Effect of Permeation Enhancers on the Release and
Permeation Kinetics of Propranolol Hydrochloride Gels through Mouse Skin
V Sai Kishore *
and TE Gopala Krishna Murthy
Bapatla College of Pharmacy ,
Bapatla-522101
*Corresponding Author
E-mail: voiceofsaikishore@yahoo.com
ABSTRACT
In the present study efforts were made to prepare
transdermal gels of Propranolol Hydrochloride using polymers like HPMC, NaCMC,
M.C ,Carbopol, PEG6000 and PVP. The gel formulations can be graded in the
following order with respect to the rates of release of drug from them: (HPMC)
< (MC) < (Carbopol) <(NaCMC) < (NaCMC +PVP)< (NaCMC+ PEG 6000).
Various permeation enhancers, namely, SLS,( 2% w/w) , 2% w/v of PEG400, DMSO and Tween 20 were
incorporated into gels with a view to improve permeability of drug. 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 case II
transport diffusion. Formulation-GP1 (NaCMC +PEG 6000+ Tween 20) shown required release rate in comparison
with other formulations and was selected as suitable
candidate to be delivered through transdermal route at controlled rate.
KEY WORDS: Propranolol Hydrochloride, Gels,
Polymers, Permeation enhancers,
Proponolol Hydrochloride (PHCL) is a non selective
β-adrenergic blocking agent. It has been widely used in the trea tment of
hypertension and many other cardiovascular disorders. PHCL is subjected to an
extensive and highly variable hepatic first pass metabolism following oral
administration, with reported systemic bioavailability of between 15 and 23%.1
As its biological half life is about 3.9 h and is eliminated rapidly, repeated
daily administrations are needed to maintain effective plasma levels that makes
it suitable candidate to be delivered through transdermal route at controlled
rate. Administration of drugs through transdermal route bypasses the first pass
metabolism and there by increases the bioavailability. The development of
technology for release of drug at controlled rate into systemic circulation
using skin as a port of entry has become popular for various reasons2 .The
transdermal entry of drug in to systemic circulation at a desired rate can be
achieved by using a suitable rate controlling membrane and a drug reservoir.3
Earlier studies proved that cellulose acetate films could be used as rate
controlling membranes for the design of TDD systems.4 With a view to design a suitable drug
reservoir, various types of gel formulations were prepared.
The gels are becoming more popular due to ease of
application and better percutaneous absorption, than other semisolids
preparations. Gels can resist the physiological stress caused by skin flexion,
blinking and mucociliary movement, adopting the shape of the applied area, and
controlling drug release. 5
To enhance the permeability of PHCL,
various permeation enhancers were incorporated into the gels. The in-vitro skin
permeation experiments are known for their value in studying the rate and
mechanism of percutaneous absorption of drugs. To study the effect of
permeation enhancers on the release and permeation kinetics of PHCL gels, those
are evaluated by studying drug diffusion through cellulose acetate membrane and
mouse skin.
MATERIALS AND METHODS:
PHCL was obtained as a gift sample from Natco Pharma, Hyderabad. Cellulose acetate (viscosity of 6% solution in 95% acetone-water mixture at 200
C having 140 CS viscosity, G.S. Chemical Testing Lab and Allied
Industries) , Ethyl acetate (Qualigens), Dibutyl phthalate (Ranbaxy
Laboratories), Sodium CMC(200-300cPs, S. D. fine-chem Ltd.; Mumbai), Carbopol
934(Arihanth traders; Mumbai) Hydroxy Propyl Methyl cellulose(50cPs S.
D. fine-chem Ltd.; Mumbai) and were Methyl cellulose (28-32%, S. D. fine-chem
Ltd.; Mumbai)
obtained commercially. All
materials were used as received.
Estimation of desired release rate:
The mathematical description of
drug release that follow zero order kinetics is based on the equation.6
,Where,K0r
is zero order rate constant for drug release, Ke is
first order rate constant for overall drug elimination, Cd
is desired drug level in the body and Vd is volume space in which
drug is distributed. For propranolol hydrochloride7 t˝ =
3.9 h, Vd = 4.3 l and Cd = 0.02 µg/ml and
therefore the desired drug release rate can be calculated as K0 r
= (0.693/3.9)×0.02 ×4.3 ×70 =1.064 mg/h
Preparation of Drug Free Films:
Solvent evaporation technique was employed in the
present work for the preparation of Cellulose acetate films. The polymer
solutions were prepared by dissolving the polymer (2% w/w Cellulose acetate) in 50 ml of Ethyl acetate-Methanol (8:2). Dibutyl
phthalate at a concentration of 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 hours the dried films were
taken out and stored in a desiccator.
Table 2: Composition of Transdermal Gels Containing Various Permeation
Enhancers
INGREDIENTS
|
GP1
|
GP2
|
GP3
|
GP4
|
Propranolol HCL (mg)
|
325
|
325
|
325
|
325
|
Sodium CMC: PEG6000 (mg) (1:1)
|
950
|
950
|
950
|
950
|
Tween 20(ml)
|
0.361
|
|
|
|
SLS (mg)
|
|
400
|
|
|
DMSO (ml)
|
|
|
0.363
|
|
PEG 400(ml)
|
|
|
|
0.357
|
Glycerin (ml)
|
2
|
2
|
2
|
2
|
Distilled water (ml) up to
|
20
|
20
|
20
|
20
|
Formulation of Drug Reservoir gels:
Different drug reservoir gels were formulated as per
the composition given in Table 1. The required quantities of polymer Sodium
carboxy methyl cellulose(Na CMC)(or) Methyl cellulose (MC)(or) Hydroxy propyl
methyl cellulose (HPMC), was weighed and transferred separately into a mortar.
It was triturated with 10 ml of water. Specified amount of Propranolol
Hydrochloride was weighed accurately and
dissolved in glycerin. The resulting drug solution was incorporated into the
polymer
dispersion slowly with continuous
trituration to obtain a gel. The gel was transferred in to a measuring cylinder
and the volume was made up to 20 ml with distilled water. As shown in the
Table1, specified amount of carbapol 940 was soaked in 15 ml of water over
night. Specified amount of propranolol hydrochloride was weighed accurately and
dissolved in glycerin. The resulting drug solution was incorporated into the
polymer dispersion with stirring at 500 rpm ,by a magnetic stirrer for 1 h. Tri
ethanolamine (0.5%) was added to brought the pH neutral and the volume was
made up to 20 ml with distilled water. Two different hydrophilic polymers viz.,
Poly vinyl pyrolidine (PVP) and Poly ethylene glycol -6000(PEG-6000) were
incorporated in 1:1 ratio (NaCMC: Polymer) into NaCMC gels in formulation G5
and formulation G6 respectively. The resulting gels were
filled in collapsible tubes.
Preparation of Gels containing permeation Enhancers:
Four different permeation enhancers namely Sodium
lauryl sulphate (SLS) (2% w/w), Tween 20(2% w/v),
Dimethyl sulfoxide (DMSO) (2% w/v) and Poly
ethylene glycol -400(PEG400) (2% w/v) were
incorporated into the (NaCMC + PEG 6000) gels. The composition of these gels
was given in Table 2.
Evaluation
of Drug Reservoir Gels:
Drug Diffusion Study:
Drug diffusion study was conducted using Franz diffusion
cell7. 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. The Proponolol Hydrochloride gel (1 gm containing 25 mg of PHCL) was
placed 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
UV-spectrophotometer at 290 nm.
Permeability Coefficient:
From the drug diffusion data the
permeability co efficient for various films was calculated using the equation8
.Pm = (Kapp. H)/A, Where, Kapp is 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).
Figure1: Diffusion Profiles Of
Propranolol Hydrochloride From Transdermal Gels
(-♦-)G1 (Transdermal gel prepared with
NaCMC)
(-■-)G 2 (Transdermal gel prepared
with Carbopo
(-+-)G 3 (Transdermal
gel prepared with Methyl cellulose)
(-▲-)G 4 (Transdermal gel prepared
with HPMC)
(-* -) G 5 (Transdermal gel prepared with
NaCMC+PVP )
(-Ĺ-)G 6
(Transdermal gel prepared with NaCMC+PEG 6000)
(-×-)G 6A* (Transdermal gel prepared with
NaCMC+PEG
6000 through mice
abdominal skin
The rate and the mechanism of release of propranolol
hydrochloride through the prepared gels were analyzed by fitting the diffusion
data into9, 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= k2t1/2,
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 , M1/Ma=Ktn,
where Mt/Ma
is 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.
In
vitro skin permeation studies:
Male wistar rats weighing between 130-160g and free
from any visible sign of disease were selected for the in vitro studies.the
hair on abdominal region was removed using a depilatory preparation one day
prior to experiment.On the day of experiment ,animals were sacrificed by
cervical dislocation and abdominal skin was excised.The fatty material adhere
to the dermis was carefully peeled off. Freshely excised rat skin of thickness
(2mm) was mounted on the donor comportment.10 Formulation G6
and Formulations GP1, GP2, GP3 and GP4 were
evaluated by studying drug diffusion through cellulose acetate membrane and
mouse skin.
RESULTS AND DISCUSSION:
In the present study efforts were
made to prepare transdermal gels of Propranolol Hydrochloride using polymers
like HPMC, NaCMC, M.C and Carbopol. To enhance the permeability of Propranolol
Hcl, various hydrophilic polymers namely PEG6000, PVP were incorporated in 1:1
ratio (NaCMC: polymer) in to the NaCMC gels. The results of the in-vitro
diffusion study from different gels across the
Cellulose acetate films prepared
with Ethylacetate -methanol (8:2) are showed in
Figure 1.
The gel formulations can be
graded in the following order with respect to the rates of release of
Propranolol Hydrochloride from them: (HPMC) < (MC) < (Carbopol)
<(NaCMC) < (NaCMC +PVP)< (NaCMC+ PEG 6000). Formulation G6
(NaCMC and PEG 6000) has showed good release pattern when compared to other gel
formulations which perhaps may be explained by the fact that PEG 6000 enhances
solubility of the drug in aqueous vehicle.
Figure 2: Diffusion Profiles of
Propranolol Hydrochloride From Transdermal Gels Containing Different Permeation
Enhancers
(-♦-) GP1 (Transdermal gel prepared
with Tween 20) (-■-) GP 2 (Transdermal gel prepared
with SLS)
(-▲-) GP 3 (Transdermal gel
prepared with DMSO)
(-×-) GP 4 (Transdermal gel prepared with
PEG 400)
The correlation coefficient values (r)
revealed that the diffusion profile 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 0.9910-1.0090 (n>1), which
indicates case II transport diffusion.11 Permeability coefficient
values (Pm) of the films towards the propranolol hydrochloride gel
was calculated from the drug diffusion data and the results were given in Table
3.
Based on permeability coefficient values Formulation G6
(NaCMC and PEG 6000) was selected for In-vitro skin permeation study .
The skin permeation showed a similar pattern as that of the diffusion profile
through rate controlling membrane, but the amount of drug permeated through the
skin was not satisfactory. Therefore, various permeation enhancers, namely, SLS,( 2% w/w) , PEG400(2% w/v), DMSO(2% w/v) and
Tween 20(2% w/v) were incorporated into gels
with a view to improve permeability of propranolol hydrochloride.
The results of the in-vitro diffusion study from
different gels containing various permeation enhancers across the Cellulose
acetate films and mice skin are shown in Figure 2.
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
0.9903-1.0110 (n>1), which indicates case II transport diffusion.
Permeability coefficient values (Pm) of the films towards the
Propranolol Hydrochloride gel was calculated from the drug diffusion data and
the results were given in Table 4.
CONCLUSION:
The permeation enhancers like
SLS,PEG 400,DMSO and Tween 20 used for increasing the permeation of drug could
be arranged in the following increasing order according to their permeation
rates : Tween 20> SLS> DMSO > PEG 400. The increased permeation rate
in all these enhancers may be due to surfactant action .These results indicated that the non ionic surfactant Tween 20 improves
the permeability characteristics of Propranolol Hydrochloride when compared
with the other permeation enhancers. Formulation
- GP1 ((NaCMC +PEG 6000+ Tween 20))
shown required release rate in comparison with other formulations and was selected as suitable candidate to be delivered
through transdermal route at controlled rate.
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