JPH11189531A - Pharmaceutical composition for transmucosal administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of maintaining the effective blood level over a long period and having antithrombotic and anticoagulant actions by including a specific aromatic amidine derivative and a transmucosal absorbefacient therein. SOLUTION: This composition is obtained by including (A) an aromatic amidine derivative represented by formula I [R<1> is H or the like; R<2> is carboxyl or the like; R<3> is H or the like; R<4> is a halogen or the like; (n) is 0-4; A is carboxyl or the like; X is a single bond or the like; Y is a (substituted)amino or the like; a group represented by formula II is indolyl or the like], its salt or solvate or a solvate of the salt of the derivative and (B) a transmucosal absorbefacient (sodium lauryl sulfate and glycerol monocaprylate or the like). In the composition, 0.0001-60 wt.% ingredient A and 0.0001-60 wt.% ingredient B are contained and the ingredient B is preferably formulated in an amount of 0.01-100 times based on the ingredient A and expressed in terms of weight ratio.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for transmucosal administration of an aromatic amidine derivative which is useful as a blood coagulation inhibitor and an agent for preventing and treating thrombus.

[0002]

2. Description of the Related Art 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. Is disclosed in JP-A-5-208946.
And WO96 / 16940.

Hitherto, 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, it is an object of the present invention to provide a new administration form of the aromatic amidine derivative.

[0005]

The inventors of the present invention have conducted various studies on the absorbability of the above-mentioned aromatic amidine derivatives by transmucosal administration. Surprisingly, the present inventors have found that this compound and a transmucosal absorption enhancer can be used. It has been found that, when used in combination, this compound is efficiently absorbed from mucous membranes such as the oral cavity and vagina, and the effective blood concentration is maintained for a long time, and the present invention has been completed.

That is, the present invention provides a compound represented by the general formula (1)

[0007]

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Wherein R ¹ represents a hydrogen atom or a lower alkoxyl group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group. , R ³ is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group,
R ⁴ represents 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, and n represents 0 to 5; an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group; 4 represents the number, A is 1-2
Hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group optionally having 1 to 4 carbon atoms,

[0009]

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Wherein 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

[0011]

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(Wherein Z represents an oxygen atom or a sulfur atom);

[0013]

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[0014] represents a group or a sulfonyl group represented by, W is a single bond or -NR ⁷ - in a group represented by (wherein, R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, mono- - or di - lower 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
Reference numeral 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. Group, an amino group which may have a substituent or an aminoalkyl group which may have a substituent,

[0015]

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The group represented by represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl.
And a solvate of the derivative, a solvate of the derivative or a solvate of a salt of the derivative, and a transmucosal pharmaceutical agent for transmucosal administration. .

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The aromatic amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative used in the composition of the present invention can be used as described above for blood coagulation. It is known that it inhibits factor X and is useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for blood clots (JP-A-5-208946 and WO 96/16940).

In the above formula (1), the lower alkyl group may be any of linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and specific examples include 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. 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, mono- Or a di-lower alkylaminocarbonyl group.

The lower alkoxyl group may have 1 to 1 carbon atoms.
6, and specific examples include a methoxyl group, an ethoxyl group, a propoxyl group, an isopropoxyl group, a butoxyl group, a secondary butoxyl group and a tertiary butoxyl group.

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 carboxymethoxyl, carboxyethoxyl, and carboxypropoxyl groups. Examples of the alkoxycarbonylalkoxyl group include methoxycarbonylmethoxyl, ethoxycarbonylmethoxyl, propoxycarbonylmethoxyl, and methoxycarbonyl. An ethoxyl group and an ethoxycarbonylethoxyl group are exemplified.

Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group and a hydroxybutyl group. C 1-4
Examples of the alkylene group 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 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. And a disubstituted asymmetric dialkylaminocarbonyl group.

The lower alkylsulfonyl group includes 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 symmetric dialkylaminothiocarbonyl group di-substituted with a lower alkyl group such as a dibutylaminothiocarbonyl group or a dipentylaminothiocarbonyl group; and an ethylmethylaminothiocarbonyl group, a methylpropylaminothiocarbonyl group, an ethylpropylaminothio group. Asymmetric dialkylaminothiocarbonyl groups disubstituted with different lower alkyl groups such as carbonyl group, butylmethylaminothiocarbonyl group, butylethylaminothiocarbonyl group, and butylpropylaminothiocarbonyl group are exemplified.

The lower alkanoyl group includes formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, etc., preferably acetyl group, propionyl group, butyryl group. And more preferably an acetyl group or a propionyl group. The lower alkanoyl group may have a substituent.

The group which can be substituted with 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, aryl group, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, lower alkylthiocarbonyl group, hydroxyl group, carbamoyl group, mono- or di-lower alkylaminocarbonyl group, etc. .

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, a quinolyl group,
Isoquinolyl group, quinazolinyl group, quinolizinyl group, quinoxalinyl group, cinnolinyl group, benzimidazolyl group, imidazopyridyl group, benzofuranyl group, naphthyridinyl group, 1,2-benzoisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxa Zolopyridyl group, isothiazolopyridyl group, benzothienyl group and the like, preferably furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyridyl group and the like, and the aryl group may have a substituent. Good.

The aryl group or the heteroaryl group may be substituted with a halogen atom, a carboxyl group, an amino group, a cyano group, a nitro group, a hydroxyl group,
Examples include a lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino group, a lower alkanoyl group, and 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 heterocycles include pyrrolidine, piperidine,
Examples thereof include imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, and morpholine. Of these, pyrrolidine and piperidine are particularly preferable. 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, 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 on 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.

The group which can be substituted on the amino portion 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, and the alkyl, alkoxyl and alkanoyl groups in each substituent preferably have 1 to 6 carbon atoms.

[0036]

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As the group represented by benzofuranyl,
Particularly preferred are groups selected from benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.

The aromatic amidine derivative represented by the general formula (1) according to the present invention, a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative 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, among the above-mentioned aromatic amidine derivatives (1), salts of the derivatives, solvates of the derivatives or solvates of the salts of the derivatives, the following compounds,
The salts or solvates thereof are preferred. 2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[((3
S) -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-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-[((3
S) -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.

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, 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, a salt thereof or a solvate thereof.

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] sulfamoylatic acid dihydrochloride is also preferred.

The substance (transmucosal absorption enhancer) which promotes transmucosal absorption of the above-mentioned amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative is Alcohol, higher alkanes, higher fatty acids,
One or more selected from polyhydric alcohol fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylene alkyl ethers, sulfoxides and amides. Among them, one or more selected from higher alcohols, higher fatty acids, polyhydric alcohol fatty acid esters, alkyl sulfates, alkylamine oxides, carboxybetaines and polyoxyalkylene alkyl ethers are more preferable. One or more selected from sulfates and polyhydric alcohol fatty acid esters are more preferable, and a combination of alkyl sulfates and polyhydric alcohol fatty acid esters is particularly preferable.

Among the above-mentioned transmucosal absorption enhancers, the higher alcohol is preferably a saturated aliphatic alcohol having 6 to 16 carbon atoms, and specific examples thereof include 1-octanol, 1-nonanol, 1-decanol and 1-dodecanol. No.

The higher alkane is preferably an alkane having 6 to 12 carbon atoms, and specific examples include n-heptane and n-heptane.
-Nonane, n-dodecane and the like.

As the higher fatty acid, a saturated or unsaturated fatty acid having 6 to 18 carbon atoms is preferable.
Sixteen saturated or unsaturated fatty acids are more preferred. Specific examples of higher fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and oleic acid.

As the polyhydric alcohol fatty acid ester,
C6-24 fatty acid esters of polyhydric alcohols are preferred, and C6-16 fatty acid esters of polyhydric alcohols are more preferred. Here, examples of the polyhydric alcohol include ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin, and sorbitan.
In addition, fatty acids that form esters with these polyhydric alcohols include caproic acid, caprylic acid, capric acid,
Lauric acid, myristic acid and the like.

Of these polyhydric alcohol fatty acid esters, polyhydric alcohol monofatty acid esters are preferable, glycerin monofatty acid ester is more preferable, and glycerin mono C ₆ -C ₁₄ fatty acid ester is further preferable. As specific examples of glycerin monofatty acid ester,
Examples include glyceryl monocaproate, glyceryl monocaprylate, and glyceryl monocaprate, among which glyceryl monocaprylate is particularly preferred.

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

As the alkyl sulfates, alkyl sulfates having 6 to 24 carbon atoms are preferable, and decyl sulfate, lauryl sulfate, tetradecyl sulfate and the like can be mentioned. Of these, alkali metal lauryl sulfate is more preferable. And sodium lauryl sulfate are particularly preferred.

As the alkylamine oxides, alkyldimethylamine oxides are preferred, having 6 to 6 carbon atoms.
Alkyl dimethyl amine oxides of 24 are more preferable, and specific examples include decyl dimethyl amine oxide, lauryl dimethyl amine oxide, tetradecyl dimethyl amine oxide and the like.

As carboxybetaines, alkyldimethylaminoacetic acids are preferable, and alkyldimethylaminoacetic acids having 6 to 24 carbon atoms are more preferable. Specific examples thereof include decyldimethylaminoacetic acid, dodecyldimethylaminoacetic acid, and tetradecyldimethylaminoacetic acid.

Examples of the polyoxyalkylene alkyl ethers include polyoxyethylene alkyl ether and polyoxypropylene alkyl ether.
Polyoxyethylene alkyl ethers are preferred, and polyoxyethylene C ₆ -C _{2 4} alkyl ether. Sulfoxides include dialkyl sulfoxides, for example, dimethyl sulfoxide. As amides, N, N-alkylacetamide, N,
N-dialkyltoluamide, N-hydroxyalkyl lactamide, and the like, more specifically, N, N-
Dimethylacetamide, N, N-diethyltoluamide,
N-hydroxyethyl lactamide and the like.

Among the above transmucosal absorption enhancers, 1-nonanol, 1-decanol, caproic acid, caprylic acid, capric acid, propylene glycol monocaprylate, glyceryl monocaprylate, lauryl dimethylamine oxide, dodecyl N, N -One or more combinations selected from dimethylaminoacetic acid, sodium lauryl sulfate and polyoxyethylene lauryl ether are more preferred, and a combination of sodium lauryl sulfate and glyceryl monocaprylate is particularly preferred.

In the pharmaceutical composition for transmucosal absorption of the present invention, the aromatic amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative with a percutaneous absorption enhancer. Although the ratio is not particularly limited, the transmucosal absorption enhancer is preferably 0.01 to 100 times by weight to the aromatic amidine derivative (1) or a salt thereof, and 0.1 to 1 times.
0 times is more preferable, and 0.2 to 5 times is particularly preferable.

The amount of the aromatic amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of the salt of the derivative in the composition of the present invention varies depending on the dosage form and the like. Is preferably 0.0001 to 60% by weight,
001 to 50% by weight is more preferable, and 0.1 to 30% by weight is particularly preferable. The amount of transmucosal absorption enhancer
The total amount is preferably 0.0001 to 60% by weight,
1 to 50% by weight is more preferable, and 0.1 to 50% by weight is particularly preferable. When two transmucosal absorption promoters are used in combination, the mixing ratio is not particularly limited, but is preferably 1/30 to 30/1 by weight.

The dosage form of the composition of the present invention is not particularly limited as long as it can be absorbed transmucosally. For example, sublingual tablets, sublingual capsules, vaginal tablets, ointments, creams,
Gels, pastas, patches and the like can be mentioned. In preparing these preparations, various conventionally known pharmaceutically acceptable carriers (additives) can be blended.

Such additives include excipients, disintegrants,
Examples include binders, lubricants, flow agents, ointment bases, emulsifiers, suspending agents, preservatives, stabilizers, water and the like.

The composition of the present invention may be administered so as to be absorbed from mucous membranes such as the oral mucosa and vaginal mucosa, but is more preferably absorbed from the oral mucosa, and is preferably used, for example, as a patch for oral mucosa. .

[0060]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3-
(7-amidino-2-naphthyl) propion hydrochloride
10 mm for 5 mg of pentahydrate (hereinafter referred to as compound A)
The drug layer solution was dissolved at a ratio of 50 μl of a phosphate buffer solution containing sodium lauryl sulfate, which is a ol / l transmucosal absorption promoter, to obtain a drug layer solution. Separately, 0.2 g of polyvinylpyrrolidone and 0.2 g of carboxyvinyl polymer were mixed using a tableting machine,
It was compressed into a donut shape. Next, a film for coating this adhesive layer (trade name: Eudragged NE30D, manufactured by Rohm)
Covered one side of the mucosal layer to obtain an adhesive layer. 50 μl of the drug layer solution was injected into the hollow portion of the adhesive layer to obtain a transmucosal preparation containing a transmucosal absorption enhancer.

Comparative Example 1 A 5 mg compound A was dissolved at a ratio of 50 μl of a phosphate buffer to obtain a drug layer solution. Separately, polyvinylpyrrolidone 0.2
g and 0.2 g of the carboxyvinyl polymer were mixed and tabletted into a donut shape using a tableting machine. Next, the adhesive layer was coated on one side of the adhesive layer with a coating film (trade name: Eudragged NE30D, manufactured by Laem) to obtain an adhesive layer. 50 μl of the drug layer solution was injected into the hollow portion of the adhesive layer to obtain a transmucosal preparation containing no transmucosal absorption enhancer.

Test Example 1 The transmucosal absorption preparations obtained in Example 1 and Comparative Example 1 were applied to the upper part of the inside of both dogs of a beagle dog that was fixed in a dorsal position under pentobarbital anesthesia. , 6 and 8 hours plasma concentrations were determined by radioimmunoassay.

As a result, as shown in FIG. 1, the preparation containing no transmucosal absorbent of Comparative Example 1 had an effective blood concentration (100 ng).
/ Ml), but the transmucosal absorption preparation containing the transmucosal absorption enhancer of Example 1 had an effective blood concentration of about 2.
It showed a 5-fold increase in drug absorption and showed an effective blood concentration of 7 hours or more after administration.

[0065]

According to the present invention, there is obtained a pharmaceutical composition for transmucosal absorption having an antithrombotic and anticoagulant effect, which has high transmucosal absorbability and can maintain an effective blood concentration for a long time. be able to.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a view showing the results of an oral mucosa absorption test in dogs.
The vertical axis represents the drug concentration in plasma (ng / ml), and the horizontal axis represents time (hour).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/38 A61K 31/38 31/40 ACB 31/40 ACB 31/415 31/415 31/425 31/425 31/445 31 / 445 47/12 47/12 E // C07D 207/12 C07D 207/12 211/44 211/44

Claims (19)

[Claims] 1. A compound of the general formula (1) 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, A represents 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups. Alkylene group or a group represented by the formula of 1 to 4 carbon atoms which may be embedded image 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), a compound represented by the formula: And W represents 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.) And R ⁶ represent 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), an aromatic amidine derivative represented by the formula: A pharmaceutical composition for transmucosal administration comprising a solvate of a derivative or a solvate of a salt of the derivative and a transmucosal absorption enhancer. (2) In the general formula (1), Is a group represented by benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl,
The composition according to claim 1, which is a group selected from naphthyl and tetrahydronaphthyl. 3. A compound represented by the general formula (1):
The composition according to claim 1, wherein the 6- to 6-membered heterocyclic group is a group containing 1 to 2 nitrogen atoms or oxygen atoms as hetero atoms. 4. A compound represented by the formula (1):
The composition according to claim 2 or 3, wherein the 6- to 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group. 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 composition according to any one of claims 1 to 4, which is a compound selected from the following group, a salt thereof, or a solvate thereof. 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-[((3
R) -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. An aromatic amidine derivative, a salt of the derivative,
A solvate of the derivative or a solvate of a salt of the derivative,
The composition according to any one of claims 1 to 5, which is selected from the following group. (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, 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. The transmucosal absorption enhancer comprises a higher alcohol,
One or two selected from higher alkanes, higher fatty acids, polyhydric alcohol fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylene alkyl ethers, sulfoxides and amides The composition according to any one of claims 1 to 6, which is the above. 8. The composition according to claim 7, wherein the higher alcohol is a saturated aliphatic alcohol having 6 to 16 carbon atoms. 9. The composition according to claim 7, wherein the higher alkane is an alkane having 6 to 12 carbon atoms. 10. The composition according to claim 7, wherein the higher fatty acid is a saturated or unsaturated fatty acid having 6 to 18 carbon atoms. 11. The polyhydric alcohol fatty acid ester,
The composition according to claim 7, which is an ester of a polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms. 12. The composition according to claim 7, wherein the terpene is selected from cineol, 1-menthol, menthone, d-limonene and nerolidol. 13. An alkyl sulfate having 6 carbon atoms.
8. The composition according to claim 7, which is an alkyl sulfate salt of from 24 to 24. 14. The composition according to claim 7, wherein the alkylamine oxide is an alkyldimethylamine oxide having 6 to 24 carbon atoms. 15. A carboxybetaine having 6 to 6 carbon atoms.
The composition according to claim 7, which is 24 alkyldimethylaminoacetic acids. 16. The composition according to claim 7, wherein the polyoxyalkylene alkyl ether is a polyoxyethylene alkyl ether. 17. The composition according to claim 7, wherein the sulfoxide is dialkyl sulfoxide, and the amide is N, N-dialkylacetamide, N, N-dialkyltoluamide or N-hydroxyalkyl lactamide. 18. The composition according to claim 7, wherein the transmucosal absorption enhancer is a combination of an alkyl sulfate ester salt and a polyhydric alcohol fatty acid ester. 19. The composition according to claim 7, wherein the transmucosal absorption enhancer is a combination of sodium lauryl sulfate and glyceryl monocaprylate.