PHARMA SCIENCE MONITOR

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1 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES FORMULATION AND EVALUATION OF TRANSDERMAL PATCHS OF DILTIAZEM HYDROCHLORIDE T. Ethiraj* and V.Ganesan Department of Pharmaceutics, The Erode College of Pharmacy, Erode, Tamilnadu, India. ABSTRACT The objective of present study was to formulate and evaluate the iontophoretic transdermal patches of diltiazem hydrochloride. The transdermal patches were prepared by solvent casting method employing hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, propylene glycol and ethyl cellulose. Transdermal patch was prepared with the aim to reduce the first pass metabolism and there by increasing the bioavailability of the drug. It also reduces the frequency of dosing which in turn improve patient compliance and reduce fluctuation in plasma drug levels. In the present study three formulations (F1-F3) with different polymers were prepared and evaluated for various physico-chemical parameter, in vitro drug permeation study and in vitro permeation by using iontophoresis. To know the mechanism of drug permeation from these formulation, the data were treated according to Zero order, First order permeation, Higuchi,s and korsmeyer equation / peppas model equation. The physico-chemical evaluation like film weight variation, thickness of the patch, folding endurance, percentage of moisture loss, percentage of moisture absorbed, drug content uniformity, viscosity of the formulation were evaluated. The comparative study of passive diffusion experiment and iontophoresis were studied. Keywords: Diltiazem, polymer, iontophoresis, transdermal patches. INTRODUCTION Transdermal delivery offer number of advantages over conventional system. The transdermal route has become one of the most successful and innovative focuses for research in drug delivery. The first transdermal patch was approved in 1981, that was Scopolamine used for suppressing nausea and vomiting associated with motion sickness. Now more than 35 transdermal products have been approved for sale in US, and approximately 16 active ingredients have been approved for use in globally. In the present decade, a good number of drugs have been reported for their transdermal application. Transdermal drug delivery (TDD) systems are drug-loaded adhesive patches which, when applied to the skin deliver the therapeutic agent, at a controlled rate, through the skin the systemic circulation and to the target organs. Transdermal drug delivery can IC Value

2 be achieved via active or passive systems, depending on whether external energy used to assist the transport of the drug through the skin. The active systems us heat, electric current (iontophoresis), sound waves (sonophoresis) transient high-voltage electrical pulses (electroporation) to enhance the delivery of drugs into the systemic circulation. Iontophoresis, which is the facilitated movement of ions across a membrane under the influence of an externally applied small electrical potential difference (0.5mA/cm 2 or less) is one of the most promising novel drug delivery system which has proved to enhance the skin penetration and the release rate of a number of drugs having poor absorption/permeation profile through the skin [1,2]. Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension, thus hypertensive individual experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensive. Literature survey reveals that transdermal patches of many pharmaceutical substances were prepared and evaluated by different methods [3-10]. Few literatures shows the formulation and evaluation of transdermal patchs of diltiazem hydro chloride using different polymers [11-13]. MATERIAL AND METHODS: Diltiazem Hydrochloride were received as gift from micro labs, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, ethyl cellulose from Colorcon Asia Pvt Ltd, propylene glycol, potassium dihydrogen phosphate from S.D. Fine chemicals, sodium hydroxide from Merck Ltd. Preparation of Trans Dermal Patches: Solvent Casting Method: The Diltiazem Hydrochloride (120mg) (F1), hydroxy propyl methyl cellulose (2%), propylene glycol (30%) and Diltiazem Hydrochloride (F2) (120mg), sodium carboxy methyl cellulose (2%), propylene glycol (30%) and Diltiazem Hydrochloride (120mg) (F3) ethyl cellulose (2%), propylene glycol (30%) were utilized for the preparation of patches (Table 1). The casting solution was prepared by dissolving the polymer in distilled water to form a 2% w/v solution and 120mg of the drug were IC Value

3 dispersed in the polymeric solution and plasticizer propylene glycol (30%) was added. The mixture was stirred using magnetic stirrer for 30 minutes. The films were prepared by casting 15ml of the solution within round aluminum foil 7.2 cm in diameter and dried c in hot air oven. The film were removed and taken for evaluation. TABLE 1: COMPOSITION OF TRANSDERMAL PATCH OF DILTIAZEM HYDROCHLORIDE S.N Ingredients F1 F2 F3 1. Diltiazem Hydrochloride 120mg 120mg 120mg 2. Hydroxy Propyl Methyl Cellulose 2% Sodium Carboxy Methyl Cellulose - 2% - 4. Ethyl cellulose - - 2% 5. Propylene Glycol 30% 30% 30% Evaluation of Transdermal Films: All the films prepared were evaluated for physical appearance, uniformity of weight, uniformity of thickness, folding endurance, percentage moisture loss, percentage moisture absorption, and drug content uniformity. The thickness of each patch was measured at the different sites using screw gauge and the average thickness was calculated. The film was cut in to 10 patches of 1cm 2 each and their average weight was calculated. Folding endurance was determined by repeatedly folding the patches until it shows any crack or break. The number of times the film could be folded with out breaking/cracking gave the value of folding endurance. Percentage moisture loss was done in a desiccator, the film as weighed and calcium chloride at 40º in a drier for at least 24 hour or more until it showed a constant weight. The moisture content was calculated from the difference between the constant weight taken and the initial weight and was reported in term of percentage (by weight) moisture content. IC Value

4 The percentage moisture absorption also done by desiccator, the film was weighed accurately and placed in to 100 ml of saturated solution of aluminum chloride (79.50 % RH). After 3 days the films were taken out and weighed, the percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight. The prepared patch was cut into small pieces and put into 10ml diffusion medium used respectively and stirred continuously using a mechanical stirrer and sample was with drawn at the end of 3 hrs and the drug content was determined spectorphotometrically at 240nm. Drug Diffusion Study: (a) Ex-Vivo Permeation Studies Diffusion parameter Medium : Phosphate buffer ph 7.2 RPM : 100 Temperature : 37 ± 1ºC Medium volume : 150 ml Drug diffusion study was conducted using Franz diffusion cell. It consists of an upper donor compartment and the lower receptor compartment surrounded by water jacket for circulation of water to maintain the temperature inside at 37 ± 1ºC the uniformity of solution in the receptor phase was maintained by stirring at high speed of 100 rpm (approx) using tiny magnetic bead the volume of receptor compartment was maintained at 150 ml. The male wistar rats were sacrificed by decapitation. The fresh abdominal skin was excised from male wistar rat weighing gm. The hair of skin was removed using depilatories, then it was kept at water bath maintained at 60ºC for 50 s and heat treated skin was cleared off its subcutaneous fatty substance and immediately kept in refrigerator at 10ºC. The rat skin was cut into appropriate size and mounted at the junction between donor and receptor chamber of diffusion. The matrix formulation to be tested was cut in 1cm 2 patches and was placed over the optimized skin. The donor compartment was clamped over it, with the help of spring making sure that there were no air bubbles in the receptor compartment. The whole system was sandwiched between the donor and the receptor compartment and secure with a clamps, with the receptor IC Value

5 compartment containing phosphate buffer solution of ph 7.2. The agitation speed of 100 rpm and temperature of 37 ± 1ºC were maintained during the experiment. Samples were analyzed for drug content using UV double beam spectrophotometer at 240nm. (b) In vitro permeation study Diffusion parameter Medium : Phosphate buffer ph 7.2 RPM : 100 Temperature : 37 ± 1 C Medium volume : 150 ml Platinum electrode : 0.1 mm thickness Electric current : 0.5 ma/cm 2 as applied for 2 h. In vitro permeation studies were carried out by using a diffusion cell with a diffusion surface area 2.3 cm 2. Diffusion cell placed on the receptor compartment acts as donor compartment. The receptor compartment was filled with phosphate buffer ph 7.2 and receptor phase was stirred with small magnetic beads to mix contents uniformly. Rat skin along with loaded polymeric film was tied and surface of the membrane dipped in the receptor fluid. The anode was placed in the donor compartment and cathode was placed in the receptor compartment. 0.5 ma/cm 2 unit of current was applied for period of 2 h by using platinum electrode. The 5 ml sample with drawn out at regular intervals up to 24 h. The drug content of collected sample was determined by UV spectrophotometer at 240 nm. After each interval the same quantity of fresh medium was replaced immediately. RESULTS AND DISCUSSION In the present study three formulations (F1-F3) with different polymer (hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose and ethyl cellulose) were prepared and evaluated for various physico-chemical parameters, In-vitro drug permeation by using iontophoresis. On the basis of physico-chemical parameter and Invitro permeation studies the best formulation was selected. Compatibility studies were performed by using FT-IR spectrophotometer. There is no appearance or disappearance of any characteristic peaks. This shows that there is no chemical interaction between the drug, polymer and excipient used in the Transdermal patches. The DSC (Differential IC Value

6 S.No. Scanning Calorimetry) analysis of Diltiazem Hydrochloride showed a single endothermic peak at 216 c ± 3 c, due to the melting of the drug. HPMC, SCMC, EC showed their respective peak at their melting range. In the DSC curve, the characteristic peak of drug and other excipients were almost unchanged indicating the absence of strong interaction between the drug and other excipients and suggesting drug and excipients are compatible with each other. The prepared transdermal patches were then evaluated for various physico-chemical tests like thickness, folding endurance, weight variation, percentage moisture loss, and percentage moisture absorption and drug content uniformity. The thickness of Transdermal patches was uniform in all formulations and they were found to be flexible and smooth. The thickness of the all film value ranged from 0.38± to 0.52± The folding endurance of all film value ranged from 158±2.516 to 172± The percentage moisture absorption of the all film value ranged from 2.14±0.14 to 6.17±0.17.The percentage age moisture loss of the all film value ranged from 1.20±0.16 to 2.58±0.09. The results of all physico-chemical tests were found to be satisfactory and shown in Table 2. Drug content (Table 3) was also found to be uniform among the all formulation and ranged from to 98.25%. TABLE 2: PHYSICO-CHEMICAL EVALUATION OF PREPARED TRANSDERMAL PATCHES Formulation code Weight variation in mg Thickness in mm Folding endurance % moisture loss % moisture absorbed 1. F1 7.67± ± ± ± ± F ± ± ± ± ± F 3 6.7± ± ± ± ±0.14 Formulation code F1 F2 F3 TABLE 3: DRUG CONTENT UNIFORMITY Percentage content of drug Mean S.D ± ± ± IC Value

7 Ex-vivo permeation studies were carried out using rat skin in a diffusion cell. The cumulative percentage drug permeation was found to be 92.78%, 99.75%, 96.75% for formulation F1, F2, and F3 respectively (Table 4) and respective graph was obtained as Figure 1. The Higuchi s plot has shown the regression value of five formulations in Table 5 which indicates that the release of drug from the patch was governed by a diffusion mechanism. TABLE 4: CUMULATIVE IN-VITRO % DRUG RELEASE RATE DATA Time in h F1 (Pa) F2 (Pa) F3 (Pa) F1(0.3 ma/cm 2 ) F1(0.5 ma/cm 2 ) F2(0.5 ma/cm 2 ) F3(0.5 ma/cm 2 ) (Pa = Passive) TABLE 5: KINETIC VALUES OBTAINED FROM DIFFERENT PLOTS OF ALL FORMULATION Formulation F1 (passive) F2 (passive) F3 (passive) F1 (0.3mA/cm 2 ) F1 (0.5mA/cm 2 ) F2 (0.5mA/cm 2 ) F3 (0.5mA/cm 2 ) Zero order plot 1 st order plot Higuchi plot R 2 R 2 R 2 R Korsmeyer peppa s plot IC Value

8 Figure 1 Comparison of in-vitro drug release profile CONCLUSION Formulation F1 was found to be best among all batches because of its consistent release rate for 24 hour and extent of drug release was 82.78%. Ex-vivo permeating studies confirmed that in-vitro drug release data correlated with the ex-vivo data observed in rat skin. The formulation F1 has achieved the object to extended release and reduced the frequency of administration, avoid the first pass effect and thus may improved the patient compliance. REFERENCES: 1. Chien YW, Robinson JR and Lee VHL: Fundamentals and applications in controlled drug delivery system. Marcel Dekker Inc., Baichwal MR: Studies on polymeric films for Transdermal use. Indian Journal Pharmaceutical Sciences 1998; 59(3): Paranjothy KLK, Thampi PP: Development of Transdermal patches of verapamil hydrochloride using sodium carboxy methyl guar as a monolithic polymeric matrix and their in-vitro release studies. Indian Journal Pharmaceutical Sciences 1991; 59(2): IC Value

9 4. Mandal SC: Designing and in-vitro evaluation of trandermal drug delivery system of diazepam. Indian Drugs1991; 28(10): Kusumdevi V, Saisivam S Maria GR, Deepti PU: Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride. Drug Development and Industrial Pharmacy 2003; 29(5): Saxena M, Mutalik S, Reddy MS: Formulation and evaluation of Transdermal patches of metoclopramide hydrochloride. Indian Drugs 2006; 43(9): Dhaval PP, Chitral MS, Gaurav NM, Santhanu LP, Tarun J P, Priresh CM, Amar KR, Pritesh KP, Rishabh SM: Development and evaluation of ethyl cellulose based transdermal films of furosemide for improved in-vitro skin permeation. AAPS PharmSci Tech 2009; 10(2): Shashikant D, Barhate, Patel MM, Ankit SS, Prashant N, Gaurav S: Formulation and evaluation of transdermal drug delivery system of Carvedilol. Journal of Pharmacy Research 2009; 2(4): Prabhu P, Marina K, Vijaynarayanan K, Harish NM, Shankar G, Mohd GA, Narayanan CR, Satyanarayanan D: Preparation and evaluation of transdermal patches of papaverine hydrochloride. International Journal of Research in Pharmaceutical Sciences 2010; 1(3): Higuchi T: Mechanism of sustained action medication. Theoretical analysis of rate release of solid drugs dispersed in solid matrices. Journal of Pharmaceutical Sciences 1963; 52: Gupta R, Mukherjee B: Development and in-vitro evaluation of diltiazem hydrochloride Transdermal patches based on povidone-ethylcellulose matrices. Drug Development and Industrial Pharmacy 2003; 29(1): Ekapol Limpongas, Kraisri umprayn: Preparation and evaluation of dilitiazem hydrochloride diffusion controlled transdermal delivery system. AAPS PharmSciTech 2008; 9(2): Hindustan AA, Chitta SK, Ravindra BV, Sasidhar CGS, Ramakrishna G, Venkatnath L, Gangadhar P, Navya K: Characterization and permeation studies of diltiazem hydrochloride- ficus reticuleta fruit mucilage trandermal patches. IC Value

10 International Journal of Pharmaceutical Science Review and Research 2010; 1(2): For Correspondence: T. Ethiraj IC Value