Journal of Pharmaceutical Investigation (2012) 42:1-7
`DOT 10.1007/s40005-012-0002-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
`
`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 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 (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” 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 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. Subedi - M.-K. Chun - H.-K. Choi (2)
`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
`NALPharmaceuticals 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
`cholinergic function (Rogers and Friedhoff 1998; Sugimoto
`et al. 1995). Commercially, donepezil is available in the
`form of tablet underthe trade name Aricept”. Initial dose is
`5 mg per day, which can be increased to 10 mg per day
`after an adjustment period ofat least 4 weeks (Rogerset al.
`1998). In mostof 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 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 (p, L-lactide-co-
`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 donepezil would
`be more appropriate in providing clinical benefit of pro-
`longed response to patients suffering from AD.
`However, due to the barrier function ofskin, notall drugs
`can be delivered transdermally (Subedi et al. 2010), In many
`cases, the absorption maynot result in sufficient 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
`
`Aa Springer
`
`0001
`
`Noven Pharmaceuticals,Inc.
`EX2021
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00174
`
`

`

`reported for donepezil (Kazunosukeet al. 2008). However,
`to achieve the sufficient transdermal flux through hairless
`mouse skin, extremely high drug loading (35% w/w) was
`used, This maylead 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
`(Teraharaet al. 2009). Salt form of donepezil precipitates in
`the adhesive matrix forming particles in the patch, which
`reducesthe aesthetic valueof 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 termsof ease of
`productionandbetter patient compliance. Therefore, there is
`a need to explore a commercially viable transdermal matrix
`based system for donepezil which can give higher flux at
`lowerdrug load, through properselection of formulation and
`processvariables.
`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
`
`R. K. Subedi et 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 showedthat the melting point of donepezil hydro-
`chloride (230°C) was reduced to around 90°C 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 andstirred 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 donepezil/enhancer for-
`mulations were determined using flow through diffusion
`cells. Permeation experiments were done onisolated hairless
`mouseskin. A system comprising a multi channelperistaltic
`pump,a fraction collector, a circulating water bath and flow-
`through diffusion cells was used. Each flow-throughcell had
`two arms, which allowed the receiver cell medium pumped
`to a fraction collector. The diffusion cell temperature was
`maintained at 37°C bycirculating water through the outer
`part of jacketed receiver cell. The surface area of receiver
`cell opening was 2 cm’, andits volume was 5.5 ml. Skin was
`excised from hairless mouse that was humanly sacrificed
`
`-23
`
`-24
`
`-25
`
`
`
`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 (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-
`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,
`-27
`—— donepezil base
`+ donepezil HCL
`
`polyisobutylene and_styrene—butadiene-styrene(PIB)
`
`
`(SBS) pressure sensitive adhesive (PSA)
`solutions
`in
`7
`7
`7
`7
`organic solvents were obtained from National Starch and
`50
`100
`150
`200
`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.
`
`c 53
`
`eL
`
`E—
`o
`aa
`a -26
`u
`
`-28
`
`0
`
`+
`250
`
`Temp (°C)
`
`Fig. 1 Differential scanning calorimetric thermogram ofdonepezil as
`base and hydrochloride salt form
`
`g) Springer
`
`0002
`
`

`

`Transdermal drug delivery system for donepezil
`
`with diethyl ether. Subcutaneous fat was removed with
`scissors and scalpel. Each of the flow-through diffusioncell
`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-ring and cell top
`wasplaced on the top of each skin. These components were
`then clamped. The amountof 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-10A), reversed-phase C;g column (4.6 x 100 mm,
`5 um, Gemini), a pump (LC-10AD), and an automatic
`injector (SIL-10A). Briefly,
`the wavelength of the UV
`detector was 315 nm, the column temperature was main-
`tained at 30°C, the flow rate was | ml/min and injection
`volume was 10 pl. 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? 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
`teflon 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 wasfiltered through Whatman™ nylon mem-
`branefilter (13 mm, 0.45 1m) and analyzed by HPLC.
`
`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°C/min from 25 to 250°C.
`
`<o 3005 —s— PIB
`E
`eeQeess SBS
`i
`----— Acrylic non functional
`/
`= 250
`— a — Acrylic hydroxy functional
`
`3 —-#—=Acrylic rubberhybrid
`Differential scanning calorimetry (DSC)
`= 200 4
`— oO— Acrylic carboxy Functional
`fs
`eh
`2
`——*— Silicone
`a3 <
`a
`= 1504
`Ss
`=
`a
`2
`
`T
`10
`
`T
`15
`
`T
`20)
`
`1
`25
`
`0)
`
`T
`5
`
`g E= v
`
`Stability
`
`Time(h)
`
`Stability studies of the optimized formulation were con-
`ducted at three different temperature conditions. Physical
`
`Fig. 2 Screening ofdifferent pressure sensitive adhesives at 10% w/w
`of drug load. Values are expressed as mean (n = 3)
`
`0003
`
`Q Springer
`
`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-10A), reversed-phase C;g column (4.6 x 150 mm,
`5 yum, Shiseido), a pump (LC-10AD), and an automatic
`injector (SIL-10A) wasused. Briefly, the wavelength of the
`UV detector was 271 nm,
`the column temperature was
`maintained at 25°C,
`the flow rate was
`| ml/min and
`injection volume was 20 ul. The mobile phase used con-
`sisted of sodiuml-decansulfonate aqueous solution/Acet-
`onitrile/70% perchloric acid = 650/350/1 (volumeratio);
`sodium |-decansulfonate concentration was 10 mM oftotal
`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 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 influence flux 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
`
`I007
`
`fof
`
`Pil
`» a a
`“_*
`a
`-
`
`=
`
`A
`-*
`
`oO
`ra
`
`
`
`

`

`R. K. Subedi et al.
`
`
`
`—— 60 um
`—o— 85 um
`—=— 100m
`—— 120 bm
`
`
`
`
`500
`
`400
`
`300
`
`200
`
`
`
`
`
`
`
`
`
`
`
`“iCumulativeamountpenetrated(t1g/em")
`
`Time (h)
`
`Fig. 4 Effect of acrylic rubber hybrid matrix thickness on the
`permeation of donepezil. Values are expressed as mean (n = 3)
`
`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”
`
`Table 1 Summary of enhancer screeningat the level of 5% w/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*
`
`l
`
`2
`3
`4
`
`5
`6
`7
`
`8
`9
`
`10
`ll
`12
`13
`
`Control
`
`Brij” 30
`Plurol olieque™ CC497
`Crovol® A 40
`
`Oleyl alcohol
`Laury! alcohol
`IPM
`
`Sugar ester P-1670
`Limonene
`
`Span™80
`Transcutol®
`IPP
`Cineole
`
`1.00
`
`2.10
`1.47
`1.32
`
`1.37
`1.34
`1.12
`
`1.33
`1.06
`
`1.25
`1.17
`1.17
`1.11
`
`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 carboxy! 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
`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
`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 Lum was chosen
`for further experiments based on better adhesive properties
`as compared to 60 im matrix.
`
`—e— 87-502 A
`oO 87-503 A
`—-e- 87-504 A
`
`*
`
`la
`
`— 400 5
`q
`S
`2
`ZB
`3a
`a,— 200 4
`
`3004
`
`
`
`1004
`
`=3&o
`
`s 2
`
`T
`5
`
`it
`10
`
`:
`15
`
`20
`
`:
`35
`
`0
`
`0
`
`Z5
`
`Oo
`
`Time (h)
`
`Fig. 3 Screening of different rubber acrylic hybrid pressure sensitive
`adhesives at 15% w/w drug load. Values are expressed as mean
`(n = 3)
`
`1.09
`Labrafil® 1944
`14
`1.04
`Incrocas” 30
`15
`
`
`16 1.29 Brij” 52
`* ER enhancementratio
`
`g) Springer
`
`0004
`
`

`

`Transdermal drug delivery system for donepezil
`
`
`
`Cumulativeamountpenetrated(ug/cm™)
`
`
`
`
`
`TOO
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
` =
`
`co
`
`—e— 87-502 A, 5%Brij 30
`=O 87-503A, 5% Brij 30
`
`o
`
`
`
`a
`
`10
`
`15
`
`20
`
`25
`
`ratios in both Duro-Tak® 87-502A and Duro-Tak® 87-504A
`matrices and waschosenforfurther experiments. Brij~ 30 is
`a surfactant which belongsto 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 shownthat
`POEalkyl ethers containing EO chain length of 2-5 and
`HLBvalue 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. 1987).
`
`Time (h)
`
`Effect of combining enhancers
`
`Fig. 5 Permeation profile 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)
`
`CC497, 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 Fig. 5, nosignificant difference was observed.
`Table 2 gives the summary of enhancer screening at
`the level of 5% v/w with 10% w/w drugload in Duro-Tak”
`87-504A acrylic rubber hybrid matrix. Among the enhancers
`screened, Brij” 30, Brij” 52, IPM, 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% v/w, with
`10% w/wof drug load in Duro-Tak™ 87-504A matrix. Values are
`expressed as mean (n = 3)
`S.
`Enhancer
`ER
`5%.
`Enhancer
`ER
`No.
`No.
`
`To further increase the transdermal flux 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 ofTDDS,presence ofadditives 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 thumbtest.
`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 flux from Brij” 30 as control.
`Only combinations of Brij® 30 with Brij” 52, Crovol® A40
`and Plurol olieque® CC497 were found to have higher
`enhancementratio as compared to Brij” 30 alone. Adhesive
`properties of patches containing combination of Brij” 30
`with Plurol olieque” CC497 or Span® 80 were foundto 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 Summaryofthe results obtained using combinationof Brij”
`1 14 ~Diisopropyl adipateControl 1.00 1.18 30 at the level of 5%v/w with selected enhancers at the level of 2.5%
`
`
`
`
`
`2
`Brij 30
`1.70
`15
`Oleyl oleate
`1.11
`v/w in Duro-Tak® 87-502A matrix containing 15% w/w drug load.
`Values are expressed as mean (7 = 3)
`
`
`
`
`3 16—LabrasolPlurol oleique” 1.02 1.19
`CC497
`Combination of enhancers
`ER
`Adhesive
`property
`
`-
`
`Crovol® A40
`
`1.20
`
`17
`
`Tween®80
`
`1.09
`
`Good
`
`0.97
`Limonene
`18
`1.11
`Oley] alcohol
`5
`Brij’ 30
`1.00
`Good
`
`
`
`6 Lauryl alcohol§0.94 19~~Glycerol 1.24
`Brij’ 30, Plurol olieque” CC497
`1.20
`Unsatisfactory
`7
`IPM
`1.22.
`20
` Diisopropy! dirrerate
`1.13
`Brij” 30, Span® 80
`0.78
`8
`Span” 80
`1.17
`21
` Crovol™ PK40
`Ll
`Brij” 30, Oleyl alcohol
`0.83
`9
`Transcutol®
`0.94
`22
` Hexyl Laurate
`1.17
`Brij” 30, Brij” 52
`1.37
`10
`~=IPP
`1.00
`23
` Octyl dodecyl ester
`0.99
`Brij” 30, Crovol® A40
`1.27
`
`
`
`
`Il 24—Isotridecyl isononanoate Cineole 1.07 0.99
`Brij’ 30, IPP
`0.80
`12.
`Brij” 52
`1.42
`25
`2-ethylhexyl
`1.05
`Brij” 30, Lauryl alcohol
`0.75
`hydroxystearate
`Brij” 30, Transcutol™
`0.70
` Diethoxylethyl
`succinate
`
`Brij” 30, Cineole
`0.81
`
`13.
`
`Alkyl 2-ethyl
`hexanate
`
`1.20
`
`26
`
`1.32
`
`0005
`
`) Springer
`
`

`

`R. K. Subedi et al.
`
`—e— 503A:504A (1:3)
`4 S03A:504A (1:1)
`—-¥-- 503A:504A (3:1)
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`Time (h)
`
`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 (nm = 3)
`
`B00)
`
`700
`
`9Invitroflux({1g/em*) 600
`
`500
`
`400
`
`300
`
`200
`
`
`T
`T
`T
`7
`7
`7
`T
`1
`6
`8
`12
`14
`16
`18
`20
`22
`
`10
`
`4
`
`Drug loading (% w/wwith respect to dry polymer)
`
`in presence of 5% v/w Brij” 30 and
`Fig. 7 Effect of drug loading,
`5% viw 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 (nm = 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% 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 ofthe physical
`and chemical stability testing. No change in morphology of
`
`combination ofBrij” 30 and Brij” 52, eachat 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-S04A 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-S04A.
`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,
`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 TDDSand the
`skin, complete skin contact over the entire delivery surface
`for the labeled application period is essential (Wokovich
`et al. 2006). If the TDDSlifts 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 variousratios.
`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 showsthe 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 figure, permeation of donepezil increased linearly up to
`15% w/w drug load. Beyond that point
`the extent of
`
`g) Springer
`
`0006
`
`

`

`Transdermal drug delivery system for donepezil
`
`Table 4 Summary of chemical and physicalstability of donepezil patch containing 15% w/w drug, 5% v/w Brij” 30 and 5% v/wBrij” 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
`
`Retrigerator
`
`l
`2
`4
`
`97.7 +£2.50
`95,5 + 1.99
`95.0 + 2.78
`
`Assay
`RT
`
`96.3 + 0.66
`96.1 + 2.42
`92.0 + 1.46
`
`40°C
`
`Physical stability
`
`96.4 + 3.62
`
`98.0 + 2.55
`94.4 + 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 oftime. Based on daily dose of 4.6 mg and average
`flux of approximately 20 jg/cem7/h,less than 30 cm? 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 assumethat 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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`
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