Journal of Biomaterials and Nanobiotechnology, 2011, 2, 576-581
doi:10.4236/jbnb.2011.225069 Published Online December 2011 (
Copyright © 2011 SciRes. JBNB
A New Liposomal-Drug-in-Adhesive Patch for
Transdermal Delivery of Sodium Diclofenac
Seyed Mojtaba Taghizadeh*, Sara Bajgholi
Novel Drug Delivery Systems Department, Polymer Science Faculty, Iran Polymer and Petrochemical Institute, Tehran, Iran.
E-mail: *
Received October 16th, 2011; revised November 19th, 2011; accepted November 30th, 2011.
Liposomes are known to have considerable potential as drug carriers such as liposomal suspension, freeze dried and
cream-based systems among many other liposomal formulations. In this study a new drug-in-adhesive patch was fabri-
cated using liposome-based nanocarrier. Transfersomes as ultra-deformable liposomes are based on phosphatidylcho-
lin 95% (phospholipon 90G) and phosphatidylcholin 50% (phosal 50PG) were prepared and further optimized in a
final acrylic patch system for effective adhesion. Th e prepared liposomes were add ed to an acrylic adhesive to obtain a
new hybrid tran sdermal patch termed as lipo-drug-in-adhesive patch system. The sodium diclofenac was selected as
a model drug and the permeation of the drug across rat skin was evaluated (P > 0.05), using the lipo-drug-in-adhesive
patch system with various percentages of transfersomes (4% - 8% w/w) and constant concentration of the drug (2%
w/w). The peel strength and tack value of samples were also examined and quantified. The maximum flux of sodium
diclofenac was observed in samples containing 8% (w/w) phosphatidylcholin 50%. The peel str ength and tack valu e in
samples containing phosphatidylcholin 50% were lower than those samples containing phosphatidylcholin 95%. It was
observed that with increased amount of liposome in drug-in-adhesive patch system, the rate of skin permeation of the
drug was also increased. It can be concluded that the developed lipo-drug-in-adhesive patch system enhances the drug
release potential of transdermal delivering systems.
Keywords: Liposome, Sodium Diclofenac, Acrylic Adhesive, Peel Strength, Tack Value
1. Introduction
Many different methods are used for drug administration,
such as oral, intravenous and intranasal ways. These
routes are not free of disadvantages, for instance patient
incompliance is the most serious limitation in intrave-
nous administration. Oral applications may have some
gastrointestinal (GI) adverse effects including peptic ul-
cer and gastrointestinal bleeding, and furthermore a sig-
nificant fraction of drug may be eliminated by first-pass
hepatic mechanism [1]. In this respect, transdermal drug
delivery route is one of the most efficient systems for
controlled drug administration, which eliminates all the
disadvantages and causes no GI adverse effects and in
general it is more patient compliant [2]. However pene-
tration of drug across skin would be slow due to high
barrier properties of skin. Therefore, advanced tech-
niques using mixtures of chemical penetration enhancers
in the form of microemulsions, micelles or liposomes
have been developed to overcome drug administration
inefficiencies over the recent decades [3,4]. Liposomes
have been known for their considerable potential such as
biocompatibility, non-immunogenicity and biodegrad-
able properties as drug carriers. Due to their inherent
structural specifities and properties liposomes are capa-
ble of encapsulating hydrophilic drugs inside their aque-
ous phase and hydrophobic drugs inside their phosphol-
ipids bilayers. Transfersomes which are elastic liposomes
introduced by Cevc et al. can easily squeeze through the
skin pores due to their more efficient permeation ability
Liposomes can be applied transdermally in many com-
positional forms, such as suspension, freeze dried, cream
and gel systems. Nevertheless the amount of released
drug depends on the dose applied by patient in the form
of cream or gel without any control in dose monitoring.
The other compositional forms such as suspension and
freeze dried liposomes require an additional preparation
stage before any application [6,7].
Drug-in-adhesive patches have been used for trans-
dermal drug delivery in recent years. These patches may
A New Liposomal-Drug-in-Adhesive Patch for Transdermal Delivery of Sodium Diclofenac577
offer benefits such as painless and easy use in delivery of
therapeutic levels of drug, reduced dose frequency com-
pared to the conventional oral dosage forms, and hardly
any gastrointestinal effect being reported with repeated
administrations [8].
In this study a new type of drug-in-adhesive patch was
fabricated using liposomal-based nanocarrier to encap-
sulate or associate sodium diclofenac as a non-steroidal-
inflammatory drug. The non-functional acrylic pressure
sensitive adhesive, Duro-Tak 4098, composed of acry-
late-vinylacetate [9], have been used in this study to fab-
ricate a new patch. The role of liposomes on drug release
characteristics of transdermal drug-in-adhesive patch in
relation to the peel strength and tack value of the whole
acrylic adhesive patch is studied and reported.
2. Materials and Methods
2.1. Materials
Acrylic adhesive Duro-Tak® 87 - 4098 was purchased
from National Starch and Chemical, USA; CoTran 9720
as a release liner, and Scotchpak 1022 as a backing layer
with thickness of 85 μm, were obtained from 3M, USA.
Sodium cholate was purchased from Sigma, USA. Phos-
pholipon® 90G and Phosal® 50 PG were kindly donated
by Phospholipid, Germany. Chloroform for high per-
formance liquid chromatography HPLC was purchased
from Acros, UK. Methanol for liquid chromatography,
and ethanol for analysis, orthophosphoric acid 85% for
analysis, di-potassium hydrogen phosphate anhydrous for
analysis were purchased from Merck, Germany. Sodium
diclofenac was kindly donated by Darou Pakhsh. Chem.
Co. Iran.
2.2. Preparation of Transfersomes
Six elastic liposomal formulations of sodium diclofenac
with compositions shown in Table 1 were prepared.
Phospholipid and surfactant were taken in a clean, dry
round-bottom flask and dissolved in solvent mixture of
chloroform/methanol (2:1). Organic solvents were re-
moved by a Buchi rotary evaporation (R-3000, Germany)
above the lipid transition temperature. The remaining
solvent was removed under vacuum overnight. The de-
posited lipid film was hydrated for 1h with the drug solu-
tion in ethanol by rotating at 60 rpm at 40˚C ± 1.0˚C us-
ing a Unimax 1010 DT shaker incubator (Heizmodul,
Heidolph, Germany). To prepare smaller liposomal vesi-
cles, large multi-lamellar vesicles (LMLV)s were probe
sonicated (Bandelin Electronic Sonopuls GmbH &
Co.KG, Germany) at 4˚C for 20 min at 40 W [10].
2.3. Characterization of Elastic Liposomal
The prepared vesicles (LMLVs) were sonicated in a
Table 1. Material compositions of transfersomes based on
phosphatidylcholin 95%.
F3 F2 F1
120 120 120 Sodium diclofenac (mg)
57.6 43.2 28.8 Sodium cholate (mg)
422.4 316.8 211.2
(*)Phosphatidylcholin 95% (mg)
3 3 3 Ethanol (mL)
(*) F4, F5, F6 formulations were made with Phosphatidylcholin 50%.
probe sonicator (Bandelin GmbH & Co. KG, Germany)
and the particle size of the vesicles before sonication was
measured by a Jenavert optical microscope (Carl Zeiss,
USA) shown in Figure 1. The smaller particle size of the
probe sonicated vesicles were measured by dynamic light
scattering (DLS) (Sematech-Goniometer SEM 633,
France). Morphology of vesicles was obtained by TEM
(Philips 400, KV80) as shown in Figure 2.
2.4. Preparation of Lipo-Drug-in-Adhesive
The prepared solution of Ta ble 1 was added into an acry-
lic adhesive and was stirred over night using rotary mixer.
The resulting six elastic liposomal formulations of so-
dium diclofenac lipodrug-in-adhesive patches (LDIAPS)s
were prepared with compositions shown as in Table 2.
This mixture was spread over the backing layer using
film applicator (Elcometer 3580) in order to obtain
patches with uniform thickness. For removing the solvent,
the coated films were kept in oven for 4 h at 32˚C to dry
and their thicknesses were measured by micrometer (mi-
tutoyo 156 - 101, Mitutoyo, Japan) with the data pre-
sented in Table 3.
2.5. Preparation of Rat Skin
Male Sprague-Dawley rats (150 - 170 g) obtained from
Razi the Vaccine & Serum Research Institute. At first,
animals were sacrificed by excessive chloroform inhala-
tion. The rodent hair was carefully removed with subse-
quent removal of subcutaneous fat layer with a scalpel.
The prepared skin was then washed with distilled water
and dried with the sterile gauze. The skin was wrapped in
an aluminum foil and kept at 30˚C [11,12].
Permission of the experiment was approved by the
Ethics Committee of the Faculty of Veterinary, Tehran
Medical University.
2.6. In Vitro Skin Perm eation
Permeation investigation was carried out using a com-
pletely removed rat abdominal skin in a well-characte-
Copyright © 2011 SciRes. JBNB
A New Liposomal-Drug-in-Adhesive Patch for Transdermal Delivery of Sodium Diclofenac
Figure 1. Vesicles’ morphology before sonication was ob-
tained by optical microscope.
Figure 2. Vesicles’ morphology was obtained by TEM.
Table 2. Material composition of patches based on phos-
phatidylcholin 95%.
120 120 120 Sodium diclofenac (mg)
57.6 43.2 28.8 Sodium cholate (mg)
422.4 316.8 211.2
(*) Phosphatidylcholin 95% (mg)
3 3 3 Ethanol (mL)
1285013140 13430 Durotack 87- 4098 (mg)
(*) F4P, F5P, F6P formulations were made with Phosphatidylcholin 50%.
rized Chien permeation system with an effective diffu-
sion area of 1 cm2 at 37˚C. Receptor compartment of dif-
Table 3. Dried thickness based of obtained patches
99 99 101 100 100 100
Thickness (µm)
fusion cell was completely filled with 3 mL of phosphate
buffer solution (PBS) with the pH 7.4 as receiver me-
dium. The rectangular film of the sample patch (2.25 cm2)
was applied to the epidermal side of the rat skin with
slight pressure and then mounted over the receptor com-
partment containing a magnetic stirrer. At predetermined
time intervals (0.5, 1.5, 3, 5, 8, 24, 48 and 72 h) the re-
ceptor medium was completely withdrawn from the re-
ceptor compartment and was replaced with fresh PBS.
The sample solutions were analyzed for sodium di-
clofenac by UV absorbance at 276 nm in 0.1 M phos-
phate buffer, pH 7.4 and methanol. The standard curve
was plotted in a concentration range of 1 - 36 µg/mL and
R2 value was found to be 0.999 [13].
The permeation profiles of sodium diclofenac are
shown in Figure 3 and the lag time and steady state flux
is presented in Table 4 (P > 0.05).
2.7. Statistical Analysis
The results were represented as mean ± SD and the sta-
tistical Analysis was carried out by analysis of variance
(ANOVA) at the 0.05 significance level.
2.8. Probe-Tack Test
Tack tests were carried out for adhesive tapes according
to ASTM D3121 using a Chemie Instruments Probe-
Tack PT-500 (Fairfield, Ohio, USA) on at least five
2.9. Peel Strength Test at 180˚
Peel tests were carried out according to ASTM D3330 on
adhesive coated tapes each with 25 mm width. After
preparation of lipo-drug-in-adhesive patches consisting
of the acrylic pressure sensitive adhesive tape/stainless
steel joints, the samples were stored at room temperature
for 20 min. Peel force in 180 direction was measured at a
peel rate of 30.50 cm/min at room temperature using a
Chemie Instruments adhesive/release tester AR-1000
(Fairfield). Peel tests were carried out on at least three
samples of each adhesive tape using steel joint [14,15].
3. Results and Discussion
According to study of Verma et al. particle size of lipo-
some plays an important role in penetration of drugs into
skin. The smaller liposome can easily pass through the
Copyright © 2011 SciRes. JBNB
A New Liposomal-Drug-in-Adhesive Patch for Transdermal Delivery of Sodium Diclofenac579
Figure 3. Cumulative sodium diclofenac permeated through
excised abdominal rat skin versus time. (a) F1P, F2P, F3P; (b)
F4P, F5P, F6P.
Table 4. Lag time and steady-state flux of sodium diclofenac
through excised rat from lipo-drug-in adhesive patc hes.
Jss (μg/cm2h) ± SD
Formulations Lag time (h)
(1 - 24 h) (24 - 72 h)
F1P 0.67 0.267 ± 0.04 0.135 ± 0.04
F2P 0.34 0.283 ± 0.05 0.150 ± 0.01
F3p 0.09 0.331 ± 0.04 0.176 ± 0.03
F4P 0.56 0.304 ± 0.04 0.169 ± 0.02
F5P 0.27 0.350 ± 0.04 0.172 ± 0.03
F6P 0.06 0.477 ± 0.11 0.231 ± 0.02
skin, whereas liposomes of larger sizes penetrate into the
deeper layers of the skin with difficulty [16].
The mean size values of sodium diclofenac containing
vesicles measured by dynamic light scattering. The parti-
cle size of transfersome based on phosphatidylcholin
50% and phosphatidylcholin 90% was 84.7 ± 0.5 nm and
72.2 ± 0.8 nm respectively.
The data show that liposomes based on phosphatidyl-
cholin 50%, of lower amount of phospholipid, are smaller
than phosphatidylcholin 95% with higher amount of pho-
spholipid. Following the addition of transfersome into
acrylic pressure sensitive adhesives the microscopic ob-
servations indicated that the dispersion of transfersome in
all the samples was uniformly distributed as in Figure 4.
The surfactant used in this study was sodium cholate.
It was observed that the presence of this surfactant may
assist transfersome particles pass through the skin pores
of stratum corneum, significantly lower than the vesicle
size, because sodium cholate renders flexibility to the
bilayer lipid membranes of transfersomes According to
Boinpally et al. by increasing the amount of sodium cho-
late in formulation, it is observed that lag time, which
obtained by extrapolation, is being decreased [17].
In the F4P, F5P, F6P phosphatidylcholin 50% may act as
chemical penetration enhancer due to the presence of
ethanol (1.5% - 2.5% w/w) and propylene glycol (33.8%
- 41.2% w/w) in the composition. As a result it would be
expected that all formulations containing phosphatidyl-
cholin 50% demonstrate maximum flux of sodium di-
cofenac [18].
The plots of cumulative amount of sodium diclofenac
released across rat skin from different formulations as a
function of time are given in Figure 3. Maximum flux of
sodium diclofenac was 0.477 ± 0.11 µg/h.cm2 from the
lipo-drug-in-adhesive patch system containing 8% (w/w)
liposome, based on phosphatidylcholin 50%, 2% (w/w)
sodium diclofenac and 90% (w/w) acrylic adhesive. The
range of flux obtained from phospholipid 50% formula-
tions is given in Table 4.
According to published reports [19,20] by enhancing
effects of liposomes of higher percentage the mean cu-
mulative amounts of sodium diclofenac release increase
across the rat skin (Figures 3(a) and 3(b)). Based on the
cumulative amount of sodium diclofenac released during
72 h, the study indicates that the order of sodium di-
clofenac passage across the epiderm is: F1P < F2P < F3P <
F4P < F5P < F6P.
As shown in Figure 5, the slopes between the time in-
tervals of 1 - 28 h are sharper in comparison with the
Figure 4. Dispersion of transfersomes in adhesive.
Copyright © 2011 SciRes. JBNB
A New Liposomal-Drug-in-Adhesive Patch for Transdermal Delivery of Sodium Diclofenac
Figure 5. Cumulative sodium diclofenac permeated through
excised abdominal rat skin versus time.
time intervals of 28 - 72 h. From the shapes of the curves
it may be concluded that during the first 28 hours the
drug release takes place mainly from the surface, beyond
which it is released from the bulk of the device. Figure 5
indicates that the drug release of the lipo-drug-in-adhe-
sive patch system from the sample series of F4P, F5P, F6P
(phospholipon 50%) was higher than the series of F1P, F2P,
F3P ( phospholipon 95%) which were due to the smaller
size parameter of former type of liposome and presence
of propylene glycol and ethanol as penetration enhancers.
Nevertheless, the addition of any chemical penetration
enhancer into the patch adhesive formulation would lower
the adhesion properties, because of the plasticizing effect
of the chemical penetration enhancers.
As shown in Table 5 by increasing the percentage of
liposome and lower adhesive concentration at the contact
surface, the adhesion properties of the lipo-drug-in-ad-
hesive patch system were decreased in samples contain-
ing phosphatidylcholin 50% relative to phosphatidylcho-
lin 95%.
4. Conclusions
Because of the general application of sodium diclofenac
in treating rheumatic disorders, in this study we tried to
formulate transdermal sodium diclofenac delivery sys-
tems with the novel design of having lipo-drug-in-adhe-
sive patches using transfersomal liposome as penetration
enhancer. The deformable liposome was prepared by
surfactant such as sodium cholate to enhance its easy
passage through the skin. It was observed that the flexi-
ble liposome in ethanol medium was compatible with the
non-functional acrylic adhesive. The release of sodium
diclofenac from the whole system across rat skin was
evaluated. Finally it was confirmed that, the release of
the drug in patches based on liposomal component such
as phosphatidylcholin 50% is higher than phosphatidyl-
cholin 95%.
Table 5. Adhesion properties of lipo-drug-in adhesive pat-
Tack (N/mm2) Peel strength (N/25mm) Formulation
4.64 4.7 F1P
4.58 4.62 F2p
2.53 3.54 F3p
3.71 3.42 F4P
3.36 3.21 F5P
2.39 3.05 F6P
5. Acknowledgements
We are very thankful to Ms. Houri Mivehchi for editing
the manuscript.
6. Declaration of Interest
Support of this work from Iran Polymer and Petroche-
mical Institute is appreciated.
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