S.Ramkanth * et al.

/ International Journal of Advances in Pharmaceutical Research

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Available Online through www.ijapronline.org

Research Paper ISSN: 2230 7583

DESIGN AND CHARACTERIZATION OF MATRIX TYPE TRANSDERMAL DRUG DELIVERY *S.Ramkanth, M.Alagusundaram1, K. Gnanaprakash1, SYSTEM USING METOPROLOL TARTARATE
1

K. Mallikarjuna Rao1, T.S. Mohammed Saleem1, K.Paneer2,, C.Madhusudhana Chetty1

1

Department of Pharmaceutics, Annamacharya College of Pharmacy, Rajampet - 516126, Kadapa (Dt), Andhra Pradesh, India.
2

Sri K.V. College of Pharmacy, Chickballapur. Karnataka 562 101 Revised on 17-12-2010 ABSTRACT Accepted on 19-12-2010

Received on 01-12-2010

Transdermal drug delivery is an alternative route for systemic drug delivery which minimizes the absorption and increases the bioavailability. Oral Metoprolol tartrate has a short elimination half life (2-3 hrs), low bioavailability (35 %) undergoes extensive first pass metabolism and frequent high doses (100 mg two divided doses for 24 hrs) are required to maintain the therapeutic level as a result, dose development toxic side effects are frequently observed, so has chosen as transdermal drug delivery system. The present study was to design and characterize transdermal drug delivery system of Metoprolol tartrate using various polymers such as HPMC, PVP by solvent casting technique. Propylene glycol (30% v/v) used as a plasticizer. The prepared formulation were evaluated for different physicochemical characteristics like thickness, folding endurance, drug content, percentage moisture absorption, percentage moisture loss and weight uniformity. The drug release characteristics of the formulation were studied in In-vitro conditions by using artificial semi-permeable membrane. In-vitro dissolution studies were performed in phosphate buffer (7.4 pH) for 12 hrs by using keshery chein apparatus. The in-vitro drug release plot has shown that the drug release followed zero order kinetics, which was evidenced from the regression value. Based on the drug release and physicochemical values obtained the formulation M VI is considered as an optimized formulation which shows higher percentage of drug release (98.92 % at 12 hour) with non-fickian type diffusion mediated mechanism. Keywords: Tansdermal drug delivery system, Metoprolol tartarate, Hydroxy propyl methyl cellulose, Polyvinyl pyrrolidine, In-vitro drug release. INTRODUCTION A recent approach to drug delivery is to deliver the drug into systemic rate using skin circulation as a site at of predetermined application. For Correspondence: S.RAMKANTH, M. Pharm., (Ph.D), Assistant Professor, Department of pharmaceutics, New boyanapalli - 516126, Rajampet, Kadapa Dist, Andhra Pradesh, India. Mobile No: +91-96183-12122, E-Mail: [email protected], A transdermal drug delivery is a formulation or device that maintains the blood concentration of the

drug within the therapeutic window ensuring that drug levels neither fall below the minimum effective concentration nor exceed the minimum toxic dose. Transdermal drug delivery promises many advantages over oral and/or intravenous administration, such as better control of blood levels, a reduced incidence of systemic toxicity, and absence of hepatic first-pass metabolism. An ideal drug to be formulated as transdermal drug

delivery should possess several physico-chemical prerequisites, such as short halflife, small molecular size, low dose treatment hypertension. of mild etc.1,2, 3 to moderate essential

Metoprolol tartarate is a drug used in the It is the proto type of cardio Its potency to block

selective beta blockers.

cardiac stimulation is similar to propronolol, but

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S.Ramkanth * et al. / International Journal of Advances in Pharmaceutical Research

Table 2. Thickness and mass of the film nearly 50 times is higher dose is needed to block is induced vasodilation. It is less likely worsen First pass asthma, but is not entirely safe. The thickness of the film was determined by screw gauge at different position by placing the film in between two glass slides with know n thickness and average thickness was calculated. For weight variation test, 3 films from each batch were weighed individually and the average weight was calculated. Drug Content Determination6 The patch 3.14cm2 was cut and added to a beaker containing 5 ml of dichloromethane and

metabolism of metaprolol tartrate is less marked than propronolol, but 90% or more is ultimately metabolized before excretion. There are slow and fast hydroxylators of metoprolol, the former may require a lower dose. The aim of the present study was to develop different transdermal matrix films with varied ratios of two polymers such as HPMC and PVP combination containing the Metoprolol tartarate drug and to perform the physicochemical and in vitro evaluation of the prepared films. The purpose was to provide the delivery of drug at a controlled rate across intact skin to achieve a therapeutically effective drug level for a longer duration of time from transdermal films. MATERIALS AND METHODS Metoprolol tartarate was obtained as a gift sample from Halmack pharma, Hyderabad, Propylene glycol, HPMC and PVP was obtained from the S.d. fine Chemicals, Inida. All other ingredients were of analytical grade. Preparation of Transdermal Film The method adopted for preparing transdermal patches was solvent casting technique. Polymer and drug was dissolved in the mixture of Dichloromethane: Ethanol mixed with magnetic stirrer for 30 mins until to get a homogenous semisolid consistency. Propylene glycol 30% v/v is added finally as a plasticizer. The prepared solution was casted in glass surface in O shaped ring and allowed to dried at room temperature for 48 hours.4,5 The dried patches were collected and stored in a desiccator until used for further study. The composition of transdermal patches containing Metoprolol tartrate has been shown in Table 1. Evaluation of Prepared Transdermal Patches Physicochemical Evaluation The prepared films were evaluated for physical appearance, weight variation, uniformity of thickness, percentage moisture uptake, percentage moisture loss, folding endurance and drug content uniformity. The values are shown in

Initial weight - Final weight PMC = -------------------------------------- X 100 volume make upto 10 ml with phosphate buffer pH 7.4. The dichloromethane solvent was evaporated using a rotary vacuum evaporator at 450C. A blank was prepared using a drug free patch treated similarly. The solutions were filtered through a 0.45 m membrane, make into suitable dilutions and absorbance were read at 243 nm in a double beam UV Visible spectrophotometer. Percentage of Moisture A absorption7 patch was kept in a preweighed The Initial weight Folding endurance10 folding endurance was measured manually for the prepared films. A strip of film (2cm) was cut evenly and repeatedly folded at the same place till it broken. The number of times the film could be folded at the place without breaking gave the exact value of folding endurance. In-Vitro Drug Release Studies In the present study, In-vitro release of Metoprolol tartarate from various matrix systems was studied using Keshery-Chien type diffusion cell using cellophane membrane.11,12 The cell consists of two chambers, the donor and the receptor compartment. The donor compartment was open at The the top receptor and was exposed was to atmosphere. compartment

desiccator at room temperature for 3 days at 84 % relative humidity containing saturated solution of aluminum chloride. After three days the patch was taken out and weighed again. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight. Final weight - Initial weight PMU = --------------------------------------X 100 Initial weight Percentage of moisture loss7, 8, 9 The percent moisture loss was carried out to check the integrity of the film at dry condition. This was carried out in the following manner. The films were weighed accurately and kept in the desiccator containing anhydrous calcium chloride. After 3 days, the films were taken out and weighed. The moisture loss was calculated using the formula

surrounded by a water jacket for maintaining the temperature at 37 1 and it was provided with sampling port. Diffusion media in the receptor compartment was stirred with magnetic needle. The diffusion medium was used phosphate buffer (pH 7.4) solution.13 The drug containing film with a support of a backing membrane was kept in the donor compartment and it was separated from the receptor compartment by standard membrane. The donor and receptor compartment hold together using clips of strong grip. The receptor

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S.Ramkanth * et al. / International Journal of Advances in Pharmaceutical Research

physicochemical evaluation and the in-vitro release plots of all other formulations were suggestive o compartment containing dissolution medium was maintained at 37 1 by circulating the water in outer jacket from organ bath. The diffusion medium was stirred with magnetic needle 2 mm in diameter and 6mm in length operated by magnetic stirrer, to prevent the formation of concentrated drug solution layer below the standard membrane. At each sampling time the solution in the receptor compartment was completely withdrawn and replaced with fresh phosphate buffer solution. The concentration of the drug was determined by UV spectrophotometrically at 243nm for the drug content.14,15 various The in-vitro datas where fitted to models such as Higuchi and kinetic e formulation M VI (2% HPMC & 2% PVP) as 11.73 0.064 and 12.57 0.019 respectiv ely which also revealed its high hydrophilicity. formulations M III (1% PVP) has shown the The f zero order release and are diffusion mediated which was evidenced from the regression value Higuchis plot. All the formulations undergo non-fickian type of release which is confirmed from the slope values obtained from the Peppas plot. The higher percentage moisture loss and percentage moisture content was found in th

Korsemayers peppas for confirming the order and mechanism of drug release. In-vitro cumulative percent drug release data for all formulations were given in Table 3 and graphically shown in Fig 1. RESULTS AND DISCUSSION In the present work efforts have been made to prepare transdermal drug delivery system of Metoprolol tartarate using the polymers HPMC and PVP, using propylene glycol as a plasticizer by solvent casting technique. The prepared patches were evaluated for physicochemical parameters and in-vitro drug release kinetic studies. The selection of polymer combinations produces clear, smooth, uniform, substantive, flexible and desired thickness film for the transdermal drug delivery systems of Metoprolol tartarate. The prepared formulation were evaluated for different Physico chemical characteristics endurance, uniformity. vitro such Drug as Thickness, Percent Folding moisture of the out in Content,

absorption, Percentage moisture loss and Weight The release studies characteristics were carried formulation were studied in in-vitro conditions. Indissolution phosphate buffer (pH 7.4) for 24 hours, in order to find out the order of release and the mechanism which predominately influences the drug release from the membrane. The slope value and the degree of linearity of graphical treatments were considered as important statistical parameters to interpret the in-vitro profile of all formulations. All the formulations shows better results for

95.56% and 98.92% at 12th hour respectively. The in-vitro drug release of M VI has shown that the lowest value of Percentage moisture absorption and Percentage moisture loss was 1.61 0.019 and 1.59 0.31 respectively which may be due to the less hydrophilic nature of the polymer used in it. The thickness of the patches varied from 0.17 to 0.43 mm. The folding endurance of the films varied from 149 to 217 no of folds. From the results obtained it was found that the folding endurance decreases as the polymer concentration increases. The drug content uniformity and the mass uniformity of the prepared formulation have shown that the process used to prepare the films in this study was capable of giving films with uniform drug content and had with shown minimum different intra batch variability. The physicochemical evaluation of the formulations physical characteristics, which change according to the presence of polymer nature and the level of the polymer. The drug release characteristics of the formulation were studied in In-vitro conditions by using artificial semipermeable membrane. In-Vitro dissolution studies were carried out in phosphate buffer (pH 7.4) for 12 hours using Keshery-Chien type diffusion cell by receptor donor compartment model. The formulation M I M VI has shown release of about 74.76%, 83.22%, 76.51%, 78.17%, The authors are thankful to Hallmak pharmaceuticals Pvt. Ltd, Hyderabad for providing the gift sample of Metoprolol tartarate and also thankful to management of Annamacharya College system drug release followed zero order kinetics, which was evinced from the regression value. The Higuchis plot has shown the regression value of 0.874, which indicated that diffusion mechanism influencing the drug release. In order to confirm this fact, Peppas plot was drawn which has shown slope value of 0.997, which confirms that the diffusion mechanism involved in the drug release was of non fickian diffusion type. The values of in-vitro data were mentioned in the Table. 3. CONCLUSION The prepared transdermal drug delivery of Metoprolol tartrate using different polymers such as HPMC and PVP had shown good promising results for all the evaluated parameters. Based on the In-vitro maximum drug release, formulation M VI (2% HPMC & 2% PVP) was concluded as an optimized formulation, which shows its higher percentage of drug release in concentration independent manner. ACKNOWLEDGEMENT

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S.Ramkanth * et al. / International Journal of Advances in Pharmaceutical Research

of Pharmacy for providing the all facilities for Formulation Code M-I M-II M-III M-IV M-V M-VI carried out this research work.

TABLES AND FIGURES Drug in mg HPMC (%) PVP (%) Plasticizer and permeation Table No: 1 Composition of transdermal patches of Metaprolol Tartarate enhancer 100 1 -30% 100 2 -v/v of 100 -1 Propylene Glycol 100 -2 100 1 1 100 2 2

S.No

1 2 3 4 5 6 Formulation M-I M-II M-III M-IV M-V M-VI

Percentag Percentage Folding Drug e moisture endurance conten moisture loss S.D S.D t absorption (%) Table No: 2 Physical Evaluation studies forprepared transdermal patches M-I 0.170.02 211.66 2.08 1.960.02 1.850.01 182. 6.244 98 M-II 0.200.06 304.66 4.50 2.660.02 2.000.014 202.335.68 99 2 4 M-III 0.190.10 220.661.52 1.610.03 1.590.31 149.005.50 99 M-IV 0.220.03 312.661.15 2.180.15 2.540.10 152.333.05 98 4 5 M-V 0.310.13 321.331.15 8.6130.0 8.1430.01 194.336.35 98 1 M-VI 0.430.01 418.331.52 12.570.01 11.730.06 2172.64 99 9 4 2 code n value of Peppas Zero Order drug release data R value of Higuchi plot 0.912 0.997 0.994 0.855 0.989 0.983 0.895 0.973 0.993 0.932 0.997 0.991 0.854 0.969 0.994 0.874 No: 3 In-Vitro data for all the 0.997 0.998 Table formulations

Formulatio n code

Thickness mm S. D

Weight Uniformity mg S.D

Figure No: 1 Zero order release plot for prepared transdermal patches of Metoprolol tartarate
Zero order release plot for transdermal patches
120

Figure No: 2 Higuchis plot for prepared transdermal patches of Metoprolol tartarate
Higuchi plot for transdermal patches of Metoprolol tartarate
120

of Metoprolol tartarate

100

80 LogCumulative %drugrelease

60

40

20

10

12

14

CumulativePercentageofdrugRele se

Cumulative %drugrelease

100

80

60

40

20

0.5

1.5

2.5

3.5

Time (h)
M-I M-II M-III M-IV M-V M-VI M-I M-II

SQRTT inHrs
M-III M-IV M-V M-VI

Figure No: 3 Peppas plot for prepared transdermal drug delivery system for Metoprolol tartrate.
Korsmeyer Peppa's plot for transdermal patches of Metoprolol tartarate

2.5

1.5

0.5

0.2

0.4

0.6

0.8

1.2

Log Time

M-I

M-II

M-III

M-IV

M-V

M-VI

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S.Ramkanth * et al. / International Journal of Advances in Pharmaceutical Research

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