Preparation of Mucoadhesive Patches for Buccal Administration of Metoprolol Succinate: in Vitro and in Vivo Drug Release and Bioadhesion
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Verma & Chattopadhyay Tropical Journal of Pharmaceutical Research February 2012; 11 (1): 9-17 © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved . Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v11i1.2 Research Article Preparation of Mucoadhesive Patches for Buccal Administration of Metoprolol Succinate: In Vitro and In Vivo Drug Release and Bioadhesion Navneet Verma 1,2* and Pronobesh Chattopadhyay 3 1College of Pharmacy, IFTM University, Moradabad-244001 (U.P.), 2Institute of Pharmacy, Bhagwant University, Ajmer-305004 (Raj.), 3Defence Research Laboratory, Tejpur-784001 (Assam), India Abstract Purpose: To develop mucoadhesive patches for buccal administration of metoprolol succinate and to evaluate their in vitro and in vivo bioadhesion. Methods: The mucoadhesive buccal patches were prepared by solvent casting technique using two different mucoadhesive polymers. The formulations were tested for in vitro drug permeation studies, buccal absorption, in vitro drug release studies, moisture absorption as well as for in vitro and in vivo bioadhesion. Results: The peak detachment force and work of adhesion for MC5 (sodium carboxymethylcellulose, i.e., Na CMC) patch were 0.87 N and 0.451 mJ respectively and the corresponding values for CH5 (chitosan) were 5.15N and 0.987 mJ. Formulation CH5 (prepared with chitosan) showed 67.1 % release, while MC5 (Na CMC) showed drug release of 81.9 % in 6 h. Basic pharmacokinetic parameters such as C max , T max and AUC total varied statistically (p < 0.05) when given by the buccal route compared with that of the solution given by the oral route. Conclusion: The results indicate that formulation of suitable bioadhesive buccal patches with the desired permeability is feasible. The development of bioadhesive buccal formulation for metoprolol succinate with a lower dose and few side effects may be attainable. Keywords: Mucoadhesive, Buccal patches, Metoprolol succinate, Sodium carboxymethylcellulose, Chitosan, Bioavailability Received: 15 May 2011 Revised accepted: 14 December 2011 *Corresponding author: E-mail: [email protected]; Tel: +91-9917731198 Trop J Pharm Res, February2012;11 (1): 9 Verma & Chattopadhyay INTRODUCTION the processing time from formulation design to clinical use [4]. Rapid developments in the field of molecular biology and gene technology has resulted in Metoprolol succinate is a non-selective and a generation of many macromolecular drugs β-adrenergic antagonist with no intrinsic including peptides, proteins, polysaccharides sympatomimetic activity and is widely used to and nucleic acids possessing superior treat essential hypertension and angina pharmacological efficacy, site specificity and pectoris. Although it is completely absorbed are devoid of untoward and toxic effects from the gastrointestinal tract, systemic However, the main impediment for the oral availability is only approximately 25 – 35 % delivery of these drugs is their extensive due to first-pass metabolism. Metoprolol presystemic metabolism and instability in succinate was selected as a model drug for acidic environment resulting in inadequate the investigation because its oral dose is 25 and erratic oral absorption [1]. Parenteral mg and half life is 3-4 h. Metoprolol succinate route of administration is the only established is metabolized primarily by aromatic ring route that overcomes these drawbacks. glucuronidation [5]. Its oxidative metabolites However, these formulations are costly, are metabolized by conjugation via require repeated administration and hence glucronidation and sulfation. A suitable show poor patient compliance,, in addition to buccal drug delivery system should be the other hazardous effects associated with flexible and possess good bioadhesive this route [2]. Over the past few decades, properties so that it can be retained in the pharmaceutical scientists have been oral cavity for the desired duration. In exploring transdermal and transmucosal addition, it should release the drug in a routes as alternative routes to the parenteral predictable manner to elicit the required route. Among the various transmucosal sites therapeutic response. The objective of this available, the buccal mucosa has been found study was to prepare mucoadhesive buccal to be a convenient and easily accessible site patches of metoprolol succinate and evaluate for the delivery of therapeutic agents for both their properties. local and systemic delivery because it has an expanse of smooth muscle which is relatively EXPERIMENTAL immobile, abundant vascularization, rapid recovery time after exposure to stress and Materials the near absence of Langerhans cells. Direct access to systemic circulation through the Metoprolol succinate was obtained as a gift internal jugular vein bypasses the hepatic first from Aarti Pharmaceuticals, India while pass metabolism leading to high drug sodium carboxymethylcellulose and chitosan bioavailability. Furthermore, these dosage were supplied by Sigma Pvt Ltd, India. The forms are self-administrable, low-cost and plasticizer, propylene glycol, was purchased have superior patient compliance [3]. from Merck (Mumbai, India). All the other reagents were of analytical grade. With the right dosage form design, the local . environment of the mucosa can be controlled Tissue preparation and manipulated to optimize the rate of drug dissolution and permeation. A rational Porcine buccal tissue from pigs was obtained approach to dosage form design requires a from local slaughter house and used within 2 complete understanding of the hours of slaughter. The tissue was stored in physicochemical and biopharmaceutical kerb buffer (pH 7.4) at 4 oC after collection. properties of the drug and excipients. The epithelium was separated surgically from Advances in experimental and computational the underlying connective tissue and methodologies will be helpful in shortening delipidized by incubation with chloroform: Trop J Pharm Res, February2012;11 (1): 10 Verma & Chattopadhyay methanol (2:1) at room temperature for 12 - Petri dish and dried in a desiccator pending 72 h, either before or after digestion with evaluation. The films were examined in order strong alkali or concentrated acid. The to select those with the best characteristics delipidized membrane was allowed to for further evaluation. equilibrate for approximately one hour in receptor buffer (kerb buffer) to regain the lost In vitro release study elasticity. Drug release from the buccal patches was In vitro drug permeation studies studied using USP type II dissolution test apparatus [8]. Patches (10 mm diameter) The buccal epithelium was carefully mounted were cut, and an impermeable backing in between the two compartments of a Franz membrane on one side of the patch. The diffusion cell with internal diameter of 1.0 cm assembly for release studies was prepared with a receptor compartment volume of 20.0 by placing the patch in contiguity with ml. A solution containing 20 ml of alcohol, cellulose acetate dialysis membrane such propylene glycol and phosphate buffer (pH that the drug release from the patch diffuses 6.8) in a ratio of 40:15:45 was placed in the through dialysis membrane. This assembly receptor compartment. The donor was placed in dissolution apparatus compartment (5 ml capacity) contained containing 500 ml of phosphate buffer (pH phenol red at a concentration of 10 µg/ml and 0 6.8) and rotating at 50 rpm at 37 ± 0.5 C. a solution of 3 ml of phosphate buffer pH 6.8 Samples (5 ml) were collected at different in which 2 mg of metoprolol succinate was time intervals and diluted with phosphate dissolved. Phenol red served as a marker buffer (pH 6.8), 2 ml of which was analysed that would not permeate the porcine buccal spectrophotometrically (UV-1800, Shimadzu, membrane. The entire set up was placed in a Japan) at 222 nm [9]. The experiment was water bath stirred by a magnetic stirrer at 37 performed in triplicate. ± 1 °C. Moisture uptake/Swelling index) studies A sample (1 ml) was collected at predetermined time intervals from the Moisture uptake gives an indication of the receptor compartment and replaced with an ability of the patches to maintain their equal volume of fresh receptor fluid [6]. The integrity after absorption of moisture. Agar experiment was conducted in triplicate. dispersion (5 %w/v) was prepared by dissolving agar in hot water [10]. The Production of bioadhesive films dispersion (20 ml) was transferred to a 4-inch diameter glass Petri dish and allowed to The films were prepared by casting [7]. solidify. Six drug-free patches from each Aqueous solution (20 ml) of the polymer formulation were selected, weighed and (either sodium CMC or chitosan), ranging placed in a vacuum oven(40 – 45 oC) from a polymer concentration of 1 – 6 %w/v, overnight prior to the study to remove any was prepared and left for 4 h for maximum residual moisture. Each patch was laminated swelling; 5 %w/v of propylene glycol (1 ml) on one side with a water-impermeable was added as plasticizer. Metoprolol backing membrane of ethyl cellulose, using succinate solution (1 ml, 2 %w/v) was mixed an adhesive, incubated at 37 0C for 1 h, and with 20 ml of the polymer solution and cast in reweighed [11]. Moisture uptake was a Petri dish 30 min later. It was dried at room o calculated as percent change in weight of the temperature (25 C) for 12 h. The films were patch. The experiment was performed in observed and checked for possible triplicate. imperfections upon