International Journal of PharmTech Research

CODEN (USA): IJPRIF ISSN : 0974-4304

Vol.5, No.1, pp 177-182, Jan-Mar 2013

Permeation Of Flurbiprofen Polymeric Films Through

Human Cadaver Skin
Rajesh S1*, Sujith S2
1
Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences,
UCSI University, Kuala Lumpur, Malaysia.
2
Department of Pharmaceutics, Crescent college of Pharmaceutical Sciences, Kannur,
Kerala, India.

*Corres. author: raajsnair@yahoo.co.in

Phone No: +60173397121

Abstract: Flurbiprofen is a non-steroidal anti-inflammatory drug widely used in the treatment of rheumatism
and non arthritic pain. Flurbiprofen is highly gastric irritant and it may produce nausea and vomiting on oral
administration, hence a transdermal drug delivery system may be suitable for flurbiprofen. The objective of this
study was to formulate and evaluate the transdermal patches of flurbiprofen using synthetic polymers and
permeation enhancers. Polymers used were polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) and the
permeation enhancers were dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Matrix type
transdermal patches of flurbiprofen were prepared by moulding technique. Thin layer chromatography (TLC) of
the films prepared showed the same Rf value as that of the pure drug thus it was concluded that no
incompatibility between the various components of the patch. The results of skin irritation study showed that no
noticeable irritation on rabbit skin indicating the skin compatibility of drug as well as polymer matrix. The
uniformity of drug content was evidenced by low S.D values and the thickness of the formulations varied from
0.15 to 0.21 mm. In vitro permeation through human cadaver skin was carried out using modified Franz
diffusion cell and the results showed that film (P4) containing PVP and PVA (1:0.5) with DMSO showed the
maximum release (83.45%) at 24 hours. The developed transdermal films of flurbiprofen showed promising
physico-chemical characteristics and good in vitro drug release.
Keywords: Transdermal, flurbiprofen, anti-inflammatory, dimethylsulfoxide, polyvinyl alcohol,
polyvinylpyrrolidone.

INTRODUCTION and painless and offers multi-day dosing.3

Transdermal drug delivery systems have been
Transdermal patch is a medicated adhesive device
developed for many drugs such as metoprolol4,
that is placed on the skin to deliver drugs for
ketoprofen5, propranolol6, labetolol hydrochloride.7
systemic effects at a predetermined and controlled
Flurbiprofen is a non-steroidal anti-inflammatory
rate.1 The major advantages associated with
drug (NSAID) widely used in the symptomatic
transdermal drug delivery is, it provides controlled
treatment of arthritis.8 Suitable long term
release of drug in to the patient and enables a steady
percutaneous absorption of flurbiprofen at a
blood level profile, avoidance of first-pass gut and
controlled rate is needed because of its short half-life
hepatic metabolism, potentially decreased side
(3-4 hours) and gastrointestinal side effects.9 Hence
effects and the rapid termination of therapy in
in the present study an attempt was made to develop
problematic cases.2 In addition, the dosage form of
transdermal patches of Flurbiprofen by employing
transdermal patches is patient friendly, convenient
Rajesh S et al /Int.J.PharmTech Res.2013,5(1) 178

polyvinyl alcohol (PVA) and polyvinylpyrrolidone c) Weight variation test16

(PVP) as polymers and polyethylene glycol 400 Prepared patches were cut in 1 cm2 pieces and
(PG400) as a plasticizer. Furthermore to improve the weight of each patch was determined by using
skin permeation, dimethylformamide (DMF) and digital balance , the average weight of each patch
Dimethy sulfoxide (DMSO) were used as and standard deviation was calculated.
permeation enhancers.10 These formulations were d) Drug content uniformity17
subjected to physico-chemical evaluation and in Each of the patches used in weight variation test was
vitro permeation studies. transferred in to a graduated glass stoppered flask
containing about 50 ml of distilled water maintained
at 45 – 50 0 C . The flasks were closed and shaken
MATERIALS AND METHODS
for 4 hours in a mechanical shaker . The solution
Flurbiprofen was received as a gift sample from was filtered , residue washed with distilled water and
Knoll Pharma, Goa, India. PVP and PVA were the filtrate made to required volume and absorbance
obtained from Central drug house Ltd. Mumbai. PG, was measured by UV spectrophotometer at 247 nm.
DMSO and DMF purchased from Ranbaxy fine Drug content of each patch was calculated from
chemicals, Mumbai, India. Cadaver skin was standard graph.
procured from Father mullers hospital e) Folding endurance15
Mangalore,India. All other materials used were of A small strip of film 2cm x 2cm was subjected to
analytical grade. Drug samples were characterized this test by folding the patch at the same place
by UV spectrophotometer. repeatedly several times until a visible crack was
observed.
Formulation of Transdermal patches f) Moisture absorption17
In the present study matrix type transdermal patches The percentage of moisture absorption was
of flurbiprofen were prepared by moulding measured by keeping the patches at 37±0.5°C and
technique.11,12 A flat square shaped moulds having 80% ± 5% RH for 2-3 days. Initial weight and final
surface area 16cm2 and height 1 cm were fabricated weight of the patches were taken. Percentage
for this purpose. The casting solutions were prepared moisture absorption was calculated using the
by dissolving weighed quantities of polymers formula:
(PVP:PVA) in water by heating on a water bath at
500C. The drug(flurbiprofen) , plasticizer (Poly % Moisture absorption
ethylene glycol 400) and penetration enhancers = (Final weight- Initial weight) ˟100
[Dimethy sulfoxide (dmso), Dimethy Initial weight
formamide(dmf)] were then added to the polymer
solution and thoroughly mixed to form a In-vitro permeation studies 18,19
homogeneous mixture and cooled. Entrapped air The in-vitro permeation of the patches were studied
bubbles were removed by applying vacuum. Casting using modified Franz diffusion cell. The cell
solution was poured in to glass moulds and were consists of two compartments, the donor and the
dried at 50 - 55 0C in hot air oven . The patches were receptor compartment. The donor compartment was
removed by peeling and cut in to square films of 4 in contact with ambient conditions of atmosphere.
cm x 4cm. These patches were kept in desiccator for The receptor compartment was in contact with
two days and then wrapped in aluminium foil. phosphate buffer (pH 7.4) and was stirred by a rod
shaped magnetic bead driven by a magnetic stirrer at
Evaluation of Transdermal patches: 50 rpm. The patch with a support of backing
Formulated patches were evaluated for Physico- membrane was kept in the donor compartment and it
chemical parameters, In-vitro diffusion, was separated from the receptor compartment by
compatibility, stability and skin irritation studies. excised human cadaver skin. The cadaver skin was
allowed to keep at room temperature and immersed
Physico- chemical parameters13,14 in distilled water for 10 to 20 minutes before the
a) Physical appearance experiment. The temperature of receptor
All the patches were visually inspected for colour, compartment was maintained at 37  1oC. Aliquots
flexibility , homogeneity and smoothness. of the receptor fluid were withdrawn at 2 hours
b) Film thickness15 interval up to 24 hours and an equivalent volume of
The thickness of the prepared patches were solution was replaced in to receptor compartment
measured at five different places using a screw with fresh fluid. The samples were analyzed for drug
gauge and mean values were calculated. content at 247 nm using UV spectrophotometer.
Rajesh S et al /Int.J.PharmTech Res.2013,5(1) 179

Thin layer chromatography (TLC) permeation enhancers. The formulated patches were
Compatibility studies are carried out to assess any subjected to various physico-chemical evaluations
incompatibility between drug and polymers. The and in vitro permeation study. The physicochemical
TLC plates having silica gel coating of 0.25 mm characteristics of the formulated patches are showed
thickness were used after activating in an oven for in Table 2. The films showed uniform drug content
one hour at 120 0C. A spot of the standard solution and minimum batch variation. The thickness of the
was put 2cm from the bottom. The sample solution patches varied from 0.15 to 0.21 mm. The minimum
was spotted 2cms apart from one another and placed standard deviation values assured that the process
in TLC chamber, which was previously saturated used for preparing the delivery system was capable
with the solvent system chloroform : acetone (4:1). of giving reproducible results. A good uniformity of
The solvent was allowed to rise at least 3/4th of the weight was observed in all the films prepared.
plate and the distance travelled by solvent front was Folding endurance was high (>200) thus assuring
noted. The spots were detected by spraying the good flexibility of the films and were able to
acidified potassium permanganate (KMno4) on to the maintain the integrity with general skin folding.
plate. The Rf value was calculated for the standard Moisture uptake capacity increased with increase in
and sample solutions using the formula concentration of PVP which can be supported by
previous reports. PVP might enhance the absorption
Rf value= Distance travelled by the of water vapour by converting the crystalline drug in
solute from the origin to amorphous state on skin surface. Compounds in
Distance travelled by the the amorphous state generally posses a high energy
solvent front from the origin state with improved solubility and the enhancement
of solubility of drug close to the skin surface
Stability studies increases thermodynamic activity that facilitates the
For any rational design and evaluation of dosage permeation rate of drug through skin.12 The in vitro
forms the stability of the active component must be permeation studies through cadaver skin showed that
a major criteria in determining their acceptance or the addition of enhancers promoted the permeation
rejection. Drugs instability is indicated by a change of drug. Among the permeation enhancers used,
in the physical appearance such as colour, odour, DMSO showed better permeation efficacy than
taste or texture of the formulation where as in other DMF. It was observed that, the patch (P4) prepared
instances chemical changes may occur which are not with polymer ratio (PVP:PVA, 1:0.5) and DMSO as
self evident and may only be ascertained through the permeation enhancer had the maximum drug
chemical analysis. To assess the stability of the release of 83.45 % at the end of 24 hours. The
formulated transdermal patches, selected films were release rate of flurbiprofen from film preparations
taken. The stability studies were carried out at room tend to increase as the PVP fraction is increased. A
temperature over a period of 60 days. The patches proposed mechanism for DMSO to improve skin
were evaluated for physical characteristics and drug permeation of drugs is, it denature the protein and on
content at regular intervals of time. application to human skin has shown to change the
intercellular keratin conformation.10
Primary skin irritation studies The Rf value of flurbiprofen was 0.318 and for the
The skin irritation study was carried out by using formulated patch was found to be 0.309. TLC of the
healthy rabbit. The hair of rabbit was shaved from prepared patches had almost same Rf value as that of
the dorsal area on both sides 24 h before the test, the drug, which shows that the drug and polymers
one side of the back serves as control for the test. are compatible with each other. Skin irritation was
The medicated patch was secured on experimental studied by modified draize test and the results
side, and the non-medicated patch was secured on showed no noticeable irritation on rabbit skin,
the control side. Then the patches were removed indicating the skin compatibility of drug as well as
after 24 h and the condition of the dorsal skin was polymer matrix. Stability studies were conducted on
examined visually. The evaluation was based on the selected formulation (P4) and results shown in
scoring method described by Draize, where the Table 3. It was observed that no significant change
scores are assigned from 0 to 4 based on the severity occurred in physical appearance, thickness, weight,
of erythema or oedema.19 folding endurance, % elongation, tensile strength
and drug content. Based on these results it can be
RESULTS AND DISCUSSION concluded that the formulated patches were
physically and chemically stable.
In the present study altogether nine (9) formulations
were prepared by varying the polymer ratio and
Rajesh S et al /Int.J.PharmTech Res.2013,5(1) 180

Table 1: Composition of Flurbiprofen Transdermal Patches.

Polymer Ratio Penetration enhancer (%)
Formulation code
Drug (%) PVP PVA DMSO DMF
P1 20 1.0 0.5 - -
P2 20 0.5 1.0 - -
P3 20 0 1.5 - -
P4 20 1.0 0.5 10 -
P5 20 0.5 1.0 10 -
P6 20 0 1.5 10 -
P7 20 1.0 0.5 - 10
P8 20 0.5 1.0 - 10
P9 0 1.5 10
All formulations carried 20% w/w PEG 400 as plasticizer.

Table 2: Physico-chemical parameters of the formulated patches

Formula tion Thickness* Weight Folding % Drug
code (mm) Variation*(mg) endurance Moisture content*
absorption* (mg/cm2)
P1 0.154  0.031 18.07  0.025 >200 4.4  0.429 3.981  0.056
P2 0.198  0.025 19.83  0.028 >200 3.6  0.396 4.00  0.038
P3 0.203  0.030 19.95  0.038 >200 3.2  0.431 3.980  0.0511
P4 0.163  0.025 20.03  0.042 >200 4.1  0.629 3.987  0.032
P5 0.206  0.024 21.36  0.022 >200 3.6  0.440 4.027  0.046
P6 0.210  0.027 21.68  0.025 >200 3.4  0.552 3.948  0.035
P7 0.158  0.034 20.30  0.038 >200 4.0  0.730 3.974  0.036
P8 0.205  0.028 20.96  0.036 >200 3.5  0.593 4.020  0.028
P9 0.209  0.022 21.05  0.032 >200 3.3  0.542 4.026  0.054
*Data are expressed as mean  S.D (n=3)

Table 3: Stabilities studies on a selected patch*

Day Physical Thickness* Weight Folding % Drug
appearance (mm) variation* endurance Moisture content*
(mg) absorption (mg/cm2)
*
0 day Smooth and 0.162  0.022 20.03  0.030 >200 4.0  0.326 3.987  0.054
flexible
15th No significant 0.163  0.031 20.10  0.035 >200 4.2  0.401 3.981  0.038
changes
30th No significant 0.163  0.025 20.15  0.033 >200 4.2  0.229 3.948  0.051
changes
60th No significant 0.164  0.020 20.25  0.038 >200 4.2  0.213 3.892  0.032
changes
*Data are expressed as mean  S.D (n=3)
Rajesh S et al /Int.J.PharmTech Res.2013,5(1) 181

Fig. 1 In vitro drug permeation through human Fig. 3 Effect of DMF on in vitro drug permeation
cadaver skin Data are expressed as mean  S.D (n=3)
Data are expressed as mean  S.D (n=3)

CONCLUSION
To avoid the extensive first-pass metabolism and
achieve the desirable penetration rate of
flurbiprofen, transdermal patches were prepared by
employing PVP and PVA as film former, and PEG
as a plasticizer. It was concluded that film (P4)
containing PVP:PVA(1:0.5) with 10% w/w DMSO
as the permeation enhancer successfully improved
the skin penetration of flurbiprofen.

Fig. 2 Effect of DMSO on in vitro drug

permeation
Data are expressed as mean  S.D (n=3)

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