JPH10167968A - Production of microparticle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject particles which are excellent in the dispersibility due to the slight adhesion and aggregation between fine-grain preparations such as microcapsules and comprise sustained-release preparations having repressive effects for bone resorption by grinding a solid consisting of specific drugs and polymers to microparticles. SOLUTION: The objective particles are obtained by grinding a solution which contains (A) a sulfur-containing heterocyclic compound (salt) of formula I [the ring A is a (substituted) benzene ring; B is carboxyl; X is -CH(OH)- and -CO-; (k) is 0 or 1; (n) is 0, 1 or 2], preferably formula II [R<1> is H and a (substituted) hydrocarbon group; R<2> and R<3> are each an alkyl], and (B) a biolytic α-hydrocarbonic high molecular polymer, e.g. a polymer having weight- average molecular weight of 3,000-30,000 and lactic acid/glycolic acid ratio of 60/40-100/0, in the presence of (C) a pulverization adjuvant, e.g. an inorganic salt (sodium chloride and the like), an organic acid (salt) (carbonate) and a saccharide (mannitol and the like). The particles have the releasing property controlled as a treating agent for bone fracture and preventive and treating drugs for osteoporosis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing microparticles. More specifically, the present invention relates to a method for producing microparticles such as microcapsules having little adhesion and aggregation between fine particle preparations and good dispersibility.

[0002]

2. Description of the Related Art As a conventional technology, for example,
EP-A-481,732 includes drugs and polylactic acid and glycolic acid / hydroxycarboxylic acid [HOCH (C
_2-8 Alkyl) COOH] copolymers are described. As a method for producing the preparation, a W / O emulsion containing an aqueous solution of a physiologically active peptide as an internal aqueous phase and an organic solvent solution of a biodegradable polymer as an oil phase is added to water or the like,
An underwater drying method for producing sustained-release microcapsules from W / O / W emulsions is described. In general, a fine particle preparation produced by an in-water drying method is difficult to obtain a high-content preparation, and the trap rate is also greatly varied between lots and easily affected by scale-up. Also, a spray drying method is known, but when a fine particle preparation is produced by this method, the problem of the trapping rate is small, but the quality such as the initial release rate varies greatly due to fluctuations in production conditions. There is a problem that the fine particle preparation has a poor dispersibility in an aqueous dispersion medium as compared with a dried product in water. Furthermore, a preparation method of obtaining a fine particle preparation by pulverizing a solid solution comprising a drug and a biodegradable polymer is also known.However, some drugs have a viscosity, and therefore, when prepared at a high content, they are usually used. However, there is a problem that the obtained solid solution cannot be sufficiently pulverized.

[0003]

[Means for Solving the Problems] In view of such circumstances,
The present inventors have conducted intensive studies to obtain a sustained-release preparation having low adhesion and aggregation between fine particle preparations such as microcapsules and a good dispersibility. State, prepare a solid solution by drying under reduced pressure or a method equivalent thereto, and pulverize the obtained solid solution in the presence of a grinding aid, so that adhesion and aggregation between the fine particle preparations is small and the drug is incorporated into the fine particle preparation. It has been found that a fine particle preparation having a high trapping ratio and a small initial release in a release test and having excellent properties can be efficiently obtained in large quantities. Further, they have found that a microparticle preparation exhibiting even better dispersibility can be obtained by coating the microparticles with a water-soluble polymer substance and / or a nonionic surfactant, thereby completing the present invention.

That is, the present invention relates to the general formula (1)

Embedded image [In the formula, ring A represents an optionally substituted benzene ring;
Is hydrogen or a hydrocarbon group which may be substituted, B is a carboxyl group which may be esterified or amidated, X is -CH (OH)-or -CO-, and k is 0 or 1. , N represents 0, 1 or 2], respectively, or a physiologically acceptable salt thereof and a biodegradable α-hydroxycarboxylic acid polymer. Method for producing microparticles, characterized in that the material is ground in the presence of a grinding aid,
(2) The sulfur-containing heterocyclic compound has a general formula

Embedded image Wherein R ¹ is hydrogen or a hydrocarbon group which may be substituted, and R ² and R ³ each represent a lower alkyl group or together represent a lower alkylene group. (3) The method for producing microparticles according to (1), (3) the method for producing microparticles according to (2), wherein R ¹ is a methyl group, and R ² and R ³ are ethyl groups, and (4) α-hydroxy. The method for producing microparticles according to the above (1), wherein the weight average molecular weight of the carboxylic acid polymer is about 3,000 to 30,000, (5) α
The hydroxycarboxylic acid polymer is lactic acid and / or
Or the method for producing microparticles according to (1), which is a high molecular weight polymer of glycolic acid; (6) the method for producing microparticles according to (1), wherein the solid is a solid solution; The method for producing microparticles according to the above (1), wherein

(8) The method for producing microparticles according to the above (1), wherein the pulverizing auxiliary is an organic acid, a salt or an inorganic salt thereof; (9) The solid matter is further treated with a water-soluble polymer substance and / or a surfactant. (10) The method for producing microparticles according to the above (1), which is pulverized together with an agent; (10) The method for producing microparticles according to the above (1), wherein the microparticles are further coated with a water-soluble polymer substance and / or a surfactant. 11) The method for producing microparticles according to the above (9) or (10), wherein the water-soluble polymer substance is polyethylene glycol. (12) The above (1), wherein the polyethylene glycol is polyethylene glycol 4000.
The method for producing microparticles according to 1), (13) the method for producing microparticles according to (9), wherein the surfactant is a nonionic surfactant, and (14) the method for producing polyoxyethylene, wherein the nonionic surfactant is polyoxyethylene. (160) the method for producing microparticles according to the above (13), which is polyoxypropylene (30) glycol; (15) the method for producing microparticles according to the above (1), wherein the solid is further pulverized with an anti-agglomeration agent; (16) A method for producing microparticles in which a pulverized solid is dispersed in an aqueous dispersion medium in the presence of an antiagglomeration agent, (17) the microparticle according to (15) or (16), wherein the antiagglomeration agent is an amino acid (18) The method for producing microparticles according to (17), wherein the amino acid is arginine or cysteine.

(19) The active ingredient (2R, 4S)-
(-)-N- [4- (diethoxyphosphorylmethyl)
Phenyl] -1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide or a pharmaceutically acceptable salt thereof and weight average molecular weight Is about 3,000 to about 3
000 and a lactic / glycolic acid ratio of about 60/40
A solid solution containing a biodegradable polymer of from 100 to 0/0, and optionally (1) a water-soluble polymer substance or / and a nonionic surfactant in the presence of a grinding aid,
And / or (2) a method for producing microparticles, which comprises pulverizing together with an amino acid which is an anti-agglomeration agent, and (20) (2R, 4S)-(−)-N as an active ingredient
-[4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-4-methyl-7,8
-Methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide or a pharmaceutically acceptable salt thereof having a weight average molecular weight of about 3,000 to about 30,00.
0 and the lactic acid / glycolic acid ratio is about 60/40 to 1
Microparticles obtained by grinding a solid solution containing a biodegradable polymer of 00/0 together with (1) a water-soluble polymer substance or (2) an amino acid which is an anti-agglomeration agent in the presence of a grinding aid. (2)
Or (1) a method for producing microparticles characterized by coating with (1) an active ingredient (2R, 4
S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-4-
Methyl-7,8-methylenedioxy-5-oxo-3-
Benzothiepine-2-carboxamide or a pharmaceutically acceptable salt thereof having a weight average molecular weight of about 3,000 to about 30,000 and a lactic acid / glycolic acid ratio of about 60
After a solid solution containing a biodegradable polymer having a ratio of / 40 to 100/0 is pulverized in the presence of a pulverization aid, microparticles obtained as required are subjected to (1) a water-soluble polymer substance and / or (2). The present invention relates to a method for producing microparticles, which is coated with an amino acid which is an aggregation preventing agent.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The sulfur-containing heterocyclic compound used in the present invention has the following formula (I):

Embedded image [In the formula, ring A represents an optionally substituted benzene ring;
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxyl group which may be esterified or amidated; X represents -CH (OH)-or -CO-;
Represents 0 or 1, and n represents 0, 1 or 2.] or a salt thereof is used as the active ingredient.

In the formula (I), examples of the substituent of the “optionally substituted benzene ring” represented by ring A include a halogen atom, a nitro group, an optionally substituted alkyl group, and a substituted or unsubstituted alkyl group. An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a mono- or di-alkoxyphosphoryl group, a phosphono group, an optionally substituted aryl group, An aralkyl group which may be substituted or an aromatic heterocyclic group which may be substituted, and the same or different 1 to 4, preferably 1 to 2 groups selected from these substituents are formed on the benzene ring. It may be substituted.

The halogen atom includes fluorine, chlorine, bromine, iodine and the like. As the alkyl group in the “optionally substituted alkyl group”, an alkyl group having 1 to 10 carbon atoms (C _1-10 alkyl: for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) , tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl, etc.) and C _3-7 cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl, etc.) and the like are used, they are For example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, a C _1-6 alkoxy group (eg, methoxy,
Ethoxy, propoxy, butoxy, hexyloxy, etc.), mono- or di- (C _1-6 alkoxy) phosphoryl groups (eg methoxyphosphoryl, ethoxyphosphoryl,
Dimethoxyphosphoryl, diethoxyphosphoryl, etc.),
1-3 may be substituted by a phosphono group or the like. Specific examples of the substituted alkyl group include, for example, trifluoromethyl, trifluoroethyl, trichloromethyl, hydroxymethyl, 2-hydroxyethyl, methoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2
-Diethoxyethyl, 2-diethoxyphosphorylethyl, phosphonomethyl and the like.

As the substituted hydroxyl group in the "optionally substituted hydroxyl group", for example, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like are used. The “alkoxy group” is preferably a C _1-10 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or nonyloxy) and C _4-6 cycloalkoxy Groups (eg, cyclobutoxy, cyclopentoxy or cyclohexyloxy, etc.) are used. The alkenyloxy group is preferably a C _2-10 alkenyloxy group,
For example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, or the like is used. The aralkyloxy group is preferably C.
_{A 7-19} aralkyloxy group, more preferably a C _6-14 aryl-C _1-4 alkoxy group (eg, benzyloxy, phenethyloxy, etc.) is used. The acyloxy group is preferably an alkanoyloxy group, for example, C _2-10
An alkanoyloxy group (eg, acetyloxy, propionyloxy, n-butyryloxy, hexanoyloxy, etc.) is used. As the aryloxy group, a C _6-14 aryloxy group (eg, phenoxy, biphenyloxy, etc.) is preferably used. These groups further have 1 to 3 substituents at substitutable positions such as the aforementioned halogen atom, hydroxyl group, C _1-6 alkoxy group, mono- or di- (C _1-6 alkoxy) phosphoryl group. It may be. Specific examples of such a substituted hydroxyl group include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxy Phenyl) ethoxy and the like.

As the substituted thiol group in the "optionally substituted thiol group", for example, an alkylthio group, an aralkylthio group, an acylthio group and the like are used. The “alkylthio group” is preferably C _1-10
Alkylthio groups (eg, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio,
Heptylthio, nonylthio, etc.) and C _4-6 cycloalkylthio groups (eg, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are used. The aralkylthio group is preferably a C _7-19 aralkylthio group, more preferably a C _6-14 aryl-C _1-4 alkylthio group, for example, benzylthio or phenethylthio. The acylthio group is preferably an alkanoylthio group, for example, a C _2-10 alkanoylthio group (eg,
Acetylthio, propionylthio, n-butyrylthio, hexanorthio, etc.) are used. These groups may be further substituted with 1 to 3 halogen atoms, hydroxyl groups, _C1-6 alkoxy groups, mono- or di- ( _C1-6 alkoxy) phosphoryl groups, and the like. Specific examples of the substituted thiol group include, for example, trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-methoxyethylthio, 4-chlorobenzylthio, 3,4-dichlorobenzylthio, 4-fluoro Benzylthio, 2- (3,
4-dimethoxyphenyl) ethylthio and the like.

The substituent of the amino group in the "optionally substituted amino group" includes the above-mentioned C _1-10 alkyl group and C _2-10 alkenyl group (eg, allyl, vinyl, 2-
Penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2
-Propen-1-yl, 3-methyl-2-butene-1-
One or two C _6-14 aryl groups or C _7-19 aralkyl groups, which are the same or different, and these substituents are the above-mentioned halogen atom, C _1-6 alkoxy group,
It may be substituted with a mono- or di- (C _1-6 alkoxy) phosphoryl group, a phosphono group or the like. Specific examples of the substituted amino group include, for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino or N-methyl-N-phenylamino, N-methyl-N- (4-chlorobenzyl) amino, N, N-di (2-methoxyethyl) amino and the like.

As the "acyl group", an organic carboxylic acid acyl group or a sulfonic acid acyl group having a C _1-6 hydrocarbon group (eg, methyl, ethyl, n-propyl, hexyl, phenyl, etc.) is used. . Examples of the “organic carboxylic acyl group” include, for example, formyl, C _1-10 alkyl-
Carbonyl group (eg, acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, octanoyl, cyclobutanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), C _2-10 alkenyl-carbonyl group (eg, crotonyl, 2-cyclohexenecarbonyl, etc.) , C _6-14 aryl-carbonyl group (eg,
Benzoyl, etc.), C _7-19 aralkyl-carbonyl group (eg, benzylcarbonyl, benzhydrylcarbonyl, etc.), 5- or 6-membered aromatic heterocyclic carbonyl group (eg, nicotinoyl, 4-thiazolylcarbonyl, etc.) , 5- or 6-membered aromatic heterocyclic acetyl groups (eg, 3-pyridylacetyl, 4-thiazolylacetyl, etc.) are used. The C
_As a sulfonate acyl group having a _1-6 hydrocarbon group,
For example, methanesulfonyl, ethanesulfonyl and the like are used. These groups may be further substituted with 1 to 3 substituents such as the above-mentioned halogen atom, hydroxyl group, _C1-6 alkoxy group, amino group and the like. Specific examples of the acyl group include, for example, trifluoroacetyl, trichloroacetyl, 4-methoxybutyryl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl, 3,4-dimethoxybenzoyl and the like.

The "mono- or di-alkoxyphosphoryl group" includes, for example, mono-C _1-6 alkoxy such as methoxyphosphoryl, ethoxyphosphoryl, propoxyphosphoryl, isopropoxyphosphoryl, butoxyphosphoryl, pentyloxyphosphoryl, hexyloxyphosphoryl and the like. A phosphoryl group, for example, a di-C _1-6 alkoxyphosphoryl group such as dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl and the like is used.
Preferably, a di-C _1-6 alkoxy group such as dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, dibutoxyphosphoryl and the like are used.
As the aryl group in the "optionally substituted aryl group", a C _6-14 aryl group such as phenyl, naphthyl, anthryl and the like are preferably used, and these are the above-mentioned C _1-10 alkyl group, halogen atom , Hydroxyl group, C
_It may be substituted with 1 to 3 alkoxy groups or the like.
Specific examples of the substituted aryl group include, for example, 4-chlorophenyl, 3,4-dimethoxyphenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydro-2
-Naphthyl and the like.

The "aralkyl group which may be substituted"
As the aralkyl group in the above, a C _7-19 aralkyl group such as benzyl, naphthylethyl, trityl or the like is preferably used. On the aromatic ring, a C _1-10 alkyl group, a halogen atom, a hydroxyl group, a C _1-6 alkoxy group is used. 1 to 3
May be substituted. Specific examples of the substituted aralkyl group include, for example, 4-chlorobenzyl, 3,4-dimethoxybenzyl, 4-cyclohexylbenzyl, 5,
6,7,8-tetrahydro-2-naphthylethyl and the like. The aromatic heterocyclic group in the “optionally substituted aromatic heterocyclic group” is preferably a nitrogen atom,
5 to 6 having 1 to 4 oxygen atoms and / or sulfur atoms
A membered aromatic heterocyclic group, for example, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl and the like are used, and these groups are the same as those described above for the C _1-10 alkyl group, halogen atom, hydroxyl group, C _1-6 alkoxy and the like. Up to three may be substituted.

When two alkyl groups are substituted adjacent to each other on the benzene ring A, they are linked to each other to form a group represented by the formula:
(CH ₂ ) _m — wherein m represents an integer of 3 to 5; an alkylene group (eg, trimethylene, tetramethylene, pentamethylene, etc.) may be formed. When substituted adjacent to each other, the formula:
O- (CH _{2) q} -O- wherein, q is an integer of 1 to 3]
May be formed (e.g., methylenedioxy, ethylenedioxy, trimethylenedioxy, etc.). In such a case, a 5- to 7-membered ring is formed together with the carbon atom of the benzene ring. In the formula (I), examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R include an alkyl group (preferably a C _1-10 alkyl group) and an alkenyl group (preferably Is a C _2-10 alkenyl group), an aryl group (preferably a C _6-14 aryl group), an aralkyl group (preferably a C _7-19 aralkyl) and the like. As the substituent on the hydrocarbon group, the aforementioned 5- to 6-membered aromatic heterocyclic group, halogen atom, di-C _1-6 alkoxyphosphoryl group, phosphono group and the like are used.

R is, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
Unsubstituted C _1-6 alkyl groups such as -butyl, pentyl, neopentyl and hexyl are preferred. In the above formula (I), B represents a carboxyl group which may be esterified or amidated. Examples of the esterified carboxyl group in the “optionally esterified carboxyl group” for B include an alkoxycarbonyl group, preferably a C _1-10 alkoxy-carbonyl group (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), aryloxy-carbonyl group, preferably C _6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl etc.), aralkyloxycarbonyl group, preferably C _7-19 An aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, etc.) is used.

The amidated carboxyl group of the "amidated carboxyl group which may be" represented by B is preferably of the ^{formula: -CON (R 4) (R} 5) wherein, R ⁴
And R ⁵ each independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted 5- to 7-membered heterocyclic group. A carbamoyl group which may be substituted. Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁴ and R ⁵ include an alkyl group, preferably a C _1-10 alkyl group (eg, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), alkenyl group, preferably C _2-10 alkenyl group (example) , Allyl, vinyl, 2-pentene-1-
Yl, 3-penten-1-yl, 2-hexen-1-yl,
3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl-2-buten-1-yl, etc.), an aryl group, preferably C _6-14 aryl groups (eg, phenyl, naphthyl, anthryl, etc.) and aralkyl groups, preferably C _7-19 aralkyl groups (eg, benzyl, naphthylethyl, trityl, etc.) are used. (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a hydroxyl group,
(iii) C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), (iv) C _1-6 alkyl group (eg,
An amino group (eg, amino, methylamino, ethylamino, dimethyl) which may be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Amino, diethylamino, dipropylamino, etc.), (v) amino group substituted with an acyl group (eg, C _1-10 alkanoyl group, etc.) (eg, acetylamino, propionylamino, benzoylamino, etc.), (vi) C _A carbamoyl group optionally substituted with a _1-6 alkyl group (eg, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), (vii) a _C1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, etc.), (viii) a mono- or di-alkoxyphosphoryl group [ , Mono - or di -C _1-6 alkoxy phosphoryl group (e.g., dimethoxyphosphoryl, diethoxyphosphoryl, ethylenedioxy phosphoryl, etc.), etc.], (ix) mono- - or di - alkoxy phosphoryl alkyl group [eg, mono - or Di-C _1-6 alkoxyphosphoryl-C _1-3 alkyl group (eg, methoxyphosphorylmethyl, ethoxyphosphorylmethyl, methoxyphosphorylethyl, ethoxyphosphorylethyl, dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl, dimethoxyphosphorylethyl, diethoxyphosphoryl) Ethyl, etc.), and (x)

Embedded image Or (xi) a phosphono group, (xii) an aromatic heterocyclic group (as defined above), and the like.

The heterocyclic group in the "optionally substituted 5- to 7-membered heterocyclic group" for R ⁴ and R ⁵ includes, for example, a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom.
A 7-membered heterocyclic group, a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, and a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and one sulfur atom or oxygen atom are used. These heterocyclic groups may be condensed with a 6-membered ring containing not more than 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. As the substituent of the heterocyclic group, R ⁴ and R ⁴
1 to 4 substituents which may be possessed by the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by Preferred examples of the 5- to 7-membered heterocyclic group represented by R ⁴ and R ⁵ include, for example, 2-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrido [2,3-
d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, quinolyl, thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl,
Furyl, pyrrolidinyl, benzothienyl, indolyl,
Imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino and the like.

R ⁴ and R ⁵ are linked together to form a compound of the formula: —NR
⁴ (R ⁵ ) may form a 5- to 7-membered ring, and examples of such a ring include morpholine, piperidine, thiomorpholine, homopiperidine, piperidine, pyrrolidine, thiazolidine, azepine and the like. Specific examples of the substituted alkyl group which is a preferred example of the “optionally substituted hydrocarbon group” for R ⁴ and R ⁵ include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2
-Dimethoxyethyl, 2,2-diethoxyethyl, 2-
Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-thienyl) ethyl, 3- (3-furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl,
2-piperidinoethyl, 2- (N, N-dimethylamino)
Ethyl, 2- (N-methyl-N-ethylamino) ethyl,
2- (N, N-diisopropylamino) ethyl, 5- (N,
N-dimethylamino) pentyl, N, N-dimethylcarbamoylethyl, N, N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, isopropoxycarbonylethyl, tert-butoxycarbonylpropyl, 2-
Diethoxyphosphorylethyl, 3-dipropoxyphosphorylpropyl, 4-dibutoxyphosphorylbutyl, ethylenedioxyphosphorylmethyl, 2-phosphonoethyl,
Specific examples of the substituted aralkyl group such as 3-phosphonopropyl include, for example, 4-chlorobenzyl, 3- (2-
Fluorophenyl) propyl, 3-methoxybenzyl,
3,4-dimethoxyphenethyl, 4-ethylbenzyl,
Substituted aryl groups such as 4- (3-trifluoromethylphenyl) butyl, 4-acetylaminobenzyl, 4-dimethylaminophenethyl, 4-diethoxyphosphorylbenzyl, 2- (4-dipropoxyphosphorylmethylphenyl) ethyl As a specific example of 4-chlorophenyl, 4-cyclohexylphenyl, 5,6,7,8
-Tetrahydro-2-naphthyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 6-methoxy-2-naphthyl, 4-
(4-chlorobenzyloxy) phenyl, 3,4-methylenedioxyphenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 4-benzoylaminophenyl, 4-diethoxycarbamoylphenyl, 4-tert-butoxycarbonylphenyl, 4-diethoxyphosphorylphenyl, 4
-Diethoxyphosphorylmethylphenyl, 4- (2-diethoxyphosphorylethyl) phenyl, 2-diethoxyphosphorylmethylphenyl, 3-diethoxyphosphorylmethylphenyl, 4-dipropoxyphosphorylphenyl, 4- (2-phosphonoethyl) phenyl Specific examples of substituted 5- to 7-membered heterocyclic groups such as, 4-phosphonomethylphenyl and 4-phosphonophenyl include, for example, 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, Methyl-2-benzothiazolyl, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4- (4-chlorophenyl) -5-methyl-2-oxazolyl, 3-phenyl-1,2, 4-thiadiazol-5-yl, 5-methyl-1,3,4-thiadiazole-
2-yl, 5-acetylamino-2-pyrimidyl, 3-
Methyl-2-thienyl, 4,5-dimethyl-2-furanyl, 4-methyl-2-morpholinyl and the like.

Among the above, ring A is preferably the same or different, and is preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group and an optionally substituted One or more of the good amino groups, more preferably one or two
Is a benzene ring which may be substituted. More preferred ring A includes a halogen atom, a C _1-10 (more preferably C _1-5 ) alkyl group, and a C _1-10 (further preferably C _1-10 )
_1-5 ) alkoxy group, formula: —O— (CH ₂ ) _q —O—
q represents an integer of 1 to 3], or an alkylenedioxy group represented by the formula: and / or C _1-10 (more preferably C _1-5 )
Is a benzene ring which may be substituted with one or two same or different groups selected from the above alkylthio groups.
Particularly preferred examples of the ring A include a compound represented by the formula: —O— (CH ₂ ) _q —
O- [wherein q is an integer of 1 to 3] is a benzene ring substituted with an alkylenedioxy group.

B is, for example, an alkoxy-carbonyl group and a formula: -CON (R ⁴ ) (R ⁵ ) wherein R ⁴ and R ⁵ are each a hydrogen atom, an optionally substituted hydrocarbon group or a substituted Or a 5- to 7-membered heterocyclic group which may be substituted]. Preferred examples of R ⁴ and R ⁵ are R
⁴ is a hydrogen atom or a C _1-10 alkyl group (eg, methyl, ethyl, propyl, etc.) and R ⁵ is a halogen (eg, fluorine,
Chlorine, bromine, etc.), _C1-6 alkoxy (eg, methoxy, ethoxy, etc.), mono- or di-alkoxyphosphoryl (eg, mono- or di- _C1-6 alkoxyphosphoryl, such as dimethoxyphosphoryl, diethoxyphosphoryl, etc.) ),
Mono- or di-alkoxyphosphorylalkyl (eg,
Substituted with mono- or di-C _1-6 alkoxyphosphoryl-C _1-3 alkyl such as dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl or C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl and the like). Phenyl or phenyl-
A C _1-3 alkyl group or a 5- or 6-membered heterocyclic group having one or two nitrogen atoms or one nitrogen atom and one sulfur atom which may be substituted by a phenyl group (eg, pyridyl Etc.). More preferred examples of R ⁴ and R ⁵ include a phenyl group in which R ⁴ is a hydrogen atom and R ⁵ is substituted by mono- or di-C _1-6 alkoxyphosphoryl-C _1-3 alkyl (eg, 4- Diethoxyphosphorylmethylphenyl).

In the above formula (I), X is -CH (OH)
-Or -CO-, preferably -CO-. In the above formula (I), k is 0 or 1, n is 0,
1 or 2, and preferably when k is 1 and n is 0. R is preferably a hydrogen atom, a C _1-6 alkyl group (eg, methyl, ethyl, etc.) or a phenyl group. More preferred examples of the compound (I) include, for example, those represented by the formula (II)

Embedded image [Wherein, R ¹ represents hydrogen or a hydrocarbon group which may be substituted, and R ² and R ³ each represent a lower alkyl group or together represent a lower alkylene group]. Active benzothiepine derivative. The formula (I
In I), the "optionally substituted hydrocarbon group" represented by R ^1, have the same meaning as "optionally substituted hydrocarbon group" represented by R, among others for example, methyl, ethyl Unsubstituted C _1-6 alkyl groups, such as, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc., are particularly preferably C _1-4 alkyl groups. The “lower alkyl group” represented by R ² and R ³ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl,
C _1-6 such as neopentyl and hexyl (preferably
C _1-4 ) alkyl groups and the like. When R ² and R ³ together represent a lower alkylene group, a phosphorylmethyl group containing these;

Embedded image Is, for example, the expression

Embedded image [Wherein, p represents an integer of 2 to 4. ]. As R ¹ , R ² and R ³ , for example, each is preferably a C _1-4 alkyl group such as methyl, ethyl and the like. The compound (II) is an optically active compound having a (2R, 4S) coordination, and is preferably free from a compound having a (2S, 4R) coordination and having an optical purity closer to 100%.

As the salt of the sulfur-containing heterocyclic compound used in the present invention, a pharmacologically acceptable salt is preferably used.
As pharmacologically acceptable salts, salts with inorganic bases, salts with organic bases, salts with basic or acidic amino acids and the like are used. Examples of the inorganic base include alkali metals (eg, sodium, potassium, etc.) and alkaline earth metals (eg, calcium, magnesium, etc.), and examples of the organic base include trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzyl. Ethylenediamine, diethanolamine, etc., are inorganic acids such as hydrochloric acid, hydrobromic acid,
Hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, etc., and organic acids include formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfone. Acids, citric acid and the like, and basic or acidic amino acids, for example, arginine, lysine, aspartic acid, glutamic acid and the like are specifically used.

Particularly preferred examples of the compound (II) include:
For example, (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5
-Oxo-3-benzothiepine-2-carboxamide (hereinafter sometimes referred to as compound A) or a salt thereof. Preferred examples of the sulfur-containing heterocyclic compound include, for example, JP-A-3-232880 and JP-A-4-234.
Sulfur-containing heterocyclic compounds having an osteogenesis promoting action described in, for example, JP-A-364179 and JP-A-5-294960 [eg, (2R, 4S)-(-)-N- [4- (diethoxyphos) Folylmethyl) phenyl] -1,2,
4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide, etc.] or a salt thereof, which is specifically described in JP-A-8-231569. Various benzothiepine derivatives are also included. These may be used in combination of two or more at an appropriate ratio.

The sulfur-containing heterocyclic compound used in the present invention is
For example, it can be produced by the method described in the above-mentioned patent publication or a method analogous thereto.

The biodegradable α-hydroxycarboxylic acid polymer in the present invention includes, for example, a compound represented by the general formula (II)
I)

Embedded image [In the formula, R ⁶ represents hydrogen or an alkyl group having 1 to 8 carbon atoms.] A polymer homopolymer, a polymer copolymer or a mixture thereof of α-hydroxycarboxylic acids represented by the formula: In the general formula (III), examples of the C _1-8 alkyl group represented by R ⁶ include methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl, t
ert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Preferably, a linear or branched alkyl group having 2 to 5 carbon atoms is used. Specific examples include, for example, ethyl, propyl, isopropyl, butyl,
Isobutyl and the like.

Preferred specific examples of the α-hydroxycarboxylic acid represented by the general formula (III) include, for example, glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, Examples include 2-hydroxycaproic acid, 2-hydroxyisocaproic acid, and 2-hydroxycapric acid. Of these, glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, and 2-hydroxycaproic acid are particularly preferred. These α-hydroxycarboxylic acids may be any of D-form, L-form and D, L-form when an optical isomer is present. One or more of the α-hydroxycarboxylic acids represented by the general formula (III) may be used in an appropriate ratio. In a polymer copolymer produced by using two or more kinds of α-hydroxycarboxylic acids represented by the general formula (III) at an appropriate ratio, the form of copolymerization may be any of random, block, and graft. . Preferably, it is a random copolymer. General formula (II
As the polymer produced using one kind of the α-hydroxycarboxylic acid represented by I), when the α-hydroxycarboxylic acid has an optical isomer, an L-form, a D-form and Any of these mixtures may be used, but D-form / L-
Preferred are those with a body (mol%) in the range of about 75/25 to about 20/80. More preferably, it is a high molecular polymer having a D-form / L-form (mol%) in the range of about 60/40 to about 25/75. Particularly preferred is a high molecular polymer having a D-form / L-form (mol%) in the range of about 55/45 to about 25/75. The high molecular weight polymer has a weight average molecular weight of about 15
The range of 00 to 30,000 is preferred. More preferably, the weight average molecular weight is in the range of about 2000-20,000. Particularly preferably, the weight average molecular weight is about 3,000
It is in the range of 15,000. Further, the degree of dispersion of the high molecular polymer is preferably about 1.2 to 4.0. Particularly preferred is a case where the degree of dispersion is about 1.5 to 3.5.

With respect to the method for synthesizing the high molecular weight polymer, a method of ring-opening polymerization of a dimer of α-hydroxycarboxylic acid represented by the general formula (III) (eg, glycolide, lactide, etc.) A method of dehydrating polycondensation of a hydroxycarboxylic acid is known. In order to obtain a relatively low molecular weight high molecular polymer used in the present invention, α represented by the general formula (III)
-A method of directly dehydrating polycondensation of hydroxycarboxylic acid is preferred. This method is described in, for example, JP-A-61-28521. As the α-hydroxycarboxylic acid used alone, glycolic acid, lactic acid, and 2-hydroxybutyric acid are preferred. Particularly preferred is lactic acid. Preferred examples of the polymer copolymer include, for example, a polymer copolymer of glycolic acid and lactic acid, glycolic acid and an alkyl group of the general formula (III) wherein R is 2 to 8 carbon atoms (eg,
High-molecular copolymer with α-hydroxycarboxylic acid which is ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, 2,2-dimethylbutyl, 2-ethylbutyl, etc. (hereinafter abbreviated as glycolic acid copolymer) And the like. Particularly preferred are a polymer copolymer of glycolic acid and lactic acid, and a polymer copolymer of glycolic acid and 2-hydroxybutyric acid.

The ratio (mol%) of lactic acid to glycolic acid in the high molecular weight copolymer of glycolic acid and lactic acid is preferably about 40 to 95 mol% for lactic acid and about 60 to 5 mol% for glycolic acid. Preferably, lactic acid is about 50-95 mol% and glycolic acid is about 50-5 mol%, and more preferably, lactic acid is about 60-90 mol% and glycolic acid is about 40-10 mol%. The average molecular weight of these high molecular weight polymers used in the present invention is preferably about 1,000 to 100,000, more preferably about 2,000 to 5,000.
0, especially in the range of about 5000 to 30,000. The degree of dispersion of the high molecular weight copolymer of glycolic acid and lactic acid (weight average molecular weight / number average molecular weight) is about 1.
2-4.0 is preferred. Particularly preferably, about 1.5 to 3.
5 The composition ratio of glycolic acid in the glycolic acid copolymer to α-hydroxycarboxylic acid of the general formula (III) wherein R ⁶ is an alkyl group having 2 to 8 carbon atoms is such that glycolic acid is about 10 to about 75 mol %, The remainder is preferably α-hydroxycarboxylic acid. More preferably, about 20 to about 75 mol% glycolic acid, with the balance being α-
This is the case when it is a hydroxycarboxylic acid. Particularly preferably, about 40 to about 70 mol% of glycolic acid is used, with the balance being α-
This is the case when it is a hydroxycarboxylic acid. These glycolic acid copolymers have a weight average molecular weight of about 2000 to 50.
000 are used. Preferably, it is a copolymer having a weight average molecular weight of about 3000 to 40,000. More preferably, the weight average molecular weight is about 8,000 to 30,000
Is a copolymer of The degree of dispersion (weight average molecular weight / number average molecular weight) of these glycolic acid copolymers is about 1.
2-4.0 is preferred. Particularly preferably, about 1.5 to 3.
5 The glycolic acid and lactic acid copolymer or glycolic acid copolymer is a production method known per se, for example,
It can be synthesized according to the method described in JP-A-61-28521 and a method analogous thereto. In the production method of the present invention, the biodegradable α-hydroxycarboxylic acid polymer used as a base of the microparticles is described in JP-A-50-17525 and JP-A-5-17525 in addition to the above publications.
6-45920, 57-118512, 57-
It can be produced according to known methods described in 150609, 62-54760, EP-A-481732, and the like, or a method analogous thereto.

In the present invention, the weight average molecular weight and the degree of dispersion mean that the weight average molecular weight is 120,000, 52,000 or less.
0, 22,000, 9,200, 5,050, 2,950,
The molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC) using nine kinds of polystyrenes of 1,050, 580 and 162 as a reference substance and the calculated degree of dispersion are shown. The measurement was performed using a GPC column KF8.
04L × 2 (manufactured by Showa Denko), RI monitor L-3300
(Manufactured by Hitachi, Ltd.) and chloroform was used as a mobile phase. Preferred examples of the mixture of the polymer or copolymer of the α-hydroxycarboxylic acid represented by the general formula (III) include, for example, an appropriate ratio of the glycolic acid copolymer (A) and the polylactic acid (B). And mixtures thereof. The glycolic acid copolymer (A) and the polylactic acid (B) have a mixing ratio (% by weight) represented by (A) / (B) of about 10 /
Used in the range of 90 to about 90/10. Preferably,
The mixing ratio (% by weight) is in the range of about 20/80 to 80/20. More preferably, it is in the range of about 30/70 to 70/30. If either of the components (A) and (B) is too large, only a preparation having almost the same drug release pattern as that obtained when the component (A) or (B) is used alone is obtained, and the release by the mixed base is obtained. A late linear release pattern cannot be expected. The decomposition and disappearance rates of glycolic acid copolymer and polylactic acid vary greatly depending on the molecular weight or composition, but generally, the decomposition and disappearance of glycolic acid copolymer
Since the elimination rate is faster, the release period can be lengthened by increasing the molecular weight of the polylactic acid to be mixed or by decreasing the mixing ratio represented by (A) / (B). Conversely, reducing the molecular weight of the polylactic acid to be mixed,
Alternatively, the emission period can be shortened by changing the mixing ratio represented by (A) / (B) to a large value. Further, the release period can be adjusted by changing the type and ratio of the α-hydroxycarboxylic acid represented by the general formula (III).

In the production method of the present invention, the solid containing the sulfur-containing heterocyclic compound and the biodegradable α-hydroxycarboxylic acid polymer is, for example, (a) a sulfur-containing heterocyclic compound and (b) ) The biodegradable α-hydroxycarboxylic acid polymer is prepared in a solution state in a solvent system capable of simultaneously dissolving (a) and (b) and dried under reduced pressure or a method analogous thereto. . As a method for producing the solutions (a) and (b), any method may be used as long as (a) and (b) finally become a solution in a solution system. The method includes, for example, mixing (a) in a solution or suspension with a solvent and (b) in a solution or suspension with a solvent, and mixing (a) in a solution or suspension with a solvent. A suspension and a mixture of (b), (b) a solution or suspension of a solvent and (a),
(A), (b) and a solvent are mixed, and (a) and (b) are made into a solution state in a solvent system. The above solvent is
After each component is mixed, it is appropriately selected so that a solvent system capable of bringing (a) and (b) into a dissolved state is obtained.

As a solvent system capable of simultaneously dissolving (a) and (b), any solvent system can be used as long as (a) and (b) can finally be in a solution state with the solvent system. Can be used. As such a solvent, specifically, for example, a solvent in which one or two or more of organic solvents of halogenated hydrocarbons are mixed at an appropriate ratio to such an extent that the dissolution of (a) and (b) is not hindered if desired. An aprotic organic solvent and a solvent to which a lower alcohol is added are used. Preferably, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and aprotic organic solvents such as acetonitrile, acetone and dioxane are exemplified. These two or more organic solvents may be mixed at an appropriate ratio and used as a solvent system. Further, if desired, lower alcohols such as methanol, ethanol and propanol may be added to the solvent system to such an extent that the dissolution of (a) and (b) is not hindered.

When preparing the solutions (a) and (b), a surfactant may be added, if desired. As the surfactant, those similar to the surfactant described below are used. The amount of the sulfur-containing heterocyclic compound to be used varies depending on the kind of the drug, the duration of the effect and the like, but the concentration in the solution is about 0.001% to about 15% (W / W), and more preferably 0.1% to about 15% (W / W). It is selected from 01% to 10% (W / W).
The amount of the biodegradable α-hydroxycarboxylic acid polymer used depends on the speed and duration of drug release, and is prepared, for example, in an amount of about 0.5 to 10,000 times (weight ratio) the benzothiepine derivative 1. However, it is preferable to use about 1 to 100 times (weight ratio) of the polymer. Drying under reduced pressure can be performed according to a method known per se. For example, a method of drying by gradually reducing the pressure in a reduced-pressure constant temperature bath, a method of drying while adjusting the degree of reduced pressure using a rotary evaporator, and the like can be mentioned. The degree of pressure reduction is preferably, for example, about 400 Torr or less. Even more preferably, it is about 300 Torr or less.
Preferably, the temperature ranges from about 10 to 70 ° C. More preferably, it is in the range of about 15 to 50 ° C. The time for performing the above operation is preferably, for example, about 1 hour to 72 hours. More preferably, the time is about 1 to 48 hours.

The thus obtained solid is pulverized in the presence of a pulverizing aid to produce microparticles. The pulverization can be carried out according to a pulverization method known per se. For example, it is carried out by using a usual pulverizer such as a turbo counter jet mill pulverizer and a supersonic jet pulverizer. In this step, the solid material is usually coarsely pulverized by a pulverizer such as a dairy needle or a power mill before being applied to the pulverizer in order to increase the pulverization efficiency. The size of the particles prepared by the coarse pulverization varies depending on the pulverization conditions and the quality (eg, particle size) of the final microparticles, but those having a particle size of 4 mm or less, preferably 2 mm or less, particularly about 1 mm to about 2 mm are preferred. preferable. The degree of pulverization may be selected according to the method of administering the microparticles, the specification of the final product, etc. For example, when used as a suspension for injection, the dispersibility and needle penetration are satisfied. The average particle diameter may be in the range of about 0.5 to 400 μm. More preferably, it is in the range of about 2 to 200 μm. When performing the above-mentioned pulverization operation, it is also effective to add a coagulation inhibitor if necessary and to perform the pulverization operation in order to prevent agglomeration of the microparticles during pulverization and storage. After the pulverizing operation, the agglomeration inhibitor may be separately mixed and added by a mixer.

As the grinding aid, a substance which is generally water-soluble, solid under the grinding conditions, and having a higher hardness than the solid material to be ground is used. The larger the difference in hardness from the object to be crushed, the better, and it is preferably a crystalline or crystalline substance. As a specific example,
For example, (1) alkali metal halides (eg, sodium chloride, potassium chloride, sodium bromide, potassium bromide, etc.), alkaline earth metal halides (eg, calcium chloride, magnesium chloride, etc.), alkali metal phosphoric acid Salts (eg, trisodium phosphate, potassium triphosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.), oxides of alkaline earth metals (eg, Inorganic salts such as magnesium oxide and calcium oxide) and hydroxides of alkaline earth metals (eg, magnesium hydroxide and calcium hydroxide); (2) organic acids such as carbonic acid and citric acid or salts thereof, alkali metals Carbonate or bicarbonate (eg, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali Carbonates of similar metals (eg, calcium carbonate, magnesium carbonate, etc.), alkali metal salts of citric acid, etc .; (3) sugar alcohols such as mannitol, sorbitol, monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, , Lactose, sucrose, maltose, etc.), amino sugars (eg, glucosamine, galactosamine, chondroitin sulfate, etc.), and polysaccharides (eg, dextrin, hydroxypropyl cellulose, etc.). One or more of these may be used in combination at an appropriate ratio. Of these, inorganic salts and water-soluble saccharides (eg, sugar alcohols, monosaccharides, disaccharides, amino sugars) are particularly preferred. Further, when pulverization is carried out under a low temperature condition below the freezing point, use of ice (water) as a pulverization auxiliary other than the above is also within the scope of the present invention. The compounding amount of the above-mentioned pulverizing auxiliary is about 0.001 to 100 times by weight based on the solid matter, and is appropriately selected depending on the average particle diameter of the target microparticles. Under the same conditions, the larger the blending amount of the grinding aid, the smaller the particle size of the obtained microparticles tends to be. The average particle size of the weight distribution of the grinding aid when charged into the grinding machine is 0.5 to 2000 μm.
m and is appropriately selected depending on the average particle diameter of the microparticles. The particle size of the obtained microparticles can be controlled by the type, amount and average particle size of the grinding aid to be blended.

As an example of a preferred embodiment of the present invention, a solid material having a mean particle size of about 1
The case of pulverization into particles of 0 to about 50 μm will be described below. A solid matter (preferably a solid solution) roughly pulverized to a particle diameter of 2 mm or less has a weight ratio of about 3 to 50% based on the solid matter.
(W / W) The mixture obtained by adding and mixing a grinding aid is supplied with a supersonic jet grinder at a supply pressure of pneumatic pressure of 0.05 to 0.5 MPa.
a: Pulverization is performed under pulverization conditions of a supply rate of a pulverized material of about 30 g / min to about 120 g / min. After the pulverization is completed, the pulverization auxiliary can be removed by washing with water or a known separation method based on a difference in particle size, if necessary. When using ice as a grinding aid, it is also useful to use a freeze-drying method as a removing means. The surface of the microparticle is coated with a water-soluble polymer substance or / and a surfactant which is water-soluble and can be administered to the human body at room temperature (about 15 to 25 ° C), and the microparticle is dispersed in a dispersion medium. Dispersibility can be improved. The coating mentioned here includes a coating of a part or the whole of the microparticle surface. It is also effective to disperse or coat the surface of the microparticles with a liquid water-soluble polymer and / or a surfactant in an amount that does not cause a problem as a preparation.

Preferred examples of the surfactant include:
For example, sorbitan fatty acid esters (eg, sorbitan monopalmitate, sorbitan sesquistearate, etc.), glycerin fatty acid esters (eg, glyceryl monostearate (self-emulsifying type), etc.), propylene glycol fatty acid esters (eg, propylene glycol monostearate) Etc.), polyoxyethylene glycerin fatty acid ester [eg, POE (15) glyceryl monostearate, etc.], polyethylene glycol fatty acid ester [eg, POE (10) monostearate, PEG distearate, etc.], polyoxyethylene alkyl ether [eg. , POE (21) lauryl ether, POE (2
0) Stearyl ether, etc.], polyoxyethylene hydrogenated castor oil [eg POE (80) hydrogenated castor oil, HCO
60, HCO50 (manufactured by Nikko Chemicals), polyoxyethylene sorbite beeswax derivatives [eg, POE
(20) sorbitol beeswax, etc.), polyoxyethylene lanolin alcohol [eg, POE (20) lanolin alcohol, etc.], polyoxyethylene sorbite fatty acid ester [eg, POE (6) sorbit hexastearate, etc.] Pluronic surfactant ( For example, nonionic surfactants such as Pluronic F68 (polyoxyethylene (160) polyoxypropylene (30) glycol), alkali metal dodecyl sulfate (eg, sodium dodecyl sulfate), alkali metal stearate (eg, stearin) And anionic surfactants of alkali metal palmitate (eg, sodium palmitate). As the liquid surfactant, for example, Tween 20, Tween
n) 80 (manufactured by Astra Powder Co., USA). One or two or more of these can be used in combination at an appropriate ratio. Preferred specific examples of the water-soluble polymer substance include dextrin, dextran sulfate, sodium chondroitin sulfate, and polyethylene glycols (eg, polyethylene glycol 1000).
(PEG 1,000) 1500, 4000, 600
0, 20000). One or two or more of these can be used in combination at an appropriate ratio.

The means for coating the surface of the microparticles with the water-soluble polymer substance and / or the surfactant is not particularly limited. For example, there is a method in which a water-soluble polymer substance and / or a surfactant are added to the pulverizing step at the same time as pulverizing the solid material or pulverizing the coarsely pulverized material. In this case, the solid water-soluble polymer substance and / or the surfactant may be premixed with the material to be pulverized or supplied separately to the pulverizer. After dissolving the agent in a suitable solvent, it may be introduced into the pulverizing step. Further, an anticoagulant and a water-soluble polymer substance and / or a surfactant are dissolved or dispersed in an appropriate solvent (eg, water, alcohol such as methanol, ethanol, etc.) and then dried. After separating the water-soluble polymer substance and the surfactant from this solution, the dried substance may be ground at the same time. Further, the dispersion or coating of the surfactant on the surface of the microparticles may be performed by mixing the microparticles with the water-soluble polymer substance and / or the surfactant after pulverizing the solid. As the mixing method, for example, a solid is pulverized and then obtained by dissolving a water-soluble polymer substance and / or a surfactant in a suitable aqueous solvent (eg, water, alcohol such as methanol, ethanol, etc.). After dispersing the micro particles,
A freeze-drying method may be used. At this time, an appropriate amount of an anti-agglomeration agent may be added. As the anticoagulant,
The agglomeration inhibitor described above can be used. In order to maintain the shape after freeze-drying, for example, mannitol, D-sorbitol,
Glucose, sucrose, lactose, dextrin,
It is also effective to add dextran sulfate, chondroitin sulfate and the like. The concentration of the water-soluble polymer and / or surfactant in the solution for dispersing the microparticles used during lyophilization is about 0.000001%
(W / v) to 10% (w / v), preferably about 0.00
01% (w / v) to 3% (w / v), more preferably
0.001% (w / v) to 0.5% (w / v) is good. In addition, a buffer (eg, phosphate buffer, citrate buffer, etc.),
The addition of an osmotic pressure adjusting agent (eg, sodium chloride, saccharides (eg, mannitol, sorbitol, lactose, etc.), etc.) is effective for making the dispersibility of the lyophilization liquid uniform. Among the above methods, a method by freeze-drying is particularly preferred. The mixing ratio of the water-soluble polymer substance and / or the surfactant to the microparticles may be within a range in which improvement in dispersibility is recognized. Specifically, the weight ratio is about 0.0.
000001 to 10 times, more preferably about 0.000
05 to 5 times is selected. More preferably about 0.000
01-0.01 times is selected.

The solid matter may be pulverized by further adding an anti-agglomeration agent. In general, a non-adhesive substance which is solid at ordinary temperature (about 15 to 25 ° C.) and can be administered to a water-soluble human body is used as the anti-agglomeration agent. Specific examples thereof include inorganic salts (eg, the above-mentioned alkali metal halides, alkali earth metal halides, alkali metal carbonates or bicarbonates, alkaline earth metal carbonates, alkali metal phosphates). Salts, alkaline earth metal oxides, alkaline earth metal hydroxides, etc.); acetic acid alkali metal salts or alkaline earth metal salts (eg, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, etc.), citric acid Organic acids and salts thereof such as acids, tartaric acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, dextran sulfate, carboxymethylcellulose, alginic acid, pectic acid and alkali metal salts or alkaline earth metal salts of these organic acids; mannitol , Sorbitol, lactose, glucose, sucrose, lactose or starches Examples, corn starch, potato starch) Water-soluble sugars such as; amino acids (e.g., glycine, phenylalanine, cysteine, arginine, etc. Preferably cysteine, arginine); protein (e.g., gelatin,
Fibrin, collagen, albumin, etc.); water-soluble celluloses (eg, crystalline cellulose, carboxymethylcellulose, etc. or salts thereof). One or more of these may be used in combination at an appropriate ratio. Among these, inorganic salts, water-soluble saccharides and amino acids are particularly preferred. The compounding ratio of the anti-agglomeration agent to the microparticles may be within a range where the anti-agglomeration effect is recognized, and specifically, about 0.001 to 100 times, preferably about 0.01 to 5 times by weight.
It is selected from 0, more preferably from about 0.1 to 10 times.

The microparticles obtained according to the present invention can be directly administered to a living body.
It can be formed into various preparations and administered, and can also be used as a raw material when producing such preparations. The above-mentioned preparations include injections (eg, intramuscular, subcutaneous, for internal administration, etc.), oral preparations (eg, powders, granules, capsules, tablets), external preparations (eg, nasal preparations, transdermal Suppositories), suppositories (eg, rectal suppositories, vaginal suppositories) and the like. The amount of drug contained in these preparations depends on the type of drug, dosage form,
Although it may vary depending on the disease to be treated, it is usually about 1 mg to about 200 mg, preferably about 3 mg / g of the preparation.
mg to about 150 mg, particularly preferably about 5 mg to about 100 mg. These preparations can be produced by a method known per se, which is generally used in the preparation process. For example, if desired, microparticles may be added to a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO60, HCO50 (manufactured by Nikko Chemicals), a pluronic surfactant (for example,
Pluronic F68, etc.) carboxymethylcellulose, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, sodium chondroitin sulfate, etc.), preservatives (eg, methylparaben, ethylparaben,
Propylparaben, ethylparaben, butylparaben,
Benzyl alcohol, chlorobutanol, etc.), tonicity agents (eg, sodium chloride, glycerin, sorbitol,
Glucose, mannitol, lactose, sucrose, sodium phosphate, etc.) and dispersed in an aqueous solvent to form an aqueous suspension, or olive oil, sesame oil, peanut oil,
It can be dispersed in vegetable oils such as cottonseed oil and corn oil, propylene glycol and the like, formed into an oily suspension, and used as an injection.

For example, in order to prepare a preparation for oral administration, the excipient (eg, lactose, sucrose, starch, etc.), disintegrant (eg, starch, calcium carbonate, etc.), binder (Eg, starch,
Gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.)
Alternatively, a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded, and then, if necessary, taste masking,
An oral preparation can be prepared by coating with a method known per se for enteric or sustained purposes. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate,
Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, West Germany, methacrylic acid
A film agent such as acrylic acid copolymerization) and a dye such as titanium oxide and red iron oxide are used.

To prepare an external preparation, for example, microparticles can be converted into solid, semi-solid or liquid nasal preparations according to a method known per se. For example, as the solid, the microparticles are used as they are,
Alternatively, excipients (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) are added and mixed to form a powdery composition. And The liquid is almost the same as the injection, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred. These are all pH regulators (eg, carbonic acid, phosphoric acid, citric acid,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.) may be added.

For example, in order to prepare a suppository, the microparticles are formed into an oily or aqueous solid by a method known per se.
It can be a semi-solid or liquid suppository. The oily base used in the above composition may be any one that does not dissolve microparticles. Examples thereof include glycerides of higher fatty acids (eg, cocoa butter, witepsols (Dynamite Nobel), etc.), and intermediate fatty acids [eg, miglyols] (Dynamite Nobel) and vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

The dosage of the microparticles obtained by the present invention is determined by the type and content of the sulfur-containing heterocyclic compound as the main drug, the dosage form, the drug release period, the animal to be administered (eg, mouse,
Rats, horses, cattle, mammals such as humans, etc.), the purpose of administration, etc., may vary, but may be any effective amount of the active ingredient. For example, a benzothiepine derivative or a salt thereof is administered to an adult (body weight 5).
0 kg) When administered to one person, the dose of a single drug can be appropriately selected from the range of about 0.35 to 70 mg. The volume of the suspension when administered as an injection can be selected from the range of about 0.1 to 5 ml, preferably about 0.5 to 3 ml.

[0046]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1: (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5
10.0 g of -tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (prepared according to JP-A-8-231569, hereinafter referred to as compound A) And a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid ratio (hereinafter, L /
Abbreviated as G ratio. ) = 85/15, weight average molecular weight 1
(4,000) 90.0 g was dissolved in dichloromethane (methylene chloride) 160 g and poured into a fluororesin coating vessel. This was put into a vacuum drier, and the solvent was removed to obtain a solid solution. After coarse grinding, mannitol 15g,
The mixture was roughly mixed with 2 g of Pluronic F68 and pulverized with a supersonic jet pulverizer (PJM-100SP, manufactured by Nippon Pneumatic) at a supply pressure of pneumatic pressure of 0.3 MPa. Put the resulting formulation in a vacuum dryer controlled shelf temperature to 45 ℃,
The pressure was kept at 0.1 to 0.05 Torr inside pressure for 3 days. A drug uptake rate of 100%, an average particle size of 32 μm, excellent dispersibility in a dispersion medium, and a preparation that was released in rat muscle for about one month were obtained.

Example 2: 1.5 g of Compound A and 6.0 g of a lactic acid-glycolic acid copolymer (L / G = 90/10, weight average molecular weight 14,000) were dissolved in 20 g of dichloromethane (methylene chloride). Poured into stainless steel container. This is put into a vacuum dryer controlled at a shelf temperature of 50 ° C.
Drying was performed at an internal pressure of 0 to 0.01 Torr. The obtained dried product was coarsely pulverized, and 1.5 g of sodium chloride and 4000.2 g of polyethylene glycol (PEG) were added and mixed. Then, a turbo counter jet mill pulverizer (TJ-
0624 Turbo Kogyo) and supply pressure pneumatic 0.2MP
a. Drug uptake rate 100%, average particle size 27
A formulation was obtained which released in μm, rat muscle over about one month.

EXAMPLE 3 1.9 g of compound A and 15.1 g of a lactic acid-glycolic acid copolymer (L / G = 85/15, weight average molecular weight 14,900) were mixed with 26.7 g of dichloromethane.
And poured into a fluororesin coating container.
This was put into a vacuum drier, and the solvent was removed to obtain a solid solution. After the coarse pulverization, 3 g of mannitol was added, and the mixture was pulverized with a supersonic jet pulverizer (PJM-100SP, manufactured by Nippon Pneumatic Industries) at a supply air pressure of 0.1 MPa. After the obtained pulverized product was dispersed in an aqueous solution in which an amino acid (arginine 3.8% or cysteine 2.7%) added as an anticoagulant after freeze-drying was dissolved, freeze-drying was performed to obtain a preparation. When about 100 mg was filled in a 9P vial, the obtained preparation was stable, with no agglomeration of particles being observed even after 4 months in a stability test at 40 ° C. and 75% RH.

Example 4 10 g of Compound A and 90 g of lactic acid-glycolic acid copolymer (L / G = 90/10, weight average molecular weight 13,000) are dissolved in 300 g of dichloromethane and poured into a fluororesin coating vessel. This is placed in a vacuum dryer controlled at a shelf temperature of 50 ° C., and dried at an internal pressure of 10 Torr or less. The resulting dried product is roughly pulverized,
20 g of sodium citrate and polyethylene glycol
After adding 2 g of (PEG) 4000 and mixing, the product passed through a sieve having an aperture of 2 mm was passed through a supersonic jet mill pulverizer (PJM-100).
SP, manufactured by Nippon Pneumatic Industries Co., Ltd.) at a supply pressure of pneumatic pressure of 0.3 MPa.

Example 5 10 g of Compound A and 90 g of a lactic acid-glycolic acid copolymer (L / G = 80/20, weight average molecular weight 15,000) are dissolved in 300 g of dichloromethane and poured into a stainless steel container. This is placed in a vacuum dryer controlled at a shelf temperature of 50 ° C., and dried at an internal pressure of 10 Torr or less. The resulting dried product is coarsely ground and lactose 20 g
And 1 g of Pluronic F68 were added and mixed, and the opening was 2 m.
m through a supersonic jet mill crusher (PJM-
(100SP, manufactured by Nippon Pneumatic Industries Co., Ltd.) and pulverized at a supply pressure of 0.2 MPa.

[0051]

According to the production method of the present invention, the particle size of the obtained microparticles can be controlled.
The sulfur-containing heterocyclic compound of the general formula (I), which is known to have a bone resorption inhibiting action, a bone metabolic improving action, an osteogenesis promoting action, and the like, requires long-term administration such as treatment for fracture, osteoporosis, etc. As a prophylactic / therapeutic agent when applied to the prevention and treatment of disease, a sustained-release preparation having excellent pharmaceutically and controlled release can be produced.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 495/04 116 C07D 495/04 116

Claims (14)

[Claims] 1. A compound of the general formula [In the formula, ring A represents an optionally substituted benzene ring;
Is hydrogen or a hydrocarbon group which may be substituted, B is a carboxyl group which may be esterified or amidated, X is -CH (OH)-or -CO-, and k is 0 or 1. , N represents 0, 1 or 2], respectively, or a physiologically acceptable salt thereof and a biodegradable α-hydroxycarboxylic acid polymer. A method for producing microparticles, comprising grinding a substance in the presence of a grinding aid. 2. A sulfur-containing heterocyclic compound represented by the general formula: Wherein R ¹ is hydrogen or a hydrocarbon group which may be substituted, and R ² and R ³ each represent a lower alkyl group or together represent a lower alkylene group. The method for producing microparticles according to claim 1. 3. The method for producing microparticles according to claim ² , wherein R ¹ is a methyl group and R ² and R ³ are ethyl groups. 4. The method for producing microparticles according to claim 1, wherein the weight average molecular weight of the α-hydroxycarboxylic acid high molecular polymer is about 3,000 to 30,000. 5. The method for producing microparticles according to claim 1, wherein the α-hydroxycarboxylic acid polymer is a polymer of lactic acid and / or glycolic acid. 6. The method according to claim 1, wherein the solid is a solid solution. 7. The method for producing microparticles according to claim 1, wherein the grinding aid is a saccharide. 8. The method for producing microparticles according to claim 1, wherein the grinding aid is an organic acid, a salt or an inorganic salt thereof. 9. The solid matter may further comprise a water-soluble polymer substance and / or
The method for producing microparticles according to claim 1, wherein the microparticles are ground together with a surfactant. 10. The microparticle is further coated with a water-soluble polymer substance and / or a surfactant.
Manufacturing method of the described microparticles. 11. The method for producing microparticles according to claim 9, wherein the water-soluble polymer substance is polyethylene glycol. 12. The method for producing microparticles according to claim 11, wherein the polyethylene glycol is polyethylene glycol 4000. 13. The method for producing microparticles according to claim 9, wherein the surfactant is a nonionic surfactant. 14. The method for producing microparticles according to claim 13, wherein the nonionic surfactant is polyoxyethylene (160) polyoxypropylene (30) glycol.