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Original Article

Matrix type transdermal patches of captopril: Ex vivopermeation studies through excised rat skin

Rajesh Sreedharan Nair*, Tai Nyet Ling, Mohamed Saleem Abdul Shukkoor,Balamurugan Manickam

Faculty of Pharmaceutical Sciences, UCSI University, No.1, Jalan Menara Gading, Kuala Lumpur 56000, Malaysia

a r t i c l e i n f o

Article history:

Received 6 June 2013

Accepted 5 July 2013

Available online 22 July 2013

Keywords:

Aloe vera

Captopril

HPMC

Menthol

PEG 400

* Corresponding author. Fax: þ60 391022614.E-mail addresses: raajsnair@yahoo.co.in,

0974-6943/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.jopr.2013.07.003

a b s t r a c t

Background/objectives: Captopril, "an ACE inhibitor" has comparatively short elimination half

life and its oxidation rate in dermal homogenate is significantly lower than that in intestinal

homogenate. So as to enhance the bioavailability and to reduce the difficulties associatedwith

captopril, it is decided to design a transdermal drug delivery system for this drug. So the

objective of this present work is to formulate and evaluate the matrix type transdermal drug

deliverysystemsofcaptopril,withdifferentpolymercombinationsandpenetrationenhancers.

Methods: Eight formulations (F1eF8) were prepared by the solvent casting technique using

varying proportions of polymers such as hydroxypropyl methylcellulose (HPMC), poly-

ethylene glycol (PEG) 400, along with the permeation enhancers such as menthol and aloe

vera at different concentrations.

Results: The FTIR results showed no abnormal peaks and thus concluded that no in-

compatibility between the drug and polymers. The skin irritation studieswere performed on

rabbits, the results showednonoticeable skin reactions, pointedout the compatibility ofdrug

aswell aspolymermatrixwith the skin.Theuniformity ofdrug contentwasevidencedby low

standard deviation (S.D) values. High folding endurance (>280) revealed that the prepared

films have good flexibility. The weight of patches were uniform and thickness varied from

0.05 to 0.13 mm. Ex vivo permeation studies through excised rat skin were carried out using

modified Franz diffusion cell, and the results showed that film (F6) containingHPMC and PEG

400 (1:1) withmenthol as a permeation enhancer demonstrated the highest drug permeation

(90.04%) at 24 h ( p < 0.05) with the transdermal flux of 54.5 mg/cm2/h.

Conclusions: The formulation coded as F6 was found to be the ideal patch, shown the

maximum drug permeation of 90.04% at the end of 24 h followed Higuchi diffusion kinetics.

Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights

reserved.

1. Introduction such as ointments, gels, creams, pastes, lotions and the most

Transdermal drug delivery system (TDDS) is designed to deliver

a therapeutic agent across the intact skin for both local and

systemic effects.1 Transdermal systems include formulations

raajsnair@gmail.com (R.S2013, JPR Solutions; Publi

commonlyavailable transdermalpatches.Transdermalpatch is

a medicated device that delivers drugs through the skin for

systemic effects at a programmed and controlled rate.2 The ad-

vantages of transdermal drug delivery is, provides controlled

. Nair).shed by Reed Elsevier India Pvt. Ltd. All rights reserved.

j o u r n a l o f p h a rm a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 7 4e7 7 9 775

releaseof thedrug to thepatientandenablesasteadyblood level

profile, avoidance of first-pass hepaticmetabolism and helps in

the rapid terminationof therapy.3 Furthermore, thedosage form

of transdermal patch is user friendly, convenient and offers

multi-day dosing. Matrix type transdermal formulations have

been developed for a number of drugs such as nitroglycerine,

ephedrine etc.4

Captopril is an angiotensin converting enzyme inhibitor

(ACE) used in the treatment of hypertension, congestive heart

failure and myocardial infarction. It has comparatively short

elimination half life ranging from 1.6 to 1.9 h, hence requires

high oral dosing.5 The impermeability of human skin is a

fundamental problem to overcome for the therapeutic use of

TDDS. Although many approaches have been proposed to

overcomethedifficulties ofmaking thedrugpenetrate through

the tough layers of the stratumcorneum, chemical permeation

enhancers shown to be the promising agents in facilitating the

transportation of drugs across the skin. In the present research

work, anefforthasbeenmade todevelopa suitablematrix type

transdermal patches containing captopril by employing

hydroxypropyl methylcellulose (HPMC) and polyethylene gly-

col (PEG) 400 as a film former at different concentrations.

Furthermore, in order to improve the skin permeation of

captopril, menthol and aloe vera were used as penetration en-

hancers. Propylene glycol (PG) employed as a plasticizer and

also possess permeation enhancers. Release and permeation

profiles of captopril from film preparations were examined in

the ex vivo studies using a Franz-type diffusion cell.

2. Materials and methods

2.1. Materials

Captopril, HPMC and PEG 400 were purchased from

Fisher scientific, Selangor, Malaysia. PG, menthol and aloe

vera were purchased from Sigma lab, Selangor, Malaysia. All

other materials used were of analytical grade. Drug

samples were characterized by UV spectrophotometer

(PerkineElmer).

2.2. Methods

2.2.1. Formulation of transdermal patchesMatrix type transdermal patches of captopril were prepared

by solvent castingmethod.6 Polymeric solution were prepared

Table 1 e Composition of captopril transdermal patches.

Formulation code Drug (%) Plasticizer (%) PG

F1 20 10

F2 20 10

F3 20 10

F4 20 10

F5 20 10

F6 20 10

F7 20 10

F8 20 10

by dissolving the polymers (HPMC, PEG 400) in purified water.

Weighed amount of captopril was dissolved in the polymeric

solution; propylene glycol (10% w/w) was incorporated as

plasticizer followed by penetration enhancer. The composi-

tion of the patches were shown in Table 1. The contents were

stirred thoroughly with a mechanical stirrer to obtain a ho-

mogeneous mixture. The contents then poured into a petri

dish and dried in hot air oven at 50 �C. After ensuring the

complete evaporation of solvent, patches of desired di-

mensions were cut. Dried patches were packed in aluminium

foil and stored in desiccators containing silica gel. The

formulated patches were evaluated within one week of

preparation.

2.3. Physico-chemical characterisation of formulatedpatches

The formulated captopril patches were evaluated for its

physical appearance, average thickness, weight variation,

drug content uniformity, moisture absorption and folding

endurance. The results were given in Table 2.

2.3.1. Physical appearanceAll the patches were visually inspected for colour, flexibility,

homogeneity and smoothness.7

2.3.2. Film thicknessThe thickness of the prepared patchesweremeasured at three

different places using a digital caliper. The mean values and

standard deviation were calculated.8

2.3.3. Weight variation testPrepared patches were cut into 1 cm2 pieces and weight of

each patch was determined by using digital balance. The

average weight of each patch and standard deviation was

calculated.9

2.3.4. Drug content uniformityEach of the measured patches used in weight variation test

was transferred into a graduated glass stoppered flask con-

taining 50 mL of distilled water, was maintained at the tem-

perature 37 � 0.5 �C. The flasks were kept closed and shaken

for 4 h in a laboratory mechanical shaker. The solution was

filtered and absorbance was measured by UV spectropho-

tometer at 210 nm.10 Drug content of each patch was esti-

mated from the standard graph.

Polymer (%) Penetration enhancer (%)

HPMC PEG 400 Aloe vera Menthol

100 e 10 e

100 e e 2

75 25 10 e

75 25 e 2

50 50 10 e

50 50 e 2

25 75 10 e

25 75 e 2

Table 2 e Physico-chemical parameters of the formulated patches.

Formulationcode

Weighta �SD (g)

Thicknessa � SD(mm)

Folding endurance� SD

Percent moistureabsorptiona (%) � SD

Drug contenta � SD(mg)

F1 0.0115 � 0.0009 0.0667 � 0.0058 >280 � 0 5.2402 � 0.4292 1.6036 � 0.0128

F2 0.0120 � 0.0012 0.0867 � 0.0115 >280 � 0 1.3739 � 0.3967 1.6164 � 0.0185

F3 0.0131 � 0.0006 0.0967 � 0.0115 >280 � 0 1.5193 � 0.7304 1.5651 � 0.0369

F4 0.0125 � 0.0003 0.1133 � 0.0115 >280 � 0 1.3425 � 0.4819 1.5328 � 0.0234

F5 0.0096 � 0.0003 0.0533 � 0.0058 >280 � 0 2.4317 � 0.6588 1.5741 � 0.0570

F6 0.0095 � 0.0002 0.0533 � 0.0058 >280 � 0 1.7622 � 0.6154 1.5487 � 0.0511

F7 0.0106 � 0.0003 0.0967 � 0.0115 >280 � 0 3.4487 � 0.5429 1.5526 � 0.0125

F8 0.0110 � 0.0004 0.1267 � 0.0252 >280 � 0 2.4373 � 0.5936 1.5682 � 0.0288

a Data are expressed as mean � S.D (n ¼ 3).

Fig. 1 e Ex vivo drug permeation of captopril patches

containing aloe vera.

j o u rn a l o f p h a rma c y r e s e a r c h 6 ( 2 0 1 3 ) 7 7 4e7 7 9776

2.3.5. Folding enduranceA small strip of film 2 cm � 2 cm was subjected to this test by

folding the patch at the same place repeatedly several times

until a visible crack was observed.3

2.3.6. Moisture absorptionThe percentage of moisture absorption was measured by keep-

ing the patches at 37� 0.5 �C and 80%� 5% RH for 3 days. Initial

weight and final weight of the patches were taken. Percentage

moisture absorption was calculated using the formula11:

% Moisture absorption ¼ ðFinal weight� Initial weightÞInitial weight

� 100

2.3.7. Fourier transform infrared spectroscopy (FTIR)FTIR spectra were taken for captopril, blank film (containing

50% HPMC and 50% PEG 400), and films loaded with drug and

penetration enhancers.12

2.3.8. Ex vivo skin permeation studiesThe experiments conducted using animals were approved by

Institutional ethics committee and performed on compliance

with the Ethics. Skin permeation study was carried out by

using hairless rat skin excised from the dorsal region of

sacrificed rat. The rate of drug release and skin permeation

was measured using modified Franz diffusion cells. The

captopril transdermal patch was kept adhered to the stratum

corneum of the skin mounted on the diffusion cells. The re-

ceptor compartment of the diffusion cell was filled with

phosphate buffer (pH 7.4) thermostated at 37 � 0.5 �C, stirredwith small magnetic spin bar. Samples (5 ml) were collected

from the receptor compartment at a predetermined time in-

tervals, and were replaced immediately with an equal volume

of fresh phosphate buffer (pH 7.4). The samples withdrawn

from receptor compartment were analysed by UV spectro-

photometer at 210 nm to determine the amount of captopril.13

2.3.9. Skin irritation studyThe skin irritation study was carried out by using healthy

rabbits (n ¼ 3). The evaluation was based on scoring method

described by Draize et al, where the scores are assigned from

0 to 4 based on the severity of erythema or oedema.14

2.3.10. Statistical analysisStatistical analysis were performed using the SPSS-18.0 pack-

age. The ex vivo permeation results obtained were tested

statistically using one-way analysis of variance (ANOVA). Post-

hoc Tukey-HSD (Honestly Significant Difference) test was

performed when there was a statistically significant differ-

ence, which was considered at p < 0.05.

3. Results and discussion

In the present study, altogether eight different formulations

were prepared by varying the polymer ratio and permeation

enhancers. The weight of the patches varied from 0.0095 to

0.0131 g (�0.0002 to� 0.0009) (Table 2)while the thickness of the

patches ranges from 0.0533 to 0.1267 mm (�0.006 to � 0.012)

(Table 2). The results indicate the physical uniformity of the

prepared patches. The minimal SD values shows that the pro-

cess used for preparing the patches is capable of formulating

patches with minimum intra batch variability. The folding

endurance value was found to be >280, was observed in all

batches. This indicates that the prepared patches have good

tensile strength,flexibility, capable towithstand themechanical

pressure and able to maintain the integrity with general skin

folding when applied. The drug content were found to be uni-

form throughout the formulated patcheswith theminimumSD

values (�0.012 to � 0.057), assuring the process adopted to pre-

pare the patches is capable of giving reproducible results. The

percentagemoisture absorptionwas calculated from theweight

difference relative to the initial weight after exposing the

Fig. 2 e Ex vivo drug permeation of captopril patches

containing menthol.

j o u r n a l o f p h a rm a c y r e s e a r c h 6 ( 2 0 1 3 ) 7 7 4e7 7 9 777

formulated patches to 85% RH. It was found that the formula-

tions containing aloe vera as the penetration enhancer had

higher rates of moisture absorption than formulations contain-

ing menthol. The formulation coded as F1 had the highest

moisture absorption rates 5.24%, where as F2 and F4 had shown

Fig. 3 e FT-IR spectrum o

Fig. 4 e FT-IR spectrum of drug

the lowest moisture absorption rates of 1.37% and 1.34%

respectively. The highest percentage moisture absorption of F1

can be attributed to the higher polydispersity index and solubi-

lity parameter of HPMC. In addition to that, the percentage of

moisture absorption was found to increase with the increasing

concentrations of PEG 400. Overall, the moisture absorption of

the formulations were low, which could protect the formula-

tions from microbial contamination and reduce bulkiness. The

FTIR spectra of captopril and formulated patches were illus-

trated in Figs. 3e5. In the IR spectrum of captopril, the peak at

2979.83 cm�1 was assigned to the asymmetric CH3 stretching

vibration, peak at 2565.75 cm�1 corresponds to theSHstretching

vibration due to the presence of thiol group. The characteristic

band at 1748.04 and 1589.98 cm�1 indicate C]O stretching vi-

bration of carboxylic acid and amide respectively. The peak at

1381.52cm�1 corresponds toCeNstretchingdue to thepresence

of tertiary amine group. The IR spectra show that no significant

chemical interaction between captopril and the various poly-

mers used.

Ex vivo drug permeation study was conducted to investigate

the sustained- release performance and serve to predict in-vivo

performanceof thedrug, the resultswere shown inFigs. 1 and2.

The drug permeation profiles were analysed by one-way

ANOVA. The results show a significant difference between the

f captopril pure drug.

and aloe vera loaded film.

Fig. 5 e FT-IR spectrum of drug and menthol loaded film.

j o u rn a l o f p h a rma c y r e s e a r c h 6 ( 2 0 1 3 ) 7 7 4e7 7 9778

groups. Tukey’s HSD test showed that the drug permeation

pattern of F2, F4, F6 and F8 are significantly different from other

groups. The cumulative percentage of drug permeated in 24 h

was found to be the highest for formulation F6 (50% HPMC, 50%

PEG 400) which had shown the drug permeation of 90.04%, fol-

lowed Higuchi diffusion kinetics (r2 ¼ 0.9954) with the trans-

dermal flux of 54.5 mg/cm2/h. The study showed that menthol

has better efficacy than aloe vera, in which the proposed mech-

anism could be by disrupting the highly ordered structure of

lipids, so that increases the drug diffusivity in the skin.3 Mean-

while, the results also indicate the amount of drug released

increasedwithan increase in theproportionof PEG400. This can

be explained due to the additive penetration enhancing effects

of both propylene glycol and PEG 400.15 Skin irritation study

showed no noticeable irritation on rabbit skin, indicating the

skin compatibility of drug as well as polymermatrix.

4. Conclusion

To enhance the bioavailability and to improve the patient

compliance, matrix type transdermal patches of captopril

were formulatedwith varying concentrations of polymers and

permeation enhancers. It can be concluded that the patch (F6)

containing HPMC and PEG 400 (1:1) with menthol as perme-

ation enhancer had the highest drug permeation (90.04%) at

24 h ( p< 0.05). However, further in-vivo studies are required to

explore these findings.

Conflicts of interest

All authors have none to declare.

Acknowledgements

The authors wish to express their sincere gratitude to Faculty

of Pharmaceutical Sciences, UCSI University, Malaysia for

providing the financial support and laboratory facilities to

carry out this research.

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