formulation and characterization of …
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FORMULATION AND CHARACTERIZATION OF TRANSDERMAL
PATCH OF METOPROLOL
Mayuri Mote, Umashri Kokatnur*, Panchaxari Dandagi and Archana Patil
Department of Pharmaceutics, KLE College of Pharmacy, Constituent Unit of KLE
Academy of Higher Education and Research, Belagavi Karnataka-590010, India.
ABSTRACT
The polymers selected for sustaining the release of drug were HPMC
K15 M and Eudragit RL 100. The patches were formulated using
combination of polymers and PEG 400 as plasticizer. The transdermal
patches were evaluated for their physicochemical properties. All the
prepared formulations showed good physical stability. The ex vivo skin
permeation studies were performed using Franz diffusion cell. The
results followed the release profile of metoprolol followed mixed
higuchi and peppas kinetic in different formulations. However, the
release profile of the optimized formulation F2 (R2 = 0.9808 peppas)
indicated that the permeation of the drug from the patches was
governed by a diffusion mechanism. Based on the observations, it can
be reasonably concluded that HPMC K15 M and Eudragit RL 100
polymers are better suited for the development of transdermal patches
of Metoprolol. Out of all the formulated patches F2 showed good
permeation in 8hrs. So F2 formulation was selected as best formulation.
KEYWORDS: Transdermal patches, Metoprolol, HPMC K15 M, Eudragit RL 100,
permeation enhancer, ex vivo skin permeation study.
INTRODUCTION
Transdermal drug delivery system is defined as the topically administered medications in the
form of patches which when applied to the skin deliver the drug, through the skin at a
predetermined and controlled rate. Transdermal therapeutic systems are also defined as a self-
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 2, 953-965 Research Article ISSN 2278 – 4357
*Corresponding Author
Umashri Kokatnur
Department of
Pharmaceutics, KLE
College of Pharmacy,
Constituent Unit of KLE
Academy of Higher
Education and Research,
Belagavi Karnataka-590010,
India.
Article Received on
03 Dec. 2020,
Revised on 23 Dec. 2020,
Accepted on 13 Jan. 2021
DOI: https://doi.org/10.17605/OSF.IO/ZFV4M
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contained, discrete dosage forms which, when applied to the intact skin, deliver the drug
through the skin at control rate to the systemic circulation.[1]
The transdermal route of administration is recognized as one of the potential routes for the
local and systemic delivery of drugs. It offers many advantages over conventional
administration such as enhanced efficacy, increased safety, greater convenience, improved
patient compliance and absence of hepatic first pass metabolism. It excludes the variables that
affect drug absorption from the gastrointestinal tract such as pH, enzymatic activity and drug
food interactions. This approach of drug delivery is more pertinent in case of chronic
disorders, such as hypertension, which require long term dosing to maintain therapeutic drug
concentration. The transdermal route of administration is capable of avoiding the hepatic first
pass effect, thus achieving higher systemic bioavailability of drugs.[2]
Metoprolol (MP) a beta1-selective adrenergic blocking agent, has become well established as
a first choice drug in the treatment of mild to moderate hypertension and stable angina and is
beneficial in post-infraction patients. It is effective when used alone or in combination with
other high blood pressure medications. Beta blocker decreases the force and rate of heart
contractions, thereby reducing the demand for oxygen and lowering blood pressure.[3]
MATERIALS AND METHODS
Materials
Metoprolol Tartrate was a gift sample from Vergo Pharma Research Pvt, Ltd goa. HPMC
K15 M was a gift sample from Colorcon Research Laboratories Pvt, Ltd and Eudragit RL 100
were gift sample from Evonika deggusa Mumbai. Polyethylene glycol 400 was a gift sample
from Hi-Media Pvt, Ltd Mumbai. All chemicals and reagents were of analytical and
pharmacopeial grade.
Method
Matrix type transdermal patches containing metaprolol were prepared by solvent casting
technique. First three formulation were prepared with HPMC K15 M and Eudragit RL 100 in
the percentage of 1.5%, 1.5%, 1.5% and 1%, 2%, 3% respectively and second three
formulation were prepared with HPMC K15 M and Eudragit RL 100 in the percentage of 2%,
2%, 2% and 0.5%, 1%, 1.5% respectively, using distilled water, ethanol and PEG 400. The
weighed quantity of polymers was soaked overnight in a beaker containing 10ml of distilled
water. The polymeric solution was then stirred for 1hour on a magnetic stirrer and metoprolol
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was added in the polymeric solution and again kept for stirring 2hours to get homogenous
solution. In another beaker weighed quantity of Eudragit RL 100 and ethanol were added.
This mixture was then added to the previous solution. The above two polymeric solution
were stirred together for 3hours on magnetic stirrer to form a homogeneous mixture. The
appropriate amount of plasticizer polyethylene glycol 400 was added to the homogeneous
mixture. Then the solution was continuously stirred for 2 hrs. Finally, the solution was set
aside for removal of air bubbles and the solution was then casted into Petri plates pre-
lubricated with glycerin. The patches were kept overnight for drying. The patch were
carefully removed after drying and cut into 4×4 centimeter square size. Patches with any
imperfections were not considered for further evaluation. The final samples of patches were
wrapped in a butter paper followed by aluminium foil and stored in the desiccator for further
use.[4]
The formulated transdermal patches of metoprolol were evaluated for the following
properties
Physical Appearance and Surface texture
This parameter was checked simply with visual inspection of patches and by feel or touch.
Thickness of patches
Thickness of the patch was measured using Vernier Calliper. The thickness was measured at
three different spots of the patches and average was taken. This is essential to ascertain
uniformity in the thickness of the patch as this is directly related to the accuracy of dose in
the patch.
Weight of the films
4×4cm2
of the patch was cut at 3 different places from the casted patch. The weight of each
patch was measured on analytical balance and average weight was calculated. It is desirable
that patches should have nearly constant weight. It is useful to ensure that a patch contains
the proper amount of excipients and API.
Folding endurance of patches
The folding endurance was measured manually for the prepared patches (4×4cm2). It is
expressed as number of times the patch is folded at the same place either to break the patch or
to develop visible cracks. This is important to check the ability of sample to withstand
folding. This also gives an indication of brittleness. This was determined by repeatedly
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folding one patch at the same place till it break. The number of times the patch could be
folded at the same place without breaking/cracking gave the value of folding endurance.[5]
Drug content uniformity
In order to ascertain the uniform distribution of the drug in the patches, the content
uniformity test was carried out utilizing the pharmaceutical standard by means of a
UV/visible spectrophotometer. The transdermal patch of specified area (4×4 cm2) was
dissolved in 100ml pH 6.8 phosphate buffer. This was then shaken in a mechanical shaker for
2hours to get a homogeneous solution and filtered. The drug content in each formulation was
determined by measuring the absorbance at 274nm after suitable dilution using a UV/visible
spectrophotometer.[6]
Moisture content
The patches were weighed individually and kept in a desiccator containing activated silica at
room temperature for 24hrs. Individual 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 final weight.[7]
Water vapour transmission
The water vapour transmission is defined as the quantity of moisture transmitted through unit
area of a patch in unit time. The water vapour transmission data through transdermal patches
are important in knowing the permeation characteristics. Glass vials of equal diameter were
used as transmission cells. These transmission cells were washed thoroughly and dried to
constant weight in an oven. About 1gm of fused calcium chloride as a desiccant was taken in
the vials and the polymeric patches were fixed over the brim with the help of an adhesive
tape. These weighed vials were stored in a humidity chamber at an RH of 80% with the
temperature set to 30ºC for a period of 24hours. The weight gain was determined every hour
up to a period of 24hours.[8]
The water vapour transmission was calculated using the equation
Rate = WL/S
Where W is gm of water permeated / 24hr.
L is thickness of the patch
S is exposed surface area of the patch
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Skin irritation study
Skin irritation is defined as a non-immunological local inflammatory reaction which is
usually reversible and characterized by erythema and edema, following single or repeated
application of a chemical to the same cutaneous site. The primary irritation to the skin due to
patch was evaluated by the Draize test using a live rabbit. The dorsal part of rabbit was
carefully shaved, and kept for 24hours under observation. The patch (4×4 cm2) was applied
on the shaved skin for 24hours. After the patch was removed, condition of the dorsal skin
were observed and classified in to five grades (points 0-4) on the basis of the following; point
0, without erythema or edema; point 1, very slight erythema or edema; point 2, obvious
erythema or edema; point 3, medium erythema or edema; point 4, strong erythema or edema
and slight incrustation.[9]
In vitro drug release study
The in vitro diffusion study is carried out by using Franz Diffusion Cell. The dialysis
membrane is taken as semi permeable membrane for diffusion. The Franz Diffusion Cell has
receptor compartment with an effective volume approximately 60ml and effective surface
area of permeation 4sq.cms. The dialysis membrane is mounted between the donor and the
receptor compartment. A weighed amount of transdermal patch is placed on one side of
membrane. The receptor medium is phosphate buffer pH 6.8. The receptor compartment is
surrounded by water jacket to maintain the temperature at 37±0.5ºC. Heat is provided using a
thermostatic hot plate with a magnetic stirrer. The receptor fluid is stirred by Teflon coated
magnetic bead which is placed in the diffusion cell. The samples were withdrawn at different
time intervals and analyzed for drug content spectrophotometrically. The receptor phase was
replenished with an equal volume of phosphate buffer at each sample withdrawn. The
samples were analyzed spectophotometrically at 274nm taking phosphate buffer pH 6.8 as
blank. The cumulative percentage drug release at various time intervals were calculated and
plotted against time.[10]
Ex vivo skin permeation studies
Ex vivo skin permeation studies were performed by using a Franz diffusion cell with a
receptor compartment capacity of 60mL. The excised rat dorsal skin (Wistar albino) was
mounted between the donor and receptor compartment of the diffusion cell. The formulated
patches (4×4cm2) were placed over the skin and tied with rubber. The receptor compartment
of the diffusion cell was filled with phosphate buffer pH 6.8. The whole assembly was fixed
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on a magnetic stirrer, and the solution in the receptor compartment was constantly and
continuously stirred using magnetic beads at 50 rpm. The temperature was maintained at 37 ±
0.5ºC. Samples of 1 ml were withdrawn at suitable time intervals of 15, 30, 90, 120, 180,
240,300,360, 420 and 480 minutes and were analysed at 274nm spectrophotometrically by
using UV-visible spectrophotometer to determine the amount of drug permeated. The
receptor phase was replenished with an equal volume of phosphate buffer each time the
sample was withdrawn.[11]
Stability studies
Stability studies are the series of tests designed to obtain information on the stability of the
pharmaceutical product in order to define its shelf life and utilization period underspecified
packaging and storage conditions.
Procedure
From the batches of transdermal patch of metoprolol, optimized formulation was tested for
stabilitystudies. Patches of optimized formulation were stored at two different storage
conditions: i) Normal Condition35°C ± 2°C/60% RH ± 5% RH and ii) Accelerated
Condition45°C ± 2°C/75% RH ± 5% RH by using stability chamber (Ajinkya IM 3500
series) for a period of 60 days. Each patch was wrapped in a butter paper followed by
aluminium foil and placed in an aluminium pouch. The patches were evaluated for water
vapour transmission, drug content and in vitro drug release after storage for 30 and 60 days.
The values for in vitro release from the patches were calculated and were compared for
change in diffusion cell.[12]
RESULTS AND DISCUSION
Physical Appearance and Surface texture
All the patches were cream white in appearance. The colour imparted may be due to the
colour of the drug used. All the patches were having smooth surface and they were elegant in
appearance.
Thickness of films
The thickness of the film was measured using a Vernier calliper and the values are given in
the Table 2. The average thickness of the films ranged from 0.198 to 0.226 mm. It was
observed that the thickness of the patches was gradually increasing with the increase in the
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amount of polymers. All the formulations showed uniform thickness. The comparative values
of thickness of all the formulations are shown in table 2.
Weight of the films
The weight of each patch was determined on analytical balance and average weight was
calculated. The mean weight of all patches ranged from 0.162 to 0.342g as shown in Table 2.
The weight of the patches was increasing with the increase in the amount of polymers. The
comparative weights of all the formulations are shown in table 2.
Folding endurance of patches
Folding endurance was determined by repeated folding of the patch at the same place till it
breaks. The number of times the patch is folded without breaking is taken as the folding
endurance value. The folding endurance values of all the formulations were found to be in the
range of 313±4.163 to 360±9.07. A result showed that as the concentration of the polymer
and plasticizer increases, folding endurance of the patch increases. The values of folding
endurance for all formulations are given in Table 2.
Water vapour transmission
Eudragit RL 100 and HPMC K15 M patch showed good water vapour permeation. The
enhancement of water vapour permeation with increase of eudragit RL 100 and HPMC K15
M is due to the irregular arrangement of molecules in the amorphous state, which usually
causes the molecules to be spaced further apart than in a crystal. Hence, the specific volume
is increased and the density is decreased compared to that of crystal, which leads to the
absorption of vapour into their interstices. All the formulations were permeable to water
vapour shown in the table 3.
Moisture content
The patches was weighed and kept in a desiccator containing calcium chloride at 40ºC in a
drier for at least 24h or more until it showed a constant weight. The moisture content was the
difference between the constant weight taken and the initial weight and was reported in terms
of percentage (by weight) moisture content (table 3).
Drug content uniformity
The drug content uniformity test was performed to ensure uniform distribution of drug. In
each case three patches were used for the study and the average drug content was calculated.
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The percentage drug content of all the formulations was found to be in the range of 90.4±1.4
to 96.35±1.08 as shown in Table 3. The results indicated that the drug was uniformly
distributed in all the formulations. As per the USP requirements, the patches found to meet
the criteria for content uniformity. The Standard Deviation (SD) value calculated for drug
content of all the formulation is very less suggesting that the drug was uniformly dispersed
throughout all the patches thus indicating reproducibility of the technique used to prepare the
patches.
In vitro drug release profile of formulation F1-F6
The in vitro drug release of Metoprolol from various transdermal patches was studied using
Franz type of diffusion cell. The permeability studies were carried out across dialysis
membrane. Sample of 1ml was withdrawn and replaced with the same volume of fresh
receptor solution, to the sampling port of the diffusion cell at predetermined time intervals till
8hrs. The absorbance of withdrawn samples was measured at 274nm to find out the
%cumulative drug release of each formulation. The experiments were done in triplicates,
simultaneously blanks were also run and the average value reported. From figure1 and 2 we
can conclude that %cumulative release of drug depends on the concentration of HPMC K15
M and Eudragit RL 100. If concentration of HPMC K15 M increases and Eudragit RL 100
decreases there would be increase in the release of drug. Decrease in the concentration of
HPMC K15 M and increase in the concentration of Eudragit RL 100 gives better sustained
release of drug. The in vitro diffusion study showed that drug permeation through the dialysis
membrane from F1, F2, F3, F4, F5 and F6 was 72.70%, 78.57%, 80.37%, 98.59%, 94.82%
and 85.04% respectively in 8hrs. The %cumulative drug release was in the order
F1<F2<F3<F6<F5<F6 respectively.
Kinetic modeling of drug release
The cumulative amount of drug permeated per square centimeter of patch through dialysis
membrane was plotted against time was fitted in zero, first and higuchi kinetic model. As
indicated in table 4, the release profile of formulations F1, F3, F4, F5, F6 followed higuchi
order kinetics. However, the release profile of optimized formulation F2 (r20.9808 for
peppas) indicated that the permeation of the drug from the patches was governed by a
diffusion mechanism.
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Ex vivo skin permeation studies
Ex vivo permeation study was performed on formulation F2 because it shows sustain drug
release; less water vapour transmission as well as optimum drug content. The ex vivo study
was carried out through rat dorsal skin using modified Franz diffusion cell apparatus. The
study was carried out for 8hrs. The percentage of drug permeated was calculated and plotted
against time and the results are shown in figure 3. The optimized transdermal patch F2
showed that 94.79% of drug was permeated through the rat dorsal skin at the end of 8hrs.
Stability studies
Stability studies were carried out on the optimized formulation F2 as per ICH guidelines for
60 days. Formulation F2 showed no major change in appearance. The results of drug content,
water vapour transmission and in vitro drug release after 30 and 60 days at different storage
conditions are shown in Table 5. Minor decrease was observed in the % drug content as well
as in the drug release values over a period of 60 days when stored at room temperature and
accelerated condition.
Hence, it can be concluded that the formulation F2 exhibited acceptable stability profile at
normal room condition (35°C ± 2°C/60% RH ± 5% RH) and at accelerated condition (45°C ±
2°C/75% RH ± 5% RH) for a period of two months.
Skin irritation test
The rabbits were used for the skin irritation test. The control group was not applied with any
formulation, the standard group was applied with the saline water (0.9%) a standard irritant
and the test group was applied with the optimized formulation F2 and it was observed for
irritation at the end of 24hrs. In case of standard group there was moderate erythema with
slightedema and score given to it was 3.2 and the test group showed no irritation. Since no
irritation persists the optimized formulation passes the skin irritation test.
Table 1: Formulation chart of metoprolol transdermal patch.
Formulation
Code
Metoprolol
(mg)
HPMC K15 M
(%w/v)
Eudragit RL
100 (%w/v)
PEG 400
(%v/w)
Ethanol
(mL)
F1 50 1.5 1.0 0.5 5
F2 50 1.5 2.0 0.5 5
F3 50 1.5 3.0 0.5 5
F4 50 2.0 0.5 0.5 5
F5 50 2.0 1.0 0.5 5
F6 50 2.0 1.5 0.5 5
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Table 2: Evaluation of surface texture, thickness, weight and folding endurance of
transdermal patches of metoprolol.
Formulation
code
Surface texture Thickness
(mm)*
Weight (g)* Folding
Endurance*
F1 Smooth 0.198±0.020 0.254±0.008 313±4.163
F2 Smooth 0.219±0.006 0.162±0.028 317±7.50
F3 Smooth 0.203±0.022 0.282±0.006 325±13.61
F4 Smooth 0.226±0.005 0.342±0.008 330±15.14
F5 Smooth 0.206±0.049 0.307±0.0193 345±10.58
F6 Smooth 0.221±0.018 0.337±0.007 360±9.07
*Data are expressed as Mean ± SD (n=3)
Table 3: Evaluation of water vapour transmission, moisture content and drug content of
transdermal patch of metoprolol.
Formulation
code
Water vapour
transmission
(gm./cm2)*
Moisture content
(%)*
Drug
content (%)*
Drug release
(%)
F1 0.034±0.008 17.25±12.42 90.4±1.4 72.70±0.002
F2 0.025±0.003 23.96±3.60 95.28±0.75 78.03±0.005
F3 0.038±0.006 11.71±2.986 92.93±2.21 80.37±0.016
F4 0.05±0.004 7.74±2.980 94.70±0.71 98.59±0.002
F5 0.036±0.009 10.14±0.951 96.35±1.08 94.82±0.014
F6 0.045±0.005 10.17±0.977 96.35±0.94 85.04±0.01
*Data are expressed as Mean ± SD (n=3)
Table 4: Kinetic modeling of drug release.
Formulation Zero
order
(R2)
First
order
(R2)
Higuchi
matrix
(R2)
Peppas Hix.
crow
Best fit
model (R2) (n)
F1 0.778 0.9338 0.9837 0.9801 0.4959 0.8952 Matrix
F2 0.6959 0.9262 0.9708 0.9808 0.4453 0.8701 Peppas
F3 0.825 0.9735 0.9873 0.9723 0.5694 0.9416 Matrix
F4 0.7395 0.741 0.969 0.9470 0.5411 0.9527 Matrix
F5 0.877 0.0.9607 0.993 0.983 0.6014 0.9878 Matrix
F6 0.612 0.626 0.699 0.6968 1.930 0.4178 Matrix
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Table 5: Stability studies of optimized formulation F2 after 30 and 60 days storage at
different conditions.
Evaluation
parameters
Optimized formulation F2
Initial
(zero
days)
Normal condition
35ºC±2ºC/60%RH ± 5%RH
Accelerated condition
45ºC±2ºC/75%RH ± 5%RH
30days 60days 30days 60days
Water vapour
transmission
gm./cm2
0.036 0.031 0.029 0.025 0.021
% drug content 96.14 96.01 95.90 95.87 95.75
In vitro drug
release (%) 78.03 77.96 77.88 77.78 77.57
Figure 1: In vitro drug release formulation of F1-F3.
Figure 2: In vitro drug release formulation of F4-F6.
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Figure 3: Comparative in vitro diffusion profile of formulation F2, pure drug and Ex
vivo skin permeation of formulation F2.
CONCLUSION
Metoprolol transdermal patch was prepared successfully, all formulated patches showed good
appearance without any imperfections. It was seen that with the increases in polymer
concentration there was increase in weight and thickness of patches. The polymer
concentration goes on increases the water vapour transmission decreases and was in the range
of 0.025mg./cm2 to 0.05gm./cm2. The moisture content was in the range of 7.74% to
23.96%, the prepared formulation were low, which help the formulations could remain stable
and reduce brittleness during long term storage. Based on the present study it can be
concluded that the transdermal administration of Metoprolol increases the bioavailability and
reduces first pass metabolism.
ACKNOWLEDGEMENT
I deeply thank Mr. Henry Walter for providing me the drug as a gift sample for my project
work.
I also thank Evonika deggusa Mumbai for providing polymers as gift sample.
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