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SUSTAINED RELAEASE MULTIPARTICULATE DRUG DELIVERY SYSTEMS OF HIGHLY WATER SOLUBLE DRUGS SYNOPSIS FOR M.PHARM. DISSERTATION SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BY PATEL DHAVALKUMAR RAJENDRABHAI I M.PHARM. DEPARTMENT OF PHARMACEUTICS DAYANANDA SAGAR COLLEGE OF PHARMACY 2008 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the candidate and PATEL DHAVALKUMAR address (in block letters) RAJENDRABHAI I M.Pharm., Department of Pharmaceutics, Dayananda Sagar College of Pharmacy, Kumaraswamy Layout, Bangalore-560078. PERMANENT ADDRESS To:Sundarpura, Ta:Bayad, Post:Ranechi, Dist:Sabarkantha, State:Gujarat (383325) 2. Name of the Instuition Dayananda Sagar College of Pharmacy, Shavige Malleswara Hills, Kumaraswamy Layout, Bangalore-560078, Karnataka. 3. Course of study and subject Master of Pharmacy in Pharmaceutics 4. Date of admission to course 21 February 2008 5. Title of the project: SUSTAINED RELAEASE MULTIPARTICULATE DRUG DELIVERY SYSTEMS OF HIGHLY WATER SOLUBLE DRUGS 6. Brief resume of the intended work: 6.1 Need of the study: Ideally, a drug should arrive rapidly at the site of action in the optimum concentration, remain for the desired time, be excluded from other sites, and be rapidly removed when the goal is achieved. However, where highly water-soluble drugs are concerned, formulation into a dosage form is tricky and complicated due to its high solubility. If the release of drug is rapid from a single dosage form, it may be beneficial for therapies where immediate onset of action is desired. But mostly drug dumping is seen with highly water soluble drugs which in turn is associated with side effects like nausea and vomiting, not to mention the aggravation of the potential side effects seen. This problem is particularly noticed with drugs having a short half-life, requiring frequent dosing of the drug to maintain steady state concentrations. The goal of designing sustained or controlled release multiparticulate delivery systems of such highly water soluble drugs is to reduce frequency of dosing thereby minimizing the occurrence of side effects and to increase the effectiveness of the drug since multiparticulates are known to disperse freely in the gastric fluids covering greater surface of absorption. In addition they also offer benefits of reducing the dose required, and providing uniform drug delivery. So in the present study, attempts will be made to establish a optimum method and polymer system of a sustained release multiparticulate delivery system for the delivery of some model highly water soluble drugs like Venlafaxine HCl and Tramadol HCl. The aforementioned drugs have been selected basically due to their high water solubility along with their attributes of short half lives, frequent dosing requirements and reported side effects seen on oral dosing. 6.2 Review of literature A study1 was conducted to develop a microspherical dosage form for Fenoterol HBr, a highly water-soluble drug by using the ethyl cellulose. The oil-in-oil solvent evaporation method efficiently encapsulated Fenoterol HBr in these ethyl cellulose microspheres. A significant increase in the encapsulation efficiency of fenoterol was observed when the drug/polymer ratio was decreased from 15% to 5% (p < 0.05). The diffusion-controlled release followed by a constant release was exhibited in these microspheres. Pseudoephedrine HCl, another highly water-soluble drug, was entrapped within poly (methyl methacrylate) microspheres by a water/oil/water emulsificationsolvent evaporation method2. Microspheres were formed after solvent evaporation and polymer precipitation. The drug content of the microspheres increased with increasing theoretical drug loading, increasing amounts of organic solvent, polymer and polymeric stabilizer, and decreased with increasing stirring time, increasing pH of the continuous phase and increased volume of the internal and external aqueous phase. Microencapsulation of highly water-soluble pharmaceuticals especially of those requiring high drug loading (more than 50%) was carried out3. Biodegradable poly (lactic acid) (PLLA) as coating material and polyvinyl alcohol as surfactant was found suitable for this purpose. Active drug substance was microencapsulated by water-in-oil-in-water technique using biodegradable poly (lactic acid) (PLLA) as coating material and polyvinyl alcohol as surfactant. To evaluate the drug physical state in microcapsules powder, DSC analysis confirmed absence of any drugpolymer interaction, X-ray diffraction patterns showed the changes of polymer crystallinity during the encapsulation procedure as well as decrease of crystallinity of the drug; SEM investigations showed the morphology of obtained product and demonstrated the drug location inside the capsule. An oral controlled release formulation matrix for highly water-soluble Ranitidine HCl was developed4 using, sodium alginate- xanthan gum- zinc acetate matrix and prepared by direct compression so as to achieve a 24 hours release profile. The in vitro release tests were carried out in simulated intestinal fluid (SIF, pH7.5) and simulated gastric fluid (SGF, pH1.2). The release of the drug in the sodium alginate formulation containing only xanthan gum completed within 12 hours in the SIF, while the drug release in the sodium alginate formulation containing only zinc acetate finished almost within 2 hours in the same medium. Only the sodium alginate formulation containing both xanthan gum and zinc acetate achieved a 24hour release profile. Evaluation of the release data showed the release mechanism for the novel formulation might be attributed to the diffusion of the drug. Poly(ethylene glycol)-terephthalate / poly (butylene terephalate) multiblock copolymer was investigated5 as possible matrix for controlled delivery of small water soluble drugs like leuprorelin acetate and vitamin B12 for sustained release. It was first prepared using a double emulsion method and addition of surfactant in this preparation led to increase microsphere entrapment efficiency, where as decrease of the PEGT copolymer content allowed the release rates from microspheres to be decreased. Leuprorelin acetate - loaded microspheres did not show same characteristics. This study shows the suitability of PEGT/PBT microspheres as controlled release system for vitamin B12, but not for leuprorelin acetate. The effect of Microcrystalline Cellulose (MCC) and Waxy cornstarch and Lactose as a cofiller, cellulose acetate phthalate (CAP) as enteric film coat used in riboflavine sodium phophate pellet on diffusion and dissolution was studies6 .The in vitro release Diffusion of drug from core to film coat containing Lactose was greater than with waxy cornstarch. Dissolution of enteric-coated waxy cornstarch had good acidic resistance in 0.1N HCl solution for at least 1 hr, others failed the test. Waxy cornstarch containing enteric pellets dissolved at SIF in 10 min, and film coated pellets had less drug dissolved than lactose containing pellets because Waxy cornstarch minimizes premature drug diffusion from core in to the film coat layer. The aim of one other study7 was to obtain a good drug incorporation and controlled release of drug from poly (glycerol adipate) backbone (PGA) nanoparticles. They were prepared by the interfacial deposition technique and the simultaneous emulsification method. Dexamethasone phosphate(DXMP) and Cytosine arabinoside (CYT-ARA) were incprporated in PGA polymer. Polymers with acyl group chain lengths containing 8 carbon atoms (C8) showed both good drug incorporation and a controlled release for DXMP while for CYT-ARA it was the unsubstituted polymer backbone that had maximum drug loading and slower release. It was concluded from the study that drug loading and release from nanoparticles are primarily influenced by the nature of interactions between the drug and polymers. 6.3 Objective of the study: The objective of the study is to develop a sustained release multiparticulate delivery system for highly water soluble drugs which are expected to 1. Maintain the therapeutic drug concentration in the blood for a prolonged period of time 2. Reduce the frequencies of drug administration 3. Reduce the dose related side effects 4. Improve patient compliance Plan of work The work will be executed as follows Preformulation studies Optimisation of Process parameters for method of preparation of the multiparticulate delivery system Formulation of different batches of the multiparticulate delivery system Evaluation of the formulations for size analysis, density, angle of repose, surface topography, encapsulation efficiency, in vitro release. Statistical evaluation of the obtained data. To perform the stability studies for selected formulations as per ICH guidelines. 7. Materials and methods 7.1 Source of data: Official Pharmacopoeia, Standard books, Pharmaceutics databases, internet, etc. 7.2 Method of collection of the data (including sampling procedure, if any): The pharmacological details of the drug will be collected from various standard books, peer reviewed national and international journals and other sources like research literature databases such as Medline, Science direct, etc. Experimental data will be collected from the evaluation of designed formulation 1. Preformulation studies like solubility, melting point, compatiblity of the drug with polymers will be carried out by IR, XRD and DSC instruments. 2. Multiparticulates of the highly water soluble drugs will be prepared by the appropriate methods like solvent evaporation method or multiple emulsion-solvent evaporation method etc. using natural, synthetic or combination of both type of polymers. 3. The multiparticulates will be evaluated for size analysis, surface characteristics, flow properties and encapsulation efficiency. 4. In-vitro release studies will be carried out by using dissolution test apparatus USP-XXIV and the data of the drug release will be subjected to statistical analysis for significance and evaluation of kinetics and mechanisms of drug release. 5. Stability studies will be carried out as per ICH guidelines. 7.3. Does the study require any investigation or interventions to be conducted or patients or other humans or animals? If so please describe briefly: No 7.4. Has ethical clearance been obtained from your institute in case of 7.3? Not applicable 8. References: 1. Lin WJ, Wu TL. Modifacation of the initial release of a highly water soluble drug from ethyl cellulose microspheres. J Microencapsul.1999; 16(5): 639-646(8). 2. Alex R, Bodmeier R. Encapsulation of water-soluble drug by a modified solvent evaporation method. 1. Effect of process and formulation variables on drug entrapment. J Microencapsul. 1990; 7(3): 347 -55. 3. Dagnija Loca, Pugovics O and Berzina-Cimdina L. Evaluation of Highly-Water Soluble Drug Physical State in Biodegradable microcapsules.14th Nordic-Baltic conference on biomedicals engineering and medical physics.2008; 20(1680-0737): 619-622. 4. Zeng W.M. Oral controlled release formulation for highly water-soluble drugs: Drug-sodium alginate-xanthan gum-zinc acetate matrix. Drug Dev Ind Pharm. 2004; 30(5): 491-95. 5. Sohier JR, Van Dijkhuizen-radersma, De Groot K and Bezemer JM. Release of small water-soluble drug from multiblock copolymer microspheres; a feasibility study. Eur J Pharm Biopharm. 2003: 62(2): 221-28. 6. Guo HX, Heinamaki and Yliruusi J. Diffusion of a Freely Water Soluble Drug in Aqueous Enteric coated Pellets. AAPS Pharm SciTech. 2002; 3(2): 1-8. 7. Sanuogita P, Paraskevi K, Sean H, Gillian A, Hutcheon and Martin CG. Drug Incorporation and release of Water-soluble drugs from novel functionalised poly (glycerol adipate) nanoparticles. J Control Release. 2008; 125(1): 59-67. 9. Signature of the candidate (PATEL DHAVALKUMAR RAJENDRABHAI) 10. Remarks of the guide: The proposed work is of significance in the formulation and delivery of highly water- soluble drugs. Hence it is recommended for registration. 11. Name and Designation (in block letters) 11.1. Guide DR.ARSHIA SHARIFF PROFESSOR AND HEAD, Department of Pharmaceutics, Dayananda Sagar College of Pharmacy, Kumaraswamy Layout, Bangalore-560078. 11.2. Signature 11.3. Co-guide if any No 11.4. Signature Not applicable 11.5. Head of the department DR.ARSHIA SHARIFF HEAD, Department of Pharmaceutics, Dayananda Sagar College of Pharmacy, Kumaraswamy Layout, Bangalore-560078. 11.6. Signature 12. 12.1. Remarks of the principal Dr. V. Murugan, 12.2 Signature Principal, Dayananda Sagar College of Pharmacy, Kumaraswamy Layout, Bangalore-560078 09343824404 [email protected] (Dr. V. Murugan)