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“DESIGN AND EVALUATION OF FAST DISSOLVING ORAL FILMS OF GRANISETRON HYDROCHLORIDE” MASTER OF PHARMACY DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE. BY RAWDA KHALIFA ALI M.PHARM – I Under The Guidance of Dr. A. R. SHABARAYA M. Pharm., Ph.D. DEPARTMENT OF PHARMACEUTICS. SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143 2010-2012 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the Candidate and Address: MS. RAWDA KHALIFA ALI 1st YEAR M.PHARM, DEPT. OF PHARMACEUTICS, SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE-574143. 2. Name of the Institution: SRINIVAS COLLEGE OF PHARMACY, VALACHIL, FARANGIPETE POST, MANGALORE-574143. 3. Course of Study and Subject: MASTER OF PHARMACY (PHARMACEUTICS) 4. Date of Admission: 29th October 2010 5. Title of the Project: DESIGN AND EVALUATION OF FAST DISSOLVING ORAL FILM OF GRANISETRON HYDROCHLORIDE. 6. Brief Resume of the intended work: 6.1 Need of the study: Among the various routes of administration, the oral route is the most acceptable for the patients. Many pharmaceutical companies have directed their research activity in reformulating existing drugs into new dosage forms. One such relatively new dosage form is the fast dissolving oral film. The oral mucosa being a highly vascularized, drugs can be absorbed directly and can enter the systemic circulation without undergoing first‐pass hepatic metabolism.1 Fast dissolving oral films, a new drug delivery system, was developed based on the technology of the transdermal patch. Rapidly dissolving or quick dissolving dosage forms have acquired great importance in the pharmaceutical industry due to their unique properties and advantages like availability of larger surface area that leads to rapid disintegrating and dissolution in the oral cavity ,so there is no need of water, accurate dosing, rapid onset of action, ease of transportability, ease of handling, pleasant taste and improved patient compliance especially for paediatric and geariatric.2 Oral film may be preferred over the mouth dissolving tablets in terms of flexibility and comfort. In addition, they can also circumvent the sticky feeling in the oral cavity associated with oral gels.3 Granisetron HCl is a 5HT3 antagoinst. It is a novel antiemetic drug, given for prevention of chemotherapy-induced nausea and for pre-and post-surgical nausea and vomiting.4 The drug is well absorbed from GIT, but its bioavailability is low due to extensive first pass metabolism. It is selected as a drug candidate, as it is not available in such dosage form. And in general, emesis is preceded with nausea and in such condition it is difficult to administer drug with a glass of water; hence it is beneficial to administer such drugs as fast dissolving films with good mouth feel.5 In the present study attempt will be made to formulate a “patient friendly” dosage form of fast dissolving oral film of Granisetron hydrochloride - a possible application to anti emesis during Cancer Chemotherapy. 6.2 - Review of literature: Basani G, et.al over viewed on fast dissolving films. They concluded that, many of the pharmaceutical companies are switching their product franchise from ODTs to ODFTs. The ODFT is a good tool for product life cycle management for increasing the patent life of existing molecules or products. Compared to some of the complicated and expensive process (like lyophilization) used to manufacture ODTs, the ODFT is relatively easy to fabricate; thus reducing the overall cost of the therapy.6 Arun A, et.al an innovative fast dissolving oral film drug delivery system and dosage form. They have concluded that fast dissolving oral films have several advantages over the conventional dosage forms. So they are of great importance during the emergency cases such as allergic reactions and asthmatic attacks whenever immediate onset of action is desired.7 Sumitha C H, et.al has designed a taste masking of Ondansetron hydrochloride by polymer carrier system and formulation of rapiddisintegrating films. Rapid dissolving film containing taste masked Ondansetron hydrochloride showed acceptable properties. The drug release profile indicated that it could be used for the oral delivery of Ondansetron hydrochloride in chronic and acute post operative or chemotherapy or radiotherapy induced emesis. Good correlation between in vitro disintegration behaviour and in the oral cavity was recognized, patient friendly dosage form has been accomplished.8 Renuka M, et.al has formulated and characterized Rapidly Dissolving Films of Cetirizine hydrochloride using Pullulan as a Film Forming Agent. It was concluded that pullullan could be used as film forming polymer for formulation of rapidly dissolving films containing Cetrizine hydrochloride. Effective film separation could be achieved using Teflon as a casting surface.9 Nagendra D K, et.al has designed a fast dissolving tablet of Granisetron hydrochloride using super disintegrant blends for improved efficacy by direct compression method with a view to enhance patient compliance.10 Choudhary D R, et.al has formulated and evaluated a quick dissolving film of Levocetirizine dihydrochloride with the aim to have rapid onset of action and increased bioavailbility in allergic condition. Various cellulose derivatives like HPMC, CMC, and HPC. Films with 3% HPMC and 10% w/v propylene glycol showed better results as compared to HPC and CMC. Films showed good mechanical properties like, tensile strength, folding endurance and % elongation in comparison to other films prepared by using HPC and CMC. These results suggest that HPMC is an excellent film former which gives rapid drug release (80% in 120 sec) amongst different cellulose derivatives used.11 Yoshifumi M, et.al has prepared a fast dissolving film for oral dosage from natural polysaccharides. In this study the thickness and surface shape were affected by the concentration of the material used for film formation. The films were able to disintegrate quickly in physiological saline.12 Tadao T, et.al has prepared a fast dissolving oral thin film containing Dexamthasone. This preparation showed excellent uniformity and stability when stored at 4o degree and 75 in humidity for up to 24 weeks. The film was disintegrated within 15 seconds after immersion in to distilled water dissolution study showed that 90% of Dexamethasone was dissolved in 5 minutes.13 Renuka S, et.al has developed a taste masked oral film of Valdecoxib, using Eudragit EPO and HPMC.The bitter taste of the drug was masked by using aspartame and menthol accompanied by the synergistic effect of Eudragit and glycerol. The films containing the higher proportion of glycerol showed higher water uptake and faster drug release at all the sampling time in the test. The study revealed that taste masked Valdecoxib films can be developed by the selection of appropriate film former and by the use of auxiliary excipients.14 Kulkarni P K, et.al have formulated and evaluated mouth dissolving film containing Rofecoxib. The film of HPMC and PVA were prepared with an objective to dissolve the film. It exhibited acceptable film endurance. Time required for the film to dissolve and release the drug was found to be 30 second and 1 minute respectively. It is concluded that mouth dissolving film can be a potential novel drug dosage form for poorly water soluble drug.15 Kunte S, et.al has developed a fast dissolving Oral Strips for the delivery of Verapamil. Thus the patient-friendly dosage form of bitter drugs such as Verapamil can be successfully formulated using this technology and it can be especially useful for geriatric, bedridden, and non cooperative patient due to its ease of administration.16 Chandak, et.al has prepared and optimized a fast dissolving oral Film of Selegiline hydrochloride which can be useful in Parkinsonism treatment. The experimental results indicated that polymer concentration; plasticizer concentration had complex effects on % drug release. It was found that the optimum values of the responses for fast release film could be obtained at optimum levels of Poly Vinyl Pyrolidine and low level of propylene glycol. The results showed that drug dissolve quickly and have good onset of action.17 Mashru RC, et.al has developed and evaluated a fast dissolving film of Sulbutamol sulphate. The prepared film was clear, transparent with smooth surface and has an acceptable mechanical characteristics and satisfactory % drug release. Tmax for fast dissolving film was lower than that of conventional tablets. A fast dissolving film of salbutamol sulphate could be helpful for fast onset asthmatic attack management.18 Cilurzo, et.al evaluated the feasibility of a fast dissolving film made of a Maltodextrin plasticized by glycerine by solvent free hot-melt extrusion technology. Loading capacity and the in vivo performances of the film were assayed by using Paracetamol as model drug because its bioavailability can be determined.19 Christopher Yu, et.al developed Oral Quick- Dissolving Strips for Rotavirus Vaccine the novel drug-delivery system is needed because rotavirus is a common cause of severe diarrhoea and vomiting in children, leading to about 600,000 deaths annually. In addition, newborns sometimes spit out the liquid, a problem that is less likely to occur with a strip that sticks to and dissolves on the tongue in less than a minute.20 Nagendra D K, et.al designed a fast dissolving Granisetron hydrochloride tablets using novel co-processed super disintegrants .It can be concluded from this study that co-processed super disintegrants of crospovidone and crosscarmellose sodium are superior to physical mixture of crospovidone and crosscarmellose sodium used in Granisetron hydrochloride fast dissolving tablets.21 Venkatalakshmi R, et.al has formulated and evaluated Granisteron hydrochloride mouth dissolving tablets In vitro dispersion, wetting time and in vivo dispersion parameters signified that cros povidone in ratio 10 mg per tablet act as good disintegrants prepared by direct compression method.22 6.3 - Objectives of the study: Specific objectives of the present study are as follows: 1) To design a fast dissolving oral film of Granisetron HCl. 2) To perform the characterization of the drug. 3) To perform In vitro evaluation studies. 4) To study Drug and excipient interaction. 5) To compare with the marketed dosage forms. 7. Materials and Methods: Materials: 1. Drug : Granisetron hydrochloride. 2. Polymers : HPMC,E-3,and K-3, Pullulan, CMC, PVP K-90, pectin, Eudragit etc 3. Plasticizers : Glycerol, di-butylpthallate, Polyethylene glycol etc. 4. Solvent : Water or Organic solvent. 5. Flavours : Intense mint , sour fruit flavour, sweet confectionary flavour etc Methods: Solvent Casting Technique. Water soluble Polymers are dissolved in water and the drug along with other excipients is dissolved in suitable solvent using a high shear processor. Flavours are added. Both mixtures are mixed to form homogenous viscous solution. Suitable plasticizer was added under constant stirring. The resultant solution was left over night at room temperature to ensure a clear, bubble-free solution. The solution was poured out into a glass Petri dish. The coated film is sent to aeration drying oven. The film is removed. Films of specific size are cut, packed in aluminium foil and stored in desiccators for evaluation. 7.1 Source of data: Review of literature from a) Journals such as International Journal of ChemTech Research. International Journal of Pharma Professional’s Research. Journal of Chemical and Pharmaceutical Research. Indian Journal of Pharmaceutical Sciences. International Journal of Pharmacy and Technology. European Journal of Pharmaceutics and Bio pharmaceutics. International Journal of Pharmaceutical Sciences Review and Research. International Journal of Pharmacy and Pharmaceutical Sciences b) Internet Browsing. c) Laboratory based studies. 7.2 – Method of Collection of Data: 1. Study of research article 2. Laboratory investigation: Evaluation of fast dissolving oral films which includes Appearance 1 Weight Variations 2 Thickness4 Percentage elongation6 Tensile strength 4 Folding endurance 2 Surface PH1 Drug content6 Disintegration/dissolving time2 a. Drug and excipients interaction: By FT-IR Spectroscopy b. In vitro drug release study: USP II dissolution by basket method. 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 8. LIST OF REFERENCES: 1. Basani G, Subash VK, Guru S, Madhusudan R Y. Overview on fast dissolving films. Int J of Pharmacy and Pharm Sci. 2010;2(3):29-33. 2. Arun A, Amrish C, Vijay S, Kamla P. Fast dissolving oral films: An innovative drug delivery system and dosage form. Int J of chem Tech research. 2010; 2(2):576-583. 3. Sumitha CH, Karuna SN, Divya B, Madhavi K, Vimal Kumar Varma M, Charbe NN .Taste masking of Ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating films. Int J of Chem research 2009;1(2):24-27. 4. Renuka M, Avani A. Formulation and Characterization of Rapidly Dissolving Films of Cetirizine hydrochloride using Pullulan as a Film Forming Agent. Indian J Pharm Educ Res.2011;45(1):72-77. 5. Nagendra k, Raju SA, Shirsand SB, Para MS. Formulation design of novel fast dissolving tablet of Granisetron hydrochloride using super disintegrant blends for improved efficacy. Int J of Research n Ayurveda and pharmacy.2010;1(2):468-474. 6. Choudhary DR, VA Patel, HV Patel, Kundawala AJ. Formulation and evaluation of quick dissolving film of Levocetirizine dihydrochloride. Int J of pharmacy and technology.2011;3(1):1740-1744. 7. Yoshifumi M, Takashi I, Kyoko K, Norihisa N, Ryosei K. Preparation of fast dissolving film for oral dosage from natural polysaccharides. Materials. 2010;(3):4291-4299. 8. Tadao T, Hirotaka Y, Naoki I, Kazuyuki H, Mayumi Y, Yasutomi k, Yoshinovi J. Preparation of fast dissolving oral thin film containing Dexamthasone. Euro J of pharmaceutics and Biopharmaceutics.2009;73(3): 361-365. 9. Renuka S, Pavikh RH, Gohel MC, Soniwala MM. Development of taste masked film of Valdecoxib for oral use. Indian J of pharm Sci.2007;69(2):320-323. 10. Kulkarni PK, Dixit M, Gunashekava K, Shahnawaz A, Kulkarni A. Formulation and evaluation of mouth dissolving film containing Rofecoxib. Int research J of pharmacy.2011;2(3):273-278. 11. Kunte S, Tandale P. Fast dissolving oral strips for the delivery of Verapamil. J of pharmacy and Bio allied Sci.2010;2(4):325-328. 12. Mashru RC, Sutariya VB, Sankalia MG, Parikh PP. Development and Evaluation of Fast Dissolving Film of Salbutamol Sulphate. Ind Pharm 2005;31(1):25–34. 13. Cilurzo F, Cupone IE, Minghetti P. Selmin F, Montanari L. Fast dissolving films made of Maltodextrins. Eur J Pharm Biopharm. 2008;70(3):895–900. 14. Nagendrakumar D, Raju S.A, Shirsand S.B Para M.S. Design of a fast dissolving Granisetron Hcl tablets using novel co–processed super disintegrants. J Biosci Tech.2009;1(1):8-14. 15. Venkatalakshmi R, Sasikala C, Swathi R, Tejaswini G, Srujana.D, Sravan k Formulation and Evaluation of Granisetron hydrochloride mouth dissolving tablet. Int. J. Ph. Sci. 2009;1(2):336-341. 16. Kalina, Santacruz E. Formulation and Evaluation of Fast dissolving Films for delivery of Triclosan to the oral cavity. AAPS Pharm Sci tech. 2008;9(2):349356. 9. Signature of the candidate (RAWDA KHALIFA ALI) 10. Remarks of the Guide 11. 11.1 Name and Designation of the Guide The work, which is assigned to MS. RAWDA KHALIFA ALI is under my guidance. Dr. A. R. SHABARAYA M.Pharm., Ph.D. Principal and Director, Srinivas College of Pharmacy Valachil, Mangalore- 574143 11.2 Signature 11.3 Name and Designation of the Co-Guide ----------- 11.4 Signature ----------- 11.5 Head of the Department Dr. A. R. SHABARAYA M.Pharm., Ph.D. Principal and Director, Srinivas College of Pharmacy, Valachil, Mangalore- 574143 11.6 Signature 12. 12.1 Remarks of the Principal Recommended and forwarded for favourable consideration. 12.2 Signature Dr. A. R. SHABARAYA