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  1. 1. FORMULATION AND EVALUATION OF FAST DISSOLVING FILM OF LISINOPRIL Synopsis Submitted to H.N.B. Garhwal (Central) University, Srinagar (Uttarakhand) For The Award of Degree of Master of Pharmacy (Pharmaceutics) By SAURABH CHANDRA MISHRA DEPARTMENT OF PHARMACEUTICAL SCIENCES H.N.B. Garhwal (Central) University Srinagar (Uttarakhand) 1
  2. 2. DEPARTMENT OF PHATRMACEUTICAL SCIENCES H.N.B Garhwal University, Chauras Campus-249161 Phone No: 01370-267395,FAX: 01346-252174,252247 Date: SYNOPSIS Title:FORMULATION AND EVALUATION OF FAST DISSOLVING FILMS OF LISINOPRIL Name of Candidate : Saurabh Chandra Mishra Enrollment Number: G1214506 Project Work: M.pharm (Pharmaceutics)2rd Year H.N.B Garhwal (central) University Srinagar(Uttarakhand) 2
  3. 3. TITLE OF THE TOPIC: “FORMULATION AND EVALUATION OF FAST DISSOLVING FILMS OF LISINOPRIL” BRIEF RESUME OF THE INTENDED WORK Introduction : Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as new drug delivery systems, because they are easy to administer and lead to better patient compliance. These delivery systems either dissolve or disintegrate in the mouth rapidly, without requiring any water to aid in swallowing.1They also impart unique product differentiation, thus enabling use as line extensions for existing commercial products. This novel drug delivery system can also be beneficial for meeting the current needs of the industry are improved solubility/stability, biological half-life and bioavailability enhancement of drugs.2,3.Although oral disintegrating tablets have an advantage of administration without choking and fast disintegration; the disintegrated materials contained in them are insoluble and remain until swallowing. In such cases formulation of fast dissolving film will be advantageous.4,5 3
  4. 4. Hypertension, commonly known as “High Blood Pressure”. Hypertension or High Blood Pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated.Blood pressure is a measurement of the force against the walls of your arteries as the heart pumps blood through the body. High blood pressure increases chances of having a stroke, heart attack, heart failure, kidney disease & early death. Commonly used prescription drugs include ACE inhibitors, alphablockers, angiotensin –ІІ receptor antagonists, beta-blockers, calcium channel blockers, diuretics etc.6Hence in the present work, an attempt will be made to prepare and evaluate oral fast dissolving film of Lisinopril for the effective management of hypertension and cardiac diseases. Review of literature: Literature survey was carried out on the proposed research work by referring various Scientific Research Journals, Internet, Helinet facilities and Science Direct. Pokharkar V et al (2007-08). Mouth dissolving tablets of Carvedilol were prepared with the purpose of delivering the drug directly into the systemic circulation and by passing the hepatic first pass metabolism with a concomitant increase in bioavailability, . The solubility of Carvedilol was improved by forming inclusion complex with cyclodextrin which was then further used for the formulation of mouth dissolving tablet. Differential scanning calorimetry and Infrared spectroscopy results indicated no incompatibilities between drug-excipient mixtures. Effect of three different superdisintegrants on disintegration was studied. The formulations were evaluated for drug content,content uniformity, friability,disintegration time and in vitro dissolution. Tablets containing Carvedilol-beta-cyclodextrin complex exhibited good tablet properties, with 90% drug dissolved within 5 min. This demonstrated the effectiveness of using various superdisintegrants and Carvedilol-beta-cyclodextrin complex in formulation of mouth dissolving tablet. 8 4
  5. 5. Aditya Dinge and Mangal Nagarsenker (2008). Triclosan (TC) containing fast dissolving films for local delivery to oral cavity was investigated by Various film forming agents, film modifiers and polyhydric alcohols were evaluated for optimizing the composition of fast dissolving films. The potential of poloxamer 407 and hydroxypropyl-β- cyclodextrin (HPBCD) to improve solubility of TC was investigated. Fast dissolving films containing hydroxypropyl methylcellulose (HPMC), xanthan gum, and xylitol were formulated. Use of poloxamer 407 and HPBCD resulted in significant improvement in the solubility of TC. Fast dissolving films containing TC-HPBCD complex and TCPoloxamer 407 were formulated and evaluated for the in vitro dissolution profile and in vitro microbiological assay. Films containing TC-Poloxamer 407 exhibited better in vitro dissolution profile and in vitro antimicrobial activity as compared to the films containing TC-HPBCD complex. Effect of incorporation of eugenol on the in vivo performance of TC-Poloxamer 407 containing films was evaluated in human volunteers. Eugenol containing films improved the acceptability of TCPoloxamer 407 films with respect to taste masking and mouth freshening without compromising the in vivo dissolution time. KUNTE SAND TANDLE P (2010)Fast dissolving films containing Verapamil were prepared and investigated. The fast dissolving strips were prepared by solvent casting technique with the help of HPMC E6 and maltodextrin. The strips were evaluated for drug content uniformity, film thickness, folding endurance, in vitro disintegration time, in vitro dissolution studies, surface pH study, and palatability study. Disintegration time showed by formulations was found to be in range of 20.4–28.6 sec. Based on the evaluation parameters, the formulation containing 2% HPMC E6 and 3.5% maltodextrin showed optimum performance against other formulations. It was concluded that the fast dissolving strips of verapamil can be made by solvent casting technique with enhanced dissolution rate, taste masking, 5
  6. 6. and hence better patient compliance and effective therapy.10 Semalty Aet al (2010)..Formulate and evaluate mucoadhesive drug delivery system of enalapril maleate . The buccal films were prepared by solvent casting technique. Sodium carboxy methyl cellulose, hydroxyl propyl methyl cellulose, hydroxylethyl cellulose and polyvinyl pyrrolidone K-90 were used as mucoadhesive polymers. Prepared films were evaluated for their weight, thickness, surface pH, swelling index, drug content uniformity, in vitro residence time, folding endurance in vitro release and permeation studies. It was found that the films containing 20 mg of enalapril maleate in sodium carboxymethylcellulose 2% w/v and hydroxyl ethyl cellulose 2% w/v (formulation F5), showed good swelling, a convenient residence time and promising controlled drug release as all the films exhibited controlled release over more than 10 h in permeation studies. It was concluded that the drug can be selected for the development of buccal film for effective therapeutic use. . Fast dissolving films of levocetrizine were prepared by solvent casting method using different grades of methocel K3, E3, E5, and E15 as film former and PG, PEG 400 and tween 80 as plasticizer. Bitterness of levocetirizine was masked by forming inclusion complex with HP-ßCD. The complex was evaluated by XRD, DSC and FT-IR. Optimized films were evaluated for mechanical properties, drug content and dissolution characteristics. The combination of methocel E15 and PEG 400 exhibited excellent mechanical properties, uniformity in drug content and in-vitro dissolution characteristics5 drug profile Lisinopril dihydrate Nomenclature: INN: Lisinopril dihydrate Chemical name: (2S) - 1- [(2S)-6-amino -2- [ [ (1S) – 1 – carboxy – 3 - phenylpropyl] amino] hexanoyl] pyrrole – 2 - carboxylic acid 6
  7. 7. Structure: Molecular formula: C21H31N3O5,2H2O Molecular weight: 441.5 Physical form: White to off white powder Solubility: Lisinopril dihydrate is soluble in water, sparingly soluble in methanol, and practically insoluble in acetone and in ethanol 7
  8. 8. Need for the study: Lisinopril is in a group of drugs called ACE inhibitors. ACE stands for angiotensin converting enzyme. Lisinopril is used to treat high blood pressure (hypertension), congestive heart failure, and to improve survival after a heart attack. Lisinopril may also be used for purposes other than those listed in this medication guide. Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications of diabetes. Onset of action is 1-2 hours. Duration of action is found to be 24 hours (once daily dosing).Absorption of the drug is found to be absorbed slowly and incompletely from GI tract(oral) and peak plasmaconcentration is achieved after 7 hours.The drug distribution i.e; protein binding is not significantly bound i.e., is up to 25%.The excretion of the drug is via urine in unchanged form of drug, and the elimination half-life of the drug is found to be 12 hours. The drug is given orally in case of hypertension. Adult dose is initially 5-10 mg daily given at bedtime to avoid precipitous fall in B.P. Patient with renovascular hypertension, volume depletion, severe hypertension; Initially 2.5-5 mg once daily. Diuretic patients are given 5 mg once daily. Maintenance of the dose i.e. 20 mg once daily up to 80 mg daily may be used if required.In case of children ≥6 years: initially up to 0.07 mg/kg( up to 5 mg once daily) can be given and adjusted the dose until desired B.P. is achieved. Bioavailability of the drug is approximately 25%, but wide range of 6-60% is also reported. 7 8
  9. 9. SALIENT FEATURES OF FAST DISSOLVING DRUG DELIVERY SYSTEM 1. Ease to administration for patients who are mentally ill, disabled and uncooperative. 2. Requires no water. 3. quick disintegration and dissolution of the dosage form. 4. Overcomes unacceptable taste of the drugs. 5. Can be designed to leave minimal or no residue in the mouth after administration and also to provide a pleasant mouth feel. 6. Allows high drug loading. 7. Ability to provide advantages of liquid medication in the form of solid preparation. 8. Adaptable and ameanable to existing processing and packaging machinery. 9. Cost- effective. The formulation of poorly water soluble drug compounds for oral delivery now present one of the greatest challenges to formulation scientist in pharmaceutical industry. The poor aqueous solubility of the drug result in variable dissolution profile hence poor bioavailability. The solubility behavior of a drug is the key determination of its oral bioavailability. Plan of work: Fast dissolving films of Lisinopril will be prepared to provide fast action in hypertension with the following objectives :9 1. To formulate Lisinopril fast dissolving films by using natural and synthetic polymers, following
  10. 10. MATERIALS & METHODS: Source of Data :  Primary literature: Journal publications  Secondary literature: Abstracts (International Pharmaceutical Abstracts), online material.  Tertiary literature: Text Books.  Prior unpublished research from our and other laboratories.  Data will be obtained from Science Direct, and other internet facilities, literature search and related articles from library of Shree Devi College of Pharmacy, Digital Library of RGUHS, Bangalore, etc. Journals  Asian Journal of Pharmaceutics  Journal of young Pharmacists  Indian Journal of Pharmaceutical Science  International Journal of Pharmacy and Pharmaceutical Science  Journal of Pharmacy Research  Digest Journal of Nano-materials & Bio-structures  Research Journal of Pharmaceutical, Biological & Chemical sciences  Journal of Liquid chromatography & related technologies 10
  11. 11. Text Books and Pharmacopoeia  Beckett AH, Stenlake JB, Practical Pharmaceutical Chemistry. 4 th ed.  Delhi: CBS Publisher and Distributors, 1997  Sethi PD, Quantitative Analysis of Drugs in Pharmaceutical Formulation,  3rded. Delhi: CBS Publisher and Distributors  Higuchi T And Brochman E, Hanseen H, Pharmaceutical Analysis, Delhi: CBS Publisher and Distributors, 2005  Mendham J, Denney RC, Barnes JD, K Thomas MJ, Vogel’s text Book of Quantitative Chemical Analysis, 6thed. Pearson education Pvt. Ltd, 2002  The Indian Pharmacopoeia, Government of India, Ministry of Health and Family Welfare, Published by The Indian Pharmacopoeia commission Gaziabad, Volume 2 & 3, 2007 Internet Browsing        11
  12. 12.  Methods of collection of data (including sampling procedures if any) : The data related to the physicochemical properties of the drug will be collected from the drug information center, various standard books, journals and other sources like research literature data bases such science direct etc. and laboratory equipments. • Attempts will be made to design fast dissolving films of Lisinopril with different polymers. • Prepared fast dissolving films will be evaluated for 1. Physical properties. 2. Drug content. 3. In vitro drug release and studying their release kinetics. 4. In vivo studies for Pharmacodynamics parameters in detail. REFERENCES : 1 Dixit R, Puthli S. Oral strip technology: Overview and future potential. J Control Release 2012;139: 94–107. 2 Arya A, Chandra A, Sharma V, PathakK. Fast dissolving oral films: An innovative drug delivery system and dosage form. Int J ChemTech Res 2010;2: 576–83. 3 Mashru C, Sutariya V, Sankalia M, ParikhP. Development and evaluation of fast-dissolving film of salbutamol sulphate. Drug Dev Ind Pharm 2005;31:25–34 4 Nishimura M, Matsuura K, Tsukioka T, Yamashita H, Inagaki N, Sugiyama T, et al. In vitro and in 12
  13. 13. vivo characteristics of prochlorperazine oral disintegrating film. Int J Pharm 2009; 368:98–102. 5 Shimoda H, Taniguchi K, Nishimura M, Matsuura K, Tsukioka T, Yamashita H, et al. Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm 2009;73: 361–5. 6 Available from [Last accessed on 2012 June 12]. 7 The American Society of Health-System Pharmacists Retrieved 3 April 2011. 8 Pokharkar V, Dhar S, Mandpe L. Studies on formulation development of mouth dissolving tablets of Carvedilol. Hindustan Antibiot Bull 2007 -2008; 49-50(1-4):21-8. 9 Dinge A and Nagarsenker M. Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity. AAPS Pharm SciTech 2008; 9(2): 349–56. 10 Kunte S and Tandale P. Formulation and Evaluation of fast dissolving films of verapamil J PharmBioallied Sci2010; 2(4): 325–8. 11 Semalty A, Semalty M, Nautiyal U. Formulation and evaluation of mucoadhesive buccal films of enalapril maleate. Indian J Pharm Sci 2010; 72(5):571-5. 12 SA Tayel, Soliman, II and D Louis. Formulation of ketotifenfumarate fast melt granulation sublingual tablet. AAPS Pharm Sci Tech 2010; 11(2): 679-85. 13 Magdy IM, Mohamed H, Muaadh A, Mohamed Ali. Buccal Mucoadhesive Films Containing Antihypertensive Drug: In vitro/in vivo Evaluation. J Chem Pharm Res 2011; 3(6):665-86. 14 Yehia SA, El-Gazayerly ON, Basalious EB. Fluconazole mucoadhesive buccal films: In vitro/in vivo performance. Curr Drug Deliv2009; 6(1): 17-27. 13
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