Evaluation of Diabecon Ds, a Polyherbal Formulation on Blood Sugar of Normal and Alloxan

FORMULATION AND EVALUATION OF HOLLOW MICROSPHERES AS GASTRORETENTIVE DRUG DELIVERY SYSTEM

SYNOPSIS FOR M.PHARM DISSERTATION

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

BY Tanuja .D I M.PHARM (Pharmaceutics) DEPARTMENT OF PHARMACEUTICS VIVEKANANDA COLLEGE OF PHARMACY Bangalore RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the candidate and address TANUJA .D (In block letters)

2. Name of the Institution VIVEKANANDA COLLEGE OF PHARMACY RAJAJINAGAR, II BLOCK BANGALORE 3. Course of Study and Subject M.PHARM and PHARMACEUTICS

4. Date of admission to the course 24 December 2012

5. Title of the topic: Formulation and Evaluation of Hollow Microspheres as Gastroretentive Drug Delivery System. 6 BRIEF RESUME OF THE INTENDED WORK 6.1 NEED FOR THE STUDY The design of oral controlled drug delivery systems (DDS) primarily aimed to achieve more predictable and increased bioavailability.1 Nowadays most of the pharmaceutical scientist is involved in developing the ideal DDS. This ideal system should have advantage of single dose for the whole duration of treatment and it should deliver the active drug directly at the specific site. Controlled release implies the predictability and reproducibility to control the drug release, drug concentration in target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose.2,3 Floating microspheres are gastroretentive drug delivery system based on non effervescent approach. They are low density systems, which have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period of time. When microspheres come in

2 contact with gastric fluid the gel formers, polysaccharides and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydro colloidal layer. The air trapped by swollen polymer lowers the density and confers buoyancy to the microspheres.4,5 Dextromethorphan hydrobromide, a centrally acting non-opoid antitussive drug. It is an effective and safe for the control of cough in patients. It is readily absorbed from the upper GIT. Dose is 10-30 mg daily in divided dose. Due to its short biological half life of 1.4-3.9 h, it requires multiple dosing (2-3 times a day). Multiple dosing leads to fluctuation in the drug blood level and often dose related adverse effects. Multiple dosing also often results in poor compliance and inefficient therapy. To increase therapeutic efficacy, reduce frequency of administration and for better patient compliance twice daily controlled release dextromethorphan hydrobromide gastroretentive dosage form is prepared to prolong the residence time in absorption region for desired period of time.6 Dextromethorphan hydrobromide belongs to the class II of biopharmaceutics classification of system (BCS), exhibits low solubility and high permeability. Hence, enhanced gastric retention time of dextromethorphan hydrobromide controlled release dosage form will increase its absorption. Therefore, dextromethorphan hydrobromide was selected as a suitable drug for the design of a gastric floating drug delivery system (GDDS) with a view to improve its oral bioavailability. 6.2 REVIEW OF LITERATURE Ichikawa et al7 developed a new multiple type of floating dosage system having a pill in the core, composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sub layers to avoid direct contact between the 2 agents. These sub layers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37º C, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/ml. Shoufeng Li et al8 reported the effect of HPMC and carbopol on the release and floating properties of gastric floating drug delivery system using factorial design. In the study HPMC K4M and K100 LV viscosity grades and carbopol 934 were used in formulating the gastric floating drug delivery system employing 2x3 full factorial designs. It was found that HPMC

3 K4M, the presence of carbopol and their interaction had significant impact on the release and floating properties of the delivery system. The decrease in the release rate was observed with an increase in viscosity of the polymeric system. The polymer with lower viscosity HPMC K100 LV was shown to be beneficial than higher viscosity polymer HPMC K4M in improving the floating properties of GFDDS. Incorporation of carbopol, however, was found to compromise the floating capacity of GFDDS and release rate of calcium. The observed difference in the drug release and the floating properties of GFDDS could be attributed to the difference in basic properties of three polymers HPMC, K4M, K100 LV and carbopol 934, due to their water uptake potential and functional group substitution. Hilton A K et al9 reported in vitro and in vivo evaluation of an oral sustained release floating dosage form of amoxycillin trihydrate. Various hydrophilic polymers were investigated, the most suitable system contained a 1:2 ratio of hydroxy propyl cellulose to drug compressed easily and was not affected by alteration in normal compaction pressure. Intrinsic dissolution studies at pH 2 showed that reduction in drug loading decreased release, which being linear with time was characteristic of an eroding matrix with a hydrated layer. Kawashima Y et al10 have reported hollow microspheres of ibuprofen with eudragit for use as floating controlled drug delivery system in the stomach. In these hollow microspheres (microballoons), loaded with drug in their outer polymer shells were prepared by a novel emulsion, solvent diffusion method. The ethanol dichloromethane solution of drug and an enteric acrylic polymer were poured into an agitated aqueous solution of poly vinyl alcohol that was thermally controlled at 40° C. The gas phase generated in the dispersed polymer droplet by the evaporation of dichloromethane formed an internal cavity in the micro sphere of the polymer with the drug. The drugs incorporated in the solidified shell of the polymer were found to be partially or completely amorphous. The floatability and packability of the resultant micro balloons were much improved compared with the raw crystals of drugs. The microballoons floated continuously over the surface of acidic dissolution media containing surfactant greater than 12 h. The drug release behavior of the microballoons was characterized as an enteric property, and the drug release rates were drastically reduced depending on the polymer concentration at pH 6.8. El Kamel A H et al11 have prepared sustained release ketoprofen floating micro particles by the emulsion-solvent diffusion technique. Four different ratios of eudragit S100 with eudragit RL were used to form the floating microparticles. It was observed that the drug retained in the floating micro particles decrease with increase in eudragit RL coated. This could be due to the permeation characteristics of this polymer that could facilitate the diffusion of a part of entrapped drug into the surrounding medium during the preparation of floating micro particles. X-ray and

4 DSC examination showed that the drug was amorphous in nature. The release rates were low in pH 1.2 HCl when compared to that in buffer pH 6.8, specially in presence of high content of eudragit S whereas in phosphate buffer pH 6.8, high amounts of eudragit S tended to give a higher release rate. Floating ability in 0.1N HCl, 0.1N HCl containing 0.02 % tween 20 and simulated gastric fluid without pepsin was also tested. The best medium tested was 0.1N HCl containing tween 20 followed by 0.1 N HCl and then by simulated gastric fluid. The formulation containing eudragit S: eudragit RL:1. F-III extrubated high percentage floating particles in all examined media. Soppimath et al12 have prepared hollow microspheres of cellulose acetate containing cardiovascular drugs using a, novel solvent diffusion-evaporation method. The method of preparation involved the addition of polymer and drug solution in ethyl acetate and an acetone mixture to the aqueous phase containing polyvinyl alcohol and stirring at 500 rpm/min for 24 h. The microspheres were then collected by decantation and dried. Joseph et al13 have developed a floating dosage form of piroxicam based on hollow polycarbonate microspheres. The microspheres were prepared by solvent evaporation technique. An encapsulation efficiency of ~95 % was achieved. The drug release behavior of the hollow microspheres was characterized as an enteric property, and the drug release rates were drastically reduced depending on the polymer concentration. Illum et al14 have developed microspheres that released the active agent in the stomach environment over a prolonged period of time. The active agent was encased in the inner core of microspheres along with rate controlling membrane of water-insoluble polymer. The microspheres were prepared by spray drying. A considerable significant correlation was detected between in vivo results and in vitro data of the dissolution rate. Lee et al15 have prepared hollow microspheres using propranolol hydrochloride, tacrine hydrochloride, theophylline and cyclosporine as model drugs. The method of preparation involved the addition of a solution containing drug and polymer to an aqueous solution of polyvinyl alcohol, under continuous stirring. The microspheres were collected by filtration and dried for 12 h at 50˚ C. The author investigated the effect of ethanol and Isopropanol on microsphere formation. Ninan Ma et al16 have developed multi-unit floating gelatin microspheres by ionotropic gelation method with calcium carbonate as the gas forming agent. Attempts were made to enhance the drug encapsulation efficiency and delay the drug release by adding chitosan to the gelation medium and by coating with eudragit, respectively. The gastrointestinal transit of the optimized floating sustained-release microspheres was compared with that of the non-floating.

5 Jain et al17 have prepared floating microspheres consisting of calcium silicate as a porous carrier, repaglinide, an oral hypoglycemic agent, eudragit S as a polymer. The optimized formulation demonstrated favourable in vitro floating and drug release characteristics. The gastroretentive behaviour of this optimized formulation was compared. 6.3 OBJECTIVES OF THE STUDY 1) To formulate hollow microspheres as gastroretentive dosage form 2) To characterize the hollow microspheres by FT-IR, SEM and DSC studies 3) To evaluate the hollow microspheres for drug content, micromeritic properties, floating lag time and in vitro buoyancy 4) To carry out in vitro drug release studies 5) To carry out stability studies on an optimized formulations as per ICH guidelines MATERIAL AND METHODS 7.1 Source of data I Primary a) Journals and publications b) Internet and medline.

II Secondary Laboratory based studies

7.2 Method of collection of data Drug to be used: Dextromethorphan hydrobromide will be used for the study. Materials to be used: Gelatin, Karaya Gum, Chitosan, Liquid paraffin, Glutaraldehyde, Tween 80, Span 80 etc., will be used. METHODOLOGY Preparation of hollow microspheres by Emulsion polymerization The microspheres are prepared by emulsion polymerization method. The polymer is dissolved in suitable aqueous media and drug is dispersed in polymer solution with continuous stirring for about 30 min. Then liquid paraffin, span 80 or tween 80 along with 1% glutaraldehyde are added. The system is constantly stirred at 1000 rpm using mechanical stirrer. The aqueous phase is completely removed by evaporation. The light oil is decanted and microspheres are collected by filtering through whatman filter paper. Analytical studies Analytical method development using UV technique.

6 Evaluation and Characterization  Drug content  Micromeritic properties  Release studies  Curve fitting analysis  Short term stability studies  Differential Scanning Calorimetry  Fourier Transform Infrared Spectroscopy  Scanning Electron Microscopy 8 REFERENCES 1. Garima, Piyush, Vishal, Arvind K. Gastroretention: A means to address regional variability in intestinal drug absorption. Pharma Tech 2003; 27(2): 50-68.

2. Mathiowitz, Edith ed: Encyclopedia of controlled drug delivery, Vol-I, New York Wiley 1999; 9-11.

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9. Hilton AK, Deasy PB. In vitro and in vivo evaluation of an oral sustained release floating dosage form of amoxicillin trihydrate. Int J Pharm 1992; 86: 79-88.

7 10. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y. Hollow microspheres for use as a floating controlled drug delivery system in the stomach. J Pharm Sci 1992; 81: 135–40.

11. El-Kamel AH, Sokar MS, Gamal SS. Preparation and evaluation of ketoprofen floating oral delivery system. Int J Pharm 2001; 220(2): 13-21

12. Soppimath KS, Kulkarni AR, Aminabhavi TM. Development of hollow microspheres as floating controlled-release systems for cardiovascular drugs: preparation and release characteristics. Drug Dev Ind Pharm 2001; 50: 15-25.

13. Joseph NJ, Lakshmi S, Jayakrishnan A. A floating-type oral dosage form for piroxicam based on hollow polycarbonate microspheres: in vitro and in vivo evaluation in rabbits. J Control Rel 2002; 79: 71-79.

14. Ping H, Davis SS, Illum, Hisbeth. Chitosan microspheres prepared by spray drying. Int J Pharm 1999; 187: 53-65.

15. Lee JH, Park TG, Choi HK. Development of oral drug delivery system using floating microspheres. J Microencapsulation 1999; 16: 715-29.

16. Ninan M, Lu X, Wanga Q. Development and evaluation of new sustained-release floating microspheres. Int J Pharm 2008; 358: 82-90.

17. Sunil K, Awasthi AM, Jain NK, Agrawal GP. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization. J Control Rel 2005;107: 300–9.