JP2002003368A - Pharmaceutical preparation for percutaneous absorption or absorption through mucous membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an administration device effective for an anticoagulant based on an aromatic amidine derivative. SOLUTION: This pharmaceutical preparation for percutaneous absorption or absorption through mucous membrane includes a medicine such as (2 S)-2-[4-[(3S)-1-acetoimido-yl-3-pyrrolidinyl)oxy]phenyl]-3-(7-amidino- 2-naphthyl) propionic acid, or the like, in a device including (a) a support film, (b) a release control membrane, (c) heat adhesion parts connecting the support film to the release control membrane, (d) a storage vessel for storing a medicine-containing liquid, (e) a liquid spill preventing lid having a fringe part whole of which is overlapped with the heat adhesion parts on the inner most side and installed with a pressure-sensitive adhesive part on its whole pheripheral part to press seal the release control membrane, (f) a press connected part formed by pressing and sealing the liquid spill preventing lid and the release control membrane in an easily releasable manner, (g) a pressure-sensitive adhesive layer, and (h) a release film placed to cover the pressure sensitive adhesive layer, and (i) the press connected part is set to be broken in the case of removing the release film from the device.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preparation for transdermally or transmucosally administering a drug useful as an agent for suppressing blood coagulation and preventing and treating thrombus.

[0002]

2. Description of the Related Art As one method of transdermally or transmucosally administering a liquid preparation containing a drug, an administration device having a storage tank (drug storage tank), a controlled release membrane and the like (hereinafter referred to as a "reservoir"). Formulations.) Have been put to practical use. The reservoir-type preparation includes a storage tank for storing a liquid preparation containing a drug (drug-containing liquid),
In general, a support film (also referred to as a support layer) that is substantially impermeable to a drug-containing liquid, a controlled release film (drug release layer) for supplying the drug-containing liquid to the skin surface or mucosal surface ), A pressure-sensitive adhesive layer for adhering the preparation to the skin or mucosal surface, and a release film for protecting the pressure-sensitive adhesive layer. The drug-containing liquid is filled in a storage tank formed between the support film and the controlled release membrane. When using the preparation, the release film is peeled off, the preparation is fixed by bringing the pressure-sensitive adhesive layer into contact with the skin or mucous membrane, and the drug release layer is brought into contact with the skin or mucous membrane. By maintaining this state, the drug-containing liquid passes from the storage tank through the drug release layer to the skin surface or mucosal surface, and the drug transdermally or transmucosally enters the body.

As a reservoir type preparation, a device for administering an active agent to the skin or mucous membrane (Japanese Patent Publication No. 4-46592) and an apparatus for administering the active agent to the skin or mucous membrane (Japanese Patent Publication No. 8-18976) Has been proposed. In these devices, a barrier is formed around the drug reservoir by a peelable heat seal to avoid the adverse effects of contact between the pressure-sensitive adhesive layer and the drug-containing liquid during storage of the drug product. The liquid cannot move to the pressure-sensitive adhesive layer (see FIG.
No. 976 discloses an embodiment of the apparatus).

[0004] However, in the reservoir type preparation described in Japanese Patent Publication No. 8-18976, the radius of the heat-bonding portion 9 (permanent heat seal) for fixing the support film 2 and the release control film 5 is peeled off. Since the radius of the heat-bonded portion 13 (peelable heat seal) is the same as that of the heat-bonded portion 13, an adhesive-uncoated portion 12 is formed between the heat-bonded portion 9 and the pressure-sensitive adhesive layer 7, and the skin surface Alternatively, when the preparation is applied to the mucosal surface, the drug-containing liquid penetrates into the gap 11 (the non-adhesion site between the support film formed outside the storage tank and the release control membrane) from this site, and However, there is a problem that the application area is not constant and a part of the drug-containing liquid is wasted. In addition, there is a problem that the air-tightness at the peelable heat-bonding portion 13 becomes poor, and the drug-containing liquid leaks or volatilizes during storage. Furthermore, the peelable heat-bonded part 1
When simultaneously forming the heat-bonded portion 3 and the permanent heat-bonded portion 9 on the side opposite to the release control film, it is difficult to control the processing of the peelable heat-bonded portion, and there is a problem that defective products are easily formed.

[0005] On the other hand, a preparation for transdermal absorption containing an aromatic amidine derivative useful as a blood coagulation inhibitor and an agent for preventing and treating thrombus is known (International Publication WO99 / 33).
458), there is teaching in this publication about administering the drug by a reservoir type administration device. Also, a pharmaceutical composition for transmucosal administration containing the above drug is known (JP-A-11-189331). However, no specific reservoir-type formulation for transdermal or transmucosal absorption of this drug is described in these publications.

[0006]

An object of the present invention is to provide the above-mentioned aromatic amidine derivatives useful as a blood coagulation inhibitor and an agent for preventing and treating thrombus as a reservoir-type preparation for percutaneous absorption and transmucosal absorption. To provide. More specifically, a reservoir device for percutaneous absorption and transmucosal absorption containing the above-mentioned drug is used by using an administration device which solves the problem of the administration device of the reservoir type formulation described in Japanese Patent Publication No. 8-18976. It is an object of the present invention to provide a formulation.

[0007]

Means for Solving the Problems The present inventors have intensively studied to provide an administration device and a preparation which solved the above-mentioned problems. As a result, so as to cover the permanent heat-sealed area,
However, the liquid leakage prevention lid is arranged on the side opposite to the storage tank with respect to the release control film so as to have a size and shape slightly smaller than the heat-bonded portion, and the entire peripheral portion is released using a pressure-sensitive adhesive. By pressure connection to the control membrane, the drug-containing liquid that has passed through the release control membrane is confined in the space formed by the liquid leakage prevention lid and the pressure connection, and stored without contacting the pressure-sensitive adhesive layer It has been found that stability can be ensured.

Further, by adopting such a means, when the release film is peeled off, the pressure-sensitive adhesive layer is exposed so as to overlap with the permanent heat-bonded portion, and the skin or the skin is spread along the permanent heat-bonded portion. It has been found that the drug-containing liquid does not penetrate into the gap (the non-adhesion site between the support film formed outside the storage tank and the release-controlling membrane) during application of the preparation, since adhesion to the mucous membrane is achieved. Furthermore, by forming the pressure connection part using a specific pressure-sensitive adhesive instead of the peelable heat-bonded part, the processing ease and processing accuracy are greatly improved,
It has been found that problems of poor airtightness such as liquid leakage and volatilization can be avoided. Then, by using an administration device employing these means, the aromatic amidine derivatives useful as a blood coagulation inhibitor and a thrombus prevention and treatment agent can be safely and efficiently transdermally and transmucosally absorbed. And it can be provided as an ideal reservoir-type preparation. The present invention has been completed based on these findings.

That is, the present invention relates to a preparation for administering a drug transdermally or transmucosally, comprising the following general formula (I):

Embedded image Wherein, R ¹ represents a hydrogen atom or a lower alkoxyl group, R ² represents a hydrogen atom, a lower alkyl group, lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group, R ³ Represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group, and R ⁴ represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group Represents a lower alkyl group or a lower alkoxyl group,
n represents a number of 0 to 4, and A represents an alkylene having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups. group or the ^{formula: -B-N (R 5)} - group represented by {wherein,
B represents a lower alkylene group or a carbonyl group; R ⁵ is a hydrogen atom or a group represented by the formula —D—W—R ⁶ (in the formula,
D represents a group represented by the formula: -C (= Z)-(wherein Z represents an oxygen atom or a sulfur atom), a group represented by the formula: -CO-CO-, or a sulfonyl group; Is a single bond or a group represented by NR ⁷ — (wherein R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di- A lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanoyl group which may have a substituent.), And R ⁶ is a hydroxyl group, a lower alkoxyl group, or a substituent A lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group;
Is a saturated or unsaturated 5- or 5-
A 6-membered heterocyclic group or cyclic hydrocarbon group, an amino group which may have a substituent or an aminoalkyl group which may have a substituent,

Embedded image Represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl), and a physiologically acceptable salt thereof. And a drug-containing liquid containing a substance selected from the group consisting of hydrates and solvates thereof, comprising: (a) a support film impermeable to the drug-containing liquid; b) a release-controlling membrane through which a drug-containing liquid can pass; (c) a heat-bonding portion for connecting the support film and the release-controlling film, wherein a plurality of orbiting heat-bonding portions: A storage tank formed of the support film, the controlled release membrane, and the innermost thermoadhesive portion for storing a drug-containing liquid; (e) a drug-containing liquid from the storage tank that has passed through the controlled-release membrane; Wherein the outer edge is at least inside the outer edge of the innermost heat-sealed portion, and the entire outer edge portion overlaps the innermost heat-sealed portion. A liquid having a shape, disposed on the opposite side of the storage tank with respect to the release control film, and provided with a pressure-sensitive adhesive portion for pressure-sealing and sealing the release control film over the entire peripheral portion thereof. (F) a pressure connection portion formed on the entire outer periphery of the liquid leakage prevention lid by press-fitting and sealing the liquid leakage prevention lid and the release control film in a state in which the liquid leakage prevention lid can be easily peeled off; A pressure connection portion formed so that its outer edge is at least 1.4 mm inward from the outer edge of the liquid leakage prevention lid; (g) the liquid leakage prevention lid covers the entirety of the liquid leakage prevention lid, and (H) a pressure-sensitive adhesive layer provided so as to cover the release control film outside the A release film arranged to cover the adhesive layer; and (i) breaking the pressure connection when removing the release film from the administration device;
The liquid leakage prevention lid and the pressure-sensitive adhesive layer existing between the liquid leakage prevention lid and the release film are removed in a state where the pressure-sensitive adhesive layer is adhered and fixed to the release film, and the other pressure-sensitive adhesive layers are released. It is intended to provide a preparation stored in an administration device, which remains in the administration device while being adhered and fixed to a control membrane.

According to a preferred embodiment of the present invention, in the general formula (I):

Embedded image Is a group represented by benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl,
The above-mentioned preparation, which is a group selected from naphthyl and tetrahydronaphthyl; in the general formula (I), the saturated or unsaturated 5- to 6-membered heterocyclic group has 1 to 1 as a hetero atom.
The above-mentioned preparation, which is a group containing two nitrogen atoms or oxygen atoms; and, in the general formula (I), a saturated or unsaturated 5-
The above-mentioned preparation is provided, wherein the 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group.

According to a further preferred embodiment, a drug containing a compound selected from the group consisting of a compound selected from the following group and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof: The above formulation containing the liquid: 2- [4-[((3S) -1-acetimidoyl-3-
Pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, (2R) -2- [4-[((3R) -1
-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (7-amidino-2
-Naphthyl) propionic acid, (+)-2- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, (+)-2-
[4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 3-
[4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5-amidinobenzo [b] thien-2-yl) butyric acid, 2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[((3R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-amidino-2-naphthyl) methyl] -N'-methylsulfamide, ethyl N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate, 4- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid, N- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl acetate acid, ethyl N-
[N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycinate, N
-[N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N
-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine;

The above preparation containing a drug-containing liquid containing a compound selected from the group consisting of the following compounds and physiologically acceptable salts thereof, and hydrates and solvates thereof: (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3-
(7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate, (+)-2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7
-Amidino-2-naphthyl) propionic acid dihydrochloride,
(+)-2- [4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3-
(5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, ethyl N- [N- [4-[(1-
Acetimidyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] glycinate dihydrochloride, and N-
[N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycine dihydrochloride, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2
-Naphthyl) methyl] sulfamoylacetic acid dihydrochloride is provided. Further, in these preparations, the above-mentioned preparations in which the pressure-sensitive adhesive portion provided on the liquid leakage prevention lid is formed by an adhesive containing an ethylene / vinyl acetate copolymer are also provided by the present invention as a preferred embodiment.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the above formula (I), which is an active ingredient of the preparation of the present invention, and a physiologically acceptable salt thereof inhibit blood coagulation factor X and act as a blood coagulation inhibitor. And it is known to be useful as a prophylactic / therapeutic agent for thrombus (JP-A-5-208946 and International Publication WO
96/16940).

In the above general formula (I), the lower alkyl group may be any of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and a specific example is a methyl group. , Ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The lower alkyl group may have a substituent, and the lower alkyl group may be substituted with a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl group. Group, lower alkoxyl group, lower alkoxycarbonyl group, mono- or di-lower alkylamino group, aryl group, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, lower alkylthiocarbonyl group, hydroxyl group, carbamoyl group, Mono- or di-lower alkylaminocarbonyl groups and the like can be mentioned.

The lower alkoxyl group has 1 to 1 carbon atoms.
6, and specific examples include methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, secondary butoxyl and tertiary butoxyl groups. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like. Examples of the carboxyalkyl group include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and the like.

Examples of the alkoxycarbonylalkyl group include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a methoxycarbonylpropyl group and an ethoxycarbonylpropyl group. . Examples of the carboxyalkoxyl group include a carboxymethoxyl group, a carboxyethoxyl group, a carboxypropoxyl group, and the like.As the alkoxycarbonylalkoxyl group,
Examples include a methoxycarbonylmethoxyl group, an ethoxycarbonylmethoxyl group, a propoxycarbonylmethoxyl group, a methoxycarbonylethoxyl group, and an ethoxycarbonylethoxyl group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxybutyl group. Examples of the alkylene group having 1 to 4 carbon atoms include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group.

As the mono- or di-lower alkylaminocarbonyl group, mono-lower alkylaminocarbonyl groups such as methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, Examples thereof include an isobutylaminocarbonyl group, a pentylaminocarbonyl group, an isopentylaminocarbonyl group, a hexylaminocarbonyl group, and an isohexylaminocarbonyl group. Further, as the dialkylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, a diisopropylaminocarbonyl group, a dibutylaminocarbonyl group, a symmetric type di-substituted with a lower alkyl group such as dipentylaminocarbonyl group. Dialkylaminocarbonyl group, and different lower alkyl groups such as ethylmethylaminocarbonyl group, methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, butylmethylaminocarbonyl group, butylethylaminocarbonyl group, butylpropylaminocarbonyl group, etc. A disubstituted asymmetric dialkylaminocarbonyl group can be mentioned.

Examples of the lower alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl,
Examples include an isopentylsulfonyl group, a hexylpropyl group, and an isohexylpropyl group.

Mono- or di-lower alkylaminothiocarbonyl groups include mono-lower alkylaminothiocarbonyl groups such as methylaminothiocarbonyl group, ethylaminothiocarbonyl group, propylaminothiocarbonyl group and isopropylaminothiocarbonyl group. Butylaminothiocarbonyl group, isobutylaminothiocarbonyl group, pentylaminothiocarbonyl group,
Examples include an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group. Further, as a dialkylaminothiocarbonyl group, a dimethylaminothiocarbonyl group, a diethylaminothiocarbonyl group, a dipropylaminothiocarbonyl group, a diisopropylaminothiocarbonyl group, a dibutylaminothiocarbonyl group, a lower alkyl group such as a dipentylaminothiocarbonyl group. Di-substituted symmetric dialkylaminothiocarbonyl group, and ethylmethylaminothiocarbonyl group, methylpropylaminothiocarbonyl group, ethylpropylaminothiocarbonyl group, butylmethylaminothiocarbonyl group, butylethylaminothiocarbonyl group, Asymmetric dialkylaminothiocarbonyl groups disubstituted with different lower alkyl groups such as butylpropylaminothiocarbonyl group can be mentioned.

Examples of the lower alkanoyl group include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like, preferably acetyl group, propionyl group. , Butyryl group,
More preferably, they are an acetyl group and a propionyl group. The lower alkanoyl group may have a substituent.

The group which can be substituted with a lower alkanoyl group includes a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl group, a lower alkoxyl group, a lower alkoxycarbonyl group, a mono- or Di-lower alkylamino, aryl, aralkyloxy, aryloxy, mercapto, lower alkylthio, lower alkylthiocarbonyl, hydroxyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, etc. Can be.

Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group and an anthryl group, and the aryl group may have a substituent. As a heteroaryl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group,
Quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, naphthyridinyl, 1,2-benzoisoxazolyl, benzoxazolyl, benzothiazolyl Group, oxazolopyridyl group, isothiazolopyridyl group, benzothienyl group, and the like, and preferably, furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyridyl group, and the like. It may have a substituent.

Examples of the groups which can be substituted on these aryl groups or heteroaryl groups include halogen atoms, carboxyl groups, amino groups, cyano groups, nitro groups, hydroxyl groups, lower alkoxy groups, lower alkoxycarbonyl groups,
Or a di-lower alkylamino group, a lower alkanoyl group, or a lower alkyl group which may have a substituent.

The saturated or unsaturated 5- or 6-membered heterocyclic group is preferably a heterocyclic group containing one or two nitrogen atoms or oxygen atoms as hetero atoms. Specific examples of such a heterocycle include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, morpholine and the like. Of these, pyrrolidine and piperidine are preferred. Examples of the saturated or unsaturated cyclic hydrocarbon group include a cyclopentyl group and a cyclohexyl group. Also, as the aminoalkyl group,
Examples include an aminomethyl group, an aminoethyl group, an aminopropyl group, and the like.

The heterocyclic group or cyclic hydrocarbon group may have a substituent. Examples of the group which can be substituted with the heterocyclic group or cyclic hydrocarbon group include a lower alkyl group, a lower alkanoyl group and a carbamoyl group. Group, monoalkylcarbamoyl group, dialkylcarbamoyl group, formimidoyl group, alkanoimidoyl group, benzimidoyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkylcarbonylalkyl group, aminoalkyl group, alkanoylamino group, alkanoylamino Examples include an alkyl group, an imino group, and an alkoxycarbonylimino group.

Examples of the group which can be substituted on the amino group of the amino group or aminoalkyl group include lower alkyl group, pyrrolidinyl group, pyrazyl group, carbamoyl group, monoalkylcarbamoyl group, dialkylcarbamoyl group, lower alkanoyl group, formimide Yl, alkanoimidoyl, benzimidoyl, and alkoxycarbonyl groups. The alkyl group, alkoxyl group, alkanoyl group and the like, and the alkyl, alkoxyl and alkanoyl moieties in each substituent preferably have 1 to 6 carbon atoms.

[0028]

Embedded image The group represented by is preferably a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.

The compound represented by the general formula (I) may have an asymmetric carbon atom. In this case, an optical isomer or a stereoisomer based on the asymmetric carbon atom exists. Any of the optical isomers, stereoisomers, and mixtures thereof may be used for preparing the drug-containing liquid contained in the preparation of the present invention. Further, in addition to the compound represented by the general formula (I) or a physiologically acceptable salt thereof, a hydrate or a solvate thereof may be used for preparing a drug-containing liquid contained in the preparation of the present invention. May be used.

The following compounds and physiologically acceptable salts thereof, and hydrates and solvates thereof are preferably used for preparing the drug-containing liquid contained in the preparation of the present invention. A substance selected from the group consisting of: 2- [4-[((3S) -1-acetimidoyl-3-
Pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, (2R) -2- [4-[((3R) -1
-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (7-amidino-2
-Naphthyl) propionic acid, (+)-2- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) meloxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, (+)-2-
[4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 3-
[4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5-amidinobenzo [b] thien-2-yl) butyric acid, 2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[((3R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2
-Indolyl) propionic acid, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]-
N-[(7-amidino-2-naphthyl) methyl] -N '
-Methylsulfamide, ethyl N- [N-4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] carbamate, 4- [N-4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] benzoic acid, N- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid, ethyl
N- [N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-
2-Naphthyl) methyl] sulfamoyl] glycinate, N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine and N- [N-4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] glycine.

The following compounds and physiologically acceptable salts thereof, and hydrates and solvents thereof are particularly preferably used for preparing the drug-containing liquid contained in the preparation of the present invention. Substances selected from the group consisting of Japanese citrates can be mentioned. (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3-
(7-amidino-2-naphthyl) propionic acid, (+)
-2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[((2
S) -1-Acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, ethyl N- [N-
[4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate, N- [N
-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine, and N- [4
-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid.

Further, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid hydrochloride pentahydrate, (+)-2- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -3- (7-amidino-2-naphthyl) propionic acid dihydrochloride, (+)-2- [4-[((2S)
-1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, ethyl N-
[N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycinate 2
Hydrochloride, N- [N-4-[(1-acetimidoyl-4
-Piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride and N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl ] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoylacetic acid dihydrochloride is also suitably used for preparing a drug-containing liquid contained in the preparation of the present invention.

Of these, (2S) -2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate is a drug contained in the preparation of the present invention. It is particularly suitably used for the preparation of a liquid containing the same.

A preferred embodiment of the administration device for use in the formulation of the invention will be described with reference to FIGS. 1 and 2, but the formulation of the invention is limited to those using this particular administration device. Never. FIG. 1 shows an enlarged cross-sectional view of an administration device 1 suitably used in the present invention. The administration device 1 is configured as a laminate of a support film 2, a release controlling film 5, a pressure-sensitive adhesive layer 7, and a release film 8. The support film 2 is a drug-containing liquid 4
And is formed of a member that is impermeable to the liquid and does not leak the drug-containing liquid 4. The release control film 5 is permeable to the drug-containing liquid, and is formed of a member that allows the drug-containing liquid to exude from the release control film and reach the skin surface or the mucous membrane surface.

The heat-bonded portion 9 is formed as a plurality of orbiting tracks (usually ring-shaped tracks), and the tracks are usually concentrically provided at appropriate intervals and have an appropriate width (for example, a seal width of about several millimeters). , Preferably 2 to 6 m
m, more preferably about 2.5 to 4.5 mm). The heat-bonded portion 9 is sometimes called a permanent heat seal, and is formed so that the support film 2 and the release control film 5 can be completely fixed so that the drug-containing liquid does not leak from the heat-bonded portion. ing.
The support film 2 is provided with an inverted cup-shaped recess (usually about 10 to 50 mm in diameter, about 0.1 to 1 mL in volume), and the innermost heat-bonded portion 9a allows the support film 2 and release control. A storage tank 3 for storing the drug-containing liquid 4 is formed as a gap between the membrane 5.

The liquid leakage prevention lid 6 is provided to prevent diffusion of the drug-containing liquid from the storage tank 3 through the release control membrane 5.
It is usually formed in a disk shape so as to cover the innermost heat-bonded portion 9a so as to substantially coincide with the outer periphery of the heat-bonded portion, but with a shape slightly smaller than that. . The outer edge of the liquid leakage prevention lid 6 is at least inside, preferably about 0.00 mm, the outer edge of the innermost heat-sealed portion 9a.
5 mm inside, more preferably 1 mm inside,
The entire outer edge portion has a shape and size so as to overlap the innermost heat-bonding portion 9a. The liquid leakage prevention lid 6
Usually, it is formed in a disk shape having a radius smaller by about 1 mm than the radius of the circle forming the outer edge of the innermost heat-bonded portion 9a. The liquid leakage prevention lid 6 is disposed on the opposite side of the release control film 5 from the storage tank so as to be in contact with the release control film 5.

In order to seal the liquid leakage prevention lid 6 to the release control film 5 by pressure bonding, a pressure-sensitive adhesive portion 6b is provided on the entire peripheral portion of the liquid leakage prevention lid 6. The liquid leakage prevention lid 6 has a thin film 6a that is impermeable to the drug-containing liquid, and is large enough to cover the entire thin film 6a, and is slightly larger than the thin film 6a. It is formed by laminating the thin film 6c with a pressure-sensitive adhesive, applying an adhesive to the entire thin film 6c, and placing the thin film 6a on the coated adhesive. By pressure bonding, the pressure-sensitive adhesive portion 6b is formed on the entire peripheral portion of the thin film 6c so as to have a width of about several millimeters from the outer edge of the thin film 6a. The pressure-sensitive adhesive portion 6b is usually formed in a ring shape so as to have a width of usually about 2 to 5 mm, preferably about 3 mm,
The inner edge is formed so as to overlap the inner edge of the innermost heat-bonded portion 9a. Normally, the radius of the circle forming the inner edge of the ring-shaped pressure-sensitive adhesive portion 6b matches the radius of the circle forming the inner edge of the innermost heat-bonded portion 9a formed in the ring shape. The radius of the circle forming the outer edge of the pressure-sensitive adhesive portion 6b is smaller by about 1 mm than the radius of the circle forming the outer edge of the innermost heat-bonded portion 9a.

The pressure connection part 10 is formed by pressing and sealing the liquid leakage prevention lid 6 and the release control film 5 so that the liquid leakage prevention lid 6 and the release control film 5 can be easily peeled off at the pressure-sensitive adhesive part 6b.
The liquid leakage prevention lid 6 is fixed to the release control film 5 in a detachable state, and the drug-containing liquid passes over the outer edge of the liquid leakage prevention lid to the pressure-sensitive adhesive layer 7. It acts as a barrier to prevent leaching. The pressure connecting portion 10 is usually formed in a ring shape so as to have an appropriate width along the pressure-sensitive adhesive portion 6b, and usually has a width of 0.4 to less than the pressure-sensitive adhesive portion 6b. 0.8
It is formed to have a width of about mm, preferably about 0.6 mm. Further, the outer edge of the pressure connection portion 10 is formed so as to be at least 1.4 mm inside the outer edge of the liquid leakage prevention lid 6 so that the liquid leakage prevention lid 6 can be peeled off together with the release film 8. , Preferably 2 mm
It is formed so as to be inside, more preferably about 2 to 2.5 mm inside. Usually, the radius of the circle forming the inner edge of the ring-shaped pressure connection portion 10 matches the radius of the circle forming the inner edge of the innermost heat-sealed portion 9a formed in the ring shape, The radius of the circle forming the outer edge of the pressure connection portion 10 can be appropriately selected according to the size of the storage tank. The drug-containing liquid 4 that has passed from the storage tank 3 through the release control film 5 is confined in a small gap between the thin film 6a and the release control film 5, and passes over the pressure connection portion 10 to form the pressure-sensitive adhesive layer 7. Never contact.

The pressure-sensitive adhesive layer 7 has a sufficient size so as to cover the entire liquid leakage preventing lid 6 and the release controlling film 5 therearound. Further, on the pressure-sensitive adhesive layer 7, a release film 8 made of a member impermeable to the drug-containing liquid is laminated. When the release film 8 is removed from the administration device 1, the pressure connection portion 10 is broken and the liquid leakage prevention lid 6 (the laminate composed of the thin film 6 a and the thin film 6 c and the pressure-sensitive adhesive layer disposed therebetween) ) And the release film 8 are removed while the pressure-sensitive adhesive layer 7 a and the liquid leakage prevention lid 6 existing between the release film 8 and the release film 8 are adhered and fixed to the release film 8. Among the pressure-sensitive adhesive layers 7, the pressure-sensitive adhesive layer 7b provided around the liquid leakage prevention lid 6 usually remains in the release device 1 in a ring shape while being adhered and fixed to the release control film 5. . With the release film 8 removed in this manner, the pressure-sensitive adhesive layer 7b is brought into contact with the skin surface or the mucous membrane surface, and the administration device 1 is fixed. The drug-containing liquid reaches the skin surface or mucosal surface through the controlled release membrane 5, and is absorbed into the body transdermally or transmucosally.

FIG. 2 is an enlarged sectional view of the administration device 2 suitably used for the preparation of the present invention. In the administration device 2, the support film 2, the storage tank 3, the release control membrane 5,
The pressure-sensitive adhesive layer 7 and the release film 8 are the same as those of the administration device 1. In the administration device 2, the liquid leakage prevention lid 6
Is composed of a thin film 6c. The thin film 6c is formed so as to substantially coincide with the outer edge of the innermost heat-bonding portion 9a so as to prevent diffusion of the drug-containing liquid from the storage tank 3 that has passed through the release control film 5, however, it is not so thin. It is slightly smaller in size and shape. The outer edge of the thin film 6c is at least inside, preferably 0.05 mm, more preferably 1 mm inside the outer edge of the innermost heat-bonded portion 9a, and the entire outer edge is the innermost heat source. It has a shape and size so as to overlap the adhesion portion 9a, and is usually formed in a disk shape having an outer edge smaller than the radius of a circle forming the outer edge of the innermost heat adhesion portion by about 1 mm. The thin film 6c is disposed on the side opposite to the storage tank with respect to the release control film 5. Also, a thin film 6 acting as a liquid leakage prevention lid
A ring-shaped pressure-sensitive adhesive portion 6b is generally provided so as to have an appropriate width over the entire peripheral portion of the thin film 6c in order to press-fit and seal c to the release control film 5. The pressure-sensitive adhesive portion 6b is usually about 2 to 5 mm, preferably 3 to 5 mm.
It is formed so as to have a width of about mm, and is formed so as to overlap the innermost heat-bonded portion 9a. Normally, the radius of the circle forming the inner edge of the pressure-sensitive adhesive portion 6b formed in a ring shape is the innermost heat-bonded portion 9 formed in the ring shape.
The radius of the circle forming the outer edge of the pressure-sensitive adhesive portion 6b is about 1 mm larger than the radius of the circle forming the outer edge of the innermost heat-bonded portion 9a. small.

The pressure connection portion 10 is formed by pressing and sealing the thin film 6c acting as a liquid leakage prevention lid and the release control film 5 at the pressure-sensitive adhesive portion 6b.
c is generally formed in a ring shape so as to have an appropriate width over the entire periphery of the thin film 6c. The thin film 6c is fixed to the release control film 5 in a detachable state, and the drug-containing liquid is It functions so as not to exude to the pressure-sensitive adhesive layer 7 beyond the outer edge of the leakage prevention lid. The outer edge of the pressure connection portion 10 is formed so as to be more than at least 1.4 mm inside the outer edge of the thin film 6c so that the thin film 6c can be peeled off together with the release film 8,
It is preferably 2 mm inside, more preferably 2 mm
It is formed so as to be about 2.5 mm inside. Usually, the radius of the circle forming the inner edge of the ring-shaped pressure connection portion 10 matches the radius of the circle forming the inner edge of the innermost heat-sealed portion 9a formed in the ring shape, The radius of the circle forming the outer edge of the pressure connection portion 10 can be appropriately selected according to the size of the storage tank. The drug-containing liquid 4 that has passed through the release control film 5 from the storage tank 3 is confined in the gap formed by the thin film 6a and the release control film 5, and exceeds the pressure connection portion, and the pressure-sensitive adhesive layer 7 Never contact.

When the release film 8 is removed from the administration device 1, the pressure connection portion 10 is broken, and the thin film 6a acting as a liquid leakage prevention lid and the pressure-sensitive adhesive portion 6 are removed.
b, and the pressure-sensitive adhesive layer 7a existing between the release film 8 and the thin film 6c is removed in a state where the pressure-sensitive adhesive layer 7a is adhesively fixed to the release film 8. Among the pressure-sensitive adhesive layers 7, the pressure-sensitive adhesive layer 7 provided around the liquid leakage prevention lid 6
b generally remains in the release device 1 in a ring shape in a state of being adhesively fixed to the release control film 5. With the release film 8 removed in this manner, the pressure-sensitive adhesive layer 7b is brought into contact with the skin surface or the mucous membrane surface, and the administration device 1 is fixed. The drug-containing liquid reaches the skin surface or mucosal surface through the controlled release membrane 5, and is absorbed into the body transdermally or transmucosally.

The material of the support film is not particularly limited as long as the drug-containing liquid is substantially impermeable, and may be made of a suitable polymer such as polyethylene, polypropylene, polyester, polyethylene vinyl acetate, and polyethylene terephthalate. A film-like support film or aluminum can be used. For example, a laminated film of polyethylene-polyvinylidene chloride-polyethylene can be suitably used. The storage tank formed in the support film can be easily formed by a method well-known to those skilled in the art, and can be formed by, for example, molding using a molding and sealing machine.

The type of the controlled release membrane is not particularly limited as long as it can permeate the drug-containing liquid at an appropriate speed. For example, a porous film can be used, and an ethylene-vinyl acetate copolymer can be used. And films of polycarbonate, polypropylene, polyethylene, polyurethane, polyethylene terephthalate, and the like. Either a porous or non-porous film may be used, but a porous film is preferably used, and more specifically, a porous polyethylene film or the like is suitable.

The member forming the liquid leakage prevention lid is not particularly limited as long as it is substantially impermeable to the drug-containing liquid. For example, a suitable material such as polyethylene, polypropylene, polyester, polyethylene vinyl acetate, polyethylene terephthalate, etc. Can be used. For example, a film obtained by laminating a polyester film is suitable. As the release film, for example, a film of aluminum, cellulose, polyester, polyethylene, polypropylene, polyethylene tetraphthalate, or the like can be used.

Examples of the pressure-sensitive adhesive for forming the pressure-sensitive pressure-sensitive adhesive portion on the liquid leakage prevention cover include ethylene-vinyl acetate copolymer, natural rubber, styrene-isoprene-styrene block copolymer, and styrene-butadiene-styrene block. Pressure-sensitive adhesives such as copolymers, polyisobutylene, acrylate copolymers, methacrylate copolymers, and silicone pressure-sensitive adhesives, among which pressure-sensitive adhesives containing an ethylene-vinyl acetate copolymer are preferred. It is. This adhesive is prepared from an ethylene / vinyl acetate copolymer resin, and commercially available products such as Toyomelt H-079B can be obtained. The pressure-sensitive adhesive layer can be appropriately selected from conventional adhesives as an adhesive capable of fixing the administration device to the skin surface or the mucous membrane surface. For example, acrylate polymer,
Pressure sensitive adhesive based on sodium carboxymethylcellulose, polyisobutene, polyisobutylene, styrene-isoprene-styrene block copolymer, natural rubber, vinyl ether copolymer, sodium polyacrylate, polydimethylsiloxane, methacrylate polymer, etc. Agents can be used. Among these, a polyisobutylene-based pressure-sensitive adhesive is preferable.

The form of the drug-containing liquid is not particularly limited as long as it is a liquid or gel-like (semi-solid) form suitable as a preparation for transdermal or transmucosal absorption. The term "drug-containing liquid" as used herein should not be interpreted as excluding semi-solid forms. As the drug-containing liquid, an appropriate liquid-form drug-containing liquid such as an aqueous solution or a non-aqueous solution such as glycerin, or an ethanol-containing aqueous solution can be used. The concentration of the drug contained in the drug-containing liquid is not particularly limited, and can be appropriately selected by those skilled in the art. The preparation method for the drug-containing liquid is not particularly limited, either, and a preparation method well-known and commonly used by those skilled in the art can be adopted according to the form. In preparing the drug-containing liquid, one or more pharmaceutical additives can be used, and their necessity and type can be appropriately selected by those skilled in the art according to the type of the pharmaceutical form. It is.

The preparation of the drug-containing liquid is not particularly limited, but a solvent generally used as an external preparation or a transdermal / transmucosal absorption promoter can be used. For example, alcohols such as isopropanol, ethanol, benzyl alcohol, nonanol, decanol and dodecanol; polyhydric alcohols such as glycerin, polyethylene glycol, propylene glycol and butylene glycol; higher alkanes such as n-heptane and n-nonane; caprylic acid , Higher fatty acids such as capric acid, lauric acid, myristic acid and oleic acid; higher fatty acid esters such as glyceryl monocaprylate, glyceryl monocaprate and isopropyl myristate; terpenes such as l-menthol and mentone; sodium lauryl sulfate Alkylamine oxides such as lauryl dimethylamine oxide, carboxybetaines such as dodecyldimethylaminoacetic acid, and oxy acids such as lactic acid, citric acid and tartaric acid. Carboxylic acid, N, N- dimethylacetamide, 2-pyrrolidone, N- octyl-2-pyrrolidone, N- methyl -
Amides such as 2-pyrrolidone and the like can be mentioned.

In addition, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose,
Water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, poly (vinyl alcohol acrylate), and polyvinylpyrrolidone; oily bases such as petrolatum and liquid paraffin; preservatives;
Emulsifiers; preservatives and the like can be used as pharmaceutical additives, but are not limited thereto.

The shape of the administration device used in the preparation of the present invention is not particularly limited, and may be any shape such as a circle, an ellipse, and a polygon, and is preferably a circle. Although the dimensions of the administration device are not particularly limited,
It is desired that the area of the surface releasing the drug is in the range of, for example, ² to 200 cm ² . The shape of the storage tank is not particularly limited as long as it can hold the drug-containing liquid,
For example, any of a columnar shape, a polygonal column, a polygonal pyramid, etc. may be used.

[0051]

EXAMPLES Reference Example 1 The preparation shown in FIG. 1 was produced. Using a molding and sealing machine, a support film (Varilon CX-26, thickness 64 μm, laminated with polyethylene-polyvinylidene chloride-polyethylene)
Asahi Kasei Kogyo Co., Ltd.) with pressure of 5 kgf / cm ² , mold temperature of 45 ° C
Then, make an inverted cup-shaped hollow with a diameter of 18 mm and a capacity of about 0.4 mL, and inject 0.4 mL of the above-mentioned ethanol / water mixture (83% by volume of ethanol), and control the release of porous polyethylene. Cover with membrane (Hypore N-710, pore size 0.05μm, thickness 25μm, Asahi Kasei Corporation), pressure 5 kgf / c
Triple thermal adhesion (innermost circle: inner diameter 20 mm, outer diameter 28 mm, seal width 4 mm) was performed concentrically at m ² and a temperature of 140 ° C. In addition, a 26 mm diameter, 100 μm thick film (polyester, PET10011, Lintec Co., Ltd.) was coated with an ethylene-vinyl acetate copolymer resin adhesive over the entire surface (20 g / m ² ) Place the adhesive side of the liquid leakage prevention lid on which a thin film (polyester, E5100, Toyobo Co., Ltd.) with a thickness of 20 mm and a thickness of 16 μm is placed on the release control membrane side, and pressurize 5 kgf / cm ² to form a ring (inner diameter) 20 mm, outer diameter 21.2
mm, seal width 0.6 mm).

As a polyisobutylene-based adhesive, VISTAN
EX MML-100 (Tonex Corporation), High Mall 4H
(Nippon Petrochemical Co., Ltd.), ESCOREZ 1202U (Tonex Co., Ltd.) mixed and dissolved in n-heptane as a solvent, and using a paint dryer (LABDRYER, Mathis), a polyester release liner treated with silicon to a thickness of 200 μm. After drying at a drying temperature of 50 ° C. for 10 minutes, the adhesive surface was covered with a silicone-treated release paper to obtain a polyisobutylene-based pressure-sensitive adhesive having a thickness of 80 μm. The polyisobutylene-based pressure-sensitive adhesive obtained by coating and drying was pressure-bonded onto a liquid leakage prevention lid at a pressure of 5 kgf / cm ² , and finally cut to a diameter of 40 mm.
Was prepared.

Example 1 (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3-
(7-amidino-2-naphthyl) propionic acid hydrochloride
A drug-containing liquid is prepared by mixing 5 parts by weight of pentahydrate, 1.5 parts by weight of capric acid, 1.5 parts by weight of nonanol, 10 parts by weight of benzyl alcohol, 60 parts by weight of absolute ethanol, and 24 parts by weight of purified water. did. Using this drug-containing liquid, a preparation of the present invention was produced in the same manner as in Reference Example 1 except for the above.

COMPARATIVE EXAMPLE 1 Instead of using a polyester film coated with an ethylene / vinyl acetate copolymer resin adhesive, a polyester film was used to bond the release film control film and the support film to each other. The administration device was manufactured in the same manner as in Example 1.

Comparative Example 2 Instead of using a polyester film coated with an ethylene / vinyl acetate copolymer resin adhesive, an aluminum vapor-deposited polyester-polyethylene laminated film was used, and this film, a release controlling film and a support were heat-sealed. An administration device was manufactured in the same manner as in Example 1 except that the film was adhered.

Comparative Example 3 An administration device was produced in the same manner as in Example 1 except that the film used for the liquid leakage prevention lid was 25 mm in diameter instead of 26 mm in diameter.

Comparative Example 4 An administration device was manufactured in the same manner as in Example 1 except that the film used for the liquid leakage prevention lid was a 29 mm diameter film instead of a 26 mm diameter film.

Test Example 1 Sealing Test Each preparation containing an ethanol / water mixture was stored in a constant temperature room at 40 ° C. (relative humidity 65%), and the weight change and drug content were measured over time. Tested the sealing of the dosing device. A 20 g weight was placed on each device and used for testing after confirming that the liquid did not leak for more than 30 minutes. Table 1 shows the results. In the table, change in weight over time is represented by the weight loss rate (%)
The average value was described.

[0059]

[Table 1]

Test Example 2: Peeling properties Film peeling properties were examined using devices having different sizes of films used for the liquid leakage preventing lid. When the release film was removed from the device, a sensory test was performed to determine whether the liquid leakage prevention lid and the pressure-sensitive adhesive layer immediately below the liquid leakage prevention lid were simultaneously removed. Table 2 shows the results. In the table, the releasability evaluation according to the size of the liquid leakage prevention lid is shown as a result of n = 10.

[0061]

[Table 2]

Test Example 3: Exudation of Drug-Containing Liquid into Pressure-Sensitive Adhesive Layer When each device was attached to a living body (skin) and applied, Comparative Example 4 was used.
In the preparation of Example 1, the drug-containing liquid migrates to the gap near the permanent heat seal portion, whereas in the preparation of Reference Example 1 and the preparation of the present invention (Example 1), the drug-containing liquid is transferred to the pressure-sensitive adhesive layer. It did not exude and maintained a constant application area.

[Brief description of the drawings]

FIG. 1 is an enlarged cross-sectional view of one embodiment (administration device 1) of an administration device used for the preparation of the present invention. In the figure,
(A) shows a stored state, and (B) shows a peeled state.

FIG. 2 is an enlarged cross-sectional view of one embodiment of an administration device (administration device 2) used in the preparation of the present invention. In the figure,
(A) shows a stored state, and (B) shows a peeled state.

FIG. 3 is an enlarged cross-sectional view of an embodiment of a prior art formulation. In the figure, (A) shows a stored state, and (B) shows a peeled state.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Dosing device 2 Support film 3 Storage tank 4 Drug-containing liquid 5 Release control film 6 Liquid leakage prevention lid 6a Thin film 6b Pressure-sensitive adhesive part 6c Thin film 7 Pressure-sensitive adhesive layer 7a Removed together with a release film Pressure-sensitive pressure-sensitive adhesive layer 7b Pressure-sensitive pressure-sensitive adhesive layer remaining on the administration device 8 Release film 9 Heat-bonded portion 9a Innermost heat-bonded portion 9b Second heat-bonded portion from inside 10 Pressure connection portion 11 Gap 12 No adhesive Coating department

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4535 A61K 31/4535 A61P 7/02 A61P 7/02 (72) Inventor Yoshiki Sugizaki Kasukabe, Saitama 8-1, Minamiei-cho, Saitama Daiichi Pharmaceutical Co., Ltd. (72) Inventor Hideo Mizu 8-1, Minamiei-cho, Kasukabe, Saitama Prefecture, Japan (72) Inventor Kazuko Korenaga 8, Minamiei-cho, Kasukabe, Saitama Address 1 F-term in Saitama Daiichi Pharmaceutical Co., Ltd. (reference) 4C076 AA73 AA74 AA81 AA94 BB31 CC11 DD37 DD41 EE05 EE07 4C086 AA01 AA02 BC07 BC21 GA03 GA07 MA16 MA32 NA10 ZA54

Claims (9)

[Claims] 1. A preparation for administering a drug transdermally or transmucosally, comprising a compound represented by the following general formula (I): Wherein, R ¹ represents a hydrogen atom or a lower alkoxyl group, R ² represents a hydrogen atom, a lower alkyl group, lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group, R ³ Represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group, and R ⁴ represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group Represents a lower alkyl group or a lower alkoxyl group,
n represents a number of 0 to 4, and A represents an alkylene having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups. group or the ^{formula: -B-N (R 5)} - group {wherein represented by, B represents a lower alkylene group or a carbonyl group, R ⁵ is a group represented by hydrogen atom or formula -D-W-R ⁶ (Wherein D is a group represented by the formula: -C (= Z)-(wherein Z represents an oxygen atom or a sulfur atom)),
Formula: a group represented by -CO-CO-, or indicates a sulfonyl group, W is a single bond or a NR ⁷ - in a group represented by (wherein, R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono - Or a di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group optionally having a substituent, or a lower alkanoyl optionally having a substituent And R ⁶
Represents a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. ) Represents X, X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, and Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon which may have a substituent. A group, an amino group which may have a substituent or an aminoalkyl group which may have a substituent; Represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl), and a physiologically acceptable salt thereof. And a drug-containing liquid containing a substance selected from the group consisting of hydrates and solvates thereof, comprising: (a) a support film impermeable to the drug-containing liquid; b) a release-controlling membrane through which a drug-containing liquid can pass; (c) a heat-bonding portion for connecting the support film and the release-controlling film, wherein a plurality of orbiting heat-bonding portions: A storage tank formed of the support film, the controlled release membrane, and the innermost thermoadhesive portion for storing a drug-containing liquid; (e) a drug-containing liquid from the storage tank that has passed through the controlled-release membrane; Wherein the outer edge is at least inside the outer edge of the innermost heat-sealed portion, and the entire outer edge portion overlaps the innermost heat-sealed portion. A liquid having a shape, disposed on the opposite side of the storage tank with respect to the release control film, and provided with a pressure-sensitive adhesive portion for pressure-sealing and sealing the release control film over the entire peripheral portion thereof. (F) a pressure connection portion formed on the entire outer periphery of the liquid leakage prevention lid by press-fitting and sealing the liquid leakage prevention lid and the release control film in a state in which the liquid leakage prevention lid can be easily peeled off; A pressure connection portion formed so that its outer edge is at least 1.4 mm inward from the outer edge of the liquid leakage prevention lid; (g) the liquid leakage prevention lid covers the entirety of the liquid leakage prevention lid, and (H) a pressure-sensitive adhesive layer provided so as to cover the release control film outside the A release film arranged to cover the adhesive layer; and (i) breaking the pressure connection when removing the release film from the administration device;
The liquid leakage prevention lid and the pressure-sensitive adhesive layer existing between the liquid leakage prevention lid and the release film are removed in a state where the pressure-sensitive adhesive layer is adhered and fixed to the release film, and the other pressure-sensitive adhesive layers are released. The preparation stored in the administration device, which remains in the administration device in a state of being adhered and fixed to the control membrane. 2. In the general formula (I), Is a group represented by benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl,
The preparation according to claim 1, which is a group selected from naphthyl and tetrahydronaphthyl. 3. In the general formula (I), a saturated or unsaturated 5- or 6-membered heterocyclic group is represented by 1 to 2 as a hetero atom.
The preparation according to claim 1 or 2, which is a group containing at least one nitrogen atom or oxygen atom. 4. The preparation according to claim 2, wherein in formula (I), the saturated or unsaturated 5- to 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group. 5. A drug-containing liquid containing a compound selected from the group consisting of the following compounds and physiologically acceptable salts thereof, and hydrates and solvates thereof. The preparation according to 1. 2- [4-[((3S) -1-acetimidoyl-3-
Pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, (2R) -2- [4-[((3R) -1
-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (7-amidino-2
-Naphthyl) propionic acid, (+)-2- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]- 3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, (+)-2-
[4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 3-
[4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5-amidinobenzo [b] thien-2-yl) butyric acid, 2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[((3R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-amidino-2-naphthyl) methyl] -N'-methylsulfamide, ethyl N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate, 4- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid, N- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl acetate acid, ethyl N-
[N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycinate, N
-[N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N
-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine. 6. A drug-containing liquid containing a compound selected from the group consisting of the following compounds and physiologically acceptable salts thereof, and hydrates and solvates thereof. The preparation according to 1. (2S) -2- [4
-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-
Naphthyl) propionic acid hydrochloride pentahydrate, (+)-
2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid dihydrochloride, (+)-2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, ethyl N- [N- [ 4-[(1-acetimidoyl-4
-Piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy ] Phenyl] -N
-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]-
N-[(7-Amidino-2-naphthyl) methyl] sulfamoylacetic acid dihydrochloride. 7. (2S) -2- [4-[((3S) -1
A drug-containing liquid containing -acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propion hydrochloride pentahydrate.
The preparation according to 1. 8. The preparation according to claim 1, wherein the pressure-sensitive adhesive portion provided on the liquid leakage preventing lid is formed of an adhesive containing an ethylene / vinyl acetate copolymer. 9. The administration according to claim 1, wherein the outer edge of the pressure connection portion is a pressure connection portion formed so as to be at least 2 mm inside the outer edge of the liquid leakage prevention lid. device.