Method for producing a microparticle

This invention provides a method for producing a microparticle which comprises pulverizing a solid preparation comprising a compound represented by the formula: ##STR1## wherein ring A is an optionally substituted benzene ring; R is a hydrogen atom or an optionally substituted hydrocarbon group; B is an optionally esterified or amidated carboxyl group; X is --CH(OH)-- or --CO--; k is 0 or 1; and n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof and a biodegradable polymer of .alpha.-hydroxycarboxylic acid in the presence of a pulverizing auxiliary, which can provide microparticles which are less adhesive and involve less aggregation and are thus excellent in drug entrapment ratio and control of drug-release in a desired particle size.

TECHNICAL FIELD 
The present invention relates to a method for producing a microparticle. 
More specifically, the method of the present invention provides a 
microparticle having good dispersion ability and which does not 
substantially adhere or aggregate together. 
BACKGROUND ART 
The prior art includes, as disclosed in EP-A-481,732, a sustained-release 
preparation comprising a drug, a polylactic acid and a glycolic 
acid-hydroxycarboxylic acid [HOCE(C.sub.2-8 alkyl)COOH] copolymer. The 
disclosed process comprises preparing a water-in-oil (W/O) emulsion 
consisting of an internal water phase consisting of an aqueous solution of 
a physiologically active peptide and an external oil phase consisting of a 
solution of a biodegradable polymer in an organic solvent, adding said W/O 
emulsion to a medium such as water and processing the resulting W/O/W 
emulsion into sustained-release microcapsules (in-water drying method). 
However, generally a microparticle prepared by the in-water drying method 
does not achieve a high drug content. In that method, the encapsulation 
rate of the microparticle varies widely among the lots and is easily 
influenced by expansion of the production scale. 
A spray-drying method is also known in the art. Although the microparticles 
produced by this method usually have an adequate encapsulation rate, the 
quality of the particles varies widely according to the changes of 
production condition. Generally, a lot of the microparticles are aggregate 
or adhere together in this method. Also, the dispersion ability of the 
particles in an aqueous dispersion solvent is reduced as compared with 
that of in-water drying method. 
Further, in the known method for preparing a microparticle by pulverizing a 
solid dispersion containing a drug and a biodegradable polymer, there is a 
problem that a solid dispersion prepared by using an adhesive drug, 
especially in a large amount, is unable to be pulverized by a general 
pulverizing technique. 
DISCLOSURE OF INVENTION 
The present inventors made extensive investigation to obtain 
sustained-release microparticles (e.g. microcapsules) which rarely 
aggregate or adhere to each other and have a good dispersion ability, and 
found that microparticles having an excellent quality, wherein aggregation 
or adhesion among the particles takes place in a small ratio, drug 
encapsulation rate is high and the initial release of drug is controlled 
in a low rate in the releasing test, could be efficiently produced on a 
large scale in a method which comprises dissolving a drug and the polymer 
in a solvent which could dissolve them together to provide a solution, 
preparing a solid dispersion by drying the resultant solution under 
reduced pressure or in a manner analogous thereto and pulverizing the 
resultant solid dispersion in the presence of a pulverizing auxiliary. 
Further, it was also found that the microparticles were imparted with a 
better dispersion ability by coating with a water-soluble polymer and/or a 
nonionic surfactant. 
The present invention was accomplished as a result of further investigation 
made based on these findings. 
Accordingly, the present invention relates to: 
(1) a method for producing a microparticle which comprises pulverizing a 
solid preparation comprising a compound represented by the formula: 
##STR2## 
wherein ring A is an optionally substituted benzene ring; R is a hydrogen 
atom or an optionally substituted hydrocarbon group; B is an optionally 
esterified or amidated carboxyl group; X is --CH(OH)-- or --CO--; k is 0 
or 1; and n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof and 
a biodegradable polymer of .alpha.-hydroxycarboxylic acid in the presence 
of a pulverizing auxiliary, 
(2) a method according to above (1), wherein the compound is a compound 
represented by the formula: 
##STR3## 
wherein R.sup.1 is a hydrogen atom or an optionally substituted 
hydrocarbon group; and R.sup.2 and R.sup.3 are independently a lower alkyl 
group or bind together to form a lower alkylene group, 
(3) a method according to above (2), wherein R.sup.1 is a methyl group, and 
R.sup.2 and R.sup.3 are ethyl group, 
(4) a method according to above (1), wherein the weight-average molecular 
weight of the polymer of the .alpha.-hydroxycarboxylic acid is about 3,000 
to about 30,000, 
(5) a method according to above (1), wherein the .alpha.-hydroxycarboxylic 
acid is lactic acid and/or glycolic acid, 
(6) a method according to above (1), wherein the solid preparation is a 
solid dispersion, 
(7) a method according to above (1), wherein the pulverizing auxiliary is a 
sugar or a sugar alcohol, 
(8) a method according to above (1), wherein the pulverizing auxiliary is 
an organic acid, a salt thereof or a salt of an inorganic acid, 
(9) a method according to above (1), wherein the solid preparation is 
pulverized with a water-soluble polymer and/or a surfactant, 
(10) a method according to above (1), which further comprises a step for 
coating the microparticle with a water-soluble polymer and/or a 
surfactant, 
(11) a method according to above (9) or (10), wherein the surfactant is a 
nonionic surfactant, 
(12) a method according to above (11), wherein the surfactant is pluronic 
F68, 
(13) a method according to above (9) or (10), wherein the water-soluble 
polymer is a polyethylene glycol, 
(14) a method according to above (13), wherein the polyethylene glycol is 
polyethylene glycol 4000, 
(15) a method according to above (1), wherein the solid preparation is 
pulverized with an antiaggregation agent, 
(16) a method according to above (1), which is followed by a step for 
dispersing the pulverized solid preparation to an aqueous dispersion 
solvent in the presence of an antiaggregation agent, 
(17) a method according to above (15) or (16), wherein the antiaggregation 
agent is an amino acid, 
(18) a method according to above (17), wherein the amino acid is arginine 
or cysteine, 
(19) a method for producing a microparticle of 
(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide or a 
pharmaceutically acceptable salt thereof as an active ingredient which 
comprises pulverizing a solid dispersion comprising the active ingredient 
and a glycolic acid-lactic acid copolymer having a weight-average 
molecular weight in the range from about 3,000 to about 30,000 and the 
ratio of lactic acid/glycolic acid is about 60/40 to 100/0 in the presence 
of a pulverizing auxiliary with or without (1) a water-soluble polymer 
and/or a nonionic surfactant (2) an amino acid as an antiaggregation 
agent, 
(20) a method for producing a microparticle of 
(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide or a 
pharmaceutically acceptable salt thereof which comprises pulverizing a 
solid dispersion comprising the active ingredient and glycolic acid/lactic 
acid copolymer having a weight-average molecular weight in the range from 
about 3,000 to about 30,000 and the ratio of lactic acid/glycolic acid is 
about 60/40 to 100/0 in the presence of a pulverizing auxiliary with 
either (1) a water-soluble polymer or surfactant, and/or (2) an 
antiaggregation agent, optionally followed by coating the resultant 
microparticle with the remaining of (1) or (2), and 
(21) a method for producing a microparticle of 
(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide or a 
pharmaceutically acceptable salt thereof which comprises pulverizing a 
solid dispersion comprising the active ingredient and glycolic acid/lactic 
acid copolymer having a weight-average molecular weight in the range from 
about 3,000 to about 30,000 and the ratio of lactic acid/glycolic acid is 
about 60/40 to 100/0 in the presence of a pulverizing auxiliary optionally 
followed by coating the resultant microparticle with (1) a water-soluble 
polymer and/or surfactant, and/or (2) an antiaggregation agent. 
In the present invention, a compound of the formula (I): 
##STR4## 
wherein ring A is an optionally substituted benzene ring; R is a hydrogen 
atom or an optionally substituted hydrocarbon group; B is an optionally 
esterified or amidated carboxyl group; X is --CH(OH)-- or --CO--; k is 0 
or 1; and n is 0, 1 or 2, or its pharmaceutically acceptable salt is used 
as an active ingredient. 
With respect to the formula (I), the substituent of the substituted benzene 
represented by ring A is exemplified by halogen atoms, nitro groups, 
optionally substituted alkyl groups, optionally substituted hydroxyl 
groups, optionally substituted thiol groups, optionally substituted amino 
groups, acyl groups, mono- or di-alkoxyphosphoryl groups, phosphono 
groups, optionally substituted aryl groups, optionally substituted aralkyl 
groups and optionally substituted aromatic heterocyclic groups. Of these 
substituents, 1 to 4, preferably 1 or 2, whether identical or not, may be 
present on the benzene ring. 
The halogen atoms include fluorine, chlorine, bromine and iodine. 
The alkyl groups of the optionally substituted alkyl groups include alkyl 
groups having 1 to 10 carbon atoms (C.sub.1-10 alkyl) such as methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 
isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, and C.sub.3-7 
cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl and 
cycloheptyl. These alkyl groups may be substituted by 1 to 3 substituents 
selected from halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 
hydroxyl groups, C.sub.1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, 
butoxy, hexyloxy), mono- or di-C.sub.1-6 alkoxyphosphoryl groups (e.g. 
methoxyphosphoryl, ethoxyphosphoryl, dimethoxyphosphoryl, 
diethoxyphosphoryl) and phosphono groups. 
The substituted alkyl groups include trifluoromethyl, trifluoroethyl, 
trichloromethyl, hydroxymethyl, 2-hydroxyethyl, methoxyethyl, 
1-methoxyethyl, 2-methoxyethyl, 2,2-diethoxyethyl, 
2-diethoxyphosphorylethyl, phosphonomethyl and so on. 
The substituted hydroxyl groups include alkoxy groups, alkenyloxy groups, 
aralkyloxy groups, acyloxy groups, C.sub.1-10 aryloxy groups and so on. 
Preferable alkoxy groups are alkoxy groups (e.g., methoxy, ethoxy, 
propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, nonyloxy) 
and C.sub.4-6 cycloalkoxy groups (e.g., cyclobutoxy, cyclopentoxy, 
cyclohexyloxy). Preferable alkenyloxy groups are C.sub.2-10 alkenyloxy 
groups such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 
2-cyclopentenylmethoxy and 2-cyclohexenylmethoxy. Preferable aralkyloxy 
groups are C.sub.7-19 aralkyloxy groups, with greater preference given to 
C.sub.6-14 aryl-C.sub.1-4 alkyloxy groups (e.g., benzyloxy, phenethyloxy). 
Preferable acyloxy groups are alkanoyloxy groups such as those having 2 to 
10 carbon atoms (e.g., acetyloxy, propionyloxy, n-butyryloxy, 
hexanoyloxy). Preferable aryloxy groups are C.sub.6-14 aryloxy groups 
(e.g., phenoxy, biphenyloxy). Further, these groups may be substituted by 
1 to 3 substituents selected from the above-mentioned halogen atoms, 
hydroxyl groups, C.sub.16 alkoxy groups, mono- or di-C.sub.1-6 
alkoxyphosphoryl groups, etc. The substituted hydroxyl groups include 
trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 
4-chlorobenzyloxy and 2-(3,4-dimethoxyphenyl)ethoxy, and so on. 
The substituted thiol groups include alkylthio groups, aralkylthio groups 
and acylthio groups. Preferable alkylthio groups are C.sub.1-10 alkylthio 
groups (e.g., methylthio, ethylthio, propylthio, butylthio, pentylthio, 
hexylthio, heptylthio, nonylthio) and C.sub.4-6 cycloalkylthio groups 
(e.g., cyclobutylthio, cyclopentylthio, cyclohexylthio). Preferable 
aralkylthio groups are C.sub.7-19 aralkylthio groups, more preferably 
C.sub.6-14 aryl-C.sub.1-4 alkylthio groups such as benzylthio and 
phenethylthio. Preferable acylthio groups are alkanoylthio groups such as 
those having 2 to 10 carbon atoms (e.g., acetylthio, propionylthio, 
n-butyrylthio, hexanoylthio). Further, these substituted thiol groups may 
be substituted by 1 to 3 substituents selected from the above-mentioned 
halogen atoms, hydroxyl groups, C.sub.1-6 alkoxy groups, mono- or 
di-C.sub.1-6 alkoxyphosphoryl groups etc. Specifically, the substituted 
thiol groups include trifluoromethylthio, 2,2,2-trifluoroethylthio, 
2-methoxyethylthio, 4-chlorobenzylthio, 3,4-dichlorobenzylthio, 
4-fluorobenzylthio, 2-(3,4-dimethoxyphenyl)ethylthio, and so on. 
As substituents of the substituted amino groups, there may be used 1 or 2 
identical or different substituents selected from the above-mentioned 
C.sub.1-10 alkyl groups, C.sub.2-10 alkenyl groups (e.g., 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-buten-1-yl), 
C.sub.6-14 aryl groups (e.g. phenyl, naphthyl) and C.sub.7-19 aralkyl 
groups (e.g. benzyl). These substituents may be substituted by the 
above-mentioned halogen atoms, C.sub.1-6 alkoxy groups, mono- or 
di-C.sub.1-6 alkoxyphosphoryl groups, phosphono groups, etc. Specifically, 
the substituted amino groups include methylamino, dimethylamino, 
ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, 
phenylamino, N-methyl-N-phenylamino, N-methyl-N-(4-chlorobenzyl)amino and 
N,N-di(2-methoxyethyl)amino, and so on. 
The acyl groups include organic carboxylic acid acyl groups and sulfonic 
acid acyl groups with a C.sub.1-6 hydrocarbon group (e.g., methyl, ethyl, 
n-propyl, hexyl, phenyl). Useful organic carboxylic acyl groups are 
formyl, C.sub.1-10 alkyl-carbonyl groups (e.g., acetyl, propionyl, 
butyryl, valeryl, pivaloyl, hexanoyl, octanoyl, cyclobutanecarbonyl, 
cyclohexanecarbonyl, cycloheptanecarbonyl), C.sub.2-10 alkenyl-carbonyl 
groups (e.g., crotonyl, 2-cyclohexenecarbonyl), C.sub.6-14 aryl-carbonyl 
groups (e.g., benzoyl), C.sub.7-19 aralkyl-carbonyl groups (e.g., 
benzylcarbonyl, benzhydrylcarbonyl), 5- or 6-membered aromatic 
heterocyclic carbonyl groups (e.g, nicotinoyl, 4-thiazolylcarbonyl) and 5- 
or 6-membered aromatic heterocyclic acetyl groups (e.g., 3-pyridylacetyl, 
4-thiazolylacetyl). Useful C.sub.1-6 sulfonic acyl groups are 
methanesulfonyl and ethanesulfonyl. These acyl groups may be substituted 
by 1 to 3 substituents selected from the above-mentioned halogen atoms, 
hydroxyl groups, C.sub.1-6 alkoxy groups, amino groups, etc. Specifically, 
the substituted acyl groups include trifluoroacetyl, trichloroacetyl, 
4-methoxybutyryl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl and 
3,4-dimethoxybenzoyl, and so on. 
The mono- or di-alkoxyphosphoryl groups include mono-C.sub.1-6 
alkoxyphosphoryl groups such as methoxyphosphoryl, ethoxyphosphoryl, 
propoxyphosphoryl, isopropoxyphosphoryl, butoxyphosphoryl, 
pentyloxyphosphoryl and hexyloxyphosphoryl, and di-C.sub.1-6 
alkoxyphosphoryl groups such as dimethoxyphosphoryl, diethoxyphosphoryl, 
dipropoxyphosphoryl, diisopropoxyphosphoryl, dibutoxyphosphoryl, 
dipentyloxyphosphoryl and dihexyloxyphosphoryl, with preference given to 
di-C.sub.1-6 alkoxyphosphoryl groups such as dimethoxyphosphoryl, 
diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, 
ethylenedioxyphosphoryl, dibutoxyphosphoryl, etc. 
The aryl groups of the optionally substituted aryl groups include 
C.sub.6-14 aryl groups such as phenyl, naphthyl and anthryl. These aryl 
groups may be substituted by 1 to 3 substituents selected from the 
above-mentioned C.sub.1-10 alkyl groups, halogen atoms, hydroxyl groups, 
C.sub.1-6 alkoxy groups, etc. Specifically, the substituted aryl groups 
include 4-chlorophenyl, 3,4-dimethoxyphenyl, 4-cyclohexylphenyl and 
5,6,7,8-tetrahydro-2-naphthyl. 
The aralkyl groups of the optionally substituted aralkyl groups include 
C.sub.7-19 aralkyl groups such as benzyl, naphthylethyl and trityl. These 
aralkyl groups may be substituted by 1 to 3 substituents selected from the 
above-mentioned C.sub.1-10 alkyl groups, halogen atoms, hydroxyl groups, 
C.sub.1-6 alkoxy groups etc. on the aromatic ring. Specifically, the 
substituted aralkyl groups include 4-chlorobenzyl, 3,4-dimethoxybenzyl, 
4-cyclohexylbenzyl and 5,6,7,8-tetrahydro-2-naphthylethyl. 
The aromatic heterocyclic groups of the optionally substituted aromatic 
heterocyclic groups include 5- to 6-membered aromatic heterocyclic groups 
having 1 to 4 atoms of nitrogen, oxygen and/or sulfur, such as furyl, 
thienyl, imidazolyl, thiazolyl, oxazolyl and thiadiazolyl. These aromatic 
heterocyclic groups may be substituted by 1 to 3 substituents selected 
from the above-mentioned C.sub.1-10 alkyl groups, halogen atoms, hydroxyl 
groups, C.sub.1-6 alkoxy groups, etc. 
Provided that two alkyl groups are present as mutually adjoining 
substituents on the benzene ring A, they may bind together to form an 
alkylene group represented by the formula: --(CH.sub.2).sub.m -- wherein m 
is an integer from 3 to 5 (e.g., trimethylene, tetramethylene, 
pentamethylene). Provided that two alkoxy groups are present as mutually 
adjoining substituents on the benzene ring A, they may bind together to 
form an alkylenedioxy group represented by the formula: 
--O--(CH.sub.2).sub.q --O-- wherein q is an integer from 1 to 3 (e.g., 
methylenedioxy, ethylenedioxy, trimethylenedioxy). In these cases, a 5- to 
7-membered ring is formed in cooperation with carbon atoms of the benzene 
ring. 
With respect to the formula (I), R is a hydrogen atom or an optionally 
substituted hydrocarbon group. 
The hydrocarbon group of the optionally substituted hydrocarbon group 
represented by R is exemplified by the above-mentioned alkyl groups 
(preferably C.sub.1-10 alkyl groups), alkenyl groups (preferably 
C.sub.2-10 alkenyl groups), aryl groups (preferably C.sub.6-14 aryl 
groups) and aralkyl groups (preferably C.sub.7-19 aralkyl groups). Useful 
substituents on the hydrocarbon group include the above-mentioned 5- or 
6-membered aromatic heterocyclic groups, halogen atoms, di-C.sub.1-6 
alkoxyphosphoryl groups and phosphono groups. 
Preferable examples of R are an unsubstituted C.sub.1-6 alkyl groups such 
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 
tert-butyl, pentyl, neopentyl and hexyl. 
With respect to the formula (I), B is an optionally esterified or amidated 
carboxyl group. 
The esterified carboxyl group represented by B is exemplified by 
alkoxycarbonyl group, preferably C.sub.1-10 alkoxy-carbonyl groups (e.g., 
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), 
aryloxy-carbonyl groups, preferably C.sub.6-14 aryloxy-carbonyl groups 
(e.g., phenoxycarbonyl), and aralkyloxycarbonyl groups, preferably 
C.sub.7-19 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl). 
The amidated carboxyl group represented by B is exemplified by an 
optionally substituted carbamoyl group represented by the formula: 
--CON(R.sup.4)(R.sup.5) wherein R.sup.4 and R.sup.5 independently are a 
hydrogen atom, an optionally substituted hydrocarbon group or an 
optionally substituted 5- to 7-membered heterocyclic group. 
The hydrocarbon group of the optionally substituted hydrocarbon group 
represented by R.sup.4 or R.sup.5 is exemplified by the above-mentioned 
alkyl groups, preferably C.sub.1-10 alkyl groups (e.g., methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 
isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl), alkenyl groups, 
preferably C.sub.2-10 alkenyl groups (e.g., 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-buten-1-yl), aryl 
groups, preferably C.sub.6-14 aryl group (e.g., phenyl, naphthyl, 
anthryl), and aralkyl groups, preferably C.sub.7-19 aralkyl group (e.g., 
benzyl, naphthyl, trityl). These hydrocarbon groups may be substituted by 
1 to 3 substituents selected from (i) halogen atoms (e.g., fluorine, 
chlorine, bromine, iodine), (ii) hydroxyl groups, (iii) C.sub.1-6 alkoxy 
groups (e.g., methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, 
hexyloxy), (iv) amino groups which may be substituted by C.sub.1-6 alkyl 
groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.) (e.g., amino, 
methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino), (v) 
amino groups substituted by acyl groups such as C.sub.1-10 alkanoyl groups 
(e.g., acetylamino, propionylamino, benzoylamino), (vi) carbamoyl groups 
which may be substituted by C.sub.1-6 alkyl groups (e.g., carbamoyl, 
methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl), (vii) C.sub.1-6 
alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl), (viii) mono- or di-alkoxyphosphoryl groups (e.g. mono- 
or di-C.sub.1-6 alkoxyphosphoryl groups such as dimethoxyphosphoryl, 
diethoxyphosphoryl, ethylenedioxyphosphoryl), (ix) mono- or 
di-alkoxyphosphorylalkyl groups (e.g. mono- or di-C.sub.1-6 
alkoxyphosphoryl-C.sub.1-3 alkyl groups such as methoxyphosphorylmethyl, 
ethoxyphosphorylmethyl, methoxyphosphorylethyl, ethoxyphosphorylethyl, 
dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl, 
dimethoxyphosphoryethyl, diethoxyphosphoryethyl), (x) a moiety represented 
by the formula: 
##STR5## 
wherein p is an integer from 2 to 4, (xi) phosphono groups, (xii) aromatic 
heterocyclic groups (the same meaning mentioned above), etc. 
The 5- to 7-membered heterocyclic group of the optionally substituted 5- to 
7-membered heterocyclic group represented by R.sup.4 or R.sup.5 is 
exemplified by 5- to 7-membered heterocyclic groups containing a sulfur, 
nitrogen or oxygen atom, 5- or 6-membered heterocyclic groups containing 2 
to 4 nitrogen atoms, and 5- or 6-membered heterocyclic groups containing 1 
or 2 nitrogen atom(s) and a sulfur or oxygen atom. These heterocyclic 
groups may be condensed with a 6-membered ring containing 2 or fewer 
nitrogen atoms, a benzene ring or a 5-membered ring containing a sulfur 
atom. 
As substituents of the substituted 5- to 7-membered heterocyclic group 
represented by R.sup.4 and R.sup.5, there may be used 1 to 4 of the same 
substituents as those for the substituted hydrocarbon group represented by 
R.sub.1 and R.sub.2 above. 
Preferable examples of the 5- to 7-membered heterocyclic group represented 
by R.sup.4 and R.sup.5 include 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 and morpholino. 
The moiety: --NR.sup.4 (R.sup.5) may form a 5- to 7-membered ring by 
binding together with R.sup.4 and R.sup.5. Such rings include morpholine, 
piperidine, thiomorpholine, homopiperidine, piperidine, pyrrolidine, 
thiazolidine and azepine. 
The substituted alkyl groups as preferable examples of the optionally 
substituted hydrocarbon group represented by R.sup.4 and R.sup.5 include 
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 
and 3-phosphonopropyl. The preferable substituted aralkyl groups include 
4-chlorobenzyl, 3-(2-fluorophenyl)propyl, 3-methoxybenzyl, 
3,4-dimethoxyphenethyl, 4-ethylbenzyl, 4-(3-trifluoromethylphenyl)butyl, 
4-acetylaminobenzyl, 4-dimethylaminophenethyl, 4-diethoxyphosphorylbenzyl 
and 2-(4-dipropoxyphosphorylmethylphenyl)ethyl. The preferable substituted 
aryl groups include 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, 
4-phosphonomethylphenyl and 4-phosphonophenyl. The preferable substituted 
5- to 7-membered heterocyclic groups include 5-chloro-2-pyridyl, 
3-methoxy-2-pyridyl, 5-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-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 
3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl and 4-methyl-2-morpholinyl. 
With respect to the formula (I), ring A is preferably a benzene ring which 
may be substituted by 1 or more, more preferably 1 or 2 substituents 
selected from 1 halogen atoms, 2 optionally substituted alkyl groups, 3 
optionally substituted hydroxyl groups, 4 optionally substituted thiol 
groups and/or 5 optionally substituted amino groups. 
More preferably, ring A is a benzene ring which may be substituted by 1 or 
2 substituents selected from the above-mentioned halogen atoms, C.sub.1-10 
alkyl groups (furthermore preferably C.sub.1-5 alkyl groups), C.sub.1 
alkoxy groups (furthermore preferably C.sub.1-5 alkoxy groups), 
alkylenedioxy groups represented by the formula: --O--(CH.sub.2).sub.q 
--O-- wherein q is an integer from 1 to 3, and/or C.sub.1-10 alkylthio 
groups (furthermore preferably C.sub.1-5 alkylthio groups). 
Most preferably, ring A is a benzene ring which may be substituted by an 
alkylenedioxy group represented by the formula: --O--(CE.sub.2).sub.q 
--O-- wherein q is an integer from 1 to 3. 
B is preferably an alkoxy-carbonyl group or a group represented by the 
formula: --CON(R.sup.4)(R.sup.5) wherein R.sup.4 and R.sup.5 independently 
are a hydrogen atom, an optionally substituted hydrocarbon group or an 
optionally substituted 5- to 7-membered heterocyclic group. 
With respect to R.sup.4 and R.sup.5 above, R.sup.4 is preferably a hydrogen 
atom or a C.sub.1-10 alkyl group (e.g. methyl, ethyl, propyl), and R.sup.5 
is preferably a phenyl or phenyl-C.sub.1-3 alkyl group which may be 
substituted by a halogen atom (e.g. fluorine, chlorine, bromine), a 
C.sub.1-6 alkoxy (e.g. methoxy, ethoxy), a mono- or di-alkoxyphosphoryl 
(preferablly a mono- or di-C.sub.1-6 alkoxyphosphoryl such as 
diethoxyphosphoryl), a mono- or di-alkoxyphosphorylalkyl (preferablly a 
mono- or di-C.sub.1-6 alkoxyphosphoryl-C.sub.1-3 alkyl such as 
diethoxyphosphoryl-methyl) or a C.sub.1-6 alkoxycarbonyl (e.g. 
methoxycarbonyl, ethoxycarbonyl), or a 5- or 6-membered heterocyclic group 
(e.g. pyridyl) which may be substituted by a phenyl and that contains 1 or 
2 nitrogen atom(s) or a nitrogen atom and a sulfur atom. 
More preferably, R.sup.4 is a hydrogen atom, and R.sup.5 is a phenyl group 
substituted by a mono- or di-C.sub.1-6 alkoxyphosphoryl-C.sub.1-3 alkyl 
(e.g. 4-diethoxyphosphorylmethylphenyl). 
With respect to the formula (I), X is --CH(OH)-- or --CO--, preferably 
--CO--. 
With respect to the formula (I), k is 0 or 1, and n is 0, 1 or 2, 
preferablly k is 1, and n is 0. 
R is preferably a hydrogen atom, a C.sub.1-6 alkyl group (e.g. methyl, 
ethyl) or a phenyl group. 
The compound (I) is preferably an optically active compound represented by 
the formula (II): 
##STR6## 
wherein R.sup.1 is a hydrogen atom or an optionally substituted 
hydrocarbon group; R.sup.2 and R.sup.3 independently are a lower alkyl 
group or bind together to form a lower alkylene group. 
In the formula (II) above, the optionally substituted hydrocarbon group 
represented by R.sup.1 is the same meanings as the above-mentioned 
hydrocarbon groups represented by R. Among them unsubstituted C.sub.1-6 
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. C.sub.1-4 
alkyl groups is most preferable. 
The lower alkyl group represented by R.sup.2 or R.sup.3 is exemplified by 
C.sub.1-6 alkyl groups (preferably C.sub.1-4 alkyl group) such as methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 
isopentyl, neopentyl and hexyl. R.sup.2 and R.sup.3 may bind together to 
form a lower alkylene group. In this case, a moiety: 
##STR7## 
may represent a moiety: 
##STR8## 
wherein p is an integer from 2 to 4. 
Preferable groups for R.sup.1, R.sup.2 and R.sup.3 include alkyl groups 
having 1 to 4 carbon atoms such as methyl and ethyl. 
The compound represented by (II) (hereinafter sometimes referred to as 
compound (II)) is an optically active compound of the (2R,4S) 
configuration, and contains substantially no compound of the (2S,4R) 
configuration. The compound (II) of which optical purity is nearly 100% is 
preferable. 
The salt of the compound used in the present invention is preferably a 
pharmaceutically acceptable salt. Examples of pharmaceutically acceptable 
salts include salts with inorganic bases, salts with organic bases and 
salts with basic or acidic amino acids. Examples of the inorganic bases 
capable of forming such salts include alkali metals (e.g., sodium, 
potassium) and alkaline earth metals (e.g., calcium, magnesium) and 
examples of the organic bases include trimethylamine, triethylamine, 
pyridine, picoline, N,N-dibenzylethylenediamine and diethanolamine, 
examples of the inorganic acids include hydrochloric acid, hydrobromic 
acid, hydroiodic acid, phosphoric acid, nitric acid and sulfuric acid, 
examples of the organic acids include formic acid, acetic acid, 
trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic 
acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid 
and citric acid, and examples of the basic or acidic amino acids include 
arginine, lysine, aspartic acid and glutamic acid. 
Most preferably, the compound (II) is, for example, 
(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide (hereinafter 
also referred to as compound A). 
The preferable examples of the present invention include the 
osteogenesis-promoting compounds disclosed in Japanese laid-open patent 
applications 232880/1991 (corresponding to EP-A-0376197), 364179/1992 
(corresponding to EP-A-0460488), 294960/1994, etc. or a salt thereof (e.g. 
(2R,4S)-(-)-N-(4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylendioxy-5-oxo-3-benzothiepine-2-carboxamide) and 
benzothiepine derivatives specifically disclosed in Japanese laid-open 
application 231569/1996 (corresponding to EP-A-0719782), These compounds 
may be used in a combination of two or more kinds in an appropriate ratio. 
The compound represented by the formula (I) for the present invention can 
be produced by the method described in the above patent publications or a 
modification thereof. 
The biodegradable polymer of .alpha.-hydroxycarboxylic acid in the present 
invention includes a homopolymer, a copolymer of .alpha.-hydroxycarboxylic 
acid represented by the formula: 
##STR9## 
wherein R.sup.6 represents a hydrogen atom or an alkyl group having 1 to 8 
carbon atoms; or a mixture thereof. 
With respect to the formula [III] above, the linear or branched C.sub.1-8 
alkyl group represented by R.sup.6 is exemplified by methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 
isopentyl, neopentyl, tert-pentyl, 1-ethylpropylt hexyl, isohexyl, 
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. 
Preferably, a linear or branched C.sub.2-5 alkyl group is used. Such alkyl 
groups include ethyl, propyl, isopropyl, butyl and isobutyl. 
The preferable embodiments of hydroxycarboxylic acid represented by the 
formula [III] is exemplified by glycolic acid, lactic acid, 
2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric 
acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid and 2-hydroxycapric 
acid, with preference given to glycolic acid, lactic acid, 
2-hydroxy-butyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methyl-butyric 
acid and 2-hydroxycaproic acid. When optical isomers of these 
.alpha.-hydroxycarboxylic acid exist, any one of D-isomer, L-isomer and 
racemic mixtures thereof may be used. 
The hydroxycarboxylic acid represented by the formula [III] may be used as 
a mixture of one or more kinds in a given ratio. 
With respect to the copolymer produced from 2 or more kinds of the 
.alpha.-hydroxycarboxylic acid represented by the formula [III], 
polymerization may be of random, block or graft type. A random copolymer 
is preferred. 
With respect to the copolymer produced from 2 or more kinds of the 
.alpha.-hydroxycarboxylic acid represented by the formula [III], 
polymerization may be of random, block or graft type. A random copolymer 
is preferred. 
The polymer of single kind of the .alpha.-hydroxycarboxylic acid 
represented by the formula [III], in the case of the 
.alpha.-hydroxycarboxylic acid having an optical isomer, although it may 
be of the D- or L-configuration or a mixture thereof, it is preferable 
that the ratio of the D-/L-configuration (mol %) falls within the range 
from about 75/25 to about 20/80. The ratio of the D-/L-configuration (mol 
%) is more preferably about 60/40 to about 25/75, and still more 
preferably about 55/45 to about 25/75. The weight-average molecular weight 
of the polymer is preferably within the range from about 1,500 to about 
30,000, more preferably about 2,000 to about 20,000, and still more 
preferably about 3,000 to about 15,000. Also, the degree of dispersion of 
the polymer is preferably about 1.2 to about 4.0, more preferably about 
1.5 to about 3.5. 
For producing the above polymers, the methods: ring-opening polymerization 
of a dimer of the .alpha.-hydroxycarboxylic acid (e.g. glycolide, lactide 
etc., and dehydration polycondensation of the .alpha.-hydroxycarboxylic 
acid) are known. For obtaining a polymer of relatively low molecular 
weight for the present invention, direct dehydration polycondensation of 
the .alpha.-hydroxycarboxylic acid represented by the formula (III) is 
preferred. This method is, for example, described in Japanese Patent 
Unexamined Publication No. 28521/1986. 
The .alpha.-hydroxycarboxylic acid singly used for polymerization is 
preferably glycolic acid, lactic acid, 2-hydroxybutyric acid, more 
preferably lactic acid. 
The preferable examples of the above-mentioned copolymers include 
copolymers of glycolic acid and lactic acid (glycolic acid/lactic acid 
copolymers) and copolymers of glycolic acid and a 
.alpha.-hydroxycarboxylic acid represented by the formula [III] wherein 
R.sup.6 is C.sub.2-8 alkyl group (e.g. ethyl, propyl, isopropyl, butyl, 
isobutyl, hexyl, 2,2-dimethylbutyl, 2-ethylbutyl, etc.) (hereinafter 
referred to as glycolic acid copolymer). Glycolic acid/lactic acid 
copolymers and copolymers of glycolic acid and 2-hydroxycarboxylic acid 
are more preferable. 
With respect to the content ratio of lactic acid and glycolic acid of the 
lactic acid/glycolic acid copolymer, lactic acid preferably accounts for 
about 40 to about 95 mol % and glycolic acid preferably accounts for about 
60 to about 5 mol %, more preferably lactic acid accounts for about 50 to 
about 95 mol % and glycolic acid accounts for about 50 to about 5 mol %, 
even more preferably lactic acid accounts for about 60 to about 90 mol % 
and glycolic acid accounts for about 40 to about 10 mol %. 
The weight-average molecular weight of the lactic acid/glycolic acid 
copolymer used in the present invention is preferably about 1,000 to about 
100,000, more preferably about 2,000 to about 50,000, still more 
preferably about 5,000 to about 30,000. 
The degree of dispersion of the lactic acid/glycolic acid copolymer 
(weight-average molecular weight/number-average molecular weight) is 
preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5. 
With respect to the content ratio of glycolic acid and the 
hydroxycarboxylic acid represented by the formula [III] wherein R.sup.6 is 
C.sub.2-8 alkyl group in the above glycolic acid copolymer, it is 
preferable that glycolic acid accounts for about 10 to 75 mol % and 
hydroxycarboxylic acid accounts for the remaining portion. More 
preferably, glycolic acid accounts for about 20 to about 75 mol %, and 
still more preferably about 40 to about 70 mol %. The weight-average 
molecular weight of the glycolic acid copolymer is normally about 2,000 to 
about 50,000, preferably about 3,000 to about 40,000, and more preferably 
about 8,000 to about 30,000. The degree of dispersion of the glycolic acid 
copolymer is preferably about 1.2 to about 4.0, more preferably about 1.5 
to about 3.5. 
The glycolic acid/lactic acid copolymer and the glycolic acid copolymer 
above can be produced by known processes, such as that described in 
Japanese laid-open application No. 28521/1986 or a method similar thereto. 
The polymers of .alpha.-hydroxycarboxylic acid used as a microparticle base 
in the production method of the present invention can be produced by the 
known method, such as described in Japanese laid-open applications 
157525/1975, 45920/1981, 118512/1982, 150609/1982 and 54760/1987 and 
EP-A-048/732 or modification thereof other than those described above. 
In the present specification, weight-average molecular weight and degree of 
dispersion are defined as the molecular weight based on polystyrene 
obtained by gel permeation chromatography (GPC) with 9 polystyrenes as 
reference substances with respective weight-average molecular weights of 
120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580 and 162, and 
degree of dispersion calculated respectively. Measurements were taken 
using a GPC column KF804L.times.2 (produced by Showa Denko, Japan) and an 
RI monitor L-3300 (produced by Hitachi, Ltd., Japan) with chloroform as 
the mobile phase. 
The preferable examples of the mixture of homopolymer or copolymer of the 
.alpha.-hydroxycarboxylic acid represented by the formula [III] include 
mixtures of the above described glycolic acid copolymer (A) and a 
polylactic acid (B) in an appropriate ratio. 
The glycolic acid copolymer (A) and the polylactic acid (B) are used in the 
mixture wherein the (A)/(B) ratio (% by weight) falls within the range 
from about 10/90 to about 90/10. The mixing ratio is preferably about 
20/80 to about 80/20, and more preferably about 30/70 to about 70/30. If 
either component (A) or (B) is in excess to such a large extent, the 
preparation obtained shows a drug release pattern almost the same as that 
which is obtained with the use of either component (A) or (B) alone and no 
linear release pattern is expected in the last stage of drug release from 
the mixed base. Although the decomposition/elimination rates of glycolic 
acid copolymer (A) and polylactic acid (B) vary widely, depending on 
molecular weight or composition, drug release duration can be extended by 
increasing the molecular weight of the polylactic acid or lowering the 
mixing ratio (A)/(B), since the decomposition/elimination rate of glycolic 
acid copolymer is usually higher than that of polylactic acid. Conversely, 
drug release duration can be shortened by decreasing the molecular weight 
of polylactic acid or increasing the mixing ratio (A)/(B). Drug release 
duration can also be adjusted by altering the kind and content ratio of 
.alpha.-hydroxycarboxylic acid represented by the formula [III]. 
In the production method of the present invention, the solid preparation 
comprising the compound represented by the formula [I] and a biodegradable 
polymer of .alpha.-hydroxycarboxylic acid can be produced by the method 
which comprises dissolving (a) a compound represented by the formula [I] 
and (b) a biodegradable polymer of .alpha.-hydroxycarboxylic acid in a 
solvent which could dissolve (a) and (b) together, followed by drying the 
solution under the reduced pressure or a method analogous thereto. Any 
method may be used for preparing the solution of (a) and (b), as long as 
(a) and (b) are finally dissolved in the solvent. The method includes for 
example (1) mixing a solution or suspension of (a) with a solution or a 
suspension of (b), (2) mixing a solution or suspension of (a) in the 
solvent with (b), (3) mixing a solution or suspension of (b) in a solvent 
with (a) or (4) dissolving a mixture of (a) and (b) into the solvent. As 
the solvent, any solvent that can disolve both (a) and (b) by mixing to 
give a solution of (a) and (b) may be properly selected. 
The solvent which can dissolve (a) and (b) together may be any solvent as 
long as (a) and (b) are finally dissolved thereinto. Specific examples of 
the solvent, include a halogenated hydrocarbon or a mixture of two or more 
kinds thereof in appropriate ratios, to which opptionally, an aprotic 
solvent and/or a lower alcohol may be added if necessary in such an amount 
as not to inhibit dissolution of (a) or (b). Halogenated hydrocarbons such 
as methylene chloride, chloroform and dichloromethane and aprotic solvents 
such as acetonitrile, acetone and dioxane are preferably used. The solvent 
may be a mixture of two or more kinds of these organic solvents in an 
appropriate ratio. Further, lower alcohols such as methanol, ethanol, 
propanol and the like may be added into the solvent in such an amount as 
not to inhibit the dissolution of (a) and (b). 
In the preparation of the solution of (a) and (b), a surfactant may be 
added if necessary. As the surfactant, examples mentioned below can be 
used. 
The amount of the compound represented by the formula [III] to be used for 
the preparation may be changed according to kind, continuation period of 
effect of drug etc. The concentration in the solution may be chosen within 
the range from about 0.001% (w/w) to about 15% (w/w), preferably from 
about 0.01% to about 10% (w/w). 
The amount of the biodegradable polymer of .alpha.-hydroxycarboxylic acid 
to be used for the preparation may be selected according to rate or 
duration of drug release. For example, while a range from about 0.5 to 
10,000-fold can be used, preferably from about 1 to about 100-fold, ratio 
by weight of the polymers relative to the active ingredient of a 
benzothiepin derivative are used. 
The method for drying under the reduced pressure may be carried out 
according to the per se known manner. 
With respect to the reduced pressure used herein, it is preferably less 
than about 400 Torr, more preferably less than about 300 Torr. 
The temperature for drying is preferably within the range from about 
10.degree. C. to about 70.degree. C., more preferably within the range 
from about 15 to about 50.degree. C. 
The reaction time of this step is preferably about 1 hour to about 72 
hours, more preferably about 1 hour to about 48 hours. 
In the present invention, microparticles are produced by pulverizing thus 
obtained solid preparation in the presence of a pulvilizing auxiliary. The 
pulverization may be carried out according to a per se known pulverizing 
manner. For example, the pulverization is done by using a conventional 
pulverizer such as a turbo counter jet mill or a ultrasonic jet mill. 
In this step, usually, the solid preparation is roughly ground into coarse 
particles before subjecting to the pulverizer, since this is convenient 
for increasing the efficiency of pulverization. Such rough grind is done 
by using mortar or conventional pulverizer such as power mill. With 
respect to the size of the coarse particles, it may be chosen based on the 
pulverization condition such as type of pulverizer or the requirements of 
the object microparticles such as particle size, from the range of the 
particle diameter up to about 4 mm, preferably up to about 2 mm, more 
preferably from about 1 mm to about 2 mm. 
In the pulverization, the size of the microparticles may be chosen based on 
the administration route or requirements of the final product etc. When 
the microcapsules are used as an injectable suspension, for instance, 
their particle size is chosen over the range preferably from about 0.5 to 
about 400 .mu.m of average particle diameter, as long as the requirements 
concerning the degree of dispersion and needle passage are met. More 
preferably, the average particle diameter is about 2 to about 200 .mu.m. 
In the above pulverizing step, it is useful for preventing aggregation of 
the microparticles during the pulverization or storage period to add an 
antiaggregation agent (an agent which prevents aggregation, coagulation or 
floculation) to the subjects and pulverize it with them according to 
necessity. 
The antiaggregation agent may be added to the microparticles and mixed by 
the mixer after pulverization. 
As the pulverizing auxiliary is generally a substance which is soluble in 
water, in a solid form under the pulverizing condition and has a hardness 
higher than that of the solid preparation to be pulverized. The larger the 
difference in the hardness between the pulverizing auxiliary and the 
subject to be pulverized, the more preferable to use it is. The 
pulverizing auxiliary is preferably a crystal or a crystalline compound. 
Specific examples of the pulverizing auxiliary include inorganic salts such 
as halogenated alkali metals (e.g. (1) sodium chloride, potassium 
chloride, sodium bromide, potassium bromide), halogenated alkali earth 
metals (e.g. calcium chloride, magnesium chloride), phosphate salt of 
alkali metals (e.g. tribasic sodium phosphate, tribasic potassium 
phosphate, dibasic sodium phosphate, dibasic potassium phosphate, 
monobasic sodium phosphate, monobasic potassium phosphate), alkali earth 
metal oxides (e.g. magnesium oxide, calcium oxide) and alkali earth metal 
hydroxide (e.g. magnesium hydroxide, calcium hydroxide); (2) organic acids 
or salts thereof such as carbonic acid, citric acid, carbonate or 
bicarbonate salt of alkali metals (e.g. sodium carbonate, potassium 
carbonate, sodium bicarbonate, potassium bicarbonate), carbonate salt of 
alkali earth metals (e.g. calcium carbonate, magnesium carbonate), citrate 
salts of alkali metals; (3) saccharides such as sugar alcohols (e.g. 
mannitol, sorbitol), monosaccharides (e.g. glucose, galactose), 
disaccharides (e.g. lactose, sucrose, maltose), amino sugars (e.g. 
glucosamine, galactosamine, chondroitin phosphate) and polysaccharides 
(e.g. dextrine, hydroxypropyl cellulose). These pulverizing auxiliaries 
may be used in combination of one or more kinds in appropriate ratio. 
Among them, inorganic salts and water-soluble saccharides are preferable. 
It is also in the scope of the present invention to use ice (H.sub.2 O) as 
a pulverizing auxiliary in addition to ones described above when 
pulverization is conducted at a low temperature not higher than the 
freezing point. 
The amount of the pulverizing auxiliary to be used may be selected within 
the range from about 0.001 to about 100 fold by weight relative to the 
solid preparation based on the average particle diameter of the desired 
microparticles, particle diameter apt to be smaller according to increase 
of the content ratio of the pulverizing auxiliary in the same pulverizing 
condition. 
The particle size of the pulverizing auxiliary subjected to the pulverizer 
is appropriately selected from the range of average particle size based on 
weight distribution from about 0.5 .mu.m to about 2000 .mu.m depending on 
the particle diameter of the desired microparticles. The particle size of 
the microparticles produced in this manner can be controlled by choosing 
the kind of content ratio and average particle diameter of pulverizing 
auxiliary. 
One of the preferable embodiments of the pulverization in case of 
pulverizing the solid preparation into microparticles having average 
particle size from about 10 to about 50 .mu.m by using supersonic jet mill 
(PJM-100SP NIPPON PNEUMATIC MFG CO. LTD.), is exemplified below. 
The solid dispersion (preferably solid solution) roughly ground into coarse 
particles having particle diameter not more than 2 mm is mixed with about 
3 to about 50% (w/w) pulverizing auxiliary relative thereto. The resulting 
mixture is pulverized by the supersonic jet mill under pressure within a 
range from about 0.05 MPa to 0.5 MPa while supplying of the subject 
mixture in a rate of about 30 g/min to about 120 g/min. 
The pulverizing auxiliary can be removed after pulverization, if necessary, 
by washing with water or using known separation manner based on the 
difference of the particle size. The freeze-drying method is also a useful 
removing method, when ice is used as the pulverizing auxiliary. 
If necessary, the dispersion ability of the microparticle to dispersion 
solvent can be improved by coating its surface with a water-soluble 
polymer and/or a surfactant which are soluble in water, administerable to 
human being and in a solid form at ordinary temperature (about 
15-25.degree. C.). Meanings of the term "coating" used herein include 
embodiments wherein a part or whole of the surface of the microparticle is 
coated. For this purpose, it is also effective that a pharmaceutically 
acceptable amount of a liquid water-soluble polymer and/or a surfactant is 
dispersed on the surface of the microparticles. 
Specific examples of the preferable surfactant include, for example, 
nonionic surfactants such as sorbitan fatty acid esters (e.g. glycerine 
monostearate (self emulsifiers) etc.), propylene glycol fatty acid esters 
(e.g. propylene glycol monostearate etc.), polyoxyethylene glycerine fatty 
acid esters (e.g. POE (15) glycerine ester etc.), polyethylene glycol 
fatty acid esters (e.g. POE (10) monostearate. PEG distearate etc.), 
polyoxyethylene alkyl ethers (e.g. POE (21) lauryl ethers, POE (20) 
stearyl ether etc.), polyoxyethylene hydrogenated castor oil derivatives 
(e.g. POE (80) hydrogenated castor oil, HCO60 HCO50 (available from Nikko 
Chemicals) etc., polyoxyethylene sorbitol-yellow bee wax derivatives (e.g. 
POE (20) sorbitol-yellow bee wax etc.), polyoxyethylene lanolin alcohols 
(e.g. POE (20) lanolin alcohol etc.O, polyoxyethylene sorbitol fatty acid 
esters (e.g. POE (6) sorbitol hexastearate etc.) and polyoxyethylene 
polyoxypropylene glycol derivatives (Pluronics (Wyandotle Chemicals Corp.) 
such as pluronic F68 (polyoxyethylene (160) polyoxypropylene (30) glycol) 
etc.); anionic surfactants such as dodecylsulfuric acid alkali metal salts 
(e.g. sodium dodecylsulfate etc.), stearic acid alkali metal salts (e.g. 
sodium stearate etc.) and palmiatic acid alkali metal salts (e.g. sodium 
palmitate etc.). Examples of the liquid surfactants includes Tweens such 
as Tween 20 and Tween 80 (available from Astra powder Co., U.S.A.). These 
surfactants may be used singly or two or more kinds may be used in 
combination in an appropriate ratio. 
Examples of the preferable water-soluble polymer include dextrins, dextran 
sulfates, chondroitin sulfate alkali metal salts (e.g. sodium chondroitin 
sulfate) and polyethylene glycols (e.g. polyethylene glycol 1,000 (PEG 
1,000), PEG 1,500, PEG 4,000, PEG 6,000, PEG 20,000). These water-soluble 
polymers may be used singly or two or more kinds may be used in 
combination in appropriate ratio. 
The means for coating microparticles with a water-soluble polymer and/or a 
surfactant is not limited. Example of the means include the method of 
adding a water-soluble polymer and/or a surfactant into the substance to 
be pulverized in the step of pulverizing either the solid preparation or 
the roughly ground solid preparation. In this method, the solid 
water-soluble polymer and/or the surfactant may be added to the 
pulverizing system together with the substance to be pulverized as a 
mixture thereof or separately from the substance. Whether liquid or solid, 
the water-soluble polymer and/or the surfactant may be supplied to the 
pulverizing system as a solution in an appropriate solvent. Composition 
prepared by drying a solution or suspension of the antiaggregation agent 
and the water-soluble polymer and/or the surfactant in an appropriate 
solvent (e.g. water, alcohols such as methanol or ethanol etc.) or these 
composites separated from the solution may be pulverized together with the 
subject to be pulverized for this purpose. 
Coating or dispersing the water-soluble polymer and/or the surfactant on 
the surface of the microparticles may be conducted by mixing them with the 
resultant microparticles obtained by pulverizing the solid preparation. 
The manner of the mixing includes freeze-drying the suspension of the 
microparticles, which is obtained by pulverizing the solid preparation in 
a solution of a solution of a water-soluble polymer and/or a surfactant 
solutions in appropriate solvent (e.g. water, alcohols such as methanol or 
ethanol etc.). An appropriate amount of any antiaggregation agent may be 
added in the suspension. The antiaggregation agent may be any of ones 
described above. The preferable examples for the purpose of maintaining 
the shape after freeze-drying includes mannitol, D-sorbitol, glucose, 
sucrose, lactose, dextrine, dextran sulfate, chondroitin sulfate and like. 
The concentration of the water-soluble polymer and/or the surfactant in 
the solution used as dispersing solvent for microparticles, in the 
freeze-drying method, is in the range from about 0.000001% (w/v) to about 
10% (w/v), preferably from about 0.0001% (w/v) to about 3% (w/v), more 
preferably about 0.001% (w/v) to about 0.5% (w/v). Further, addition of a 
buffering agent (e.g. phosphate buffer, citric buffer etc.), an osmotic 
pressure adjustor (e.g. sodium chloride, saccharides (e.g. mannitol, 
sorbitol, lactose) etc.) or the like is also effective to make more 
uniform the dispersion ability in the solvent for freeze-drying method. 
Among the above-mentioned manners for coating, the method using the 
freeze-drying is preferable. 
The content ratio of the water-soluble polymer and/or the surfactant 
relative to the microparticles to be coated is not limited as long as they 
can improve the dispersion ability of the microparticles. Specifically, 
the ratio is chosen from the range from about 0.0000001 to about 10-fold, 
preferably about 0.000005 to about 5-fold, more preferably about 0.00001 
to about 0.01-fold by weight. 
As the antiaggregation agent, use is generally made of a non-adhesive 
substance which is soluble in water, administerable to the human and is in 
a solid form at the ordinary temperature (about 15.degree. C. to 
25.degree. C.). Specific examples include, for example, inorganic salts 
(e.g. the above described halogenated alkali metal salts, halogenated 
alkali earth metal salts, carbonate salts or bicarbonate salts with alkali 
metal, carbonate salts of alkali earth metal, phosphate salts with alkali 
metal, oxide of alkali earth metal, hydroxide of alkali earth metal etc.); 
alkali metal salts or alkali earth metal salts with acetic acid (e.g. 
sodium acetate, potassium acetate, magnesium acetate, calcium acetate 
etc.); organic acids (e.g. citric acid, tartric acid, malic acid, succinic 
acid, salicilic acid, chondroitin sulfuric acid, dextran sulfuric acid, 
carboxymethyl cellulose, arginic acid, pectic acid etc.) and salts thereof 
(e.g. alkali metal salts, alkali earth metal salts etc.); water-soluble 
saccharide (e.g. mannitol, sorbitol, lactose, glucose, sucrose, starchs 
(e.g. corn starch, potate starch) etc.); amino acids (e.g. glycine, 
phenylalanine, cysteine, arginine etc., preferably cysteine or arginine); 
proteins (e.g. gelatine, fibrine, coragen, albumin); water soluble 
cellulose (e.g. crystalline cellulose, carboxymethyl cellulose or salts 
thereof); and a like. These may be used in combination with one kind or 
two or more kinds in appropriate ratio. Among them, inorganic salts, water 
soluble saccharides and amino acids are preferable. 
The amount of the antiaggregation agent to be used relative to the 
microparticle may not be limited as long as it has the effect of 
minimizing aggregation, and specifically selected from the range from 
about 0.001 to about 100-fold, preferably about 0.01 to about 50-fold, 
more preferably about 0.1 to about 10-fold by weight. 
The thus-obtained microparticle can be administered as such or in the form 
of various dosage forms. It may be used as a starting material for 
producing such dosage forms. Examples of the dosage forms include 
injections (e.g., intramuscular, subcutaneous or visceral injections 
etc.), oral preparations (e.g., capsules, granules, powders, tablets 
etc.), external preparations (e.g., transnasal preparation, percutaneous 
preparations etc.) and suppositories (e.g., rectal suppository, vaginal 
suppository etc.). 
The drug content in these dosage forms varies depending on the kind of the 
drug, dosage form, target disease etc. The contents may generally be 
chosen within the range from about 1 mg to about 200 mg, preferably about 
3 mg to about 150 mg, more preferably about 5 mg to about 100 mg relative 
to the 1 g of the whole preparation. 
These pharmaceutical preparations can be produced by a per se known method 
conventionally used in the pharmaceutical manufacturing field. 
An injectable preparation can be prepared by, for example, suspending the 
microcapsules in an aqueous solvent such as water, if necessary, a 
dispersing agent (e.g., Tween 80, HCO-60, carboxymethyl cellulose 
(including carboxymethyl cellulose sodium), sodium alginate, etc.), a 
preservative (e.g., methyl paraben, propyl paraben, etc.), an isotonizing 
agent (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.) etc. may 
be added, to yield an aqueous suspension, or by dispersing it in a 
vegetable oil such as olive oil, sesame oil, peanut oil, cotton seed oil 
or corn oil or propylen glycols, to yield an oily suspension, whereby a 
practically usable sustained-release preparation is obtained. 
A preparation for oral administration can be prepared according to a per se 
known method, for example, mixing microparticles along with diluents (e.g. 
lactose, sucrose, starch etc.), disintegrators (e.g. starch, calcium 
bicarbonate etc.), binders (e.g. starch, arabia gum, 
carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropylcellulose 
etc.), lubricants (e.g. talc, magnesium stearate, polyethylene 
glycol.6,000 etc.) etc., and subjecting the mixture to compression molding 
or filling the mixture into a capsule, if necessary followed by subjecting 
the resultant product to a known coating method for purposes such as 
masking the taste, enteric coating and prolongation, to provide the oral 
dosage form. As the coating agent, film forming agents such as 
hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose 
hydroxypropylcellulose polyoxyethylene glycol, Tween 80, Pluroric F68, 
cellulose acetate futalate, hydroxypropylmethylcellulose futalate, 
hydroxymethylcellulose acetate succinate and Eudragit (Rohm & Pharm 
Germany); methacrylic acid/acrylic acid copolymer and coloring agents such 
as titanium oxid or iron sesquioxide are used. 
As a external preparation, for example, a transnasal preparation in a form 
of solid, semi-solid or liquid can be prepared using the microparticles 
according to the per se known method. The microparticles can be used as 
such or mixed with diluents (e.g. glycol, mannitol, starch, 
microcrystalline cellulose etc.), thickeners (e.g. natural gums, cellulose 
derivatives, acrylic acid polymers etc.), etc., to provide the solid 
transnasal preparation in a form of powder composition. The liquid 
preparation can be prepared in a form of oily suspension or aqueous 
suspension by the same manner as the above-mentioned injectable 
preparation. The semi-solid preparation is preferably prepared in a form 
of an aqueous or oily gel or an ointment. Any of these preparations may 
comprise pH adjuster (e.g. carbonic acid, phosphonic acid, citric acid, 
hydrogen chloride, sodium hydroxide, etc.), antiseptics (e.g. 
p-hydroxybenzoate esters, chlorobutanol, benzalkonium chloride etc.) and 
the like. 
In the case where microparticles are formulated into a suppository, an oily 
or aqueous suppository in a form of solid, semi-solid or liquid can be 
prepared from them in accordance with a per se known method. Oleaginous 
base used in these compositions may be any one as long as it cannot 
dissolve the microparticles, and examples of such oleaginous base includes 
higher fatty acid glycerides (e.g. cacao butter, Witepsols (Dinamitenovel 
Co.) etc.), middle chain fatty acids (e.g. MIGLYOLS (Dinamitenovel Co.) 
etc.) and vegetable oils (e.g. sesame oil, soybean oil, cotton seed oil 
etc.), aqueous base used therein includes polyethylene glycols and 
propylene glycols, for instance. Base for aqueous gel includes natural 
gums, cellulose derivatives, vinyl polymers and acrylic acid polymers, for 
instance. 
The dosage of the microparticles produced in the present invention may be 
an effective amount of the active ingredients, i.e. the compound 
represented by the formula [I], although depending on type and content of 
the compound, duration of drug release and subject animals (e.g. mouse, 
rat, horse, cattle, human etc.) etc. 
For example, when benzothiepine derivatives or a pharmaceutically 
acceptable salt thereof are administered to an adult subject in need 
(weighing 50 kg ) in a form of the microparticle produced in the present 
invention for treating a bone disease, its dosage can be selected from the 
range from about 0.35 mg to about 70 mg based on the active ingredient per 
administration. 
When the microparticles are administered in the form of suspension 
injection, volume of injection may be chosen within the range from about 
0.1 ml to about 5 ml, preferably about 0.5 ml to about 3 ml. 
Since the particle size of the resultant microparticles can be well managed 
according to the production method of the present invention, there can be 
provided a sustained-release preparation having excellent pharmaceutical 
properties and well controlled drug release, as a useful medicament for 
preventing/treating bone diseases which need long dosage periods of 
administration, which comprises a compound represented by the formula [I], 
known to have a bone resorption suppressing activity, 
bone-metabolism-improving activity and osteogenesis-promoting activity. 
BEST MODE FOR CARRYING OUT THE INVENTION 
The present invention is hereinafter described in more detail by means of 
the following working examples, which are not to be construed as 
limitative.

EXAMPLE 
Example 1 
In 160 grams of dichloromethane were dissolved 10.0 g of 
(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-me 
thyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide (prepared 
according to Japanese Patent Laid Open Publication No. Hei8-231569 
(hereinafter, referred to as "Compound A") and 90 grams of dl-lactic 
acid/glycolic acid copolymer (hereinafter referrd to as "copoly 
(dl-lactic/glycolic acid)") The lactic acid/glycolic acid ratio 
(hereinafter simply abbreviated as (L/G))=85/15; Weight-average molecular 
weight: 14,000. The resultant solution was poured into a container coated 
with fluorine-containing resin. The container was put in a vacuum drier to 
evaporate the solvent. The resultant solid dispersion was roughly ground 
and mixed with mannitol (15 g) and polyoxyethylene (160) polyoxypropylene 
(30) glycol (Pluronic F68) (2 g). The resultant mixture was powdered by a 
supersonic jet mill (PJM-100SP of NIPPON PNEUMATIC MFG CO. LTD.) under 0.3 
MPa pressure of the compressed supplying gas. The resultant powder was 
kept in a vacuum drier at 45.degree. C. under an inside pressure of 0.1 to 
0.05 Torr for 3 days. Particles whose encapsulation rate of drug was at 
100%, having an average particle diameter of 32 .mu.m, having excellent 
dispersion ability in dispersion medium and gradually releasing the active 
ingredient for about 1 month in the muscle of rats were obtained. 
Example 2 
In dichloromethane (20 g) were dissolved Compound A (1.5 g) and copoly 
(lactic/glycolic acid) (L/G=90/10. Weight-average molecular weight: 
14,000) (6.0 g). The resultant solution was poured into a stainless steel 
container, and the container was dried in a vacuum drier at 50.degree. C. 
under an inner pressure of 10 to 0.01 Torr. The resultant dried substance 
was roughly ground, followed by addition of sodium chloride (1.5 g) and 
polyethyleneglycol 4000 (0.2 g) and mixing. The resultant mixture was 
pulverized in a turbocounter jet mill (TJ-0624 of Turbo Industry) under 
0.2 MPa pressure of compressed supplying gas. There were obtained 
particles whose drug encapsulation rate is 100%, which have an average 
particle diameter of 27 .mu.m and can gradually release the active 
ingredient for about 1 month in the muscle of rats. 
Example 3 
In dichloromethane (26.7 g) were dissolved Compound A (1.9 g) and copoly 
(lactic/glycolic acid) (L/G=85/15. Weight-average molecular weight: 
14,900) (15.1 g). The resultant solution was poured into a container 
coated with fluorine-contained resin. The container was put in a vacuum 
drier to evaporate the solvent. The resultant solid dispersion was roughly 
ground, followed by addition of mannitol (3 g). The resultant mixture was 
pulverized by a supersonic jet mill (PJM-100SP of NIPPON PNEUMATIC MFG CO. 
LTD.) under 0.1 MPa pressure of compressed supplying gas. The resultant 
powder was dispersed in an aqueous amino acid solution (containing 
arginine acid 3.8% or cysteine 2.7%), followed by being freeze-dried to 
provide particles. One hundred mg of the particles were filled into a 9P 
vial and subjected to a stability test at 40.degree. C. 75% RH for 4 
months, and found to be stable without causing any agglomeration between 
particles. 
Example 4 
In dichloromethane (300 g) are dissolved the Compound A (10 g) and copoly 
(dl-lactic/glycolic acid) (L/G=90/10. Weight-average molecular weight: 
13,000) (90 g). The resultant solution is poured into a container coated 
with fluorine-contained resin, and the container is dried in a vacuum 
drier at 50.degree. C. under an inner pressure not higher than 10 Torr. 
The dried substance thus obtained is roughly ground, followed by addition 
of sodium citrate (20 g) and the polyethylene glycol 4000 (2 g) and 
mixing. The mixture is sieved to collect the particles which pass through 
the sieve of 2 mm mesh. The resultant particles are pulverized by a 
supersonic jet mill (PJM 100sp of NIPPON PNEUMATIC MFG CO. LTD.) under 0.3 
MPa pressure of compressed supplying gas. 
Example 5 
In dichloromethane (300 g) a re dissolved Compound A (10 g) and copoly 
(dl-lactic/glycolic acid) (L/G=80/20. Weight-average molecular weight: 
15,000) (90 g). The resultant solution is poured into a container coated 
with fluorine-contained resin. The container is dried in a vacuum drier at 
50.degree. C. under the inner pressure not higher than 10 Torr to dry the 
solution. The dried substance is roughly ground, followed by addition of 
mannitol (20 g). The mixture is sieved to collect the particles which pass 
through the sieve of 2 mm mesh. The resultant particles are pulverized by 
a supersonic jet mill (PJM-100SP of NIPPON PNEUMATIC MFG CO. LTD.) under 
0.2 MPa pressure of compressed supplying gas. 
Industrial Applicability 
According to the production method of the present invention, there can be 
produced efficiently and on a large scale, a sustained-release preparation 
having excellent pharmaceutical properties and well-controlled 
drug-release. The microparticles produced by the method of the present 
invention is useful as a medicament for preventing/treating bone diseases 
which need long dosage period of administration, which comprises a 
compound represented by the formula [I], known to have a bone resorption 
suppressing activity, bone-metabolism-improving activity and 
osteogenesis-promoting activity.