+i] 8}3]2] (2003), A] 33 A al 2%
`J. Kor. Pharm. Sci., Vol. 33, No. 2, 79-84 (2003)
`
`Penetration Enhancementof B,-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 4.37+0.34 pg/hr/cm? 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® showedhigher flux thanall other enhancerstested.
`
`Key words—Tulobuterol, Enhancer, Pressure sensitive adhesive, Transdermal drug delivery
`
`Tulobuterol (o-|(zert-butylamino)methy]] benzyl alcohol) is
`a novel bronchodilator; as one of the B2-agonist agents, it has
`superior selective activity on the B,- receptor’ than other
`agents in this class. Oral dosage form” and inhaler 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 hypokalemia**’ were emerged partic-
`ularly after oral administration, and these disadvantagesrestrict
`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 B-agonist agents waned within 6 hr after the inhalation.”
`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 amountto producethe therapeutic effect.Thus, in
`
`
`te =¥o] Bb ESE | Aabpz
`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
`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-
`etration enhancers are widely used to achieve sufficient ther-
`apeutic cfficacy 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 ethy] 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.
`
`coated magnetic bar, to maintain sink condition. The hairless
`mouse skin was mounted on eachreceivercell, 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
`2cm*, 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.”
`
`<
`Ss,
`M, =CxV+3+ ¥)Si (when n2>2)
`i=l
`
`Si
`M,=CxV+3" (when n=1)
`
`Where M, is cumulative amount permeated; C is concen-
`tration in the receiver cell; V is volume ofthe receivercell; S,
`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-
`
`In vitro diffusion experiment
`A flow-through diffusion cell system consisting of a mul-
`phase column (Alltima C8, Alltech Association, IL) was used.
`tichannelperistaltic pump (205S, Watson Marlow, UK), a frac-
`The column temperature was maintainedat 30°C byathin foil
`tion collector
`(Retriever
`IV,
`ISCO Inc., NE, USA),
`a
`temperature controller (CH 1445, SYSTEC, MN). The flow
`circulating water bath (RB-10, JeioTech, South Korea), and
`flow-through diffusion cells was used. The flow-through cell
`rate was 1 ml/min. The mobile phase consisted of methanol/
`consisted of two side arms, which enabled conduction of
`water/phosphoric acid (37/62.9/0.1).
`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 cm’, and the cell volume was ca. 5.5 ml.
`Full-thickness hairless mouse skin was excised from the
`
`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.
`
`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 showedthat 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)
`
`

`

`Penetration Enhancement of B,-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`81
`
`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
`graited acrylic adhesive may bepartially 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.'® 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 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 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.
`showsthe permeation of tulobuterol from the mixture of matri-
`
`
`
`
`_. 140 5
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`25
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`30
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`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; (©) Styrenc-butadienc-styrene; (W) Polyisobutylene; (7)
`Silicone.
`
`
`
` 20 CumulaitveAmountPermeated(pg/cm’)
`
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`120 4
`
`100 |
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`15
`20
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`Time (hr)
`
`Time (hr)
`
`Figure 2—Effects of acrylic pressure sensitive adhesive on the per-
`meation of tulobutero) across hairless mouse skin. Each pomt rep-
`resents average of three measurements. (@) Acrylic-polyethylene
`oxide grafted; (©) Acrylic-highly cross-linked; (W ) Acrylic-no
`functional group; (7) Acrylic-OH functional group.
`
`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; (Q)
`Grafted-AA:AA-OH (7:3); (W ) Grafted-AA:AA-OH (6:4); (V)
`Acrylic-OH.
`
`J. Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`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
`adhesive.'*!) 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
`
`480~——_—_——___—_——____—-
`
`
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`
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`
`CumulaitveAmountPermeated(ug/em’)
`
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`
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`
`
`
`

`

`82
`
`Byung-Do Kim and Hoo-Kyun Choi
`
`
`
`
`
`
`
`CumulalitveAmountPermeated(g/cm
`
` )
`“
`180
`160 |
`
`140
`
`120
`
`
`
`
`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 +—
`
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`
`10
`
`15
`
`20
`
`25
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`30
`
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`
`Figure 5-Effect of various vehicles on the permeation of tu-
`{obuterol 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; (©) PG; (W) IPM; (V) OA.
`
`
`200
`
`120 5
`
`80 |
`
`0
`
`5
`
`10
`
`15
`
`25
`
`1
`20
`
`1
`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% ofthe
`weight of acrylic adhesive polymer. Each point represents average
`of three measurements. (@) Span 20; (C) Span 80; (W) Plurolole-
`ique; () Control.
`
`0
`
`5
`
`10
`
`45
`
`20
`
`25
`
`30
`
`Time(hr)
`
`Figure 4—Effect of matrix thickness on the amountof tulobuterol
`permeatedacrosshairless mouse skin. Each point represents average
`of three measurements. (@) 70 um; (©) 60 um; (F%) 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 the skin.
`The effect of thickness on the amount of tulobuterol per-
`meated across the hairless mouse skin as a function of timeis
`shown in Figure 4. The matrix had same drug concentration
`(2.77% w/w); therefore, as the thickness of the adhesive matrix
`increased, the amountof drug within the matrix increased pro-
`portionally. Four different matrices were prepared with the
`thickness of 30 (um, 50 um, 60 um, and 70 uum,respectively.
`After 30 br, the total amounts of tulobuterol permeated were
`34.543.9 ugiem’, 77.149.3 ug/em’, 101.1484 be/cem? and
`131.1+10.1 ug/em? for the matrices with the thickness of 30
`uum, 50 um, 60 um, and 70 [tm, respectively. It is interesting
`to note that the fraction of loaded tulobuterol permeated from
`the adhesive matrix increased from 40% to over 60% as thc
`thickness of the matrix increased from 30 Jum to 70 um. The
`tulobuterol is highly permeable compoundand asthe 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 B2-Selective Agonist, Tulobuterol, Across Hairless Mouse Skin
`
`83
`
` 200
`
`180
`160 |
`3 140 4
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`120 4
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`100 |
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`
`ers used. Plurol oleique® showed the most potent enhancing
`effect followed by Span® 80 and Labrafil® 2609. The other
`enhancersdid not provide significant enhancementeffects. The
`flux of the tulobuterol from polyethylene oxide grafted acrylic
`adhesive matrix containing Plurol oleique® was fairly high
`(12.5+2.78 ug/hr/cm”) initially, but it was gradually decreased
`(2+0.04 ug/ht/em’) 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-
`dynamicactivity 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.!” Also,
`Park'®suggested that the enhancer containing EO 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), C18:2
`(HLB 8) were more effective than C 8/10, C 8/10 (HLB 1),
`C8/10 CHLB 2). The enhancement of Span® 80 (C18) was
`higher than that of Span® 20 (C11). Thoughonly 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 alky] chain length and medium HLB enhancedthe
`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 andsize 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 tulobutcrol obtained using Plurol olcique® and
`the daily dose of 2 mg, the size of transdermal patch would be
`approximately 10 cm’.
`
`References
`
`1) C.K. Fan and PJ. Barnes, Respiratory and allergic disease, J
`Br Med. J., 296, 29-33 (1988).
`
`J, Kor. Pharm. Sci., Vol. 33, No. 2(2003)
`
`ro
`
`9&
`
`2 &£
`
`=a &
`
`204
`
`3 —
`
`6
`
`0)
`
`5
`
`10
`
`15
`Time(hr)
`
`20
`
`25
`
`30
`
`Figure 7—Fffect of various vehicles on the permeation of tu-
`lobuterol across hairless mouse skin from polycthylene oxide graft-
`ed acrylic adhesive. The amount of each vehicle used was 5% ofthe
`weightof acrylic adhesive polymer. Each point represents average
`
`of three measurements. (@) Control; (©) Labrafac PG; (W) La-
`
`
`
`brafil 2609; (7) GTC; (I) Lauroglycol; (1) Miglyol840; (@)
`Crodamol.
`
`Table I-Physicochemical Properties of Enhancers Usedin this
`Study
`
` Enhancer HLB Ilydrophobic portion
`
`1
`
`8
`
`
`
`Crodamol CAP
`C18/C16,C14
`Crodamol GTC
`C8/C10
`Isopropyl Myristate
`cl4
`Labrafac PG
`C8/10
`Labrafil 2609
`C18:2
`Lauroglycol
`C12
`Miglyol 840
`C8/10
`Oleyl alchol
`C18
`6
`Plurol oleique cc 497
`C18:1
`8.6
`Span 20
`Cll
`
`Span 80 C18 43
`
`
`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 amountof 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 L Each tested
`enhancer was added to acrylic adhesive at 5%. Although
`tulobuterol ilself 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. Miguel and L.N. Miguel, Tulobuterol
`Asthma: Single Dose Ranging and Repeated Oral Dose
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`
`11) HLS. Tan and W.R. Pfister, Pressure-sensitive adhesives for
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`12)T. Kokubo, K. Sugibayashi and Y. Morimoto, Interaction
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`therapeutic system, Pharm. Res., 11, 104-107 (1994).
`13) ¥-J. Cho and H.-K. Choi, Enhancement of percutaneous
`absorption of ketoprofen: effect of vehicles and adhesive
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