JPH10231254A - Pharmaceutical composition for improving oral absorption - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of efficiently and safely absorbing a medicine having low oral absorption property by adding a specific hydrophilic substance to the medicine. SOLUTION: This pharmaceutical composition is obtained by adding a hydrophilic substance such as a glycerol ester of a fatty acid to a medicine [e.g. an aromatic amidine derivative of the formula (R<1> is H, a lower alkoxy, etc.; R<2> is H, a lower alkyl, etc.; R<3> is H, carboxyl, etc.; R<4> is H, a halogen, etc.; (n) is 0-4; A is one or two hydroxyalkyl groups, carboxyl, etc.; X is a single bond or O; Y is a (substituted) 5-6 membered heterocyclic group, etc.)]. A formulation amount of the hydrophilic substance in the composition is preferably 0.1-5g, based on 1g medicine. Oral absorption property of the medicine can be improved by further adding preferably 0.1-10mol cyclodextrins (e.g. β-cyclodextrin) to 1mol of the medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for improving the oral absorption of a drug which is hardly absorbed by oral administration.

[0002]

2. Description of the Related Art Some drugs do not have the expected pharmacological effects by oral administration due to low absorption in the digestive tract.

[0003] Intravenous or intramuscular injection of these drugs having low oral absorbability has been conventionally performed. However, in the case of administration by injection, in addition to pain and muscular disorder, it is complicated to use. There are various problems.

[0004] In order to solve these problems, there have been proposed methods utilizing the absorption promoting effect of various additives (absorption promoters). However, depending on the absorption enhancer, its use can cause mucosal damage. Furthermore, improving the permeability of the digestive tract membrane, which is one of the barriers of the living body, is to absorb various components unnecessary for the living body,
In addition, the absorption enhancer itself may be toxic due to absorption, which may cause safety problems.

[0005] As described above, a method for efficiently absorbing a drug having low oral absorbability and having high safety has not been obtained by the prior art.

[0006]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned drawbacks of the prior art, and has as its object to provide a pharmacological effect which can be expected by oral administration because of its low absorption in the digestive tract. The goal is to improve the oral absorption of drugs that cannot be obtained in a safe manner.

[0007]

Means for Solving the Problems The present inventors diligently studied a solution for improving the oral absorption of a drug which cannot obtain the expected pharmacological effect by oral administration. As a result, by adding lipophilic substances such as glyceryl esters of fatty acids and glycerin, which are widely used as foods and pharmaceuticals and have been confirmed to be highly safe,
The present inventors have found that oral absorption of a drug is improved, and completed the present invention.

[0008] Further, by adding cyclodextrins widely used as foods and pharmaceuticals and confirmed to be highly safe in addition to lipophilic substances, the oral absorption of the drug is further improved. The present invention has been completed.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to (1) a pharmaceutical composition containing a drug and a lipophilic substance, and (2) a pharmaceutical composition containing a drug, a lipophilic substance and cyclodextrins. .

Hereinafter, the present invention will be described.

In the present invention, the drug is not particularly limited, and extracts (extracts, tinctures, etc.) of naturally derived crude drugs, compounds isolated from the extracts, chemically synthesized compounds, etc. Including. The drug may be a single component or a mixture of two or more. When the drug is a compound, it includes a salt of the compound, various pharmaceutically acceptable solvates of the compound (for example, water), and a solvate of a salt of the compound. It also includes these polymorphs.

When an asymmetric carbon is present in the structure of a compound and an optical isomer or a stereoisomer based on the asymmetric carbon is present, any of these optical isomers, stereoisomers and mixtures of these isomers are included in the present invention. included.

The salt of the compound is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, hydroiodide, phosphorus Acid salts, nitrates, mineral salts such as sulfates, methanesulfonate, 2-hydroxyethanesulfonate, organic sulfonates such as p-toluenesulfonate, acetate, propionate, oxalate, Organic carboxylates such as malonate, succinate, glutarate, adipate, tartrate, maleate, malate, and mandelate can be mentioned.

In the present invention, the drug is not particularly limited. For example, a drug that has sufficient pharmacological effects even when administered orally despite its low absorption in the gastrointestinal tract can reduce the dose of the drug and reduce side effects by increasing the oral absorption It is. In addition, a drug that does not have a sufficient pharmacological effect by oral administration due to low absorption in the digestive tract can have a promising pharmacological effect by increasing the oral absorption. In general, many drugs having low absorption in the digestive tract have high hydrophilicity.

In the present invention, as the drug, particularly, a basic compound can be mentioned. The basic compound as a drug means a compound having one or more basic groups such as an amino group and an amidino group in its chemical structure.
The position of the basic group in the chemical structure is not particularly limited. For example, the basic group may be present at or near the center of the chemical structure, may be present only at one end or its vicinity, or may be present at both ends or its vicinity. .

In the present invention, the aromatic amidine derivative as a drug is included in the basic compounds described above, and means a compound having an aromatic amidine structure in the chemical structure. Specifically, a derivative represented by the general formula (1), a salt of the derivative, a solvate of the derivative, a solvate of the derivative, and the like described in JP-A-5-208946 and WO 96/16940. Solvates of the salts of the derivatives and the compounds shown below can be mentioned.

[0017]

Embedded image

These compounds are already known and can be produced by a known production method.

Among them, a 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 is preferable as the drug.

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 may have a carbon number of Any of linear, branched or cyclic alkyl groups of 1 to 6 may be mentioned, and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a secondary butyl group, Tertiary butyl group,
Examples include a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

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.

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.

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 a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, and a hexanoyl 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.

The heteroaryl group includes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl. , 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,
Preferably, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyridyl group and the like can be mentioned, and the aryl group may have a substituent.

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 thereof 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 or oxygen atoms as a hetero atom. 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 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 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.

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.

Also,

[0040]

Embedded image The group represented by is preferably a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, 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, among the above-mentioned aromatic amidine derivatives, salts of the derivatives, solvates of the derivatives or solvates of the salts of the derivatives, the derivatives represented by the general formula (1), Or a solvate of the derivative or a solvate of the salt of the derivative is preferable as the drug, and among them, the following are preferable.

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-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-
Acetimidyl-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, 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 and N- [N-4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl] glycine.

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 lipophilic substance in the present invention is a substance having a low affinity for water, and examples thereof include higher alcohols, fatty acids, fatty acid salts, esters of fatty acids with alcohols or polyhydric alcohols, and the like. it can. These are also widely present as components of fats and oils, lipids and the like in the natural animal and plant kingdoms. Natural fats and oils and natural lipids containing these can also be mentioned as lipophilic substances in the present invention.

Hereinafter, higher alcohols, fatty acids, fatty acid salts, esters of fatty acids with alcohols or polyhydric alcohols as lipophilic substances in the present invention will be described.

Examples of the lipophilic higher alcohol include linear, branched or cyclic alcohols having 6 or more carbon atoms, such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, and 2-octyldodecanol. And 2-hexyldecanol.

The lipophilic fatty acid includes 6 to 13 carbon atoms.
Saturated or unsaturated medium-chain fatty acids having 14 to 2 carbon atoms
2, long-chain fatty acids of saturated or unsaturated type, for example, medium-chain fatty acids such as caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, undecylenic acid and lauric acid. Can be.

Further, as long-chain fatty acids, myristic acid,
Pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linoleic acid,
Linolenic acid, nonadecanoic acid, arachinic acid, eicosenoic acid, arachidonic acid, behenic acid and the like can be mentioned.

Examples of the fatty acid salts include alkali metal salts and alkaline earth metal salts of the above fatty acids.
Examples of the alkali metal salt include a sodium salt and a potassium salt, and examples of the alkaline earth metal salt include a magnesium salt and a calcium salt. Specific examples include sodium caproate, sodium caprylate, sodium myristate, sodium palmitate and the like.

Examples of the esters of fatty acids with alcohols or polyhydric alcohols include the esters of the above fatty acids with alcohols or polyhydric alcohols. The alcohol here is a linear, branched or cyclic monohydric alcohol having 1 to 8 carbon atoms, and examples thereof include methanol, ethanol, isopropanol and butanol. The polyhydric alcohol is not particularly limited as long as it is a compound having two or more alcoholic hydroxyl groups in a molecule, and specifically, ethylene glycol, polyethylene glycol, propylene glycol, and polypropylene glycol , Glycerin, polyglycerin, sorbitan and the like. Of these, glycerin and polyglycerin are preferred in the present invention.

Specific examples of esters of fatty acids and alcohols include butyl myristate, isopropyl palmitate, methyl stearate, ethyl linoleate and the like.

Examples of esters of fatty acids and polyhydric alcohols include fatty acid ethylene glycol ester, fatty acid propylene glycol ester, fatty acid polyethylene glycol ester, fatty acid polypropylene glycol ester, fatty acid glycerin ester, fatty acid glycerin acetate, fatty acid glycerin lactate, Examples include fatty acid glycerin citrate, fatty acid glycerin succinate, fatty acid glycerin diacetyl tartaric acid ester, and fatty acid polyglycerin ester.

The ester of a fatty acid and a polyhydric alcohol is
When one or more hydroxyl groups of the polyhydric alcohol and the fatty acid are ester-bonded and a plurality of hydroxyl groups are ester-bonded to the fatty acid, the fatty acids may be the same or different. As fatty acids that form esters with polyhydric alcohols, medium-chain fatty acids and long-chain fatty acids are preferred.

In the present invention, among esters of fatty acids and polyhydric alcohols, esters of fatty acids with glycerin or polyglycerin are preferable, and esters of medium-chain or long-chain fatty acids with glycerin or polyglycerin are particularly preferable. preferable.

Specifically, glyceryl caproate, glyceryl caprylate, glyceryl caprate, glyceryl palmitate, glyceryl stearate and hydrogenated tallow fatty acid glyceride can be mentioned. Glycerin caprate ester is preferred.

In the present invention, the lipophilic substance may be a single component or a mixture of two or more.

The lipophilic substance of the present invention is preferably an ester of a fatty acid and a polyhydric alcohol, and more preferably a glyceryl ester of a fatty acid and glycerin or polyglycerin. Among them, glyceryl esters of fatty acids and glycerin are more preferred. Among them, glyceryl esters of medium-chain fatty acids and glycerin, and glyceryl esters of long-chain fatty acids and glycerin are preferred, particularly triglyceryl esters of medium-chain fatty acids and glycerin, monoglyceryl esters of long-chain fatty acids and glycerin, and long Triglyceryl esters of chain fatty acids and glycerin are preferred.

Specifically, glyceryl tricaprylate, glyceryl tricaprate, hydrogenated tallow fatty acid triglyceride, glyceryl tripalmitate and glyceryl monostearate are preferable, and a mixture of glyceryl tricaprylate and glyceryl tricaprate, Particular preference is given to mixtures of glyceryl tricaprylate, glyceryl tricaprate and hydrogenated tallow fatty acid triglycerides, glyceryl tricaprylate, glyceryl tricaprate and glyceryl monostearate.

The blending amount (blending ratio) of the lipophilic substance in the pharmaceutical composition of the present invention may be appropriately adjusted depending on the kind of the drug, etc. Is preferable, and the amount is more preferably 0.5 to 15 times.

By adding a lipophilic substance to the drug,
Although the oral absorption of a drug is improved, the addition of cyclodextrins can further improve the oral absorption of a drug.

The term “cyclodextrin” in the present invention means a group consisting of cyclodextrin and a derivative of cyclodextrin. Specifically, examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives of these cyclodextrins.

The cyclodextrins of the present invention include:
Water-soluble cyclodextrins are preferable, and examples thereof include water-soluble β-cyclodextrin and water-soluble γ-cyclodextrin, and water-soluble derivatives of these cyclodextrins. β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, methyl-
β-cyclodextrin, methyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-
γ-cyclodextrin, sulfobutyl-β-cyclodextrin, sulfobutyl-γ-cyclodextrin and the like.In the present invention, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl- β-cyclodextrin is preferred, and β-cyclodextrin is particularly preferred.

The amount of the cyclodextrin in the pharmaceutical composition of the present invention may be appropriately adjusted depending on the type or the amount of the drug and the lipophilic substance, and the higher the amount of the cyclodextrin, the higher the absorption. An improvement effect can be expected. The amount (mixing ratio) is preferably from 0.1 to 10 mol, more preferably from 0.3 to 7 mol, per 1 mol of the drug.

In the present invention, a particularly preferred pharmaceutical composition is (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl]-
Pharmaceutical composition containing 3- (7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate, lipophilic substance and cyclodextrins, (+)-2- [4-[(1
Pharmaceutical composition containing -acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid dihydrochloride, a lipophilic substance and cyclodextrins, (+)- 2- [4-[((2
S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, lipophilic substances and cyclodextrins Pharmaceutical compositions,
N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoylacetic acid dihydrochloride, a pharmaceutical composition containing a lipophilic substance and cyclodextrins, ethyl N- [N- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Pharmaceutical compositions containing phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride, lipophilic substances and cyclodextrins, and N- [N-4-[(1 -Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-
Pharmaceutical composition containing amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride, a lipophilic substance and cyclodextrins.

Among them, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Pharmaceutical compositions containing propionic acid hydrochloride pentahydrate, lipophilic substances and cyclodextrins are particularly preferred.

Since the pharmaceutical composition of the present invention contains a drug, especially a water-soluble drug and a lipophilic substance, the possible forms of the preparation include semisolid preparations such as emulsion preparations, suspensions and gel preparations. Can be mentioned. In addition, these emulsion preparations, suspensions and semisolid preparations such as gels may be in the form of capsules filled in capsules such as microcapsules, soft capsules and hard capsules. Capsules are preferred in consideration of the patient's ease of taking and the like.

For preparation of the preparation, it can be produced by a generally known method, and may include an excipient, a disintegrant, a binder, a lubricant, a flow agent, a dispersant, a suspending agent, an emulsifier,
Pharmaceutical additives such as preservatives and stabilizers can be added as appropriate.

Examples are shown below, but the present invention is not limited by these examples.

[0071]

【Example】

Comparative Example 1 (2S) -2- [4-[((3S) -1-
Acetimidyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propion hydrochloride pentahydrate (hereinafter abbreviated as compound A).
5 mg was dissolved in 0.5 ml of physiological saline, and rat (SD male rat, 8 weeks old, body weight 230-270 g,
n = 5), orally administered using an oral probe under no anesthesia. After administration, the animals were anesthetized with ether for 0.5, 1, 2, 4 and 8 hours, blood was collected from the jugular vein, and the compound A in the obtained plasma was measured by high performance liquid chromatography (HPLC). The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) were determined from the change in the plasma concentration of the obtained compound A.

Compound A is disclosed in JP-A-5-20894.
As described in Japanese Patent Publication No. 6 (1994), it inhibits blood coagulation factor X and is useful as a blood coagulation inhibitor or an agent for preventing or treating thrombus.

Example 1 0.5 mg of Compound A was added to 0.5 mg
ml of medium-chain fatty acid triglyceride (mixture of glycerin tricaprylate and glyceryl tricaprate) [trade name: Miglyol 812 neutral oil, Mitsuba Trading Co., Ltd.], and orally administered to rats in the same manner as in Comparative Example 1. After administration, blood was collected and compound A in plasma was measured to determine AUC and Cmax.

Example 2 0.5 mg of Compound A was mixed with 6.38 mg of β-cyclodextrin in a molar ratio of 5 times the amount of Compound A, and 0.5 ml of medium-chain fatty acid triglyceride [trade name: Miglyol] 812 neutral oil (mixture of glyceryl tricaprylate and glyceryl tricaprate), Mitsuba Trading Co., Ltd.), and orally administered to rats in the same manner as in Comparative Example 1, blood was collected, and blood was collected. Compound A was measured to determine AUC and Cmax.

Example 3 7.29 mg of γ-cyclodextrin was added in place of β-cyclodextrin in Example 2, and the mixture was orally administered to rats in the same manner as in Comparative Example 1, and blood was collected. , AUC and Cmax were determined by measuring compound A in plasma.

Example 4 In Example 2, olive oil was used instead of the medium-chain fatty acid triglyceride, and the mixture was orally administered to rats in the same manner as in Comparative Example 1, blood was collected, and compound A in plasma was collected. AUC and Cmax
I asked.

Example 5 Instead of the medium-chain fatty acid triglyceride in Example 2, a mixture of medium-chain fatty acid triglyceride and tripalmitic acid glycerin ester (medium-chain fatty acid triglyceride: tripalmitic acid glycerin ester = 9: 1 (weight) Ratio)) and orally administered to rats in the same manner as in Comparative Example 1, blood was collected, and compound A in plasma was measured to determine AUC and Cmax.

Table 1 shows AUC and Cmax obtained in Comparative Example 1 and Examples 1 to 5.

[0079]

[Table 1]

[Comparative Example 2] Compound A was dissolved in physiological saline, and the compound was dissolved in a monkey (female, wild cynomolgus monkey, body weight of 2.4 to 3.3 kg, n = 4) at 2 mg / m1 / kg. Under anesthesia, it was orally administered using an oral mergen tube. At 0.5, 1, 2, 3, 4, and 8 hours after the administration, blood was collected from the femoral vein, and the concentration of Compound A in the obtained plasma was measured by radioimmunoassay. From the change in the plasma concentration of the obtained compound A, AUC and Cma
x was determined.

Example 6 A 6-mg compound A was mixed with 62.8 mg of β-cyclodextrin in a molar ratio of 4.1 times, and 70.3 mg of a medium-chain fatty acid triglyceride (trade name: Miglyol 812 neutral oil, The suspension in Mitsuba Trading Co., Ltd.) was filled in a gelatin capsule (No. 5), and one capsule was orally administered to monkeys. Blood was collected in the same manner as in Comparative Example 2 to obtain Compound A in plasma. AUC and Cmax were determined by measurement.

Example 7 6 mg of Compound A was mixed with 30.6 mg of β-cyclodextrin in a molar ratio of 2.0 times, and 89.4 mg of medium-chain fatty acid triglyceride (trade name: Miglyol 812 neutral oil, Seamless microcapsules (diameter 2 mm) suspended in Mitsuba Trading Co., Ltd.)
, And microcapsules were orally administered so that the dose of Compound A was 6 mg / head, blood was collected in the same manner as in Comparative Example 2, and Compound A in the plasma was measured.
C and Cmax were determined.

Example 8 Instead of the medium chain fatty acid triglyceride in Example 6, a medium chain fatty acid triglyceride and a hydrogenated tallow fatty acid triglyceride (trade name: Tr
Example 6 using 70.3 mg of a mixture (ifat T52, Nikko Chemical Co., Ltd.) (medium chain fatty acid triglyceride: hydrogenated tallow fatty acid triglyceride = 9: 1 (weight ratio)).
A monkey was orally administered to the monkey in the same manner as described above, blood was collected, and compound A in plasma was measured to determine AUC and Cmax.

Example 9 Instead of the medium chain fatty acid triglyceride in Example 6, medium chain fatty acid triglyceride and glyceryl monostearate (trade name: C
Using a mixture of UTINA GMS-RP (Henkel) (medium chain fatty acid triglyceride: glyceryl monostearate = 19: 1 (weight ratio): 70.3 mg, orally administered to monkeys in the same manner as in Example 6, Blood was collected and AUC and Cmax were determined by measuring Compound A in plasma.
I asked.

Example 10 The mixture 7 of Example 9 except that the mixing ratio of the medium chain fatty acid triglyceride to the glyceryl monostearate was changed from 19: 1 to 39: 1.
0.3 mg was orally administered to monkeys in the same manner as in Example 6, blood was collected, and compound A in plasma was measured to determine AUC and Cmax.

Table 2 shows AUC and Cmax obtained in Comparative Example 2 and Examples 6 to 10.

[0087]

[Table 2]

[0088]

As is clear from the results of Tables 1 and 2, a pharmaceutical composition containing the drug of the present invention and a lipophilic substance, or a pharmaceutical composition containing the drug, a lipophilic substance and cyclodextrins The product showed excellent oral absorption compared to oral administration of the drug alone (Comparative Example 1 and Comparative Example 2).

Claims (27)

[Claims] 1. A pharmaceutical composition comprising a drug and a lipophilic substance. 2. A pharmaceutical composition comprising a drug, a lipophilic substance and cyclodextrins. 3. The method according to claim 1, wherein the drug is a basic compound, a salt of the compound,
3. The pharmaceutical composition according to claim 1, which is a solvate of the compound or a solvate of a salt of the compound. 4. The drug according to claim 1, wherein the drug is an aromatic amidine derivative, a salt of the derivative, a solvate of the derivative, or a solvate of a salt of the derivative. Pharmaceutical composition. 5. The drug according to claim 1, wherein the drug is 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. 5. The pharmaceutical composition according to any one of the above items 4. 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, and A represents 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups. An optionally substituted alkylene group having 1 to 4 carbon atoms or a compound represented by the formula: 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-
A group represented by R ⁶ (where 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.) 6. In the general formula (1), Is a group represented by benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl,
The pharmaceutical composition according to claim 5, which is a group selected from naphthyl and tetrahydronaphthyl. 7. A compound represented by the general formula (1):
The pharmaceutical composition according to claim 5 or 6, wherein the 6- to 6-membered heterocyclic group is a group containing one or two nitrogen atoms or oxygen atoms as hetero atoms. 8. A compound represented by the general formula (1):
The pharmaceutical composition according to any one of claims 5 to 7, wherein the 6- to 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group. 9. An aromatic amidine derivative, a salt of the derivative,
A solvate of the derivative or a solvate of a salt of the derivative,
9. A device selected from the following group:
The pharmaceutical composition according to any one of the above. 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) 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-[((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-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 and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoyl] glycine. 10. The aromatic amidine derivative, a salt of the derivative, a solvate of the derivative, or a solvate of a salt of the derivative is selected from the following group: The pharmaceutical composition according to claim 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, 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. 11. The method according to claim 1, wherein the lipophilic substance is one or a mixture of two or more selected from the group consisting of higher alcohols, fatty acids, esters of fatty acids and alcohols, and esters of fatty acids and polyhydric alcohols. Claim 10
The pharmaceutical composition according to any one of the above. 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the lipophilic substance is a glyceryl ester of a fatty acid and glycerin. 13. The lipophilic substance is a glyceryl ester of a medium-chain fatty acid and glycerin.
3. The pharmaceutical composition according to any one of 2. 14. The medicament according to any one of claims 1 to 12, wherein the lipophilic substance is a mixture of a glyceryl ester of a medium-chain fatty acid and glycerin and a glyceryl ester of a long-chain fatty acid and glycerin. Composition. 15. The pharmaceutical composition according to claim 1, wherein the lipophilic substance is a mixture of glyceryl caprylate and glyceryl caprate. 16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the lipophilic substance is a triglyceryl ester of a medium-chain fatty acid and glycerin. 17. The method according to claim 1, wherein the lipophilic substance is a mixture of glycerin tricaprylate, glyceryl tricaprate and glyceryl monostearate.
The pharmaceutical composition according to Item. 18. The pharmaceutical composition according to claim 1, wherein the lipophilic substance is a mixture of glycerin tricaprylate, glyceryl tricaprate and hydrogenated tallow fatty acid triglyceride. Composition. 19. The pharmaceutical composition according to any one of claims 2 to 18, wherein the cyclodextrin is a water-soluble cyclodextrin. 20. A cyclodextrin comprising β-cyclodextrin, γ-cyclodextrin, and water-soluble β-cyclodextrin.
One or two selected from the group consisting of cyclodextrin derivatives and water-soluble γ-cyclodextrin derivatives
The pharmaceutical composition according to any one of claims 2 to 19, which is a mixture of two or more species. 21. The pharmaceutical composition according to any one of claims 2 to 20, wherein the cyclodextrin is β-cyclodextrin. 22. Any one of claims 1 to 21.
An emulsion preparation containing the pharmaceutical composition described in the above item. 23. Any one of claims 1 to 21.
A suspension containing the pharmaceutical composition according to the above item. 24. Any one of claims 1 to 21
A capsule containing the pharmaceutical composition according to Item. 25. A capsule containing the suspension according to claim 23. 26. (2S) -2- [4-[((3S)-
1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate, glycerin tricaprylate, glyceryl tricaprate, glyceryl monostearate And a pharmaceutical composition containing β-cyclodextrin. 27. A capsule containing the pharmaceutical composition according to claim 26.