Journal of Pharmaceutical Investigation {2012) 421—?
`DOI ltl.ltltl?ts4fl(JflS-tl12-(1002-y
`
`' RESEARCH ARTICLE
`
`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
`
`Iii October 201 | (Accepted: 28 November 201 I lPuhlis-hed online: Ill January 2t} [2
`Received:
`If) The Korean Society of Pharmaceutical Sciences and Technology and Springer Dordreehl lel'l
`
`Abstract The effects of diffeient formulation variables
`
`on the transderinal 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.
`lzl combination of acrylic rubber
`hybrid adhesives (Duro~Tak® 87—503A and Duro—Tak®
`87—504A} provided good adhesion force and high flux of
`donepezil. Significant increase in flux was obtained using
`Brij'm 30, Brijo") 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 Bl'ljo'?’ 30 and Brijw 52, each at the
`level of 5% WW with 15% WW drug load in H combi-
`nation of Duro—Tak® 8Y—503A and Duro—Tak® 87—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 - Transdermal drug delivery -
`Percutaneous penetration - Chemical enhancers -
`Alzheimer‘s disease
`
`R. K. Subutli - M.—K. Chun - H.—K. Choi [5.3%]!
`BKZI Project Team. College of Pharmacy. Chosun University.
`375 Seosuk—dong. Dong—gu. Gwangju SUI-T59. South Korea
`c-rnail: hgchoi®chosun.ac.kr
`
`LP. Ryoo - C. Moon
`NAL Pharmaceuticals Ltd, Monmouth Junction. New Jersey,
`USA
`
`is a centrally acting reversible acetylcholines-
`Donepezil
`tearase inhibitor and exerts
`its therapeutic effect by
`increasing acetylcholine concentrations and enhancing
`cholinergie function (Rogers and Friedhoff 1998: Sugimoto
`et al. 1995}. Commercially, donepezil is available in the
`form of tablet under the trade name Arieept‘m. 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 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 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 donepezi]
`(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 donepeai] as monthly subcuta—
`neous injection has been reported (Zhang et al. 2007). The
`microparticles were prepared using poly (o. I.-lactide-eo-
`glycolide) 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 transdermal product of donepezi] 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 al. 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 transderrnal product
`of donepezil. Matrix based transdertnal system has been
`
`@ Springer
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2021
`
`Mylan Tech, Inc. v. Noven Pharma, Inc.
`IPR2018-00174
`
`

`

`R. K. Suhcdi et 31.
`
`Methods
`
`Patch preparation
`
`Since patches prepared using salt form showed very low
`permeability (data not shown). donepezi] 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. I). 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 rate
`
`Skin permeation rates of various donepezilienhancer for—
`mulations were determined using flow through diffusion
`cells. Permeation experiments were done on isolated hairless
`mouse skin. A system comprising a multichannel 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
`ceil opening was 2 cm2. and its volume was 5.5 ml. Skin was
`excised from hairless mouse that was humanly sacrificed
`
`
`
`-23
`
`.24
`
`C E
`
`13 -25
`E5
`cu
`E.
`:
`8 —26
`LIJ
`
`Q7 — donepezil base
`-donapeziIHCL
`
`-23
`
`
`.
`i
`.
`.
`.
`U
`50
`100
`150
`200
`250
`
`Temp (00)
`
`Fig. 1 Differential scanning calori metric thcrmogram of donepezil as
`base and hydrochloride salt form
`
`reported for donepezil (Kazunosuke et al. 2008). However,
`to achieve the sufficient transdermal flux through hairless
`mouse skin, extremely high drug loading (35% wtw} 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 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
`oleate (Plurol olieque® CC49i), 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). lsopropyl pal—
`mitate (IPP).
`isopropyl myristate (1PM), PEG-12 palm
`kernel glycerides (Crovol® PK40), and PEG-20 almond
`glycerides (Crovolei A40) were obtained fmm 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
`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). Ail
`other chemicals were reagent grade or above and were used
`without further purification.
`
`@_ Springer
`
`0002
`
`

`

`'l‘ransdcrma] drug delivery system for doncpezil
`
`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 0.015 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—Iing and cell top
`was placed on the top of each skin. These comp0nents 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
`
`Donepezii was analyzed by HPLC system (Shimadzu
`Scientific Instruments, MD), consisting of a UV detector
`(SPD-IOA), reversed-phase C”; column (4.6 x 100 mm,
`5 pm. Gemini). a pump (LC—IOAD), and an automatic
`injector (SlL-IOA]. 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 Acetonitrile/
`phosphate buffer 0.1 M with triethanolamine (0.01% vtv}
`adjusted to pH 2.? with 85% phosphoric acid (30:70}.
`
`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 Paratilm®. Then, the samples
`were sonicated for 30 min followed by stirri n g 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 (I3 mm, 0.45 pm} and analyzed by HPLC.
`
`Dtfierential scanning calorimetry (DSC)
`
`Thermal analysis was carried out to characterize donepezil
`hydrochloride and base form, using a DSC unit (Pyr‘is 6
`DSC. Perkin-Elmer. Netherlands).
`Indium was used to
`
`calibrate the temperature scale and enthalpic tesponse.
`Samples were placed in aluminum pans and heated at a
`scanning rate of 5°Ct‘rnin from 25 to 250°C.
`
`
`
`.
`5
`
`.
`10
`
`.
`ii
`
`.
`20
`
`.
`25
`
`.
`
`0
`
`o
`
`2 s
`
`E3
`
`U
`
`Stability
`
`Time (h)
`
`Stability studies of the optimized formulation were con-
`ducted at three different temperature conditions. Physical
`
`Fig. 2 Screening ot'different pressure sensitive adhesives at 10% wlw
`of drug load. Val ucs are expressed as mean (it = 3)
`
`0003
`
`@ Springer
`
`stability of the patches kept in refrigerator (Tl—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 C's column {4.6 x 150 mm.
`5 pm, Shiseido), a pump (LC—IOAD), and an automatic
`injector (SlL—IOA) was used. Briefly, the wavelength of the
`UV detector was 27] nm,
`the column temperature was
`maintained at 25°C,
`the flow rate was
`1 mlfmin and
`
`injection volume was 20 pl. The mobile phase used con-
`sisted of sodiuml-decansulfonate aqueous solutiontAcet-
`onitriler’?0% perchloric acid 2 65085011 (volume ratio};
`sodium l—decansulfonate concentration was l0 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
`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 P13 matrix, followed
`
`300 _ —-I— PlB
`.............O 335
`———-r——— Acrylic non functional
`—- -—o — . Acrylic hydroxy functional
`/
`— —I — Acrylic rubber hybrid
`/ / /.
`—--fl--— Acrylic carboxy functional
`—— + — Silicone
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`
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`
`15“ -
`
`

`

`'é
`
`R. K. Suhedi et al.
`
`
`
`400
`
`300
`
`300
`
`100
`
`Cumulativeamountpenetrated(pglcm'i
`
`
`
`
`
`+ raopm
`—0— 85 um
`+ Ititipm
`+ lzttum
`
`
`
`
`
`
`
`
`by highly crossed linked acrylic adhesive containing
`carboxyl
`functional group, Duro-Tak‘E’ 8126?? This
`could be due to the interaction between amine group of
`donepezil and carboxyl group of the adhesive. ln previoas
`study. low permeation rate of tactine 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, DUTO—Tak® iii—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 8?—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 maeromer
`and hydroxyethyl aerylate monomer
`(Foreman et
`al.
`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.
`
`+ ST-SUEA
`----o---- git—50ft A
`~+~ s'i-jtux
`
`'
`
`//
`
`A 400 -
`”E
`:33
`E
`3 300 ~
`3E
`(-1_.
`
`zoo-
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`
`';
`
`g Inn ~
`
`
`
`E.
`
`EU
`
`0
`
`n
`
`I
`5
`
`’
`In
`
`I
`I3
`
`I
`an
`
`I
`35
`
`Time (h)
`
`Fig. 3 Screening of different rubber acrylic hybrid pressure sensitive
`adhesives at
`[5% wfw drug load. Values are expressed as mean
`(it = 3)
`
`E Springer
`
`0004
`
`0
`
`5
`
`It!
`
`15
`
`2t]
`
`25
`
`Time (h)
`
`Fig. 4 Effect of acrylic rubber hybrid matrix thickness on the
`permeation of donepezil. Values are expressed as mean (a = 3}
`
`Effect of enhancer
`
`To reversibly overcome the barrier properties of stratum
`corneum. penetration enhancers are commenly 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% vi'w with
`15% wi'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% vi‘w with
`IS% wfw drug load in Duro-Takug 81502A acrylic rubber hybrid
`matrix. Values are expressed as mean (it = 3)
`S. No.
`Enhancer
`
`ER“:
`
`1
`
`2
`3
`4
`
`S
`b
`7
`
`8
`9
`
`10
`I
`|
`u
`:3
`
`Comm]
`
`Brufl 30
`Plunol olieque'g' CC497
`Cmvur“ A 40
`
`Oleyl alcohol
`Lauryl alcohol
`IPM
`
`Sugar ester P4610
`Limonene
`
`Span®'so
`Transeutolm
`mp
`Chmde
`
`[no
`
`2.n}
`L47
`1.32
`
`[.37
`[.34
`112
`
`[.33
`[.06
`
`1.25
`Ll?
`Ln
`LH
`
`L09
`Lamafifm1944
`14
`[.04
`lneroeasr’c 30
`15
`i6 1.29 Brflg 52
`
`
`’3 ER enhancement ratio
`
`

`

`'l‘raltsdernta] drug delivery system for donepezil
`
`701'l
`
`
`
`
`
`
`
`Cumulativeamountpenetrated(ttgt’cm‘l
`
`(100
`
`500
`
`400
`
`300
`
`200
`
`l 00
`
` D
`
`+ more A. ser- Brij an
`-----o 87-503A.5‘}t Brij 30
`
`.o
`
`
`
`t:
`
`‘JI
`
`5
`
`[5
`
`2t!
`
`25
`
`ratios in both Duro-Tak® 82-502A and Du ro-Takfij 8?-504A
`
`matrices and was chosen for further experiments. Brij'® 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 al. 2000). Brij® 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. [987).
`
`Time (h)
`
`Effect of combining enhancers
`
`Fig. 5 Permeation profile of donepczil at [5% drug load. in presence
`of 5% anj 30‘”. from Durtt—Takm 87-502A and Doro-"raw 87—503A
`matrices, (a = 3)
`
`CC497, Crovol® A40, oleyl alcohol, lauryl alcohol, sugar
`ester 13-1670, 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® 82—50313. As
`
`can be seen in Fig. 5, no significant difference was observed.
`Table 2 gives the summary of enhancer screening at
`the level of 5% vt‘w with [0% wl'w 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% W‘w. with
`|0% who of drug load in onto—Talc” 537—504;». matrix, Values are
`expressed as mean (it = 3)
`S.
`Enhancer
`ER
`5.
`Enhancer
`ER
`No.
`No.
`
`1
`
`2
`
`4
`
`5
`6
`7
`
`s
`9
`[0
`l
`|
`
`12
`
`13
`
`Control
`
`Brijw 30
`Pluro] oleiqucr'ii
`C0191l
`
`Crovolw' A 40
`
`Oleyl alcohol
`Laury] alcohol
`[PM
`
`Span‘“‘ 80
`Transcutolq"
`[PF
`Cineole
`
`Brij'g 52
`
`1.00
`
`1.70
`1.02
`
`1.20
`
`1. | l
`0.94
`[.22
`
`to'
`0.94
`[.00
`1.07
`
`1.42
`
`14
`
`[5
`[6
`
`[7
`
`[8
`[9
`20
`
`21
`22
`23
`24
`
`25
`
`Alky] 2—ethyl
`hexanate
`
`1.20
`
`26
`
`Diisopropyl adipate
`
`Oleyl oleate
`Labrasol
`
`Tween!" 80
`
`Limonene
`Glycerol
`Diisopropyl dirrerate
`
`Crovol'” PK40
`Hexyl Laurate
`Octyl dodecyl ester
`Isotridecy] isononanoate
`
`2—cthylhexyl
`hydroxystearatc
`Dicthoxylethyl
`succinate
`
`HS
`
`[J I
`|.|9
`
`[.09
`
`0.9}I
`1.24
`1.13
`
`l.ll
`LI?
`0.99
`0.99
`
`[.05
`
`[.32
`
`To further increase the transdermal flux of donepezil, effect
`of combining selected enhancers at the level of 2.5% viw
`with 5% vlw of Brij® 30 was studied. Especially for drug in
`adhesive type ofTDDS, presence ofadditives can modify the
`mechanical characteristics of PSA, and might make the
`adhesive more susceptible to creept’cohesive failure. Hence,
`adhesive properties ofthe 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% why drug load. Enhancement
`ratios were calculated using flux from Brij® 30 as control.
`Only combinations of Brij® 30 with Brij® 52. Ctovol® A40
`and Plurol olieque® C0497 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® (SC-49'? 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 Brijog
`30 at the level of 5% vlw with selected enhancers at the level of 25%
`
`WW in Duro—Takm 87—502A matrix containing [5% wtw drug load.
`Values are expressed as mean (it = 3)
`Combination of enhancers
`
`ER
`
`Adhesive
`property
`
`Good
`Unsatisfactory
`
`1.00
`Brijt‘ 30
`[.20
`Brijm 30, Floral olieque'10 C019?
`0.78
`Brij® 30. spans" 80
`0.33
`soft 30. Oleyl alcohol
`[.37
`Brij‘i" 30. Brij‘m’ 52
`1.27
`Bar” 30. Crovol‘g" A40
`0.30
`Brut" 30, [PP
`0.75
`Brij’j'" 30, Lauryl alcohol
`Brij‘E 30. 'rranscutoll‘i'
`0.70
`
`Brut” 30. Cineole
`0.8l
`
`Good
`
`0005
`
`@ Springer
`
`

`

`R. K. Suhcdi et ai.
`
`.+ 503A1304A tl:3l
`- 0-
`503A:504A l |:ij
`—+— 503A:504A (3:11
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`
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`
`Cumulativeamountpenetratedtugfcm‘)
`
`
`
`
`
`\—v
`
`combination of Brij® 30 and Brijq” 52, each at the level of5%
`vi’w. was selected for further studies.
`
`Effect of combination matrix
`
`Patches made with Duro-Takfi'G 87-504A showed superior
`adhesion properties to those formulated in Duro-Tak®
`87—503A or Duro-Tak® 81502.4 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® 8?—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 2» Duro—Tak® 8?—502A a» bum—rareE iii—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. 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,
`transderrnal 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 transderrnal 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 a]. 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® 81504151 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% wt'w drug in Duro-Tak® 87-504A and 20% wr‘w
`drug in Duro-Takfi‘g 87-503A were mixed at various ratios.
`Figurefi shows the permeation of donepezil
`from such
`combination matrices. Based on the higher permeation
`profile obtained, 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® 37-504A matrix. As seen in
`
`the figure, permeation of donepezil increased linearly up to
`15% wfw drug load. Beyond that point
`the extent of
`
`Time in)
`
`Fig. 6 Effect of combining Duto—Tak'je 87-50391 and lfJurowTak‘q'O 87-
`504A matrices at various ratios on the permeation of donepczil.
`Values are expressed as mean (it = 3)
`
`$00
`
`T00
`
`”J
`
`Invitroflux(pglcm‘) 600
`
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`
`500
`
`300
`
`2tx}
`
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`I
`6
`3
`10
`| 2
`| 4
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`| 8
`20
`22
`
`4
`
`Drug loading (% wtw with respect to dry polymer)
`
`in presence of 5% WW Brij® 30 and
`Fig. 7 Effect of drug loading,
`5% vtw BrijQC 52, on the permeation of donepezil
`from H
`combination of Duro-Tak'E 87-503A and Duro-Takug 87-504A matrix.
`Values are expressed as mean (in = 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% vi‘w with IS% wt'w drug load in 1:1
`combination of Duro-Takf‘J 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
`
`E Springer
`
`0006
`
`

`

`'l‘ransderma] drug delivery system for donepczil
`
`Table 4 Summary of chemical :u‘id physical stability ofdonepezil patch containing |5% wlw drug. 5% vi’w Brij'F' 30 and 5% vlw Brij'F' 52 in 1:]
`combination matrix of Dum—Tak'k' 81—503A and Doro—Tait? 82—504A. Values are expressed as mean :l: standard deviation in = 3)
`
`Month
`
`Refrigerator
`
`1
`2
`3
`
`97.7 i 2.50
`95.5 :1: L99
`95.0 d: 2.28
`
`Assay
`RT
`
`96.3 i 0.66
`96.] d: 2.42
`92.0 :‘l: [.46
`
`40°C
`
`Physical stability
`
`96.4 :I: 3.62
`
`98.0 i 2.55
`94.4 d: 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 donepezi] 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 ugi’cmgi’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.
`
`References
`
`Breuer MM ([979) The interaction between surfactruns and kerati~
`nous tissues. J Soc Cosmet 30:41—64
`
`for
`(2002) Novel acrylic adhesives
`Cantor AS, Wirtanen DJ
`transdermal drug delivery. Phru‘rna Technol N Am 26(l):28—38
`da Silva CHTP. Campo VL. Carvalho l. Taft CA (2006) Molecular
`modeling, docking and ADMET studies applied to the design of
`a novel hybrid for treatment of Alzheimer‘s disease. J Mol Graph
`Model 25169—175
`
`Foreman PB. Shah SM. Chandran R, Eaton PS (2003) Rubber—acrylic
`adhesive formulation. US Patent No. 20030l66767
`Hai NT. Kiln J. Park E—S. Chi
`S—C (2008) Formulation and
`biophannaccutical evaluation of transdennal patch containing
`benztropine. Int J Pharm 35155450
`Hanatani A. Sekiya J. Teraslii S, Nishi S. Washiro S, Akcini H (2008)
`Stabilized donepezil-containing patch preparation. US Patent
`200810131490 A]
`
`Kanious D (2006) Device for transdermal administration of drugs
`including acrylic polymers. US Patent 20080078602 Al
`Kazunosuke A. Yasunari M, Takaaki T (2003) Transderrnal absorp-
`tion patch. US Patent No. 200810138388 A]
`Kiln B—D. Choi H—K (2003) Penetration enhancement of Ifig—selective
`agonist. tulobuterol. across hairless mouse skin. .l Kor Pharm Sci
`33:79—84
`Kim J-H. Cho Y]. Choi H-K (2000) Effect of vehicles and pressure
`sensitive adhesives on the permeation of tacrine across hairless
`mouse skin. Int J Pharm 196:105—113
`Nakanishi M. Terahara T. Michinaka Y. Aida K, Hattori W. Kuroda
`Takao (2009) Transdermale absorbable Donepezil Prieparation.
`US Patent No. 20090175929A1
`
`Park ES, Chang SY, Hahn M. Chi SC (2000) Enhancing effect of
`polyoxyethylene alky] ethers on the skin permeation of ibupro-
`fen. IntJ Pharm 209:]0—1 19
`
`Park JK. Choy YB, Oh HUI, Kim JY, Hwang S—J. Choy l—l—I (2008)
`Controlled release of donepezi] intercalated in smectite clays. Int
`J Pharm 359: l98—204
`Rogers SL. Friedhoff LT (I998) Long—term efficacy and safety of
`donepezil
`in the treatment of Alzheimer‘s disease: an interim
`analysis of the results of a US multicenter open label extension
`study. Eur Neuropsyehopharmaco] 8:67—75
`Rogers SL. Farlow MR, Doody RS. Mohs R. Friedhoff LT ([998) A
`24—week. double—blind. placebo—controlled trial of donepezil
`in
`patients with Alzheimer’s disease. Neurology 50:136—145
`Subcdi RK. 0h SY. Chun M—K. Choi H—K (2010) Recent advances in
`transdermal drug delivery. Arch Pharm Res 33:339—35l
`Sugimoto H, limura Y, Yamanishi Y. Yamatsu K ([995) Syntheses
`and structure— activity relationships of acetylcholinesterase
`inhibitors:
`l-benzyl-4—[(5.6-dimethoxy~l—oxoindan-2—yl)methyl}
`piperidine hydrochloride and related compounds. J Med Chem
`381482141829
`
`Terahara T. Kazunosuke A, Namhito H, Shuji S (2008) Pharmaceu—
`tical preparation of percutaneous absorption type. US Patent No.
`20080138388Al
`
`Valia KH. Ramaraju VS (2008) Transdermal methods and systeln for
`Alzheimer‘s disease. US Patent No. 2008021113
`l.
`Vcnkatraman S. Gale R (1998) Skin adhesives and skin adhesion:
`transdermal drug delivery systems. Biomaterials [9:] l [9—] I36
`Walters KA, Walker M. Olejnik 0( I93?) Non—ionic surfactant effects
`on hairless mouse skin permeability characteristics.
`J Pharm
`Pharmacol 40:525—529
`
`Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug
`Deliv 56:603F618
`Wokovich AM, Proddutufi S. Daub WH. Hussein AS. Buhsc LF
`(2006) Transdermn] drug delivery system (TDDS) adhesion as a
`critical
`safety, efficacy and quality attribute. Eur
`J Pharm
`Biopharm 64: [—8
`Zhang P. Chen L. Gu W. Xu 2. Gao Y. Li Y {2007) In vitro and in
`vivo evaluation of donepezil-sustained release microparticles for
`the treatment of Alzheimer’s disease. Biomater‘ials 28:l882—
`1888
`
`0007
`
`@ Springer
`
`