Chitosan Loaded Mucoadhesive Microspheres of Gliclazide - Journal

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A B S T R A C T RGUHS Journal of Pharmaceutical Sciences Formulation and Evaluation of Mucoadhesive Buccal Drug Delivery System of Metoprolol Tartrate by Using Central Composite Design 1 2 Prakash Rao B* and Gandhi Purvesh Original Research Article 1 Department of Pharmaceutical Technology, Karnataka College of Pharmacy, Bangalore, Karnataka, India. 2. Department of Pharmaceutics, Visveswarapura Institute of Pharmaceutical Sciences, Bangalore, Karnataka, India. The central composite design was used to develop the controlled release buccoadhesive tablets containing metoprolol tartrate as drug candidate. Carbopol 934P and hydroxy propyl cellulose (HPC) were taken as formulation factors (independent variables). Bioadhesive strength, drug release after 8 hours, T and release exponent (n) were taken as responses (dependent variables). The polymers had 50% significant effect on bioadhesive strength and in vitro drug release. It was found that carbopol gives higher bioadhesive strength than HPC. Comparatively HPC controls the drug release greater than carbopol. The optimized formulation follows non-Fickian release mechanism. The FT-IR and DTA studies indicate no physico-chemical interaction. Stability studies revealed that optimized formulation was stable. The predicted values of drug release at 8 hrs, bioadhesive strength, T release exponent, n are 64.26%, 44.84 gm, 6.10 50%, hrs, 0.658 and actual values are 60.45%, 43.52 gm, 6.46 hrs, and 0.673 respectively. Keywords: Metoprolol tartrate, Central composite design, Buccoadhesive, Hydroxy propyl cellulose, Carbopol 934, DTA INTRODUCTION In recent years, the transmucosal route like oral cavity, ocular, nasal, rectal, vaginal offers the many advantages than the peroral route. These include an avoidance of both hepatic and intra-alimentary canal metabolism within GI tract. The oral mucosal cavity for drug administration has received much more attention because of its unique advantages over other oral transmucosal routes. The buccal route is suitable for sustain and controlled release administration of drug because of its less permeability and buccal mucosa has expanse of smooth and relatively immobile mucosa. The sublingual route is suitable for rapid onset of action because of its high 1 permeability of the mucosa and rich blood supply . And the problems such as hepatic first pass metabolism and degradation of drug in GIT can be overcome by using the buccal route. Buccal drug delivery facilitates safe and easy 2 removal of dosage form in cause of toxicity . Various buccal 3 adhesive dosage forms like discs, microspheres and bilayered 4 tablets have been prepared and reported by several research 5 groups . Mucoadhesive polymers are essential in the development of buccal drug delivery system. This polymer provides intimate contact between the dosage form and the absorbing tissue and 6 increase the retention time . Increasing the retention time of the dosage form is essential in the development of this system RGUHS Journal of Pharmaceutical Sciences Received: 18/1/2011, Modified: 22/5/2011, Accepted: 1/6/2011 146 and it has been reported that increase in retention time with 7, 8 an increase in the mucoadhesivity of the system . In the literature, buccoadhesive drug delivery system for drugs like 9 10 11 carvedilol , clotrimazole and sodium fluoride are reported. Metoprolol Tartrate (MT) is a selective beta receptor blocker 1 used in treatment of several diseases of the cardiovascular system, especially in hypertension, angina pectoris, cardiac arrhythmias and myocardial infraction. The half life of MT is 3 to 4 hours. Metoprolol is completely absorbed after oral administration, but bioavailability is low (< 40%) because of 12 first pass metabolism . The short half life and severe first pass metabolism of metoprolol tartrate make it suitable for administration via buccal route that provides controlled drug delivery and by passing first pass effect. The effect of the quantity of carbopol 934 (A) and expanded form of HPC (B) were selected as independent variables. In vitro bioadhesive strength, drug release after 8 hours, T 50% (Time for 50% drug release) and diffusion coefficient (n) were selected as response variables. Computer-aided optimization technique, using central composite design (CCD), was employed to investigate the effect of two independent variables (factors) on drug release parameters and bioadhesive 13 strength . All response variables were fitted to linear, quadratic, 2FI model and regression analysis was carried out to get a quantitative relationship between the dependable and the analysed independent variables. RJPS, Jul - Sep, 2011/ Vol 1/ Issue 2
OBJECTIVES 1) To formulation of controlled mucoadhesive buccal drug delivery system by using central composite design. 2) To improve the bioavailability by passing the first pass effect. 3) To perform the evaluation studies for thickness, hardness, weight variation, friability and In vitro drug release. MATERIALS AND METHOD Materials Prakash Rao B et al./ Formulation and Evaluation of Mucoadhesive Buccal Drug Delivery System of Metoprolol Tartrate by Using Central Composite Design Metoprolol Tartrate was obtained as a gift sample from Novartis pharmaceutical LTD (Mumbai, India). Carbopol 934P and magnesium stearate were purchased by S.D Fine Chem. LTD. (Mumbai, India). HPC was received as gift sample from Strides Arco labs LTD (Bangalore, India). All other chemicals and reagents were of analytical grade. 14 Experimental Design Central composite design (CCD) was selected for the development of the formulation. CCD has three groups of design points, two-level factorial or fractional factorial design points, axial points (sometimes called "star" points) and central points. Central points are usually repeated 4-6 times to get a good estimate of experimental error. Central composite designs have 5 levels of each factor: -Alpha, -1, 0, 1, and +Alpha (Table 1). Effect of carbopol (A) and effect of HPC (B) was selected as independent variables. Higher (+1) and lower (-1) value of the independent variables were selected and calculate the alpha value. These values were put in the optimization software and get the different formulation given in the (Table 2). The drug release after 8 hours (R 1), bioadhesive strength (R 2), T 50% (time for 50% of drug release) (R3) and diffusion coefficient (n) (R4) were selected as responses. Preparation of Buccal Tablet Buccal tablets of MT were prepared by direct compression method. All the ingredients without magnesium stearate were accurately weighed and mixed in mortar with a pestle for 10 minutes to get the uniform powder. After sufficient mixing of drug and polymer, magnesium stearate was added and mixed for 3 min. The blended powder was compressed into tablets by using the Rimek mini press –I compression machine. The quantities of various ingredients are shown in (Table 2). Evaluation of Buccal Tablets Thickness Thickness of the tablet was measured by using the digital vernier callipers (Aerospace, china).Thickness is expressed in 15 millimeters. Hardness The hardness of the tablet was measured using the Monsanto hardness tester (Scientific engineering corp., Delhi, India). It 2 16 is expressed in Kg/cm . Weight Variation Test 20 Tablets were taken from each batch and individually weighed by Electronic balance. Average weight of the tablets was calculated and deviation from the actual weight was 16 determined. 16 Friability Friability generally refers to the loss in weight of tablets in the containers due to the removal of fines from the tablet surface. Friability generally reflects poor cohesion of tablet ingredients. 10 tablets were weighed, initial weight of these tablets were recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions. Then, tablets were removed from friabilator, dusted off the fines and Table 2: List of working formulations Run Carbopol( X 1 ) HPC ( X 2 ) Design (mg) (mg) point F-1 65.00 65.00 Centre F-2 65.00 65.00 Center F-3 15.50 65.00 Axial F-4 65.00 65.00 Centre F-5 30.00 30.00 Fact F-6 30.00 100.00 Fact F-7 100.00 30.00 Fact F-8 100.00 100.00 Fact F-9 65.00 65.00 Centre F-10 114.50 65.00 Axial F-11 65.00 15.50 Axial F-12 65.00 114.50 Axial F-13 65.00 65.00 Centre Each formulation contain 50 mg of MT Table 1: Factors and their corresponding levels implemented for the construction of CCD Independent variable(Factor) -Alpha( α) -1 0 +1 +alpha(α) Carbopol 15.50 30 65 100 114.50 HPC 15.50 30 65 100 114.50 147 RJPS, Jul - Sep, 2011/ Vol 1/ Issue 2
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