FORMULATION AND CHARACTERIZATION OF …

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Umashri et al. World Journal of Pharmacy and Pharmaceutical Sciences

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.

REFERENCE

1. Vyas SP, Khar RK. Transdermal Drug Delivery. Controlled Drug Delivery Concepts and

Advance, 2001; 411-28.


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2. Gandhi A, Jana S, Paul A, Sheet S. Metaprolol tartrate containing glutaraldehyde cross-

linked chitosan-polyvinyl pyrrolidone matrix transdermal patch: preparation and

characterization. Journal of pharma SciTech, 2014; 3(2): 72-4.

3. Tripati KD, Antihypertensive drugs. Essentials of medical pharmacology. 7th edition;

Jaypee publishers. 2013; 558: 148-9.

4. Mohd Amjad, Mohd Ehtheshamuddin, Chand S. Formulation and Evaluation of

Transdermal patches of Atenolol. Advance Research in pharmaceuticals and Biologicals.

2011; 1(2): 109-19.

5. Pate N kunal, patel K Heta, patel N Vishnu. Formulation and Characterization of Drug in

Adhesive Transdermal Patches of Diclofenac Acid. International Journal of Pharmacy

and Pharmaceutical Sciences, 2012; 4(1): 297-9.

6. Allena Ravi Teja, Yadav KS Hemant, Sandina Swetha. Preparation and Evaluation of

Transdermal Patches of Metformin Hydrochloride using natural polymer for sustained

release. International Journal of Pharmacy and Pharmaceutical Sciences, 2012; 4(3):

298-302.

7. Divya N, Hemalatha R, Nirosh M. Fabrication and Evaluation of Transdermal Matrix

Patches of Metoprolol Tartrate. International journal of Research Science, 2012; 2(4):

138-42.

8. Bharkatiya Meenakshi, Nema Rajesh Kumar, BhatnagarMahip. Development and

Characterization of Transdermal patches of Metoprolol Tartrate. Research Article, 2010;

3(2): 130-4.

9. Tomoko Akimoto, Yu Nagase. Novel transdermal drug penetration enhancer: synthesis

and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group.

Journal of Controlled Release, 2003; 88: 243-52.

10. Sheth S Nirav, Mistry B Rajan. Formulation and Evaluation of transdermal patches and to

study permeation enhancement effect of eugenol. Journal of Applied Pharmaceutical

Science. 2011; 1(3): 96-101.

11. Abdul Shukkoor Mohamed saleem. Matrix type transdermal patches of captopril: Ex vivo

permeation studies through excised rat skin. Journal of pharmacy Research, 2013; 6:

774-9.

12. Harsoliya M S, Patel V M, Modasiya M. Development and Evaluation of Transdermal

Drug Delivery System of naproxen Drug with Chitosan for Treatment of Arthritis.

International Journal of Pharmaceutical & Biological Archives, 2012; 3(2): 363-7.

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