April Journal-2009.p65 - Association of Biotechnology and Pharmacy

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Current Trends in Biotechnology and Pharmacy Vol. 3 (2) 188-196, April 2009. ISSN 0973-8916 Transdermal Drug Delivery System for Atomoxetine Hydrochloride – In vitro and Ex vivo Evaluation Mamatha T 1 , Venkateswara Rao J 1* , Mukkanti K 2 and Ramesh G 3 1 Sultan–Ul–Uloom College of Pharmacy, Road No.3, Banjarahills, Hyderabad-500034, (A.P.), India 2 Centre for Environment, Jawaharlal Nehru Technological University, Kukatpally Hyderabad-500072 (A.P.), India 3 Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences Kakatiya University, Warangal- 506 009 (A.P.), India *For Correspondence: jvrao1963@yahoo.co.in Abstract Monolithic matrix type transdermal drug delivery systems (TDDS) of atomoxetine hydrochloride (A-HCl) were prepared by the film casting on a mercury substrate and characterized by physicochemical characteristics like thickness, weight variation, drug content, flatness, folding endurance and in vitro drug release studies, ex vivo skin permeation studies. Eight formulations (carrying Eudragit RL100 and Hydroxypropyl methyl cellulose 15 cps in the ratios of 8:2, 6:4, 4:6, 2:8 in formulations A-1, A-2, A-3, A-4 and Eudragit RS 100 and Hydroxypropyl methyl cellulose 15 cps in the same ratios in formulations B-1, B-2, B-3, B-4 respectively) were prepared. All formulations carried 20 mg of drug, A-HCl, 10% w/w of propylene glycol as penetration enhancer, 10% w/w of dibutyl phthalate as plasticizer in ethanol. The formulations exhibited uniform thickness, weight and good uniformity in drug content. The maximum drug release in 24 hrs for A-series formulations was 95.52 % (A- 3) and for B-series, it was 89.55 % (B-4). Again formulations A-3 (Kp = 3.53 X 10 -2 cm h -1 ) and B-4 (Kp = 3.20 X 10 -2 cm h -1 ) exhibited the best skin permeation potential in the respective series. On the basis of in vitro drug release and ex vivo skin permeation performance, formulation A-3 was found to be better than the other seven formulations. The results of the study show that A-HCl could be administered transdermally through the matrix type TDDS for effective control of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Keywords: Transdermal, atomoxetine hydrochloride, propylene glycol, Eudragit, HPMC. Introduction Delivery of drugs into systemic circulation via skin has generated a lot of interest during the last decade as transdermal drug delivery systems (TDDS) offer many advantages over the conventional dosage forms and oral controlled release delivery systems notably avoidance of hepatic first pass metabolism, decrease in frequency of administration, reduction in gastrointestinal side effects and improves patient compliance (1). Matrix based transdermal formulations have been developed for a number of drugs such as metoprolol (2), nitrendipine (3), ephedrine (4), ketoprofen (5), propranolol (6), labetolol hydrochloride (7) and triprolidine (8). Atomoxetine hydrochloride (A-HCl) is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors and is the first non-stimulant medication approved for the management of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. In vitro and Ex vivo Evaluation
Current Trends in Biotechnology and Pharmacy Vol. 3 (2) 188-196, April 2009. ISSN 0973-8916 A-HCl is well absorbed after oral administration with peak plasma concentrations in 1 to 2 hours after a dose. Bioavailability is about 94% in poor metabolisers but only 63% in extensive metabolisers. Atomoxetine is metabolized primarily via the cytochrome P450 isoenzyme CYP2D6 to the active metabolite 4- hydroxyatomoxetine; a minority of the population are poor metabolisers and experience plasma concentrations about 5 times those in extensive metabolisers. The half life of atomoxetine is about 5.2 hours in extensive and 21.6 in poor metabolisers (9). A-HCl due to its low therapeutic dose (10-100 mg) and substantial biotransformation in liver becomes it ideal candidate for design and development of transdermal therapeutic system. A-HCl in transdermal formulations provides sustained blood levels over a prolonged period, which is required for control of ADHD. In spite of several advantages offered by transdermal route, only a few drug molecules are administered transdermally because the formidable barrier nature of stratum corneum. Two major approaches to increase transdermal permeation rate include physical techniques (iontophoresis, electroporation, sonophoresis, and microneedles) and use of chemical penetration enhancers (PE) such as solvents, surfactants, fatty acids, and terpenes. Propylene glycol (PG) is the most commonly used pharmaceutical excipients and have been widely employed to enhance the transdermal flux of many drugs (10-14). Various mechanisms of action have been attributed to the PG for its penetration enhancement capabilities such as increased thermodynamic activity (15), increased skin/vehicle partitioning of the drug (16), and alteration of barrier property by interacting with skin components. PG may reduce barrier property of skin by causing conformational changes either in lipid acryl chains (17) or protein domains (18) or by partial lipid extractions (19). 189 The objective of this study was to formulate transdermal patches of A-HCl and to evaluate the effect of PG in drug release. Materials and Methods Materials Atomoxetine HCl, Eudragit RL 100 (ERL) (Rohm Pharma GmbH, Germany) and Eudragit RS 100 (ERS) (Rohm Pharma GmbH, Germany) were procured from Aurobindo Pharmaceuticals (Hyderabad, India). Liquid mercury, dibutyl phthalate (DBP), hydroxypropyl methyl cellulose (HPMC), propylene glycol (PG), disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium chloride were purchased from S.D. Fine Chemicals Limited, India. All the materials used were of analytical grade. Preparation of TDDS The composition of various formulations is given in Table 1. The polymeric solution (10% w/ v) was prepared by dissolving ERL-100/ ERS- 100 and HPMC in different ratios, along with A- HCl, DBP and PG in ethanol. The solution was poured into a glass ring placed on the surface of liquid mercury kept in a petridish. The solvent was allowed to evaporate under ambient conditions (temperature 32 0 C and relative humidity 45%) for 24 hours. Aluminum foil was used as backing film. The polymer was found to be self sticking due to the presence of eudragit polymers along with plasticizer. The patches were cut to give required area and stored in airtight container till further use. Physicochemical Evaluation Thickness and Weight Variation The thickness of the patches was assessed at 6 different points using screw gauze. For each formulation, three randomly selected patches were used. For weight variation test, 3 films from each batch were weighed individually and the average weight was calculated (Table 2). Mamatha et al
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April Journal-2009.p65 - Association of Biotechnology and Pharmacy

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