FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES OF METOPROLOL

The anti-hypertensive transdermal patches in the perspective of enhancing the bioavailability as well as in improving patient compliance, it has appear as a substitute for oral route permit self-administration, controlled and sustained drug delivery. This study will investigate the effects of metoprolol Succinate in treatment of hypertension with the interaction of hydroxy propyl methyl cellulose and ethyl cellulose. The present research work concludes that the patches prepared with different ratios of polymers shows sustained drug release for long period of time confirms that the delivery system prepared can be suitably used as sustained and controlled drug delivery. The Transdermal Patches of drug metoprolol Succinate can be utilized in the diseases hypertension, myocardial infarction and congestive heart failure, etc. It offers high patient compliance by ease in administration.


Introduction
Hypertension is the chronic elevation of blood pressure that, in the long term, causes and and organ damage & results in increased morbidity and mortality occurs due to the abnormal functioning of the arterial pressure related to the central nervous system [1], rennin-angiotensin-aldosterone system endothelial dysfunction, genes and even due to certain environmental factors.
The basic component of Transdermal Drug Delivery System [2] includes inert polymer matrix in which the drug is dissolved or dispersed providing support & platform for drug release. There are Two basic designs of the patch system;  Matrix or Monolithic: The polymer matrix [3] holds a large quantity of drug and controls the release from the device.
 Reservoir or Membrane: The rate controlling membrane [4] made of a polymer present between the drug layer and the adhesive layer that provides the rate limiting barrier for drug release from the device.
Many of the technologies have been successfully developed to provide the rate control over the release and skin permeation of drugs [5].

Materials and Methods:
Materials: Determination of λ max : The UV spectrum of Metoprolol succinate was analyzed spectrophotometrically by using spectrophotometer (UV-1800 Shimadzu). 100 mg of the drug was accurately weighed and dissolved in sufficient quantity of Phosphate buffer (pH 6.8) and the final volume was made up to 100 ml to prepare the stock solution of solution of 1000 μg/ml. From the stock solution 1 ml was withdrawn and volume was made up to 100 ml with Phosphate buffer to obtain the solution of 10 μg/ml [7]. The resultant solution was scanned from 200 to 400 nm and the spectrum was recorded to obtain maximum wavelength λ max . Preparation of Calibration Curve of Metoprolol succinate in phosphate buffer (pH 6.8):100 mg of Metoprolol succinate [8] was accurately weighed and dissolved in sufficient quantity of phosphate buffer (pH 6.8) and the final volume was made up to 100 ml to prepare the stock solution of solution of 1000 μg/ml. From the stock solution 1 ml was withdrawn and volume was made up to 10 ml with phosphate buffer to obtain the solution of100 μg/ml. This solution was further diluted to prepare solutions of 5μg/ml to 30μg/ml. Absorbances of each solution was measured at 223nm [9] using Shimadzu UV-1800 Spectrophotometer using pH 6.8 phosphate buffer as a reference standard. The calibration curve was prepared for solutions of 5μg/ml to 30μg/ml. Compatibility studies: FT-IR Spectroscopy: FT-IR spectroscopy was employed to ascertain the compatibility the drug Metoprolol Succinate and the selected polymers, FT-IR spectra of pure drug Metoprolol succinate was taken separately [10]. Further drug and polymers (HPMC and Ethyl cellulose) were mixed in the same ratio as shown in table 2 and scanned using Shimadzu FT-IR.

Formulation of Transdermal Patches:
Transdermal Patches of Metoprolol Succinate were prepared by solvent evaporation method. The polymer ethyl cellulose & HPMC were taken in required amount. About 20ml of solvent mixture of methanol:dichloromethane in the ratio of 1:1 was added and stirred well. When the polymers completely solublized in mixture of solvent, added 0.5ml dibutylphthlate act as a plasticizer [11]. Then added 50mg of the drug metoprolol succinate to the polymer solution and finally added the 0.2ml of permeation enhancer dimethyl sulphoxide. This mixture was placed at one side for sometime to exclude any entrapped air and was then transferred into a previously cleaned and dried petri plate. Then the plate was kept a side for solvent evaporation and was covered by funnel to control evaporation of solvent. Allowed to dry at room temperature overnight [12], The dried films were separated and the backing membrane used was aluminium foil and stored in desiccators These films were further evaluated. Evaluation of transdermal patches of metoprolol succinate: The physicochemical evaluation of transdermal patches is based on following parameters; Physical Appearance: All the prepared Transdermal Patches were observed visually for colour, clarity, smoothness and flexibility [13]. Surface PH Measurement: The pH of prepared transdermal patches was measured with the help of calibrated pH meter. The average of three readings was recorded for patch [13,14]. Thickness of Patch: The thickness of each transdermal patch was measured at six different places using a digital vernier calliper and average thickness of patches was measured [11,14]. Weight Uniformity: The three different patches from each formulation weighed on electronic weighing balance and calculated the average weight of three patches. The individual weight should not deviate from the average weight of patch [15]. Folding Endurance: This test is done to determine the following capacity of the patches subjected to frequent extreme conditions of folding [16]. The folding endurance was determined by repeatedly folding a small strips of films at the same place till it broke. Flatness: Three longitudinal patches were cut from each patch at different portion like centre, left, and right side. The initial length of strip was measured and then kept for two hours at room temperature. The variations in length due to non uniformity in flatness were measured by determing percent constriction by using the following formula [17]-

Percentage Moisture Loss:
The percentage moisture loss test is used to check the integrity of transdermal patches at drug condition. Accurately weighed of three 1 cm patches were kept in dessicators containg anhydrous calcium chloride [18] and exposed to an atmospheric room temperature.

Percentage Moisture Absorption: The Percentage
Moisture Absorption test is carried out to check the physical stability of trandermal patches at high humid conditions. The weight of three 1 cm patches were weight accurately and then placed in dessicators containing saturated solution of potassium chloride , with the relative humidity 84% [18,19]. The patches were removed after three days, weight and Percentage Moisture Absorption was calculated by the following formula-Tensile Strength: To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. A pointer on the thread is used to measure the elongation of the film [17,19]. The weight just sufficient to break the film is noted. The tensile strength can be calculated using the following equation.
Tensile strength= F/a.b (1+L/l) F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point. Water Vapour Permeability: Glass vials of the same diameter were washed thoroughly and dried to a constant weight in an oven. About 1 gm of fused Calcium chloride was taken in the vials & the polymeric transdermal patches about 1cm 2 area were fixed over the brim with the help of an adhesive tape. Then the vials were weighed and stored in a humidity chamber at 85 % RH condition for a period of 24 hours [20]. The vials were removed and weighed at various time intervals like 3, 6 and 24 hr to note down the weight gain. Water Vapour Permeability = W/A, Water Vapour Permeability is expressed in gm/m 2 per 24 hours; W is the amount of vapour permeated through the patch (gm/24 hrs). A is the surface area of the exposure samples (m 2 ). Drug Content: The prepared patches of 1 cm2 were cut in three equal parts and kept in a 100 ml pH 6.8 phosphate buffer [21] and stirred for 24 hours and filtered. The filtrate was suitably diluted and determined by UV Spectrophtometer, the drug content then calculated by the mean of three patches. In Vitro Drug Release: In vitro drug release study of prepared metoprolol succinate transdermal patches was carried out by using USP Paddle Type II dissolution test apparatus at 750 rpm in 900 ml of pH 6.8 phosphate buffer medium at the temperature 37± 0.5˚C for 24 hours [22]. 5 ml of samples were withdrawn at predetermined time interval, filtered, diluted suitably and analysed by UV Spectrophtometer at 223 nm. Stability Studies: Stability Studies were conducted according to the ICH guidelines [21,23] by storing the transdermal drug delivery system samples at 40± 0.5˚C and 75±5%. Relative humidity for two months. The samples were withdrawn at 0, 30 and 60 days and analyze suitability for the drug content.

Result and Discussion:
λ max Determination: U.V. Spectrophotometer (Shimadzu 1800) was used to determine absorption maxima of the drug Metoprolol Succinate. The max for drug Metoprolol Succinate in Phosphate Buffer pH 6.8 was found at 223nm. Figure 1 shows the λ max of Metoprolol Succinate in Phosphate Buffer pH 6.8.  (Metoprolol Succinate) was prepared in Phosphate Buffer pH 6.8 at 223nm shows the UV absorption. A straight line with R 2 = 0.998 for Phosphate Buffer pH 6.8 was found, indicating that the drug follows Beer's law within the specified concentration range.