Journal of Pharmaceutical Investigation {20! 2] 4211—?
`DOI I 0. I 00?!5400054) I 2—0fli2—y
`
`RESEARCH ARTICLE
`
`Formulation and in vitro evaluation of transdermal drug delivery
`system for donepezil
`
`Robhash Kusam Subedi - Jc-Phil Ryoo .
`Cheol Moon - Myung-Kwan Churn -
`Hoo-Kyun Choi
`
`i8 October 201 1 fAcecplcd: 23 November 2011 {Published online: 20 Januaryr 2012
`Received:
`© The Korean Society of Pharmaceulieal Sciences and Technology and Springer Dordrechi 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 flow-
`through diffusion cell system at 37°C. The penetration of
`donepezil from the matrices was found to be influenced by
`the nature of adhesives. 1:1 combination of acrylic rubber
`hybrid adhesives ItDuro—Tak‘Lo 87—503A and Duro—Tak®
`8Y—504A) provided good adhesion force and high flux of
`donepezil. Significant increase in flux was obtained using
`Brijoo 30. Brijm 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% vfw with IS% wt‘w drug load in 1:1 combi-
`nation of Duro—Tak‘” 87—503A and Duro—Tak® Sit—504A
`matrix was found to be the best. No significant 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 - Transdennal drug delivery -
`Percutaneous penetration - Chemical enhancers -
`Alzheimer’s disease
`
`
`
`R. K. Suhedi - M.—K. Chun - H.-K. Clioi I531}
`3K2] Project Team, College of Pharmacy. Chosun University,
`375 Seosuk-dong. Dong—gu. Gwangju 501—759. South Korea
`e—mail: hgehoi@chosun.ac.kr
`
`J.—P. Ryoo - C. Moon
`NAL Pharmaceuticals Ltd. Monmouth Junction. New Jersey.
`USA
`
`Donepezil is a centrally acting reversible aeetylcholines—
`tearase inhibitor and exerts its
`therapeutic effect by
`increasing aeetylcholine concentrations and enhancing
`cholinergic function (Rogers and Friedhoff i998; Sugimoto
`et al. 1995). Commercially. donepezil
`is available in the
`form of tablet under the trade name Aricept‘i’. Initial dose is
`5 mg per day. which can be increased to It) 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 Alzheimer’s 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 a]. 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. 200?). The
`microparticles were prepared using poly (D, L—lactide—co
`glycolidc) by an oil—water emulsion solvent evaporation
`technique. However. due to the better patient compliance.
`controlled delivery of drug, ease of administration as well
`as termination. a transderma] product of donepezil would
`be more appropriate in providing clinical benefit 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 a]. 2010). In many
`cases. the absorption may not result in sufficient plasma drug
`concentration. Various studies have been conducted. along
`with their pros and cons, to develop transderma] product
`of doncpezi]. Matrix based transderma] system has been
`
`@ Springer
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2021
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`IPR2018-O1119
`
`

`

`R. K. Subedi el al.
`
`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 (230°C) was reduced to around 90°C after the
`conversion (Fig. l). 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 sufficiently. The mixture
`was cast on release liner coated with silicone and solvent
`
`was removed by evaporation at 80°C 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 rare
`
`Skin permeation rates of various donepezilr’enhancer for—
`mulations were determined using flow 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 flow-
`through diffusion cells was used. Each flow—through cell had
`two arms, which allowed the receiver cell medium pumped
`to a fraction collector. The diffusion cell temperature was
`maintained at 37°C by circulating water through the outer
`part of jacketed receiver cell. The surface area of receiver
`cell opening was 2 cm2, and its volume was 5.5 ml. Skin was
`excised from hairless mouse that was humanly sacrificed
`
`
`
`-23
`
`-24
`
`C3
`
`.8 -25
`Em
`E.
`I:
`.g -26
`m
`
`2.; — donepezil base
`donepezil HCL
`
`.23
`
`
`1
`.
`'
`'
`so
`100
`150
`200
`
`I
`250
`
`0
`
`Temp (00)
`
`Fig. I Diifercntial scanning calorimetric thennogram of donepezil as
`base and hydrochloride salt form
`
`reported for donepezil (Kazunosuke et a]. 2008). However,
`to achieve the sufficient transdermal flux through hairless
`mouse skin, extremely high drug loading (35% wr‘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 el al. 2009). Salt form of donepezil precipitates in
`the adhesive matrix forming particles in the patch, which
`reduces the aesthetic value of the patch. Reservoirtype patch
`system was also described for delivery of Alzheimer’s
`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 flux 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
`oleale (Plurol olieque® CC497), propylene glycol mono
`laurate (Lauroglycol), and polyoxy glycerate (Labrafil®
`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-
`mitale (IPP),
`isopropyl myristate (1PM), 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,
`polyisobulylene
`(P13)
`and
`styrene—butadiene—styrene
`(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 purification.
`
`@ Springer
`
`0002
`
`

`

`Trausdermal drug delivery system for donepezil
`
`with diethyl ether. Subcutaneous fat was removed with
`scissors and scalpel. Each of the flow—through diffusion cell
`components was connected via silicone rubber tubing with
`an internal diameter of 0.0l5 inches. The receiver cell was
`
`filled with a pH 6 buffer solution and the media was stirred
`by Teflon-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
`Scientific Instruments, MD), consisting of a UV detector
`(SPD—IOA), reversed—phase C13 column (4.6 x 100 mm,
`5 pm, Gemini), a pump (LC710AD), and an automatic
`injector (SIL—lUA). Briefly,
`the wavelength of the UV
`detector was 315 nm, the column temperature was main-
`tained at 30°C, the flow rate was I mlt'min and injection
`volume was 10 pl. Mobile phase consisted of Acetonitrilet'
`phosphate buffer 0.1 M with triethanolamine (0.01% vtv)
`adjusted to pH 2.7 with 85% phosphoric acid (30t70).
`
`Content analysis
`
`4 cm2 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
`tefion coated magnetic bar was added. The container was
`then capped and sealed with Parafilm®. Then, the samples
`were sonicated for 30 min followed by stirring for 12 h. The
`backing membrane was removed from the container, washed
`with ethyl acetate to remove the PSA matrix, and weighed.
`The solution was filtered through Whatman® nylon mem-
`brane filter (13 mm, 0.45 pm) and analyzed by HPLC.
`
`DWerentiai 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 5°Ct'min from 25 to 250°C.
`
`stability of the patches kept in refrigerator (2—8°C). room
`temperature (RT) and 40°C 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
`Scientific Instruments. MD), consisting of a UV detector
`(SPD-IOA). reversed-phase Cm column (4.6 x 150 mm,
`5 pm, Shiseido), a pump (LC—IOAD), and an automatic
`injector (SIL—IOA) was used. Briefly, the wavelength of the
`UV detector was 271 nm,
`the column temperature was
`maintained at 25°C.
`the flow rate was
`1 mltmin and
`
`injection volume was 20 pl. The mobile phase used con—
`sisted of sodiuml—decansulfonate aqueous solutionJ'Acet—
`onitrilet'i0% perchloric acid 2 650t350t1 (volume ratio);
`sodium l-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-
`nepezi] was investigated using silicone, PIB, SBS, acrylic
`and acrylic rubber hybrid adhesive matrixes. Permeation
`profile of donepezil from various PSA matrices is shown
`in Fig. 2. Solubility of donepezil was found to be inad—
`equate in silicone and P13 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 influence flux of drug from PSA across the
`skin (Hai et al. 2008; Venkatraman and Gale 1998). The
`permeation rate was lowest in the FIR matrix, followed
`
`nl
`,_., 300 + PIB
`
`.0...
`335
`
`—— +—— Acrylic non functional
`—---fl----- Acrylic hydroxy functional
`— + — Acrylic rubber hybrid
`—- —D— -— Acrylic carhoxy functional
`
`l
`
`/
`
`/
`/ /.
`
`
`
`
`
`
`
`
`
`Cumulativeamountpenetrated(ugtcm
`
`
`
`25“
`
`200
`
`[50
`
`[00
`
`U1 D
`
`D
`
`Stability
`
`Time (h)
`
`Stability studies of the optimized formulation were con-
`ducted at three different temperature conditions. Physical
`
`Fig. 2 Screening of different pressure sensitive adhesives at 10% wtw
`of drug load. Values are expressed as mean (it = 3}
`
`0003
`
`4r; Springer
`
`

`

`R. K. Subcdi et al.
`
`+ scum
`—0— 25 am
`+
`10011171
`—c~— 120 um
`
`/
`
`.
`
`.
`
`51x1
`
`a.
`",1
`o
`31'
`3 41111
`
`"3'
`
`11111
`
`penetrated 21111
`Cumulativeamount
`
`
`A
`
`/‘
`
`1
`10
`
`1
`1 5
`
`I'
`2o
`
`I
`25
`
`I}
`
`a
`
`_.../: ..
`I
`5
`
`Time (h)
`
`Fig. 4 Effect of acrylic rubber hybrid matrix thickness on the
`permeation of donepezi]. Values are expressed as mean (in = 3)
`
`Effect of enhancer
`
`To reversibly overcome the barrier properties of stratum
`comeum, penetration enhancers are commonly employed
`in the transdermal systems (Williams and Barry 2004).
`Enhancer screening was carried out with both Duro-Talv;®
`87-502A and 87-504A matrices. Table 1 gives the sum-
`mary of enhancer screening at the level of 5% vr'w with
`15% wr'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®
`
`Table 1 Summary of enhancer screening at the level of 5% w'w with
`15% wr'w drug load in Duro-Tak® ST-SIHA acrylic rubber hyblid
`matrix. Values are expressed as mean (:1 = 3)
`
`S. No.
`
`I
`
`2
`3
`4
`
`5
`6
`'1'
`
`8
`9
`
`10
`I 1
`12
`
`13
`
`Enhancer
`
`Control
`
`Brijm 30
`Plurol oliequem C0119?
`Crovol‘E A 40
`
`Oleyl alcohol
`Laury] alcohol
`[PM
`
`Sugar ester P-lGYO
`Limonene
`
`Span.‘E so
`Transculolag
`IPP
`
`Cineole
`
`ER*
`
`1.00
`
`2.10
`1.471I
`1.32
`
`1.3'1'
`1.34
`1.12
`
`1.33
`1.06
`
`1.25
`1.17
`1.111'
`
`1.1]
`
`+ 87—502 A
`........0 815031"
`—+- Sit—504 A
`
`”Y
`
`/
`
`
`
`
`
`by highly crossed linked acrylic adhesive containing
`carboxyl
`functional group. Duro—Tak® 8?—26??. 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 a1. 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 flux 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
`a1.
`2003}. Higher flux 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 profile of donepezil was unchanged when matrix
`increased from 65 to 85 um (Fig. 4). However, further
`increase in matrix thickness resulted in lower permeation
`profile of donepezil. Matrix thickness of 85 um was chosen
`for further experiments based on better adhesive properties
`as compared to 60 um matrix.
`
`m] _
`
`3m -
`
`200 -
`
`
`
`Cumulativeamountpenetrated(ugicmfi 8
`
`‘3
`
`Jr
`
`11]
`
`15
`
`20
`
`25
`
`Time (h)
`
`Fig. 3 Screening of different rubber acrylic hybrid pressure sensitive
`adhesives at 15% wr'w drug load. Values are expressed as mean
`(11 = 3)
`
`1.09
`Labrafil‘i’ 1944
`14
`1.04
`lncrocas‘i’ 30
`l5
`16 1.29 Brijm 52
`
`
`’3 ER enhancement ratio
`
`@ Springer
`
`0004
`
`
`
`
`
`
`
`G
`
`
`
`

`

`Transdermal drug delivery system for donepezil
`
`'l'llll ~
`
`—0— 37-50: 14.5% Brij 30
`--------o sir-scan. 5a Brij 30
`
`..o
`
`6”” -
`
`500 ~
`
`400 ~
`
`200 ~
`
`100*
`
`
`
`
`
`Cumulativeamountpenetrated(ugl'cmz)
`
` u—u
`
`
`
`0
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`ratios in both Duro-Tak® 87-502A and Duro-Tak® 87-504A
`
`matrices and was chosen for further experiments. BriquJ 30 is
`a surfactant which belongs to the class of polyoxyethylene
`(POE) alkyl ethers. The E0 chain length and HLB value of
`Brij® 30 is 4 and 9.7 respectively. Studies have shown that
`POE alkyl ethers containing E0 chain length of 2—5 and
`HLB value 7—9 are effective promoters for the percutaneous
`absorption of drug molecules (Park et a1. 2000). an® 30
`could efficiently 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).
`
`Time (h)
`
`Effect of combining enhancers
`
`Fig. 5 Permeation profile of donepezil at 15% drug load. in presence
`015% Brij 3099, from Duro-Tak® 87-502A and Duro-Tak® 87-503A
`matrices. (M = 3)
`
`C0497"1 Crovol® A40, oleyl alcohol, lauryl alcohol, sugar
`ester P—1670, Span® 80 and Brij® 52 significantly enhanced
`the in vitro flux 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 Fi g. 5, no significant difference was observed.
`Table 2 gives the summary of enhancer screening at
`the level of 5% vl'w with 10% wlw drug load in Duro-Tak®
`87—504A acrylic rubber hybrid matrix. Among the enhancers
`screened, Brij® 30, Brij® 52, 1PM, glycerol and diethoxy—
`ethyl
`succinate were associated with the significant
`enhancing effect. Brij® 30 provided highest enhancement
`
`Table 2 Effect of penetration enhancers, at the level of 5% WW, with
`10% wl'w of drug load in Duro—‘l‘ak‘Lo 81—50414 matrix. Values are
`expressed as mean (11 = 3)
`S.
`Enhancer
`ER
`S.
`Enhancer
`ER
`No.
`No.
`
`1
`
`2
`3
`
`4
`
`5
`6
`'1'
`
`3
`9
`10
`l
`l
`
`12
`
`l3
`
`Control
`
`Brij‘i’ 30
`Plurol oleique‘Lo
`CC497
`
`Crovolw A 40
`
`Oleyl alcohol
`Lauryl alcohol
`IPM
`
`Spain" 30
`Transcutolm
`[PP
`Cineole
`
`Brij® 52
`
`1.00
`
`1.10
`1.02
`
`1.20
`
`1.] 1
`0.94
`1.22
`
`1.17
`0.94
`1.00
`1.0"}I
`
`1.42
`
`14
`
`15
`16
`
`17
`
`18
`19
`20
`
`21
`22
`23
`24
`
`25
`
`Alkyl 2—ethyl
`hexanate
`
`1.20
`
`26
`
`Diisopropyl adipate
`
`Oleyl oleate
`Labrasol
`
`Tween0g 80
`
`Limonene
`Glycerol
`Diisopropyl dirrerate
`
`Crovolf" PK40
`Hexyl Laurate
`Octyl dodecyl ester
`Isotridecyl isononanoale
`
`2—ethylhexy1
`hydroxystearate
`Diethoxylethyl
`succinate
`
`1.18
`
`1.11
`1.19
`
`1.09
`
`0.97
`1.24
`1.13
`
`1.11
`1.171I
`0.99
`0.99
`
`1.05
`
`1.32
`
`To further increase the transdermal flux of donepezil. effect
`of combining selected enhancers at the level of 2.5% vlw
`with 5% vfw 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 creepl'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% wr'w drug load. Enhancement
`ratios were calculated using flux from Brij® 30 as control.
`Only combinations of Brij® 30 with an® 52, Crovol® A40
`and Plurol olieque® CC49? 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 flux and adhesion properties.
`
`Table 3 Summary of the results obtained using combination of Brij®
`30 at the level 015% vilw with selected enhancers at the level of 2.5%
`
`vl'w in Dum—Tak® 87—502A matrix containing 15% wt'w drug load.
`Values are expressed as mean (11 = 3}
`Combination of enhancers
`ER
`Adhesive
`properly
`
`Brij® 30
`
`an® 30, Plurol oliequem c0497
`Brij® 30. Spanm 80
`an? 30. Oleyl alcohol
`Brij® 30, Brij® 52
`Bn’j‘” 30, crovor‘a A40
`Brij® 30, IPP
`
`100
`
`1.20
`0.78
`083
`1.37
`1.27
`0.80
`
`Good
`
`Unsatisfactory
`
`Good
`
`0.75
`3111‘?“ 30, Lauryl alcohol
`any” 30. Transcutol‘”
`0.70
`
`Brij® 30. Cineole
`0.81
`
`0005
`
`it; Springer
`
`

`

`6
`
`R. K. Subcdi el al.
`
`) asE
`
`1
`
`+ 503A:504AH:3J
`----o---- 503A:504A(1:I1
`—+- snsnzsrnncsm
`
`. 0
`
`§
`
`3
`
`
`
` g Cumulativeamountpenetratedtpgi’cm
`
`combination ofBrij® 30 and Brij® 52, each at the level of5%
`w’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 tackified. 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
`DuronTak® 877504451 matrix was studied. Benefit 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% wfw 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% wi’w drug in Duro—Tak® 87—504A and 20% wrw
`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
`profile 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® 37-503A and Duro-Tak® 87-504A matrix. As seen in
`
`the figure, permeation of donepezil increased linearly up to
`15% wr'w drug load. Beyond that point
`the extent of
`
`
`
`
`
`
`
`3
`
`o
`
`5
`
`1'0
`
`1'5
`Time (h)
`
`2h
`
`25
`
`Fig. 6 Effect of combining Duro—Tak® 37-50% and Dim—Tax3g 8?—
`504A matrices at various ratios on the permeation of donepezil.
`Values are expressed as mean (it = 3}
`
`
`
`Invitroflux(ugfcmz)
`
`'2‘§§§§
`200i
`
`§
`
` t r r r r I
`
`t
`
`
`
`
`4
`6
`8
`10
`12
`14
`16
`18
`2'0
`22
`
`Drug loading (% wt'w with respect to dry pol ymer)
`
`Fig. 7 Eflect of drug loading, in presence of 5% vlw an® 30 and
`5% vfw Brij‘i’ 52, on the permeation of donepezil
`from H
`combination of Dum—Tak® 87—503A and Duro—Tak‘i’ 87—504A matrix.
`Values are expressed as mean (it = 3)
`
`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% vl'w with 15% MW 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
`
`@ Springer
`
`0006
`
`

`

`Transdermal drug delivery system for donepezil
`
`7
`
`Table 4 Summary of chemical and physical stability of donepezil patch containing |5% wfw drug. 5% vi'w Brij‘m 30 and 5% viw Brij'jo 52in lzl
`
`Combination matrix of Duro—Takqg 87—5034 and Doro—Tab”) 82—50414. Values are expressed as mean :: standard deviation (a = 3)
`
`Month
`
`Refrigerator
`
`]
`2
`3
`
`
`97.? :: 2.50
`95.5 :t 1.99
`95.0 :t 2.78
`
`Assay
`
`RT
`
`96.3 :1: 0.66
`96.1 :t 2.42
`92.0 :I: 1.46
`
`40°C
`
`Physical stability
`
`96.4 :I: 3.62
`98.0 :I: 2.55
`94.4 :I: 3.42
`
`Refrigerator
`
`Clear
`Clear
`Clear
`
`RT
`
`Clear
`Clear
`Clear
`
`40°C
`
`Clear
`Clear
`Clear
`
`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 40°C did not show significant decline in
`assay values during the study period of 3 months.
`
`Conclusion
`
`The obtained flux 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
`flux 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
`flux of approximately 20 ug/cmzr'h, less than 30 cm2 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
`
`is feasible to
`it
`times more permeable than human skin,
`develop multiple day transdermal drug delivery system for
`donepezil using a reasonable patch size.
`
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