INTRODUCTION:
The development of transdermal drug delivery systems using polymeric materials
has become popular for various reasons. Among various types of transdermal drug delivery systems developed, membrane
controlled type utilizes a thin polymeric film as a rate controlling membrane,
which delivers the drug from the reservoir to the systemic circulation for an
extended period of time. The permeability of drug through polymeric film
dependent on characteristics of the polymer1- 2casting solvent3-
4 and plasticizer5-6 was used. In the present work,
eudragitL100 and Eudragit RLPO films were prepared
and evaluated as rate controlling membranes for transdermal
drug delivery systems. Propranolol hydrochloride7, which requires
controlled release due to its short biological half life (3.9h), was used as a
model drug.
MATERIALS AND METHODS:
Materials Used:
Propranolol hydrochloride was obtained as a gift sample
from Natco Pharma;
Hyderabad. Eudragit RLPO Natco
Pharma; Hyderabad. Eudragit
RL100 (Himedia; Mumbai). Acetone (Qualigens;
Mumbai). Ethyl Acetate, Dichloromethane, Chloroform (S. D. fine-chem. Ltd.;
Mumbai) Dibutyl Phthalate (Ranbaxy Laboratories; New
Delhi) was obtained commercially. All materials were used as received.
Preparation of drug free films:
Casting on mercury surface
technique was employed in the present work for the preparation of Eudragit RL100and Eudragit RLPO
films. In each case films were prepared using solutions of the polymer in
various solvents. Acetone, chloroform, dichloromethane and ethyl acetate were
used as solvents in the preparation of films. Dibutyl
phthalate was included as a plasticizer in the preparation films at a
concentration of 15% w/w of the polymer (or 8% w/v of the polymer solution). 8
ml of the polymer solution was poured in a glass bangle (6.4 cm diameter)
placed on a mercury 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, Thickness uniformity, Folding Endurance, Water vapour Transmission and Drug Diffusion Study and
Permeability Coefficient. The
thickness of the films was measured by a ‘dial caliper’. 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 1.0 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 KCl (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 72h. 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.
Where, W= Water vapour transmitted in gms.
L= Thickness of the film in cm.
S= 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 0.25% W/V of drug solution was poured into
the donor compartment. Magnetic stirrer was set at 100 rpm and whole assembly
was maintained at 37 + 2 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 290 nm11.
Permeability
Coefficient:
From the drug diffusion data the
Permeability Co efficient for various films was calculated using the equation
Where, Kapp = Diffusion rate constant (mg/h)
calculated from the slope of the linear drug (d/p) diffusion profiles. H =
Thickness of the film (cm), A = Surface area of the film (cm2).
The rate and mechanism of release of prapranolol hydrochloride through the prepared films were
analyzed by fitting the diffusion datainto12,zero-order equation,
Q=Q0-k0t, Where Q
is the amount of drug release at time t, and k0is the release rate.
First order equation, is LnQ=LnQ0-k1t
Where k1is the release rate constant and Higuchi. Equation, Q=k2t1/2, Where Q is the amount of drug release at time
t, and k2 is the diffusion rate constant. The
diffusion data was further analyzed to define the mechanism of drug
release by applying the diffusion data following the empirical equation,M1/Mœ=ktn,
where Mt/Mœ
is the fraction of the drug released at time t, K is a constant and n
characterizes of the mechanism of drug
release from the formulations during diffusion process.
Statistical Evaluation:
The relevance of difference in the in-vitro diffusion rate profile was
evaluated statistically. The data were
tested by one way analysis of variance (P<0.05) (ANOVA).
Skin Irritation
Test:
A primary skin irritation test was
performed on six healthy rabbits, weighing between 2 to 3.5 kg. The patch of
area 3.14cm2 was used as a test patch. The dorsal surface of rabbits was
cleared well and the hair was removed by using a depilatory preparation. The
skin was cleared with rectified spirit. The transdermal
film was placed on the dorsal surface of the abdominal skin with the help of an
adhesive tape. The patches were removed after 24 hr and the skin was examined
for erythema and edema.
RESULTS AND DISCUSSION:
In the present work, Eudragit RL100 and Eudragit RLPO films showed good film forming properties.
The method of casting on mercuric surface was 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 from 5-15% 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 dibutyl
phthalate was included as a plasticizer in the preparation of eudragitL100, Eudragit RLPO films at a concentration of 15%w/w of the
polymer All the films prepared were
evaluated for uniformity of thickness, folding endurance, water vapour transmission and drug diffusion and permeability
characteristics. Thickness measurements of films prepared in various solvents
are given in table 1. Low standard deviation values in the film thickness
measurements ensured uniformity of thickness in each film. The method of
casting on mercuric surface was found to be given reproducible results with
regard to film thickness. The folding endurance was measured manually and folding
endurance was found to be high in Eudragit RLPO films
compared with Eudragit RL100 films. Folding endurance
is decreased in the order of films in various solvents is as follows. Water vapour
transmission studies indicated that all the films prepared (both Eudragit RL100 and Eudragit RLPO)
were permeable to water vapour. Water vapour transmission through the films followed zero order
kinetics. The results are given in table 2.And shown in fig1 and 2.
The water vapour transmission (Q) was more in the case of cellulose
acetate films when compared to ethyl cellulose. Water vapour
transmission values indicating that the cellulose acetate films were more
permeable to water vapour. The rate of water vapour transmission was decreased in the order of films in
various solvents is as follows.
Ethyl acetate >
acetone> dichloromethane> chloroform.
Drug diffusion
through various films was studied with propranolol
hydrochloride as a model drug by using Franz diffusion cell. All the films were
found to be permeable to Propranolol hydrochloride and the results are given in
table 2and shown in fig 3 and 4. The correlation coefficient values (r) were
reported in Table 3. These values revealed that the dissolution profiles follow
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 1.056-1.071 (n>1), which indicates super case II
transport diffusion13.
Permeability coefficient values (Pm) of the films towards the propranolol hydrochloride was calculated from the drug
diffusion data and the results were given in table 3. The rate of permeability
coefficient was decreased in the order of films in various solvents is as
follows.
Ethyl acetate >
acetone> dichloromethane> chloroform.
The relevance of
difference in the in-vitro diffusion
rate profile was evaluated statistically.
Statistical analysis by using
One-way analysis of variance (P<0.05) proves that films prepared with
various polymers and casting solvents have significant difference in diffusion
of Proponolol Hydrochloride. Skin Irritation studies
were conducted according to the procedure described earlier. The examination of
applied area indicated neither erythema nor edema.
Hence it was concluded that the transdermal gels were
free from skin irritation. The results obtained in the present study thus
indicated that the solvent used has significant influence on the water vapour transmission, drug diffusion and permeability of the
films. Shown high Permeability coefficient values (Pm) of the Eudragit RLPO films towards the propranolol
hydrochloride was high when compared to the Permeability coefficient values of Eudragit RL100 films. Among all the films, Eudragit RLPO films prepared with Ethylacetate
shown high Permeability when compared to other films. Among all the films, Eudragit RLPO films prepared with Ethylacetate
Permeability when compared to other films.