RESEARCH ARTI CLE

Formulation and in vitro evaluation of transdermal drug delivery

system for donepezil
Robhash Kusam Subedi

Je-Phil Ryoo

Cheol Moon

Myung-Kwan Chun

Hoo-Kyun Choi
Received: 18 October 2011 / Accepted: 28 November 2011 / Published online: 20 January 2012
The Korean Society of Pharmaceutical Sciences and Technology and Springer Dordrecht 2012
Abstract The effects of different formulation variables
on the transdermal absorption of donepezil were investi-
gated. The permeation of donepezil from various pressure
sensitive adhesive matrices was evaluated using ow-
through diffusion cell system at 37C. The penetration of
donepezil from the matrices was found to be inuenced by
the nature of adhesives. 1:1 combination of acrylic rubber
hybrid adhesives (Duro-Tak

87-503A and Duro-Tak

87-504A) provided good adhesion force and high ux of

donepezil. Signicant increase in ux was obtained using
Brij

30, Brij

52, and their combination, as penetration

enhancers. Manual assessment using thumb test revealed
that patches containing combination of enhancers pos-
sessed good adhesive properties. The formulation con-
taining combination of Brij

30 and Brij

52, each at the

level of 5% v/w with 15% w/w drug load in 1:1 combi-
nation of Duro-Tak

87-503A and Duro-Tak

87-504A
matrix was found to be the best. No signicant alteration in
morphology and assay values were observed during the
physical and chemical stability tests conducted for the
study period of 3 months.
Keywords Donepezil Transdermal drug delivery
Percutaneous penetration Chemical enhancers
Alzheimers disease
Donepezil is a centrally acting reversible acetylcholines-
tearase inhibitor and exerts its therapeutic effect by
increasing acetylcholine concentrations and enhancing
cholinergic function (Rogers and Friedhoff 1998; Sugimoto
et al. 1995). Commercially, donepezil is available in the
form of tablet under the trade name Aricept

. Initial dose is
5 mg per day, which can be increased to 10 mg per day
after an adjustment period of at least 4 weeks (Rogers et al.
1998). In most of the cases, it is not convenient for patients
suffering from Alzheimers disease (AD) to comply with
the self-medication schedule. Moreover, various side
effects including diarrhea, nausea, anorexia, and muscle
convulsion are reported (da Silva et al. 2006). These
adverse effects are mainly due to increase in gastric acid
secretion caused by enhanced cholinergic activity through
the gastrointestinal tract. Donepezil-nanoclay hybrids have
been suggested to reduce the adverse effects of donepezil
(Park et al. 2008). It was reported that clay used in the
study could reduce the acidity by absorbing proton and
control the drug release behavior. As an alternative to oral
delivery, microparticles of donepezil as monthly subcuta-
neous injection has been reported (Zhang et al. 2007). The
microparticles were prepared using poly (D, L-lactide-co-
glycolide) by an oilwater emulsion solvent evaporation
technique. However, due to the better patient compliance,
controlled delivery of drug, ease of administration as well
as termination, a transdermal product of donepezil would
be more appropriate in providing clinical benet of pro-
longed response to patients suffering from AD.
However, due to the barrier function of skin, not all drugs
can be delivered transdermally (Subedi et al. 2010). In many
cases, the absorption may not result in sufcient plasma drug
concentration. Various studies have been conducted, along
with their pros and cons, to develop transdermal product
of donepezil. Matrix based transdermal system has been
R. K. Subedi M.-K. Chun H.-K. Choi (&)
BK21 Project Team, College of Pharmacy, Chosun University,
375 Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
e-mail: hgchoi@chosun.ac.kr
J.-P. Ryoo C. Moon
NAL Pharmaceuticals Ltd, Monmouth Junction, New Jersey,
USA
1 3
Journal of Pharmaceutical Investigation (2012) 42:17
DOI 10.1007/s40005-012-0002-y
reported for donepezil (Kazunosuke et al. 2008). However,
to achieve the sufcient transdermal ux through hairless
mouse skin, extremely high drug loading (35% w/w) was
used. This may lead to crystallization of drug in the polymer
matrix and may cause problem with adhesive force. Another
study suggested the use of salt form that is converted to the
base form in situ within the matrix type delivery system
(Terahara et al. 2009). Salt form of donepezil precipitates in
the adhesive matrix forming particles in the patch, which
reduces the aesthetic value of the patch. Reservoir type patch
system was also described for delivery of Alzheimers
pharmaceuticals, particularly donepezil (Valia and Rama-
raju 2008). The matrix patches are slimmer and smaller than
the reservoir patch, and are preferred both in terms of ease of
production and better patient compliance. Therefore, there is
a need to explore a commercially viable transdermal matrix
based system for donepezil which can give higher ux at
lower drug load, through proper selection of formulation and
process variables.
The present study was conducted to investigate the
feasibility of developing stable matrix based transdermal
system for donepezil. In vitro permeation studies were
done to characterize passive diffusion with various
adhesives and chemical enhancers. Effect of different
formulation variables on permeation of donepezil was
evaluated.
Materials and methods
Materials
Donepezil hydrochloride was generous gift from Samil
Pharmaceuticals (Seoul, South Korea). Polyglyceryl-3
oleate (Plurol olieque

CC497), propylene glycol mono

laurate (Lauroglycol), and polyoxy glycerate (Labral

1944) were obtained from Gattefosse (Paramus, NJ, USA).

PEG sorbitan monooleate (Tween

80), sorbitan monool-

eate (Span

80), propylene glycol (PG), oleyl alcohol was

purchased from Junsei Chemicals (Japan). Isopropyl pal-
mitate (IPP), isopropyl myristate (IPM), PEG-12 palm
kernel glycerides (Crovol

PK40), and PEG-20 almond

glycerides (Crovol

A40) were obtained from Croda

(Parsippany, NJ, USA). Lauryl alcohol (R)-(?) Limonene,
Brij

30 and Brij

52 were purchased from Sigma

Chemical (St. Louis, MO, USA). Acrylic rubber hybrid,
polyisobutylene (PIB) and styrenebutadienestyrene
(SBS) pressure sensitive adhesive (PSA) solutions in
organic solvents were obtained from National Starch and
Chemical Company (Bridgewater, NJ, USA). Silicone PSA
was obtained from Dow Corning (Midland, MI, USA). All
other chemicals were reagent grade or above and were used
without further purication.
Methods
Patch preparation
Since patches prepared using salt form showed very low
permeability (data not shown), donepezil hydrochloride
was converted to the free base form using equimolar
amount of sodium hydroxide. Differential scanning calor-
igrams showed that the melting point of donepezil hydro-
chloride (230C) was reduced to around 90C after the
conversion (Fig. 1). The drug solution was obtained by
dissolving donepezil in ethyl acetate, and permeation
enhancer(s) were added. Adhesive solution and drug
solution were mixed and stirred sufciently. The mixture
was cast on release liner coated with silicone and solvent
was removed by evaporation at 80C for 20 min. Then the
dried adhesive layer was laminated onto the backing
membrane. The drug and enhancers are expressed as
weight % with respect to dry PSA polymer throughout the
article.
Measurement of in vitro skin permeation rate
Skin permeation rates of various donepezil/enhancer for-
mulations were determined using ow through diffusion
cells. Permeation experiments were done on isolated hairless
mouse skin. A system comprising a multi channel peristaltic
pump, a fraction collector, a circulating water bath and ow-
through diffusion cells was used. Each ow-through cell had
two arms, which allowed the receiver cell medium pumped
to a fraction collector. The diffusion cell temperature was
maintained at 37C by circulating water through the outer
part of jacketed receiver cell. The surface area of receiver
cell opening was 2 cm
2
, and its volume was 5.5 ml. Skin was
excised from hairless mouse that was humanly sacriced
Temp (
o
C)
0 50 100 150 200 250
E
n
d
o
t
h
e
r
m

d
o
w
n
-28
-27
-26
-25
-24
-23
donepezil base
donepezil HCL
Fig. 1 Differential scanning calorimetric thermogram of donepezil as
base and hydrochloride salt form
2 R. K. Subedi et al.
1 3
with diethyl ether. Subcutaneous fat was removed with
scissors and scalpel. Each of the ow-through diffusion cell
components was connected via silicone rubber tubing with
an internal diameter of 0.015 inches. The receiver cell was
lled with a pH 6 buffer solution and the media was stirred
by Teon-coated magnetic bar. The prepared patch was
placed on the stratum corneum and the excised skin was
mounted onto each receiver cell. And O-ring and cell top
was placed on the top of each skin. These components were
then clamped. The amount of drug permeated across the skin
was calculated from the cumulative release. The samples
were collected every 4 h for 24 h and assayed by HPLC.
Analytical method
Donepezil was analyzed by HPLC system (Shimadzu
Scientic Instruments, MD), consisting of a UV detector
(SPD-10A), reversed-phase C
18
column (4.6 9 100 mm,
5 lm, Gemini), a pump (LC-10AD), and an automatic
injector (SIL-10A). Briey, the wavelength of the UV
detector was 315 nm, the column temperature was main-
tained at 30C, the ow rate was 1 ml/min and injection
volume was 10 ll. Mobile phase consisted of Acetonitrile/
phosphate buffer 0.1 M with triethanolamine (0.01% v/v)
adjusted to pH 2.7 with 85% phosphoric acid (30/70).
Content analysis
4 cm
2
patch samples were cut, and weighed. Release liner
was separated and weighed. Backing membrane containing
the matrix was transferred in 50 ml vial with screwed cap
(Schott Duran). Then, 50 ml of HPLC grade methanol and
teon coated magnetic bar was added. The container was
then capped and sealed with Paralm

. Then, the samples

were sonicated for 30 min followed by stirring for 12 h. The
backing membrane was removed fromthe container, washed
with ethyl acetate to remove the PSA matrix, and weighed.
The solution was ltered through Whatman

nylon mem-
brane lter (13 mm, 0.45 lm) and analyzed by HPLC.
Differential scanning calorimetry (DSC)
Thermal analysis was carried out to characterize donepezil
hydrochloride and base form, using a DSC unit (Pyris 6
DSC, Perkin-Elmer, Netherlands). Indium was used to
calibrate the temperature scale and enthalpic response.
Samples were placed in aluminum pans and heated at a
scanning rate of 5C/min from 25 to 250C.
Stability
Stability studies of the optimized formulation were con-
ducted at three different temperature conditions. Physical
stability of the patches kept in refrigerator (28C), room
temperature (RT) and 40C oven were monitored visually
at different time intervals. Chemical stability was assessed
using previously reported stability indicating analytical
method (Hanatani et al. 2008). HPLC system (Shimadzu
Scientic Instruments, MD), consisting of a UV detector
(SPD-10A), reversed-phase C
18
column (4.6 9 150 mm,
5 lm, Shiseido), a pump (LC-10AD), and an automatic
injector (SIL-10A) was used. Briey, the wavelength of the
UV detector was 271 nm, the column temperature was
maintained at 25C, the ow rate was 1 ml/min and
injection volume was 20 ll. The mobile phase used con-
sisted of sodium1-decansulfonate aqueous solution/Acet-
onitrile/70% perchloric acid = 650/350/1 (volume ratio);
sodium 1-decansulfonate concentration was 10 mM of total
mobile phase.
Results and discussion
Selection of pressure sensitive adhesive matrix
The effect of the PSA matrix on the permeation of do-
nepezil was investigated using silicone, PIB, SBS, acrylic
and acrylic rubber hybrid adhesive matrixes. Permeation
prole of donepezil from various PSA matrices is shown
in Fig. 2. Solubility of donepezil was found to be inad-
equate in silicone and PIB adhesive matrices and some of
donepezil was suspended in the matrix. The glass transi-
tion temperature of PSA, interaction between the drug and
functional group of PSA, adhesive force and many other
properties can inuence ux of drug from PSA across the
skin (Hai et al. 2008; Venkatraman and Gale 1998). The
permeation rate was lowest in the PIB matrix, followed
Time (h)
0 5 10 15 20 25
C
u
m
u
l
a
t
i
v
e

a
m
o
u
n
t

p
e
n
e
t
r
a
t
e
d

(
g
/
c
m
2
)
0
50
100
150
200
250
300 PIB
SBS
Acrylic non functional
Acrylic hydroxy functional
Acrylic rubber hybrid
Acrylic carboxy functional
Silicone

Fig. 2 Screening of different pressure sensitive adhesives at 10% w/w

of drug load. Values are expressed as mean (n = 3)
Transdermal drug delivery system for donepezil 3
1 3
by highly crossed linked acrylic adhesive containing
carboxyl functional group, Duro-Tak

87-2677. This
could be due to the interaction between amine group of
donepezil and carboxyl group of the adhesive. In previous
study, low permeation rate of tacrine was observed due to
the interaction between the amine group of tacrine and
carboxyl group of acrylic adhesive (Kim et al. 2000).
Permeation rate of donepezil in the acrylic rubber hybrid
adhesive matrix, Duro-Tak

87-502A was highest fol-

lowed by silicone, Dow Corning BioPSA

7-4302. Fur-
ther study on different kinds of acrylic rubber hybrid
adhesives containing hydroxyl functional group revealed
that Duro-Tak

87-504A provided higher ux for do-

nepezil (Fig. 3). Permeation of donepezil from Duro-Tak

87-502A and 87-503A matrices was similar. Acrylic

rubber hybrid PSAs are prepared from an acrylic polymer
grafted with a hydrogenated rubber. The hybrid PSA
comprises of polymer from ethylene-butylene macromer
and hydroxyethyl acrylate monomer (Foreman et al.
2003). Higher ux obtained for donepezil from acrylic
rubber hybrid PSAs could be attributed to the suitable
polar monomer favorably affecting the thermodynamic
behavior of donepezil in the matrix (Cantor and Wirtanen
2002).
Since matrix thickness is an important functional char-
acteristics of matrix based transdermal system, its effect on
the permeation of donepezil was also investigated. Per-
meation prole of donepezil was unchanged when matrix
increased from 65 to 85 lm (Fig. 4). However, further
increase in matrix thickness resulted in lower permeation
prole of donepezil. Matrix thickness of 85 lm was chosen
for further experiments based on better adhesive properties
as compared to 60 lm matrix.
Effect of enhancer
To reversibly overcome the barrier properties of stratum
corneum, penetration enhancers are commonly employed
in the transdermal systems (Williams and Barry 2004).
Enhancer screening was carried out with both Duro-Tak

87-502A and 87-504A matrices. Table 1 gives the sum-

mary of enhancer screening at the level of 5% v/w with
15% w/w drug load in Duro-Tak

87-502A acrylic rubber

hybrid matrix. Due to higher solubility of donepezil in
Duro-Tak

87-502A acrylic rubber hybrid matrix, drug

load was increased to 15%. Brij

30, Plurol olieque

Time (h)
0 5 10 15 20 25
C
u
m
u
l
a
t
i
v
e

a
m
o
u
n
t

p
e
n
e
t
r
a
t
e
d

(
g
/
c
m
2
)
0
100
200
300
400
87-502 A
87-503 A
87-504 A
Fig. 3 Screening of different rubber acrylic hybrid pressure sensitive
adhesives at 15% w/w drug load. Values are expressed as mean
(n = 3)
Time (h)
0 5 10 15 20 25
C
u
m
u
l
a
t
i
v
e

a
m
o
u
n
t

p
e
n
e
t
r
a
t
e
d

(
g
/
c
m
2
)
0
100
200
300
400
500
60 m
85 m
100 m
120 m

Fig. 4 Effect of acrylic rubber hybrid matrix thickness on the

permeation of donepezil. Values are expressed as mean (n = 3)
Table 1 Summary of enhancer screening at the level of 5% v/w with
15% w/w drug load in Duro-Tak

87-502A acrylic rubber hybrid

matrix. Values are expressed as mean (n = 3)
S. No. Enhancer ER*
1 Control 1.00
2 Brij

30 2.10
3 Plurol olieque

CC497 1.47
4 Crovol

A 40 1.32
5 Oleyl alcohol 1.37
6 Lauryl alcohol 1.34
7 IPM 1.12
8 Sugar ester P-1670 1.33
9 Limonene 1.06
10 Span

80 1.25
11 Transcutol

1.17
12 IPP 1.17
13 Cineole 1.11
14 Labral

1944 1.09
15 Incrocas

30 1.04
16 Brij

52 1.29
* ER enhancement ratio
4 R. K. Subedi et al.
1 3
CC497, Crovol

A40, oleyl alcohol, lauryl alcohol, sugar

ester P-1670, Span

80 and Brij

52 signicantly enhanced
the in vitro ux of donepezil from Duro-Tak

87-502A
matrix. The enhancing effect of Brij

30 was compared
between Duro-Tak

87-502A and Duro-Tak

87-503A. As
can be seen in Fig. 5, no signicant difference was observed.
Table 2 gives the summary of enhancer screening at
the level of 5% v/w with 10% w/w drug load in Duro-Tak

87-504Aacrylic rubber hybrid matrix. Among the enhancers

screened, Brij

30, Brij

52, IPM, glycerol and diethoxy-

ethyl succinate were associated with the signicant
enhancing effect. Brij

30 provided highest enhancement

ratios in both Duro-Tak

87-502A and Duro-Tak

87-504A
matrices and was chosen for further experiments. Brij

30 is
a surfactant which belongs to the class of polyoxyethylene
(POE) alkyl ethers. The EO chain length and HLB value of
Brij

30 is 4 and 9.7 respectively. Studies have shown that

POE alkyl ethers containing EO chain length of 25 and
HLB value 79 are effective promoters for the percutaneous
absorption of drug molecules (Park et al. 2000). Brij

30
could efciently disrupt the lipid arrangements in SC via
both hydrophilic and lipophilic molecular mechanism,
thereby enhancing the penetration of donepezil (Breuer
1979; Walters et al. 1987).
Effect of combining enhancers
To further increase the transdermal ux of donepezil, effect
of combining selected enhancers at the level of 2.5% v/w
with 5% v/w of Brij

30 was studied. Especially for drug in

adhesive type of TDDS, presence of additives can modify the
mechanical characteristics of PSA, and might make the
adhesive more susceptible to creep/cohesive failure. Hence,
adhesive properties of the patches containing combination of
enhancers were also assessed manually using thumb test.
Table 3 provides the summary of results obtained using
combination of Brij

30 with selected enhancers in Duro-

Tak

87-502A matrix at 15% w/w drug load. Enhancement

ratios were calculated using ux from Brij

30 as control.
Only combinations of Brij

30 with Brij

52, Crovol

A40
and Plurol olieque

CC497 were found to have higher

enhancement ratio as compared to Brij

30 alone. Adhesive
properties of patches containing combination of Brij

30
with Plurol olieque

CC497 or Span

80 were found to be
unsatisfactory. Brij

52 could be added up to 5% in addition

to 5% Brij

30 without impairing the adhesive property of

the patch. Based on the ux and adhesion properties,
Time (h)
0 5 10 15 20 25
C
u
m
u
l
a
t
i
v
e

a
m
o
u
n
t

p
e
n
e
t
r
a
t
e
d

(
g
/
c
m
2
)
0
100
200
300
400
500
600
700
87-502 A, 5% Brij 30
87-503A, 5% Brij 30

Fig. 5 Permeation prole of donepezil at 15% drug load, in presence

of 5% Brij 30

, from Duro-Tak

87-502A and Duro-Tak

87-503A
matrices. (n = 3)
Table 2 Effect of penetration enhancers, at the level of 5% v/w, with
10% w/w of drug load in Duro-Tak

87-504A matrix. Values are

expressed as mean (n = 3)
S.
No.
Enhancer ER S.
No.
Enhancer ER
1 Control 1.00 14 Diisopropyl adipate 1.18
2 Brij

30 1.70 15 Oleyl oleate 1.11

3 Plurol oleique

CC497
1.02 16 Labrasol 1.19
4 Crovol

A 40 1.20 17 Tween

80 1.09
5 Oleyl alcohol 1.11 18 Limonene 0.97
6 Lauryl alcohol 0.94 19 Glycerol 1.24
7 IPM 1.22 20 Diisopropyl dirrerate 1.13
8 Span

80 1.17 21 Crovol

PK40 1.11
9 Transcutol

0.94 22 Hexyl Laurate 1.17

10 IPP 1.00 23 Octyl dodecyl ester 0.99
11 Cineole 1.07 24 Isotridecyl isononanoate 0.99
12 Brij

52 1.42 25 2-ethylhexyl
hydroxystearate
1.05
13 Alkyl 2-ethyl
hexanate
1.20 26 Diethoxylethyl
succinate
1.32
Table 3 Summary of the results obtained using combination of Brij

30 at the level of 5% v/w with selected enhancers at the level of 2.5%

v/w in Duro-Tak

87-502A matrix containing 15% w/w drug load.

Values are expressed as mean (n = 3)
Combination of enhancers ER Adhesive
property
Brij

30 1.00 Good
Brij

30, Plurol olieque

CC497 1.20 Unsatisfactory

Brij

30, Span

80 0.78
Brij

30, Oleyl alcohol 0.83 Good

Brij

30, Brij

52 1.37
Brij

30, Crovol

A40 1.27
Brij

30, IPP 0.80

Brij

30, Lauryl alcohol 0.75

Brij

30, Transcutol

0.70
Brij

30, Cineole 0.81

Transdermal drug delivery system for donepezil 5
1 3
combination of Brij

30 and Brij

52, each at the level of 5%

v/w, was selected for further studies.
Effect of combination matrix
Patches made with Duro-Tak

87-504A showed superior

adhesion properties to those formulated in Duro-Tak

87-503A or Duro-Tak

87-502A matrix. It is because,

among the acrylic rubber hybrid PSAs, only Duro-Tak

87-504A is tackied. However, highest drug loading was

possible in Duro-Tak

87-503A matrix. Drug loading

capacity was studied using various levels of drug load in
each matrix. The rank order obtained was Duro-Tak

87-503A[Duro-Tak

87-502A[Duro-Tak

87-504A.
The level of drug loading up to which clear patches could
be made determined the drug loading capacity of the
matrix. Therefore, to obtain superior adhesion and perme-
ation properties, combination of Duro-Tak

87-503A and
Duro-Tak

87-504A matrix was studied. Benet of mixing

PSAs for the improvement of adhesion properties is a
known art. Kanios described the combination of acrylic-
based polymers with silicone-based polymers to optimize
drug solubility and skin adhesion (Kanious 2006). Simi-
larly, transdermal patch of tulobuterol formulated in
polyethylene grafted acrylic polymer was mixed with
acrylic adhesive containing hydroxyl functional group to
improve the peeling off effect in the presence of water
(Kim and Choi 2003). Adhesion of transdermal patch to the
skin is an important factor directly related to drug delivery
and therapeutic effects. Since drug absorption process is
determined by partitioning of drug between TDDS and the
skin, complete skin contact over the entire delivery surface
for the labeled application period is essential (Wokovich
et al. 2006). If the TDDS lifts off or partially detaches from
the skin surface, it may lead to change of drug absorption
in an unpredictable manner. In the worst case, it could lead
to therapeutic failure. Drug load up to 10% w/w in Duro-
Tak

87-504A resulted in clear patches. Whereas, higher

amount of drug could be loaded in Duro-Tak

87-503A
matrix without visible particles. Solutions of PSAs con-
taining 10% w/w drug in Duro-Tak

87-504A and 20% w/w

drug in Duro-Tak

87-503A were mixed at various ratios.

Figure 6 shows the permeation of donepezil from such
combination matrices. Based on the higher permeation
prole obtained, 1:1 combination was selected for further
study.
The effect of drug loading in the combination matrix
selected was also studied in the presence of combination
enhancers. Figure 7 shows the effect of drug loading on the
permeation of donepezil from 1:1 combination of Duro-
Tak

87-503A and Duro-Tak

87-504A matrix. As seen in

the gure, permeation of donepezil increased linearly up to
15% w/w drug load. Beyond that point the extent of
increase was reduced, indicating the matrix is almost sat-
urated with the drug.
Stability
In order to explore the commercial viability, stability
studies were also conducted with the optimized formula-
tion containing combination of Brij

30 and Brij

52, each
at the level of 5% v/w with 15% w/w drug load in 1:1
combination of Duro-Tak

87-503A and Duro-Tak

87-
504A matrix. Patches were checked visually for any
change during the study period. Chemical stability of the
patches was check periodically by using stability indicating
analysis method. Table 4 provides summary of the physical
and chemical stability testing. No change in morphology of
Time (h)
0 5 10 15 20 25
C
u
m
u
l
a
t
i
v
e

a
m
o
u
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t

p
e
n
e
t
r
a
t
e
d

(
g
/
c
m
2
)
0
200
400
600
800
503A:504A (1:3)
503A:504A (1:1)
503A:504A (3:1)
Fig. 6 Effect of combining Duro-Tak

87-503A and Duro-Tak

87-
504A matrices at various ratios on the permeation of donepezil.
Values are expressed as mean (n = 3)
Drug loading (% w/w with respect to dry polymer)
4 6 8 10 12 14 16 18 20 22
I
n

v
i
t
r
o

f
l
u
x

(
g
/
c
m
2
)
200
300
400
500
600
700
800

Fig. 7 Effect of drug loading, in presence of 5% v/w Brij

30 and
5% v/w Brij

52, on the permeation of donepezil from 1:1

combination of Duro-Tak

87-503A and Duro-Tak

87-504A matrix.
Values are expressed as mean (n = 3)
6 R. K. Subedi et al.
1 3
the patch was observed. At 3rd month, patches stored in RT
showed slight decline in the assay value. However, during
content analysis, no peak other than the peak of donepezil
was observed. Chemical stability of patches stored in
refrigerator and 40C did not show signicant decline in
assay values during the study period of 3 months.
Conclusion
The obtained ux and the adhesive properties of the patch
suggest that therapeutic amount of donepezil could be
systemically delivered with a reasonable patch size. Con-
sidering the half life of 70 h for donepezil and high initial
ux obtained from the optimized formulation, it may be
possible to transdermally deliver donepezil for an extended
period of time. Based on daily dose of 4.6 mg and average
ux of approximately 20 lg/cm
2
/h, less than 30 cm
2
active
patch surface area is required to deliver therapeutic amount
of donepezil for a period of 3 days through hairless mouse
skin. However, the permeation rate of donepezil has not
been compared between hairless mouse skin and human
skin. Even if we assume that the hairless mouse skin is two
times more permeable than human skin, it is feasible to
develop multiple day transdermal drug delivery system for
donepezil using a reasonable patch size.
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Table 4 Summary of chemical and physical stability of donepezil patch containing 15% w/w drug, 5% v/w Brij

30 and 5% v/w Brij

52 in 1:1
combination matrix of Duro-Tak

87-503A and Duro-Tak

87-504A. Values are expressed as mean standard deviation (n = 3)

Month Refrigerator Assay 40C Physical stability
RT Refrigerator RT 40C
1 97.7 2.50 96.3 0.66 96.4 3.62 Clear Clear Clear
2 95.5 1.99 96.1 2.42 98.0 2.55 Clear Clear Clear
3 95.0 2.78 92.0 1.46 94.4 3.42 Clear Clear Clear
Transdermal drug delivery system for donepezil 7
1 3