Effect of Casting Solvent and Polymer on Permeability of Glipizide through Rate Controlling Membrane for Transdermal Use

V. Sai Kishore* and P. Saikrishna

Bapatla College of Pharmacy, Bapatla-522101.

ABSTRACT:

In the present work, Eudragit RL100, Eudragit RLPO and Eudragit RS 100 films were prepared and evaluated as rate controlling membrane for transdermal drug delivery systems. Acetone, chloroform, dichloromethane and ethyl acetate were used as solvents in the preparation of films. Dibutyl phthalate at a concentration of 15% w/w of the polymer was used as a plasticizer in the preparation films. Casting on mercuric surface technique was employed for the preparation of films. The dry films were evaluated for physical appearance, thickness uniformity, folding endurance, water vapour transmission, drug diffusion and permeability coefficient. Both water vapour transmission and Drug diffusion rate followed zero order kinetics. The results obtained in the present study thus indicated that the polymers and solvents used in the preparation of films have shown significant influence on the water vapour transmission, drug diffusion and permeability of the films.

KEYWORDS: Polymer, solvents, Water Vapour Transmission, Drug diffusion and Permeability Coefficient.

INTRODUCTION:

The development of transdermal drug delivery systems using polymeric materials has 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 Eudragit RL100, Eudragit RLPO and Eudragit RS 100 films were prepared and evaluated as rate controlling membranes for transdermal drug delivery systems. Glipizide, an important drug of the sulphonylurea class, is currently available for treating hyperglycaemia in Non-insulin dependent diabetes mellitus (NIDDM), but has been associated with severe and sometimes fatal hypoglycaemiaand gastric disturbances, such as nausea, vomiting, heartburn, anorexia and increased appetite after oral therapy.⁷ Because antidiabeticdrugs are usually intended to be taken over a long period patient compliance is also very important. Glipizide (molecular weight 445.5 Da) showed favorable partition coefficients (log octanol/buffer: 0.36 ± 0.08; isopropylmyristate/buffer: 0.28 ± 0.12) andnegligible skin degradation.^8,9 Hence, in the present study, we have formulated membrane-moderated transdermal systems of glipizideand evaluated to study the influence of casting solvent and polymer on permeability of glipizide.

MATERIALS AND METHODS:

Glipizide was obtained as a gift sample from Natco Pharma, Hyderabad. Eudragit RL-100, Eudragit RL-PO and Eudragit RS-100 were obtained from Rohm Pharma (Darmstadt, Germany).

Acetone, Chloroform, Dichloromethane and Ethyl acetate (Qualigens) and Dibutyl phthalate (Ranbaxy Laboratories) were obtained commercially. All materials were used as received.

Preparation of drug free films:

Casting on mercuric surface technique was employed in the present work for the preparation of drug free films. The films were prepared by dissolving the polymer (Eudragit RS100, Eudragit RL100 And Eudragit RLPO) in various solvents namely Acetone, chloroform, dichloromethane and ethyl acetate. Dibutyl phthalate at a concentration of 15% w/w of the polymer was used as a plasticizer in the preparation of films. Eight ml of the casting solution was poured in a glass bangle (6.2 cm diameter) containing mercury placed on a horizontal flat surface. The rate of evaporation was controlled by inverting a funnel over the Petri plate. After 24 hours the dried films were taken out and stored in a desiccator.

Evaluation of transdermal films:

All the films prepared were evaluated for physical appearance, uniformity of thickness, folding endurance, water vapour transmission and drug diffusion and permeability characteristics. The thicknesses of the films were measured by a ‘Screw Gauge’. The mean of the five observations were calculated. 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 endurance⁸.

For the study of water vapour transmission (WVT) rate, vials of equal diameter were used as transmission cells. These cells were washed thoroughly and dried in an oven. About 1 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 h.

From increase in weights the amount of water vapour transmitted and the rate at which water vapour transmitted were calculated by using the following formula⁹.

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. A aliquot of 10 ml of the 0.02 % W/V solution of drug (Glipizide) 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 h. The volume withdrawn was replaced with equal volume of fresh buffer solution. Samples were analyzed for drug content using a U V spectrophotometer at 223 nm.

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).

TABLE 1: PROPERTIES OF TRANSDERMAL FILMS

FORMULATION	THICKNESS (µm)	FOLDING ENDURANCE	WATER VAPOUR TRANSMISSION (Q X 10⁴ g/cm² 24 hrs)	PERMEABILITY COEFFICIENT (Pm X 10³ mg/cm.h)
F1 (ERS+A)	36.80+0.15	177	3.782	1.5
F2 (ERS+DCM)	35.40+0.17	207	3.511	1.3
F3 (ERS+C)	37.00+0.26	278	3.205	0.8
F4 (ERS+EA)	37.60+0.26	146	3.758	1.9
F5 (ERL+A	34.40+0.65	112	3.719	1.8
F6 (ERL+DCM)	37.80+0.37	188	3.317	1.4
F7 (ERL+C)	36.80+0.15	216	4.502	0.9
F8 (ERL+EA)	37.60+0.28	119	6.49	2.1
F9 (EPO+A)	36.60+0.15	254	4.394	2.00
F10 EPO+DCM)	37.60+0.14	238	3.748	1.7
F11(EPO+C)	37.20+0.13	208	3.376	1.2
F12 (EPO+EA)	38.00+0.14	182	4.744	2.4

ERS: Eudragit RS100; ERL: Eudragit RL100; EPO 100: Eudragit RL PO, A: Acetone; DCM: Dichloromethane; C: Chloroform; EA: Ethyl acetate.

RESULTS AND DISCUSSION:

In the present work, Eudragit RS100, Eudragit RL100 And Eudragit RLPO films were prepared and evaluated as rate controlling membrane for transdermal drug delivery systems. The Casting on mercuric surface technique were found to be giving thin uniform films. The films prepared with polymer alone were found to be brittle. To prevent embrittlement a plasticizer, dibutyl phthalate was tried at various concentrations ranging from10-50% w/w of the polymer. 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 15% w/w of the polymer was found to give good flexible films. Hence, dibutyl phthalate was included as a plasticizer in the preparation of at a concentration of 30% w/w of the polymer (or 8% w/v of the polymer solution.).

Thickness measurements of films prepared in various solvents are given in Table1. Low standard deviation values in the film thickness measurements ensured uniformity of thickness in each film. The folding endurance was measured manually and are given in Table 1 .Water vapour transmission studies indicated that all the films were permeable to water vapour. Water vapour transmission through the films followed zero order kinetics. The results are given in Table 1 and shown in Fig. 1(A), Fig.1 (B) and Fig.1 (C).

Fig 1: Water vapour transmission profiles of Eudragit RS100 films (A) Eudragit RL100 films (B) and Eudragit RL PO Films (C) casted with various solvents

A: Ethyl Cellulose Films Eudragit RS100 films

B: Eudragit RL100 films

C. Eudragit RL PO films

(A) (-♦-) F1 (Eudragit RS100 films prepared with acetone); (-■-) F2 (Eudragit RS100 films prepared with dichloromethane); (-▲-) F3 (Eudragit RS100 films prepared with chloroform); (-×-) F4 (Eudragit RS100 films prepared with ethyl acetate); (B) (-♦-) F5 (Eudragit RL100 films prepared with acetone); (-■-) F6 (Eudragit RL100 films prepared with dichloromethane); (-▲-) F7 (Eudragit RL100 films prepared with chloroform); (-×-) F8 (Eudragit RL100 films prepared with ethyl acetate) (C) (-♦-) F9 (Eudragit RLPO films prepared with acetone); (-■-) F10 (Eudragit RLPO films prepared with dichloromethane); (-▲-) F11 (Eudragit RLPO films prepared with chloroform); (-×-) F12(Eudragit RLPO films prepared with ethyl acetate)

These values were found to be influenced by the casting solvent employed in the preparation of films. Based on water vapour transmission coefficient (Q) values the solvents can be ranked as Ethylacetate> acetone> dichloromethane> chloroform.Based on the water vapour transmission coefficient (Q) values the formulations can be arranged as Eudragit RLPO.> Eudragit RL100.> Eudragit RS100.

Fig 2: Diffusion profiles of Glipizide through Eudragit RS100 films (A) Eudragit RL100 films (B) and Eudragit RL PO Films (C) casted with various solvents

A: Eudragit RS100 Films

B: Eudragit RL100 films

C: Eudragit RL PO Films

Drug diffusion through various films were studied with Glipizide as a model drug by using Franz diffusion cell. All the films were found to be permeable to Glipizide and diffusion profiles are shown in Fig. 2(A), Fig.2 (B) and Fig.2(C).Permeability coefficient values (Pm) of the films towards the Glipizide 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 in three cases. Ethyl acetate> acetone> dichloromethane> chloroform. Based on the permeability coefficient (Pm) values the formulations can be arranged as Eudragit RLPO.> Eudragit RL100.> Eudragit RS100.

CONCLUSION :

The results obtained in the present study thus indicated that the polymers and solvents used in the preparation of films have been shown significant influence on the water vapour transmission, drug diffusion and permeability of the films. Among all the films, Eudragit RLPO films prepared with Ethylacetate showed the desired permeability coefficient (Pm) when compared to other films.

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Received on 27.02.2011

Modified on 24.03.2011

Accepted on 22.05.2011

Research J. Science and Tech. 3(4): July-August. 2011: 180-183