INTRODUCTION:

The development of transdermal drug delivery systems using polymeric materials have become popular for various reasons. Among the various types of transdermal drug delivery systems developed, membrane controlled type utilizes a thin polymeric film as rate controlling membrane, which delivers the drug from the drug reservoir to the systemic circulation for an extended period of time. The Permeability of drug through polymeric film is dependent on characteristics of the polymer^1,2, casting solvent^3,4 and plasticizer^5,6used. In the present work Cellulose acetate films were prepared and evaluated as rate controlling membrane for transdermal drug delivery systems. Diltiazem hydrochloride and Propranolol hydrochloride, which requires controlled release due to their short biological half lives⁷, were used as model drugs.

MATERIALS AND METHODS:

Diltiazem hydrochloride and Propranolol hydrochloride were obtained as a gift samples from Natco Pharma, Hyderabad. Cellulose acetate (S.D. Fine Chem), Acetone, Chloroform, Dichloromethane and Ethyl acetate

(Qualigens), Dibutyl phthalate (Ranbaxy Laboratories) and Propylene glycol (S. D. Fine Chem) were obtained commercially. All materials were used as received.

Preparation of drug free films:

The solvent evaporation technique was employed in the present work for the preparation of Cellulose acetate films. The films were prepared with Cellulose acetate by employing different casting solvents namely Acetone-methanol (8:2), chloroform-methanol (8:2), dichloromethane-methanol (8:2), and ethyl acetate-methanol (8:2) . Dibutyl phthalate at a concentration of 40% w/w of the polymer was used as a plasticizer in the preparation of films. The cellulose acetate films made from its solution in dichloromethane-methanol (8:2) incorporating dibutyl phthalate were found to be brittle. In those cases propylene glycol at 40% w/w of the polymer was used as a plasticizer. 20 ml of the polymer solution was poured in a Petri plate (9.4 cm diameter) placed on a horizontal flat surface. The rate of evaporation was controlled by inverting a funnel over the Petri plate. After 24 h the dried films were taken out and stored in a desiccator.

Evaluation of Transdermal Films:

Thickness Uniformity:

The thickness of the films were measured by a ‘venire calipers’. The mean of the five observations were calculated.

TABLE 1: Diffusion Characteristics of Cellulose Acetate Films Prepared With Various Casting Solvents

FORMULATION	ZERO ORDER RATE CONSTANT (K) VALUE (mg/h)	DIFFUSION EXPONENT VALUE (n)	PERMEABILITY COEFFICIENT (Pm X 10³ mg/cm.h)	T₅₀ (h)	T₉₀ (h)
D1 (CA;A+M)	3.824	1.1670	3.81	6.53	11.76
D2 (CA;DCM+M)	3.391	1.1588	3.72	7.37	13.27
D3 (CA;C+M)	2.908	1.1590	3.31	8.59	15.47
D4 (CA;EA+M)	5.271	1.1600	5.51	4.74	8.53
P1 (CA;A+M)	3.231	1.0772	3.365	3.86	6.96
P2 (CA;DCM+M)	2.334	1.0574	2.645	5.35	9.63
P3 (CA;C+M)	1.594	1.0360	1.868	7.83	14.10
P4 (CA;EA+M)	4.104	1.3147	4.272	3.04	5.48

D: Diltiazem hydrochloride; P: Propranolol hydrochloride ; CA: Cellulose acetate; A: Acetone; DCM: Dichloro methane; C: Chloroform; EA: Ethyl acetate; M: Methanol

Folding Endurance⁸:

The folding endurance was measured manually for the prepared films. A strip of film (2x2 cm) was cut evenly and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking gave the exact value of folding endurance.

Water Vapor Transmission (W.V.T) Rate⁹:

For this study vials of equal diameter were used as transmission cells. These cells were washed thoroughly and dried in an oven. About 1.0 g of Calcium chloride was taken in the cell and the polymeric films measuring 3.14 Cm² area were fixed over the brim with the help of an adhesive. The cells were weighed accurately and initial weight is recorded, and then kept in a closed desiccator containing saturated solution of potassium chloride (about 200 ml). The humidity inside the desiccator was measured by a hygrometer, and it was found to be in between 80 – 90 % RH. The cells were taken out and weighed after 18, 36, 54 and 72 hrs. From increase in weights the amount of water vapour transmitted and the rate at which water vapour transmitted were calculated by using the following formula.

WVT rate = WL/S, Where, W is Water vapour transmitted in gms, L is thickness of the film in cm, S is exposed surface area in cm²

Drug Diffusion Study¹⁰:

Drug diffusion study was conducted using Franz diffusion cell. The receptor compartment was filled with 15 ml of phosphate buffer having pH 7.4 as diffusion media. Polymeric film was mounted on the donor compartment with the help of an adhesive. 10 ml of the 0.5 % W/V of drug (diltiazem hydrochloride) or 0.25 % W/V of drug (Propranolol hydrochloride) solution was poured into the donor compartment. Magnetic stirrer was set at 50 rpm and whole assembly was maintained at 32 + 0.5 ⁰C. The amount of drug released was determined by withdrawing 1 ml of sample at regular time intervals for 3 hours. The volume withdrawn was replaced with equal volume of fresh buffer solution. Samples were analyzed for drug content using a U V spectrophotometer at 237nm¹¹ for diltiazem hydrochloride and at 290nm¹² for propranolol hydrochloride .

Permeability Coefficient:

From the drug diffusion data the permeability co efficient for various films was calculated using the equation .P_m= (K_app. H)/A, Where, K_appis Diffusion rate constant (mg/h) calculated from the slope of the linear drug (d/p) diffusion profiles , H is thickness of the film (cm), A is surface area of the film (cm²).

The rate and the mechanism of drug release through the prepared films were analyzed by fitting the diffusion data into¹³, zero-order equation, Q=Q₀–k₀t,where Q is the amount of drug released at time t, and k₀ is the release rate. First order equation, Ln Q=Ln Q₀ – k₁t, where k₁ is the release rate constant and Higuchi’s equation, Q= k₂t^1/2, where Q is the amount of the drug released at time t and k₂ is the diffusion rate constant. The diffusion data was further analyzed to define the mechanism of release by applying the diffusion data following the empirical equation , M_t /M_a=Ktⁿ, where M_t/M_ais the fraction of drug released at time t. K is a constant and n characterizes the mechanism of drug release from the formulations during diffusion process.

RESULTS AND DISCUSSION:

The solvent evaporation technique was found to be giving thin uniform films. The films prepared with polymer alone were found to be brittle. To prevent embitterment a plasticizer, dibutyl phthalate was tried at various concentrations. Preliminary experiments indicated that lower concentrations of dibutyl phthalate were found to give rigid and brittle films where as higher concentrations gave soft films. Dibutyl phthalate at a concentration of 40% w/w of the polymer was found to give good flexible films.

All the films prepared were evaluated for uniformity of thickness, folding endurance, water vapour transmission and drug diffusion and permeability characteristics. The film thickness measurements ensured uniformity of thickness in each film. The solvent evaporation technique was found to be given reproducible results with regard to film thickness. The folding endurance was measured manually and offered good mechanical strength and flexibility. Water vapour transmission studies indicated that all the films prepared were permeable to water vapour. Water vapour transmission through the films followed zero order kinetics and was shown in the figure 1 . The rate of water vapour transmission was decreased in the order of films in various solvents is as follows. Ethylacetate-methanol (8:2)> dichloromethane-methanol (8:2)> acetone-methanol (8.2)> chloroform-methanol (8:2).

Fig 1: Water Vapour Transmission Profiles of Cellulose Acetate Films Casted With Various Solvents

(-♦-) Cellulose acetate films prepared with acetone

(-■-) Cellulose acetate films prepared with dichloromethane

(-▲-) Cellulose acetate films prepared with chloroform

(-×-) Cellulose acetate films prepared with ethyl acetate

Drug diffusion through various films were studied with diltiazem hydrochloride and propranolol hydrochloride as a model drugs by using Franz diffusion cell. All the films were found to be permeable to diltiazem hydrochloride and propranolol hydrochloride . The correlation coefficient values (r) revealed that the diffusion profiles follows zero order kinetics and the mechanism of drug release was governed by peppas model. The diffusion exponent of release profiles (slope) has a value of (n>1), which indicates Super Case II transport diffusion . Permeability coefficient values (Pm) of the films towards the drugs was calculated from the drug diffusion data and the results were given in table 1. The rate of permeability coefficient was decreased in the order of films in various solvents is as follows Ethylacetate-methanol (8:2)>acetone-methanol (8:2)> chloroform-methanol (8:2). dichloromethane- methanol (8:2)

The results obtained in the present study thus indicated that the casting solvents used in the preparation of films have been shown significant influence on the water vapour transmission, drug diffusion and permeability of the films. Cellulose acetate films employed with ethyl acetate:methanol in 8:2 ratio as casting solvent shown high Permeability when compared to other films for both drugs .

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Received on 21.02.2009 Modified on 19.04.2009

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 698-700