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FORMULATION AND EVALUATION OF ORAL SUSTAINED RELEASE SUSPENSIONS OF TORSEMIDE MICROENCAPSULATION USING ION EXCHANGE RESINATES SYNOPSIS FOR M.PHARM DISSERTATION SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE. BY G.Rudrasekhar Reddy B.pharm UNDER THE GUIDANCE OF Mr.B.R.Kirupakr M.Pharm, DEPARTMENT OF PHARMACEUTICS, SRI K.V. COLLEGE OF PHARMACY, CHICKBALLAPUR, KARNATAKA-562101, 2011-2012 RAJIV GANDHI UNIVERSITY OF HEALTH AND SCIENCES, KARNATAKA BANGALORE ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1 NAME OF THE CANDIDATE & ADDRESS G.RUDRASEKHARREDDY, SRI K.V COLLEGE OF PHARMACY, M.G.ROAD, CHICKABALLAPUR(DIST), KARNATAKA-562101. PERMANENT ADDRESS S/O G.NAGIREDDY, BYRAPURAM (VILLAGE AND POST), KOTHACHERUVU (MANDAL), PENUKONDA(TALUK), ANANTAPUR(DIST), ANDHRA PRADESH. PIN : 515110 2 NAME OF THE INSTITUTE SRI K.V.COLLEGE OF PHARMACY, M.G.ROAD, CHICKBALLAPUR (DIST), KARNATAKA-562101 3 COURSE OF THE STUDY MASTER OF PHARMACY (PHARMACEUTICS) 4 DATE OF ADMISSION 5 TITLE OF THE TOPIC 21-10-2011 FORMULATION AND EVALUATION OF ORAL SUSTAINED RELEASE SUSPENSIONS OF TORSEMIDE MICROENCAPSULATION USING ION EXCHANGE RESINATES 6. 6. BRIEF RESUME OF INTENDED WORK 6.1 NEED FOR STUDY: The goal of any drug release system is to provide a therapeutic amount of drug to the proper site in the body, to achieve and maintain the desired drug concentration at the site of action1. This objective points towards to most important aspects of drug delivery, namely spatial placement and temporarily delivery of the drug. The sustained release system induces any period of time. If the system is successfully maintaining a constant drug level in blood or targeted tissue, it is considered as controlled release system. An oral sustained release suspension could be the best suitable dosage form for the geriatric patients, because of the easiness of swallowing and flexibility in the administration of the dosage. Many therapeutic benefits could be gained by incorporating functions of sustained drug release into suspension dosage forms. They include improvement of rate and extent of drug absorption, the higher patient compliance, reduce the side effects and taste masking for bitter drugs 2,3 . Reduction of side effects and improvement of bioavailability can be achieved by fabricating a drug with sustained or controlled released and incorporating it into a suspension. A larger part of attention has been devoted to the development of oral liquid dosage forms containing sustained release drugs. Hence, it is desirable to develop a well-formulated sustained release suspension. Torsemide is a pyridine-sulfonylurea type loop diuretic mainly used in the management of edema associated with congestive heart failure. It is also used at low doses for the management of hypertension. It is marketed under the brand name Demadex, for the treatment of edema associated with congestive heart failure, renal disease or hepatic disease, also for the treatment of hypertension alone or in combination with other antihypertensive agents. Torsemide inhibits the Na+/K+/2Cl--carrier system (via interference of the chloride binding site) in the lumen of the thick ascending portion of the loop of Henle, resulting in a decrease in reabsorption of sodium and chloride. This results in an increase in the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and high aldosterone levels promote sodium reabsorption at the distal tubules and by increasing the delivery of sodium to the distal renal tubule, torsemide indirectly increases potassium excretion via the sodium-potassium exchange mechanism. Torsemide's effects in other segments of the nephron have not been demonstrated. Thus torsemide increases the urinary excretion of sodium, chloride and water, but it does not significantly alter glomerular filtration rate, renal plasma flow or acid-base balance. Torsemide's effects as a antihypertensive are due to its diuretic actions. By reducing extracellular and plasma fluid volume, blood pressure is reduced temporarily, and cardiac output also decreases4,5. Torsemide is soluble in water,methanol6, Physico chemical properties of torsemide like hydrophilicity, moderatly hygroscopic, low molecular weight etc., make it as a ideal candidate for administration by oral sustained release suspension. The different methods for sustaining the release of drugs are described by ariens. One of the methods to sustain the drug release is the use of ion exchange resins. In the present work, torsemide was absorbed on cationic exchange resin, amberlite [ IR-120] and later a coating of ethyl cellulose was given. Then these resonates was formulated into a suspension form, which can release the drug in a slow controlled manner, the dissolution rate and bio-availability from suspensions are reported to the adversely affected by the suspending agents which are used to increase the viscosity of the media to maintain uniform dispersion during storage7,8 . In the present study an attempt is made to evaluate different suspending agents for their stability for the formulation of sustained release suspension containing torsemide microcapsules. 6.2 REVIEW OF THE LITERATURE: 1. Mahore J G et al., Ion exchange resins are cross-linked water insoluble polymercarrying, ionizable functional groups. IER have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles. Research over the last few years has revealed that IER are equally suitable for drug delivery technologies, including controlled release, transdermal, nasal, topical and taste masking.Drug resin complexation converts drug to amorphous form leading to improved drug dissolution9. 2. Manish R et al., Eudragit RS100 coated ion exchange resinate of Ambroxol Hcl were prepared using Indion-244 by Solvent evaporation method. Among the various formulation of microcapsule (drug resinate Eudragit ratio) prepared. An ideal formulation (drug resinate 1:1) and 10% eudragit coating was selected for the formulation of sustained release suspension. This suspension was evaluated for physical stability, redispersibility and in vitro drug release pattern10. 3. Sompur C K et al., Has review an article on approach for development of oral sustained release suspension which review rapidly changing conventional dosage form of pharmaceutical drug delivery are being replaced by new drug delivery system.One search drug delivery sustained on controlled release drug delivery system i.e on oral pharmaceutical suspensions has been one of the most fevarable dosage form are pediatric and geriatric patents 11. 4. Suthar A M et al., Non‐compliance which is mostly associated with bitter taste can lead to worsening of diseased condition The purpose of this research was to prepare palatable liquid formulation by masking the intensely bitter taste of metronidazole (MNZ). Taste masking was done by complexing of MNZ with different rasins Kyron T‐114, Kyron T‐134 and Indion 234 in different ratios. Prepared suspensions were tested for drug content, in vitro drug release, taste masking, stability study, and molecular properties. Kyron T‐134 at pH 8 showed potential to prepare palatable formulation with MNZ. Thus to overcome taste problem of traditional paediatric dosage form, IER is dominating method to prepare palatable liquid formulation of MNZ12. 5. Malay Kumar Samanta et al., Microspheres of Ferrous Sulphate were prepared by congealable disperse-phase encapsulation technique with Agar, Agar and Hydroxy propyl methyl cellulose mixture, and Ethylcellulose. Suspension of Agar and Hydroxy propyl methyl cellulose mixture showed a better sustained release than Agar and Ethylcellulose13. 6. Katare O K, Jain S K, Vyas S P et al., Polymers and copolymers of acrylic series were synthesised and drug embedded matrices were prepared by common solvent solution evaporation technique. Suspension adjuvants were blended with the fine particles of drug embedded matrix and the formulated suspension of alpha-methyl dopa was investigated for in vitro release and stability. Results indicated possibility of preparing a sustained release dry suspension of alpha-methyl dopa14. 7. Bhalekar et al., In the present study resinates of verapamil HCl were formulated using Indion resins. Drug loading process was optimized with respect to drug:resin ratio, pH of loading solution, and particle size of resin. Resinates were characterized using XRPDHence resinates were incorporated in pellets using extrusion spheronization to achieve desired release pattern. Optimum drug loading was seen at pH of 3.5 in drug resin ratio of 1:1 and was seen to increase with temperature. XRPD studies revealed verapamil to be present in amorphous form in resinates 15. 8. Kadam A U et al., An oral controlled release suspension of chlorpheniramine maleate was prepared using ion-exchange resin technology. A strong cation exchange resin Indion 244 was utilized for the sorption of the drug and the drug resinates was evaluated for various physical and chemical parameters. The drug-resinate complex was microencapsulated with a polymer Eudragit RS 100 to further retard the release characteristics. Stability study indicated that elevated temperature did not alter the sustained release nature of the dosage form indicating that polymer membrane surrounding the core material remained intact throughout the storage period16. 6.3 OBJECTIVES OF THE STUDY: 1) Compatability studies between torsemide and polymers used. 2) Development of the calibration curve of torsemide. 3) Formulation of torsemide resonates. a) Preparation of drug resinates. b) Determination of ion exchange capacity. 4) Formulation of microencapsules of torsemide resinates using solvent evaporation technique. 5) Evaluation of the microencapsule of torsemide resonates. a) Determination of percentage yield. b) Determination of the drug content. c) Determination of particle size in microcapsule. d) In vitro drug release from the microcapsules 6) Preparation of suspensions. 7) Physical stability of suspensions. 8) In-vitro release studies from suspensions 9) Stability studies as per ICH guidelines. 7 MATERIAL AND METHODS: 7.1.MATERIALS: Drug: Torsemide. Polymer: Ethyl cellulose, Cyclohexane, Light liquid paraffin, carboxy methyl cellulose. All other materials used were analytical grade. 7.2. METHODS: Preparation of the microencapsulation by solvent evaporation technique. Preparations of the suspension using microencapsulation and different suspending agents. 7.3. SOURCE OF DATA: The literature survey will be done by referring the abstracts & articles of all the National and International journals of pharmaceutical sciences. The day to day development in this area will be updated by literature survey through epublishing and current periodicals in library of Sri K.V. College of Pharmacy, Chickballapur. 7.4. Does the study require any investigations to be conducted on humans or animals? No 7.5. Has ethical clearance been obtained from your institution in case of above? Not applicable 7.6. Duration of the study: The study will be conducted over a period of 9 months. 7.7. Place of study: Department of Pharmaceutics, Sri K.V.College of Pharmacy, Chickballapur. 8 REFERENCES 1. Gennaro A D. Remington’s Pharmaceutical Sciences,18thed. Pennsylvania:Mack Publishing Co;1990:p.1676-7. 2. Samanta M K, Udayakumar T, Suresh B. Preparation of suspensions microspere Indian J Pharm Sci, 57(5);1995:189-93. 3. Swarbrick J, Boylan J C. Encyclopedia of Pharmaceutical Technology, Vol-8, New York; Marcel Dekker; 1993-P.204-9. 4. URL: http://www.drugbank.ca/drugs/DB00214 5. URL: http://en.wikipedia.org/wiki/Torsemide 6. URL: www.chemicalbook.com/ChemicalProductProperty_EN_CB1397929.htm 7. Ariens E J. Drug design, New York;Academic press;1973:(4):p.47. 8. Howard S A, Mauger J W, Hsieh J W, Amin K, Preparation of suspensions microspere J Pharm. Sci; 1979:p.1475. 9. Mahore J G, Wadher K J, Umekar M J, Bhoyar P K. ion exchange resins: pharmaceutical application and recent advancement. Int J Pharm Sci Rev Res 2010;1:8-13. 10. Manish R, Bhise Y Raju, Thenge R, Krodhi G, Mahajan. Formulation and evaluation of Sustained release suspension of Ambroxol Hcl Using Ion Exchange Resin. Int J Pharm Tech Res. Oct-Dec 2009:1(4),1322-5. 11. Sompur C K, Doijad R C, Patil S M, Maske A P. An approch for development of oral sustained releasesuspension. Int J Pharm Bio Sci 2011;2:320-9. 12. Suthar A M, Patel M M . Formulation and evaluation of taste masked suspension of metronidazole. Int J App Pharm 2011;3:16-9. 13. Malay Kumar Samanta, sustained Udaykumar T, Suresh B. Preparation and evaluation of release preparations of ferrous sulphate. Ind J Pharm sci 1995;5:189-93. 14. Katare O P, Jain S K, Vyas S P. Sustained release dry suspension for reconstitution of alpha-methyl dopa. Ind J Pharm Sci 1988;50:1:19-22. 15. Bhalekar M R , Avari J, Umalkar R A . Preparation and in vitro evaluation of sustained release drug delivery system for verapamil HCL. Ind J Pharm Sci 2007;69:418-22. 16. Kadam A U, Sakarkar D M, Kawtikwar P S. Development and evaluation of oral controlled release chlorpheniramine-ion exchange resinate suspension. Ind J Pharm Sci 2008;70(4):531–4. 9 SIGNATURE OF THE CANDIDATE 10 REMARKS OF THE GUIDE 11 11.1 NAME AND DESIGNATION OF GUIDE G.RUDRASEKHARREDDY The proposed research work is original and designed on rational basis. It would be a good contribution. Mr.B.R.KIRUPAKR M.Pharm, ASSOC PROFESSOR , Department of Pharmaceutics, Sri K.V. College of Pharmacy, CHICKBALLAPUR-562101. GUIDE SHIP REFERENCE NO. OF ACA\CDC\PGT-Mph\SKVCPC\46\2010-11 RGUHS 11.2 SIGNATURE 11.3 CO-GUIDE NOT APPLICABLE 11.4 SIGNATURE NOT APPLICABLE 11.5 HEAD OF THE DEPARTMENT Mr.N.SURESH M.Pharm, (PhD.) PROFESSOR AND HEAD Department of Pharmaceutics, Sri K.V. College of Pharmacy, CHICKBALLAPUR-562101, 11.6 SIGNATURE 12 [N.SURESH] 12.1 REMARKS AND SIGNATURE OF PRINCIPAL Dr. D. SHESHADRI SHEKAR M.Pharm., PhD