JP2001055332A - Iontophresis preparation containing aromatic amidine derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation which can express an excellent transdermal absorption-stimulating property and can inhibit the blood coagulation factor X to express actions such as an anti-thrombogenic action and an anticoagulant action by including a specific aromatic amidine derivative. SOLUTION: This preparation for iontophresis contains an aromatic amidine derivative of formula I [R1 is H or a lower alkoxy; R2 is H, a lower alkyl or the like; R3 is H, carboxy or the like; R4 is H, a halogen or the like; (n) is 0 to 4; A is a 1 to 4C alkylene which may one or two hydroxyalkyl groups or the like, or the like; X is a single bond, O or the like; Y is a group of formula II or the like], its salt or the like. The compound of formula I include 2- 4-[((3S)-1-acetimidioyl-3-pyrrolidinyl)oxy]phenyl}-3-(7-amidino-2-naph thyl) propionic acid. The preparation may further contain a solvent (preferably water or a lower alkyl) and a transdermal absorption-stimulating agent (preferably a >=2C saturated aliphatic alcohol or the like).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preparation for iontophoresis of an aromatic amidine derivative (pharmaceutical composition for percutaneous administration by iontophoresis) which is useful as a blood coagulation inhibitor and an agent for preventing and treating thrombus.

[0002]

2. Description of the Related Art Iontophoresis is a transdermal absorption promotion system using electricity, and its principle is as follows.
In the electric field between the anode and the cathode, which is mainly caused by current, the molecules of the drug molecules are determined based on the force of the positively charged molecules moving from the anode to the cathode and the negatively charged molecules moving from the cathode to the anode. Skin barrier-To promote penetration. For example, JP-A-8
317997 describes the use of iontophoresis to enhance the transdermal absorption of calcitonin.

On the other hand, JP-A-5-208946 discloses that a compound having an aromatic amidine structure in its chemical structure inhibits blood coagulation factor X and is useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for thrombus. And International Publication WO96
/ 16940.

Heretofore, intravenous administration and oral administration have been generally used as administration forms of these drugs acting on the blood coagulation system, and other administration forms have hardly been studied.

Accordingly, an object of the present invention is to provide a transdermal dosage form by iontophoresis as a new dosage form of the aromatic amidine derivatives.

[0006]

The present inventors have made various studies on the percutaneous absorbability of the aromatic amidine derivatives, and surprisingly, this compound is efficiently absorbed from the skin by iontophoresis. And found that the present invention was completed.

That is, the present invention provides a preparation for iontophoresis containing an aromatic amidine derivative represented by the following general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative. Is provided.

[0008]

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[In the formula, the following symbols indicate the following, respectively. R ¹ : hydrogen atom or lower alkoxyl group; R ² : hydrogen atom, lower alkyl group, lower alkoxyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group; R ³ : hydrogen atom, carboxyl group, alkoxy group A carbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group; R ⁴ : a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group or a lower alkoxyl group; A: 1 to 2 hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl groups which may have 1 to 4 carbon atoms. Alkylene group, or a group of the formula

[0010]

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In the formula, E represents a lower alkylene group or a carbonyl group, and R ⁵ is a hydrogen atom or a group represented by the formula —D—W—R ⁶ (where D is a group represented by the formula

[0012]

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Wherein Z represents an oxygen atom or a sulfur atom. >,formula

[0014]

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And W 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 group. It represents an alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-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 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. . )｝;

X: a single bond, an oxygen atom, a sulfur atom or a carbonyl group; Y: a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, a substituent An amino group which may have or an aminoalkyl group which may have a substituent;

[0017]

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A group selected from the group consisting of indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl;

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The aromatic amidine derivative represented by the above general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative used in the preparation of the present invention is as described above. It is known to inhibit blood coagulation factor X and to be useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for thrombus.

In the aromatic amidine derivative represented by the general formula (1), the salt of the derivative, the solvate of the derivative or the solvate of the salt of the derivative according to the present invention, the lower alkyl group has 1 carbon atom. And any of a linear, branched or cyclic alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, and tertiary butyl. , Pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The lower alkyl group may have a substituent. Examples of the group which can be substituted with the lower alkyl group include a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl 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 And mono- or di-lower alkylaminocarbonyl groups.

As the lower alkoxyl group, one having 1 to carbon atoms is used.
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 and a butoxycarbonyl group.

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 and a carboxypropoxyl group. Examples of the alkoxycarbonylalkoxyl group include a methoxycarbonylmethoxyl group, an ethoxycarbonylmethoxyl group, a propoxycarbonylmethoxyl group, Examples include 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.

Examples of the mono-lower alkylaminocarbonyl group include a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a butylaminocarbonyl group, an isobutylaminocarbonyl group, a pentylaminocarbonyl group and an isopentyl. Examples include an aminocarbonyl group, a hexylaminocarbonyl group, and an isohexylaminocarbonyl group.

The di-lower alkylaminocarbonyl group includes a lower alkyl group such as a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, a diisopropylaminocarbonyl group, a dibutylaminocarbonyl group and a dipentylaminocarbonyl group. A di-substituted symmetric dialkylaminocarbonyl group, and an ethylmethylaminocarbonyl group,
Methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, butylmethylaminocarbonyl group,
Asymmetric dialkylaminocarbonyl groups disubstituted with different lower alkyl groups such as butylethylaminocarbonyl group and butylpropylaminocarbonyl group can be exemplified.

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

Examples of the mono-lower alkylaminothiocarbonyl group include a methylaminothiocarbonyl group, an ethylaminothiocarbonyl group, a propylaminothiocarbonyl group, an isopropylaminothiocarbonyl group, a butylaminothiocarbonyl group, an isobutylaminothiocarbonyl group, Examples include a pentylaminothiocarbonyl group, an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group.

Examples of the di-lower alkylaminothiocarbonyl group include dimethylaminothiocarbonyl, diethylaminothiocarbonyl, dipropylaminothiocarbonyl, diisopropylaminothiocarbonyl, dibutylaminothiocarbonyl, dipentylaminothiocarbonyl and the like. A symmetric dialkylaminothiocarbonyl group di-substituted with a lower alkyl group, and ethylmethylaminothiocarbonyl group, methylpropylaminothiocarbonyl group, ethylpropylaminothiocarbonyl group, butylmethylaminothiocarbonyl group, butylethyl Asymmetric dialkylaminothiocarbonyl groups disubstituted with different lower alkyl groups such as aminothiocarbonyl group and butylpropylaminothiocarbonyl group can be exemplified.

Examples of the lower alkanoyl group include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, and hexanoyl group. Among these, an acetyl group, a propionyl group and a butyryl group are preferred, and an acetyl group and a propionyl group are particularly preferred. The lower alkanoyl group may have a substituent.

The group which can be substituted for the 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 group, ant-
And aralkyloxy, aryloxy, mercapto, lower alkylthio, lower alkylthiocarbonyl, hydroxyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, and the like.

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.

The heteroaryl group includes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl. Group, cinnolinyl group, benzimidazolyl group, imidazopyridyl group, benzofuranyl group, naphthyridinyl group, 1,2-
Benzoisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolopyridyl group, isothiazolopyridyl group, benzothienyl group and the like,
Furyl, thienyl, pyrrolyl, imidazolyl,
Pyridyl groups and the like are particularly preferred. The aryl group may have a substituent.

Examples of the group which can be substituted on the aryl group or the heteroaryl group include a halogen atom, a carboxyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, and a mono-alkoxy group. Or a di-lower alkylamino group, a lower alkanoyl group,
Examples thereof include 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 or oxygen atoms as a hetero atom. Specific examples of such a heterocyclic ring include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrol, imidazole, pyrazine, pyrrolidinone, piperidinone, and morpholine. Of these, pyrrolidine and piperidine are preferred. Examples of the saturated or unsaturated cyclic hydrocarbon group include a cyclopentyl group and a cyclohexyl group. Examples of the aminoalkyl group include an aminomethyl group, an aminoethyl group, and an aminopropyl group.

The heterocyclic group or cyclic hydrocarbon group may have a substituent. Examples of the group which can be substituted on the heterocyclic group or cyclic hydrocarbon group include lower alkyl group, lower alkanoyl group, 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.

The group which can be substituted on the amino group of the amino group or the aminoalkyl group includes a lower alkyl group,
Examples include a pyrrolidinyl group, a pyrazyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a lower alkanoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, and an alkoxycarbonyl group. The alkyl group, alkoxyl group, alkanoyl group and the like shown here have 1 carbon atom.
To 6 are preferable.

[0041]

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

The aromatic amidine derivative represented by the general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative according to the present invention has an asymmetric carbon atom. In such a case, optical isomers or stereoisomers based on asymmetric carbon atoms exist, and all of these optical isomers, stereoisomers, and mixtures thereof are included in the present invention.

In the present invention, examples of the aromatic amidine derivative represented by the general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative include the following. .

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-[((3S) -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- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] 2-naphthyl) propionic acid
-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-[((2
S) -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; N- [N-4-[( 1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoyl] glycine; and a salt of each of the above compounds; a solvate of each of the above compounds; and a solvate of a salt of each of the above compounds.

Particularly preferred is (2S) -2- [4
-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-
Naphthyl) propionic acid, (+)-2- [4-[(1-
Acetimidyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[((2S) -1-acetimidoyl-2-) Pyrrolidinyl) methoxy] phenyl] -3
-(5-amidinobenzo [b] thien-2-yl) propionic 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] glycine, and salts, solvates, and solvates of these salts.

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, N- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic 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 is preferred.

The solvent used in the preparation for iontophoresis of the present invention is not particularly limited, and may be selected from those generally acceptable in terms of pharmaceutically.
Water, one containing one or more selected from lower alcohols and polyhydric alcohols, more preferably,
Those containing (A) water and (B) one or more selected from lower alcohols and polyhydric alcohols are selected.

Specifically, water and lower alcohols such as ethanol and isopropyl alcohol, propylene glycol, 1,3-butylene glycol, glycerin, sorbitan, ethylene glycol, polyethylene glycol 300 and polyethylene glycol 400 (PE
G400) and buffers such as a phosphate buffer and an acetate buffer. One or more of these can be used. The amount of these solvents is not particularly limited, but is 1 to 99.% of the total amount of the components of the preparation.
It is preferably 9% by weight, more preferably 40 to 99.9% by weight.

In the present invention, the above-mentioned amidine derivative, a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative, which promotes the percutaneous absorption of a substance (transdermal absorption enhancer) is prepared. It can be compounded inside. Such transdermal absorption enhancers include alcohols and polyvalent alcohols.
, Higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylene alkyl ethers, sulfoxides and amides. One or more of these can be used. In particular, it is more preferable to use one or more selected from alcohols, higher fatty acids, higher fatty acid esters, terpenes, and amides.

Among the above-mentioned percutaneous absorption enhancers, the alcohols are preferably saturated aliphatic alcohols having 2 to 18 carbon atoms and arylalkanols having 7 to 14 carbon atoms, and specific examples thereof include ethanol. -C 2 to C.I., isopropanol, etc.
Alkanol, benzyl alcohol, etc. having 4 to 7 carbon atoms
2, aryl alcohol, 1-octanol, 1-nonanol, 1-decanol, 1-dodecanol, stearyl alcohol and the like.

The higher fatty acid is preferably a saturated or unsaturated fatty acid having 6 to 18 carbon atoms. Specific examples of the higher fatty acid include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, oleic acid and the like. Can be

As the higher fatty acid ester, a monohydric alcohol or a polyhydric alcohol having 6 to 24 carbon atoms is preferable, and a polyhydric alcohol having 6 to 24 carbon atoms.
Are more preferred. Here, examples of the polyvalent alcohol include ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin, and sorbitan. Examples of the fatty acids that form esters with these polyhydric alcohols include caproic acid, caprylic acid, capric acid, lauric acid, and myristic acid.
Specific examples of the higher fatty acid ester include glycerin monocaproate, glyceryl monocaprylate, and glycerin monocaprate.

Examples of the terpenes include monoterpenes and sesquiterpenes, and specific examples are cineole and
l-menthol, menthone, d-limonene, nerolide
And the like.

The amides include N, N-dialkylformamide, N, N-dialkylacetamide,
Examples include N, N-dialkyltoluamide, N-hydroxyalkyl lactamide, pyrrolidone, N-alkylpyrrolidone, etc. More specifically, N, N-dimethylformamide, N, N dimethylacetamide, N, N-diethyl Toluamide, N-hydroxyethyl lactamide, 2-pyrrolidone, N-octyl-2-pyrrolidone,
N-methyl-2-pyrrolidone and the like.

The amount of the transdermal absorption enhancer is not particularly limited, but is preferably 0.001 to 0.001 based on the total amount of the components of the preparation.
60% by weight, more preferably 0.01 to 50% by weight,
Particularly preferably, it is 0.1 to 40% by weight.

The preparation for iontophoresis of the present invention comprises:
In order to prevent the formulation from leaking and evaporating, and to accurately adhere the formulation to a living body (skin), it is preferable to add a thickener. In this case, it is preferable to use a water-soluble polymer. However, an anionic water-soluble polymer consisting only of an acidic group is not preferred. Preferred thickeners include polyacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene oxide, poly-N-vinylacetamide, agarose, starch, sodium alginate, ethylcellulose, dextrin, Gelatin, starch derivatives, water-soluble polymers such as polyvinyl alcohol, and more preferably, polyacrylamide, polyvinylpyrrolidone,
Examples thereof include polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene oxide, poly-N-vinylacetamide, and agarose, and one or more of those described above can be used. The amount of these thickeners is not particularly limited, but is 0.1 to 0.1% of the total amount of the components of the preparation.
60% by weight is preferable, and 0.1 to 20% by weight is more preferable.

In the present invention, various conventionally known pharmaceutically acceptable carriers (additives) can be further blended as required. Examples of such additives include emulsifiers, suspending agents, preservatives, stabilizers, and those generally used as a base component for external use.

The dosage form of the preparation for iontophoresis of the present invention is not particularly limited, and may be a liquid dosage form, a patch type, a reservoir, or the like.
Any dosage form, such as a mold or a matrix, may be used.

Further, as the electrode used for iontophoresis, platinum, carbon, silver, silver chloride electrodes and the like can be used, but any material having a conductive property may be used. Also, as the energizing method, DC type, pulse type,
Any method such as a pulse depolarization type can be applied. The current density is not particularly limited, but is 0.001 to 0.5 mA / cm ^2.
Is preferable, and 0.01 to 0.5 mA / cm ² is more preferable. 0.001 mA / cm is a little show skin permeation enhancing less than ^2, because in the case of 0.5 mA / cm ² greater than showing the skin irritation is not preferable.

[0064]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 D (2S) -2- [4-[(3S) -1-
Acetimidyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propion hydrochloride pentahydrate (hereinafter, referred to as compound A) is 0.0
It was dissolved in 5 M pH 6.8 phosphate buffered saline (PBS) to prepare a 1 mg / ml solution.

Test Example 1 (Effect of current density; in vitro
ro skin permeability test) Under the following experimental conditions, circulate warm water at 37 ° C in advance.
Hairless mouse skin immediately after removal into a warm horizontal diffusion cell
, A platinum wire-electrode is attached to each cell,
A receiver cell was filled with each solution. Donor-suitable
From 1 hour to 4 hours (applied for 3 hours), predetermined current
A constant current DC of density was provided. Dissolve receiver at predetermined time intervals
Take 200 μl of the sample as a sample, and
-The bar solution was returned to the receiver cell. This operation at 24:00
The sample collected is quantified by HPLC
The cumulative permeation amount Q of the compound A per unit area (μg /
cm ^Two). No current applied at all for reference
A permeation test was carried out in the same manner under the same experimental conditions except for Compound A.
Of accumulated permeation Q per unit area (μg / cm^Two)
Calculated. <Experimental conditions> Experimental apparatus: horizontal diffusion cell Skin membrane: female hairless mouse, intact abdominal skin, 8 weeks old Experimental temperature: constant temperature water circulation at 37 ° C. Donor solution: solution prepared in Example 1 Receiver solution: 0. 05M pH 6.8 phosphate buffered saline (PBS) Items to be studied: (1) Current density 0.001 mA / cm^Two3 hours application (2) Current density 0.01 mA / cm^Two, 3 hours application (3) Current density 0.3 mA / cm^TwoApplied for 3 hours (4) Current density 0.5 mA / cm^Two, 3 hours application (Reference example) No current application (0 mA / cm^Two)

Table 1 shows the obtained results. In Reference Example, Compound A did not permeate the skin at all, but when iontophoresis was applied, excellent skin permeation promoting properties were exhibited. In particular, at a current density of 0.01 mA / cm ² or more,
It shows better permeability.

[0067]

[Table 1]

Example 2 Compound A was added in an amount of 0.5% (W /
V), 0.5% (W / V) of nonanol, and 0.1% (W / V) of polyoxyethylene monolaurate as a surfactant.
/ V) and mixed and dissolved in pH 6.8 phosphate buffered saline to prepare a donor solution.

Example 3 0.5% (W /
V), and ethanol was adjusted to pH 20% (W / V).
6.8 The mixture was dissolved in phosphate buffered saline to prepare a donor solution.

Example 4 Compound A was added in an amount of 0.5% (W /
V), polyethylene glycol 400 at 20% (W /
V) was mixed and dissolved in phosphate buffered saline (pH 6.8) to prepare a donor solution.

Example 5 Compound A was added in an amount of 0.5% (W /
V) and capric acid were mixed and dissolved in a phosphate buffered saline (pH 6.8) to a concentration of 0.01% (W / V) to prepare a donor solution.

Example 6 Compound A 20 mg, polyacrylamide 500 mg, glycerin 2 g and water 7.48 g
Was added and uniformly mixed to prepare a gel-like preparation for iontophoresis.

Example 7 Compound A (20 mg), ethyl cellulose (250 mg), hydroxypropyl cellulose (2)
7.48 g of water was added to 50 mg and 2 g of glycerin, and mixed uniformly to prepare a gel-like preparation for iontophoresis.

Test Example 2 (Effect of accelerator and solvent: in
In vitro skin permeability test) Each of the solutions prepared in Examples 2 to 5 was used as a donor solution, and each was supplied with current at a current density of 0.1 mA / cm ^2. The skin permeability of Compound A from each donor solution was measured, and the cumulative permeation amount per unit area Q (μg / cm ² ) and skin permeation rate Flux (μg / cm ² / hr) were calculated. For reference, the skin permeability of Compound A from each donor solution when no electricity was supplied was measured in the same manner, and the cumulative permeation per unit area and the skin permeation rate were also calculated.

Table 2 shows the obtained results. As is evident from Table 2, the skin permeation further improved when combined with iontophoresis than when only the percutaneous absorption enhancer or solvent was added.

[0076]

[Table 2]

Examples 8 to 17, Comparative Examples 1 and 2 A predetermined amount of each of the polymer powders shown in Table 3 was mixed with glycerin (20% W /
W), added to purified water with stirring, and kept stirring until the polymer was dissolved. After leaving the obtained gel for 12 hours or more, compound A (0.5% W / W) was added,
Each formulation was prepared by mixing uniformly.

[0078]

[Table 3]

Example 18 Agarose (5% W / W)
Was added to purified water, heated to 80 ° C., and stirred and dissolved. After standing in a cool place for 12 hours or more, Compound A (0.5% W /
W) was added and mixed uniformly to prepare a preparation.

Comparative Example 3 A carboxyvinyl polymer (2% W / W) was added to purified water and stirred, and a small amount of triethylamine was added thereto to obtain a transparent gel.
After standing for 2 hours or longer, Compound A (0.5% W / W) was added and mixed uniformly to prepare a preparation.

Test Example 3 (Effect of water-soluble polymer; in v
In vitro skin permeability test) Using a vertical diffusion cell as an experimental device, each of the preparations of Examples 8 to 18 and Comparative Examples 1 to 3 was applied as a donor preparation to the donor side in an amount of 2.5 ml, and the current density was 0.3 mA. / Cm ²
The experiment was carried out in the same manner as in Test Example 1 except that the skin permeability of Compound A from each of the donor preparations was measured, and the cumulative permeation Q per unit area (μg / cm ² ) and skin permeation The speed Flux (μg / cm ² / hr) was calculated.

Table 4 shows the obtained results. As is clear from Table 4, the preparations using the other water-soluble polymers show superior skin permeability as compared with the preparations using the anionic polymer consisting only of an acidic group.

[0083]

[Table 4]

Example 19 Compound A was added at 3% (W /
W), 3% of poly-N-vinylacetamide (W /
W) and glycerin were mixed and dissolved in purified water so as to have a glycerin concentration of 20% (W / W), and uniformly mixed to prepare a gel iontophoresis preparation.

Example 20 Compound A 3% (W / W)
Poly-N-vinylacetamide 3% (W / W), capric acid 1.5% (W / W), nonanol 1.5% (W / W)
W), benzyl alcohol 10% (W / W), ethanol 74.5% (W / W), purified water 6.5% (W / W), and mixed until uniform, gel A preparation for iontophoresis was prepared.

Test Example 4 (in vitro using pig skin)
ro skin permeability test) Instead of hairless mouse skin, Yucatan mic
An experiment was conducted in the same manner as in Test Example 3 except that the preparations of Example 19 and Example 20 were used as donor preparations, using ropig skin (porcine skin), and the skin permeability of Compound A from each donor preparation was measured. Then, the accumulated permeation amount Q per unit area (μg / cm ² ) was calculated. For reference, the skin permeability of Compound A from each of the donor preparations when current was not applied at all was measured in the same manner, and the cumulative permeation amount per unit area and the skin permeation rate were calculated.

Table 5 shows the obtained results. As is evident from Table 5, those using iontophoresis in combination with those containing only a percutaneous absorption enhancer and / or a solvent show superior skin permeability.

[0088]

[Table 5]

[0089]

As described above, according to the present invention, it is possible to obtain a percutaneous absorption preparation by iontophoresis, which has excellent percutaneous absorption promoting properties and has antithrombotic, anticoagulant and other actions.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) // A61N 1/30 A61N 1/30

Claims (12)

[Claims] 1. An iontophore containing an aromatic amidine derivative represented by the following general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative.
Preparation for cis. Embedded image (1) [Wherein the following symbols indicate the following, respectively. R ¹ : hydrogen atom or lower alkoxyl group; R ² : hydrogen atom, lower alkyl group, lower alkoxyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group; R ³ : hydrogen atom, carboxyl group, alkoxy group A carbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group; R ⁴ : a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group or a lower alkoxyl group; A: 1 to 2 hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl groups which may have 1 to 4 carbon atoms. Alkylene group or a group represented by the formula ## STR2 ## In the formula, E represents a lower alkylene group or a carbonyl group, and R ⁵ represents a hydrogen atom or a formula -D-W-
A group represented by R ⁶ , wherein D is a group represented by the formula: Wherein Z represents an oxygen atom or a sulfur atom. 〉, The formula Wherein W 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 A lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanoyl group which may have a substituent. R ⁶ is 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 which may have a substituent. -Represents a benzyl group. X: a single bond, an oxygen atom, a sulfur atom or a carbonyl group; Y: a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, a substituent An amino group which may have or an aminoalkyl group which may have a substituent; A group represented by: a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl; 2. In the general formula (1), a saturated or unsaturated 5
The preparation for iontophoresis according to claim 1, wherein the heterocyclic group having 6 to 6 members is a group containing 1 to 2 nitrogen atoms or oxygen atoms as hetero atoms. 3. A compound represented by the general formula (1):
The preparation for iontophoresis according to claim 1 or 2, wherein the 6- to 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group. 4. An aromatic amidine derivative, a salt of the derivative,
A solvate of the derivative or a solvate of a salt of the derivative,
The preparation for iontophoresis according to any one of claims 1 to 3, wherein the preparation is one or more selected from the following groups. 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-
[((3S) -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- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] 2-naphthyl) propionic acid
-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] 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; N-
[N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycine; and a salt of each of the above compounds; a solvate of each of the above compounds; and a solvate of a salt of each of the above compounds. 5. An aromatic amidine derivative, a salt of the derivative,
A solvate of the derivative or a solvate of a salt of the derivative,
The preparation for iontophoresis according to any one of claims 1 to 4, wherein the preparation is one or more selected from the following groups. (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; 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. 6. The preparation further comprises at least one solvent.
The preparation for iontophoresis according to any one of claims 1 to 5, comprising at least one species. 7. The preparation for iontophoresis according to any one of claims 1 to 5, wherein the preparation further contains at least one or more of a solvent and a transdermal absorption enhancer. 8. The preparation for iontophoresis according to claim 6, wherein the solvent is one or more selected from water, lower alcohols and polyhydric alcohols. 9. The preparation for iontophoresis according to claim 7, wherein the percutaneous absorption enhancer is one or more selected from the group consisting of a saturated aliphatic alcohol having 2 or more carbon atoms and a higher fatty acid. . 10. The preparation for iontophoresis according to any one of claims 1 to 9, further comprising at least one kind of a thickener in the preparation. 11. The thickener is one or two selected from the group consisting of polyacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene oxide, poly-N-vinylacetamide, and agarose. The preparation for iontophoresis according to claim 10, which is the above water-soluble polymer. 12. A current density of 0.001 to 0.5 mA / c.
^{2. An} iontophoresis is performed by supplying electricity at m2.
12. The preparation for iontophoresis according to any one of items 11 to 11.