US008029820B2
`
`a2) United States Patent
`US 8,029,820 B2
`(10) Patent No.:
`Oct. 4, 2011
`(45) Date of Patent:
`Shirai et al.
`
`(54)
`
`PATCHES CONTAINING TULOBUTEROL
`
`(56)
`
`References Cited
`
`(75)
`
`Inventors: Sadanobu Shirai, Takamatsu(JP);
`Masahiro Yamaji, Higashikagawa(JP):
`Osamu Yoshimoto, Takamatsu (JP):
`Mamoru Naruse, Itano-gun(JP);
`Kenichi Hattori, Tokushima(JP);
`Takako Sueda, Aki-gun (JP)
`
`(73) Assignee: Teikoku Seiyaku Co., Ltd.,
`Kagawa-Ken(JP)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by0 days.
`
`(21) Appl. No.:
`
`10/524,858
`
`(22)
`
`PCT Filed:
`
`Jun. 16, 2004
`
`.......... 424/448
`
`U.S. PATENT DOCUMENTS
`5,254,348 A
`10/1993 Hoffmann etal.
`5,312,627 A *
`5/1994 Stroppolo etal.
`5,639,472 A
`6/1997 Yamamotoetal.
`5,866,157 A *
`2/1999 Higoetal. wo... 424/448
`6,117,447 A
`9/2000 Nakanoetal.
`7,056,528 BL*
`6/2006 Bracht wc. 424/440
`FOREIGN PATENT DOCUMENTS
`199668374
`5/1997
`0 788 792
`8/1997
`1 074 251
`2/2001
`63-10716
`1/1988
`5-194202
`8/1993
`7-285854
`10/1995
`11-228395
`8/1999
`97/144 11
`4/1997
`01/2853 1
`4/2001
`
`AU
`EP
`EP
`JP
`JP
`JP
`JP
`WO
`WO
`
`OTHER PUBLICATIONS
`
`B. D. Kim et al., “The penetration enhancement of fi2-selective
`agonist, tulobuterol, across the hairless mouse skin”, Proceedings—
`28th International Symposium on Controlled Release of Bioactive
`§ 371 (c\(1),
`Materials and 4th Consumer & Diversified Products Conference, vol.
`(2), (4) Date:~~Feb. 18, 2005
`1, pp. 167 to 168, 2001.
`
`(86)
`
`PCT No.:
`
`PCT/JP2004/008777
`
`(87)
`
`PCT Pub. No... WO2004/112770
`
`PCTPub. Date: Dec. 29, 2004
`
`
`
`* cited by examiner
`
`Primary Examiner — Robert A Wax
`Assistant Examiner — Hasan Ahmed
`
`Prior Publication Data
`(65)
`(74) Attorney, Agent, or Firm—Wenderoth, Lind & Ponack,
`L.L.P.
`US 2005/0220852 Al
`Oct. 6, 2005
`
`(30)
`
`Foreign Application Priority Data
`
`Jun. 20, 2003
`
`(IP) cecececcessestesseesteseeseess 2003-176799
`
`(51)
`
`Int. Cl.
`(2006.01)
`AGIF 13/02
`(52) US. CL oceee 424/448; 424/449
`(58)
`Field of Classification Search ......000000000.0.... None
`See applicationfile for complete searchhistory.
`
`ABSTRACT
`(57)
`A patch containing tulobuterol in the low concentration and
`havingthe stable release-controllability, prepared by laminat-
`ing an adhesivelayer consisting of a rubber, an adhesive resin
`and a plasticizer on a backing, wherein 1 to 4 w/w %of
`tulobuterol in the lower concentrationas an active ingredient
`and 0.1 to 3 w/w % ofa higherfatty acid as a drug-releasing
`controlling agent are contained in the adhesive layer.
`
`4 Claims, 4 Drawing Sheets
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2016
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00174
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 1 of 4
`
`US 8,029,820 B2
`
`FIG 1
`
`
`
`
`
`Turobuterol-serumconcentration(ng/mL)
`
`60.0
`
`40.0
`
`30.0
`
`
`
`
`
`50.0 -- @-- Comp. example 1
`
`20.0
`
`10.0
`
`0.0
`
`hour
`
`0002
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet2 of 4
`
`US 8,029,820 B2
`
`FIG 2
`
`250
`
`—@®— Example 1
`- -C- -- Comp. example 2
`---A&-- Comp. example 3
`
`(g/cm?)
`Permeationamountofturobuterol
`
`
`SoOo
`
`50
`
`0
`
`4
`
`8
`
`12
`
`hour
`
`16
`
`20
`
`24
`
`0003
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet3 of 4
`
`US 8,029,820 B2
`
`FIG 3
`
`180
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`
`
`
`
`Permeationamountofturobuterol(g/cm)
`
` —@®— Ex. 1 (4°C)
`—o— Ex.1 (40°C)
`--M™ -- Comp. ex. 1 (4°C)
`--O--- Comp. ex. 1 (40°C)
`-+-M&-- Comp. ex. 4 (4°C)
`->--+ Comp. ex. 4 (40°C)
`~*-@-- Comp. ex. 6 (4°C)
`~*&-- Comp. ex. 6 (40°C)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0004
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet4 of 4
`
`US 8,029,820 B2
`
`FIG 4
`
`
`—®— Ex. 4 (12 hours)
`—O— Ex. 4 (2 months)
`---HE-- Comp. ex. 5 (12 hours)
`---O+-- Comp. ex. 5 (2 months)
`
`(g/cm?)
`Permeationamountofturobutero!
`
`
`0005
`
`

`

`US 8,029,820 B2
`
`1
`PATCHES CONTAINING TULOBUTEROL
`
`TECHNICAL FIELD
`
`The present inventionrelates to a dermally absorbable type
`patch containing tulobuterol.
`
`BACKGROUNDART
`
`Various dermally absorbable type preparations containing
`tulobuterol have been recently proposed as preparations mak-
`ing up the demerits of the oral preparation containing
`tulobuterol (See Japanese Patent Publication A 11-228395,
`Japanese Patent No, 2753800 (Japanese Patent Publication A
`7-285854), WO 97/14411 and Japanese Patent No. 2633089
`(Japanese Patent Publication A 5-194202)).
`A patch prepared by dissolving tulobuterol into an adhe-
`sive has such a demerit as the duration necessary to sustain its
`effective serum concentration is not attained.
`
`techniques to increase the concentration of
`Therefore,
`tulobuterol or to contain much amountof it by thickening an
`adhesive layer have beentried.
`For example, in Japanese Patent Publication A 11-228395,
`a tulobuterol-patch which has a structure to fully dissolve
`tulobuterol is proposed. However, whensuch a patchis 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. For
`example, even if the preparation has a good quality just after
`preparingit, with the passage oftimethere is a possibility that
`drug-release pattern becomesdifferent fromoneat the earlier
`time because tulobuterol crystallizes in the adhesive layer or
`changes ofthe concentration occurs.
`In general essential physical properties such as adhesivity
`and shape retention of a patch are broken downandit is
`impossible to stably release the drug when a large amount of
`ingredients, whichare either essential or unessential, are con-
`tainedin the patch.
`Inregard to a patch containing much amountoftulobuterol,
`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.
`
`a
`
`ba
`
`Al
`
`a43
`
`Further, in regard to a patch in which tulobuterol is much
`dissolved in the higher concentration, it can not help contain-
`ing much amountof 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 tulobutero] in an adhesive (see
`W0O97/14411), 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 dermally
`absorbable type patch whichis aimed for a longlasting prepa-
`ration oftulobuterol.
`
`5
`
`60
`
`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 summer,
`tulobuterol in crystals, suspensions or microcapsules con-
`tained in the patchdissolves and onthe contrary, owing to the
`temperature dropping in winter, the dissolved tulobuterol
`
`65
`
`2
`beginsto crystallize. Also in case of laminated type prepara-
`tions, owing to changes ofcircumstances, movement(trans-
`fer) 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 andthere is a possibility to give the influence to the
`therapeutic effect of tulobuterol.
`Aswell, these patches require complex techniques for sus-
`pending tulobuterol, microcupsulation ofit and stable blend-
`ing it into the matrix, and selectionofthe conditionfor recrys-
`tallization of it in the matrix, construction of the matrix and
`the reservoir layer, laminating, etc. They are problematic.
`
`DISCLOSURE OF INVENTION
`
`The object of the present invention is to provide a patchin
`whichtulobuterol is contained in the lower concentration, but
`the patch has controllability 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 anability to
`easily control drug-releasing pattern, is hardly influenced by
`changesofthe 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. Thus the present invention has been com-
`pleted.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`shows changes of a passage with time of
`1
`FIG.
`tulobuterol-serumconcentration 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 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
`tulobuterol-permeability on extracted rat-skin in case of
`applying patches of Example 4 and Comparative example5.
`
`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 1
`to 4 w/w % of tulobuterol as an active
`ingredient and 0.1 to 3 w/w %of a higher fatty acid, prefer-
`ably C11-22 fatty acid, especially preferably C14-18 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 w/w % ofthe rubber, 20 to 70 w/w
`% ofthe adhesive resin to 60 w/w % of the plasticizer are
`contained in the above adhesivelayer.
`In regard to patches containing tulobuterol which have
`been traditionally proposed, it has been considered thatit is
`essential to blend an acrylic adhesive which has a large polar
`
`0006
`
`

`

`US 8,029,820 B2
`
`a
`
`3
`or reactive group, or an adhesiveresin havinga large polarity
`such as a rosin in an adhesive layer.
`Howeverthe patchrelatedto 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 changesof the
`passage withtime.
`The constitution of the patch preparation of the present
`inventionis illustratively explained below.
`Tulobuterol whichis contained as an active ingredient in
`the preparationofthe present invention is dermally absorbed
`and exhibits an effect as a bronchodilator, and the preparation
`is characterized in containing tulobuterolin its small amount
`of 1~4 w/w %. Whenthe amountis less than 1%, the area of
`application must be broadenedin order to make the therapeu-
`tic effects exhibit. When the amountis beyond 4 w/w %,it is
`necessary to admix other ingredients to control the drug-
`=)
`release because the concentration of the drug becomes high 2
`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 anactivity to stably control release patternoftulobuterol,
`and is used for the drug-release controlling agent. The higher
`fatty acid includes C, ,_,,) preferably C,._, fatty acid, such as
`linolic acid, linolenic acid, oleic acid, stearic acid, palmitic
`acid, lauric acid, myristic acid, isostearic acid, ricinolic acid,
`etc., especially preferably oleic acid and stearic acid.
`The amount is 0.1~3 w/w %, preferably 0.2~2 w/w %,
`more preferably 0.3~1 w/w %. When the amountts less than
`0.1 w/w %, tulobuterol is quickly released, and when the
`amount is beyond 3 w/w %, the drug-release is excessively
`controlled. Therefore these amounts are not preferable.
`The rubber admixed inthe present preparationhas anabil-
`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-
`erablystyrene.isoprene block copolymer.
`The amountis usually 5-35 w/w %, preferably 10-30 w/w
`%, especially preferably 15-25 w/w %. When the amount is
`less than 5 w/w %, the strength of the adhesive does not
`become enough, and whenthe amountis beyond 35 w/w %,
`the strength becomes too high and the sticking power
`decreases.
`
`30
`
`40
`
`4
`The amount is usually 5-60 w/w %, in accordance with the
`amounts ofa 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 g/m*, preferably
`50~150 g/m?. When the weight is less than 20 g/m’,
`the
`sticking power becomes very weak and whenthe weightis
`beyond 200 g/m’, 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 backing1s 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 whenreleasing 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 onthereon.
`The liner
`is preferable one which does not absorb
`tulobuterol, such a polyester film as polyethyleneterephtha-
`late (PET) etc., or its laminated film. The liner is preferable
`easily releasable from an adhesive whenit is released. If
`necessary, a release agent such assilicon resin may be spread
`onthe adhesive surface ofthe liner.
`
`The suitable method for preparing the present preparation
`is adry method. For example, constituents of an adhesive are
`dissolved in an organic solvent and the resulting solutionis
`uniformly spread out on the oneside ofthe liner. The treated
`liner is dried to remove the solvent and is stuck onthe back-
`ing. Thus prepared patchis 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 100-200° C. and then, spread onthe 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 patternof tulobuterol, etc.,
`
`become unstable and the high processing technique is neces
`sary for preparingit. Therefore, this method can not be chosen
`as the first option fromthe practical viewpoint.
`
`EXAMPLE
`
`Thepresentinvention is explained by illustrating examples
`and test-examples, but the present invention is not limited by
`these examples.
`
`Example 1
`
`Adhesive
`Tulobuterol
`Oleic acid
`Styrene - isoprene -
`styrene block copolymer
`Saturated alicyclic hydrocarbon
`(Petroleum resin)
`Polybutene
`Liquid paraffin
`
`Content (w/w %)
`2
`0.5
`20
`
`48
`
`10
`19
`
`The adhesive agent admixedin the present preparation has
`anability to control the adhesive strength of an adhesive. The
`adhesive agent includes petroleumresin, polyterpene resin,
`polyolefin resin, saturated alicyclic hydrocarbonresin, etc.,
`especially preferably petroleumresin, and saturated alicyclic
`hydrocarbonresin.
`The amountis usually 20-70 w/w%, preferably 30-60 w/w
`%, especially preferably 40-55 w/w %. When the amount is
`less than 20%, the adhesivity of the adhesive agent does not
`become enough, and whenthe amountis beyond 70 w/w %,
`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 andis used to
`delicately control essential physical properties, such as stick-
`ing power, strength and improvementofsensibility. The plas-
`ticizer includes a liquid resin, an oil, liquid paraffin, poly-
`butene, etc., especially preferably liquid paraffin and
`polybutene.
`
`50
`
`60
`
`65
`
`0007
`
`

`

`US 8,029,820 B2
`
`5
`-continued
`
`6
`According to the above indications and in the same manner
`as in the method of Example 1, a patch was prepared.
`
`Adhesive
`
`Content (ww%)
`
`5
`
`Example 4
`
`
`
`0.5
`Dibutylhydroxytoluene
`L100. g/m?
`Weight of adhesive
`PET 10 pm
`Backing
`Liner
`PET 75 pm
`(Release coating on one side)
`
`
`Content (w/w%)
`3
`0.3
`20
`
`Adhesive
`10 Tulobuterol
`Oleic acid
`Styrene « isoprene -
`According to the above indications, tulobuterol and oleic
`styrene block copolymer
`42
`acid weredissolved in a suitable amountoftoluene (Solution
`‘Petitesnea. hydrocarbonresin
`10
`A). Onthe other hand,styrene.isoprene.styrene block copoly-
`15 Polybutene
`23.5
`mer, saturated alicyclic hydrocarbonresin, polybutene,liquid
`Liquid peraffin
`ee ein?
`paraffin and dibutylhydroxytoluene were mixed witha suit- Wesitetaikohe
`PET12 pm
`able amountoftoluene until being homogenous (Mixture B).
`Backing
`PET 75 pm
`Liner
`The solution A and the mixture B werestirred until being
`(Release coating on one side)
`homogenous, and the mixture was spread on the release
`coated surface ofthe polyethyleneterephthalate (PET) linerin
`the amount of 100 g/m? and dried. The PET backing was
`laminated on the adhesive side ofthe liner and the product
`wascut in a suitable size to be packed in a sealed package.
`
`According to the above indications and in the same manner
`as in the method of Example 1, a patch was prepared.
`
`bo La
`
`Comparative Example 1
`
`Example 2
`
`The commercially available crystalline type tulobuterol
`patch (Trade name: Hokunalin tape prepared by Hokuriku
`Seryaku K.Is.): ‘lulobuterol: 10 w/w %, 2 mg/sheet, size of
`30 sheet: 10 cm?
`
`Adhesive
`Content (w/w%)
`
`Tulobuterol
`2.5
`Oleic acid
`1
`Styrene + isoprene -
`25
`styrene block copolymer
`43
`Saturated alicyclic hydrocarbon
`(Petroleumresin)
`8
`Polybutene
`20
`Liquid paraffin
`0.5
`Dibutylhydroxytoluene
`125 g/m?
`Weightofadhesive
`PET 3.5 um/paper
`Backing
`PET 75 um
`Liner
`(Release coating on one side)
`
`Accordingto the aboveindications and in the same manner
`as in the method of Example 1, a patch was prepared.
`
`Example 3
`
`35
`
`40
`
`45
`
`50
`
`Comparative Example 2
`
`By using the same ingredients as in Example 2 provided
`that in place ofthe oleic acid 1 w/w %,liquid paraffin 1 w/w
`% was used, a patch was prepared in the same mannerasin the
`method of Example 1.
`
`Comparative Example 3
`
`By using the same ingredients as in Example 2 provided
`that in place ofsaturated alicyclic hydrocarbon 43 w/w %,
`rosin glycerin ester 43 w/w % was used, a patch was prepared
`in the same manneras in the method of Example 1.
`
`Comparative Example 4
`
`
`
`Adhesive
`
`Content (wiw%)
`5.5
`56.8
`
`
`
`
`styrene block copolymer
`.
`.
`.
`37.7
`Diolefin - olefin copolymer
`Content (w/w%)
`Adhesive
`
`
`55 siohtofadhesive 250 g/m?
`Tulobuterol
`2
`Weight of adhesive
`250 g/m
`Sweetie
`seat
`Backing
`PET 25 um
`Stearic acid
`0.7
`:
`=
`.
`Liner
`PET 75 um
`.
`.
`Styrene « isoprene -
`18
`(Release coating on one side)
`.
`.
`
`styrene block copolymer
`Saturated alicyclic hydrocarbon resin
`Oyunresin)
`Liquid paraffin
`Dibutylhydroxytoluene
`oT
`F* mee
`Weight of adhesive
`liner
`
`60
`
`50
`According to the above indications, styrene.isoprene.sty-
`5
`rene block copolymer and diolefin.olefin block copolymer
`23.8
`were stirred at 150° C. Thereto was added tulobuterol and the
`0.5
`]
`7
`2
`stirred mixture was passed through betweenrelease treated
`vari
`PET 20 an
`PETS PETliner and PET backing during being kept at 110° C. and
`65
`(Release coating on one side)
`it was rolled under the constant pressure in order to become
`250 g/m? in thickness. The obtained patch was cut in a suit-
`able size to be packed in a sealed package.
`
`0008
`
`

`

`US 8,029,820 B2
`
`7
`This preparation1s a highly concentrated, highly contained
`and soluble type tulobuterol patch prepared by the method of
`example (sample 2a) of Japanese Patent No. 2633089.
`
`
`Comparative Example 5
`
`Adhesive
`Tulobuterol
`Styrene + isoprene -
`styrene block copolymer
`Diolefin - olefin copolymer
`Weight of adhesive
`Backing
`
`Liner
`
`Adhesive layer 5-1
`Content (w/w %)
`1
`61.3
`
`Adhesive layer 5-2
`Content (w/w%)
`3.5
`56.8
`
`37.7
`50 g/m?
`PET 25 um
`(Release coating on
`one side)
`PET 75 wm
`(Release coatingon
`one side)
`
`37.7
`200 g/m?
`PET 25 um
`(Release coating on
`one side}
`PET 75 um
`(Release coating 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 PET 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
`preparationis a laminated and soluble type tulobuterol patch
`prepared by the method of Japanese Patent No. 2633089.
`
`
`Comparative Example 6
`
`Adhesive
`Tulobuterol
`Isopropyl myristate
`Styrene + isoprene -
`styrene block copolymer
`Polyisobutylene
`Saturated alicyclic hydrocarbonresin
`(Petroleumresin)
`Weight of adhesive
`Backing
`Liner
`
`Content (w/w%)}
`3
`40
`38.5
`
`3.5
`Ll
`
`40 g/m?
`PET 25 pm
`PET 75 pm
`(Release coating on one side)
`
`According to the above indications, styrene.isoprene.sty-
`rene block copolymer, polyisobutylene and saturated alicy-
`clic hydrocarbonresin were mixed until being homogenous.
`To the mixture were added and mixed tulobuterol and isopro-
`pyl myristate until being homogenous. The solution was
`spread on the surface of release treated PET in the amount of
`40 g/m? dried and stuck on PETbacking. Thus obtained
`preparation was cut in a suitable size to be packed ina sealed
`package.
`This preparation was a highly concentrated and soluble
`type tulobuterol patch prepared by example 8 of Japanese
`Patent Publication A 11-228395.
`Test 1
`Apatch of Example 1 (tulobuterol: 2 w/w %, size: 10 cm”)
`and a commercially available patch of Comparative example
`1 were applied to the back ofa hair-cut rat respectively. Two,
`four, eight, ten and twenty four hours later, the blood was
`taken and tulobuterol
`levels in serum were measured by
`HPLC. Changes of the passage withtime of tulobuterol levels
`
`8
`in serumon application of patches of Example | and Com-
`parative example 1 were shown in FIG. 1.
`From this test result,
`it was suggested that a patch of
`Example 1 maintained for a long time tulobuterol levels in
`serum as same as the commercialized patch of Comparative
`example 1, which contains 5 times amount oftulobuterol as
`muchas the patch of Example | has. Therefore, it was shown
`that the patch ofthe present invention was a lower concen-
`trated and soluble type patch, and had anability to control the
`drug-release for a long time.
`Furthermore, accordingto the disclosure of WO97/14411,
`the crystalline type tulobuterol patch requires to adjust the
`average particle size oftulobuterol within 2~20 um, 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 of abdomenofa hair-cut rat was extracted and
`fitted ona Frantz-diffusioncell. Phosphate-buffer was used as
`a reservoir solution and the cell was kept to stir at 37° C.
`duringtest.
`A patch of Example 1, and patches of Comparative
`examples 2 and 3 were cut ina circle having diameter 13 mm
`(Tulobuterol of Example 1 and Comparative examples: 2 w/w
`%, 200 g/cm”), and the circles fitted on the extracted skin.
`Smal] amountofthe reservoir solution was fromtime to time
`taken and the amount of permeatedtulobuterol was measured
`by HPLC (Drug permeationtest on rat-extracted skin).
`Changesof the passage with time of permeated tulobuterol
`in case ofapplication of patches of Example 1 and Compara-
`tive examples 2 and 3 were shown in FIG.2.
`Example1: tulobuterol; 2 w/w %, 200 g/cm?
`Comparative example 2 and 3: tulobuterol; 2 w/w %, 200
`ugiom?
`Fromthis test result, the amount of permeated tulobuterol
`in regard to the patch of Example 1 was constant in changes of
`the passage with time. On the other hand, in regard to the
`patch of Comparative example 2 without containing a higher
`fatty acid, it showed the tendency that the amount ofthe
`permeated drug increased and the duration decreased at a
`latter half. Furthermore, in Comparative example 3 contain-
`ing rosin glycerinester 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 dueto the
`changesof preservation temperature, patches of Example1,
`Comparative examples 1, 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 fromrat wascarried out.
`
`In case ofapplication of patches of Example 1, Compara-
`tive examples 1, 4 and 6, changes ofthe passage with time of
`the permeation of tulobuterol were shown in FIG. 3. The
`drug-permeationrate due to changesofpreservation tempera-
`ture was shownin Table 1.
`Example 1: tulobuterol; 2 w/w %, 200 ug/em?
`Comparative example |:
`tulobuterol; 10 w/w %, 200
`jig/em?
`
`a
`
`ba
`
`bo La
`
`30
`
`Al
`
`60
`
`65
`
`0009
`
`

`

`US 8,029,820 B2
`
`9
`(Crystalline Type Tulobuterol Patch)
`Comparative example 4: tulobuterol; 5.5 w/w %, 1375
`ug/em? (Highly concentrated, highly contained and soluble
`type tulobuterol patch)
`Comparative example 6: tulobuterol; 5 w/w %; 200 Lg/em?
`(Highly concentrated and soluble type tulobuterol patch)
`
`
`
`TABLI](I) 1
`
`Rate of drug permeated amount due to changes
`ofpreservation temperature on cach sample
`
`10
`changesof the passage with time. Evenif the adhesive had the
`higher drug concentration, the drug permeation 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 ofthe drug
`was averaged during a long time and therefore the control of
`the drug-release was injured.
`
`a
`
`INDUSTRIAL APPLICABILITY
`
`The patch of the present invention is prepared by dissolv-
`Comparative Comparative
`Comparative
`Test
`ing tulobuterol in the lower concentrationin an adhesive layer
`example 4
`example 6
`example 1
`Example 1
`example
`and thereto adding a higher fatty acid, a rubber, an adhesive
`162%
`44%
`65%
`goo"
`Rate of
`agent andaplasticizer in a suitable amount respectively, can
`perneation
`easily control the tulobuterol release pattern and is excellent
`in changes of the passage with timeof release pattern.
`Furthermore, according to the present invention, essential
`physical properties on a patch such as adhesivily and shape
`retention are suitably adjusted and by simplifying the method
`for preparation, the patch ofthe present inventionhas follow-
`ing advantages comparing with the knowntulobuterol-patch:
`(1) Despite fact that the content oftulobuterol is less, the
`effect can be optimized accordingto the therapeutic object as
`the patch of the present invention shows sufficient tulobuterol
`release amountandit is possible to widely and simply control
`the tulobutero] release amount.
`
`*Example ofcalculation: {permeation amount of Example | (4° C.) (8 hr)}/{permeation
`amount of Example 1 (40° C.) (8 hr)} x LOO
`
`From this test result, it was shown that the drug permeated
`amount on a patch of Example 1 was constant and hardly
`influenced by changes ofpreservation temperature.
`On the other hand, it was shownthat the group of Com-
`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 portionin the
`adhesive was changed and dueto the high concentrationofthe
`drug, the degree of saturation inthe adhesive was changed, or
`since the drug was easy to separate fromthe constituents of
`the additive, it was possible that the amount of permeation of
`the drug was greatly changed up and down.
`Test 4
`
`ba
`
`bo La
`
`(2) The adjustment of essential properties as a patch is
`possible together with controlling the release amount and
`releasing pattern of tulobuterol. Therefore, it becomes pos-
`sible to provide a patch whichis 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.
`
`Theinvention claimed is:
`
`1. A patch prepared by laminating an adhesive layer con-
`sisting of a rubber, an adhesive resin other than an acrylic
`adhesive, a plasticizer, 1 to 4 w/w % oftulobuterol as anactive
`ingredient and 0.1 to 3 w/w % ofa higher fatty acid as a
`drug-release controlling agent on a backing.
`2. The patch according to claim 1 wherein 5 to 35 w/w% of
`the rubber, 20 to 70 w/w % ofan adhesive resin and 5 to 60
`w/w% of a plasticizer are contained in the adhesive layer.
`3. The patch according to claim 1 whereinthe higherfatty
`acid is C,,_55 fatty acid.
`4. The patch according to claim 1 wherein the adhesive
`resin is selected from the group consisting of petroleum resin,
`polyterpene resin, polyolefin resin and saturated alicyclic
`hydrocarbonresin.
`
`Influence on Drug-Release by Preservation Term
`In order to see the influence on drug-release by preserva-
`tion term, by using two kinds of patches of Example 4, which
`was prepared 12 hours before and which was preserved for 2
`months at room temperature, and twokinds of patches pre-
`pared by sticking layers 5-1 and 5-2 in Comparative example
`5, which was prepared 12 hours before, and which waspre-
`served for 2 months at room temperature, in the same manner
`as in Test 2, the drug permeation test on the skin extracted
`fromrat 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 ofpermeated tulobuterol
`in case of applicationof patches of Example 4 and Compara-
`tive example 5 were shown in FIG.4.
`Example 4: tulobuterol; 3 w/w %, 240 pg/em?
`Comparative example 5: (adhesive layer 5-1) tulobuterol; 1
`w/w%, 50 g/cm*+(adhesive layer 5-2) tulobuterol: 5.5 w/w.
`%, 1108 pe/em?
`(Laminated Patch)
`Fromthis test result, it was shownthata patch of Example
`4 was constant in drug permeation amount with changes of
`the passage with time.
`On the other hand, in regard to a patch of Comparative
`example 5, the drug permeation amount wasincreased with
`
`40
`
`45
`
`0010
`
`