of7ll«!-Slxl(2003), 4 33 ^ ^1 2$.
`J. Kor. Pharm. Sci., Vol. 33, No. 2, 79-84 (2003)
`
`Penetration Enhancement of Pi-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`Byung-Do Kim and Hoo-Kyun Choi1^
`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 370C. 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 4.37±0.34 |ig/hr/cm2 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 sensitive adhesive, Transdermal drug delivery
`
`Tulobuterol (a-[(?ert-butylamino)methyl] benzyl alcohol) is
`a novel bronchodilator; as one of the p2-agonist agents, it has
`superior selective activity on the P2- receptor^ than other
`agents in this class. Oral dosage form2' and inhaler type3) 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 Pa-agonist agents waned within 6 hr after the inhalation.6'
`The utilization of transdermal route for systemic action of
`drugs has brought out an important number of new clinical
`applications,7' 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.8' Thus, in
`
`Tel: 062)230-6367 E-mail: hgchoi@chosun.ac.kr
`
`an attempt to overcome the problems arising from skin imper­
`meability and biological variability, various approaches to
`9, 10)
`reduce the skin barrier resistance have been investigated.
`In TDD applications, adhesives are used to maintain inti-
`mate contact between 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 transdermal drug delivery system,
`The pen-
`12,13)
`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 (Crodamol® 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
`copolymer 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 Coming (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 80oC for about
`20 min. The dried film was laminated onto a backing film.
`
`In vitro difTusion experiment
`A flow-through diffusion cell system consisting of a mul­
`tichannel peristaltic pump (205S, 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 370C 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 4 hr for 32 hr.
`
`Data reduction
`The following equation was used to calculate the amount of
`the compound permeated.14'
`Mn = CxV +Y +
`S
`
`(when n>2)
`
`"
`
`i = 1
`
`S,
`Mn = CxV + -2 (when n=l)
`
`Where Mn 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-10A), a pump (LC-10AD), and automatic injec­
`tor (SIL-10AD). 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 30oC 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
`mined. Figure 1 shows the time course profiles of the
`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.
`
`

`

`Penetration Enhancement of {^-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`81
`
`„ 140
`E
`
`120
`3 100
`%
`«
`E
`«> 80
`a.
`
`§ 60
`£
`<
`« 40
`
`J5
`I 20
`3
`o
`
`0
`
`X.
`
`O
`
`. o
`
`.o
`
`X
`* &
`/
`/
`y
`/ •
`/ y
`/ x?
`//S
`
`•O
`
`o
`
`O '
`
`O'
`
`0
`
`5
`
`10
`
`25
`
`30
`
`20
`15
`Time (hr)
`Figure 1-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. (•) Acrylic-no functional
`group; (O) Styrene-butadiene-styrene; (•) Polyisobutylene; (V)
`Silicone.
`
`Styrene-Butadiene-Styrene (SBS) adhesive matrix showed the
`lowest permeation rale.
`It has been reported that the flux of a drug from acrylic adhe­
`sive matrix depended on the functional group of the acrylic
`adhesive.13,15' 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
`
`x
`
`_ v
`
`V"
`
`^ X"
`
`X
`
`• o
`
`30
`
`25
`
`0
`
`5
`
`10
`
`E
`.o
`120
`J
`1
`ts100
`<D
`E
`5 80
`a.
`£
`§ 60
`E
`<
`d> 40
`a
`iS
`| 20
`3
`o
`
`0
`
`. O" - o •
`15
`20
`Time (hr)
`Figure 2-EfFects of acrylic pressure sensitive adhesive on the per­
`meation of tulobuteroi across hairless mouse skin. Each point rep­
`resents average of three measurements. (•) Acrylic-polyethylene
`oxide grafted; (O) Acrylic-highly cross-linked; (T ) Acrylic-no
`functional group; (V) Acrylic-OH functional group.
`
`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 aciylic 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 matrix.16' 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
`matrix, resulting in the decreased permeation rate of
`tulobuterol. Judging from these results, it is very important to
`consider the physicochenucal 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 hydrophilic 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-
`
`„ 180
`<N E
`« 160
`3
`140
`
`%
`o 120
`E
`I 100 -
`
`4^
`§ 80 -
`o
`E
`< 60
`4)
`£
`3
`E 20
`3 o
`
`40
`
`.
`
`- o
`
`O"
`
`.
`
`p
`W
`
`0 /
`
`o
`
`-v
`
`/ ^7
`
`0
`
`0
`
`5
`
`10
`
`25
`
`30
`
`15
`20
`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. (#) Acrylic-polymer grafted; (O)
`Grafted-AA:AA-OH (7:3); (• ) Grafted-AA:AA-OH (6:4); (V)
`Acrylic-OH.
`
`J. Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`

`

`82
`
`Byung-Do Kim and Hoo-Kyun Choi
`
`o
`
`O"
`
`• • "^7
`
`O
`
`^W'
`
`^7
`
`/
`
`9"
`
`/ ^
`/
`//.S*
`
`5
`
`10
`
`25
`
`30
`
`0
`
`180
`
`€4 E
`-y 160
`5
`140
`"§
`% <£ 120
`§
`0)
`2 100
`C
`3 80 -
`o
`E
`< 60
`0>
`x* 40
`ss
`s
`i 20
`o
`0
`
`15
`20
`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. (•) 70 (im; (O) 60 |lm; (•) 50 pm; (V)
`30 pm.
`
`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 the 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 jam, 50 pm, 60 pm, and 70 pm, respectively.
`After 30 hr, the total amounts of tulobuterol permeated were
`34.5±3.9 lig/cmr, 77.1+9.3 pg/cm2, 101.1+8.4 pg/cm2 and
`131.1+10.1 pg/cm2 for the matrices with the thickness of 30
`pm, 50 pm, 60 pm, and 70 pm, 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 pm 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)
`
`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-
`
`_ 160
`CM E
`140
`I
`V. 120
`0)
`(0
`0) E 100
`«
`Q.
`
`80
`
`. o
`
`p
`/
`
`-c®
`
`3 o
`E 60
`<
`o > 40
`«
`i 20
`3
`O
`0
`
`J.
`
`0
`
`5
`
`10
`
`25
`
`30
`
`15
`20
`Time (hr)
`Figure 5-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. (•) Control; (O) PG; (•) IPM; (V) OA.
`
`.-200
`E o
`o>
`r 160
`73 0)
`<Q
`<D
`E
`i 120
`CL
`c
`g 80
`E
`<
`>
`'H 40 '
`E
`D «
`
`o
`
`0
`
`o '
`
`^7
`
`o
`
`. V''
`
`/
`
`o
`
`o
`
`V7
`
`/
`/
`/
`/
`/
`/ D-
`
`/
`
`/p;.
`
`5
`
`10
`
`25
`
`30
`
`15
`20
`Time (hri
`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. (•) Span 20; (O) Span 80; (•) Plurol ole-
`ique; (V) Control.
`
`

`

`Penetration Enhancement of ^-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`83
`
`200
`
`180
`
`g> 160
`
`® 140
`13
`
`J £ 120
`
`<D
`
`100 -
`
`80
`
`X
`c
`O
`E
`< 60
`> i 40
`E 20 -
`3 o
`
`0
`
`s*
`
`/
`
`/
`
`/
`
`/
`/
`
`4^
`
`S-"
`
`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
`(12.5±2.78 (ig/hr/cm2) initially, but it was gradually decreased
`(2±0.04 lig/hr/cm2) 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
`hand, the flux of polyethylene oxide grafted acrylic matrix
`containing span® 80 maintained pseudo steady state through­
`out permeation 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 EO chain showed
`better ability to promote the penetration of piroxicam.17) Also,
`Park18' suggested that the enhancer containing EO chain length
`2-5, HLB value 7-9 and an alkyl chain length CI6-18 were
`very effective to increase the skin permeation of ibuprofen. In
`the present study, C18:l (HLB 6), C18 (HLB 4.3), C18:2
`(HLB 8) were more effective than C 8/10, C 8/10 (HLB 1),
`C8/10 (HLB 2). The enhancement of Span® 80 (CI8) was
`higher than that of Span® 20 (CI 1). Though only a limited num-
`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 oleique® and
`the daily dose of 2 mg, the size of transdermal patch would be
`approximately 10 cm2.
`
`References
`
`1)C.K. Fan and P.J. Barnes, Respiratory and allergic disease,/.
`Br. Med. J., 296, 29-33 (1988).
`
`J. Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`0
`
`5
`
`10
`
`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. (•) Control; (O) Labrafac PG; (T) La-
`brafil 2609; (V) GTC; (•) Lauroglycol; (•) Miglyol840; (•)
`Crodamol.
`
`Table l-Physicochemical Properties of Enhancers Used in this
`Study
`
`Enhancer
`Crodamol CAP
`Crodamol GTC
`Isopropyl Myristate
`Labrafac PG
`Labrafil 2609
`Lauroglycol
`Miglyol 840
`Oleyl alchol
`Plurol oleique cc 497
`Span 20
`Span 80
`
`HLB
`
`1
`
`2
`8
`4
`
`6
`8.6
`4.3
`
`Hydrophobic portion
`C18/C16,C14
`C8/C10
`C14
`C8/10
`C18:2
`C12
`C8/10
`C18
`C18:l
`C l l
`C18
`
`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 I. 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
`
`2)A.TJ. Miguel and L.N. Miguel, Tulobuterol in Childhood
`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 P2-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) K.R. Patel, Prolonged treatment with oral and inhaled
`tulobuterol does not induce airway tachyphylaxis. Lung, 168.
`Suppl/210-218 (1990).
`6) B. Waldeck, Adrenoceptor agonists and asthma-100 years of
`development, Eur. J. Pharmacol., 445, 1-12 (2002).
`7)J.R.B.J. Brouwers, Advanced and controlled drug delivery
`systems in clinical disease management, Pharm. World Set,
`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. Hadgraft, Pharmaceutical Skin Penetration
`Enhancement, Marcel Dekker, New York. (1993).
`10) A. Naik, Y.N. Kalia and R.H. Guy, Transdermal drug delivery:
`Overcoming the skin barriers function, PSTT., 3, 318-325
`(2000).
`
`11)H.S. Tan and W.R. 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 transdermal
`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. Angello, Mathmatical analysis and
`optimization of 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, I. 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 percutaneous
`absorption of piroxicam via salt formation with ethanolamines,
`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)
`
`