Effect of Combination of Hydrophilic and Hydrophobic
Polymers on Transdermal Drug Delivery Systems
Properties
U. D. Shivhare*
Sharad Pawar
College of Pharmacy, Wanadongri, Hingna Road,
Nagpur - 441 110, India.
ABSTRACT:
The matrix-type controlled transdermal drug delivery
systems were prepared by solvent evaporation method using methanol:
dichloromethane (1:1) as solvent for HPMC and ethanol as solvent for Eudragit RL 100 and
Eudragit RS 100 (ERL 100 and ERS 100). In the evaluation tests it was found that
formulation batch L1 (96.40%) was having more release as compared to
formulation L2 (95.52%) but later had much better physicochemical properties
and shown cumulative percentage diffusion 96.60% in 24 h. The transdermal patches were evaluated for their In vitro dissolution test and in vitro diffusion test, skin irritation
test. Scanning electron microscopy was performed to characterize the
transdermal patch.
KEYWORDS: HPMC E15; Atenolol;
Solvent Evaporation Method; Transdermal
Patch; Dimethyl Sulphoxide
INTRODUCTION:
Transdermal
drug delivery system is a class of novel drug delivery system. It has been used
to administer those drugs, which undergo first pass metabolism on oral
administration or undergo degradation when pass through gastrointestinal tract,
have short biological half-life or have poor absorption from gastrointestinal
tract. TDDS are designed to deliver the drug at a controlled rate through skin
into the systemic circulation.
Atenolol, a β-blocker, is prescribed widely in diverse
cardiovascular diseases viz. hypertension, angina pectoris, arrhythmias and
myocardial infarction. The drug is also frequently indicated in the
prophylactic treatment of migraine. The literature survey reveals that the drug
release rate of conventional tablet was very high initially and the cumulative
released percentage was upto 90% within 30 min. Such
tablet is usually administered 2-3 times a day and found to exhibit
fluctuations in the plasma drug levels, resulting
either in manifestation of side effects or reduction in drug concentration at
the receptor site (Longxiao, 2002).
In
order to avoid such problems and to achieve maximum therapeutic efficacy with
preprogrammed delivery of dose of drug, to prolong drug release by avoiding its
initial high release rate and to control its release within therapeutic range
with minimum side effect, the transdermal route is good alternative.
EXPERIMENTAL:
Materials
Atenolol
was received as gift sample obtained from ZIM Labs, Nagpur, India
and Eudragit RL 100 and Eudragit
RS 100 were received as gift sample from Rohm Pharma,
Germany.
HPMC E15
Potassium dihydrogen phosphate, Ethanol, Methanol and
Dichloromethame were purchased from
purchased from Loba Chemie,
Mumbai. Sodium chloride and Potassium
chloride were purchased from The
Merck Co., Mumbai. n-octanol
was purchased from S. D. Fine Chemicals Mumbai. All the other chemicals, reagents and solvents used
were of AR grade.
Partition coefficient of Atenolol:
Atenolol solution, 1 mg/ml concentration in 25 ml
of n-octanol was prepared in a separating funnel and
shaken with an equal volume of phosphate buffer of pH 7.4 (aqueous phase) for
10 min and allowed to stand for 2 h at room temperature. Both aqueous phase and
organic phase were collected separately and centrifuged at 2000 rpm for 5 min
and they were analyzed for the drug concentration using UV spectrophotometer
(UV–Visible Spectrophotometer, UV–1601, Shimadzu, Japan) at 224.5 nm. The
Partition coefficient was calculated by taking the ratio drug concentration in
n-octanol and drug concentration in aqueous phase.
Average of triplicate readings was taken (Garala, 2009).
Ko/w = 
(5)
Where,
Co - Concentration in octanol
Cw - Concentration in phosphate buffer
Investigation of physicochemical compatibility of drug
and polymer:
FTIR (FTIR Spectrophotometer, 8400S,
Shimadzu, Japan) method was used to detect any interaction between the drug and
the polymers. The IR spectra of pure Atenolol, ERL
100, ERS 100, and HPMC were taken. Also the IR spectra of drug: polymer (1:1)
ratio was taken. Any change in basic peak of the drug indicates interaction
between drug and polymer.
Method
of preparation of the transdermal drug delivery systems (TDDS) (table-1):
The
transdermal patches of Atenolol were prepared by
solvent evaporation method. The matrix-type controlled transdermal drug
delivery systems were prepared by using methanol: dichloromethane (1:1) as
solvent for HPMC and ethanol as solvent for ERL 100 and ERS 100. The casting
solution was prepared by using 5% w/v polymer in their respective casting
solvents. For the different batches of formulations the polymer solution in
different proportions were mixed and stirred on magnetic stirrer to give
homogenous clear solution, Atenolol was added slowly
to the polymer solution and stirred thoroughly to obtain a uniform solution. Dibutyl phthalate (DBP), as a plasticizer, and dimethyl sulphoxide (DMSO), as
penetration enhancer, were added and stirred. The polymeric solution of drug
was poured onto the mercury surface and covered with inverted funnel, then
dried at room temperature in a dust-free environment. After 24 h, the patch was
cut into 5.31 cm2 pieces. The transdermal patches were stored in a
desiccator containing fused calcium chloride until further use (Shivhare, 2009).
Table 1: Composition of Atenolol
Polymeric Transdermal Patches
|
Formulation
code
|
Atenlol (mg)
|
Polymers
|
DBP (mg)
|
DMSO (mg)
|
|
HPMC E 15 : ERL100
|
HPMC E 15 :
ERS 100
|
|
L1
|
250
|
4 : 1
|
----
|
80
|
80
|
|
L2
|
250
|
3 : 2
|
----
|
80
|
80
|
|
L3
|
250
|
2 : 3
|
----
|
80
|
80
|
|
L4
|
250
|
1 : 4
|
----
|
80
|
80
|
|
S1
|
250
|
----
|
4 : 1
|
80
|
80
|
|
S2
|
250
|
----
|
3 : 2
|
80
|
80
|
|
S3
|
250
|
----
|
2 : 3
|
80
|
80
|
|
S4
|
250
|
----
|
1 : 4
|
80
|
80
|
DBP:
Dibutyl pthalate; DMSO: Dimethyl sulphoxide
Physicochemical evaluation of the patches
The
transdermal patches were evaluated for the following physicochemical properties
Percentage moisture absorption
A
weighed transdermal patch was kept in a desiccator and exposed to 84% relative
humidity (a saturated solution of aluminum chloride) at room temperature for 24
h. It was taken out and weighed until a constant weight for the patch was
obtained. The percentage of moisture absorption was calculated as the
difference between final and initial weight with respect to initial weight.
Percentage moisture
absorption =
------------- (6)
Percentage
moisture absorption of various formulation batches under consideration are given in table 2.
Percentage moisture content
The
transdermal patches were weighed individually and kept in desiccator containing
activated silica at room temperature for 24 h. Individual transdermal patches
were weighed repeatedly until they showed a constant weight. The percentage of
moisture content was calculated as the difference between initial and final
weight with respect to initial weight.
Percentage moisture content =
----------------- (7)
Percentage
moisture content of various formulation batches under consideration is given in
table 2.
Percentage moisture loss
Accurately weighed transdermal patches of each
formulation batch were kept in a desiccator and exposed to an atmosphere of 98%
relative humidity (containing anhydrous calcium chloride) at room temperature
and weighed after 3 d. The percentage of moisture loss was calculated as the
difference between initial and final weight with respect to initial weight (Anitha, 2010).
Percentage moisture loss =
------------------
(8)
Percentage moisture loss
of various formulation batches under consideration are given in table 2.
Water vapor transmission rate (WVT Rate):
Glass vials of equal diameter were used as transmission
cells. These transmission cells were washed thoroughly and dried in an oven.
Then, in these dried cells about 1 g anhydrous calcium chloride was placed and
the polymer patch from each batch of formulation was fixed over the brim. The
cells were accurately weighed and then they were kept in a closed desiccator
containing saturated solution of potassium chloride to maintain a humidity of
84%. The cells were taken out and weighed after 24 h of storage (Rao, 2007).
Water
vapor transmission rate =
---------------- (9)
WVT rate is
usually expressed as the number of g of moisture gained/cm2/h.
WVT rate of
various formulation batches under consideration are given in table 2.
Mass variation:
The transdermal patches were subjected to mass
variation by individually weighing 5 individual transdermal patches
of same formulation. Such determinations were carried out for each formulation
of Atenolol transdermal patch.
Mass variations of various formulation batches under
consideration, are given in table 2.
Thickness:
The
thickness of transdermal patches were measured by
using Screw gauge. Thickness was measured at five different points on the same
patch and average of five readings was taken.
Thicknesses of various formulation
batches under consideration are given in table 2.
Folding
endurance:
It was determined by repeatedly folding the
transdermal patch at the same place until it broke. The test was carried
out to check the efficiency of the plasticizer and the strength of the patch,
prepared using varying ratios of the polymers. The number of times the
patch could be folded at the same place without breaking/cracking gave
the value of folding endurance (Anitha, 2010).
Folding endurance of various formulation batches are
given in table 2.
Flatness:
Longitudinal strips were cut out from each
transdermal patch, one from the center and two from either side. The length of
each strip was measured. The variation in the length because of non-uniformity
in flatness was measured by determining percent constriction, considering 0%
constriction is equivalent to 100% flatness.
% Constriction = 
-------------------- (10)
Where L1 = initial length of
each strip
L2 = final length of each strip
Flatness and appearance of various formulation
batches under consideration are given in table 2.
Drug content:
A
transdermal patch was cut into 5 equal parts and put in a 50 ml buffer (pH
7.4). This was then shaken in a mechanical shaker for 24 h to get a homogeneous
solution and filtered. The drug content was determined spectrophotometrically
at 224.5 nm after suitable dilution.Drug content of
various formulation batches are given in table 2.
TABLE 2: PHYSICOCHEMICAL
CHARACTERISATION OF TRANSDERMAL PATCHES
|
Form
ulation
|
% Moisture Absorption
(Mean ± SD)
|
% Moisture Content
(Mean ± SD)
|
%
Moisture Loss
(Mean ± SD)
|
WVT Rate (g/cm2/h)×10-4
(Mean ± SD)
|
Mass
Variation
(mg)
(Mean ± SD)
|
Thickness
(mm)
(Mean ±SD)
|
Folding Endurance
(Mean ±SD)
|
% Drug content (Mean ±SD)
|
% Flatness (Mean ± SD)
|
|
L1
|
17.28 ± 0.031
|
6.53 ± 0.071
|
2.28 ± 0.031
|
1.359 ± 0.057×10-4
|
158 ± 0.630
|
0.22 ± 0.008
|
28.4 ± 1.350
|
99.24 ± 0.114
|
100%
|
|
L2
|
14.41 ± 0.023
|
5.50 ± 0.022
|
3.91 ± 0.022
|
1.839 ± 0.014×10-4
|
156 ± 1.170
|
0.19 ± 0.007
|
43 ± 1.098
|
98.72 ± 0.083
|
100%
|
|
L3
|
9.12 ± 0.045
|
6.19 ± 0.011
|
6.19 ± 0.021
|
2.563 ± 0.280×10-4
|
154 ± 0.741
|
0.17 ± 0.006
|
47.8 ± 0.971
|
97.72 ± 0.164
|
100%
|
|
L4
|
8.00 ± 0.089
|
3.89 ± 0.014
|
6.59 ± 0.066
|
2.701 ± 0.284×10-4
|
152 ± 1.019
|
0.14 ± 0.006
|
50.4 ± 1.019
|
96.62 ± 0.130
|
100%
|
|
S1
|
13.10 ± 0.027
|
6.71 ± 0.043
|
2.75 ± 0.029
|
1.581 ± 0.052×10-4
|
157 ± 0.631
|
0.20 ± 0.007
|
28.2 ± 0.740
|
99.02 ± 0.130
|
100%
|
|
S2
|
9.60 ± 0.024
|
5.71 ± 0.021
|
3.30 ± 0.024
|
2.411 ± 0.040×10-4
|
156 ± 0.683
|
0.18 ± 0.007
|
41.2 ± 1.160
|
98.24 ± 0.114
|
100%
|
|
S3
|
5.05 ± 0.031
|
4.23 ± 0.032
|
4.51 ± 0.031
|
3.681 ± 0.074×10-4
|
154 ± 0.741
|
0.16 ± 0.005
|
46.4 ± 0.804
|
97.24 ± 0.151
|
100%
|
|
S4
|
4.80 ± 0.017
|
3.81 ± 0.012
|
5.07 ± 0.087
|
4.080 ± 0.044×10-4
|
151 ± 0.748
|
0.13 ± 0.006
|
52.4 ± 1.019
|
96.36 ± 0.114
|
100%
|
Each value represents mean ± SD, n =5
In vitro drug release (dissolution study) of transdermal patch:
A
modified stainless steel disc assembly USP Apparatus 5, paddle over disc
assembly (USP Tablet Dissolution apparatus 5, DISSO 2000, Lab India) was used
for the assessment of the release of the drug from the transdermal patches. The transdermal drug delivery system (TDDS)
was mounted on the disc and placed at the bottom of the dissolution vessel. The
dissolution medium was pH 7.4 and the apparatus was equilibrated to 32 ± 0.5 °C. The apparatus was operated at 50 rpm. Samples were
withdrawn at appropriate time intervals upto 24 h and
were filtered through Whatmann filter paper no.42 and
then analyzed for absorbance by using UV–Visible Spectrophotometer (UV–1601) at
224.5 nm after suitable dilution. Cumulative % drug release were calculated and
plotted against time (Aqil, 2002).
The
plot of % cumulative drug release vs. time (h) was plotted for transdermal
patches are depicted as figure 3 and treatment of drug release data with
different kinetic equations are depicted as table 3.
IN VITRO DIFFUSION STUDY:
The in
vitro diffusion study was
performed in a modified Keshary-Chien cell of
capacity 15 ml using cellophane membrane. The cellophane membrane was activated
by boiling it in phosphate buffer pH 7.4, followed by keeping it in the buffer
for overnight. A section of membrane was cut, measured, and placed on the
dermal side of the membrane in the donor compartment facing the drug matrix
side of the transdermal patch to the membrane and backing membrane
upward. The holder containing the membrane and formulation was placed on the
receiver compartment of the modified diffusion cell, containing phosphate
buffer pH 7.4. The temperature of the diffusion cell was maintained at 32 ± 0.5 °C by circulating water jacket.
This whole assembly was kept on a magnetic
stirrer and solution in the receiver compartment was constantly and
continuously stirred during the whole experiment using magnetic bead. The
samples were withdrawn (1 ml) at different time intervals and an equal amount
of phosphate buffer pH 7.4 was replaced. Absorbances
of the samples were read spectrophotometrically at 224.5 nm taking phosphate
buffer solution, pH 7.4, as blank (Shivhare, 2009).
The plot of % cumulative drug diffused vs.
time (h) was plotted for transdermal patch is depicted as figure 4, and
cumulative amount of drug permeated (µg/cm2)/h is depicted as figure
5, and flux vs. time (h) are depicted as figure 5.
Scanning electron microscopy
study (SEM):
The
external morphology of the transdermal patch was
investigated by Scanning Electron Microscopy (SEM) using JSM 6380A (JOEL,
Japan). Transdermal
patch of suitable size was cut and fixed over brass
brim. Then coated with platinum by ion sputtering using Auto fine coater
JFC–1600 for 20 s at 1.1V under argon atmosphere and then mounted onto metal
stubs using double-sided carbon adhesive tape and the scanning electron
micrographs were taken (Figure 6).
DISCUSSION:
Partition coefficient:
The
results of Partition coefficient,logarithmic
value of partition coefficient (log P), was experimentally found to be 0.29.
The result obtained also indicates that the drug possesses sufficient lipophilicity for easy penetration of drug through the skin
which fulfills the criteria for the formulation of Atenolol
into a transdermal patch.
Figure 1: Infrared spectrum of Atenolol
Figure 2: Infrared spectrum of mixture of Atenolol,
ERS 100, ERL 100 and HPMC E15
FTIR spectroscopy:
Infrared
spectroscopic studies were performed to assess any interaction between the drug
and the polymers. FTIR data of Atenolol (Figure 1)
showed characteristic peaks at 3360 cm-1 due to N-H stretching for amine, 2942
cm-1 due to aliphatic C-H stretching, 1652 cm-1 due to C=O group stretching,
1254 cm-1 and 1186 cm-1 due to C-N amine stretching and 3041 cm-1 due to
aromatic ring stretching respectively.
The data obtained suggested
that there was no interaction between the drug (Figure 1) and the polymer
because principal peaks of the drug and the drug-polymer mixture were nearly
similar (Figure 2). Thus IR result suggested that the drug and polymers were
compatible.
Moisture absorption and moisture content:
The
results of moisture absorption and moisture content studies were shown in Table
2. The moisture absorption in the formulation batches ranges from 8 ± 0.089 to
17.28 ± 0.031% and 4.8 ± 0.017 to 13.1 ± 0.027% (for formulation L series and
formulation S series respectively). The moisture content in the transdermal
patches ranges from 3.89 ± 0.014 to 6.53 ± 0.071% and 3.81 ± 0.012 to 6.71 ±
0.046% (for formulation L series and formulation S series respectively). The
results revealed that the moisture absorption and moisture content was found to
be decreased with decreasing the concentration of hydrophilic polymer (HPMC).
Moisture loss:
Percentage
moisture loss study (Table 2) was carried and results indicated that the
transdermal patch L4 with HPMC: Eudragit RL100 (1:4)
showed maximum (6.59 ± 0.066) % moisture loss for L series and S4, (5.07 ±
0.087) % ,for S series which could be attributed to
its hydrophobic nature. As expected, with decreased in HPMC content in both the
series, the values of percentage moisture loss increased in accordance with
their increased lipophilic nature. The transdermal
patches having the
polymers HPMC and ERL 100 in (4:1) ratio i.e. formulation L1 showed the least %
moisture loss 2.28 ± 0.031. The small moisture content in the formulations
helps them to remain stable and from being a completely dried and brittle
patch.
Water vapor transmission rate:
Water
vapor transmission rate appeared (Table 2) maximum with the patch formulated
with Eudragit RS100 in 4:1 with HPMC. As anticipated,
with decreased in HPMC concentration the values of percentage water vapor
transmission rate increased in accordance with their increasing hydrophobic
nature. The transdermal patch L1 having HPMC: ERL 100 in (4:1) ratio was having
least % WVTR.
Mass variation:
Mass
variation study was carried for total patch and individual patch (Table 2). It
was found to vary between 794.8 ± 0.547 to 759.4 ± 0.547 mg and 158 ± 0.630 to
151 ± 0.748 mg respectively. Results indicated that formulation
batches L1 and S1 was having highest mass, while formulation batch S4
was having the least mass among the formulation batches.
Thickness:
The
thickness (Table 2) of the transdermal patches varied from 0.13 ± 0.006 to 0.22
± 0.008 mm. Formulation L1 was having the maximum thickness i.
e. 0.22 ± 0.008 mm while S4 was having the least 0.13 ± 0.006 mm.
Folding endurance:
Folding
endurance study (Table 2) was carried and results ranged from 28.4 ± 1.350 to
50.4
± 1.019 and 28.2 ± 0.740 to 52.4 ± 1.019 for
formulation L series and formulation S series respectively. The results showed that with decreased in HPMC ratio
in different formulations folding endurance was increased. Folding endurance
test results indicated that the transdermal patches would maintain the
integrity with general skin folding when applied.
Flatness study:
Flatness
study (Table 2) indicated, the formulations L1 and S1 were having hazy appearance,
while the other were transparent. It also indicated that all the formulations
were 100% flat in nature and the transdermal patches would adhere to the skin
surface properly.
Drug content:
The
drug content analysis and the weight uniformity (Table 2) of the prepared
formulations had shown that the process adopted for casting the transdermal
patches was capable of giving patches with uniform drug content and with
minimum intra batch variability.
In
vitro dissolution study:
In vitro dissolution study is shows that the slope of the curve
obtained after plotting the mean cumulative amount released per batch vs. time
for each batch was taken. It showed that formulation L1 (96.40%) was having
more release as compared to formulation L2 (95.52%) and S1 (89.55%). In the
present study it was observed that, as the concentration of hydrophilic polymer
(HPMC) decreased in the formulations, the drug release rate was decreased
substantially, however it was very nominal in formulation L1. It also suggested
that, the addition of hydrophilic component to an insoluble film former tends
to enhance the release rate. Hence comparing all the data and release profiles,
formulation L1 and L2 among L series and formulation S1 among S series were
chosen as good release showing formulations out of which S1 and L1 were hazier
as compared with S2 and L2.
TABLE 3: TREATMENT OF
DRUG RELEASE DATA WITH DIFFERENT KINETIC EQUATIONS
|
Formulation
|
Zero order
|
First order
|
Higuchi’s
model
|
Peppa’s
model
|
Diffusion coefficient
(n)
|
|
R2
|
|
L1
|
0.979
|
0.910
|
0.915
|
0.991
|
0.711
|
|
L2
|
0.981
|
0.929
|
0.903
|
0.992
|
0.833
|
|
L3
|
0.965
|
0.878
|
0.921
|
0.989
|
0.743
|
|
L4
|
0.972
|
0.981
|
0.940
|
0.986
|
0.732
|
|
S1
|
0.962
|
0.948
|
0.906
|
0.990
|
0.802
|
|
S2
|
0.968
|
0.887
|
0.876
|
0.981
|
0.827
|
|
S3
|
0.986
|
0.959
|
0.883
|
0.988
|
0.775
|
|
S4
|
0.953
|
0.849
|
0.824
|
0.982
|
0.789
|
The
in vitro release profiles were
applied on various kinetic models in order to find out the mechanism of drug
release. The best fit with the highest correlation coefficient was shown in
zero-order, first order and followed by Higuchi’s equations as given in table
3. The rate constants were calculated from the slope of the respective plots.
The data obtained were also put in Korsmeyer-Peppa’s
model in order to find out n value, which describes the drug release mechanism.
The n value of transdermal patches of different formulation
batches were ranged between 0.711 and 0.833, indicating that the
mechanism of drug release was Non-Fickian or
anomalous transport.
Formulation
batch L2 composing polymer HPMC E 15: ERL 100 (3:2) was found to release the
drug (95.52%) upto 24 h and possess good physicohemical properties and hence was considered optimum
for further in vitro diffusion study,
scanning electron microscopy study.
In
vitro diffusion study
In vitro diffusion study from L2 formulation batch was studied.
Formulation L2 had shown cumulative percentage diffusion 96.60 ± 0.120 in 24 h
and it exhibited the 8991.525 μg/cm2
cumulative amount of drug permeation.
Figure 3: In vitro drug release of Atenolol from formulation batches L1 to S4
Figure 4: In vitro diffusion of Atenolol from
formulation batch L2
Figure 5: In vitro diffusion
flux of Atenolol from formulation batch L2
Scanning electron microscopy:
Scanning
electron microscopy (SEM) was performed for L2 formulation batch to reveal
surface morphology of the transdermal patch (Figure 6). It had shown the
uniform distribution of drug in the polymer matrix.
Figure 6: SEM
photograph of the transdermal patch of optimized formulation batch L2
CONCLUSION:
In
present work, a TDDS for Atenolol was formulated by
solvent evaporation method using HPMC (E 15), ERL 100 and ERS 100 polymers. The
transdermal patches were transparent and the drug remained dispersed
homogeneously in the polymer matrix Atenolol
possesses all requisite qualities required for controlled drug delivery system
in the form of transdermal patches.ERL 100 transdermal patches were more
permeable than ERS 100 patches. The ERL polymer swells more than ERS due to its
higher concentration of hydrophilic quarternary
groups. HPMC (E 15 LV) is a good film former.Among
the various polymeric combinations the formulation L2 comprising of polymers
HPMC and ERL 100 in 3:2 ratio had shown a maximum release 96.40% in controlled
manner upto 24 h. L2 followed Korsmeyer-Peppa’s
model in dissolution study. It fulfilled the requirement of good TDDS.
ACKOWLEDGMENT:
A special thanks to Zim Laboratories Pvt.
Ltd., Nagpur, for providing the gift Sample of Atenolol
and Rohm Pharma, Germany for providing the gift
Sample of Eudragit RL 100 and Eudragit
RS 100 required for this work.
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