5 1800

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OTHER PARAMETERS

The following studies were carriedout • Viscosity of the Polymer Organic Phase• Yield of Microspheres• Particle size analysis• Scanning electron microscopy• Fourier Transform Infrared Spectroscopy

(FT-IR): • Drug entrapment efficiency

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In vitro Drug Release Study

• In vitro drug release studies were carried out for all products in USP type II fitted with six rotating basket dissolution test apparatus. The microspheres were evaluated for drug release using 900 ml of simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) for 10 hour maintained at 37 ± 0.1 °C and stirred at 100 rpm.

• sink conditions were maintained• Withdrawn samples were analysed

spectrophotometrically at 233nm using a UV-Visible double beam Spectro- photometer.

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RESULTS AND DISCUSSION

• The present study was aimed at not only to improve the buoyancy of Microspheres, but also to release the drug in the acidic pH in controlled fashion. Also, to make a formulation having density lower than the gastric contents, using mixture of two polymers of different permeability characteristics. 

• The two polymers are selected in such a way that one will give initial burst release, which is essential from therapeutic point of view, while the other will control the drug release by maintaining the buoyancy 

• Eudragit RL 100 contain higher amount of quaternary ammonium groups, which renders it more permeable. It was evident that addition of eudragit RL100 increased the permeability of the microspheres to the surrounding dissolution medium due to the swelling nature of the polymer.

• In addition to this, the porous nature of the microsphere produces an upward motion of the dosage form to float on the gastric contents11

* All values are expressed as mean ± SD, n=3

In vitro drug release profile data

Cumulative % drug released of coded formulations

in 0.1 M HCI at pH 1.2 in Phosphate buffer at pH 6.8

Time Al Bl AlBl MKT Al Bl AIBI MK

(hr)

1 43.59 24.11 37.31 21.3 46.51 25.16 38.1 23.17

± 1.03 ±1.98 ±2.23 ±1.l7 ±1.05 ±1.12 ±1.01 ±1.l5

2 47.08 27.21 41.03 33.15 49.25 29.07 42.3 37.11

±1.02 ±1.15 ±2.15 ±2.18 ±1.63 ±1.l8 ±1.49 ±1.43

3 56.11 31.03 49.25 39.59 57.69 33.51 47.41 41.39

±1.15 ±1.93 ±2.13 ±2.57 ±1.46 ±2.13 ±1.63 ±1.23

4 69.15 39.17 58.31 48.91 71.85 41.25 61.05 53.22

±1.23 ±1.23 ± 2.35 ±1.8 ±1.23 ±2.23 ±1.87 ±1.47

5 74.21 47.51 64.17 57.07 73.49 49.69 66.31 59.71

±1.93 ±1.03 ±1.97 ±2.23 ±1.89 ±2.43 ±1.98 ±1.56

6 77.16 53.79 67.52 68.33 79.71 56.22 69.43 67.33

±1.54 ±1.l2 ±2.96 ±1.54 ±1.57 ±2.47 ±2.13 ±1.41

7 79.51 57.88 71.69 79.24 84.22 59.31 73.34 76.15

±1.29 ±1.99 ±2.57 ±1.47 ±1.63 ±2.51 ±2.23 ±1.l4

8 81.75 59.18 73.41 83.03 86.39 67.75 77.15 87.21

±1.27 ±1.05 ±1.97 ±1.97 ±1.17 ±2.41 ±2.54 ±1.23

9 82.07 64.61 75.16 87.41 87.15 69.19 79.03 89.08

±1.23 ±1.97 ±2.13 ±2.13 ±1.87 ±2.17 ±1.67 ±1.18

10 83.13 67.22 77.21 91.57 89.61 71.81 81.35± 1. 94.55

±1.98 ±1.07 ±1.98 ±2.57 ±1.56 ±1.98 17 ±1.12

* All values are expressed as mean ± SD, n=3

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RESULTS AND DISCUSSION• In vitro dissolution studies of all batches of micro pheres ,micro pheres made of

eudragit RL I 00 showed good flow properties, maximum floating tendency, but faster in vitro drug release rate in both simulated gastric media (pH 1.2) and phosphate buffer (pH 6.8). The prepared microspheres made of eudragit RL I 00 showed maximum drug release of 81-83% within 8-10 hours in 0.1 M HCI. However, the same micro pheres showed higher amount of drug release, 85-89% in phosphate buffer (pH 6.8) as compared to the release in 0.1 M HCI

• Likewise, microspheres made of CAB showed good flow properties, minimum floating behaviour but slower rate of invitro drug release initiated by lag time in both the dissolution media, as compared to the eudragit RLIOO microspheres. It is observed from the release profile that around 59-67% drug released in 0.1M HCI and 67-71% drug released in phosphate buffer (pH 6.8) within 8-10 hours.

• It was also evident that combination of eudragit RL I 00 and CAB imparts a synergi tic increase in the relative viscosity compared to the single polymers. The addition of eudragit RL I 00 to CAB polymer increases the permeability of the microspheres to dissolution medium due to the swelling nature of eudragit RLIOO. Moreover, eudragit RL 100 contain higher amount of quaternary ammonium groups, which renders it more permeable. This would increase the porosity of CAB membrane and minimizes the lag time initiated by CAB microspheres

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CONCLUSION

• The combination polymer at polymer to polymer ratio 1:1 helps to leach out the drug from its matrices and exhibits an initial rapid drug release for the first 2 to 3 hours and then slower drug release.

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TASTE MASKING AND FORMULATION OF OFLOXACIN RAPID DISINTEGRATING TABLETS AND ORAL SUSPENSION

INTRODUCTION

• With the advancement in technology and experience, pharmaceuticals are prepared and administered to patients in more compliant and efficient manner. Rapid disintegrating tablets are the new improved dosage forms developed especially for the young and the elderly patients who find inability to swallow tablets and capsules due to under developed muscular,nervous system and dysphagia.

• When this type of tablet is placed into the mouth, the saliva serves to rapidly dissolve the tablet usually in about 30 seconds.The critical formulation problem is the masking of bitter taste associated with most of the drugs and this can be overcome by taste masking techniques such as:

1.polymer coating,

2.complex formation,

3. granulation,

4.microencapsulation and

5.use of ion exchange resins). 15

INTRODUCTION

• Ofloxacin is widely used antibacterial drug recommended in the treatment of chronic bronchitis, respiratory/ENT infections, nonspecific urethritis, gonorrhoea, atypical pneumonia, leprosy, cervicitis.

• One of the major drawbacks of this drug is its bitter taste which may give rise to patient noncompliance when formulated as conventional dosage forms.

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OBJECTIVE

• In the present study taste masking of bitter drug ofloxacin was achieved by preparing taste masked granules using a pH sensitive polymer, Eudragit E- 100. These granules were then formulated into rapidly disintegrating tablets using the technique of super- disintegrant addition. Also a suspension dosage form was prepared using taste- masked granules of ofloxacin.

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Materials

• Ofloxacin

• Eudragit E-I 00

• Microcrystalline cellulose

• Sodium starch glycolate

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Preparation of taste-masked granules

• Ofloxacin was thoroughly mixed with varying amounts of powdered Eudragit E-I00. Then 10% ethanol was added to this mixture in a glass beaker and a gel was prepared.

• The prepared gel was manually pressed out using a syringe. After extrusion of the gel, ethanol was removed by evaporation overnight at room temperature.

• Subsequently the solidified gel was crushed into granules using a pestle and mortar.

• The drug: polymer ratio which produced taste masked granules was used for further studies.

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Formulation of rapidly disintegrating tablets (RDTs)

• The prepared Eudragit E-I00 granules of ofloxacin were compressed into (RDTs) by using microcrystalline cellulose (MCC) as directly compressible binder and sodium starch glycolate (SSG) as the super- disintegrant.

• Flavoring was done with menthol to give the tablets more palatable feel. Magnesium stearate was added as the lubricant while mannitol was added as the diluent.

• Similarly control tablets were prepared using pure drug instead of taste masked granules. Different ratios of the super-disintegrant, SSG and the binder, MCC were investigated for the formulation of ofloxacin ROTs and the ratio that gave the minimum disintegrating time along with acceptable hardness was chosen for the formulation of the final batch of tablets.

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Effect of sodium starch glycolate (SSG) and microcrystalline cellulose (MCC) ratio on the

disintegration time of ofloxacin RDTs

Formulation code

SSG: MCC Disintegration time (s)

Tablet

strength

(hardness in kg/cm')

OF-1 1:0.5 7.00 ± 0.94 0.5

OF-2 1:1.0 15.00 ± 1.36 1.0

OF-3 1:2.0 52.00 ± 1.11 1.5

OF-4 1:3.0 58.00 ± 1.31 2.5

OF-5 1:4.0 63.00 ± 0.97 3.0

OF-6 1:5.0 84.00 ± 1.54 3.5

OF-7 1:6.0 86.00 ± 2.01 4.0

OF-8 1:8.0 98,00± 1.73 4.5

OF-9 1:10 119.00 ± 0.63 5.5

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Evaluation of RDTs

• The force required to break the tablet (tensile strength) was measured using Monsanto hardness tester.

• For the measurement of in vitro disintegration time a modified dissolution apparatus (paddle type) was used. 900 ml of water maintained at 37°C and stirred with a paddle at 100 rpm was used as the disintegration fluid.

• In vitro dissolution studies were carried out using USP XXIII Dissolution apparatus II (paddle type). A tablet was placed in a basket and rotated at 50 rpm. The release profile was studied both in phosphate buffer at pH 6.8 and hydrochloric acid buffer pH 1.2.

• The taste evaluation was done using spectrophotometric method and by panel testing. For panel testing, 20 healthy human volunteers, of either sex, in the age group of 20-30 years were selected out of 31 volunteers

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RESULTS AND CONCLUSIONS• Sensory evaluation for taste by the panel confirmed the tasteless

characteristics of the granules as none of the subjects felt bitter taste even after keeping in mouth for 20-30 s. Hence, this technique of taste- masking using a pH-sensitive polymer was found to be effective in masking the bitter taste of the drug.

 • The taste masked granules were compressed into rapidly

disintegrating tablets. Different ratios of the super-disintegrant, SSG and the directly compressible binder, Ratios of SSG: MCC below ratio 1: 1 gave very less disintegration times (less than 19 s) but the tablet hardness was very low.

• All the ratios above 1:3 (i.e., Formulations OF-5 to OF-9) gave high disintegration times and therefore, were rejected. Formulation OF-4 gave acceptable hardness as well as rapid disintegration. Therefore, it was selected for the preparation of final batch of RDTs.

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CONCLUSION

• To conclude, efficient taste masking was achieved for the bitter drug ofloxacin using the technique of granulation. Patient compliant dosage forms i.e. oral liquid suspension and rapidly disintegrating tablets that had good taste were successfully formulated. These studies suggest that these patient friendly taste masked dosage forms may be useful for children and elderly patients.

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DESIGN AND EVALUATION OF BUCCAL PATCHES OF GRANISETRON HYDROCHLORIDE

INTRODUCTION

• Granisetron hydrochloride (5 HT) receptor antagonist) is a drug used in the management of nausea and vomiting induced by cytotoxic chemotherapy and for prevention and treatment of post-operative nausea and vomiting.

• The drug is well absorbed from the gastrointestinal tract, but its oral bioavailability is low (60%) due to extensive first-pass metabolism. Since buccal route bypasses first- pass effect.

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APPROACHES

• The physico-chemical properties of GRN, its suitable biological half-life (3-4 h) and low molecular weight (348.9) make it suitable candidate for administration by buccal route, There are several reported studies on administration of drugs via buccal route, as patches or discs.

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Materials

• Granisetron hydrochloride (GRN)• chitosan (65 cps)• hydroxypropyl methylcellulose

(HPMC 15 cps), • ethyl cellulose (Ee), • polyvinyl pyrrolidone (PVP K-30) and

propylene glycol

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Method of preparation of buccal patches

• PVP (16.7% by weight of polymers) was used as mucoadhesive polymer and propylene glycol (30-50% of the polymer weight) as plasticizer.

• The weighed quantity of HPMC was properly dispersed in aqueous acetic acid solution (1% vlv, 25 ml). Then weighed quantity of chitosan was taken and mixed with the above solution.

• PVP was accurately weighed and dissolved in the filtered solution. The required quantity of plasticizer propylene glycol and aspartame (2% by weight of polymers) were added. Then the drug was dispersed uniformly in the viscous solution with continuous stirring.

• The resultant mixture was poured into specially fabricated glass moulds (5x5 cm) lined with aluminum foil. Drying was carried out at room temperature for 24 h.

• Small patches of (l x 1 cm in size) containing 1.12 mg of granisetron hydrochloride (equivalent to 1 mg granisetron) were cut with the help of sharp pen knife.

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Formulation

Chitosan- Chitosan- HPMC Propylene

Code HPMC (mg) (mg) glycol Ratio (mg)

CH1 1:2 250 500 225

CH2 1: 1 375 375 225

CH3 2:1 500 250 225

CH4 1:2 250 500 300

CH5 1:1 375 375 300

CH6 2:1 500 250 300

CH7 1:2 250 500 375

CH8 1:1 375 375 375

CH9 2:1 500 250 375 29

Evaluation of buccal patches

• Thickness of the films was determined using a micrometer screw gauge.

• Bioadhesive strength of all the formulations was tested; i.e., weight required to pull off the formulation from mucus tissue is recorded as mucoadhesion bioadhesion strength. This parameter for the film was measured on a modified physical balance. A self designed and locally fabricated apparatus was used for determination of tensile strength and percent elongation at break, which measure the mechanical strength of the film.

• In vitro drug release study was carried out using the beaker method as described by Ilango R et al.

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RESULTS AND DISCUSSION In the present work attempt has been made to prepare buccal films of granisetron

hydrochloride, an anti-emetic drug (5-HT3 antagonist). A total of nine mucoadhesive patches of GRN were prepared and evaluated for biological, physical and mechanical parameters.

According to work plan, the films were evaluated for their • appearance, • surface texture,• thickness, • weight variation, • folding endurance, • swelling index, • tensile strength, • elongation at break, • in situ bioadhesion strength, • drug content uniformity, • in vitro drug release, • short-term stability and • drug-excipient interaction.

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Film Mean Mean Folding Swelling Tensile Elongation In vitro Mean

Code Thickness Weight" endurance Index Strength' At break' Biadhesion Drug

(mm) (mg) (dynes/ (%) Strength' Content

cm'xltl') (gm) %

CHI 0.20 9.77 92.66 45.60 1.79 5.01 3.93 97.96 (0.01) (0.36) (4.50) (0.36) (0.03) (0.078) (0.15) (2.28)

CH, 0.30 10.29 74.00 38.10 1.62 4.30 3.80 96.36

(0.02) (0.36) (4.72) (0.36) (0.08) (0.051 ) (0.20) (1.64)

CH3 0.22 10.26 52.66 36.90 1.86 5.75 4A3 96AO

(0.01) (0.35) (4.72) (0.35) (0.09) (0.070) (0.21) (0.76)

CH. 0.23 9.81 117.66 49AO 1.52 3.17 3.25 98.16

(0.01) (0.28) (2.51) (0.28) (0.06) (0.075) (0.13) (IA2)

CH, 0.29 11.70 83.33 40.60 1.92 5.04 3.90 96.24

(0.03) (0.38) (3.51 ) (0.38) (0.03) (OAI ) (0.23) (0.52)

CH. 0.23 10.68 60.00 38.25 2.08 6.57 4.33 96.33

(0.02) (OAO) (4.58) (OAO) (0.10) (0.231) (0.15) (0.72)

CH7 0.22 9.91 135.66 47.15 1.78 6.09 3.96 96.90

(0.02) (0.33) (4.50) (OAO) (0.02) (0.133) (0.16) (1.89)

CH. 0.34 11.75 99.38 43.60 2.06 7.18 4.16 99.21

(0.03) (OAO) (5.13) (0.33) (0.04) (0.032) (0.09) (0.55)

CH9, 0.20 9.86 79.33 33.80 2.13 7.31 5.56 96.78

(0.02) (0.22) (6.50) (0.22) (0.07) (0.096) (0.16) (0.51) 32

RESULTS AND DISCUSSION• The results revealed that the release of drug is dependent on polymer ratio

as well as on plasticizer (PG) concentration.

• The films were quite flexible as shown by measurement of folding endurance . The folding endurance of films goes on increasing as we increase the concentration of HPMC or propylene glycol. The maximum folding endurance as shown by formulation CH7 is approximately 135.

• There was significant correlation between tensile strength and polymer composition. The tensile strength of film increases as we increase the concentration of chitosan and plasticizer concentration does not have much effect.

• The mucoadhesivity (in vitro bioadhesion strength) of all the films of varying ratios of polymers was tested and was found to increase as the proportion of chitosan in the film increases . This may be due to the fact that positive charges on the surface of chitosan could give rise to strong electrostatic interaction with mucus or negatively charged mucous membrane.

• Drug release from the films was found to be largely dependent on polymer ratio and plasticizer concentration and increases with an increase in the concentration of HPMC and plasticizer.

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RESULTS AND DISCUSSION • Formulation CH8containing chitosan and HPMC in I: I ratio with a plasticizer

concentration of 50% by weight of polymer has shown promising results and displayed t50 and t70 values of 1.75 and 2.75 h respectively and released more than 90% of drug in 5 h and it has got reasonably good tensile strength and mucoadbesive properties

SI. No. Formulation code t50 (b) t.70 (b) Cumulative % Drug release in

5b·±SD

1 CHI 2.25 3.30 86.50±1.28 2

2 CH2 2.25 3.60 78.18±1,283

3 CH3 2.26 4.50 71.07±1.764

4 CH. 1.75 3.00 88.46±1.00 5

5 CHs 2.24 3.50 87.85±1.326

6 CH6 2.21 4.25 79.27±0.50 7

7 CH7 1.52 2.80 91.25±1.738

8 CH8 1.75 2.75 90.37±1.73 9

9 CH9 2.15 3.75 80.49±1.62 34

CONCLUSION

• The results of the present study indicated that buccal patches of the drug GRN can be successfully prepared using a combination of chitosan and HPMC (15cps). The formulation CH8(containing the above polymers in a ratio of 1: 1 and plasticizer concentration of 50% by weight of polymer) has emerged as the promising buccal drug delivery system of GRN and displayed t50 and t70 values of 1.75 and 2.75 h respectively and released more than 90% of the drug in 5 h, with reasonably good tensile strength and mucoadhesive properties.

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REFERENCES• Indian Journel For Pharmaceutical Education And Research(ILPER),

Volume-43(2),April-June 2009, Preparation and In vitro Evaluation of Gastric Floating Microcapsules of Metformin HCl, Bipulath*, L.K. ath', B.Mazumdarl, .K.Sharma, M.K.Sarkar ,p.177-184.

 • Indian Journel For Pharmaceutical Education And Research(ILPER),

Volume-43(2),April-June 2009, Taste Masking and Formulation of Ofloxacin Rapid Disintegrating Tablets and Oral Suspension, Shishu*, Varun Rishi Kapoor and Kamalpreet, p.150-155.

 • Indian Journel For Pharmaceutical Education And Research(ILPER),

Volume-44(1),April-January-March 2010, Design and Evaluation of Buccal Patches of Granisetron Hydrochloride, Swamy P.V.*, Amitkumar T., Shirsand S.B., Patil A. N. and Laeeq Farhana, p.95-102

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