chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914

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Chemical Engineering Research and Design

journal homepage: www.elsevier.com/locate/cherd

Characterization, in vitro release and permeation studies of

nicotine transdermal patches prepared from deproteinized
natural rubber latex blends

Jirapornchai Suksaeree a , Prapaporn Boonme a , Wirach Taweepreda b ,

Garnpimol C. Ritthidej c , Wiwat Pichayakorn a,∗
a Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112, Thailand
b Department of Materials Science and Technology, Faculty of Science, Prince of Songkla University, Songkhla 90112, Thailand
c Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330,

Thailand

a b s t r a c t

The nicotine transdermal patches (NTPs) are available used for smoking cessation; however, they still should be
developed for high efficacy and low cost. In this study, deproteinized natural rubber latex (DNRL) blended with
hydroxypropylmethyl cellulose (HPMC) and dibutylphthalate (DBP) were used as matrix membrane for nicotine (NCT)
delivery. Several techniques, i.e., FT-IR, XRD, DSC, and SEM were used to characterize the compatibility of each
ingredient in the blended patches. A backing layer was used to protect NCT from volatilization. Five different types
of backing layer were evaluated for their effects on in vitro release and skin permeation of NCT from the formulated
matrix membranes. The backing layer with highest moisture vapor transmission rate (MVTR) and lowest oxygen
transmission (OT) supposed to give higher NCT release and skin permeation due to increasing of skin hydration and
its occlusive effect. The kinetic of in vitro release and permeation was demonstrated the monophasic slow release
pattern which confirmed by first order and zero order kinetics, respectively. Therefore, the backing layer could be
appropriated and used conveniently in the preparation of NTPs.
© 2011 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

Keywords: Deproteinized natural rubber latex; Hydroxypropylmethyl cellulose; Nicotine transdermal patches; Trans-
dermal drug delivery; Backing layer

1. Introduction TDDSs consist of release liner, adhesive layer and backing

Transdermal drug delivery systems (TDDSs) are effectively
alternative systems to deliver the drugs with small molecules
into systemic blood circulation via the skin (Barry, 2001;
Ghafourian et al., 2010). They provide several advantages over
the conventional drug therapy including avoid first-pass bio-
transformation and metabolism, minimize absorption and
metabolism variations, possibly to attain sustained and con-
stant drug levels, increase drug bioavailability and efficacy,
provide good patient compliance, and enable fast drug delivery
termination by removing the systems (Davidson et al., 2008; Li
Wan Po, 1993; Wang et al., 2002; Wokovich et al., 2006). Mainly,
layer. Backing layer is chosen for appearance, flexibility and
need for occlusion such as polyester, polyethylene and poly-
olefin. In addition, the backing additives protect the leaching
out and diffusion of excipients, drug out of the patches (Lei
et al., 2010). An overemphasis on the chemical resistance often
may lead to stiffness and high occlusivity to moisture vapor
and air, which cause the TDDSs to lift and possibly irritate the
skin during long-term wear (Wokovich et al., 2006). The color
of the backing layer may be a clear and colorless, flesh-colored
or metalized. In addition, the backing layer can be categorized
into two types, i.e., an occlusive backing, that does not allow
air or steam to pass through and a non-occlusive backing, that

∗
Corresponding author. Tel.: +66 74 288842; fax: +66 74 428148.
E-mail address: wiwat.p@psu.ac.th (W. Pichayakorn).
Received 29 August 2011; Received in revised form 30 October 2011; Accepted 4 November 2011
0263-8762/$ – see front matter © 2011 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cherd.2011.11.002
 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914
allows air or water vapor to pass through. Selection of backing
layer type depends on the objective of usage, patch size or skin
contact.
Nicotine (NCT) is a pyridine alkaloid derived from the
tobacco plant (Furer et al., 2010). Although, it is easily to absorb
and permeate through the skin when applied topically and
can across the blood–brain barrier, it is a volatile compound
(Abu-Huwaij et al., 2011; Dome et al., 2010; Gilbert, 2004). Thus,
this research interested to study the occlusive effect on in vitro
release and skin permeation by using different backing layer
types.
Natural rubber latex (NRL) obtained from Hevea brasilien-
sis composes of cis-1,4-polyisoprene polymer (Rippel et al.,
2005) which has interesting characteristics, such as ease of
manipulate, low cost, natural angiogenesis, biocompatible
material, excellent elasticity and flexibility, and ease for film-
forming (Roberts, 1998; Sruanganurak et al., 2006). Herculano
and co-worker reported the NRL membrane as protein delivery
system by incorporation of the bovine serum albumin (BSA)
into the latex solution for guided bone regeneration (GBR)
which could control the BSA released for 18 days (Herculano
et al., 2009). Moreover, the NRL could also be used in con-
trolled release of metronidazole from their excellent matrix
films for up to 310 h (Herculano et al., 2010, 2011). How-
ever, colloidal NRL reported that it is covered by proteins and
phospholipids and the International Union of Immunological
Societies (IUIS) warns that 14-NRL proteins (HEV b1-14) can
cause latex allergy (Raulf-Heimsoth et al., 2007; Wakelin and
White, 1999; WHO/IUIS Allergen Standardization Committee,
1984). High safety deproteinized natural rubber latex (DNRL)
for pharmaceutical applications was in-house developed by
our research group by enzymatic deproteinization to remove
the protein from fresh NRL in order to avoid the problem
of latex allergy which were previously reported (Kawahara
et al., 2004; Perrella and Gaspari, 2002; Raulf-Heimsoth et al.,
2007; Wakelin and White, 1999; Yeang et al., 2002; Zucker-
Pinchoff and Stadtmauer, 2002). No reports about using DNRL
as a special raw material for pharmaceutical applications were
found.
The aim of this study was to prepare the nicotine transder-
mal delivery systems in patch dosage forms (NTPs) by using
DNRL blended with hydroxypropylmethyl cellulose (HPMC)
and dibutylphthalate (DBP). FT-IR spectroscopic, DSC ther-
mograms, X-ray diffraction and SEM were characterized the
compatibility of the patch. Moreover, the effects of five differ-
ent backing layer types on in vitro release and skin permeation
of NCT were also studied comparing with the commercial
nicotine transdermal patches.
2. Materials and methods
2.1. Materials
DNRL was prepared in-house from the fresh NRL collected
from Hevea brasiliensis (RRIM 600 clone) by enzyme depro-
teinized and centrifugation processes. Briefly, fresh NRL was
deproteinized at 37 ± 2 ◦ C, pH 7–8 for 48 h with 0.2 parts per
hundred (phr) alcalase enzyme (Calbiochem, Germany) using
1% sodium dodecyl sulfate (P.C. drug center; Thailand) as
stabilizer and 2% Uniphen P-23 (the combination of methyl-
paraben, ethylparaben, propylparaben, isobutylparaben and
butylparaben, Induchem, Switzerland) as preservative. Rub-
ber latex was separated and washed with distilled water by
907
centrifugation, redispersed in distilled water, and then kept
in the refrigerator before used.
(−)-Nicotine (>99%) was purchased from Merck (Germany).
HPMC (grade E5) was purchased from Onimax (Thailand). DBP
was purchased from Fluka (USA). Polyacrylic ester (Voncoat
AN868-S: a special self crosslink type acrylic ester copoly-
mer emulsion) as adhesive layer was gifted by Siam chemical
industry (Thailand). The different types of backing layer
(Table 1) were gifted by 3M (Singapore). The other chemicals
were of analytical grade.
2.2. Preparation of NTPs
HPMC E5 was dissolved in distilled water to obtain 10% (w/v)
solution. The HPMC 15 phr was mixed homogeneously into
DNRL either with or without DBP 10 phr. NCT aqueous solution
with suitable concentration obtained from the preliminary
study was mixed into the DNRL blended mixtures, and stored
at 4 ◦ C overnight to eliminate the air bubbles. After that, the
backing layer was cut in a circular shape with area 70.88 cm2 ,
and placed into the Petri-dish and then the films could be pre-
pared by pouring the mixtures on the backing layer and dried
by hot air oven at 70 ± 2 ◦ C for 4 h. The adhesive layer was
coated by pouring the 80% (w/v) polyacrylic ester solution onto
the NCT matrix films, and then it was dried in hot air oven at
70 ± 2 ◦ C for 30 min again. The dry NTPs were peeled-off from
Petri-dish and the NCT content in the NTPs was modulated to
get the final concentration of 2.5 mg/cm2 .
2.3. Characterization of the each component and
blended films
The each component and blended films were scanned at a res-
olution of 4 cm−1 with 16 scans over a wave number region of
400–4000 cm−1 using Fourier transform infrared (FT-IR) spec-
trophotometer (Model Spectrum One, Perkin Elmer, USA). The
prepared transparent thin films were examined using Attenu-
ated Total Reflection FT-IR (ATR-FTIR) technique. The HPMC
powder was mixed with dry potassium bromide (KBr) and
ground into a fine powder using an agate mortar before com-
pressing into a KBr disc sample, while the NCT and DBP were
pasted onto KBr disc sample.
Differential scanning calorimetry (DSC) (Model DSC7,
Perkin Elmer, USA) was used to investigate the endothermic
transition of the substances from −100 ◦ C to 180 ◦ C at the heat-
ing rate of 10 ◦ C/min under liquid nitrogen atmosphere. The
5–10 mg of blended films or raw materials was transferred to
aluminum crimp pan which hermetically sealed, and empty
sealed pan was used as reference.
The X-ray diffractometer (XRD) (Model WI-RES-XRD-001,
Philips analytical, The Netherlands) was employed to study of
the DNRL film and blended films. The generator operating volt-
age and current were 40 kV and 45 mA, respectively as X-ray
source, angular 5–90◦ (2), and step angle 0.02◦ (2)/s.
Film surface and cross section morphologies of the film for-
mulations were examined by scanning electron microscopy
(SEM) (Model JSM-5800 LV SEM, JEOL, Japan) in an appropriate
magnification.
2.4. In vitro NCT release study
In vitro NCT release from the NTPs DNRL blended patches
and a commercial NTPs (Nicotinell TTS-20; 1.75 mg/cm2 ) was
investigated using a modified Franz-type diffusion cell (Model
908 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914

Table 1 – Difference types and properties of backing layer.

Code Backing layer types MVTR (g/m2 /24 h) OT (ml/m2 /24 h)

Backing layer 1 3MTM ScotchpackTM 1109 backing (polyester film laminate) <1 5
Backing layer 2 3MTM ScotchpackTM 9735 backing (polyester film laminate) 7 80
Backing layer 3 3MTM ScotchpackTM 9733 backing (polyester film laminate) 17 80
Backing layer 4 3MTM CoTranTM 9720 backing (polyethylene monolayer film) 6 3840
Backing layer 5 3MTM CoTranTM 9722 backing (polyolefin monolayer film) 6 6400

MVTR = moisture vapor transmission rate; OT = oxygen transmission.

57-951-016, Hanson Research Corporation, USA) with the by HPLC method. Triplicate observations of each sample were
effective diffusion area of 1.77 cm2 . The receptor medium measured.
was 12 ml isotonic phosphate buffer solution (PBS) pH 7.4 Cumulative amount of drug (Qn , mg/cm2 ) in the three
which was thermoregulated with a water jacket at 37 ± 0.5 ◦ C preparations in the receptor chamber was plotted as a func-
and stirred constantly at 100 rpm with magnetic stirrer tion of time. The cumulative amount of nicotine released and
(Pongjanyakul et al., 2003). The patches preparations were cut permeated through pig skins was determined based on the
in a circular shape and directly placed between the donor following Eq. (4).
and receptor cells without any membrane. One ml recep-
n−1
tor solution was withdrawn at 0.5, 1, 2, 3, 4, 6, 8, 12 and Cn V0 + i=1
Ci Vi
24 h time interval, and an equal volume of freshly PBS was Qn = (4)
A
then replaced. The NCT concentrations in these samples were
determined by HPLC method. Triplicate observations of each where Cn stands for the drug concentration of the recep-
sample were measured. The kinetic of NCT release was inves- tor medium at each sampling time (mg/cm3 ), Ci is the drug
tigated as following Eqs. (1)–(3).

Qt = Q0 + K0 t (1)

log Qt = log Q0 + K1 t (2)

Qt √
= KH t (3)
Q0

where Qt is the amount of nicotine released or permeation

(mg) in the time (t, h) and Q0 is the initial amount of nicotine
(mg) in the formulation. K0 is the zero constant rate (mg/h),
K1 is the first constant rate (mg/h) and KH is the Higuchi’s con-
√
stant rate (mg/ h) (Costa and Sousa Lobo, 2001; Siepmann and
Peppas, 2001).

2.5. In vitro skin permeation study

In vitro skin permeation of NCT from patches was also per-

formed using a modified Franz-type diffusion cell (Venter
et al., 2001), and hairless pig skin was applied as partition-
ing membrane (Meyer et al., 1978; Simon and Maibach, 2000).
The newborn pigs of 1.4–1.8 kg weight and died with natu-
ral causes shortly after birth, were freshly purchased from
a local pig farm in Songkhla Province, where is regulated by
Department of Livestock Development, Thailand. Full thick-
ness flank pig skin was excised, surgically removed hair off,
and the subcutaneous fat and other extraneous tissues were
trimmed with a scalpel, cleaned with PBS, blotted dry, wrapped
with aluminium foil and stored frozen. Before permeation
experiments, this isolated skin was soaked overnight in PBS,
and mounted on the Franz diffusion cells which the stra-
tum corneum faced upward on the donor compartment. The
NTPs were laid onto the isolated skin as same as the release
study. The receptor compartment was 12 ml PBS pH 7.4 which
stirred constantly at 600 rpm by magnetic stirrer, and tem-
perature was maintained at 37 ± 0.5 ◦ C (Hwang et al., 1997;
Pongjanyakul et al., 2000, 2003). One ml receptor solution was
withdrawn at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h time interval, and
an equal volume of fresh PBS was then immediately replaced. Fig. 1 – (A) FT-IR spectra, (B) DSC thermograms, and (C) XRD
The NCT concentrations in these samples were determined patterns of each component and blended films.
 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914
Fig. 2 – Schematic illustrations of (A) structure of NTPs. SEM micrographs of (B) the cross section of NTPs, surface
morphologies of (C) NCT-matrix layer and (D) adhesive layer before NCT release.
concentration of the sample (mg/cm3 ), and V0 and Vi stand
for the volumes of the receiver solution and the sample (ml),
respectively. A is the area of skin tissue or the diffusion surface
area (cm2 ) through which drug permeation takes place (Zhu
et al., 2008a,b). The slope of the linear portion plot between
the steady state values of the cumulative amount of nicotine
permeated (mg/cm2 ) and time (h) was represented as the per-
meation rate (Jss , mg/cm2 h) (Taghizadeh et al., 2010) that were
calculated by the skin flux from the following Eq. (5).
 dQ  1
Jss = × (5)
dt ss A the difference between multiple data sets) for significance at
where (dQ/dt)ss is the amount of drug passing through the
skin per unit time at a steady-state (mg/h) (Lee et al., 2005).
Then, the permeability coefficient (Kp , cm/h) was deduced by
dividing the flux by the initial drug loaded (mg/cm3 ) as Eq. (6).
JSS
KP = (6)
C0
where C0 represents the drug donor concentration data
(mg/cm3 ) (Mehdizadeh et al., 2006; Tirnaksiz and Yuce, 2005).
2.6. HPLC condition for NCT analysis
The NCT solution collected from the receptor of Franz diffu-
sion cell was filtered through a cellulose acetate membrane
(0.22 ␮m pore size). Then, the NCT analysis was carried out
using an HPLC system (Agilent 1100 series, Thermo elec-
tron corporation, USA) with a column (BDS HYPERSIL® C18,
150 mm × 4.6 mm diameter, 5 ␮m particle size, Thermo sci-
entific, USA). The mobile phase consisted of 0.05 M sodium
acetate:methanol (9:1, v/v) containing 1.3% triethanolamine,
and the pH was adjusted to 4.2 with acetic acid. The flow
rate was 0.7 ml/min, and the injection volume was 10 ␮l. The
absorbance was detected by the UV detector at the wavelength
909
of 260 nm. The NCT amount was calculated comparing with
the validated calibration curve. The HPLC method provided
good accuracy, precision and linearity in the required concen-
tration range (2–60 ␮g/ml) of NCT solutions in PBS.
2.7. Statistic analysis
The average value for each experiment was subsequently cal-
culated and presented as mean ± standard deviation value.
All results were statistically evaluated using one-way analy-
sis of variance followed by post hoc analysis (for comparison of
p < 0.05.
3. Results and discussion
3.1. DNRL characteristics
From our unpublished study, DNRL having 39.55% dry rubber
content was produced by alcalase treatment. The total protein
in DNRL was reduced for more than 89.21% compared with
initial protein content in NRL. This DNRL could be reproduced
for several times which had the similar properties. They could
be kept in the refrigerator for more than 4 months, and used
for the DNRL blending matrix films in this experiment.
3.2. Characteristics of the each component and
blended films
Compatibility of DNRL with blending HPMC and DBP was
also confirmed by FT-IR spectra, DSC thermograms, and
XRD diffractograms (Fig. 1). For FT-IR study (Fig. 1A), the
DNRL spectrum was district the principle peak at 3035 cm−1
( CH streching), 2963–2856 cm−1 (C–H streching), 1664 cm−1
(C C streching), 1449–1376 cm−1 (C–H bending), and 830 cm−1
(C CH wagging). The HPMC showed the broad spectrum at
910 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914
Fig. 3 – (A) NCT release profile from NTPs with different backing layer types (n = 3). SEM micrographs of the cross section of
NTPs (B) before NCT release and (C) after NCT release.
3446 cm−1 due to a stretching vibration in the hydroxyl group
(Anuar et al., 2007; Larsson et al., 2010; Wang et al., 2007a;
Wang and Xu, 2006). The FT-IR spectra of neat liquid NCT
was recorded the band around of 3400 cm−1 (–OH, large peak
of water), 2968–2778 cm−1 (C–H stretching), 1677 cm−1 (aro-
matic C C stretching), 1577 cm−1 (aromatic C N stretching),
903 cm−1 (pyridinic C–H bending) and 716 cm−1 (the out of
plane bending of the C–H bond of the monosubstituted pyri-
dinic cycle). The major peaks of DNRL and HPMC were also
found in the DNRL/HPMC blended film. It was also found a
slightly broader peak at 1738 cm−1 which be a C O stretch-
ing of DBP in the DNRL/HPMC/DBP matrix film. Furthermore,
the NCT/DNRL/HPMC/DBP matrix film was also found a shift
of aromatic ring bending band at 715 cm−1 of NCT. Thus, no
markedly changeable spectrum was observed indicating com-
patibility of each ingredient in blended film (Paul et al., 1988),
similarly to the results reported for polymer blends (Wang
et al., 2007b; Yin et al., 2006; Zaccaron et al., 2005).
From the DSC chromatograms of both raw materials and
blended films were not changed in range 0 ◦ C to 180 ◦ C. Thus,
Fig. 1B showed the DSC chromatogram in only range between
−100 ◦ C and 0 ◦ C which only the major temperature transition
appeared as the glass transition temperature (Tg ) at around
−64.794 ◦ C of DNRL film. HPMC was found not to change during
this range, while that of DNRL/HPMC blends was −64.785 ◦ C.
The DBP blends slightly reduced the Tg of DNRL/HPMC/DBP
blends film to −67.752 ◦ C. Furthermore, the DSC thermogram
of NCT could be seen that an endothermic peak at −88.206 ◦ C
which was due to the melting point of NCT (The Physical
and Theoretical Chemistry Laboratory, 2009). Similarly, ther-
mograms of NCT/DNRL/HPMC/DBP blends film was exhibited
slightly reduced the Tg to −69.730 ◦ C comparing their blank
films which indicated the slightly change in the structure of
blended films. No disguised signal in DSC thermograms indi-
cated the compatibility of each ingredient in blended film
which did not show the significant shift of Tg in these range
(Utracki, 2002).
The XRD patterns (Fig. 1C) of blended films showed only the
broad halo spectrum which same as DNRL alone. The HPMC
diffractogram disappeared from the spectrum of blended
films, due to its less amounts in the blended film. This result
demonstrated to a larger domain of amorphous phase of DNRL
blended films. Moreover, the addition of NCT in blended films
showed the same XRD pattern as blank films which indicated
the compatibility of all ingredients without crystalline stage
of drug (Wang et al., 2007b).
The SEM (Fig. 2) was used to confirm the high resolu-
tion microscopic morphology in each film. The structure of
NTPs was expected as Fig. 2A. It was in accordance with
cross section morphology of NCT matrix patch (Fig. 2B). This
 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914 911

designed film consisted of three layer such as adhesive layer,

3.6856 ± 0.2014

0.0802
0.5094
0.7906
1.3573
0.5604
0.2309
matrix layer and backing layer. The surface morphology of

(×10−3 cm/h)
NCT-matrix layer was observed in the patch that was smooth

±
±
±
±
±
±
surface (Fig. 2C), and after adhesive layer were coated in NCT-

3.5281
9.1987
5.9211
6.7554
4.8776
4.0509
matrix layer, the morphology showed ruggedness and not

Kp a
smooth (Fig. 2D).

0.0322 ± 0.0018

0.0008
0.0051
0.0079
0.0136
0.0056
0.0024
3.3. In vitro NCT release

(mg/cm2. h)

±
±
±
±
±
±
0.0354
0.0922
0.0594
0.0677
0.0489
0.0406
The monophasic slow release pattern was found (Fig. 3A)

Jss a
and the effect of different backing layer types on the NCT
release profile was observed. The NCT release from NTPs
without backing layer was close to that of the commer-

Higuchi’s
cial Nicotinell TTS-20. Furthermore, the addition of backing

model

0.9004

0.8889
0.9244
0.8593
0.8628
0.8643
0.8785
layer significantly increased the NCT release rate. However,
the five different types of backing layer provided similar
release pattern on their NCT release. The NCT release from
five types of backing layer were found in ranged backing
layer 1 > 3 > 2 > 4 > 5. However, when comparing among studies

Permeation kinetics

Kinetics pattern (r2 )

0.9943

0.9941
0.9613
0.9726
0.9686
0.9816
0.9890
order
First
backing layers, different backing layer provided not signifi-
cant difference in NCT release amounts. This indicated some
effects of backing layer on drug release. Occlusive conditions
created by the backing layer increased the release of NCT

0.9987

0.9988
0.9963
0.9940
0.9955
0.9963
0.9977
order
transport from the polymer matrix layer. The backing layer

Zero
protected the undesirable evaporation or diffusion of NCT to
the outer surface of the patch and prevented the delivery sys-
tem. This result was consistent with a previous study which

0.2575 ± 0.0163

0.0385
0.0044
0.0116
0.0084
0.0180
0.0124
reported the backing layer capability of siliconized PET film
(Cilurzo et al., 2008), Eudragit® RS (Diaz del Consuelo et al.,

±
±
±
±
±
±
2007), ethyl cellulose (Abu-Huwaij et al., 2011), artificial silk

0.4085
0.0473
0.0426
0.0462
0.0461
0.0353
(rayon acetate) (Minghetti et al., 2003). However, the kinet-
Table 2 – The in vitro NCT release, and skin permeation kinetics of DNRL/HPMC blended films.

Ka

ics of NCT release from these blending patch dosage forms

showed the dissolution mechanism. Nicotine release was pro-
Higuchi’s

portional to the amount of nicotine remaining in its patch

model

0.9688

0.9881
0.9825
0.9720
0.9723
0.9753
0.9827
(Costa and Sousa Lobo, 2001) which confirmed by first order
kinetics as describes in Table 2. These results demonstrated
that the added backing layer effectively retarded the release
and preserved the incorporated drug, and thus a longer drug
release period could be expected. Furthermore, the cross sec-
(r2 )

0.9363

0.9772
0.9901
0.9827
0.9867
0.9856
0.9879
order
First

tion morphology of these patches showed the dense films

Kinetics pattern
Release kinetics

without cracking or cavity (Fig. 3B). However, the cross sec-

tion morphology films after NCT release study presented the
various numbers of pore and cavity, and the patches became
Calculated from the best fit equation which provided the highest r2 .

rough (Fig. 3C) comparing before NCT release (Fig. 3B). The
0.7865

0.8520
0.8158
0.7860
0.7860
0.7938
0.8324
order
Zero

NCT was dissolved by water penetrating through into the poly-

mer matrix, while NCT released occurred via diffusion through
the polymer matrix. Thus, the pores and roughness might
NCT (mg/cm2 )

be attributed to the diffusion of NCT molecules and some

erosion of polymer matrix in patches. Since it was generally
recognized that drug release from HPMC matrices follows two
mechanisms, drug diffusion through the swelling layer and
1.75

2.5

release by matrix erosion of the swollen layer (Bajdik et al.,

AL = adhesive layer; BL = backing layer.

2008; Kamel et al., 2008; Sebti et al., 2003). These results related
to their release patterns.
NCT/DNRL/HPMC(15)/DBP/AL/BL1
NCT/DNRL/HPMC(15)/DBP/AL/BL2
NCT/DNRL/HPMC(15)/DBP/AL/BL3
NCT/DNRL/HPMC(15)/DBP/AL/BL4
NCT/DNRL/HPMC(15)/DBP/AL/BL5
NCT/DNRL/HPMC(15)/DBP/AL

3.4. In vitro NCT skin permeation

From previous reports, anatomical, physiological and bio-

chemical of the pig skin resembled human skin (Roberts and
Walters, 2007; Simon and Maibach, 2000), thus, in vitro skin
Formulas

permeation study, the pig skin was chosen as barrier between

Nicotinell
TTS-20

NTPs and receptor medium. The amount of NCT perme-

film

ation could be decreased when comparing with NCT amount

a

released from NTPs which the results were consistent with

912 chemical engineering research and design 9 0 ( 2 0 1 2 ) 906–914
Fig. 4 – (A) NCT permeation profile from NTPs with different
backing layer types (n = 3). (B) Schematic representation of
NCT releases directly from main NCT-matrix layer after
backing layer added.
a another study of nicotine (Opanasopit, 1995; Pongjanyakul
et al., 2003) and lercanidipine hydrochloride (Mamatha et al.,
2010). As in Fig. 4A, the patches without backing layer which
released the larger NCT amount, but showed the lower NCT
permeation comparing with Nicotinell TTS-20. This might be
due to no enhancer effect from DNRL/HPMC/DBP blending
preparation. Moreover, the addition of backing layer also sig-
nificantly affected their permeation pattern which the skin
permeations of NCT from all DNRL/HPMC patches were zero
order kinetics (Table 2). In generally, the addition of backing
layer also significantly affected their permeation pattern that
was known to improve drug penetration. The backing layer
might also have an occlusive effect which shown to increase
drug permeability (Diaz del Consuelo et al., 2007; Zhai and
Maibach, 2002, 2004). In this research, the backing showed a
significant improvement of efficiency of the higher skin per-
meation of NCT due to its occlusive effect which comparing
to non-backing layer (Nicoli et al., 2006). After added of the
backing layer, this indicated for decrement of NCT evapora-
tion from upper side of matrix layer, which increased the
NCT permeation through the skin (Fig. 4B). Comparison of
the effect of moisture vapor transmission rate (MVTR), the
increasing MVTR backing increased NCT permeation because
of the increasing of hydration at the skin (Williams and Barry,
2004). Moreover, the effect of oxygen transmission (OT) was
the important factor giving the occlusive effect and affecting
the skin permeation of NCT. The lowest OT backing affected
the highest occlusive phenomena, and the highest skin per-
meation occurred. Thus, the skin permeation of NCT could
also be adjusted by backing type.
4. Conclusion
Blending DNRL with HPMC and DBP provided the suitable
matrix membrane for NTPs. In addition, the compatibility of
each ingredient in the blended films was confirmed by FT-
IR spectra, DSC thermograms, and XRD diffractograms. SEM
photograph observed the smooth surface and dense films.
However, the cross section morphology films after NCT release
presented more pores and cavities. Moreover, in vitro release
and skin permeation studies of NCT from matrix films were
affected by type of backing layer due to their occlusion effects.
The NTPs without backing layer showed slower release and
skin permeation, while the NTPs with backing layer showed
significantly faster release and skin permeation depending on
the MVTR and OT properties. The results indicated that the
film formulation composed of DNRL blended with HPMC was
suitable for developing NTPs which could also be adjusted by
backing layer due to occlusion effects.
Acknowledgments
The authors would like to acknowledge the Prince of Songkla
University, the Thailand Research Fund, and the Office of Com-
mission on Higher Education, Ministry of Education (Grant No.
MRG5180243) for financial supports. We thank Siam Chemical
Industry and 3M Company for providing some materials in this
study.
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