Application of Chitosan to Modulate Hpmc-ec Based Controlled Release Tramadol Matrix System

Tramadol hydrochloride, highly water soluble drug was chosen as candidate drug for formulation of controlled release drug delivery owing to its undesirable side effects like abdominal pain, anorexia which were likely to happen after administration of conventional drug delivery of tramadol. The objective of present study was to design and investigate the performance of hydrophilic and hydrophobic matrix system in controlling release of tramadol. Moreover the effect of Chitosan and its water soluble form as release retarding agent was investigated as polymeric matrix systems accompany the problem of initial burst release. Polymers such as HPMC and ethyl cellulose were used and controlled release tablets were prepared by direct compression. Further they were subjected to evaluation of flow properties, tablet properties and in vitro dissolution. All the batches depicted improvement in flow property and compressibility. It was observed that all the batches had uniform thickness and reflected uniform behaviour during compression process. In, in-vitro drug release studies, the drug release was found to be completed within 10 hours. Further addition of ethyl cellulose was found to control the drug release to certain extent. All formulations without Chitosan and water soluble Chitosan gave initial burst release followed by steady state release. However incorporation of Chitosan and water soluble Chitosan impaired the initial burst release indicating better and more controlled drug release. Thus Chitosan and water soluble Chitosan could be best suited to modulate HPMC-EC based controlled release Tramadol matrix system with minimal burst and maximal controlled release. Keyword: Tramadol HCl, HPMC, Ethyl cellulose, Chitosan, water soluble Chitosan. Introduction: Tramadol hydrochloride, a synthetic opioid of amino cyclohexanol group, is a centrally acting analgesic. It is an effective centrally acting analgesic with weak opioid agonist properties. Tramadol has been Y. N. Gavhane* et al. International Journal Of Pharmacy & Technology IJPT | April-2013 | Vol. 5 | Issue No.1 | 5165-5174 Page 5166 proved to be effective in both experimental and clinical pain without causing serious cardiovascular or respiratory side effects. The half-life of the drug is about 5.5 hours and the usual oral dosage regimen is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400 mg/day. But, Tramadol HCL is associated with certain side effects, like abdominal pain, anorexia and it may also induce psychic and physical dependence. So, a controlled release dosage formulation of Tramadol is desirable to reduce the frequency of administration and to improve patient compliance [1] by minimizing the fluctuations in blood concentration, and thereby decreasing the risk of side effects and showing uniform pharmacological response. [2] For drugs like Tramadol HCL having high water solubility, a mix of hydrophilic and hydrophobic polymers are suitable as matrixing agents for developing sustained-release dosage forms [3]. Hydrophilic polymer matrix systems are advantageous for their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance [4]. Hydrophobic polymers provide several advantages, ranging from good stability at varying pH values and moisture levels to well-established safe applications. But most of the polymeric matrix systems studied for controlled drug release show the problem of initial burst release and need the process of coating which is rather costlier and time consuming complicated process needing sophisticated instruments [2]. So aim of the present study was to formulate controlled release matrix system of Tramadol HCL without any initial burst release. In the present study, various matrix systems were de-signed and tested for controlled delivery of tramadol HCL. The objectives of the study were (1) to investigate the performance of hydrophilic and hydrophobic matrix systems in controlling the release of this freely soluble drug, and (2) to investigate the effect of Chitosan and its water soluble form as a release-retarding agent controlling burst release. Materials and methods: Materials: Tramadol hydrochloride was obtained from Unichem Laboratories Ltd., Mumbai, India as gift sample. Chitosan and Water Soluble Chitosan were gift sample from Mahatani Chitosan Pvt. Ltd., Ahmedabad, India. HPMC K 100M and ethyl cellulose were purchased from Colorcon Asia Pvt Ltd Mumbai, India. All other chemicals, solvents and reagents were of analytical grade. Y. N. Gavhane* et al. International Journal Of Pharmacy & Technology IJPT | April-2013 | Vol. 5 | Issue No.1 | 5165-5174 Page 5167 Preparation of Controlled release Tablets: Controlled release tablets of Tramadol Hydrochloride were prepared by direct compression using two polymers viz. HPMC and ethyl cellulose. Before blending of drug and other excipients, they were sifted through sieve no. 20. Drugs and other excipients were blended for 10 mins. Then, subsequently this powder mixture was blended for 5 mins with magnesium stearate, Aerosil and Micro Crystalline Cellulose (MCC). This mixture was directly compressed to get the tablets. Preparation of different batches and concentrations of drug, polymer and excipients used in the batches is depicted in table 1. [5] Table-1: Preparation of different batches. Batches A1 A2 A3 A4 A5 A6 A7 A8 Tramadol 300 300 300 300 300 300 300 300 HPMC 117 130 117 130 80 50 80 50 EC 32.5 32.5 45.5 45.5 35.5 20.5 35.5 20.5 Chitosan --------60 90 ----WSC ------------60 90 Magnesium Stearate 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 Aerosil 3.25 3.25 3.25 3.25 3.25 3.25 3.25 3.25 MCC 190.75 177.75 177.75 190.75 164.75 141.75 164.75 141.75 Evaluation of tablets [6] The flow properties of prepared powdered mixtures were investigated by measuring the bulk density, tapped density, Carr’s index and packing factor. The bulk and tapped densities were measured in a 50 ml graduated measuring cylinder. The sample contained in the measuring cylinder was tapped mechanically by means of constant velocity rotating cam. The initial bulk volume and final tapped volume were noted from which, their respective Y. N. Gavhane* et al. International Journal Of Pharmacy & Technology IJPT | April-2013 | Vol. 5 | Issue No.1 | 5165-5174 Page 5168 densities were calculated. The angle of repose of the prepared granules was determined by the funnel method suggested by Neumann. The prepared tablets were evaluated for weight variation, hardness, thickness, friability, and drug content. Pfizer hardness tester was used for the determination of hardness. In weight variation test twenty tablets were selected at a random and average weight was calculated. Then individual tablets were weighed and the weight was compared with an average weight. The tablet was placed in contact between the plungers and the handle was pressed, the force of the fracture was recorded. In this work, for each formulation the hardness of 6 tablets was evaluated. The crown-to-crown thicknesses of ten tablets from each batch were determined using vernier calipers. The Friability of the tablets was determined using Roche friabilator (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula: F = (1W0 / W) × 100 Where, W0 is the weight of the tablets before the test and W is the weight of the tablets after the test. For determination of drug content at least three tablets from each formulation were weighed individually, pulverized, and diluted to 250ml with sufficient amount of phosphate buffer pH 6.8. After that an aliquot of the filtrate was diluted and analyzed spectrophotometrically at 268nm. In vitro Dissolution study was performed at 37oC using Type II (paddle) Dissolution Test Apparatus USP XXI MODEL (LABINDIA Tablet dissolution test apparatus). 900 ml of distilled water was used as dissolution medium. Study was carried out for 16 hours at 50 rpm. 5 ml Aliquot was taken at each time interval. Samples were analyzed spectrophotometrically at 268 nm using SHIMDZU UV – 1700 spectrophotometer. Evaluation has been done in triplicate. Results and Discussion Various physical parameters evaluated for blended powders were found within official limits. Carr’s index values were below 20 which indicated excellent flowability [7]. A Hausner ratio of <1.25 indicated powder’s free flowing nature [7]. The results of evaluation of micromeritic properties are displayed in table 2. Y. N. Gavhane* et al. International Journal Of Pharmacy & Technology IJPT | April-2013 | Vol. 5 | Issue No.1 | 5165-5174 Page 5169 Table-2: Evaluation of Powder Properties. Batches Bulk Density (g/mL) Tapped Density