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DEVELOPMENT AND EVALUATION OF HOLLOW MICROSPHERE BASED FLOATING TABLETS FOR THE DELIVERY OF AN ANTI-HYPERTENSIVE DRUG M. Pharm. Dissertation Protocol Submitted to Rajiv Gandhi University of Health Sciences, Karnataka Bangalore– 560041 By Mr. PAVAN WALVEKAR B. Pharm. Under the Guidance of Prof. S. P. THAKKER M. PHARM Department of Pharmaceutics S.E.T’s COLLEGE OF PHARMACY S. R. Nagar, Dharwad–580002 2013 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. NAME OF THE CANDIDATE AND ADDRESS Mr. PAVAN WALVEKAR DEPT. OF PHARMACEUTICS SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD-580002 2. NAME OF THE INSTITUTION SET’s COLLEGE OF PHARMACY, S. R. NAGAR, DHARWAD-580002 3. COURSE OF STUDY AND MASTER OF PHARMACY IN PHARMACEUTICS SUBJECT 4. DATE OF ADMISSION TO JANUARY 2013 COURSE 5. TITLE OF THE TOPIC DEVELOPMENT AND EVALUATION OF HOLLOW MICROSPHERE BASED FLOATING TABLETS FOR THE DELIVERY OF AN ANTI-HYPERTENSIVE DRUG. 1 6. BRIEF RESUME OF THE INTENDED WORK 6.1 NEED FOR THE STUDY Site specific delivery of bioactive molecules have recently been of great interest in the field of pharmaceutical research, to achieve desired concentration of drugs at the site of action; to avoid exposure of rest of the drug to the other parts of the body; to reduce the frequency of administration; to reduce toxic effects and increase patient compliance1. Most convenient route of administration is by oral route. The oral controlled delivery is advantageous for reduction in drug’s blood level fluctuations, dosing frequency and adverse side effects as well as improved overall health care costs, patient convenience and compliance. Although, attempts have been made to develop oral controlled release delivery systems, yet certain limitations like unsatisfactory and variable drug absorption, uncontrolled gastric transit time etc., have established the urgent need of the more intelligent drug delivery systems, which can either prolong the transit time, or provide effective concentration locally. The two approaches of gastro retentive and colon based controlled delivery have been widely utilized to overcome these barriers. However, due to some associated complications such as low pH in the stomach, presence of digestive enzymes, typical residence time at different parts of the alimentary canal etc., makes difficulties for effective treatment using these drugs. There are various approaches using Novel Drug Delivery Systems (NDDS) to avoid these problems. One of the methods is floating drug delivery system. These systems works on the principle that are based on swelling, inflation, adhesion, low density system and ion exchange resin system mechanisms to increase the gastro retention of dosage forms2. Gastro retentive systems can remain in the gastric region for several hours and hence can significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment. It also has applications for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients3. 2 In the present protocol, we propose the use of hollow microspheres for developing floating tablets to deliver an antihypertensive drug “amlodipine”. Amlodipine belongs to the category of calcium channel blockers of anti-hypertensive drugs. It is a dihydropyridine calcium antagonist that inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. However, due to the slow absorption of amlodipine, we propose gastroretentive dosage form for once in a day administration4. 3 6.2 REVIEW OF LITERATURE: In this work development of hollow microspheres as floating controlled-release systems for cardiovascular drugs were prepared and release characteristics were studied. Hollow microspheres of cellulose acetate polymer loaded with four cardiovascular drugs (nifedipine, nicardapine hydrochloride, verapamil hydrochloride, and dipyridamole) were prepared by a novel solvent diffusion-evaporation method. The microspheres showed smooth surfaces, with free-flowing and good-packing properties. Scanning electron microscopy confirmed their hollow structures, with sizes in the range 489–350 μm. The microspheres tended to float over the gastric media for more than 12 h. The release of the drugs loaded microspheres were controlled for more than 8 h. The release kinetics followed different transport mechanisms depending on the nature of the drug molecules5. Chitosan hollow microspheres were prepared by employing uniform sulfonated polystyrene particles as templates. The chitosan was adsorbed onto the surface of the sulfonated polystyrene templates through the electrostatic interaction between the sulfonic acid groups on the templates and the amino groups on the chitosan. Subsequently, the adsorbed chitosan was crosslinked by adding glutaraldehyde. After the removal of the sulfonated polystyrene core, chitosan hollow microspheres were obtained. It was observed that the longer the sulfonation time used, the smaller the size of the hollow particles and the thicker the chitosan wall obtained. Fourier transform infrared spectrometry was used to characterize the component of the microspheres. The morphologies of the PS templates and the chitosan microspheres were observed by transmission electron microscopy and scanning electron microscopy. The controlled release behavior of the chitosan hollow microspheres was also primarily investigated6. In a design based on hollow microspheres responsive to various stimuli comprised a promising approach for the development of multifunctional and efficient systems for various nanomedicine-related applications. Authors prepared poly(methacrylic acid-co-N,N'methylenebis(acrylamide)-co-poly(ethyleneglycol) methyl ether methacrylate-co-N,N'- bis(acryloyl)cystamine) (PMAAS-S) hollow microspheres following a two-stage distillation precipitation polymerization procedure. Magnetic and silver nanocrystals were chemically grown on the surface of the hollow polymer microspheres, which resulted in a composite system with interesting properties. The performance of the composite hollow microspheres as magnetic hyperthermia mediators and their surface enhanced Raman spectroscopy 4 activity. Assessment of Daunorubicin-loaded PMAAS-S hollow microspheres performance as effective drug carriers were carried out through drug release experiments upon application of different pH and reducing conditions. pH and redox responsiveness as well as basic mechanisms of release profiles. Furthermore, in vitro cytotoxicity of empty and drug-loaded PMAAS-S hollow microspheres against MCF-7 cancer cells were investigated in order to evaluate their performance as drug carriers7. Microspheres of copolymeric N-vinylpyrrolidone and 2-ethoxyethyl methacrylate for the controlled release of nifedipine were formulated. Microspheres were prepared by varying the amount of NVP with respect to EOEMA. Nifedipine, a water-insoluble antihypertensive drug, was loaded into these microspheres by the oil in water emulsion technique followed by solvent evaporation. Release data were analyzed using an empirical relation in order to elucidate the kinetics of the nifedipine release. This analysis indicated that a Fickian transport mode operates in this system8. In this study polymer blends used to prepare nifedipine loaded hollow microspheres for a floating-type oral drug delivery system were prepared and evaluated. Hollow microspheres containing nifedipine were prepared by a solvent diffusion-evaporation method using various ratios of PVP and EC co-dissolved with drug in ethanol/ether (5:1, v/v) The hollow microspheres were found to float in release medium for more than 24 h, and floating capacities were not be influenced by mixing PVP. In vitro release profiles of hollow microspheres prepared using EC along showed an initial burst release to some extent, and the cumulative release percentage were less than 55% after 24 h9. Polystyrene/polycarbonate composite hollow microspheres by microencapsulation method were successfully prepared and characterized. Fourier-transform infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry and thermogravimetric analysis were used for the characterization of the obtained hollow microspheres. SEM images showed that there were a big cavity and some small cavities inside the composite hollow microspheres, and the hollow microspheres prepared at 420C presented better morphology and smaller size distribution compared with that prepared at higher temperature of solvent evaporation10. 5 A new simple method was developed by the authors for the formation of hollow polyethersulfone microspheres was reported in this paper. Coaxial electrospraying equipment and nonsolvent precipitating bath were used to produce hollow microspheres in one step. The properties of the core solution affected the formation of hollow polyethersulfone microspheres. The supporting layer formed by the micro-phase that was caused by the phase separation of the core or shell solution exhibited as the key factor for the formation of hollow polyethersulfone microspheres. This method provided a new simple way to form hollow polymer microspheres and can be extended to other polymers to prepare hollow microspheres in one step11. Hollow microsphere exhibit to be a potential approach for gastric retention. The recent developments of floating drug delivery system including approaches to design singleunit and multiple-unit floating systems, mechanism of floating microspheres, methods of preparation of hollow microsphere, list of polymers used in hollow microspheres, characterization of hollow microspheres and their classification and formulation aspects were covered in a review12. Opened hollow microspheres of organoclays were prepared via spray drying the suspension of modified Na+- montmorillonite with alkylsulfonate. The microstructure and thermal properties of these opened hollow spheres were characterized by means of wideangle X-ray diffraction, field emission scanning electron microscopy and thermogravimetric analysis. On the basis of the morphological investigation authors observed that the organoclays containing alkylsulfonate with different molecular length, the formation of the opened hollow microspheres were found to be related to the intercalation structure of the organoclays. The larger the interlayer distance of the organoclays was, the more the opened hollow microspheres were formed. Moreover, intercalating Co2+ ion within MMT galleries of the opened hollow microspheres via ion exchange could be applied to in situ synthesize clay/carbon nanotubes (clay/CNTs) composite by chemical vapor deposition after reduction13. Nearly monodispersed silica-poly (methacrylic acid) (SiO2-PMAA) core-shell microspheres were synthesized by distillation-precipitation polymerization from 3(trimethoxysilyl) propylmethacrylate-silica (SiO2-MPS) particle templates. SiO2-PMAASiO2 trilayer hybrid microspheres were subsequently prepared by coating of an outer layer of SiO2 on the SiO2-PMAAcore-shell microspheres in a sol-gel process. pH-Responsive PMAA hollow microspheres with flexible (deformable) shells were obtained after selective 6 removal of the inorganic SiO2 core from the SiO2-PMAA core-shell microspheres by HF etching14. Hollow hydroxyapatite microspheres as a device for controlled delivery of proteins were successfully prepared. Hollow hydroxyapatite (HA) microspheres (106–150 µm) with a hollow core diameter equal to 0.6 the external diameter and a mesoporous shell wall were prepared by allow temperature glass conversion route and evaluated as a device for controlled delivery of a model protein, bovine serum albumin15. 6.3 OBJECTIVE OF STUDY: Objectives of proposed research are, Preparation of blank hollow microspheres by solvent-evaporation technique/spray drying technique. Preparation of hollow microspheres of amlodipine in different loadings. Preparation of solid unit dosage forms of amlodipine containing hollow microspheres as well as blank microspheres. Evaluation parameters: a. Spectral analysis: Various spectral analysis such as SEM, FTIR, DSC and 7 XRD of blank as well as drug loaded microspheres. b. In-vitro tests: Particle size and buoyancy tests for microspheres prepared. Determination of drug content and drug loading efficiency. In-vitro drug release. c. Formulation of solid unit dosage forms containing blank hollow microspheres. d. Formulation of solid unit dosage forms containing drug loaded hollow microspheres. e. Evaluation of solid unit dosage forms for various tests. f. In-vitro release kinetics studies will be undertaken. MATERIALS AND METHODS : A. MATERIALS: Drug: Amlodipine Polymers: Chitosan, Eudragit, Cellulose acetate pthalate B. METHOD: Preformulation studies Solubility Melting point pH UV Analysis Preparation of solid unit dosage forms. These systems are prepared by suitable punching machine. 7. 8 Evaluation: Interaction studies of drug polymer by using FTIR. Surface topography by SEM. Particle size distribution of prepared microparticles by microscopic technique and drug nature by DSC/XRD. Drug entrapment efficiency. In vitro release kinetic study. 7.1 SOURCE OF DATA : Text books www.sciencedirect.com www.informahealth care.com www.ijps online.com 7.2 Method of collection of data: The data will be collected from various standard journals, prepared formulations, in vitro evaluation and various standard reference books, & other sources like research literature data bases such as Science Direct etc. 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVENTION TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO PLEASE MENTION BRIEFLY. ---------No ----------- 9 7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3? ------------- Not applicable ---------- 10 8. REFERENCES: 1. Soppimath KS, Kulkarni AR, Rudzinski WE, Aminabhavi TM. Microspheres as floating drug delivery systems to increase gastric retention of drugs. Drug Metabolism Reviews 2001;33:149-160. 2. Chien YW. Novel Drug Delivery Systems. 2nd ed. New York (NY): informa health care; 139,164. 3. Jain NK. Introduction to Novel Drug Delivery Systems. 1st Ed. Delhi: Vallabh Prakashan; 2010; 35,36,40. 4. Brunton LL, Lazo JS, Parker KL. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th Ed. New York (NY): Mc Graw Hill; 2005; 857. 5. Soppimath KS, Kulkarni AR, Aminabhavi TM. Development of Hollow Microspheres as Floating Controlled-Release Systems for Cardiovascular Drugs: Preparation and Release Characteristics. 2001; 27: 507-515. 6. Haiming Li, Wang M, Song Li, Xuewu Ge. Uniform chitosan hollow microspheres prepared with the sulfonated polystyrene particles templates. Colloid Polym Sci 2008;286:819-825. 7. Chatzipavlidis A, Bilalis P, Tziveleka LA, Boukos N, Charitidis CA, Kordas G. Nanostructuring the Surface of Dual Responsive Hollow Polymer Microspheres for Versatile Utilization in Nanomedicine-Related Applications. Langmuir 2013; 29:9562−9572. 8. Kumar SV, Shelke NB, Prasannakumar S, Sherigara BS, Aminabhavi TM. Microspheres of copolymeric N-vinylpyrrolidone and 2-ethoxyethyl methacrylate for the controlled release of nifedipine. J Polym Res 2011;18:359–366. 9. Zhao L, Wei Yu, Yu Yu, Zheng W. Polymer Blends Used to Prepare Nifedipine Loaded Hollow Microspheres for a Floating-type Oral Drug Delivery System:In Vitro Evaluation. Arch Pharm Res 2010;33:443-450. 10. Jie Li, Wang S, Liu H, Wang S, You L. Preparation and characterization of polystyrene/polycarbonate composite hollow microspheres by microencapsulation method. J Mater Sci 2011;46:3604-3610. 11. Zhang Q, Wang L, Wei Z, Wang X, Long S, Yang J. A new simple method to 11 prepare hollow PES microspheres. Colloid Polym Sci 2012;290:1257–1263. 12. Gholap SB, Banarjee SK, Gaikwad DD, Jadhav SL, Thorat RM. Hollow microsphere: A Review. International Journal of Pharmaceutical Sciences Review and Research 2010;1:74-79. 13. Du X, Jiang Z, Meng X, Wang Z, Yu H, Li M,Tang T. Syntheses of Opened Hollow Clay Microspheres through a Spray-Drying Approach and Their Derivative Clay/Carbon Nanotubes Composites. J. Phys. Chem. C 2008;112:6638-6642. 14. Li G, Liu G, Kang ET, Neoh KG, Yang X. pH-Responsive Hollow Polymeric Microspheres and Concentric Hollow Silica Microspheres from SilicaPolymer Core-Shell Microspheres. Langmuir 2008;24:9050-9055. 15. Fu H, Rahaman MN, Day DE, Brown RF. Hollow hydroxyapatite microspheres as a device for controlled delivery of proteins. J Mater Sci: Mater Med 2011;22:579-591. 12 9. SIGNATURE OF CANDIDATE 10. REMARK OF THE GUIDE The above information and literature has been extensively investigated, verified and was found to be correct. The present study will be carried out under my supervision and this project is proposed for financial support from AICTE, under RPS scheme. 11. 11.1 NAME AND DESIGNATION OF THE GUIDE Prof. S. P. THAKKER., M. Pharm, PROFESSOR AND HEAD DEPT.OF PHARMACEUTICS, S E T’s COLLEGE OF PHARMACY, S. R. NAGAR, DHARWAD-580002. 11.2 SIGNATURE 11.3 NAME AND DESIGNATION OF CO-GUIDE 11.4 SIGNATURE 11.5 HEAD OF THE DEPARTMENT Dr. A. R. Kulkarni., M. Pharm, Ph.D PROFESSOR AND HEAD DEPT.OF PHARMACOLOGY S E T’s COLLEGE OF PHARMACY, S. R. NAGAR, DHARWAD-580002. Prof. S. P. THAKKER., M. Pharm. PROFESSOR AND HEAD, DEPT.OF PHARMACEUTICS, S E T’s COLLEGE OF PHARMACY, S. R. NAGAR, DHARWAD-580002. 11.6 SIGNATURE 12. 12.1 REMARK OF THE PRINCIPAL The above mentioned information is correct and I recommend the same for approval. 12.2 SIGNATURE Dr. V. H. Kulkarni., M. Pharm., Ph.D. PROFESSOR AND PRINCIPAL, S E T’s COLLEGE OF PHARMACY S. R. NAGAR, DHARWAD-580002. 13