INTRODUCTION:

Transdermal therapeutic drug delivery systems are designed for controlled drug delivery through the skin into systemic circulation maintaining consistent efficient concentration of drug and reducing dose of the drug and its related side effects^1,2. Iso-sorbide dinitrate is an antianginal drug that improves perfusion of the myocardium, reduce its metabolic demand and produce vasodilatation, and act by relaxing vascular smooth muscle. Oral bioavailability is approximately 22% because of fist-pass metabolism. Half-life of ISDN varies with the route of administration³.The drug with low molecular weight, low dose, and low melting point, frequent dosing makes an ideal drug candidate for transdermal administration⁴. It is reported that ISDN penetrates through the skin and produce sufficient drug concentration in the blood when administered externally. It is also reported that ISDN is an ideal candidate for prolonged systemic therapy⁵. Ethyl cellulose show good film forming properties. The method of casting on mercury surface was found to give thin uniform films. Dibutyl phthalate at a concentration of 40% w/w of polymer acts as an efficient plasticizer. The method was also found to give reproducible results. Films of different thickness could be cast with different volumes of polymer solutions⁶. The permeability of ethyl cellulose film can be increased by addition of PEG-4000 and is reproducible⁷.

Received on 30.04.2010 Modified on 18.05.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1175-1177

The aim of the present investigation was to develop transdermal drug delivery matrix systems using ethyl cellulose, PEG-4000 and dibutyl phthalate 40% w/w as a plasticizer for an anti-anginal drug, Iso-sorbide dinitrate. The physicochemical properties like thickness uniformity, elongation percentage, tensile strength, folding endurance were evaluated. The in-vitro evaluation of the different formulations was carried out on rat’s abdominal skin model using Keshary-Chein diffusion cell. An attempt was also made to establish the best possible combination of polymeric ratio of the formulations.

MATERIALS AND METHODS:

Iso-sorbide dinitrate obtained from BPRL, Bangalore, as a gift sample; Ethyl Cellulose 20cps (Ethoxyl content 48-49.5%) from Himadia, Laboratories Pvt Ltd.23, Vadhani Ind.Est.LBS.Marg, Mumbai-400006. India; PEG-4000 from Molychem. Ltd. Mumbai; All other reagents and chemicals used were of analytical grade.

Preparation of PolymericTransdermal Films:

Pure ISDN is a powerful explosive in excessive heat, hence it is diluted with 60% lactose and then used in the formulation⁸.

The polymeric transdermal films of composition mentioned in Table-1 were prepared by solution casting technique by employing a glass substrate. The films were prepared by dissolving ethyl cellulose in a solvent system. PEG-4000, dibutyl phthalate were then incorporated. Drug equivalent to the dose of each casting film was then added and dissolved. Five ml of above solution was poured within the glass bangles of 5 cm diameter, placed on mercury surface in a petridish. The rate of evaporation was controlled by inverting the funnel over the petridish. After 24 h the formed films were taken out and stored in a desiccator for further use⁶.

Evaluation of Polymeric Medicated Transdermal Films:

The medicated polymeric films were evaluated for thickness uniformity, percentage elongation at break, tensile strength, folding endurance and weight uniformity. In-vitro skin permeation studies, skin irritation tests and formulation compatibility tests like thin layer chromatography was carried out.

The films were inspected for color, clarity and surface properties. Weight uniformity was carried out by weighing the films on a digital balance (Afcosit). The average of three observations from each formulation was reported as a result⁵. The thickness of the films was measured by dial caliper (Mitotoyo, Japan) at different points on each film and average of 5 observations was reported as a result⁶. The drug content was determined as described by Bhalla et.al⁹. Spectrophotometric analysis was carried out by using U.V spectrophotometer (shimadzu-1201) at 550nm against blank formulation solution⁸.

The mean percent elongation at break and tensile strength were measured by using an instrument designed in the laboratory by using following formulae¹⁰.

Percent elongation at break = (I_B-I_O) X100 / I_o

Where, I_{o =}Original length of film.

I_B= Length of film at break when stress is applied.

Tensile strength = Break force / a.b (1+dL / L)

Where, a = Width of test film.

b = Thickness of test film.

dL = Elongation at break.

While break force = Weight required to break the film.

In-vitro skin permeation study:

It was carried out for all formulated transdermal films in triplicate by using Keshary-Chein diffusion cell of 12 ml capacity, which consists of a receptor and a donor compartments. Excised rat abdominal skin was sandwiched between donor and receptor compartment of the diffusion cell. So that the transdermal film from donor compartment was placed in intimate contact with skin. A Teflon bead was placed in receptor compartment filled with 12 ml of distilled water. Content of receptor compartment were stirred at 100 rpm throughout the experiment. Temperature was maintained at 37 + 2°C. The amount of drug released was determined by withdrawing one ml sample at specific time of intervals for 24 h. The sample volume withdrawn was replaced with equal volume of fresh and prewarmed distilled water. Samples were then analyzed by U.V spectrophotometer at 550 nm⁹.

Skin Sensitive Tests:

The primary skin sensitive tests were performed as eight healthy male albino rabbits weighing between 2.0 – 3.5 kg. Adhesive tape USP was used as a control film. The films were removed after a period of 24 h with the help of alcohol swab. The skin was examined for erythema or oedema¹¹.

Thin Layer Chromatography Studies:

Formulated ingredients compatibility was determined by thin layer chromatography technique. 20ul of ether extract of formulations containing 2 mg of iso-sorbide dinitrate were applied to silica gel glass plates between the reference standard which are 3 cm adjacent. The plates were kept in an enclosed chamber saturated previously with the toluene, the mobile phase. The mobile phase was allowed to rise on the plates to a sufficient level. The distance traveled by the solvent front is noted. The sample and reference standard spots were then detected by drying in a current of air and sprayed with 1% w/v of solution of diphenylamine in methanol and exposed for 15 minutes to U.V light. The principle spot in the chromatogram obtained with sample corresponds to that of reference standard spot. The RF value was calculated for both the standard and compared, using the formulae⁸.

RF value = Distance traveled by solute from origin

Distance traveled by solvent from origin

RESULT AND DISCUSSION:

In this investigation, various matrix type transdermal films containing Iso-sorbide dinitrate with variable combinations of EC and PEG-4000 were prepared and prolonged release of the drug through the matrix films was demonstrated.

The physicochemical parameters and the release characteristics were studied on the formulated films. The mean thickness readings indicate that all films were approximately uniform in thickness. Folding endurance was found to be 200 + 9 45 to 260 + 5.36 (Tablt-1). It was found that films with high proportion of PEG-4000 showed reduction in the folding endurance, while films without PEG-4000 showed optimum folding endurance. With the increase in the proportion of PEG-4000 in the film, the tensile strength and thickness of the film was found to increase (Table-1), but variation in percentage of elongation was found to insignificant over different proportions of EC and PEG-4000. Formulation F1 showed less percentage of elongation and high tensile strength in comparison to F5, which indicated that the films containing more proportions of the EC are relatively more strong and tough compared to the films containing more proportion of PEG-4000.

The cumulative percentage of drug permeated as a function of time through rat’s abdominal skin is presented in Fig-1. From the figure it is evident that high proportion of PEG-4000 enhances permeation rate. Formulation F1 with higher concentration of EC showed prolonged permeation of drug in comparison to other formulated films. It was observed that from the formulation F1, 65.004% of the drug was permeated in 24 h, whereas the permeation was 98.120% from the formulation F5 within 24 h study. Compatibility of drug with formulation ingredients was determined by TLC method showed similar Rf values with respect to standard. This indicates that the drug is not reacted with either the solvent or the formulation ingredients.

The primary skin irritation tests indicate no erythema or oedema of all the formulated polymeric films of Iso-sorbide dinitrate for transdermal therapeutic use.

The in-vitro permeation studies using rat’s abdominal skin showed that the formulations containing high proportion of PEG-4000 are showed zero-order release kinetics and are suitable for once a day drug delivery. The films containing high proportion of EC showed suitability for a prolonged dosage regimen for a period of more than 24 h. The results of this investigation for formulating prolonged transdermal therapeutic drug delivery matrix systems of iso-sorbide dinitrate can be designed for an efficient prolonged treatment in angina, cardiac arrhythmia, and in hypertension.

ACKNOWLEDGEMENT:

Authors are thankful to BPRL Bangalore for providing the gift sample and KLE Society Belgaum.

References:

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2. Robinson JR, Lee VHL. Controlled drug delivery; Fundamentals and Applications.2^nd ed. New York: Marcel Dekker; 1987.

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Received on 19.05.2010 Modified on 24.05.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page1170-1174