ENHANCING ORAL BIOAVAILABILITY OF CARVEDILOL USING SOLID DISPERSION TECHNIQUE Original Article MARGRIT AYOUB, AZZA HASAN, HANAN EL NAHAS, FAKHR-ELDIN GHAZY Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt Email: margrit_marmar@yahoo.com Received: 22 Jan 2016 Revised and Accepted: 17 May 2016 ABSTRACT Objective: Carvedilol (CRV) is a beta blocker drug that is basically used for the treatment of hypertension, heart failure and arrhythmias. The objective of this study is to increase the oral bioavailability of CRV by using solid dispersions to enhance its solubility and dissolution rate. Methods: Various preparations of CRV-solid dispersions (SDs) and physical mixtures (PMs) were prepared using different carriers; polyethylene glycol (PEG) 4000, polyvinyl pyrrolidone (PVP) K30 and tartaric acid. Effect of type and concentrations of carriers on solubility and dissolution of CRV were studied. Selected CRV-SDs and PMs that showed the best solubility and dissolution were exposed for further investigations e. g. Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and X-ray diffraction (XRD). In addition, the oral antihypertensive activity of the optimized formula compared to pure CRV was evaluated in induced hypertensive adult albino male rats. Results: All carriers enhanced the dissolution rate of CRV. Tartaric acid had the most persuasive effect on the rate and the extent of dissolution of CRV, followed by PEG4000 and PVP. FTIR, DSC and XRD diffraction revealed an interaction between CRV and tartaric acid with the possibility of a polymorphic change in CRV. The optimized formula CRV-tartaric acid (SD 1:0.3) causes a marked increase in the antihypertensive activity compared to pure CRV. Conclusion: Tartaric acid is a promising and efficient carrier for improving the solubility, dissolution and oral bioavailability of CRV. Keywords: Carvedilol, Solid dispersion, Physical mixture, Hypertension, Oral bioavailability © 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) INTRODUCTION Therapeutic effectiveness of a drug depends on upon the bioavailability and the solubility of drug molecules. The poor solubility and low dissolution rate of poorly water-soluble drugs in the aqueous gastrointestinal fluids often causes insufficient bioavailability. Therefore, it is necessary to enhance dissolution of these drugs to ensure maximum therapeutic utility [1]. The most promising method for promoting dissolution is the formation of a solid dispersion in a proper carrier. The solid dispersion reduces particle size and therefore increases the dissolution rate and absorption of drugs. The term “solid dispersion” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the melting (fusion) method, a solvent method, or fusion solvent-method [2, 3]. Carriers commonly used in solid dispersions (SDs) are PEG's of high molecular weight, polyvinyl pyrrolidones, urea, cyclodextrins, sugars, cellulose derivative and others [4, 5]. Carvedilol (CRV) ((±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxy- phenoxy) ethyl] amino]-2-propanol) is a beta-blocker used to treat high blood pressure and heart failure. CRV is practically insoluble in water and exhibits pH dependent solubility. The solubility of CRV is limited because of its protonation, resulting in situ hydrochloride salt formation which exhibits less solubility in acidic medium [6]. Many studies showed significant enhancement in the solubility of CRV by using solid dispersions, for example; Cyclodextrins [7], Gelucire 50/13 [8], PVP K30 [9] and Poloxamer 188 [10]. Most of the previous literature on CRV concerned with the in vitro study, and nearly none of them give an interest with studying oral bioavailability of the CRV-SDs. The Aim of the present work was to enhance aqueous solubility of CRV by solid dispersion technique using carriers such as PEG 4000, polyvinylpyrrolidone PVP K30 and tartaric acid. Effect of variables e.g. type and concentration of carriers will be studied. The carrier that showed highest solubility and dissolution of CRV would be exposed to further investigations e. g. FTIR, DSC and XRD. Oral bioavailability of the optimized formula of the selected carrier of CRV SDs would be evaluated by measuring the antihypertensive activity in induced hypertensive adult albino male rats. MATERIALS AND METHODS Materials CRV (kindly supplied by Amoun Co., Egypt), Methanol, polyethylene glycol (PEG) 4000, polyvinyl pyrrolidone (PVP) K30 and tartaric acid (kindly supplied by Nasr Pharmaceuticals Chemicals Co., Egypt). All other chemicals were of analytical grade. Solubility studies Solubility studies were carried out according to the method of Higuchi and Connors, 1965 [11]. An excess of CRV (10 mg) was placed into 25-ml glass vial containing various concentrations of each carrier in 10 ml distilled water. All glass vials were closed with stopper and cover sealed with cellophane to avoid solvent loss. The content of the suspension was equilibrated by shaking in a thermostatically controlled water bath at 25 o After attainment, the equilibrium, the content of each vial was then filtered through a double filter paper (Whatman 42). The filtrate was suitably diluted and assayed spectrophotometrically at 242 nm to measure the amount of dissolved drug. There was no interference from all used carriers at this wavelength. The solubility of CRV in water at the same temperature was also determined following the same procedure mentioned above [12]. C for 24 h. Preparation of physical mixtures (PMs) Physical mixtures (PMs) were prepared by triturating appropriate quantities of CRV and carriers using a mortar and pestle and then transferred to a vacuum desiccator until use [9]. International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 8, Issue 7, 2016