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“FORMULATION AND OPTIMIZATION OF ACECLOFENAC GEL” MASTER OF PHARMACY DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE. BY ARUN GOKUL T.S Under The Guidance of Mr.KRISHNANANDA KAMATH K. M. PHarm., DEPARTMENT OF QUALITY ASSURANCE SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143 2011-2013 1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1 Name of the Candidate and Address: Mr. ARUN GOKUL T.S. DEPT. OF QUALITY ASSURANCE, SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE-574143. 2 Name of the Institution: 3 Course of Study and Subject: 4 Date of Admission: 5 Title of the Project: SRINIVAS COLLEGE OF PHARMACY, VALACHIL, FARANGIPETE POST, MANGALORE-574143. MASTER OF PHARMACY (QUALITY ASSURANCE) 15 th JULY 2011 “FORMULATION AND OPTIMIZATION OF ACECLOFENAC GEL”. 2 6 BRIEF RESUME OF THE INTENDED WORK: 6.1 INTRODUCTION : The optimization of pharmaceutical formulations with regard to one or more attributes has always been a subject of importance and attention for pharmaceutical scientists in formulation research. The word optimized simply implies to make as perfect, effective or functional as possible. Hence, optimization of a product or process is the determination of the experimental conditions resulting in its optimal performance.1 The delivery of drug through the skin has long been a promising concept because of the ease of the access, large surface area, vast exposure to the circulatory and lymphatic networks and non invasive nature of the treatment. The U.S.P. defines gels as a semisolid system consisting of dispersion made up of either small inorganic particle or large organic molecule enclosing and interpenetrated by liquid. Gels are typically formed from a liquid phase that has been thickened with other components.1 Aceclofenac is a Non steroidal anti inflammatory drug(NSAID) having excellent anti-inflammatory and analgesic activity but NSAID produces GIT ulceration, liver and kidney trouble especially in case of oral administration. Aceclofenac is used in treatment of Osteoarthritis, Rheumatoid arthritis, Acute lumbago, and Dental pain condition. However like other NSAIDs, oral administration of this drug is also associated with severe gastrointestinal side effects like ulceration and gastro intestinal bleeding liver and kidney trouble. The solution of this problem lies in the fact that, topically applied NSAIDs are safer than and as efficacious as oral NSAIDs. Furthermore, the topical route of administration has a high patient compliance, which derives from it being non-invasive and the long interval between applications. Topical administration also provides a means to obtain constant systemic drug levels.5 Hence, the need of the study is two-fold, first to develop an Aceclofenac gel with very good skin permeability of the drug. Second to develop a theoretical relationship that may be used to optimize the gel formulation. 3 6.2 – REVIEW OF LITERATURE: Aukunuru J, Boneppally C, Guduri V 1 prepared and optimized ibuprofen ointment with a potential for both topical and systemic delivery of the drug. A co-solvency technique with a trial and error approach was used to develop a 10% ibuprofen ointment in petrolatum base, with the entire drug dissolved in the base. An insertion cell was used to evaluate drug release from the formulations. Further, factorial design multiple regression (FDMRA) analysis, a statistical optimization technique, was used in the optimization of the final formulation. Best fit equations for optimization purposes including various fluxes (initial, steady-state and total) and diffusion coefficient as dependent variables and the concentrations of co-solvents as independent variables were obtained using SAS programme. Dependent variables strongly depended (p<0.05) on the independent variables and followed the polynomial equations generated. Rabia B, Muhammad HS, Nousheen A, Durriya H, Masud-ur-rehman 2 have formulated and optimized ibuprofen tablets by direct compression method. In order to obtain the best, optimized product, nine different formulations were developed. Diluents (X1), disintegrant (X2) and lubricant (X3) were taken as independent variables. Weight variation (Y1), thickness (Y2), length and width (Y3), hardness (Y4), friability (Y5), disintegration (Y6), Dissolution (Y7) and pharmaceutical assay (Y8) were studied as response variables. The results of all nine formulations were found within the acceptable limits conforming to those given in official compendia. However, f-6 was selected as an optimized product on the basis of high dissolution (99.05%) and assay (100.04%). Mathure DM, Bhalekar1 MR, Mathure DM, Padalkar RR, Dawane BS , Chobe SS 3 have formulated and statistically optimized controlled release pellets of Cetrizine Dihydrochloride. The objective of this study was to formulate controlled release pellets of Cetrizine dihydrochloride and optimize the effect of formulation variables i.e. concentration of Eudragit RLPO and ethyl cellulose. The experimental design selected was 32 full factorial designs using these two variables. Drug release after 24 hr and t50% were evaluated as 4 response parameters. Polymers were coated onto the drug loaded pellets using pan coater. It was observed that the concentrations of polymers directly affected the drug release profile. The effect of the variables and behaviour of the system was studied using response surface plots. The optimized formulation showed drug release of 96.22% in 24 hr and t50% of 11hr 54 min. The results of this study revealed that the pellets of Cetrizine dihydrochloride coated with 1:5 ratio of Eudragit RLPO: Ethyl cellulose showed optimum controlled release. Ajay S, Jolly P, Rajesh P4 have prepared and optimized Aceclofenac Proniosomes using central composite design and carry out stability studies. Three independent variables selected were molar ratio of drug to lipid (X1), surfactant loading (X2) and volume of hydration (X3). Based on central composite design, 16 batches of proniosomes were prepared by slurry method and evaluated for the percentage drug entrapment (PDE) and mean volume diameter (MVD). The PDE and MVD (dependent variables) and the transformed values of independent variables were subjected to multiple regressions to establish a second order polynomial equation. Contour plots were constructed to further elucidate the relationship between the independent and dependent variables. The conformity of the polynomial equations was checked by preparing three checkpoint batches. From the computer optimization process and contour plots, predicted levels of independent variables X1, X2, and X3 (-0.77, -0.8 and 0 respectively), for an optimum response of PDE with constraints on MVD were determined. The optimized batch was subjected to stability studies. The polynomial equations and contour plots developed using central composite design allowed us to prepare proniosomes with optimum responses. Proniosomes stored refrigerated and at room temperature, were both found to be stable. Kashyap N, Jadon PS, Naruka PS, Chauhan CS 5 have formulated Aceclofenac Gel Using Poloxamer 407. Poloxamer 407 is used primarily as a thickening agent and gel former, but also as a co emulsifier and consistency enhancer in creams and liquid emulsions. The Aceclofenac gels were prepared by using different concentration of Poloxamer 407 for topical drug delivery with an 5 objective to increase transparency and spreadability. The transparency of prepared batch A9 was good as compared to the marketed gel. The percent drug release was 97.11 and 98.66 from A9 and marketed gel respectively in 120 min. No irritation was observed by skin irritation test. Stability studies under accelerated condition showed satisfactory results. It can be concluded that Poloxamer 407 gel containing Aceclofenac showed good consistency, homogeneity, spreadability and stability and has wider prospect for topical preparations. Bhosale UV, Kusumam Devi6 V have formulated and optimized mucoadhesve Nano Drug delivery system of acyclovir. Acyclovir is an antiviral drug, used for treatment of herpus simplx viral infection with an oral bio availability of only 10-20%. Mucoadhesive polymeric nano drug delivery systems of acyclovir have been designed and optimized using 23 full factorial designs. Poly (lactic –co-glycolic acid) was used as polymer along with polycarbophil as muco adhesive polymer and Pluronic F68 as stabilizer. From the preliminary trials the constraints for independent variables X1 (amount of PLGA), X2(amount of pluronic F68) and X3 (amount of poly carbophil) have been fixed. The dependent variables that were selected for the study were particle size (Y1), %drug entrapment (Y2), and % drug release in 12h (Y3). The derived polynomial equations were verified by check point formulation. 6.3 OBJECTIVES OF THE STUDY: 1. To formulate and evaluate Aceclofenac gel with various concentration of base. 2. To optimize the prepared Aceclofenac gel using ‘ UNSCRAMBLER- CAMO ’ ( Software for Multivariate data analysis ) 6.4 MATERIALS AND METHODS: 6 Materials: 1. Drug :Aceclofenac 2. Gelling agent : Carbopol or Sodium CMC base 3. Excipients : Linseed oil, Methyl salicylate, Menthol, Methyl paraben, SLS, Isopropyl alcohol, Propylene glycol etc. Methods: Aceclofenac gel shall be prepared either by using carbopol base or by sodium CMC base. Selection of independent and dependent variables for optimization of the formulation. The prepared gel is then evaluated for pH, viscosity, membrane permeability and Drug content studies will be carried out. pH of gel can be determined using digital pH meter. About 2 gm of gel is stirred in distilled water till a uniform suspension effected. The volume is then make up to 40 ml and pH of solution is measured.8 Viscosity of the gel can be measured by brook field viscometer.8 Drug content in the gel can be determined by taking 1 gm gel in a 100 ml volumetric flask and dissolve with little amount of methanol and mixture is shaken till solution is affected. The volume is made up to 100 ml with methanol. The solution is filtered and further dilutes 5 ml to 500 ml with methanol. The absorbance of solution is measured at 275 nm.8 The membrane permeability studies of various formulations of Aceclofenac gel can be carried out using Kesharychien diffusion cell. The receptor compartment is filled with saline phosphate buffer of pH 7.4 and methanol (90:10) and keeps at 32±0.5oc stirred with the help of magnetic stirrer. Methanol 10% is added to maintained sink condition. About 200-300mg of gel is placed on cellulose chamber. One ml of sample is withdrawn from receptor compartment at 1, 2, 3, 4, 5, 6, 7, 8 hour and replaced with same volume of medium. All samples are diluted up to 10ml with medium and analysed at 275nm.9 Optimization by the use of ‘UNSCRAMBLER- CAMO ’software.. 7 7.1 SOURCE OF DATA: 7 Review of literature from a) Journals such as Journal of Chemical and Pharmaceutical Research Indian Journal of Pharmaceutical Sciences International journal of biopharmaceutical & toxicological research Tropical Journal of Pharmaceutical Research International journal of drug development and research. b) Internet Browsing. www.pharmainfo.net www.sciencedirect.com www.rxlist.com www.pubmed.com www.medline.com c) Laboratory based studies. 7.2 Method of Collection of Data: 1. An Overview of Aceclofenac gel. 2. Results of formulation and Evaluation of Aceclofenac gel using different gelling agents. 3. Optimization results of formulated Aceclofenac gel using ‘UNSCRAMBLER - CAMO ’ ( Software for Multivariate data analysis ) 4. Results of statistical analysis data 7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly. - Not applicable 7.4 Has ethical clearance been obtained from your institution in case of 7.3? - Not applicable LIST OF REFERENCES: 8 8 1. Aukunuru J, Boneppally C, Gunduri V. Preparation, Characterization and Optimization of Ibuprofen ointment intended for Topical and Systemic delivery Tro J Pharm Res 2007;6(4):855-60. 2. Rabia B, Muhammad HS, Nousheen A, Durriya H, Masud-ur-rehman. Formulation development and optimization of ibuprofen tablet by direct compression method. Pak. J. Pharm. Sci 2008; 21(2):113-20. 3. Mathure DM, Bhalekar MR, Mathure DM, Padalkar RR, Dawane BS, Chobe SS. Formulation and statistical optimization of controlled release pellets of cetrezine dihydrochloride. Der Pharmacia Lettre 2011, 3(3):443-52. 4. Ajay S, Jolly P, Rajesh P. Preparation, Characterization, Optimization, stability studies of Aceclofenac proniosomes. Iran j Pharm Res 2008; 7(4):237-46. 5. Kashyap N, Jadon PS, Chauhan CS, Naruka PS. Formulation development and Characterization of Aceclofenac gel using Poloxamer 407. J.Chem.Pharm.Res 2010; 2(4):357-63. 6. Bhosale UV, Kusum Devi V. Formulation and Optimization of Mucoadhesive nano drug delivery system of Acyclovir. Pharmbit 2010; XXII (2):94-104. 7. Shaji S, Pasha ST, Srinivasan S, Ray S. Design and Optimization of a Multiparticulate gastro retentive dosage form for better control of gastric activity. J Pharm Sci & tech 2009; 1(1):40-7. 8. Aijaz AS, Siddique SA, Siddique AR, Zahid Z. Formulation development and Characterization of Aceclofenac gel containing linseed oil and ginger oleoresin. Int J Pharma Tech Res 2011; 3(3):1448-53. 9. Japan P, Brijesh P, Kaushal P, Manish P. Formulation and evaluation of Topical Aceclofenac gel using different gelling agents. Int J Drug Dev. & Res 2011; 3(1):156-64. 10. Ravi K, Patil MB, Sachin RP, Mahesh SP. Evaluation of anacardium occcidetale gum as gelling agent in Aceclofenac gel. Int.J. PharmTech Res 2009, 1(3):695-703. 11. Sundar LT, Sunny K, Kapil K. Development and Optimization of Aceclofenac nano particles by 32 factorial design. Int j Bio & Tox Res 2011; 1(2):108-14. 12. Noushin B, Naghmeh H, Seyed M F, Bijan S.Formulation and optimization of Captopril sublingual tablets using D-optimal design. Iran j Pharm Res 2008; 7(4):259-67. 9 9 Signature of the candidate (ARUN GOKUL T.S) 10 Remarks of the Guide Krishnananda Kamath K, 11 11.1 Name and Designation of the Guide Asst. Professor,Dept. of Quality Assurance Srinivas college of pharmacy 11.2 Signature 11.3 Name and Designation of the Co-Guide 11.4 Signature 12 ----------- ----------- Head of the Department Dr. E.V.S. Subramanyam, Professor and Head, Dept of Quality Assurance Srinivas college of Pharmacy 12.1 Signature 13 Recommended and forwarded for consideration. 13.1 Remarks of the Principal 13.2 Signature Dr. A. R. SHABARAYA Principal, Srinivas College of Pharmacy, Valachil, Mangalore 10 11