aalfliixuzom), at 33 a Xi] 2a
`J. Kor. Pharm. Sci, Vol. 33, No. 2, 79-84 (2003)
`
`Penetration Enhancement of flz—Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`Byung—Do Kim and Hoo-Kyun Choi+
`College of Pharmacy, Chosun University, Gwangju 501-759, Korea
`(Received March 15, 2003 - Accepted April 21, 2003)
`
`ABSTRACT—The effects of various pressure sensitive adhesives (PSA) and enhancers on the percutaneous absorption of
`tulobuterol were investigated. The permeation rate of tulobuterol through hairless mouse skin from various adhesives was
`evaluated using a flow-through diffusion cell system at 37°C. The permeability of tulobuterol was variable depending on
`the physicochemical property of the PSA. The permeation rate of tulobuterol from polyethylene oxide grafted acrylic adhe—
`sive matrix was higher than that from other PSA matrices. The flux of tulobuterol was 4.37i0,34 ug/hr/cmZ from poly-
`ethylene oxide grafted acrylic adhesive matrix. When the effects of various enhancers on the percutaneous absorption of
`tulobuterol from grafted acrylic adhesive were evaluated, Plurol oleique® showed higher flux than all other enhancers tested.
`
`Key words—Tulobuterol, Enhancer, Pressure sensitivc adhesive, Transdermal drug delivery
`
`Tulobuterol (0e[(tert—butylamino)methyl] benzyl alcohol) is
`a novel bronchodilator; as one of the Bz-agonist agents, it has
`superior selective activity on the I32— receptorli’
`than other
`agents in this class. Oral dosage form” and inhalcr type” of
`tulobuterol have been widely used to prevent or diminish air-
`way obstruction of the patients. Yet, side effects such as
`
`tremor, palpitations or hypokalemia4’5) were emerged partic-
`ularly after oral administration, and these disadvantages restrict
`the oral use of the drug. In addition, extended duration of drug
`action is required to offer protection for nocturnal asthma dur-
`
`ing a whole nights sleep. Unfortunately, bronchodilating effect
`of Bz-agonist agents waned within 6 hr after the inhalationf”
`The utilization of transdermal route for systemic action of
`drugs has brought out an important number of new clinical
`
`applications,” such as pain treatment, hormone therapy, smok-
`ing cessation, and etc. An application of transdermal drug
`delivery system (TDD) has certain benefits such as producing
`sustained, constant, and controlled drug plasma concentration.
`enhancing bioavailability and bypassing hepatic first-pass
`metabolism. This may be accompanied with the decrease in
`dose frequency required for chronic treatment and,
`thus,
`
`improving patient compliance. Therefore, it can be expected
`that an application of TDD type formulation of tulobuterol
`might offer several advantages over the conventional dosage
`forms. However, in spite of many advantages of TDD, mar—
`keted transdermal drug delivery systems are available for only
`a few drugs. Most of investigated drugs did not cross the skin
`in adequate amount to produce the therapeutic effect.” Thus, in
`
`
`Ty.L.
`
`151301] ea eeie oi assure
`Tel : 062)230-6367 E-mail :hgchoi@chosun.ac.kr
`
`an attempt to overcome the problems arising from skin imper-
`rneabilily and biological variability, various approaches to
`reduce the skin barrier resistance have been investigated. 9‘ 10)
`In TDD applications, adhesives are used to maintain inti-
`mate contact betweerr the patch and the skin surface. Many
`classes of adhesives are available that might be considered for
`use with TDD; particularly pressure sensitive adhesives
`
`(PSAs) are preferred”) Because the physicochemical prop—
`erties of PSA can affect the permeation of a drug from PSA
`across the skin, the selection of appropriate PSA is important
`
`in designing transderrnal dnig delivery system?” The pen-
`etration enhancers are widely used to achieve sufficient ther-
`apeutic efficacy and account for essential components in TDD
`system. The permeation rate, the compatibility with incor—
`porated components, and the skin adhesion must be con-
`sidered in the selection of PSA.
`
`In this study, we investigated the influence of the natures of
`pressure—sensitive adhesives and the functional groups in
`acrylic adhesive on the permeation rate of tulobuterol across
`hairless mouse skin. Moreover, we evaluated the effect of var-
`
`ious enhancers on the penetration rate of tulobuterol from an
`acrylic PSA matrix.
`
`Experimental
`
`Materials
`
`Tulobuterol was a gift from Jeil Pharm, Co. (Seoul, South
`Korea). Propylene glycol monolaurate (Lauroglycol®), Pro—
`pylene glycol carprylate/caprate (Labrafac® PG), PEG-8 glyc-
`eryl caprylate/caprate (Labrasol®), PEG—8 glyceryl linoleate
`(Labrafil® 2609) and polyglyceryl—3 oleate (Plurol oleique® cc
`
`79
`
`  
`
`

  
`
`MYLAN - EXHIBIT 1010
`
`

`

`80
`
`Byung-Do Kim and Hoo—Kyun Choi
`
`497) were purchased from Masung Co. (Seoul, South Korea).
`
`Propylene glycol .dicaprylate (Miglyol® 840) was obtained
`from Hiils America (Somerset, NJ, USA). Cetearyl octanoate
`
`and isopropyl myristate (Crodarnol® CAP), PEG-12 palm ker—
`nel glycerides (Crovol® PK40) were obtained from Croda (Par—
`sippany, NJ, USA). Sorbitan monolaurate (Span® 20), Sorbitan
`monooleate (Span® 80), Oleyl alcohol and Propylene glycol
`were purchased from Junsei Chemical Co. Ltd (Tokyo, Japan).
`Acrylic, polyisobutylene and styrene-butadien—styrene block
`copolyrner pressure-sensitive adhesive solutions in organic sol-
`vents were obtained from National Starch and Chemical Com—
`
`pany (Bridgewater, NJ, USA). Silicone pressure sensitive
`adhesive was obtained from Dow Corning (Midland, MI,
`USA). All other chemicals were reagent grade or above and
`were used without further purification.
`
`Preparation of adhesive matrices
`
`Tulobuterol was dissolved in ethyl acetate. Then, PSA solu—
`tions were mixed well with tulobuterol solution with or without
`
`enhancers. PSA matrices were prepared by casting the above
`solution on a polyester release liner coated with silicone while
`silicone adhesive matrix was prepared on a flurocarbondia—
`crylate—coated release liner. They were set at room temperature
`for 10 min and were subsequently oven-dried at 80"C for about
`20 min. The dried film was laminated onto a backing film.
`
`In vitro diffusion experiment
`A flow-through diffusion cell system consisting of a mul-
`tichannel peristaltic pump (2058, Watson Marlow, UK), a frac-
`tion collector
`(Retriever
`IV,
`ISCO Inc., NE, USA),
`a
`circulating water bath (RB-10, JeioTech, South Korea), and
`flow-through diffusion cells was used. The flow—through cell
`consisted of two side arms, which enabled conduction of
`
`receiver cell media via a peristaltic pump to a fraction col-
`lector. The temperature of receiver cell media was maintained
`at 37°C by circulating constant temperature water through the
`outer jacket of the receiver cell. The surface area of the receiver
`
`cell opening was 2 cm2, and the cell volume was ca. 5.5 ml.
`Full—thickness hairless mouse skin was excised from the
`
`fresh carcasses of animals that were humanely sacrificed with
`diethyl ether. Subcutaneous fat and capillary blood vessels
`were removed carefully with a scissors and scalpel. Prelim—
`inary experiment showed that the use of abdominal or dorsal
`
`skin had practically no influence on permeation profile of
`tulobuterol. Each of the flow—through diffusion cell compo—
`nents was connected via Teflon tubing (i.d. 0.015 inches). The
`receiver cell was filled with a pH 7.4 phosphate buffer solution
`and the media were stirred by an externally driven, Teflon—
`
`J. Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`coated magnetic bar, to maintain sink condition. The hairless
`mouse skin was mounted on each receiver cell, and the top cell
`
`was placed onto each skin. These components were then
`clamped securely in place. Any air bubbles that remained in
`the receiver cell were removed. A disc with a surface area of
`
`2cm2, was cut out using a punch, and applied to the epidermal
`side of the skin with slight pressure before being mounted on the
`receiver cell. The samples were collected every 4hr for 32 hr.
`
`Data reduction
`
`The following equation was used to calculate the amount of
`
`the compound permeated”)
`
`Sn
`M,,=C><V+—2—+;;Sl (when n22)
`
`Mn=CXV+% (when n: 1)
`
`Where M“ is cumulative amount permeated; C is concen-
`tration in the receiver cell; V is volume of the receiver cell; Sn
`
`is total amount in the nth sample.
`
`Assay
`Tulobuterol was analyzed by an HPLC system (Shimadzu
`Scientific Instrument, MD, Kyoto, Japan), consisting of a
`detector (SPD-lOA), a pump (LC-lOAD), and automatic injec-
`tor (SIL—lOAD). The wavelength of UV detector was 210 nm
`and the retention time of tulobuterol was 4.3 min, A reversed-
`
`phase column (Alltima C8, Alltech Association, IL) was used.
`The column temperature was maintained at 30"C by a thin foil
`temperature controller (CH 1445, SYSTEC, MN). The flow
`rate was 1 ml/min. The mobile phase consisted of methanol/
`water/phosphoric acid (37/62.9/0.1).
`
`Resluts and Discussion
`
`Effect of pressure sensitive adhesive matrices
`The selection of PSA is very important in the development
`of TDD formulation of a drug. To compare the permeation rate
`of tulobuterol from PSA matrices, the permeation profile of
`tulobuterol from polyisobutylene (PIB), styrene-butadiene-sty—
`rene (SBS), silicone, and acrylic PSA matrices were deter—
`
`shows the time course profiles of the
`mined. Figure 1
`cumulative amount of tulobuterol permeated across hairless
`mouse skin from various adhesive matrices without penetration
`
`enhancers. Among the PSA matrices tested, polyisobutylene
`(PIB) showed the highest degree of tulobuterol permeation.
`Acrylic PSA and silicone provided similar permeation rate.
`
`

`

`
`
`
`
`
`
`CumulaitveAmountPermeated(rig/cm“)
`
`Penetration Enhancement of fiziselective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`81
`
`
`140 ,
`
`_| NO
`
`100 .
`
`
`NO
`
`02USOO
`
`tulobuterol across hairless mouse skin. The polyethylene oxide
`grafted acrylic adhesive provided a higher permeation rate, fol-
`lowed by acrylic adhesive without a functional group. The
`highest permeation rate obtained from polyethylene oxide
`grafted acrylic adhesive may be partially due to the fact that the
`increased hydrophilicity due to grafted polyethylene oxide
`modified thermodynamic activity of tulobuterol
`in spite of
`same drug content. The highly cross-liked acrylic adhesive
`provided the lowest permeation rate. The cross—linking of PSA
`is one of several techniques used to increase the loading level
`of the active or excipients in the PSA mauix.[°) Though cross—
`
`linking improves cohesive strength of PSA, it could decrease
`the release rate of a drug from the matrix. In other words.
`cross-linking hinders the mobility of tulobuterol within PSA
`
`resulting in the decreased permeation rate of
`matrix,
`tulobuterol. Judging from these results, it is very important to
`consider the physicochemical property of the PSA and the
`active substance to select appropriate PSA in the development
`of TDD product.
`Another important criterion in the selection of PSA is the
`adhesive force of PSA. As discussed abOve, although poly—
`ethylene oxide grafted acrylic adhesive showed the highest flux
`of tulobuterol. its relative lrydrophilic nature caused peeling off
`from the skin when the matrix was wetted with water. There—
`
`fore. mixing with the acrylic adhesive with higher tack would
`be beneficial to increase adhesiveness of the matrix. Figure 3.
`shows the permeation of tulobuterol from the mixture of matri-
`
`
`
`_L onO
`
`0
`
`5
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`Time (hr)
`
`Figure l—Effects of type of pressure sensitive adhesive on the per—
`meation of tulobuterol across hairless mouse skin. Each point rep—
`resents average of three measurements. (O) Acrylic—no functional
`group; (O) Styrcnc—butadienc—styrene; (V) Polyisobutylene; (V)
`Silicone.
`
`Styrene-Butadiene—Styrene (SBS) adhesive matrix showed the
`lowest permeation rate.
`
`It has been reported that the flux of a drug from acrylic adhe—
`'sive matrix depended on the functional group of the acrylic
`adhesivems) The effect of chemical nature of acrylic adhesive
`matrix on the permeation of tulobuterol across hairless mouse
`skin was evaluated. Figure 2 shows the effect of functional
`group of acrylic adhesive matrix on the permeation of
`
`
`140
`
`_L NO
`
`100 -
`
`L
`
`m0
`
`a:O
`
`bO
`
`
`
`
`
` MO CumuiaitveAmountPermeated(pg/cm”)
`
`
`
`, O
` . . o
`
`
`O--
`0‘
`:WO.. ~-O'
`15
`20
`25
`5
`10
`30
`
`0
`
`Time (hr)
`
`Figure Z—Effects of acrylic pressure sensitive adhcsivc on the per—
`meation of tulobuterol across hairless mouse skin. Each point rep—
`resents average of three measurements (0) Acrylic-polyethylene
`oxide grafted; (O) Acrylic-highly cross-linked; (V) Acrylic-no
`functional group; (V) Acrylic-OH functional group.
`
`
`
`CumulaitveAmountPermeated(uglcmz)
`
`
`
`
`
`.5 a:O
`
`.s po
`
`120 ~
`
`100 .
`
`ND
`
`
`Ah0’WOOO rr
`
`O
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Time (hr)
`
`Figure 3—Effects of mixing of acrylic pressure sensitive adhesive
`on the permeation of tulobuterol acrOSs hairless mouse skin. Each
`sample contained 5% of Plurol oleique®. Each point represents av-
`erage of three measurements. (0) Acrylic-polymer grafted; (O)
`Grafted—AAzAA-OH (7:3); (V) Grafted-AAzAA—OH (6:4); (V)
`Acrylic—OH.
`
`.1. Ker. Pharm. Sci, Vol. 33, N0. 2(2003)
`
`

`

`82
`
`Byung-Do Kim and Hoo—Kyun Choi
`
`
`
`
`
`
`
`
`
`CumulaltveAmountPermeated(uglcmz)
`
`
`
`a:onOO _..__r
`
`hD
`
`'5’
`
`
`
`
`dAmen0O —.—44
`
`140
`
`120
`
`100 -
`
`
`
`the occlusive effect of the matrix increased, resulting in the
`increased flux of tulobuterol.
`
`Effect of enhancers in PSA matrix
`
`To develop a matrix type transdermal delivery system for a
`drug. an appropriate enhancer is required to enhance the per-
`
`l
`v
`
`.L 0'90
`
`
`
`
`
`
`
`CumulaitveAmountPermeated(uglcmz)
`
`O
`
`5
`
`1 0
`
`1 5
`
`20
`
`25
`
`30
`
`Time (hr)
`
`Figure S—Effect of Various vehicles on the permeation of tu-
`lobuterol across hairless mouse skin from polyethylene oxide graft—
`ed acrylic adhesive. The amount of each vehicle used was 5% of the
`weight of acrylic adhesive polymer. Each point represents average
`of three measurements. (0) Control; (O) PG; (V) 1PM; (V) OA.
` )
`N
`200
`
`
` 100 ‘
`
`.1_nNIF0O
`
`80 -
`
`60
`
`40
`
`20-
`
`O
`
`
`
`
`
`_| atO
`
`120 -
`
`w0
`
`.5O
` O
`
`I
`
`r
`
`l
`
`
`
`CumulativeAmountsPermeated(pg/cm
`
`
`
`
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Time (hr)
`
`Figure 6—Effect of various vehicles on the permeation of tu—
`lobuterol across hairless mouse skin from polyethylene oxide graft—
`ed acrylic adhesive. The amount of each vehicle used was 5% of the
`weight of acrylic adhesive polymer. Each point represents average
`of three measurements. (C) Span 20; (O) Span 80; (V) Plurol ole-
`ique; (V) Control.
`
`D
`
`5
`
`10
`
`1 5
`
`20
`
`25
`
`30
`
`Time (hr)
`
`Figure 4—Effect of matrix thickness on the amount of tulobuterol
`permeated across hairless mouse skin. Each point represents average
`of three measurements. (0) 70 um; (O) 60 um; (V) 50 um; (V)
`30 um.
`
`ces manufactured with polyethylene oxide grafted acrylic
`adhesive and acrylic adhesive with hydroxyl functional group
`at various weight fractions. Penetration rate was gradually
`decreased as the amount of acrylic adhesive with hydroxyl
`functional group increased, while adhesive force of the matrix
`
`was improved. These results suggested that mixing various
`acrylic PSAs could modify the adhesive force and the per—
`meation rate of a drug across die skin.
`
`The effect of thickness on the amount of tulobuterol per—
`meated across the hairless mouse skin as a function of time is
`
`shown in Figure 4. The matrix had same drug concentration
`(2.77% w/w); therefore, as the thickness of the adhesive matrix
`
`increased, the amount of drug within the matrix increased pro-
`portionally. Four different matrices were prepared with the
`
`thickness of 30 um, 50 um, 60 um, and 70 um, respectively.
`After 30 hr, the total amounts of tulobuterol permeated were
`
`34.5i3.9 ug/cmz, 77.1193 ug/cmz, 101.1i8.4 ug/cm2 and
`131.1:101 ug/cm2 for the matrices with the thickness of 30
`
`um, 50 um, 60 um, and 70 um, respectively. It is interesting
`to note that the fraction of loaded tulobuterol permeated from
`the adhesive matrix increased from 40% to over 60% as the
`
`thickness of the matrix increased from 30 um to 70 pm. The
`tulobuterol is highly permeable compound and as the thickness
`of the matrix increased, it seemed that the occlusive effect of
`
`adhesive matrix increased. The occlusive effect is usually pro-
`vided by backing membrane, however, as the thickness of the
`adhesive matrix increased, the matrix also contributes to occlu-
`sive effect to some extent. As the thickness of matrix increased,
`
`J. Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`

`

`Penetration Enhancement of BZ-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`83
`
` 200
`
`ers used. Plurol oleique® showed the most potent enhancing
`effect followed by Span® 80 and Labrafil® 2609. The other
`enhancers did not provide significant enhancement effects. The
`flux of the tulobuterol from polyethylene oxide grafted acrylic
`adhesive matrix containing Plurol oleique® was fairly high
`(12.5i2.78 ug/hr/cmz) initially, but it was gradually decreased
`(2i0.04 ug/hr/cmz) with time. Almost 80% of tulobuterol in
`PSA matrix containing Plurol oleique® was penetrated in less
`than 20 hr, which resulted in the rapid reduction of thermo-
`dynamic activity of tulobuterol in the PSA matrix. In the other
`
`the flux of polyethylene oxide grafted acrylic matrix
`hand,
`containing span® 80 maintained pseudo steady state through-
`out pcrrneation study.
`It has been reported that the efficacy of enhancers depends
`on alkyl chain length, HLB value, and ethylene oxide chain
`length of surfactant. The nonionic surfactant with medium
`HLB, and an alkyl chain length of C18 and E0 chain showed
`
`better ability to promote the penetration of piroxicamf” Also,
`Parkls) suggested that the enhancer containing E0 chain length
`2-5, HLB value 7—9 and an alkyl chain length C16-18 were
`very effective to increase the skin permeation of ibuprofen. In
`the present study, C18:1 (HLB 6), C18 (HLB 4.3), C1822
`(HLB 8) were more effective than C 8/10, C 8/10 (HLB l),
`
`C8/10 (HLB 2). The enhancement of Span® 80 (C18) was
`higher than that of Span® 20 (Cl 1). Though only a limited numi
`ber of non—ionic surfactants were evaluated in this study for the
`enhancement of the permeation of tulobuterol, some surfactants
`having longer alkyl chain length and medium HLB enhanced the
`penetration of tulobuterol across hairless mouse skin better than
`that having shorter alkyl chain length and low HLB. These
`results suggested that HLB and an alkyl chain of enhancer also
`influenced tulobuterol absorption-enhancing ability.
`In conclusion, the penetration rate of tulobuterol can be suf-
`ficiently increased by using appropriate selection of a PSA and
`an enhancer. The nature of PSA significantly affected the per-
`meation rate of the drug across the skin. Thus, physico-
`chemical properties of PSA should be considered before the
`selection of the matrix. HLB value and size of the alkyl chain
`length of surfactants were also important
`factors for the
`enhancement of skin permeation of tulobuterol. Based on the
`
`average flux of tulobuterol obtained using Plurol olcique® and
`the daily dose of 2 mg, the size of transdermal patch would be
`
`approximately 10 cm2.
`
`References
`
`1) CK. Fan and RJ. Barnes, Respiratory and allergic disease,1.
`Br. Med. J., 296, 29-33 (1988).
`
`.l, Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`180
`
`160 ‘
`
`140 ~
`
`120 ~
`
`100 -
`
`80-
`
`60-
`
`40*
`
`20-
`
`
`
`
`0
`
`
`t
`.
`1
`4
`
`
`
`
`
`
`
`CumulaitveAmountsPermeated(pg/cmz)
`
`0
`
`5
`
`1O
`
`20
`
`25
`
`30
`
`15
`Time (hr)
`
`Figure 7—Effect of various vehicles on the permeation of tu-
`lobuterol across hairless mouse skin from polyethylene oxide graft-
`ed acrylic adhesive. The amount of each vehicle used was 5% of the
`weight of acrylic adhesive polymer. Each point represents average
`
`
`of three measurements. (0) Control; (0) Labrafac PG; (Y) La—
`
`
`brafil 2609; (V) GTC; (I) Lauroglycol;
`(
`) Migly01840; (Q)
`Crodamol.
`
`l
`
`Table l—Physicochemica/ Properties of Enhancers Used in this
`Study
` Enhancer HLB Hydrophobic portion
`
`
`Crodamol CAP
`Cl 8/C16,Cl4
`Crodamol GTC
`C8/C10
`Isopropyl Myristate
`C 14
`Labrafac PG
`C8/10
`Labrafil 2609
`C 1 8 :2
`Lauroglyeol
`C 12
`Migly01840
`C8/10
`Oleyl alchol
`C18
`6
`Plurol oleique cc 497
`C18:1
`8.6
`Span 20
`C l l
`
`Span 80 C 18 4.3
`
`
`2
`8
`4
`
`meation rate and/or to solubilize the drug. The effect of some
`enhancers on the permeation of tulobuterol from polyethylene
`oxide grafted acrylic adhesive matrix was investigated to iden-
`tify the optimum permeation enhancer. The effects of various
`enhancers on the amount of tulobuterol permeated across hair—
`less mouse skin from grafted acrylic adhesive matrix are
`
`shown in Figures 5, 6, and 7. The physicochemical properties
`of the enhancers used are shown in Table 1. Each tested
`
`enhancer was added to acrylic adhesive at 5%. Although
`tulobuterol itself is highly permeable compound, the perme—
`ation rate of tulobuterol
`from acrylic adhesive matrices
`increased by 1.06—1.42 fold higher depending on the enhanc—
`
`

`

`84
`
`Byung-Do Kim and Hoo-Kyun Choi
`
`in Childhood
`2) A.T.J. Migiel and LN. Miguel, Tulobuterol
`Asthma: Single Dose Ranging and Repeated Oral Dose
`Comparative studies, J. Int. Med. Res., 14, 228-235 (1986).
`3) D. Charpin, Acute and long-term effectiveness of tulobuterol
`inhaler, a New BZ-agonist, in the treatment of asthma, Lung,
`Suppl. 194-201 (1990).
`4) K.R. Patel, Bronchodilating effect of inhaled tulobuterol. A
`new beta2 agonist in patients with asthma, Respiration, 46.
`Suppl 1. 116 (1984).
`5) KR. Patel, Prolonged treatment with oral and inhaled
`tulobuterol docs not induce airway tachyphylaxis, Lung, 168.
`Supp1.‘210—218 (1990).
`6) B. Waldeck, Adrenoceptor agonists and asthma-100 years of
`,development, Eur. J. Phanngcol,,.445, 1-12 (2002).
`7) J.R.B.J. Brouwers, Advanced and controlled drug delivery
`systems in clinical disease management, Pharm. World Sci,
`18, 153-162 (1996).
`8) M. Guyot, F Fawaz, Design and in vitro evaluation of
`adhesive matrix for transdermal delivery of propranolol, Int. J.
`Pharm, 204, 171-182 (2000).
`9) K.A. Walters, J. Hadgrafi, Pharmaceutical Skin Penetration
`Enhancement, Marcel Dekker, New York. (1993).
`10) A. Naik, Y.N. Kalia and RH. Guy, Transdermal drug delivery:
`Overcoming the skin barriers function, PSTT, 3, 318-325
`(2000).
`
`ll)H.S. Tan and WR. Pfister, Pressure-sensitive adhesives for
`transdermal drug delivery systems, PSTT., 2, 60-69 (1999).
`12) T. Kokubo, K. Sugibayashi and Y. Morimoto, Interaction
`between drugs and pressure-sensitive adhesive in transdennal
`therapeutic system, Pharm. Res., 11, 104-107 (1994).
`13) Y.-J. Cho and H.-K. Choi, Enhancement of percutaneous
`absorption of ketoprofen: effect of vehicles and adhesive
`matrix, Int. J. Pharm, 169, 95—104 (1998).
`14) H.K. Choi and J.T. Angelic, Mathrnatical analysis and
`optimization bf flowthrough diffusion cell system, Pharm.
`Res, 11, 595-599 (1994).
`15) J.—H. Kim, Y.-J. Cho and H.-K. Choi, Effect of vehicles and
`pressure sensitive adhesives on the permeation of tacrine
`across hairless mouse skin, Int. J. Pharm, 196, 105-113
`(2000).
`16) H. Tan, S. Lydzinski, 1. Zhang, K. Puwar and P. Foreman,
`Enhancer-Resistance acrylic preSsure sensitive adhesive for
`transdermal system, Pharm. Res, 14. Suppl. S—318 (1997).
`17) H.-A. Cheong and H.—K. Choi, Enhanced pcrcutaneous
`absorption ofpiroxicam Via salt formation with ethanolarnines,
`Pharm. Res, 19, 1375—1380 (2002).
`18) E.—S. Park, S.—Y. Chang, M. Hahn and S.-C. Chi, Enhancing
`effect of polyoxyethylene alkyl ethers on the skin permeation
`of ibuprofen, Int. J. Pharm, 209, 109-119 (2000).
`
`J. Kor. Pharm. Sci, Vol. 33, No. 2(2003)
`
`