TW201332592A - Transdermally absorbed preparation - Google Patents

Transdermally absorbed preparation Download PDF

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TW201332592A
TW201332592A TW101139504A TW101139504A TW201332592A TW 201332592 A TW201332592 A TW 201332592A TW 101139504 A TW101139504 A TW 101139504A TW 101139504 A TW101139504 A TW 101139504A TW 201332592 A TW201332592 A TW 201332592A
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acid
adhesive layer
percutaneous absorption
carbon atoms
preparation
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Chinese (zh)
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Katsuyuki Inoo
Daiki Takano
Masato Watanabe
Norihiro Kanayama
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Kyorin Seiyaku Kk
Teikoku Seiyaku Kk
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

To provide a transdermally absorbed preparation having excellent transdermal absorbability of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutylamide or a pharmaceutically acceptable salt thereof contained therein. [Solution] A transdermally absorbed preparation comprising a support and an acrylic adhesive agent layer that is formed on the surface of the support and contains 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutylamide or a pharmaceutically acceptable salt thereof, wherein the acrylic adhesive agent layer additionally contains oleic acid and a carboxylic acid having 2-10 carbon atoms.

Description

經皮吸收型製劑 Percutaneous absorption preparation

本發明係有關含有以4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽作為有效成分之經皮吸收型製劑。 The present invention relates to a transdermal absorption preparation containing 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyricamine or a pharmaceutically acceptable salt thereof as an active ingredient.

已知4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺(咪達那新)(imidafenacin)係具有選擇性M1/M3毒蕈鹼受體拮抗作用之化合物，可作為例如膀胱過動症所伴隨之頻尿、尿失禁之治療用藥。 It is known that 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramine (imidafenacin) has selective M1/M3 muscarinic receptor antagonism. The compound can be used as a therapeutic drug for frequent urination and urinary incontinence associated with bladder hyperactivity.

咪達那新的投藥劑型，除經口固形製劑之外，目前提案有經皮吸收型製劑(例如專利文件1以及2)。採用經皮吸收型製劑對例如高齡的患者等，可容易進行咪達那新的投藥。另外，亦可抑制採用經口投藥有時會產生之一時性的血中濃度之上升。 In addition to oral solid preparations, imidamic new dosage forms are currently proposed to have percutaneous absorption preparations (for example, Patent Documents 1 and 2). The use of a percutaneous absorption type preparation can be easily administered to midazolam, for example, to a patient of an advanced age. In addition, it is also possible to suppress an increase in blood concentration which is sometimes caused by oral administration.

專利文件1：國際公開第2005/011683號說明書 Patent Document 1: International Publication No. 2005/011683

專利文件2：國際公開第2006/082888號公報 Patent Document 2: International Publication No. 2006/082888

一般而言，由於皮膚具有防止異物侵入體內的屏障功能，藉由經皮投藥時藥物之吸收性，與經口投藥等方式相比為低，且製成經皮吸收型製劑時，常難以確保表現藥效 所必須的血中濃度。因此，能夠以經皮吸收型製劑之劑型進行投藥的藥物相當有限。咪達那新自皮膚的吸收性相當低，因此，目前正尋求以經皮吸收型製劑投藥時經皮吸收性之改善。 In general, since the skin has a barrier function of preventing foreign matter from intruding into the body, the absorption of the drug by transdermal administration is low compared with the manner of oral administration, and it is often difficult to ensure that it is prepared as a percutaneous absorption preparation. Performance The necessary blood concentration. Therefore, a drug which can be administered in a dosage form of a percutaneous absorption type preparation is rather limited. The absorption of midazoda from the skin is rather low, and therefore, improvement in transdermal absorbability when administered in a percutaneous absorption preparation is currently being sought.

本發明有鑑於現狀，以提供對4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽，具有優異的經皮吸收性之經皮吸收型製劑為目的。 The present invention is directed to the present state of the art to provide 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine or a pharmaceutically acceptable salt thereof, which has excellent transdermal absorbability. A percutaneous absorption preparation is intended for the purpose.

本發明之實施方式係如下所述。 Embodiments of the invention are as follows.

1)一種經皮吸收型製劑，其係具有支持體，以及形成於該支持體表面上，含有4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽之丙烯酸系黏著劑層，該丙烯酸系黏著劑層進而含有油酸以及碳數2~10之羧酸。 1) A percutaneous absorption type preparation having a support and formed on the surface of the support, comprising 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutamine or The acrylic pressure-sensitive adhesive layer is a pharmaceutically acceptable salt, and the acrylic pressure-sensitive adhesive layer further contains oleic acid and a carboxylic acid having 2 to 10 carbon atoms.

2)如1)項之經皮吸收型製劑，其中該丙烯酸系黏著劑層進而含有癸酸以及克羅他米通(Crotamiton)。 2) The percutaneous absorption preparation of item 1, wherein the acrylic adhesive layer further contains citric acid and Crotamington.

3)如1)或2)項之經皮吸收型製劑，其中該碳數2~10之羧酸係乳酸。 3) The percutaneous absorption type preparation according to item 1) or 2), wherein the carboxylic acid having 2 to 10 carbon atoms is lactic acid.

4)如1)~3)項中任一項之經皮吸收型製劑，其中該丙烯酸系黏著劑層進而含有碳數6~20之脂肪酸之酯。 The percutaneous absorption type preparation according to any one of the items 1 to 3, wherein the acrylic pressure-sensitive adhesive layer further contains an ester of a fatty acid having 6 to 20 carbon atoms.

5)如4)項之經皮吸收型製劑，其中該碳數6~20之脂肪酸之酯係十四酸異丙酯。 5) The percutaneous absorption preparation according to item 4), wherein the ester of the fatty acid having 6 to 20 carbon atoms is isopropyl myristate.

另外，本發明之其他方式係有關含有丙烯酸系黏著 劑、油酸以及碳數2~10之羧酸，且促進4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽之經皮吸收之組成物。該組成物可使用為例如構成經皮吸收型製劑之黏著劑層之組成物。 In addition, other aspects of the invention relate to the inclusion of acrylic adhesives. Agent, oleic acid and a carboxylic acid having a carbon number of 2 to 10, and promoting 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramine or a pharmaceutically acceptable salt thereof The composition of the skin absorption. The composition can be used, for example, as a composition of an adhesive layer constituting a percutaneous absorption type preparation.

根據本發明，可提供對4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽，具有優異的經皮吸收性之經皮吸收型製劑。 According to the present invention, 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramine or a pharmaceutically acceptable salt thereof can be provided, which has excellent transdermal absorbability. Absorbent formulation.

以下，針對本發明之一實施方式進行詳細說明。 Hereinafter, an embodiment of the present invention will be described in detail.

本實施方式之經皮吸收型製劑係具有支持體，與形成於該支持體表面上，含有丙烯酸系黏著劑之丙烯酸系黏著劑層(以下亦簡稱之為黏著劑層)。黏著劑層係含有有效成分之4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽。 The percutaneous absorption type preparation of the present embodiment has a support and an acrylic pressure-sensitive adhesive layer (hereinafter also referred to as an adhesive layer) containing an acrylic pressure-sensitive adhesive formed on the surface of the support. The adhesive layer is an active ingredient of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine or a pharmaceutically acceptable salt thereof.

且於下述之說明中為使讀者容易理解，將游離型之4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽，總稱為咪達那新。 And in the following description, for ease of understanding by the reader, the free form of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine or a pharmaceutically acceptable salt thereof, Known as Midana New.

另外，本說明書中經皮吸收型製劑係指貼附於皮膚上，以皮膚為介而使藥物吸收至體內之醫藥劑型。以皮膚為介而被導入體內之藥物係例如藥物被吸收至微血管內，順著血流而被送達作用部位。 Further, the percutaneous absorption type preparation in the present specification means a pharmaceutical dosage form which is attached to the skin and which is absorbed into the body by the skin. A drug introduced into the body, such as a drug, is absorbed into the microvessels and is delivered to the site of action along the bloodstream.

進而，本說明書中，將有效成分之咪達那新以外的混合於丙烯酸系黏著劑層之成分，總稱為添加劑。添加劑中含有油酸、碳數2~10之羧酸以及因應需要而混合之其他成分(癸酸以及克羅他米通(Crotamiton)、碳數6~20之脂肪酸之酯、以及/或其他成分)。 Further, in the present specification, a component other than the active ingredient of imidazin mixed with the acrylic pressure-sensitive adhesive layer is collectively referred to as an additive. The additive contains oleic acid, a carboxylic acid having 2 to 10 carbon atoms, and other components (such as citric acid and Crotamiton, an ester of a fatty acid having 6 to 20 carbon atoms, and/or other components) if necessary. ).

進而，本說明書中，黏著劑層中所含各成分，相對於黏著劑層之全成分之比例，係意指由丙烯酸系黏著劑、咪達那新以及添加劑所構成之黏著劑層之全部質量為基準。但作為基準的黏著劑層之全質量中，並不包含製造時有時會使用之有機溶媒。 Further, in the present specification, the ratio of each component contained in the adhesive layer to the total composition of the adhesive layer means the entire quality of the adhesive layer composed of the acrylic adhesive, imidaxin, and the additive. As the benchmark. However, the entire mass of the adhesive layer as a standard does not include an organic solvent which may be used at the time of manufacture.

並未特別限制構成黏著劑層之丙烯酸系黏著劑，相關業者可適當選擇其構成。 The acrylic adhesive constituting the adhesive layer is not particularly limited, and the related art can appropriately select the constitution.

丙烯酸系黏著劑可以例如由單1種的丙烯酸酯所形成之丙烯酸酯單聚合物、由2種以上的丙烯酸酯所形成之共聚合物、丙烯酸酯與其他功能性單體之共聚合物、或可由該等之混合物而形成。 The acrylic adhesive may, for example, be an acrylate single polymer formed of a single acrylate, a copolymer formed of two or more acrylates, a copolymer of an acrylate and other functional monomers, or It can be formed from such a mixture.

丙烯酸酯可使用例如(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸戊酯、(甲基)丙烯酸己酯、(甲基)丙烯酸庚酯、(甲基)丙烯酸辛酯、(甲基)丙烯酸壬酯、(甲基)丙烯酸癸酯等。可與丙烯酸酯進行共聚合之功能性單體可使用例如(甲基)丙烯酸羥乙酯、(甲基)丙烯酸羥丙酯等含有羥基之單體、(甲基)丙烯酸醯胺、二甲基(甲基)丙烯酸醯胺等含有醯胺基之單體、或(甲基)丙烯酸、衣康 酸、馬來酸等含有羧基之單體等。 As the acrylate, for example, methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, amyl (meth)acrylate, hexyl (meth)acrylate, (meth)acrylic acid can be used. Heptyl ester, octyl (meth) acrylate, decyl (meth) acrylate, decyl (meth) acrylate, and the like. As the functional monomer copolymerizable with the acrylate, for example, a hydroxyl group-containing monomer such as hydroxyethyl (meth)acrylate or hydroxypropyl (meth)acrylate, decyl (meth)acrylate or dimethyl group can be used. a monomer containing a guanamine group such as (meth)acrylic acid amide or (meth)acrylic acid or itacon A monomer containing a carboxyl group such as an acid or maleic acid.

具體而言，丙烯酸系黏著劑可使用丙烯酸．丙烯酸辛酯共聚合物、丙烯酸2-乙基己酯．丙烯酸2-乙基己酯．甲基丙烯酸十二酯共聚合物、或丙烯酸2-乙基己酯．乙烯吡喀烷酮共聚合物等。 Specifically, acrylic adhesives can use acrylic acid. Octyl acrylate copolymer, 2-ethylhexyl acrylate. 2-ethylhexyl acrylate. Dodecyl methacrylate copolymer, or 2-ethylhexyl acrylate. A vinylpyrrolidone copolymer or the like.

並未特別限制黏著劑層中所混合之丙烯酸系黏著劑相對於全成分之比例，可採用例如50~90質量%(較佳為50~80質量%)。 The ratio of the acrylic adhesive to be mixed in the adhesive layer to the total component is not particularly limited, and may be, for example, 50 to 90% by mass (preferably 50 to 80% by mass).

黏著劑層中之有效成分之咪達那新具體係包含4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽。 The imidaxin specific component of the active ingredient in the adhesive layer comprises 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine or a pharmaceutically acceptable salt thereof.

咪達那新可以溶解型、或溶解型與非溶解型之混合之任一種而摻混於本發明之製劑中。另外，溶解型係指於黏著劑層中咪達那新呈現完全溶解的狀態，更詳細係指於黏著劑層中，咪達那新之結晶無法以目視或以光學顯微鏡觀察之狀態。反之，非溶解型係指咪達那新以結晶或非結晶狀態存在於黏著劑層中。溶解型的咪達那新以皮膚為介而被吸收至體內。另外，非溶解型之咪達那新雖然不會直接被吸收至體內，但伴隨著經皮吸收，溶解型的咪達那新逐漸減少，非溶解型的咪達那新會變化為溶解型。亦即，非溶解型的咪達那新係溶解型的咪達那新之供給源。 The imidaxin may be incorporated into the preparation of the present invention in a soluble form or a mixture of a dissolved form and a non-dissolved form. In addition, the dissolution type refers to a state in which the imidaxin is completely dissolved in the adhesive layer, and more specifically refers to a state in which the crystal of imidad in the adhesive layer cannot be visually observed or observed by an optical microscope. Conversely, a non-dissolving type means that imidaxin is present in the adhesive layer in a crystalline or amorphous state. Dissolved midazolam is absorbed into the body by the skin. In addition, although the non-dissolved midazolidin is not directly absorbed into the body, with the percutaneous absorption, the dissolved type of imatinar is gradually reduced, and the insoluble type of imidaxin is changed to the soluble form. That is, the non-dissolved midazoin is a new source of dissolved midazo.

本實施方式的經皮吸收型製劑中，黏著劑層中所含之咪達那新，自快速的經皮吸收性以及皮膚黏著性等品質安定之觀點而言，以溶解型為佳。 In the percutaneous absorption type preparation of the present embodiment, the imidaxin contained in the adhesive layer is preferably a dissolution type from the viewpoint of quality stability such as rapid transdermal absorbability and skin adhesion.

4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺之藥學上認可之鹽，可舉出例如鹽酸鹽、硫酸鹽或溴化氫酸鹽等無機酸鹽、或馬來酸鹽、富馬酸、醋酸鹽，草酸鹽、酒石酸鹽、或苯磺酸等有機酸鹽。 The pharmaceutically acceptable salt of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine may, for example, be a mineral acid such as a hydrochloride, a sulfate or a hydrogen bromide. An organic acid salt such as a salt or a maleate, fumaric acid, acetate, oxalate, tartrate or benzenesulfonic acid.

並未特別限制黏著劑層中所混合之咪達那新相對於全成分之比例，可採用例如1~30質量%(較佳為2~20質量%)。 The ratio of imidaxin to the total component mixed in the adhesive layer is not particularly limited, and may be, for example, 1 to 30% by mass (preferably 2 to 20% by mass).

本實施方式的經皮吸收型製劑中，黏著劑層中含有油酸以及碳數2~10之羧酸。藉由於黏著劑層中含有油酸以及碳數2~10之羧酸，可提高咪達那新之經皮吸收性。 In the percutaneous absorption type preparation of the present embodiment, the adhesive layer contains oleic acid and a carboxylic acid having 2 to 10 carbon atoms. By adding oleic acid and a carboxylic acid having a carbon number of 2 to 10 in the adhesive layer, the new transdermal absorbability of imidae can be improved.

油酸可作為例如使咪達那新溶解於丙烯酸系黏著劑之溶解劑。 Oleic acid can be used, for example, as a solubilizing agent for dissolving midazolam in an acrylic adhesive.

碳數2~10之羧酸係與油酸相同，可作為溶解劑。碳數2~10之羧酸可舉出例如醋酸、丙酸、酪酸、戊酸或庚酸等。進而，碳數2~10之羧酸，亦可使用具有醇性或酚性的氫氧基之羧酸之羥酸。羥酸可舉出例如乳酸、酒石酸或檸檬酸等。本實施方式中，自咪達那新之溶解性之觀點而言，以使用羥酸為佳，進而以使用乳酸更佳。 The carboxylic acid having 2 to 10 carbon atoms is the same as oleic acid and can be used as a solvent. Examples of the carboxylic acid having 2 to 10 carbon atoms include acetic acid, propionic acid, butyric acid, valeric acid or heptanoic acid. Further, as the carboxylic acid having 2 to 10 carbon atoms, a hydroxy acid having a carboxylic acid having an alcoholic or phenolic hydroxyl group can also be used. The hydroxy acid may, for example, be lactic acid, tartaric acid or citric acid. In the present embodiment, it is preferable to use a hydroxy acid from the viewpoint of solubility of imidazin, and it is more preferable to use lactic acid.

並未特別限制黏著劑層中所混合之油酸以及碳數2~10之羧酸相對於全成分之比例。油酸之比例相對於黏著劑層中所混合之全成分，可採用例如2~20質量%(較佳為5~15質量%)。另外，碳數2~10之羧酸之比例，相對於黏著劑層中所混合之全成分，可採用例如0.5~30質量%(較佳為1~20質量%)。 The ratio of oleic acid mixed in the adhesive layer and carboxylic acid having a carbon number of 2 to 10 to the total composition is not particularly limited. The ratio of oleic acid can be, for example, 2 to 20% by mass (preferably 5 to 15% by mass) based on the total amount of the components mixed in the adhesive layer. Further, the ratio of the carboxylic acid having 2 to 10 carbon atoms may be, for example, 0.5 to 30% by mass (preferably 1 to 20% by mass) based on the total amount of the components mixed in the pressure-sensitive adhesive layer.

另外，本實施方式的經皮吸收型製劑中，於含有咪達那新的丙烯酸系黏著劑層中，除油酸以及碳數2~10之羧酸之外，以進而含有癸酸以及克羅他米通為佳。 Further, in the percutaneous absorption type preparation of the present embodiment, in the acrylic adhesive layer containing imidaxin, in addition to oleic acid and a carboxylic acid having 2 to 10 carbon atoms, it further contains tannic acid and ketone. He is best.

癸酸與油酸及碳數2~10之羧酸相同，可作為溶解劑。 Tannic acid is the same as oleic acid and carboxylic acid with 2 to 10 carbon atoms.

克羅他米通可作為例如咪達那新對體內之吸收促進劑。 Crotamiton can be used as an absorption enhancer for, for example, midazolam in the body.

本實施方式的經皮吸收型製劑中，藉由於黏著劑層中含有癸酸以及克羅他米通，可進而提高咪達那新之經皮吸收性。進而，更佳之實施方式，係於含咪達那新之經皮吸收型製劑之黏著劑層中，除油酸、乳酸等碳數2~10之羧酸、癸酸以及克羅他米通之外，進而含有後述之十四酸異丙酯等碳數6~20之脂肪酸之酯。 In the percutaneous absorption type preparation of the present embodiment, since the adhesive layer contains citric acid and crotamiton, the transdermal absorbability of imidaxin can be further improved. Further, a more preferred embodiment is a carboxylic acid, a citric acid or a crotamiton which has a carbon number of 2 to 10, such as oleic acid and lactic acid, in an adhesive layer containing a new transdermal absorption preparation of imidaxin. Further, it further contains an ester of a fatty acid having 6 to 20 carbon atoms such as isopropyl myristate described later.

並未特別限制黏著劑層中所混合之癸酸以及克羅他米通相對於全成分之比例，例如癸酸之比例相對於黏著劑層中所混合之全成分，可採用0.1~20質量%(較佳為0.5~15質量%)。另外，克羅他米通之比例，相對於黏著劑層中所混合之全成分，可採用例如0.1~10質量%(較佳為0.5~10質量%)。 The ratio of citric acid mixed in the adhesive layer and the ratio of crotamiton to the total component is not particularly limited. For example, the ratio of citric acid to the total component mixed in the adhesive layer may be 0.1 to 20% by mass. (preferably 0.5 to 15% by mass). Further, the ratio of crotamiton can be, for example, 0.1 to 10% by mass (preferably 0.5 to 10% by mass) based on the total components mixed in the adhesive layer.

進而，本實施方式的經皮吸收型製劑中，除油酸及碳數2~10之羧酸之外，藉由於含咪達那新之黏著劑層中進而含有碳數6~20之脂肪酸之酯，使黏著劑層之物性最適化，同時可更加提高咪達那新的經皮吸收性。 Further, in the percutaneous absorption type preparation of the present embodiment, in addition to oleic acid and a carboxylic acid having 2 to 10 carbon atoms, a fatty acid having 6 to 20 carbon atoms is further contained in the adhesive layer containing imidaxin. The ester optimizes the physical properties of the adhesive layer and enhances the new transdermal absorbability of midazo.

碳數6~20之脂肪酸之酯，可用作例如提高丙烯酸系 黏著劑之黏著性之軟化劑。碳數6~20之脂肪酸之酯可舉出例如十四酸異丙酯、十六酸異丙酯或油酸油酯等。本實施方式中以使用十四酸異丙酯為佳。碳數6~20之脂肪酸之酯相對於黏著劑層中所混合之全成分，可採用2~50質量%，較佳為5~40質量%。 An ester of a fatty acid having 6 to 20 carbon atoms, which can be used, for example, to improve acrylic acid Adhesive softener for adhesives. Examples of the ester of a fatty acid having 6 to 20 carbon atoms include isopropyl myristate, isopropyl palmitate or oleic acid ester. In the present embodiment, it is preferred to use isopropyl myristate. The ester of the fatty acid having 6 to 20 carbon atoms may be used in an amount of 2 to 50% by mass, preferably 5 to 40% by mass based on the total amount of the components mixed in the adhesive layer.

本實施方式中，於黏著劑層內亦可進而含有其他成分作為添加劑。其他的含有成分可舉出例如其他溶解劑、其他軟化劑、其他吸收促進劑、緩和皮膚刺激劑以及抗氧化劑中之1種或2種以上。 In the present embodiment, other components may be further contained as an additive in the adhesive layer. The other components may be one or more selected from the group consisting of other solvents, other softeners, other absorption enhancers, skin light irritants, and antioxidants.

溶解劑可舉出例如高級脂肪酸酯(十六酸異丙酯或油酸油酯等)、高級醇(月桂醇、異丙醇、異硬酯醇、辛十二醇或油醇等)、脂肪酸(異硬酯酸、月桂酸、己二酸、癸二酸或肉荳蔻酸等)、二元酸酯類(癸二酸二乙酯、癸二酸二異丙酯或己二酸二異丙酯等)、三乙酸丙酯、苯甲醇、乳酸十八醇酯、辛基十二醇乳酸酯、液體石蠟或該等之2種以上之混合物。 Examples of the solvent include, for example, a higher fatty acid ester (isopropyl hexadecanate or oleic acid ester), a higher alcohol (lauryl alcohol, isopropanol, isostearyl alcohol, octadecanol or oleyl alcohol). Fatty acid (isochatty acid, lauric acid, adipic acid, sebacic acid or myristic acid), dibasic acid ester (diethyl sebacate, diisopropyl sebacate or dipic acid) Propyl ester, etc.), propyl triacetate, benzyl alcohol, octadecyl lactate, octyldodecanol lactate, liquid paraffin or a mixture of two or more thereof.

軟化劑可舉出液體石蠟等石蠟油、角鯊烷、角鯊烯等動物油、杏仁油、橄欖油、茶樹油、蓖麻子油、妥爾油、花生油等植物油、矽油、聚丁烯、中鏈脂肪酸三甘油酯、單硬酯酸甘油酯、肉荳蔻酸異丙酯、己二酸二異丙酯、二丙二醇或該等之2種以上之混合物。 Examples of the softening agent include paraffin oil such as liquid paraffin, animal oil such as squalane and squalene, vegetable oil such as almond oil, olive oil, tea tree oil, castor bean oil, tall oil, and peanut oil, eucalyptus oil, polybutene, and medium chain. Fatty acid triglyceride, glyceryl monostearate, isopropyl myristate, diisopropyl adipate, dipropylene glycol or a mixture of two or more thereof.

吸收促進劑可舉出例如三乙酸丙酯、脂肪酸或脂肪族醇類(月桂酸、肉荳蔻酸、油醇、異丙醇、月桂醇或異丙二醇、丙二醇等)、脂肪酸酯(單月桂酸甘油酯、單油酸 甘油酯、乳酸十八醇酯、辛基十二醇乳酸酯、月桂酸單甘油酯、油酸單甘油酯、月桂酸丙二醇酯、油酸丙二醇酯、山梨糖醇月桂酸酯或山梨糖醇油酸酯等)，或該等之2種以上之混合物。 Examples of the absorption enhancer include propyl triacetate, a fatty acid or an aliphatic alcohol (lauric acid, myristic acid, oleyl alcohol, isopropanol, lauryl alcohol or isopropyl glycol, propylene glycol, etc.), and a fatty acid ester (single lauric acid). Glyceride, monooleic acid Glycerides, octadecyl lactate, octyldodecanol lactate, lauric acid monoglyceride, oleic acid monoglyceride, propylene glycol laurate, propylene glycol oleate, sorbitol laurate or sorbitol An oleate or the like, or a mixture of two or more of these.

緩和皮膚刺激劑可舉出例如甘油、尿囊素(Allantoin)、抗組織胺藥物(苯海拉明(diphenhydramine)等)、消炎劑(甘草酸(glycyrrhizic acid)等)、類固醇藥物，或該等之2種以上之混合物。 Examples of the skin irritant for alleviating the skin include glycerin, allantoin, an antihistamine (diphenhydramine, etc.), an anti-inflammatory agent (glycyrrhizic acid, etc.), a steroid drug, or the like. A mixture of two or more kinds.

抗氧化劑可舉出例如二丁基羥基甲苯(BHT)、DL-α-生育醇、棕櫚酸抗壞血酯，或該等之2種以上之混合物。 The antioxidant may, for example, be dibutylhydroxytoluene (BHT), DL-α-tocopherol, ascorbyl palmitate, or a mixture of two or more of these.

進而亦可含有其他成分作為添加劑。具體可舉出例如石油樹脂(Quintone或Alcon等)；界面活性劑(聚氧乙烯硬化蓖麻油20、聚氧乙烯硬化蓖麻油60、聚氧乙烯山梨糖醇脂肪酸酯(聚山梨醇酯20、聚山梨醇酯60、聚山梨醇酯80或聚氧乙烯山梨糖醇單月桂酯等)、聚氧乙烯脂肪酸酯(聚氧乙烯(40)硬脂酸酯等)、山梨糖醇脂肪酸酯(山梨糖醇單油酸酯、山梨糖醇三油酸酯、山梨糖醇單月桂酸酯或山梨糖醇倍半油酸酯等)、自行乳化之甘油硬酯酸酯、甘油硬酯酸酯、山梨糖醇硬酯酸酯、蔗糖脂肪酸酯、聚乙二醇400、聚桂醇、磷酸鈉聚氧乙烯月桂醚、磷酸聚氧乙烯油醚、聚氧乙烯壬基酚醚、聚氧乙烯辛基酚醚、聚氧乙烯聚氧丙二醇(聚氧乙烯(120)聚氧丙烯(40)二醇、聚氧乙烯(160)聚氧丙烯(30)二醇或聚 氧乙烯(20)聚氧丙烯(20)二醇等)、聚氧乙烯聚氧丙烯癸基十四醇醚、烷基芳基聚醚醇、聚氧乙烯十六烷基醚、聚氧乙烯油基胺、聚氧乙烯山梨糖醇聚醚蜜蠟、月桂酸二乙醇胺、硬酯醇、二元酸雙酯(癸二酸二乙酯等)、角鯊烷、十六烷醇或聚西托醇1000等)；香味料(薄荷油、橘子油、洋甘菊油、留蘭香葉油、丁香油、松節油、松油、雪松油、佛手柑油、尤加利油、薰衣草油、玫瑰油、白花春黃菊花油、祕魯香脂、d-樟腦、dl-樟腦、d-龍腦、dl-龍腦、dl-薄荷腦、l-薄荷腦、香葉醇、甲基水楊酸、肉桂醛或胡椒醛等)，或該等之2種以上之混合物。 Further, other components may be contained as an additive. Specific examples thereof include petroleum resin (Quintone or Alcon, etc.); surfactant (polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 60, polyoxyethylene sorbitan fatty acid ester (polysorbate 20, Polysorbate 60, polysorbate 80 or polyoxyethylene sorbitan monolaurate, etc., polyoxyethylene fatty acid ester (polyoxyethylene (40) stearate, etc.), sorbitol fatty acid ester (sorbitol monooleate, sorbitol trioleate, sorbitol monolaurate or sorbitol sesquioleate, etc.), self-emulsifying glyceryl stearate, glyceryl stearate , sorbitol stearate, sucrose fatty acid ester, polyethylene glycol 400, polyglycerol, sodium polyoxyethylene lauryl ether, polyoxyethylene ether ether, polyoxyethylene nonylphenol ether, polyoxyethylene Octyl phenol ether, polyoxyethylene polyoxypropylene glycol (polyoxyethylene (120) polyoxypropylene (40) diol, polyoxyethylene (160) polyoxypropylene (30) diol or poly Oxyethylene (20) polyoxypropylene (20) diol, etc.), polyoxyethylene polyoxypropylene decyltetradecyl ether, alkyl aryl polyether alcohol, polyoxyethylene cetyl ether, polyoxyethylene oil Amine, polyoxyethylene sorbitol beeswax, lauric acid diethanolamine, stearyl alcohol, dibasic acid diester (diethyl sebacate, etc.), squalane, cetyl alcohol or polycitrate Alcohol 1000, etc.; flavoring material (menthol oil, orange oil, chamomile oil, spearmint oil, clove oil, turpentine, pine oil, cedar oil, bergamot oil, eucalyptus oil, lavender oil, rose oil, white flower spring Yellow chrysanthemum oil, Peru balsam, d-camphor, dl-camphor, d-borneol, dl-borneol, dl-menthol, l-menthol, geraniol, methyl salicylic acid, cinnamaldehyde or piperonal Etc.), or a mixture of two or more of these.

本實施方式之經皮吸收型製劑係可藉由於支持體上形成丙烯酸系黏著劑層而製造。另外，為於被使用前保護該黏著劑層，以使用離型紙(release liner)覆蓋黏著劑層為佳。並未特別限定本實施方式經皮吸收型製劑之製造方法，相關業者可適當選擇。 The percutaneous absorption type preparation of the present embodiment can be produced by forming an acrylic pressure-sensitive adhesive layer on a support. Further, in order to protect the adhesive layer before use, it is preferred to cover the adhesive layer with a release liner. The method for producing the percutaneous absorption type preparation of the present embodiment is not particularly limited, and can be appropriately selected by a related art.

本實施方式之經皮吸收型製劑係可藉由一般稱為熱融法之方法及稱為溶媒法之方法製造。 The percutaneous absorption type preparation of the present embodiment can be produced by a method generally called a hot melt method and a method called a solvent method.

以熱融法為基礎時，例如可使咪達那新、添加劑與丙烯酸系黏著劑之混合物(基劑成分)熱融解後，再塗布於剝離薄膜或支持體上而形成黏著劑層。接著，藉由使已形成之黏著劑層，與支持體或剝離薄膜相互貼合，獲得經皮吸收型製劑。 In the case of the hot-melt method, for example, a mixture of a mixture of an additive and an acrylic adhesive (base component) may be thermally melted, and then applied to a release film or a support to form an adhesive layer. Next, a percutaneous absorption type preparation is obtained by bonding the formed adhesive layer to the support or the release film.

另外，以溶媒法為基礎時，可將例如咪達那新、添加劑與丙烯酸系黏著劑之混合物溶解於甲醇、乙醇、醋酸乙 酯、氯仿或己烷等有機溶媒後，再於剝離薄膜或支持體上進行伸展以及塗工。其次，乾燥去除溶媒後形成黏著劑層。接著，藉由使已形成之黏著劑層，與支持體或剝離薄膜相互貼合，獲得經皮吸收型製劑。 In addition, based on the solvent method, a mixture of, for example, imidaxin, an additive and an acrylic adhesive can be dissolved in methanol, ethanol, and acetic acid. After an organic solvent such as ester, chloroform or hexane, stretching and coating are performed on the release film or support. Next, an adhesive layer is formed after drying to remove the solvent. Next, a percutaneous absorption type preparation is obtained by bonding the formed adhesive layer to the support or the release film.

另外，並未特別限定黏著劑層的大小及厚度，相關業者可適當設定。 Further, the size and thickness of the adhesive layer are not particularly limited, and those skilled in the art can appropriately set them.

並未特別限定本實施方式經皮吸收型製劑之支持體的素材，相關業者可適當設定，可使用例如具有伸縮性或非伸縮性之支持體。可選自例如布、不織布、聚氨基甲酸乙酯、聚酯、醋酸聚乙烯酯、聚偏二氯乙烯、聚乙烯、聚對苯二甲二乙酯(PET)、鋁箔等，或該等之複合素材中選擇。 The material of the support of the percutaneous absorption type preparation of the present embodiment is not particularly limited, and can be appropriately set by a related art, and for example, a support having stretchability or non-stretchability can be used. Can be selected, for example, from cloth, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (PET), aluminum foil, etc., or the like. Select from composite material.

另外，並未特別限定剝離薄膜的素材，相關業者可適當選擇。具體例可舉出聚乙稀薄膜、PET薄膜或聚丙烯薄膜經矽被覆者。 Further, the material of the release film is not particularly limited, and a person skilled in the art can appropriately select it. Specific examples include a polyethylene film, a PET film, or a polypropylene film which are coated with a crucible.

咪達那新(imidafenacin)具有對於膀胱、氣管、消化道等平滑肌之毒蕈鹼受體M3以及M1選擇性的拮抗作用。因此，本實施方式之經皮吸收型製劑，可適用於例如膀胱過動症(OAB：Over Active Bladder)所伴隨之頻尿、尿失禁、氣喘、慢性阻塞性肺部疾病(COPD：Chronic Obstructive Pulmonary Disease)或腸道激躁症(IBS：Irritable Bowel Syndrome)等之預防以及/或治療用藥。 Imidanacin has selective antagonism of muscarinic receptors M3 and M1 in smooth muscles such as bladder, trachea and digestive tract. Therefore, the percutaneous absorption type preparation of the present embodiment can be applied to, for example, frequent urination, urinary incontinence, asthma, chronic obstructive pulmonary disease (COPD: Chronic Obstructive Pulmonary) associated with Overactive Bladder (OAB). Prevention and/or therapeutic use of diseases such as Disease or Irritable Bowel Syndrome.

使用本實施方式之經皮吸收型製劑之咪達那新投藥方法，可因應預防或治療對象之疾病型態，與投藥對象之患 者狀態而適當設定。例如投藥可為1天2次或1天1次進行貼附之方式。另外，亦可採用於就寢前與於發生需要的狀況前進行貼附之投藥方式。 The imidaxin new administration method using the percutaneous absorption preparation of the present embodiment can prevent or treat the disease type of the subject, and the patient suffers from the administration Set as appropriate. For example, administration can be carried out twice a day or once a day. In addition, it is also possible to use a method of administration before bedtime and before the situation in which the need arises.

並未特別限制貼附部位，可為例如耳後、腕部、下腹部等腹部、胸部、背部、腰部、臀部、大腿部內側或脛骨內側等腳部等。 The attachment portion is not particularly limited, and may be, for example, the abdomen, the chest, the back, the lower back, the abdomen, the chest, the back, the waist, the buttocks, the inside of the thigh, or the inside of the tibia.

本實施方式中並未特別限制黏著劑層中所含之咪達那新量，可因應預防或治療對象之疾病型態、黏著劑層的大小、投藥時間或目標之咪達那新的血中濃度等而設定，例如可使製劑中或1次的投藥劑中摻混有約0.1mg~約30mg。 In the present embodiment, the amount of midazodia contained in the adhesive layer is not particularly limited, and may be prevented or treated according to the disease type of the subject, the size of the adhesive layer, the administration time, or the target of the new blood. The concentration is set to be, for example, about 0.1 mg to about 30 mg may be blended in the preparation or once in the administration.

根據本實施方式之經皮吸收型製劑，藉由於丙烯酸系黏著劑層中含咪達那新，同時亦含有油酸以及碳數2~10之羧酸，可提高咪達那新的經皮吸收性。另外，藉由於黏著劑層中含有癸酸以及克羅他米通(Crotamiton)，可提高咪達那新的經皮吸收性。進而藉由黏著劑層含有碳數6~20之脂肪酸之酯，可提高咪達那新的經皮吸收性。 According to the percutaneous absorption type preparation of the present embodiment, since the acrylic adhesive layer contains imidaxin, and also contains oleic acid and a carboxylic acid having 2 to 10 carbon atoms, the transdermal absorption of imidae can be improved. Sex. In addition, by adding citric acid and Crotamiton to the adhesive layer, the new transdermal absorbability of imidae can be improved. Further, by adding an ester of a fatty acid having 6 to 20 carbon atoms in the adhesive layer, the new transdermal absorbability of imidae can be improved.

如此，可達成提高咪達那新的經皮吸收性之結果，根據本實施方式之經皮吸收型製劑，可例如使咪達那新以皮膚為介，在循環血液中效率極佳地吸收。另外，亦可避免經口投藥時可發現之血中濃度急遽升高所伴隨引起的副作用。因此，本實施方式之經皮吸收型製劑，極適用於膀胱過動症(OAB)所伴隨之頻尿、尿失禁、氣喘、COPD或IBS等之預防以及/或治療用藥。 Thus, the result of improving the transdermal absorbability of imidad can be achieved. According to the percutaneous absorption type preparation of the present embodiment, for example, midazolam can be absorbed into the blood in an efficient manner in the circulating blood. In addition, side effects caused by a sudden increase in blood concentration which can be found when administered orally can be avoided. Therefore, the percutaneous absorption type preparation of the present embodiment is highly suitable for the prevention and/or therapeutic use of frequent urination, urinary incontinence, asthma, COPD or IBS accompanying overactive bladder (OAB).

【實施方式】 [Embodiment] 〔實施例〕 [Examples]

以下藉實施例進而詳細說明本發明，但本發明之經皮吸收型製劑並未僅限定於實施例所記載之方式。 Hereinafter, the present invention will be described in detail by way of examples, but the percutaneous absorption type preparation of the present invention is not limited to the embodiment described in the examples.

[實施例1] [Example 1]

將9g之4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺、3g之乳酸、7g之油酸、0.9g之癸酸，溶解於100g之甲醇。再於該溶液中添加17g之十四酸異丙酯以及2g之克羅他米通，充分混合後做為主藥液。之後，於305.5g之固形濃度20%的丙烯酸．丙烯酸辛酯共聚合物/醋酸乙酯溶液(黏著劑重量為61.1g)中，加入主藥液並充分混合，調製為黏著劑溶液。使用塗工機將黏著劑溶液塗布於75μm厚的PET薄膜上，使乾燥後之膏體重量為約80g/m2而均勻塗布，於約80℃的溫度條件下乾燥10分鐘後形成黏著劑層。將形成之黏著劑層與支持體(15μm厚的PET薄膜)貼合，製成實施例1之經皮吸收型製劑。 9 g of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamine, 3 g of lactic acid, 7 g of oleic acid, and 0.9 g of citric acid were dissolved in 100 g of methanol. Further, 17 g of isopropyl myristate and 2 g of crotamiton were added to the solution, and the mixture was thoroughly mixed to prepare a main solution. After that, at 305.5g of solid concentration of 20% acrylic acid. In the octyl acrylate copolymer/ethyl acetate solution (the weight of the adhesive was 61.1 g), the main drug solution was added and thoroughly mixed to prepare an adhesive solution. The adhesive solution was applied to a 75 μm thick PET film using a coating machine, and the dried paste weight was uniformly coated at about 80 g/m 2 , and dried at a temperature of about 80 ° C for 10 minutes to form an adhesive layer. . The formed adhesive layer was bonded to a support (15 μm thick PET film) to prepare a percutaneous absorption type preparation of Example 1.

[實施例2~4，以及比較例1~14] [Examples 2 to 4, and Comparative Examples 1 to 14]

除了變更所含成分的比例之外，藉由與實施例1相同的方法，調製實施例2~4，以及比較例1~14之經皮吸收型製劑。實施例及比較例中黏著劑層所含成分之量示於圖1。 The percutaneous absorption type preparations of Examples 2 to 4 and Comparative Examples 1 to 14 were prepared in the same manner as in Example 1 except that the ratio of the components contained was changed. The amounts of the components contained in the adhesive layer in the examples and comparative examples are shown in Fig. 1.

[In vitro生體內大鼠皮膚通透性試驗方法] [In vitro test method for rat skin permeability]

剝離HWY系雄性無毛大鼠(hairless rat)(10~11週齡)(體重260~280g)的腹部皮膚( 15mm)，將真皮側作為接受層側(receptor)，並將其裝置於已使37℃溫水於外圍部位循環之經皮吸收儀(Franz cell)(開口面積：1.77cm2)。其次於皮膚角質層側貼上實施例以及比較例之各經皮吸收型製劑( 14mm)。使用作為接受液之PBS緩衝溶(pH7.4)，並經時性的收集該接受液。 Stripping the abdominal skin of HWY male hairless rat (10-11 weeks old) (body weight 260~280g) 15 mm), the dermis side was used as a receptor layer, and it was placed in a Franz cell (opening area: 1.77 cm 2 ) which had been circulated at 37 ° C in warm water at the peripheral portion. Next, the percutaneous absorption preparations of the examples and the comparative examples were attached to the side of the stratum corneum of the skin ( 14mm). The solution was collected by PBS buffer (pH 7.4) as a receiving solution and collected over time.

對於已收集之接受液中咪達那新的濃度，以下述測定條件，藉由極致液相層析法(UPLC(Ultra Performance Liquid Chromatography))進行測定。 The concentration of midazolam in the collected receiving liquid was measured by UPLC (Ultra Performance Liquid Chromatography) under the following measurement conditions.

(UPLC條件) (UPLC condition)

注入量：7.5μL Injection volume: 7.5μL

檢測器：紫外線吸光光度計(測定波長：222nm) Detector: UV spectrophotometer (measuring wavelength: 222 nm)

管柱：AQUITY UPLC BEH C8 2.1＊50mm(1.7μm)，Waters製 Column: AQUITY UPLC BEH C8 2.1 * 50mm (1.7μm), made by Waters

管柱溫度：30℃ Column temperature: 30 ° C

移動相：A液；900mL之經1000倍稀釋的磷酸，以及100mL之HPLC用四氫呋喃 Mobile phase: solution A; 900 mL of 1000-fold diluted phosphoric acid, and 100 mL of HPLC tetrahydrofuran

B液；10%甲醇 B liquid; 10% methanol

A液：B液=850：150 Liquid A: B liquid = 850: 150

流量：約0.7mL/min(咪達那新的保持時間約0.8 min) Flow rate: about 0.7mL/min (Midana new holding time is about 0.8 Min)

自測定結果，計算各採樣點每1cm2製劑之累積藥物通透量(μg/cm2)，並將時間-累積藥物通透量之間的關係圖表化。其後，自該圖表計算出累積藥物通透量之迴歸曲線，並以其傾斜程度作為藥物通透速度之FLUX值。 From the measurement results, the cumulative drug permeation amount (μg/cm 2 ) per 1 cm 2 of the preparation at each sampling point was calculated, and the relationship between the time-cumulative drug permeation amount was graphed. Thereafter, a regression curve of the cumulative drug permeation amount was calculated from the graph, and the degree of inclination was used as the FLUX value of the drug permeation rate.

(FLUX：貼附貼劑後，自1cm2製劑面積經皮吸收每1小時之經皮藥物吸收量) (FLUX: Percutaneous drug absorption per hour after percutaneous absorption from a 1 cm 2 preparation area after patch application)

所得之FLUX值示於圖2。 The resulting FLUX value is shown in Figure 2.

實施例1之FLUX值，實施例1為16.46μg/cm2/hour，實施例2為13.09μg/cm2/hour，實施例3為12.08μg/cm2/hour，以及實施例4為11.82μg/cm2/hour，另一方面，比較例中最高之FLUX值亦僅為9.81μg/cm2/hour(比較例13)。 Example FLUX value of 1, Example 1 was 16.46μg / cm 2 / hour, Example 2 was 13.09μg / cm 2 / hour, Example 3 was 12.08μg / cm 2 / hour, and Example 4 was 11.82μg /cm 2 /hour, on the other hand, the highest FLUX value in the comparative example was also only 9.81 μg/cm 2 /hour (Comparative Example 13).

實施例1~4之經皮吸收型製劑，與比較例之經皮吸收型製劑相比，均顯示較高的咪達那新之經皮吸收性。特別於含有癸酸以及克羅他米通之實施例1之經皮吸收型製劑，確認具有較其他實施例更高之經皮吸收性。 The transdermally absorbable preparations of Examples 1 to 4 showed higher transdermal absorbability of midazolam as compared with the percutaneous absorption type preparation of the comparative example. Particularly, the percutaneous absorption type preparation of Example 1 containing citric acid and crotamiton was confirmed to have higher transdermal absorbability than the other examples.

〔產業上之可利用性〕 [Industrial Applicability]

本發明之經皮吸收型製劑，極適用於膀胱過動症(OAB)所伴隨之頻尿、尿失禁、氣喘、慢性阻塞性肺部疾病(COPD)及腸道激躁症(IBS)等之預防以及/或治療用藥。 The percutaneous absorption preparation of the invention is highly suitable for frequent urination, urinary incontinence, asthma, chronic obstructive pulmonary disease (COPD) and intestinal irritation (IBS) associated with overactive bladder (OAB). Prevention and / or treatment medication.

[圖1]表示實施例及比較例之經皮吸收型製劑之黏著劑層中所含成分之組成表。 Fig. 1 is a table showing the composition of components contained in the adhesive layer of the percutaneous absorption type preparations of the examples and the comparative examples.

[圖2]表示實施例及比較例之經皮吸收型製劑之FLUX值之柱狀圖。 Fig. 2 is a bar graph showing the FLUX value of the percutaneous absorption type preparations of the examples and the comparative examples.

Claims (5)

一種經皮吸收型製劑，其特徵係具有支持體，以及形成於該支持體表面上，含有4-(2-甲基-1-咪唑基)-2,2-二苯基丁醯胺或其於藥學上認可之鹽之丙烯酸系黏著劑層，其中該丙烯酸系黏著劑層進而含有油酸以及碳數2~10之羧酸。 A transdermal absorption preparation characterized by having a support and formed on the surface of the support, comprising 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutamine or An acrylic pressure-sensitive adhesive layer of a pharmaceutically acceptable salt, wherein the acrylic pressure-sensitive adhesive layer further contains oleic acid and a carboxylic acid having 2 to 10 carbon atoms. 如申請專利範圍第1項之經皮吸收型製劑，其中該丙烯酸系黏著劑層進而含有癸酸以及克羅他米通(Crotamiton)。 The percutaneous absorption type preparation of claim 1, wherein the acrylic adhesive layer further contains citric acid and Crotamington. 如申請專利範圍第1或2項之經皮吸收型製劑，其中該碳數2~10之羧酸係乳酸。 The percutaneous absorption type preparation according to claim 1 or 2, wherein the carboxylic acid having 2 to 10 carbon atoms is lactic acid. 如申請專利範圍第1~3項中任一項之經皮吸收型製劑，其中該丙烯酸系黏著劑層進而含有碳數6~20之脂肪酸之酯。 The percutaneous absorption type preparation according to any one of claims 1 to 3, wherein the acrylic pressure-sensitive adhesive layer further contains an ester of a fatty acid having 6 to 20 carbon atoms. 如申請專利範圍第4項之經皮吸收型製劑，其中該碳數6~20之脂肪酸之酯係十四酸異丙酯。 The transdermal absorption preparation of claim 4, wherein the ester of the fatty acid having 6 to 20 carbon atoms is isopropyl myristate.
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