JP4860164B2 - Seamless capsule - Google Patents

Description

  The present invention relates to a seamless capsule that improves the absorption efficiency of a drug having low absorbability in the digestive tract.

Some drugs do not have the expected pharmacological effects by oral administration because of their low absorption in the gastrointestinal tract.
Intravenous or intramuscular injection of these drugs with low oral absorption has been conventionally performed. However, in the case of administration by injection, various problems such as pain and muscular disorders and complicated use are caused. Has a point.
In order to solve these problems, a method using an absorption promotion effect by various additives (absorption accelerators) has been proposed. However, some absorption enhancers can cause mucosal damage. Furthermore, improving the permeability of the gastrointestinal tract membrane, which is one of the barriers of the living body, can cause various components unnecessary for the living body to be absorbed, and the absorption enhancer itself may be absorbed to show toxicity. The above problem also occurs.
As an effective method for efficiently absorbing drugs with low oral absorbability, enteric preparations that are coated with an enteric coating agent on tablets with highly disintegrating excipients and disintegrants are known. However, it is not satisfactory in terms of absorption efficiency.
In general, drugs that are inactivated or reduced in efficacy by gastric juice, drugs that stimulate the gastric mucosa, drugs that inhibit the digestive action of the stomach, etc. are applied to enteric preparations, and for the purpose of maintaining the efficacy of the drug Also enteric preparations are made. In fact, an example in which bifidobacteria that are inactivated or reduced in efficacy by gastric juice is applied to a seamless capsule is known (Non-Patent Document 1), but a drug with low absorbability in the digestive tract (non-absorbable drug) There is no known seamless capsule coated with an enteric coating agent for the purpose of improving oral absorbability.

JP 2001-139462 A PHARM TECH JAPAN 1999 Vol. 15 No. 12 p. 55-68

  The subject of this invention is improving the absorbability of the drug which cannot exhibit the effect which can be expected by oral administration by a highly safe method, since the absorbability in the digestive tract is low.

  As a result of earnest research, the present inventors have found that a seamless capsule having a drug solution or dispersion in the innermost layer and an enteric coating layer in the outermost layer can improve the absorption of the drug in the digestive tract. The headline was newly found and the present invention was completed.

That is, the present invention relates to a seamless capsule containing a hardly absorbable drug in the innermost layer, and relates to the following inventions.
(1) A seamless capsule having a drug solution or dispersion in the innermost layer and an enteric coating layer in the outermost layer.
(2) The above (1) having a drug solution or dispersion in the innermost layer, a hydrophobic substance in the second layer from the inside, a polymer gel layer in the third layer from the inside, and an enteric coating layer in the outermost layer ) Seamless capsule described.
(3) The seamless capsule according to (1) above, wherein an enteric coating layer is provided on a seamless capsule having a drug solution or dispersion in the innermost layer.
(4) The seamless capsule according to (1) above, wherein an enteric coating layer is provided on a seamless capsule in which the innermost layer is a drug solution or dispersion, the intermediate layer is a hydrophobic substance, and the outermost layer is a polymer gel layer.
(5) The seamless capsule according to the above (2) or (4), wherein the hydrophobic substance is one or a combination of two or more selected from the group consisting of sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil and lecithin.
(6) The seamless capsule according to the above (2) or (4), wherein the polymer gel layer contains a polymer gelling agent and optionally a polyhydric alcohol.
(7) The polymer gelling agent is selected from the group consisting of gelatin, carrageenan, ferceleran, agar, glucomannan, alginic acid, locust bean gum, tamarind gum, guar gum, gum arabic, pectin, pullulan, xanthan gum and gellan gum The seamless capsule according to (6) above, which is a combination of two or more.
(8) The seamless capsule according to the above (6), wherein the polyhydric alcohol is one or a combination of two or more selected from the group consisting of ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin and sorbitan.
(9) The seamless capsule according to any one of the above (1) to (8), wherein the enteric coating layer contains an enteric coating agent and, optionally, a plasticizer.
(10) Enteric coating agent is cellulose acetate phthalate, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose trimellitate, methacrylic acid copolymer, methacrylic acid acrylic The seamless capsule according to (9) above, which is one or a combination of two or more selected from the group consisting of an ethyl acid copolymer and a methyl methacrylate copolymer.
(11) The seamless capsule according to (9), wherein the plasticizer is one or a combination of two or more selected from the group consisting of triethyl citrate, propylene glycol, polyethylene glycol, and triacetin.
(12) The seamless capsule according to any one of (1) to (11), wherein the solvent or dispersion medium of the drug solution or drug dispersion is water.
(13) The seamless capsule according to any one of (1) to (12), wherein the drug is a hardly absorbable drug.
(14) The seamless capsule according to any one of (1) to (12), wherein the drug is a hydrophilic drug.
(15) The seamless capsule according to any one of (1) to (14) above, which is for improving gastrointestinal absorption of a drug.

As will be apparent from the examples described later, the seamless capsule of the present invention is superior to the enteric preparation described in Patent Document 1 proposed for efficiently absorbing a drug having low oral absorbability. ) Absorption improved effect.
Therefore, the seamless capsule of the present invention can not only improve the oral absorption of drugs that exhibit difficulty in oral absorption, but also reduce the dose of drugs that do not exhibit particular difficulty in oral absorption, reducing side effects. It is possible to avoid the effects of meals.

  The seamless capsule of the present invention is a seamless capsule having a drug solution or dispersion in the innermost layer and an enteric coating layer in the outermost layer. Of these, a seamless capsule having a drug solution or dispersion in the innermost layer and having an enteric coating layer is preferable. The seamless capsule of the present invention has a drug solution or dispersion in the innermost layer, a hydrophobic substance in the second layer from the inside, a polymer gel layer in the third layer from the inside, and an enteric coating layer in the outermost layer. Among them, seamless capsules, in which an enteric coating layer is provided on a seamless capsule comprising an innermost layer of a drug solution or dispersion, an intermediate layer of a hydrophobic substance, and an outermost layer of a polymer gel layer, are preferred.

  The seamless capsule containing the drug solution or dispersion in the innermost layer according to the present invention may be manufactured based on a known method, and the raw material of the seamless capsule is liquidized by using a double or triple nozzle called a dropping method. (E.g., Non-Patent Document 1 mentioned above, JP-A-49-59789, JP-A-51-8176, JP-A-60-17234, JP-A-7- No. 69867).

  In the present invention, the hydrophobic substance and the polymer gel layer constituting the seamless capsule are seamless capsule film substances, and the hydrophobic substance is not particularly limited. For example, sucrose fatty acid ester, glycerin A fatty acid ester, hydrogenated oil, lecithin, etc. can be mentioned, These may be used alone or in combination of two or more. The hydrophobic substance is preferably 10 to 50% by weight, more preferably 20 to 40% by weight, based on the total weight of the film substance and the drug solution (drug dispersion).

  The polymer gel layer is composed of a polymer gelling agent and optionally a polyhydric alcohol. The polymer gelling agent is not particularly limited, and examples thereof include gelatin, carrageenan, fur celerane, agar, glucomannan, alginic acid, locust bean gum, tamarind gum, guar gum, gum arabic, pectin, pullulan, xanthan gum, A gellan gum etc. can be mentioned. These may be used alone or in combination of two or more. The polyhydric alcohol is not particularly limited, and examples thereof include ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin, and sorbitan. These may be used alone or in combination of two or more. The polymer gel layer is preferably from 3 to 30% by weight, more preferably from 5 to 25% by weight, based on the total weight of the film substance and the drug solution (drug dispersion).

In the method for producing a seamless capsule of the present invention, when a dropping method using a triple nozzle is used, the drug solution or dispersion to be enclosed in the seamless capsule is discharged from the innermost nozzle and is hydrophobic from the intermediate nozzle. The active substance is discharged, and the polymer gel layer material is discharged from the outermost nozzle. When the material of the hydrophobic substance and the polymer gel layer is solid or semi-solid under the production conditions of the seamless capsule, it is preferably liquefied by heating or the like and discharged. The resulting seamless capsule has a three-layer structure. The seamless capsule of the present invention can be produced by applying a normal enteric coating to this three-layered seamless capsule. That is, an enteric coating agent, and optionally a plasticizer, an appropriate solvent or dispersion medium is added to produce an enteric coating solution, and the enteric coating solution is applied to the seamless capsule according to the present invention (specifically, , Coating) and drying, the seamless capsule of the present invention can be produced.
The seamless capsule of the present invention can also be produced using a dropping method using a quadruple nozzle. That is, the drug solution or dispersion liquid to be sealed in the seamless capsule is discharged from the innermost nozzle, the hydrophobic substance is discharged from the second nozzle from the inner side, and the polymer gel layer is discharged from the third nozzle from the inner side. The seamless capsule of the present invention can be manufactured by discharging the material of the present invention and discharging the material of the enteric coating layer from the outermost nozzle. When the material of the hydrophobic substance, the polymer gel layer, and the enteric coating layer is solid or semi-solid under the production conditions of the seamless capsule according to the present invention and the seamless capsule of the present invention, it is liquefied by heating or the like. It is preferable to discharge.

  The enteric coating layer of the seamless capsule of the present invention is composed of an enteric coating agent and, optionally, a plasticizer. The enteric coating agent is not particularly limited, and may be appropriately selected based on the optimum pH of the drug at the absorption site of the intestine, the interaction with the drug, and the like. Examples of enteric coating agents include cellulose-based polymers such as cellulose acetate phthalate, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, carboxymethylethylcellulose, and hydroxypropylmethylcellulose trimellitate. Examples thereof include methacrylic acid polymers such as acid copolymers, ethyl methacrylate acrylate copolymers, and methyl methacrylate methacrylate copolymers. These may be used alone or in combination of two or more. The plasticizer is not particularly limited, and examples thereof include triethyl citrate, propylene glycol, polyethylene glycol, and triacetin. The composition amount of the enteric coating layer in the seamless capsule of the present invention is usually 1 to 50% by weight, preferably 2 to 30% by weight, based on the total weight of the seamless capsule of the present invention. The enteric coating layer may exceed the above range depending on the optimum pH of the drug and the selected enteric coating agent.

In the present invention, when a compound represented by the following general formula (1), a salt thereof, or a solvate thereof is used as a drug, an enteric coating agent is one that dissolves at pH 4.0 to 7.0. It is preferable to use, and it is more preferable to use what dissolves at pH 5.0 to 6.5. Specific examples include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and carboxymethylethylcellulose. Since these cellulose polymers can adjust the dissolution pH by changing the substitution degree of the substituent, a desired dissolution pH may be appropriately set and the substitution degree of the substituent may be changed.
The particle size (Φ) of the seamless capsule of the present invention is usually 1 to 15 mm, preferably 3 to 12 mm. The particle size can be controlled by the production conditions of the seamless capsule and the production conditions when applying the enteric coating layer.

  The drug solution or drug dispersion contained in the innermost layer of the seamless capsule of the present invention can be obtained by dissolving or dispersing the drug in a suitable solvent or dispersion medium. The solvent or dispersion medium is not particularly limited, and examples thereof include water and lower alcohols having 1 to 6 carbon atoms. The blending amount of the drug solution or drug dispersion in the seamless capsule of the present invention may be set as appropriate depending on the concentration of the drug solution or drug dispersion contained in the seamless capsule, the desired drug effect by the drug, etc. And usually 1 to 90% by weight, preferably 5 to 80% by weight, based on the total weight of the drug solution (drug dispersion).

  The drug according to the present invention is not particularly limited, and includes a natural herbal extract (extract, tincture, etc.), a compound isolated from the extract, a chemically synthesized compound, and the like. The drug may be a single component or a mixture of two or more. When the drug is a compound, a salt of the compound, various pharmaceutically acceptable solvates of the compound (for example, water), and a solvate of the salt of the compound are included. Also, they should not be limited to certain crystal polymorphs.

  When an asymmetric carbon is present in the structure of the compound, any optical isomer or stereoisomer based on it exists, and any of these optical isomers, stereoisomers, or a mixture thereof is related to the present invention. Included in drugs.

  The salt of the compound is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, hydroiodide, phosphate, Mineral salts such as nitrate and sulfate, methanesulfonate, 2-hydroxyethanesulfonate, organic sulfonate such as p-toluenesulfonate, acetate, propionate, oxalate and malonate And organic carboxylates such as succinate, glutarate, adipate, tartrate, maleate, malate and mandelate.

  The drug according to the present invention is not particularly limited. For example, drugs that have sufficient pharmacological effects even when administered orally despite their low absorption in the gastrointestinal tract can reduce the dose of drugs by further increasing their oral absorption and reduce side effects. It is also possible to make it. In addition, since the absorption in the gastrointestinal tract is low, a drug for which a sufficient pharmacological effect cannot be obtained by oral administration can have an expected pharmacological effect by increasing the oral absorption. In general, many drugs having low hydrophilicity in the digestive tract have high hydrophilicity. In addition, since the use of the seamless capsule of the present invention can eliminate the influence of meals on drugs, it can also be applied to drugs that are easily affected by meals.

  In the present invention, examples of preferable drugs include basic compounds. The basic compound as a drug means a compound having one or more basic groups such as an amino group and an amidino group that may be substituted in the chemical structure. In addition, 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 the vicinity thereof, or may be present at both ends or the vicinity thereof. .

  In the drug according to the present invention, the compound having an amidino group which may be substituted is included in the basic compound described above, and a compound having an amidino group which may be substituted in the chemical structure thereof. means. Specifically, the general formula (1) as described in JP-A-5-208946 and International Publication WO96 / 16940.

[Wherein R ¹ represents a hydrogen atom or a lower alkoxyl group;
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 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl 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,
n represents a number from 0 to 4,
A represents an alkylene group having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups, or a formula

A group represented by the formula {wherein B represents a lower alkylene group or a carbonyl group, R ⁵ represents a hydrogen atom or a group represented by the formula -DW-R ⁶ (wherein D represents a formula

A group represented by the formula (wherein Z represents an oxygen atom or a sulfur atom),
formula

A group represented by or a sulfonyl group,
W is a single bond or a group represented by —NR ⁷ — (wherein R ⁷ is a hydrogen atom, carbamoyl group, lower alkoxycarbonyl group, mono- or di-lower alkylaminocarbonyl group, lower alkylsulfonyl group, mono- or A di-lower alkylaminothiocarbonyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkanoyl group).
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 represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group,
Y has a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, an amino group which may have a substituent, or a substituent. An aminoalkyl group which may be

Is a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl.
, A solvate of the compound, a solvate of the salt of the compound, the following compound, and the like.

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

  Especially, in this invention, the compound represented by General formula (1), its salt, or those solvates are preferable as a drug.

In the compound represented by the general formula (1) according to the present invention, examples of the lower alkyl group include straight-chain, branched or cyclic alkyl groups having 1 to 6 carbon atoms. Specific examples As methyl group, ethyl group, propyl group, isopropyl group, butyl group, secondary butyl group, tertiary butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. be able to.
The lower alkyl group may have a substituent, and examples of the group that can be substituted for the lower alkyl group include a halogen atom, carboxyl group, carbamoyl group, amino group, cyano group, nitro group, lower alkanoyl group, lower group Alkoxyl group, lower alkoxycarbonyl group, mono- or di-lower alkylamino group, aryl group, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, lower alkthiocarbonyl group, hydroxyl group, carbamoyl group, mono- or A di-lower alkylaminocarbonyl group etc. can be mentioned.

Examples of the lower alkoxyl group include those having 1 to 6 carbon atoms, and specific examples thereof include methoxyl group, ethoxyl group, propoxyl group, isopropoxyl group, butoxyl group, secondary butoxyl group and tertiary group. A butoxyl group etc. can be mentioned.
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, and a carboxypropyl group.
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, and a methoxycarbonylethoxyl group. Group, ethoxycarbonylethoxyl group and the like.
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 mono- or di-lower alkylaminocarbonyl group, as mono-lower alkylaminocarbonyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, isobutylaminocarbonyl Group, pentylaminocarbonyl group, isopentylaminocarbonyl group, hexylaminocarbonyl group, isohexylaminocarbonyl group and the like. Further, as a dialkylaminocarbonyl group, a symmetric type which is disubstituted with a lower alkyl group such as a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, a diisopropylaminocarbonyl group, a dibutylaminocarbonyl group, a dipentylaminocarbonyl group, etc. 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 may be mentioned.
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, an isopentylsulfonyl group, a hexylpropyl group, and an isohexylpropyl group. Can be mentioned.
As mono- or di-lower alkylaminothiocarbonyl group, as mono-lower alkylaminothiocarbonyl group, methylaminothiocarbonyl group, ethylaminothiocarbonyl group, propylaminothiocarbonyl group, isopropylaminothiocarbonyl group, butylamino Examples thereof include a thiocarbonyl group, an isobutylaminothiocarbonyl group, a pentylaminothiocarbonyl group, an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group. In addition, the dialkylaminothiocarbonyl group is a lower alkyl group such as a dimethylaminothiocarbonyl group, a diethylaminothiocarbonyl group, a dipropylaminothiocarbonyl group, a diisopropylaminothiocarbonyl group, a dibutylaminothiocarbonyl group, a dipentylaminothiocarbonyl group, or the like. Di-substituted symmetrical dialkylaminothiocarbonyl group, and ethylmethylaminothiocarbonyl group, methylpropylaminothiocarbonyl group, ethylpropylaminothiocarbonyl group, butylmethylaminothiocarbonyl group, butylethylaminothiocarbonyl group, An asymmetrical dialkylaminothiocarbonyl group that is disubstituted with a different lower alkyl group such as a butylpropylaminothiocarbonyl group.
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, and preferably an acetyl group, a propionyl group, and a butyryl group. And more preferably an acetyl group or a propionyl group. The lower alkanoyl group may have a substituent.
Examples of the group that can be substituted with the lower alkanoyl group include 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 group. Examples thereof include an alkylamino group, an aryl group, an aralkyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group, a lower alkylthiocarbonyl group, a hydroxyl group, a carbamoyl group, and a mono- or di-lower alkylaminocarbonyl group.
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.
Heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxalinyl, cinnolinyl Benzimidazolyl group, imidazopyridyl group, benzofuranyl group, naphthyridinyl group, 1,2-benzisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolopyridyl group, isothiazolopyridyl group, benzothienyl group, etc. Preferably, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyridyl group, and the like can be given. The aryl group may have a substituent.
Examples of the group that can be substituted with these aryl groups or heteroaryl groups include halogen atoms, carboxyl groups, amino groups, cyano groups, nitro groups, hydroxyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, mono- or di-lower groups. Examples thereof include an alkylamino group, a lower alkanoyl group, and a lower alkyl group which may have a substituent.
The saturated or unsaturated 5- to 6-membered heterocyclic group is preferably a heterocyclic group containing 1 to 2 nitrogen atoms or oxygen atoms as a hetero atom. Specific examples of such a heterocyclic ring include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, morpholine and the like. Of these, pyrrolidine and piperidine are preferred. Examples of the saturated or unsaturated cyclic hydrocarbon group include a cyclopentyl group and a cyclohexyl group. 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, and examples of the group that can be substituted for the heterocyclic group or cyclic hydrocarbon group include a lower alkyl group, a lower alkanoyl group, a carbamoyl group, a mono group. Alkylcarbamoyl group, dialkylcarbamoyl group, formimidoyl group, alkanoimidoyl group, benzimidoyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkylcarbonylalkyl group, aminoalkyl group, alkanoylaminoalkyl group, alkanoylaminoalkyl group, Examples include an imino group and an alkoxycarbonylimino group.
Examples of the group that can be substituted on the amino part of the amino group or aminoalkyl group include a lower alkyl group, a pyrrolidinyl group, a pyrazyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a lower alkanoyl group, a formimidoyl group, Examples thereof include an alkanoimidoyl group, a benzimidoyl group, and an alkoxycarbonyl group. In addition, as for carbon number, such as an alkyl group shown here, an alkoxyl group, an alkanoyl group, 1-6 are preferable.
Also,

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

  The compound represented by the general formula (1) according to the present invention may have an asymmetric carbon atom. In this case, an optical isomer or a stereoisomer based on the asymmetric carbon atom exists. Any of optical isomers, stereoisomers, and mixtures thereof are included in the drug according to the present invention.

In the present invention, among the above-mentioned compounds having an amidino group which may be substituted, salts thereof or solvates thereof, the compounds represented by formula (1), salts thereof or solvates thereof are drugs. 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-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 acetic 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-acetimidoyl-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] sulfamoyl acetic 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.

Furthermore, (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid hydrochloride 5 water Japanese,
(+)-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 salt,
N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl acetic 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 seamless capsule of the present invention may be administered as it is to humans, or may be used as a capsule by filling it with a normal formulation technique, and granulated, tableted, etc. It can be formulated into tablets, granules and the like. Examples of the dosage form of the seamless capsule of the present invention include capsules, tablets, granules and the like.

  Hereinafter, the present invention will be described with reference to examples. However, the present invention should not be limited to these examples.

Example 1 Production of Seamless Capsules Using a concentric triple nozzle, Φ4.0 mm seamless capsules having the composition shown in Table 1 were produced. That is, one liquid (2S) -2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propion from the inner nozzle An aqueous solution of acid hydrochloride pentahydrate (hereinafter abbreviated as “compound A”) was heated to 40 ° C. from an intermediate nozzle, and a mixture of two liquid hardened oils and soybean lecithin was added to 60 ° C. from an outer nozzle. Three warm gelatin aqueous solutions were discharged into vegetable oil cooled to 5.0 ° C. flowing down at a flow rate of 0.15 m / s in the ratios shown in Table 1, respectively. Formed. These were dried in an atmosphere adjusted to a temperature and humidity of 20 ° C. and 50% RH to obtain seamless capsules.

Table 1

Example 2 Production of Seamless Capsule Seamless capsules having a composition shown in Table 2 and having a diameter of 9.0 mm were produced using a concentric triple nozzle. That is, using a concentric triple nozzle, one solution of Compound A from the inner nozzle is heated to 60 ° C. from the outer nozzle, and a mixture of two-component hardened oil and soybean lecithin heated from the middle nozzle to 40 ° C. The three gelatin aqueous solutions were discharged into vegetable oil cooled to 5.0 ° C. flowing down at a flow rate of 0.4 m / s in the ratios shown in Table 2 to form three-layer seamless capsules continuously. . These were dried in an atmosphere adjusted to a temperature and humidity of 20 ° C. and 50% RH to obtain seamless capsules.

Table 2

Example 3 Production of seamless capsules having an enteric coating layer About 50 seamless capsules of Example 1 (about 1.7 g) and about 300 g of pseudo-tablets of almost the same size, a coating machine (HCT-MINI: Freund Sangyo Co., Ltd.) Hydropropylpropyl cellulose acetate succinate (trade name: AQOAT AS-MF (manufactured by Shin-Etsu Chemical Co., Ltd.)) 8% (w / w) and triethyl citrate 0.8% (w / w) ethanol / 567 g of a dichloromethane / water (= 43: 43: 5 (w / w / w)) solution was sprayed and dried to obtain enteric seamless capsules.

Comparative Example 1 Enteric Tablets A mixed powder of Compound A, erythritol and crospovidone was tableted using a single tableting machine to obtain a bare tablet. Using this coating tablet (HCT-MINI: manufactured by Freund Sangyo Co., Ltd.), 8% (w / w) of hydroxypropylcellulose acetate succinate (trade name: AQOAT AS-MF (manufactured by Shin-Etsu Chemical Co., Ltd.)) A solution of triethyl citrate 0.8% (w / w) in ethanol / dichloromethane (= 1: 1 (w / w)) was sprayed to obtain enteric tablets having the following composition per tablet.

Ingredient Compound A 6.425 mg
Erythritol 5.45mg
Crospovidone 0.625mg
Hydroxypropyl methylcellulose acetate succinate 1.875mg
(Product name: AQOAT AS-MF)
Triethyl citrate 0.188mg
Total 14.563 mg

Test Example 1 Dissolution Test The seamless capsule obtained in Example 3 and the enteric tablet obtained in Comparative Example 1 were added in 500 mL of the Japanese Pharmacopoeia first liquid according to the Japanese Pharmacopoeia 13th revised dissolution test method 2 method (paddle method). After confirming that it did not elute for 2 hours, the seamless capsule was transferred to 500 mL of JP 2nd liquid. From the elution profile, T75% -T25% (difference between the time for the elution rate to reach 75% and the time for it to reach 25%) was determined as an elution rate index. The results are shown in Table 3. As is apparent from Table 3, the seamless capsule (Example 3) of the present invention and the existing enteric tablet (Comparative Example 1) showed rapid dissolution in a neutral solution.

Table 3 Dissolution test results

Test Example 2 Oral administration test (1)
A monkey (female, cynomolgus monkey, body weight of about 3 kg, n = 6) fasted for 16 hours with the seamless capsule obtained in Example 3 and the enteric tablet obtained in Comparative Example 1 under anesthesia, using an oral Margen tube, One capsule or 1 tablet / head was orally administered. Similarly, Compound A was dissolved in purified water, and an aqueous solution of Compound A was orally administered to monkeys (female, cynomolgus monkey, body weight of about 3 kg, n = 6) so as to be 6.425 mg / 2.5 mL / head.
After administration, blood was collected from the femoral vein up to 10 hours every hour to obtain plasma. The area under the plasma concentration-time curve (AUC) and the maximum blood concentration (Cmax) were determined from the change in plasma concentration of Compound A in the obtained plasma. The results are shown in Table 4. As is clear from Table 4, the seamless capsule of the present invention (Example 3) shows a significantly higher AUC as compared with the aqueous solution of Compound A, and the effect is similar to that of the existing enteric tablet (Comparative Example 1). there were. Furthermore, regarding the gastric excretion time, the existing enteric tablet (Comparative Example 1) has a large variation among individuals, whereas the seamless capsule (Example 3) of the present invention is within 1 hour, and the gastric excretion is It was found that there was an effect of suppressing time variation.

Table 4. Results of monkey oral administration test (mean ± SD, n = 6)

Test Example 3 Oral administration test (2)
A monkey (female, cynomolgus monkey, body weight approximately 3 kg, n = 6) in fasting conditions (feeding more than 16 hours before administration) and postprandial conditions (feeding 2 hours before administration), with a fiberscope from the oral cavity under ketamine intramuscular anesthesia After inserting and inserting the distal end of the catheter into the duodenum, one seamless capsule obtained in Example 3 set at the distal end or one enteric tablet obtained in Comparative Example 1 was extruded together with 5 ml of water. Similarly, an aqueous solution of Compound A (6.425 mg / 2.5 mL) was administered. After administration, blood was collected from the femoral vein at 0.5 hr, 1 hr, 2 hr, 3 hr, and 4 hr to obtain plasma. The area under the plasma concentration-time curve (AUC) and the maximum blood concentration (Cmax) were determined from the plasma concentration transition of Compound A in the obtained plasma, and the ratio of AUC after fasting administration to fasting administration (postprandial administration) AUC / AUC of fasting administration). The existing enteric tablet (Comparative Example 1) and Compound A aqueous solution were obtained in Example 3 while the AUC values after administration / A Fasting administration AUC values were 0.5 and 0.1, respectively. The seamless capsule was 0.9, and it was found that the seamless capsule of the present invention was not affected by meals and could be administered after meals.

As is clear from the above examples, the seamless capsule of the present invention showed an excellent effect of improving oral absorption compared with the conventional enteric preparation.
Therefore, the seamless capsule of the present invention can not only improve the oral absorption of drugs that exhibit difficulty in oral absorption, but also reduce the dose of drugs that do not exhibit particular difficulty in oral absorption, reducing side effects. And the variation in gastric excretion time was suppressed. Moreover, since the influence of a meal can be avoided, the seamless capsule of the present invention is excellent as a pharmaceutical preparation.

Claims (13)

Drug solutions or dispersions innermost layer, the hydrophobic substance second layer from the inside, polymer gel layer Third layer from the inside, with an enteric coating layer in the outermost layer, a seamless capsule, the hydrophobic A seamless capsule wherein the substance is one or a combination of two or more selected from the group consisting of sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil and lecithin . The seamless capsule according to claim 1, wherein the polymer gel layer contains a polymer gelling agent. The seamless capsule according to claim 2 , wherein the polymer gel layer further contains a polyhydric alcohol. The polymer gelling agent is one or more selected from the group consisting of gelatin, carrageenan, furseleran, agar, glucomannan, alginic acid, locust bean gum, tamarind gum, guar gum, gum arabic, pectin, pullulan, xanthan gum and gellan gum. The seamless capsule according to claim 2, which is a combination. The seamless capsule according to claim 3 , wherein the polyhydric alcohol is one or a combination of two or more selected from the group consisting of ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin and sorbitan. The seamless capsule according to any one of claims 1 to 5 , wherein the enteric coating layer contains an enteric coating agent. The seamless capsule according to claim 6 , wherein the enteric coating layer further comprises a plasticizer. Enteric coating agent is cellulose acetate phthalate, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose trimellitate, methacrylic acid copolymer, ethyl methacrylate acrylate copolymer The seamless capsule according to claim 6, which is one or a combination of two or more selected from the group consisting of methyl methacrylate and a methyl methacrylate copolymer. The seamless capsule according to claim 7 , wherein the plasticizer is one or a combination of two or more selected from the group consisting of triethyl citrate, propylene glycol, polyethylene glycol and triacetin. The seamless capsule according to any one of claims 1 to 9 , wherein the solvent or dispersion medium of the drug solution or drug dispersion is water. The seamless capsule according to any one of claims 1 to 10 , wherein the drug is a poorly absorbable drug. The seamless capsule according to any one of claims 1 to 10 , wherein the drug is a hydrophilic drug. The seamless capsule according to any one of claims 1 to 12 , which is for improving gastrointestinal absorption of a drug.