U3008029820B2
`
`(12:. United States Patent
`USSJn9£20B2
`Shirai et a].
`(45) Date of Patent:
`Oct. 4, 2011
`
`(10) Patent N0.:
`
`(54)
`
`PATCHES CONTAINING TULOBUTEROL
`
`(56)
`
`References Cited
`
`(75)
`
`Inventors: Sadanobu Shirai. lakamatsu (JP):
`Masahiro Yamaji, [[igashikagawa (JP):
`()samu Yoshimoto. 'l'akamalsu (JP):
`Mamoru Naruse. Itano-gtm (JP):
`Kenichi Hattori. Tokushinia (J P);
`Takako Sueda, Aki-gun (JP)
`
`(73) Assignee: Teikoku Seiyaku (70., Ltd“
`Kagawa—Ken (JP)
`
`( ’3‘
`
`1 Notice:
`
`Subject to any disclaimer. the term ol'thjs
`patent is extended or adjusted under 35
`USE. 154(b) by () days.
`
`(21) Appl. No:
`
`10t524,858
`
`(22)
`
`PCT Filed:
`
`Jun. 16, 2004
`
`(86)
`
`PCT No.:
`
`PC’I‘IJP20041'008777
`
`H“ (on),
`(2). (4) Date:
`
`Feb. 18, 2005
`
`PCT Pub. No.: W020041'112770
`
`PC" Pub. Date: Dec. 29, 2004
`
`
`
`4245448
`
`424F448
`
`424-"449
`
`US. PATENT DOCUMENTS
`5.254.348 A
`1051993
`Ilofll‘nann ct a1.
`5,312,627 A ’3
`5.31994 Stroppolo et a1.
`5.639.422 A
`6:"1997 Yamamoto et :11.
`5,366,157 A *
`251999
`Iligo et a1.
`6.112.442 A
`92000 Nakano ct a1.
`7,056,528 B1“
`632006 Brachl
`FOREIGN PA'l‘liN'l‘ DOCUMENTS
`199668374
`531997
`0 738 792
`831997
`1 (174 251
`23211111
`63-10716
`l-"l988
`5-194202
`8-"1993
`1285854
`1031995
`1 l—2283‘)5
`831999
`97.31441 1
`431997
`[11.528531
`4-"2001
`
`O'l‘llL'lR l‘UBLlCA'l‘IONS
`
`AU
`EP
`1".P
`JP
`JP
`JP
`JP
`W0
`W0
`
`B. 1). Kim et a1.. “The penetration enhancement ol‘ [iZ—seleclive
`agonist. tnlobuterol. across the hairless mouse skin”. Proceedings—
`28th International Symposium on Controlled Release of Bioactlve
`Mal erials and 4| h Consumer & Diversified Products Conference. vol.
`1. pp. 16'? to 168. 2001.
`
`* cited by examiner
`
`Primary Examiner — Robert A Wax
`Assistant Examiner — Hasan Ahmed
`
`(87)
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 20050220852 Al
`
`Oct. 6. 2005
`
`(74) .4 Home}; Agent, or Fina
`L.L.P.
`
`chdcroth, Lind 8:. Potlack.
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Jun. 20- 2003
`
`(JP)
`
`2003-176799
`
`(51)
`
`Int. Cl.
`A6IF 13/02
`4241448; 4241449
`(52) U.S. (ll.
`..
`None
`(58)
`Field of Classification Search
`See application file for complete search history.
`
`(2006.01)
`
`A patch containing tulobuterol in the low concentration and
`having the stable release—controllability. prepared by laminat—
`ing an adhesive layer consisting o la rubber, an adhesive res in
`and a plasticizer on a backing. wherein l to 4 wr’w " :1 of
`tulobutero] in the lower concentration as an active ingredient
`and 0.1 to 3 wtw % ofa higher fatty acid as a drug—releasing,
`controlling agent are contained in the adhesive layer.
`
`4 Claims, 4 Drawing Sheets
`
`Noven Pharmaceuticals, Inc.
`EX2016
`
`0001
`
`Mylan Tech, Inc. v. Noven Pharma, Inc.
`|PR2018-00174
`
`

`

`US. Patent
`
`Oct. 4, 2011
`
`Sheet 1 of4
`
`US 8,029,820 32
`
`FIG 1
`
`c» .O o
`
`
`
`
`
`Turobuterol-serumconcentration(ng/mL)
`
`- - I- -- Comp. example 1
`
`E
`
`
`50.0 --O— Example 1
`
`40.0
`
`30.0
`
`20.0
`
`10.0
`
`P o
`
`hour
`
`0002
`
`

`

`US. Patent
`
`Oct. 4, 2011
`
`Sheet 2 of4
`
`US 8,029,820 32
`
`FIG 2
`
`250
`
`+ Example 1
`
`(pg/cmz)
`Permeationamountof1urobuter01
`
`
`
`- 'D' ' ' Comp. example 2
`
`. - .A- - - Comp. example 3
`
`C]D
`
`50
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`hour
`
`0003
`
`

`

`US. Patent
`
`Oct. 4, 2011
`
`Sheet 3 of 4
`
`us 8,029,820 32
`
`FIG 3
`
`180
`
`0') C3
`
`4:.O
`
`120
`
`100
`
`80
`
`60
`
`40
`
`
`
`
`
`Permeationamountofturobuterol(pg/cmz)
`
`—+— Ex. 1 (4°C)
`
`
`
`
`
`
`
`
`
`—o—- Ex. 1 (40°C)
`
`- - -l- -- Comp. ex. 1 (4°C)
`
`- - D - - Comp. ex. 1 (40°C)
`-- -A- - - Comp. ex. 4 (4°C)
`
`A- - - Comp. ex. 4 (40°C)
`
`- 4- - - Comp. ex. 6 (4°C)
`
`”0-- Comp. ex.6 (40°C)
`
`
`
`0004
`
`

`

`US. Patent
`
`Oct. 4, 2011
`
`Sheet 4 of4
`
`US 8,029,820 32
`
`
`
`FIG 4
`
`120
`
`+ Ex. 4 (12 hours)
`
`-—0— Ex. 4 (2 months)
`
`O! O
`
`100
`
`-
`
`- -l - - Comp. ex. 5 (12 hours)
`
`- - -EI- - - Comp. ex. 5 (2 months)
`
`
`
`
`
`Permeationamountofturobuterol(pg/cm?)
`
`AC)
`
`20
`
`0005
`
`

`

`USSflZQBZOBZ
`
`l
`PATCHES CONTAINING 'l‘UI.()BU'I'lCR()I.
`
`'l‘liCIINlCAl. l-‘ll-LII)
`
`The present invention relates to a dermally absorbable type
`patch containing tulobuterol.
`
`BACKGROUND ART
`
`Various dermally absorbable type preparations containing
`tulobuterol have been recently proposed as preparations mak-
`ing up the demerits o l' the oral preparation containing
`tulobuterol (See Japanese Patent Publication A 11-228395,
`Japanese Patent No, 2753800 (Japanese Patent Publication A
`7-285854), WO 97114411 and Japanese Patent No. 2633089
`(Japanese Patent Publication A 5494202)).
`A patch prepared by dissolving tulobuterol into an adhe—
`sive has such a demerit as the duration necessary to sustain its
`ell‘cctive sertun concentration is not attained.
`
`techniques to increase the concentration of
`Therefore,
`tulobuterol or to contain much amount of it by thickening an
`adhesive layer have been tried.
`l-‘or example, in Japanese Patent Publication A l 1-228395.
`a tulobuterol—patch which has a structure to fully dissolve
`tulobuterol is proposed. However. when such a patch is pre—
`served for a long time due to the high concentration of
`tulobuterol, the preparation is apt to receive the influence by
`changes of circumstances such as temperature. etc.
`l"or
`example, even if the preparation has a good qual ity just after
`preparing it, with the passage oftime there is a possibility that
`drug-release pattern becomes different from one at the earlier
`time because tulobuterol crystallizes in the adhesive layer or
`changes of the concentration occurs.
`In general essential physical properties such as adhesivity
`and shape retention of a patch are broken down and it is
`impossible to stably release the drug when a large alnount of
`ingredients, which are either essential or unessential, are con—
`tained in the patch.
`In regard to a patch containing much amount oftulo buterol,
`when the amount of an adhesive is too much. the essential
`physical properties become worse and during application of
`the patch, it gives an uncomfortable feeling to a patient and
`there is also a possibility to drop it out due to rubbing with
`clothes.
`
`Further, in regard to a patch in which tulobuterol is much
`dissolved in the higher concentration. it can not help contain—
`ing much amount of tulobuterol and therefore, it
`is neither
`economical nor practical.
`On the other hand, a patch in which both soluble type
`tulobuterol and crystalline type tulobuterol are contained in
`the specific rates (see Japanese Patent No. 2753800). a patch
`prepared by recrystallizing tulobuterol in an adhesive (see
`WOQ7i’l44l l). a patch consisting of tulobuterol and a spe-
`cific co-polymer, wherein tulobuterol is suspended or micro-
`capsulized and they are included in the adhesive layer, or a
`patch prepared by constructing matrix layers. adhesive layers
`or reservoir layers, and by laminating theses layers [see Japa-
`nese Patent No. 2633089), etc., were proposed as a derinally
`absorbable type patch which is aimed for a long lasting prepa-
`ration of tulobuterol.
`
`However, in regard to these patches. when they are pre—
`served for long time, they are apt to receive the influence by
`changes of circumstances such as temperature, etc. For
`example, owing to the temperature rising in sununer,
`tulobuterol in crystals. suspensions or microcapsules con-
`tained in the patch dissolves and on the contrary. owing to the
`temperature dropping in winter, the dissolved tulobuterol
`
`5
`
`7t]
`
`2‘?
`
`30
`
`35
`
`4t]
`
`5t]
`
`60
`
`65
`
`2
`
`begins to crystallize. Also in case of laminated type prepara-
`tions, owing to changes ol'circumstances. movement (traits-
`[er] of ingredients such as tulobuterol and other ingredients
`occurs between matrix laminated layers and reservoir—layers.
`and the release pattern of tulobuterol
`from the patch is
`changed and there is a possibility to give the influence to the
`therapeutic elfect of tulobuterol.
`As well, these patches require complex techniques for sus—
`pending tulobuterol, microcupsulation ofit and stable blend-
`ing it into the matrix, and selection ofthe condition for recrys-
`tallization of it in the matrix, construction of the matrix and
`the reservoir layer, laminating, etc. They are problematic.
`
`DISCLOSURE OF INVEN’I‘ION
`
`The object ofthe present invention is to provide a patch in
`which tulobuterol is contained in the lower concentration. but
`the patch has oontrollability of stable drug—release.
`The present inventors have been extensively studied in
`consideration of the above problems and as a result, have
`found that a patch prepared by containing tulobuterol in the
`lower concentration in an adhesive layer which was prepared
`by suitably combining a higher fatty acid, a rubber. an adhe—
`sive resin and a plasticizer, shows unexpectedly the drug—
`release in therapeutically effective amount and an ability to
`easily control drug—releasing pattem, is hardly influenced by
`changes ofthe passage with time and furthermore has essen—
`tial physical properties such as adhesivity and shape preten—
`sion which are adjustable, and the process for preparation
`thereof is simple. 'Ihus the present invention has been com-
`pleted.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`shows changes of a passage with time of
`FIG. 1
`tulobuterol—serum concentration in case of applying patches
`of Example 1 and Comparative example 1.
`FIG. 2 shows changes of the passage with time of
`tulobuterol—permeability on extracted rat—skin in case of
`applying patches of 1 Example 1, Comparative example 2 and
`Comparative example 3.
`FIG. 3 shows changes of the passage with time of
`tulobuterol—permeability on extracted rat—skin in case of
`applying patches of Example 1, Comparative example 1.
`Comparative example 4 and Comparative example 6.
`FIG. 4 shows changes of the passage with time of
`tulobutcrol-permeability on extracted rat-skin in case of
`applying patches of 1 Example 4 and Comparative example 5.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`Namely, the present invention relates to a patch containing
`tulobuterol prepared by laminating an adhesive layer consist-
`ing of a rubber, an adhesive resin and a plasticizer on a
`backing, wherein l
`to 4 wi’w % of tulobuterol as an active
`ingredient and 0.] to 3 wfw % of a higher fatty acid. prefer-
`ably Cl 1—22 fatty acid, especially preferably C 14—18 fatty
`acid as a drug-release controlling agent are contained in the
`said adhesive layer.
`The present invention also relates to a patch containing
`tulobuterol. wherein 5 to 35 wr‘w % ofthe rubber, 20 to 70 wi’w
`% of the adhesive resin to 60 wi’w % of the plasticizer are
`contained in the above adhesive layer.
`In regard to patches containing tulobuterol which have
`been traditionally proposed, it has been considered that it is
`essential to blend an acrylic adhesive which has a large polar
`
`0006
`
`

`

`USSflZQBZOBZ
`
`3
`or reactive group, or an adhesive resin having a large polarity
`such as a rosin in an adhesive layer.
`] lowever the patch related to the present invention does not
`need such substances. and that it is found that to blend such
`
`substances in an adhesive layer is not rather preferable
`because such substances cause to give great influences to
`release pattern of tulobuterol and stability in changes of the
`passage with time.
`The constitution of the patch preparation of the present
`invention is illustratively explained below.
`Tulobuterol which is contained as an active ingredient in
`the preparation of the present invention is dermally absorbed
`and exhibits an effect as a bronchodilator. and the preparation
`is characterized in containing tulobuterol in its small amount
`of l~4 wtw %. When the amount is less than 1%. the area of
`application must be broadened in order to make the therapeu—
`tic effects exhibit. When the amount is beyond 4 wtw “u. it is
`necessary to admix other ingredients to control the drug-
`release because the concentration of the drug becomes high
`and the drug is contained much. And as a result. there is a
`possibility to break down essential physical properties as a
`patch. These amounts therefore. are not preferable.
`The higher fatty acid admixed in the present preparation
`has an activity to stably control release pattern oftulobuterol,
`and is used for the drug-release controlling agent. The higher
`fatty acid includes C 1 1-22) preferably C 1+ ,3 fatty acid, such as
`linolic acid, linolenic acid. oleic acid. stearic acid, palmitic
`acid, lauric acid, myristic acid. isostearic acid. r'icinolic acid.
`etc.. especially preferably oleic acid and stearic acid.
`The amount is 0.l—-3 wiw %. preferably 0.2—-2 wlw %.
`more preferably (}.3—-l wt'w "/11. When the amount is less than
`0.1 wtw %, tulobuterol is quickly released. and when the
`amount is beyond 3 wfw ”/6, the drug-release is excessively
`controlled. Therefore these amounts are not preferable.
`The rubber admixed in the present preparation has an abil—
`ity to control the strength ofan adhesive. The rubber includes
`a natural rubber, a synthetic rubber. such as isoprene rubber,
`styrene—butadiene rubber, styrene.butadiene block copoly—
`mer, styrene.isoprene block copolymer, preferably a syn-
`thetic rubber from the viewpoint of quality, especially pref—
`erably styreneisoprene block copolymer.
`The amount is usually 5—35 wfw %. preferably 10—30 wt'w
`%, especially preferably 15-25 wtw “a. When the amount is
`less than 5 wtw 96. the strength of the adhesive does not
`become enough, and when the amount is beyond 35 wfw %,
`the strength becomes too high and the sticking power
`decreases.
`
`The adhesive agent admixed in the present preparation has
`an ability to control the adhesive strength ofan adhesive. The
`adhesive agent includes petroleum resin, polyterpene resin.
`polyolefin resin, saturated alicyclic hydrocarbon resin. etc.,
`especially preferably petroleum resin. and saturated alicyclic
`hydrocarbon resin.
`The amount is usually 20—70 wfw %. preferably 30—60 wfw
`%, especially preferably 40-55 wtw “a. When the amount is
`less than 20%, the adhesivity of the adhesive agent does not
`become enough, and when the amount is beyond 70 wfw %,
`the sticking power becomes too high. Therefore.
`these
`amounts are not preferable.
`The plasticizer admixed in the present preparation has an
`ability to control the viscosity of the adhesive and is used to
`delicately control essential physical properties, such as stick—
`ing power, strength and improvement of sensibility. The plas—
`ticizer includes a liquid resin, an oil, liquid parallin, poly-
`butene, etc., especially preferably liquid para [lin and
`polybutene.
`
`10
`
`15
`
`m 'JI
`
`30
`
`4o
`
`50
`
`tit]
`
`65
`
`4
`
`The amount is usually 5 -6[) wt'w %_. in accordance with the
`amounts 0 fa rubber and an adhesive agent contained.
`The preparation of the present invention is prepared by
`wrapping the adhesive layer having the above mentioned
`constituents with both a backing and a release liner. The
`weight of the adhesive layer is 20~200 gir‘mg, preferably
`50-] 50 g’mz. When the weight is less than 20 gi’mz,
`the
`sticking power becomes very weak and when the weight is
`beyond 200 g/m2, the sticking power becomes excessively
`strong and therefore. there is a possibility to injure the applied
`skin. Furthermore, to increase the weight without any object
`is not preferable from the economical viewpoint.
`The backing is not limited as long as it is usually used and
`thereon an adhesive can be extended. However. a preferable
`backing is one that does not give excessively undesirable
`feeling to the skin during application and fully keep the adhe—
`sive in order not to remain on the skin when releasing off. Also
`the preferable backing is one which does not absorb
`tulobuterol. such a polyester film as polyethyleneterephtha—
`late (PET), a polypropylene film, and paper, a fabric, or an
`unwoven fabric laminated on thereon.
`The liner
`is preferable one which does not absorb
`tulobuterol, such a polyester film as polyethyleneterephtha—
`late (Pli’l‘) etc., or its laminated film. The liner is preferable
`easily releasable from an adhesive when it is released. If
`necessary, a release agent such as silicon resin may be spread
`on the adhesive surface of the liner.
`
`The suitable method for preparing the present preparation
`is a dry method. For example, constituents ofan adhesive are
`dissolved in an organic solvent and the resulting solution is
`uniformly spread out on the one side of the liner. The treated
`liner is dried to remove the solvent and is stuck on the back-
`
`ing. Thus prepared patch is cut in a suitable size to be packed
`in a sealed package.
`A hot—melt method as another method is considered.
`
`Namely the constitutions of an adhesive are blended and
`melted at about IOU—200° C . and then, spread on the liner at
`the same temperature. The preparation is cooled to prepare a
`patch.
`This method has a merit in the viewpoint not to use an
`organic solvent, but the constituents are denatured to some
`extent as the heat charge is very large. Therefore. essential
`physical properties and the release pattern of tulobuterol, etc .,
`
`become unstable and the high processing technique is nece‘
`sary for preparing it. 'lherefore, this method can not be chosen
`as the first option from the practical viewpoint.
`
`liXAMPI .]i
`
`The present invention is explained by illustrating examples
`and test-examples, but the present invention is not limited by
`these examples.
`
`Example 1
`
`.J\tl|tL‘Si\-'C
`Tulebuterol
`Oleic acid
`Stynme - isopreue -
`styrene block copolymer
`Sanlmted alicyclic hydrocarbon
`(Petroleum resin]
`Polybutene
`Liquid pamffm
`
`Content (w.-'w %)
`2
`0.5
`2t]
`
`48
`
`10
`19
`
`0007
`
`

`

`5
`-continued
`
`6
`According to the above indications and in the same manner
`as in the method of Example 1, a patch was prepared.
`
`USSflZQBZOBZ
`
`Adhesive
`
`(.‘on1en1 (wi‘w "/n)
`
`0.5
`
`Example 4
`
`Dibutylhydroxytolu ene
`Weigh ofarihesive
`Backing
`Liner
`
`IIJO gi'm2
`PET 10 pm
`PET "5 pm
`(Release coating on one side}
`
`
`According to the above indications, tulobuterol and oleic
`acid were dissolved in a suitable amount of toluene (Solution
`A). l[)n the other hand. styrene.isop re ne.slyrcne block copoly-
`mer. saturated alicyclic hydrocarbon resin, polybutene, liquid
`paraffin and dibutylhydroxytoluene were mixed with a suit—
`able amount oftoluene until being hontogenous (Mixture B).
`
`The solution A and the mixture B were stirred until being
`homogenous, and the mixture was spread on the release
`coated surface ofthe polyethyleneterephthalate (PET) liner in
`the amount of 100 grin2 and dried. The PET backing was
`laminated on the adhesive side of the liner and the product
`was cut in a suitable size to be packed in a sealed package.
`
`Example 2
`
`Adhesive
`Content fut-"w “/u}
`
`Tulobulerol
`2.5
`Oleic acid
`1
`SLyrene ' isoprene '
`25
`styrene block copolymer
`Saturated alicyclic hydrocarbon
`(Petroleum resin]
`8
`Polybntene
`20
`Liquid paraffin
`0.5
`Dibutylhydroxnoluene
`125 g-"mz
`Weight ol‘adhesive
`PET 3.5 tun-"paper
`Backing
`PET "5 run
`Liner
`[Release coating on one side)
`
`43
`
`According to the above indications and in the satne tnanner
`as in the method of lixample l. a patch was prepared.
`
`Example 3
`
`Adhesive
`Tulobuterol
`Stearie acid
`Styrene - isoprene -
`styrene block copolymer
`Saturated alicyclic hydrocarbon resin
`(l’chuicuiii JesiitJ
`Polybutene
`Liquid paraffin
`1)th:lylhydroxytolucne
`Weight nl‘arihesive
`Backing
`Liner
`
`(.‘nnlelu (wi‘w Ufa)
`2
`[LT
`13
`
`50
`
`5
`23.3
`[1.5
`9t] gfni2
`PET 3.5 umFUnwoven fabric
`PET ?5 pm
`(Release coating on one side}
`
`10
`
`1.5
`
`m 'JI
`
`30
`
`4n
`
`50
`
`u: 'JI
`
`an
`
`65
`
`
`
`Conten1 [w.-'w Ufa]
`3
`0.5
`EU
`
`.J\d|1esive
`'l'ulobuterol
`Oleic acid
`Styrene - isoprene -
`slyrene block copolymer
`Saturated alicyclic hydrocarbon resin
`(Petroleum resin)
`10
`Polybutene
`23.5
`Liquid paraffin
`1.0
`Dibutylhydroxytolucne
`80 g-"m2
`Weight of adhesive
`Pli'l' 13 pm
`Backing
`PET T5 um
`Liner
`[Release coating on one side)
`
`4?.
`
`According to the above indications and in the same manner
`as in the method ofExainple l, a patch was prepared.
`
`Comparative Example 1
`
`The commercially available crystalline type tulobuterol
`patch (Trade name: llokunalin tape prepared by IIokuriku
`Seiyaku K.K.): 'l‘ulobuterol: 10 wfw "/6, 2 mg} sheet. size o l'
`sheet:
`|0cm2
`
`Comparative lixample 2
`
`By using the same ingredients as in lixample 2 provided
`that in place of the olcic acid 1 wx’w “/6, liquid paraffin l wfw
`‘Vo was used. a patch was prepared in the same manner as in the
`method of Example 1.
`
`Comparative lixample 3
`
`By using the same ingredients as in Example 2 provided
`that in place of saturated alicyclic hydrocarbon 43 wfw %,
`rosin glycerin ester 43 wfw % was used, a patch was prepared
`in the same manner as in the method of Example 1.
`
`Comparative lixample 4
`
`
`
`Adhesive
`
`
`styrene block copolymer
`31?
`Diolefin - olefin copolymer
`3.50 g-‘mz
`Weight nl‘mihesive
`PET 25 um
`Backing
`PET ?5 tan
`Liner
`[Release coating on one side)
`
`Content (w-"w %]
`5.5
`56.8
`
`According to the above indications, styrene.isoprene.sry-
`rene block copolymer and diolefinclei‘in block copolymer
`were stirred at 150° C. Thereto was added tulobuterol and the
`
`stirred mixture was passed through between release treated
`PET liner and PET backing during being kept at 1 10° C. and
`it was rolled under the constant pressure in order to becotne
`250 gi'm2 in thickness. The obtained patch was cut in a suit-
`able size to be packed in a sealed package.
`
`0008
`
`

`

`USSflZQBZOBZ
`
`7
`This preparation is a highly concentrated, highly contained
`and soluble type tulobuterol patch prepared by the method of
`example [sample 2a) ofJapanese Patent No. 2633089.
`
`
`Comparative Example 5
`
`Adhesive
`Tulobuterol
`Styrene - isoprene -
`styrene block copolynter
`Diolcfin - olefin copolymer
`Weight of adhesive
`Backing
`
`Liner
`
`Adhesive layer 5-1
`Content twfw ‘Voj
`1
`61.3
`
`Adhesive layer 5—2
`Content {wtw %)
`5.5
`56.8
`
`31]"
`50 g-"m’
`PET 25 um
`[Release cord Eng on
`one side)
`I-‘I'L'I' 15 fun
`[Release cord in}; on
`one side)
`
`33".?
`200 gtm’
`PET 25 1,1111
`{Release coat ing on
`one side}
`1’] ET T5 tun
`[Release coat ing on
`one side}
`
`According to the above indications. an adhesive layer 5—1
`and an adhesive layer 5-2 were prepared in the same manner
`as in Comparative example 4. After removing each PI {T back-
`ing. each adhesive surface was stuck each other to prepare a
`laminated tulobuterol patch preparation. The preparation was
`cut in a suitable size to be packed in a sealed package. This
`preparation is a laminated and soluble type tulobuterol patch
`prepared by the method of Japanese Patent No. 2633089.
`
`
`Comparative Example 6
`
`Adhesive
`Tulohuterol
`Isopropy] myristate
`Styrene - isoprene -
`styrene block copolynter
`l’olyisobutylene
`Saturated alicyclic hydrocarbon resin
`[Petroleum resin]
`Weight ol‘arlhesive
`Backing
`Liner
`
`(.‘onlen1 [wi'w Ufa)
`5
`4t!
`38.5
`
`3.3
`I 1
`
`4t} giro2
`PET 25 pm
`PET T5 pm
`[Release coating on one side}
`
`According to the above indications, styreneisoprenesty—
`rene block copolymer, polyisobutylene and saturated alicy-
`clic hydrocarbon resin were mixed until being homogenous.
`To the mixture were added and mixed tulobuterol and isopro—
`py1 myristate until being homogenous. The solution was
`spread on the surface of release treated PIiT in the amount of
`40 gm2 dried and stuck on PET backing. Thus obtained
`preparation was cut in a suitable size to be packed in a sealed
`package.
`This preparation was a highly concentrated and soluble
`type tulobuterol patch prepared by example 8 of Japanese
`Patent Publication A 1 1-228395.
`Test 1
`
`A patch of Example 1 (tulobuterol: 2 wtw %, size: 10 c1112]
`and a commercially available patch ot'Comparative example
`1 were applied to the back of a hair—cut rat respectively. Two,
`four, eight. ten and twenty l'our hours later. the blood was
`taken and tulobuterol
`levels in serum were tneasured by
`I II-’I .C. Changes ofthe passage with titne o [tulobuterol levels
`
`8
`in serum on application of patches of Iixample l and Com-
`parative example I were shown in FIG. '1.
`From this test result.
`it was suggested that a patch of
`Example I maintained for a long time tulobuterol levels in
`serum as same as the commercialized patch ot'Comparative
`example 1. which contains 5 times amount of tulobuterol as
`much as the patch of Example I has. Therefore, it was shown
`that the patch of the present invention was a lower concen—
`trated and soluble type patch. and had an ability to control the
`drug—release for a long time.
`Furthermore, according to the disclosure 0 fWO 971’1441 I.
`the crystalline type tulobuterol patch requires to adjust the
`average particle size 0 f tulobuterol within 2-20 tun, in order
`to stabilize the drug—release from the patch and its duration.
`Therefore. due to crystallizing tulobuterol during adjusting
`the particle size in the adhesive layer, the ageing process for
`controlling time and temperature is required.
`On the contrast. the patch of Example 1 is a lower concen—
`trated and soluble type tulobuterol patch and has drug-release
`ability without containing its crystals. Therefore,
`it was
`cleared that the process for preparing for this patch did not
`require the above mentioned complex ageing processes and
`the patch could be prepared by a very simple procedure.
`Test 2
`The skin ofabdornen of a hair—cut rat was extracted and
`
`fitted on a Frantz-diITusion cell. Phosphate-buffer was used as
`a reservoir solution and the cell was kept to stir at 37° C.
`during test.
`A patch of Example 1, and patches of Comparative
`examples 2 and 3 were cut in a circle having diameter 13 mm
`[Tulohnterol ofExample 1 and Comparative examples: 2 wrw
`%, 200 ttgfcmz], and the circles fitted on the extracted skin.
`Small amount of the reservoir solution was from time to time
`
`taken and the amount of permeated tulobuterol was measured
`by IIPIC (Drug permeation test on rat-extracted skin).
`Changes of the passage with time ofpennealed tulobuterol
`in case oi'application ofpatches of Example 1 and Compara—
`tive examples 2 and 3 were shown in l-‘ICi. 2.
`Example 1: tulobuterol; 2 wtw %_. 200 ttgi’cm2
`Comparative example 2 and 3: tulobuterol: 2 wr’w "/11, 200
`luster“:
`From this test result. the amount of permeated tulobuterol
`in regard to the patch ot‘Example l was constant in changes of
`the passage with time. ()n the other hand, in regard to the
`patch oi'Comparative example 2 without containing a higher
`fatty acid. it showed the tendency that the amount of the
`permeated drug increased and the duration decreased at a
`latter half. Furthennore, in Comparative example 3 contain-
`ing rosin glycerin ester having polarity, the drug permeability
`greatly decreased.
`Test 3
`
`Influence on Drug—Release by Preservation Temperature
`In order to check the influence on drug-release due to the
`changes of preservation temperature, patches of I Example 1.
`Comparative examples I. 4 and 6 were preserved in incubator
`kept at 4" C. and 40" C. respectively for 3 weeks. and then the
`temperature was adjusted to room temperature. In the same
`manner as Test 2 the drug permeation test on the skin
`extracted from rat was carried out.
`
`In case of application ot‘patches of Example 1. Compara-
`tive examples 1= 4 and 6. changes oi'the passage with time of
`the permeation of tulobuterol were shown in FIG. 3. The
`drug—permeation rate due to changes oi'p reservation tempera—
`ture was shown in Table 1.
`
`Example I: tulobuterol; 2 wfw %, 200 ugfcm2
`Comparative example I:
`tulobuterol:
`IO wfw “/11. 200
`pacml
`
`10
`
`15
`
`m 'JI
`
`30
`
`4o
`
`50
`
`fit]
`
`65
`
`0009
`
`

`

`USSflZQBZOBZ
`
`9
`(Crystalline Type 'l‘ulobuteriol Patch)
`Comparative example 4: tulobuterol: 5.5 wlw "A1. 1375
`ugl'cm2 (l lighly concentrated. highly contained and soluble
`type tulobuterol patch)
`Comparative example 6: tulobuterol; 5 wi'w %; 200 pgtcm2
`(Highly concentrated and solub.e type tulobuterol patch)
`
`
`
`TABLE 1
`
`Rate of drug permeated amount due to changes
`of preservation temperature on each sample
`
`lixample 1
`89‘1’5‘
`
`(.‘omp amt ive
`example 1
`65 Ufa
`
`(.‘omparaJ ive
`example 4
`162%
`
`(.‘omparat ive
`example 6
`44%
`
`Test
`example
`Rate of
`penneation
`
`‘Emuiple of calculation: {permeation amount ol'lixamplc I
`amonntofExample ] {40" C'.] IS hr}} x 100
`
`(-4" C.) (3 hr)}-"{permcat.ion
`
`l-‘rom this test result, it was shown that the drug permeated
`amount on a patch of Example 1 was constant and hardly
`influenced by changes of preservation temperature.
`[)n the other hand, it was shown that the group of (Tom-
`parative examples was apt to receive the influence by the
`changes of preservation temperature.
`This fact suggested that due to changes of preservation
`temperature, the rate of crystals and dissolved portion in the
`adhesive was changed and due to the high concentration ofthe
`drug, the degree of saturation in the adhesive was changed. or
`since the drug was easy to separate from the constituents of
`the additive, it was possible that the amount of permeation of
`the drug was greatly changed up and down.
`Test 4
`
`Influence on Drug—Release by Preservation Term
`In order to see the influence on drug—release by preserva—
`tion term, by using two kinds ofpatches ofoample 4. which
`was prepared 12 hours before and which was preserved for 2
`months at room temperature, and two kinds of patches pre-
`pared by sticking layers 5-1 and 5-2 in Comparative example
`5, which was prepared 12 hours before, and which was pre-
`served for 2 months at room temperature, in the same manner
`as in Test 2, the drug permeation test on the skin extracted
`from rat was carried out. In regard to patches of Comparative
`example 5. the 5—1
`layer side which was lower in the drug
`concentration was applied to the skin.
`Changes ofthe passage with time ot'permeated tulobuterol
`in case of application of patches of] ixample 4 and Compara-
`tive example 5 were shown in l-‘ICr. 4.
`Example 4: tulobuterol: 3 wfw %. 240 ugjcn‘i2
`Comparative example 5: (adhesive layer 5—1)tulobuterol; l
`wt'w %, 50 itgfcnfifiadhesive layer 5—2) tulobuterol: 5.5 wfw
`%, 1108 itgi’cm2
`(Laminated Patch)
`From this test result, it was shown that a patch of Example
`4 was constant in drug permeation amount with changes of
`the passage with time.
`[)n the other hand, in regard to a patch of Comparative
`example 5, the drug permeation amount was increased with
`
`10
`
`15
`
`m 'JI
`
`30
`
`4o
`
`50
`
`10
`changes ofthe passage with time. liven ifthe adhesive had the
`higher drug concentration, the drug penneation amount was
`controllable by sticking the layers having the lower drug
`concentration, but it was considered that the transfer between
`adhesive layers occurred and the concentration of the drug
`was averaged during a long time and therefore the control of
`the drug—release was injured.
`
`INDI lSTRlAl . APPLICABILITY
`
`The patch of the present invention is prepared by dissolv-
`ing tulobuterol in the lower concentration in an adhesive layer
`and thereto adding a higher fatty acid, a rubber. an adhesive
`agent and a plasticizer in a suitable amount respectively, can
`easily control the tulobuterol release pattem and is excellent
`in changes of the passage with time of release pattern.
`Furthermore, according to the present invention, essential
`physical properties on a patch such as adhesivity and shape
`retention are suitably adjusted and by simplifying the method
`for preparation, the patch ofthe present invention has follow—
`ing advantages comparing with the known tulobuterol—patch:
`(l J Despite fact that the content oftulobuterol is less, the
`effect can be optimized according to the therapeutic object as
`the patch 0 fthe present invention shows sufficient tulobuterol
`release amount and it is possible to widely and simply control
`the tulobuterol release amount.
`
`(2) The adjustment of essential properties as a patch is
`possible together with controlling the release amount and
`releasing pattem of tulobuterol. Therefore, it becomes pos-
`sible to provide a patch which is therapeutically effective and
`has physical properties suitable to the skin condition.
`(3) During preservation, the influence by changes of cir-
`cumstances is less and the quality is stably kept for a long
`term.
`
`(4) The preparation method is very simple and practical.
`
`The invention claimed is:
`
`l. A patch prepared by laminating an adhesive layer con-
`sisting of a rubber, an adhesive resin other than an acrylic
`adhesive, a plasticizer, l to 4 wr‘w % ol'tulobuterol as an active
`ingredient and 0.1 to 3 wi’w % of a higher fatty acid as a
`drug—release controlling agent on a backing.
`2. The patch according to claim 1 wherein 5 to 35 wi’w % of
`the rubber, 20 to 70 wt'w % of an adhesive resin and 5 to 60
`wr’w % of a plasticizer are contained in the adhesive layer.
`3. The patch according to clailn 1 wherein the higher fatty
`acid is (7. “22 fatty acid.
`4. The patch according to claim 1 wherein the adhesive
`resin is selected from the group consisting o fpetroleum resin.
`polyterpene resin, polyolefm resin and saturated alicyclic
`hydrocarbon resin.
`
`0010
`
`