Formulation and Evaluation of Pulsatile s2

PREPARATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF FLURBIPROFEN FOR GASTRORETENTIVE DRUG DELIVERY

Synopsis for M.Pharm Dissertation submitted to the Rajiv Gandhi University of Health Sciences Karnataka, Bangalore.

Mr. VENKATESH.GAVINI M.Pharm. Part-I

Under the guidance of

Professor. K.SENTHIL KUMAR , M.Pharm, Department of pharmaceutics, Sarada Vilas College of Pharmacy

SARADA VILAS COLLEGE OF PHARMACY, KRISHNAMURTHYPURAM, MYSORE-4. 2010-2011 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE. ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE VENKATESH.GAVINI AND ADDRESS (IN BLOCK M PHARM, PART –I LETTERS) DEPARTMENT OF PHARMACEUTICS SARADA VILAS COLLEGE OF PHARMACY, KRISHNAMURTHYPURAM-570004, MYSORE, KARNATAKA. 2. NAME OF THE INSTITUTION SARADA VILAS COLLEGE OF PHARMACY, MYSORE. 3. COURSE OF STUDY AND SUBJECT MASTER OF PHARMACY IN PHARMACEUTICS. 4. DATE OF ADMISSION OF COURSE 10-09-2010 5. TITLE OF TOPIC PREPARATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF FLURBIPROFEN BY W/O EMULSIFICATION SOLVENT EVAPORATION METHOD. 6. BRIEF RESUME OF THE INTENDED WORK 6.1 Need for the study ENCLOSURE - I 6.2 Review of the literature ENCLOSURE - II 6.3 Objectives of the study ENCLOSURE – III

MATERIALS AND METHODS

7.1 Source of data ENCLOSURE – IV

7.2 Method of collection of data ENCLOSURE - V

7.3Does studies require any ENCLOSURE – VI investigations or interventions to be conducted on patients or other human or animal? If so, please

describe briefly. 7.4 Has ethical clearance been obtained ENCLOSURE – VI from your institution in case of 7.3

8. LIST OF REFERENCES ENCLOSURE – VII 9. SIGNATURE OF CANDIDATE

10. REMARKS OF GUIDE RECOMMENDED

NAME AND DESIGNATION OF 11. 11.1 Guide Mr. K.SENTHIL KUMAR., M.Pharm. PROFESSOR DEPARTMENT OF PHARMACEUTICS, SARADA VILAS COLLEGE OF PHARMACY, KRISHNAMURTHYPURAM- 570004,MYSORE, KARNATAKA.

11.2 Signature

11.3 Co guide (if any) Not applicable.

11.4 Signature Not applicable.

11.5 Head of department Dr.C.JAYANTHI, M.Pharm,PhD PROFESSOR AND HEAD DEPARTMENT OF PHARMACEUTICS, SARADA VILAS COLLEGE OF PHARMACY, KRISHNAMURTHYPURAM-570004, MYSORE, KARNATAKA.

11.6 Signature

12. 12.1 Remarks of the Principal RECOMMENDED & FORWARDED

12.2 Name and designation of principal Dr.K.HANUMANTHACHAR JOSHI. M.Pharm, Ph.D. PRINCIPAL, SARADA VILAS COLLEGE OF PHARMACY, KRISHNAMURTHYPURAM-570004, MYSORE, KARNATAKA.

12.3 Signature 6.0 BRIEF RESUME OF THE INTENDED WORK

ENCLOSURE - I

6.1 Need for the study

Oral controlled release systems continue to be the most popular ones among all the drug delivery systems as it offers several advantages over the conventional systems like: 1. Improve patient’s compliance and convenience due to less frequent dosing of drug. 2. Reduction in fluctuation of steady state plasma level and therefore helps in better control of disease condition. 3. Maximum utilization of drug enabling reduction in total amount of dose administered. 4. Reduction in health care cost through improved therapy, shorter treatment period and less frequency of dosing. The problem frequently encountered with controlled release dosage forms is the inability to increase the residence time of the dosage form in the stomach and proximal portion of the small intestine, due to the rapid gastrointestinal transit phenomenon of the stomach which may consequently diminish the extent of absorption of many drugs since almost most of the drug entities are mostly absorbed from the upper part of the intestine, therefore it would be beneficial to develop a sustained release formulation which remain at the absorption site for an extended period of time. Several approaches have been immersed to prolong the residence time of the dosage forms at the absorption site and one of these is the development of oral controlled release bio-adhesive system. Various gastrointestinal mucoadhesive dosage forms, such as discs, microspheres and bi-layered tablets, have been thoroughly prepared and reported by several research groups. Nonsteriodal anti-inflammatory drugs (NSAIDs) are amongst the most commonly prescribed medications in the world. Almost all the NSAIDs available in the market have severe side effects. As awareness of the GI side effects associated with NSAIDs increases, safety becomes a primary requisite in treatment. A trend in NSAID development has been to improve therapeutic efficacy and reduce the severity of GI (Gastric Intestinal) side effects through altering dosage forms by modifying release of the formulations to optimize drug delivery. One such approach is using polymeric microspheres as carriers of drugs. Microspheres can be defined as solid, approximately spherical particles ranging from 1 to 1000 μm they are made up of polymeric, waxy or other protective materials. Developing microspheres of Flurbiprofen will provide constant and prolonged therapeutic effect, which will reduce the dosing frequency and thereby improve the patient compliance. Apart from oral administration they could also be injected in to the body due to the spherical shape and smaller size. Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects, thus the aim of the research is to formulate mucoadhesive microspheres of Flurbiprofen and carry out its evaluation. The objective of the study was to develop mucoadhesive microspheres of Flurbiprofen and to carry out its evaluation. Mucoadhesive microspheres containing Flurbiprofen were prepared by w/o emulsification solvent evaporation method using mucoadhesive polymers like Sodium carboxy methyl cellulose (Sod. CMC), Hydroxy propyl methyl cellulose (HPMC), Carbopol 934.

ENCLOSURE - II

6.2 Review of the literature

1) Harris.D et al have worked on the methods to increase the gastrointestinal transit and used the process of bioadhesion for this purpose. He used four potential bioadhesive polymers presented in a number of different formulations, was investigated in the rat. Formulations were dosed orally, and GI transit was assessed by killing animals at various intervals and sectioning the GI tract. Significant differences in oro-caecal transit were obtained with certain formulations, with 4% and 5% solutions of Carbopol 934 showing delays of 25% in transit to the ileo-caecal junction. 2) Khosla.R and Davis.S.S et al studied the influence of the putative bioadhesive polycarbophil, on the gastric emptying of a pellet formulation in three fasted subjects. The pellets were radiolabelled with technetium-99m. Gastric emptying was measured using the technique of gamma scintigraphy. The pellets emptied from the stomach rapidly and in an exponential manner. Polycarbophil did not retard the gastric emptying of the pellets. 3) Lee.J.H , Park.T.G and Choi.H et al conducted experiments on mucoadhesive microspheres and prepared them by an interpolymer complexation and solvent evaporation method, using chitosan and poly(acrylic acid) (PAA), to prolong the gastric residence time of the delivery system. The Fourier transform infrared results showed that microspheres were formed by an electrostatic interaction between the carboxyl groups of the PAA and the amine groups of the chitosan. X-ray diffraction and differential scanning calorimetry analysis showed that enrofloxacin in the chitosan-PAA microsphere was molecularly dispersed in an amorphous state. Scanning electron microscopy of the surface and the quantity of mucin attached to the microspheres indicated that chitosan-PAA microspheres had a higher affinity for mucin than those of chitosan alone. The swelling and the dissolution of the chitosan-PAA microspheres were found to be dependent on the pH of the medium. The rate of enrofloxacin released from the chitosan-PAA microspheres was slower at higher pH; therefore, based on their mucoadhesive properties and morphology, the chitosan-PAA microspheres can be used as a mucoadhesive oral drug delivery system. 4) Bodde H.E, De Vries M.E and Junginger et al investigated on novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) .He studied the release of the peptide drugs like buserelin, octreotide and insulin from SPH and SPHC polymers and the developed delivery systems, stability of these peptides during the release and the integrity of insulin in the polymeric matrix of SPHC. Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer. All peptides studied in contact with SPHC polymer were stable under different environmental conditions (ambient temperature, 37 °C, light and darkness and at pH values 3.2 and 7.2). FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. Release profiles of all peptides from the developed delivery systems showed a time-controlled release profile: after a short lag time of 10–15 min, a burst release of peptides occurred during which more than 80% of peptide was released within 30–45 min. In conclusion, the present delivery systems based on SPH and SPHC show appropriate in vitro properties for application in peroral peptide drug delivery of buserelin, octreotide and insulin, and are therefore promising for further in vivo evaluation. 5) Lueben.H.L et al worked on two different classes of bioadhesive excipients which have been approved by the FDA, the anionic charged poly (acrylic acid) derivatives and the cationic charged chitosans, with respect to their ability to improve intestinal peptide drug absorption. It was found that both polycarbophil and the chitosan derivatives Daichitosan® VH and chitosan- glutamate (SeaCure® + 210) enhance the absorption of the peptide drug 9-desglycinamide, 8- arginine vasopressin (DGAVP) in the vertically perfused intestinal loop model of the rat. Recent studies demonstrated that the two poly (acrylates) polycarbophil and Carbopol® 934P are able to inhibit the activity of the proteolytic enzyme trypsin at pH 6.7, which may lead to an increased stability of the peptide drug in the intestine. The depletion of Ca2+ out of the incubation medium due to the Ca2+ binding properties of the poly (acrylates) is discussed as a possible mechanism of action. Because of the observation that depletion of Ca2+ can additionally cause an opening of tight junctions, the influence of polycarbophil on the paracellular integrity of Caco-2 monolayers was also investigated by measurements of transepithelial electrical resistance (TEER) as well as by visualization studies using confocal laser scanning microscopy. At pH 4.0, apically applied polycarbophil tended to decrease TEER values stronger than the control solution, whereas at pH 7.0 no pronounced changes of TEER could be observed. At pH 7.4, polycarbophil was only able to increase the paracellular permeability of the hydrophilic model compound fluorescein-isothiocyanate-dextran (Mw 4000) when applied to the basolateral side of the Caco2 cell monolayer. In conclusion, bioadhesive polymers are promising absorption promoting agents for peroral delivery of peptide drugs and their mechanism of action is probably a combination of inhibiting protease activities and modulating the intestinal epithelial permeability. 6) Nagahara. N, Masafumi Nakao, Mayumi Tada et al studied the effect of mucoadhesive microspheres of amoxicillin on Helicobacter pyroli and found that the microspheres reside in gastrointestinal tract for extended period for almost 2 to4 hours more than the other formulations like 0.5% methyl cellulose suspension. In conclusion, the mucoadhesive microspheres more effectively cleared H. pylori from the gastrointestinal tract than the 0.5% methylcellulose suspension due to the prolonged gastrointestinal residence time resulting from mucoadhesion. 7) Singh U.V and Udupa.N et al prepared methotrexate (MTX) loaded poly (lactic-co- glycolic) acid (PLGA) microspheres by emulsion solvent evaporation technique. The mean diameter of the microspheres was affected by the type of emulsion stabilizer, polymer concentration, aqueous and organic phase volume and stirring speed. The in vitro release was triphasic and was dependent on copolymer composition and molecular weight of the polymer. Antitumor efficacy in Sarcoma-180 tumor bearing mice exhibited increased volume doubling time (18 ± 2.7 days) compared to plain subcutaneous injection of methotrexate (8 ± 0.7 days). Preliminary pharmacokinetic studies following subcutaneous administration of MTX loaded PLGA microspheres illustrated the controlled release of the drug. The studies demonstrated the feasibility of employing PLGA as an effective carrier for antineoplastic drug like methotrexate. 8) Baranovsky V.Yu and Kotlyarsky I.V et al studied heterogeneous radical polymerization of methacrylic acid (MAA) in benzene in the presence of poly(ethylene glycol) (PEG) and poly(N-vinyl pyrrolidone) (PVP) . The products of the polymerization are the interpolymer complexes of poly(methacrylic acid) (PMAA) with PEG and PVP. In spite of the daughter polymer PMAA being insoluble in the reaction medium, the polymerization proceeds via a template mechanism which is generally similar to the template polymerization of MAA in the presence of the same templates under homogeneous conditions. In a heterogeneous polymerization, competition between the two templates is possible: the PMAA macro radical with high selectivity chooses the much stronger template PVP.

9) Ofokansi KC, Adikwu MU and Okore VC et al worked on soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.

10) Aithal KS and Udupa N et al prepared microspheres containing norfloxacin and ciprofloxacin using Sodium and calcium alginates and the possible drug-excipient chemical interaction was evaluated by various spectral methods. There was no chemical interaction between these drugs and the alginates. The dissolution and diffusion of these drugs were delayed and the stability at various accelerated stability conditions was improved on entrapment of these drugs in alginates.

11) Chowdary KPR and Rao YS et al studied on methods to develop, characterize, and evaluate mucoadhesive microcapsules of glipizide employing various mucoadhesive polymers for prolonged gastrointestinal absorption. Glipizide, an effective anti-diabetic that requires controlled release owing to its short biological half life of 3.4 ± 0.7 hours, was used as the core in microencapsulation. The mucoadhesive microcapsules were evaluated by in vitro and in vivo methods for controlled release.

ENCLOSURE – III

6.3 Objectives of the study : The specific objective of the study is : 1. To prepare the mucoadhesive microspheres containing Flurbiprofen. 2. To carry out the evaluation parameters for the prepared microspheres. 3. To study the drug polymer compatability and surface morphology of the prepared microspheres. 4. To carry out the in-vitro release studies and stability studies of the prepared microspheres. Materials : 1) DRUG : Flurbiprofen a non steroidal anti-inflammatory drug (NSAID).

2) POLYMERS: Hydroxy propyl methyl cellulose (HPMC),Sodium carboxy methyl cellulose (CMC) (high viscosity grade), Carbopol 934, Liquid paraffin, Span 80(emulsifying agent), n-Hexane(washing microspheres) and Ethanol.

M ethod :

 Preparation of microspheres by: Interpolymer complexation method. Solvent evaporation method. Emulsion solvent diffusion method. Solvent diffusion-evaporation technique. etc. Evaluation :

1. Compatibility study by Fourier Transform Infra Red (FTIR). 2. Surface Morphology by Scanning Electron Microscopy (SEM). 3. Particle size distribution of prepared microspheres. 4. Drug entrapment efficiency. 5. In vitro release studies. 6. Differential Scanning Calorimetery (DSC)/ Powder X-ray Diffractometry (PXRD).

ENCLOSURE – IV

7.1. Source of data The preliminary data required for the experimental study was obtained from :-

7.0 1. CD-Rom search available at National center for scientific information (NCSI).Indian institute of sciences (IISC), Bangalore. 2. Journals 3. Analytical chemistry books 4. Library 5. Relevant books 6. Internet sources 7. Scientific abstracts.

ENCLOSURE-V

7.2. Method of collection of data

Data on drug was collected through literature survey and from physicochemical data base such as solubility in various solvents, pH of the drug solution and compatibility of the drug with various polymers.

A)Preparation : Mucoadhesive microspheres of Flurbiprofen are prepared by w/o emulsification and solvent evaporation method.

B) Characterization: Characterization of microspheres, compatibility study by FTIR, surface morphology by SEM, particle size distribution, drug entrapment efficiency, in vitro release study, solid state by DSC/ PXRD.

ENCLOSURE- VI 7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.

7.4. Has ethical clearance been obtained from your institution in case of 7.3?

NOT APPLICABLE

ENCLOSURE – VII

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5) Lueben HL, Lehr CM, Rentel CO, Noach AB, de Boer JAG, Verhoef JC, Junginger HE.Bioadhesive polymers for the peroral delivery of peptide drugs. J Control Release. 1994 ; 29: 329–38. 6) Nagahara N, Akiyama Y, Nakao M, Tada M,Kitano M, Ogawa Y. Mucoadhesive microspheres containing amoxicillin for clearance of Helicobacter pylori. Antimicrob. Agents Chemother. 1998; 42: 2492–94. 7) Singh UV, Udupa N. In vitro characterization of methotrexate loaded poly(lactic-co- glycolic) acid microspheres and antitumor efficacy in Sarcoma-180 mice bearing tumor. Pharm Acta Helvetiae.1997; 72 : 165–73. 8)Baranovsky VYu, Kotlyarsky IV, Etlis VS, Kabanov VA. Template polymerization of methacrylic acid in the presence of poly(ethylene glycol) and poly(n-vinylpyrrolidone) in benzene. Eur Polym J 1992 ; 28: 1427–32. 9)Ofokansi KC, Adikwu MU, Okore VC. Preparation and evaluation of Mucin-Gelatin Mucoadhesive Microspheres for Rectal Delivery of Ceftriaxone sodium, Drug Dev. Ind Pharm 2007; 33 : 691-700. 10) Aithal KS, Udupa N. Preparation & Evaluation of Alginate microspheres containing Norfloxacin & Ciprofloxacin, Ind J Pharm Sci 1996; 59 (2): 61-7. 11) Chowdary KPR., Rao YS. Design and Evaluation of Mucoadhesive Microcapsules of Glipizide for Oral Controlled Release. AAPS Pharma Sci Tech 2003 ; 4(3) : E11-19. 12) Chowdary KPR, Rao YS, Narayana T.V. Mucoadhesive Microspheres. The Ind Pharm 2006 ; V (43) : 29-31.

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FROM VENKATESH.GAVINI M.Pharm , PART 1 Dept Pharmaceutics, Sarada Vilas College of Pharmacy, Krishnamurthypuram, Mysore – 5700 004 To The Registrar (Evaluation) Rajiv Gandhi University of Health Sciences, 4th “T ” Block, Jayanagar, Bangalore , Karnataka – 560 041 (Through proper channel) Sub : Submission of Synopsis of Dissertation Respected Sir, Herewith , I am submitting synopsis of dissertation work “ PREPARATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF FLURBIPROFEN FOR GASTRORETENTIVE DRUG DELIVERY” for registration in M.Pharm (Pharmaceutics) of Rajiv Gandhi University of Health Sciences,Bangalore, Karnataka. Kindly accept the same and acknowledge.

Thanking you.

Yours faithfully,

(Venkatesh.Gavini) Place : Mysore Date :

Guide : PRINCIPAL

Mr.K.SENTHIL KUMAR M.Pharm, SARADA VILAS COLLEGE OF PHARMACY

PROFESSOR, MYSORE – 570 004

SARADAVILAS COLLEGE OF PHARMACY

MYSORE – 570 004