JP2001316296A - Controlled release preparation for biologically active compound having poor solubility to water, method for producing the same and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a controlled release preparation improved in release hindrance and stabilizing of a biologically active compound having poor solubility to water and capable of being in dustrially produced. SOLUTION: This sustained release preparation is obtained by including the biologically active compound having poor solubility to water, an ingredient prepared by carrying out a water treatment of a polyvalent metallic compound having poor solubility to water and a biodegradable polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a sustained-release preparation of a physiologically active compound which is hardly soluble in water, a method for producing the same, and a use thereof.

[0002]

2. Description of the Related Art A sustained-release preparation of a physiologically active compound containing a polyvalent metal which is hardly soluble in water and a biodegradable polymer has been developed.
For example, it is disclosed in JP-A-09-221420, JP-A-11-315034, JP-A-11-322631 and the like, and it has been confirmed that release control and stabilization of a physiologically active compound can be achieved. However, in the production of these sustained-release preparations, for example, an emulsion (S / O emulsion) containing a poorly water-soluble bioactive compound, a poorly water-soluble polyvalent metal and a biodegradable polymer is prepared. In this case, a stirring operation for several hours to half a day or more was required. On the other hand, a polyvalent metal compound that is hardly soluble in water is almost insoluble in water, and it is generally known that the rate of binding to water is extremely slow.For example, zinc oxide has a solubility in water. Is almost insoluble at 0.42 mg / 100 ml (18 ° C), and the rate at which it combines with water to form zinc hydroxide is extremely low, according to the Dictionary of Chemistry.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a sustained-release preparation of a physiologically active compound, which has improved control and stabilization of the release of the physiologically active compound and can be produced by a method suitable for mass production. Provides manufacturing methods and applications.

[0004]

In order to solve the above-mentioned problems, in particular, an emulsion containing a water-insoluble bioactive compound, a water-insoluble polyvalent metal and a biodegradable polymer is prepared for a short time. (Preferably within 1 hour) As a result of intensive studies on a method for producing a sustained-release preparation of a physiologically active compound which can be prepared in less than 1 hour, the components obtained by treating zinc oxide with water and the physiologically active compound which is hardly soluble in water are obtained. An emulsion containing a biodegradable polymer can be prepared in a short time, and in a sustained-release preparation obtained by removing water and a solvent from the emulsion, a high-content They have found that it is possible to release the active compound slowly and control the release, and as a result of further studies, they have completed the present invention.

That is, the present invention provides: (1) a component obtained by treating a poorly water-soluble physiologically active compound or a poorly water-soluble polyvalent metal compound with water (for example, a poorly water-soluble polyvalent metal compound; Polyvalent metal compounds, etc., which are obtained by mixing water and which are hardly soluble in water-treated water; here, the polyvalent metal compounds which are hardly soluble in water-treated water are partially or entirely insoluble in water. A sustained-release preparation containing a polyvalent metal compound (which may be an unmodified compound) and a biodegradable polymer; (2) the above-mentioned (1), wherein the bioactive compound is a non-peptidic compound (3) a sustained-release preparation according to the above (1), wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof; (4) an angiotensin II antagonistic activity The compound is a non-peptidic compound (5) the sustained release preparation according to (3), wherein the compound having an angiotensin II antagonistic activity is a compound having an oxygen atom in the molecule; (6) angiotensin II antagonist The sustained release preparation according to the above (3), wherein the compound having an action is a compound having an ether bond or a carbonyl group; (7) the compound having an angiotensin II antagonistic action is a compound of the formula (I)

Embedded image (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. (8) a sustained release preparation according to the above (3), wherein the compound is a compound represented by the formula: The above-mentioned (3), wherein the compound having an angiotensin II antagonistic activity is losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan or tasosartan. (9) a compound having an angiotensin II antagonistic activity is 2
-Ethoxy-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof (3).
(10) The compound having an angiotensin II antagonistic activity is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4. -Yl] methyl] benzimidazole-7-carboxylate or a salt thereof, wherein the sustained release preparation according to the above (3); (11) the compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2′- (2,5-dihydro-5
-Oxo-1,2,4-oxadiazol-3-yl)
Biphenyl-4-yl] methyl] benzimidazole-
(12) a sustained-release preparation according to (3), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer; 13) the sustained-release preparation according to the above (12), wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer; (14) the composition molar ratio of lactic acid and glycolic acid is 100/0
(13) the sustained release preparation according to the above (13), wherein the weight average molecular weight of the polymer is 3,000 to 50,
(16) The sustained release preparation according to (1), which is for injection; (17) The sustained release preparation according to (1), wherein the polyvalent metal is zinc. (18) the polyvalent metal compound is zinc oxide;
(19) The sustained release preparation according to (1), further comprising a polyvalent metal; (20) the sustained release preparation according to (19), wherein the polyvalent metal is zinc. (21) removing water and a solvent from a liquid containing a bioactive compound that is hardly soluble in water, a component obtained by treating a water-soluble polyvalent metal compound with water and a biodegradable polymer; (22) The sustained release preparation according to (21), wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof. (23) water-soluble physiologically active compound, a component obtained by treating a water-insoluble polyvalent metal compound with water, a biodegradable polymer and a liquid containing a polyvalent metal, Wherein the solvent is removed. (19) the method for producing a sustained-release preparation according to (19); (24) the method for producing a sustained-release preparation according to (23), wherein the bioactive compound is a compound having angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof. (25) a pharmaceutical composition comprising the sustained-release preparation according to the above (1); (26) the above-mentioned (2) which is an agent for preventing or treating cardiovascular diseases.
(27) The composition according to the above (25), which is a prophylactic / therapeutic agent for hypertension; (28) The composition according to the above (25), which is a prophylactic / therapeutic agent for abnormal blood pressure circadian variability. (29) the composition according to the above (25), which is a prophylactic / therapeutic agent for organ damage; (30) a component obtained by treating a water-insoluble polyvalent metal compound with water to obtain a water-insoluble polyvalent metal compound; The sustained-release preparation according to the above (1), which is a component obtained by mixing a valent metal compound and water; (31) a bioactive compound that is hardly soluble in water, a polyvalent metal compound that is hardly soluble in water, and water. (32) A method for producing a sustained-release preparation of a poorly water-soluble bioactive compound, wherein water and the solvent are removed from an emulsion obtained by mixing with an organic solvent solution of a biodegradable polymer; Dissolving soluble polyvalent metal compound and water in organic solvent of biodegradable polymer The emulsion obtained by mixing with water to disperse the physiologically active compound slightly soluble,
(34) a method for producing a sustained-release preparation of a poorly water-soluble physiologically active compound, which comprises removing water and a solvent; (33) a sustained-release preparation obtained by the production method according to (31); (36) The sustained-release preparation according to the above (33), wherein the water to be mixed serves as a release controlling agent for the poorly soluble physiologically active compound in water; (35) the sustained-release preparation obtained by the production method according to the above (32); ) The sustained-release preparation according to the above-mentioned (35), wherein the water to be mixed is a release controlling agent for the poorly soluble physiologically active compound in water; (37) a component obtained by treating a poorly water-soluble polyvalent metal compound with water. In the presence of a water-soluble bioactive compound and a biodegradable polymer-containing liquid containing a biodegradable polymer, characterized by removing water and solvent, from a sustained-release formulation of poorly water-soluble bioactive compound (38) adjusting the amount of water to be treated (39) the method of (37), wherein a bioactive compound that is hardly soluble in water and a polyvalent metal compound that is hardly soluble in water are biodegradable in the presence of water. (37) wherein water and the solvent are removed from the emulsion obtained by mixing the polymer with an organic solvent solution.
(40) A water-insoluble bioactive compound is added to an emulsion obtained by mixing a water-insoluble polyvalent metal compound with an organic solvent solution of a biodegradable polymer in the presence of water. (41) The method according to the above (37), wherein the water and the solvent are removed; (41) a water-insoluble bioactive compound, a water-insoluble polyvalent metal compound and water are added to the internal phase. An emulsion containing an organic solvent solution of a biodegradable polymer in the external phase.

[0006] In the specification of the present application, the term "poorly soluble in water" refers to the water or physiological salt necessary to dissolve 1 g of solute within 30 minutes when vigorously shaking at 20 ± 5 ° C every 5 minutes for 30 seconds. The amount of water is 100 ml or more, preferably 10 ml
It means 00 ml or more, more preferably 10,000 ml or more. The physiologically active compound in the present invention includes mammals (eg, humans, cows, pigs, dogs, cats, mice,
A biologically active compound that is effective for the prevention and treatment of disease states and diseases in rats, rabbits, etc., and is slowly released or stabilized by interacting with components obtained by treating water-soluble polyvalent metal compounds with water. It is not particularly limited as long as it is a peptide, and may be peptide or non-peptidic, but non-peptidic is preferable, and among them, a bioactive compound having a molecular weight of about 200 to 3000 is preferable, and particularly, a molecular weight is about 300 ~
A bioactive compound of 2000 is preferred. Preferable examples of the "water-insoluble bioactive compound" used in the present invention include a compound having an angiotensin II antagonistic action (a compound having an angiotensin II receptor antagonistic action), a prodrug thereof, or a salt thereof. No. Angiotensin II antagonistic activity in the present invention, competitively or non-competitively inhibits the binding of angiotensin II to angiotensin II receptor on the cell membrane,
Attenuates the strong vasoconstriction and vascular smooth muscle growth induced by angiotensin II and alleviates the symptoms of hypertension. The compound having an angiotensin II antagonism used in the present invention may be either peptide or non-peptide, but a compound having a non-peptide antagonism, which has an advantage of a long action time, is preferable. As the compound having an angiotensin II antagonistic action, a compound having an oxygen atom in the molecule is preferable, and a compound having an ether bond or a carbonyl group (the carbonyl group may form a hydroxyl group by resonance) is preferable. Preferably, a compound having an ether bond or a ketone derivative is more preferable, and an ether derivative is particularly preferable. The non-peptidic compound having angiotensin II antagonistic activity is not particularly limited, but imidazole derivatives are disclosed in JP-A-56-71073, JP-A-56-71074, JP-A-57-98270 and JP-A-57-98270. JP-A-58-157768, USP 4,35
No. 5,040 and US Pat. No. 4,340,598, and also EP-253310, EP-291969, E
P-324377, EP-403158, WO-910
0277, JP-A-63-23868 and JP-A-1-117876 disclose improved imidazole derivatives, and US Pat. No. 5,183,899;
EP-323841, EP-409332 and JP-A-1-287707 disclose pyrrole, pyrazole and triazole derivatives.
880, 804, EP-0392317, EP-039
9732, EP-0400835, EP-42592
1, EP-59136 and JP-A-3-63264 disclose benzimidazole derivatives.
For example, azaindene derivatives are disclosed in
EP-407342 and the like disclose a pyrimidone derivative, EP-411766 and the like disclose a quinazoline derivative, EP-430300 and the like disclose a xanthine derivative, EP-434038 and the like disclose a condensed imidazole derivative, No. 4,442,473 disclose pyrimidinedione derivatives, EP-443568, etc. disclose thienopyridone derivatives, and EP-445.
811, EP-483683, EP-518033, E
P-520423, EP-588299, EP-603
712 and the like disclose a heterocyclic compound. Journal of Medicinal Chemistry (Journa
l of Medicinal Chemistry, Vol. 39, No. 3, 625-6
56, 1996), representative compounds among them are described. As the compound having a non-peptide angiotensin II antagonistic action, in addition to the compounds described in the above-mentioned known literature, any non-peptide compound having an angiotensin II antagonistic action may be used, and among them, losartan ( Losartan (DuP753)), Eprosartan (SK & F108566), Candesartan cilexetil (TCV-
116)), Valsartan (CGP-48933), Telmisartan (BIBR277), Irbesartan (Irbesartan (SR47436)), Tasosartan (Tasosa)
rtan (ANA-756)), olmesartan, and metabolically active substances thereof (such as candesartan) are preferably used.

[0007] Non-peptidic compounds having angiotensin II antagonistic activity include, for example, compounds of the formula (I)

Embedded image (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. And a hydrocarbon residue which may have a substituent (preferably, a hydrocarbon residue which may have a substituent and binds through an oxygen atom). Benzimidazole derivatives or salts thereof are preferably used. In the above formula (I), as a group capable of forming an anion as R ¹ (a group having a hydrogen atom that can be released as a proton),
For example, (1) carboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-
NHSO ₂ CF ₃ ), (4) phosphoric acid group, (5) sulfonic acid group, (6) 5 to 7 members (preferably 5 to 6 members) containing one or more of N, S and O )) A monocyclic optionally substituted heterocyclic residue.

The above-mentioned "5- to 7-membered (preferably 5- to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or more of N, S, and O" Is, for example,

Embedded image

Embedded image And the bond between the heterocyclic residue represented by R ¹ and the phenyl group to which the heterocyclic residue is bonded is as described above when g in the above formula represents —NH— or the like. Carbon-
The bond may be formed not only through a carbon bond but also through one of a plurality of nitrogen atoms. For example, if R ¹

Embedded image In the above formula, g is _{-CH 2 -, - NH -,} - O- or -
S (O) m-,> = Z,> = Z 'and> =
Z ″ represents a carbonyl group, a thiocarbonyl group, or an optionally oxidized sulfur atom (eg, S, S (O),
S (O) ₂ or the like (preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group);
Represents an integer of 0, 1 or 2.

[0009] R¹Examples of the heterocyclic residue represented by
For example, oxadiazolone ring, oxadiazolothione ring or
Is a proton donor such as a thiadiazolone ring.
NH- and -OH groups and calcium as a proton acceptor
Bonyl group, thiocarbonyl group or sulfinyl group, etc.
Are preferred. Also, R¹Indicated by
Heterocyclic residues combine with cyclic substituents to form a fused ring
May be ¹As a heterocyclic residue represented by
Is preferably a 5- to 6-membered ring, more preferably a 5-membered ring residue. R¹
As the heterocyclic residue represented by

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) m, wherein m has the same meaning as described above) (among others, 2,5-dihydro-
5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5 Oxo-1,2,4-thiadiazol-3-yl, especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) is preferred.

The heterocyclic residue (R ¹ ) has tautomers as shown below. For example,

Embedded image There are three tautomers of a ', b' and c 'such as

Embedded image Is a heterocyclic residue containing all of the above a ′, b ′ and c ′.

The group capable of forming an anion as R ¹ is
At a substitutable position, it may be protected with an optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). Examples of the optionally substituted lower (C _1-4 ) alkyl group include (1) a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like. A lower (C _1-4 ) alkyl group which may be substituted with 1 to 3 phenyl groups (eg, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.); (C _1-4 ) alkoxy-lower (C _1-4 ) alkyl group (eg,
Methoxymethyl, ethoxymethyl, etc.), (3) Formula -C
H (R ⁴ ) -OCOR ^{5 wherein} R ⁴ is (a) hydrogen,
(B) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.) ), shows the (c) linear or branched lower alkenyl group or (d) a cycloalkyl group of 3-8 carbon atoms 2-6 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁵ Is (a) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl,
t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (b) a linear or branched lower alkenyl group having 2-6 carbon atoms, (c) a cycloalkyl group having 3-8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.); (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen A lower alkenyl group having 2-3 carbon atoms substituted by an atom, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc. (eg, , Such as those having an alkenyl moiety such as vinyl, propenyl, allyl and isopropenyl, such as cinnamyl); (e) optionally substituted aryl groups (eg, halogen atoms such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4) alkyl, lower (C _1-4) such as phenyl or naphthyl group which may have a like alkoxy), (f) the number of carbon atoms -6 linear or branched lower alkoxy groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, Neopentyloxy, etc.),
(G) a linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (h) a cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy,
Such as cycloheptyloxy), (i) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl,
Cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ))
Lower alkoxy groups having 1 to 3 carbon atoms (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc.) substituted with alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety), (j) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or optionally substituted Aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 )
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (eg, having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy such as cinnamyloxy) Or (k) an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy And the like, which may have a phenoxy or naphthoxy group). Also,
The group capable of forming an anion as R ¹ is, for example, the above-mentioned optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). In addition to the protecting group, at a substitutable position, a lower (C _1-4 ) alkyl group which may be substituted (for example, the “substituted or substituted” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). And lower (C _1-4 ) alkyl groups which may be mentioned), a halogen atom,
Nitro, cyano, lower (C _1-4 ) alkoxy, 1-2
And may have a substituent such as amino which may be substituted with a plurality of lower (C _1-4 ) alkyl.

In the above formula, a group capable of forming an anion as R ¹ (a group having a hydrogen atom which can be released as a proton) is a group which can be converted under biological or physiological conditions (for example, in vivo enzyme). Or a group capable of forming an anion by a reaction such as oxidation, reduction, or hydrolysis in a living body (so-called prodrug), or a cyano or N-hydroxycarbamimidoyl group. (—C (＝ N—OH) —NH ₂ ) or (1) a carboxyl group, (2) a tetrazolyl group, each of which is protected by an optionally substituted lower (C _1-4 ) alkyl group or an acyl group. (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5)
Sulfonic acid group, (6) one or two of N, S, O
A 5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing at least one heterocyclic residue which forms an anion represented by R ¹ by a chemical reaction. It may be a group that can be converted into a group that can be converted (a so-called synthetic intermediate).

R ¹ is optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl. Groups (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
Optionally protected with carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl) or cyano, N-hydroxycarbamimidoyl (Preferably cyano), and particularly preferably tetrazolyl.

In the above formula, X represents that an adjacent phenylene group and a phenyl group are bonded directly or preferably via a spacer having an atomic chain of 2 or less (preferably a direct bond). Any of divalent chains having 1 or 2 atoms constituting the straight chain portion may be used, and may have a side chain. Specifically, lower (C _1-4 ) alkylene having 1 or 2 atoms constituting a straight chain portion, —CO—, —O—, —S—, —NH—, —CO
_{-NH -, - O-CH 2} -, - S-CH 2 -, - CH = C
H- and the like. In the above formula, n represents an integer of 1 or 2 (preferably 1).

In the above formula, ring A represents a benzene ring which may further have a substituent other than substituent R ² , and examples of the substituent include (1) halogen (eg, F, Cl, Br
), (2) cyano, (3) nitro, (4) optionally substituted lower (C _1-4 ) alkyl, (5) lower (C
_1-4 ) alkoxy, (6) optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-di-lower (C _{1 -4} )
Alkylamino (eg, dimethylamino, etc.), N-arylamino (eg, phenylamino, etc.), alicyclic amino (eg, morpholino, piberidino, piperazino, N-phenylpiperazino, etc.), formula (7) -CO-D '
[Wherein D 'is a hydroxyl group or an alkyl moiety is a hydroxyl group, lower (C _1-4 ) alkoxy, lower (C _2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), lower (C _1-6 ) alkoxycarbonyl Oxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or lower (C _3-6 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.)
Represents a lower (C _1-4 ) alkoxy which may be substituted with, or (8) an optionally substituted lower (C _1-4 ) alkyl (an anion as R ¹ described above) And the same as the "optionally substituted lower (C _1-4 ) alkyl group" exemplified as the protecting group for the group capable of forming) or acyl (eg, lower (C _2-5 ) alkanoyl Benzoyl, etc.), which may be protected with tetrazolyl, a trifluoromethanesulfonic acid amide group, a phosphoric acid group or a sulfonic acid group.
These substituents are each substituted at a substitutable position on the benzene ring.
In addition to the substituent R ² , the substituent which the ring A further has may be a lower (C _1-4 ) alkyl which may be substituted (eg, a hydroxyl group, a carboxyl group, Lower (C) which may be substituted with halogen, etc.
_1-4) alkyl, etc.), are preferred, such as halogen, ring A other than the substituent R ² is more preferably has no substituent.

In the above formula, examples of the group capable of forming an anion as R ² (group having a hydrogen atom capable of being released as a proton) include (1) a carboxyl group which may be esterified or amidated , (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5) and a sulfonic acid group. these groups are optionally substituted Lower alkyl groups (the same as the “optionally substituted lower (C _1-4 ) alkyl group” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). ) Or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
A group capable of forming an anion or a group capable of forming an anion under biological or physiological conditions (for example, an in vivo reaction such as oxidation, reduction, or hydrolysis by an in vivo enzyme); Either may be used.

The carboxyl that may be esterified or amidated as R ² includes, for example, a compound of the formula —CO
-D [wherein D is (1) a hydroxyl group, (2) optionally substituted amino (for example, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _{1- 4} ) alkylamino etc.) or (3) optionally substituted alkoxy {examples: (i) an alkyl moiety is a hydroxyl group, optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkyl) Amino, N, N-di-lower (C _1-4 ) alkylamino, piperidino, morpholino, etc., halogen, lower (C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio, lower (C _3-8 ) Cycloalkoxy or optionally substituted dioxorenyl (eg, 5-methyl-2-oxo-
A lower (C _1-6 ) alkoxy group optionally substituted with 1,3-dioxolen-4-yl or the like, or (ii)
Formula —O—CH (R ⁶ ) —OCOR ^{7 wherein} R ⁶ is (a)
Hydrogen, (b) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, Neopentyl), (c) a linear or branched lower alkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁷ is (a) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n -Pentyl, isopentyl, neopentyl, etc.), (b) a linear or branched lower alkenyl group having 2 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen Atom, nitro, lower (C _1-4 ) alkyl, lower (C
_1-4 ) a lower alkenyl group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group optionally having an alkoxy or the like (eg, vinyl such as cinnamyl, propenyl,
(E) an aryl group which has an alkenyl moiety such as allyl and isopropenyl, and (e) an optionally substituted aryl group (eg,
Halogen atoms such as phenyl, p-tolyl and naphthyl, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.), (f) carbon A linear or branched lower alkoxy group of the formula 1-6 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec
-Butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a linear or branched lower alkenyloxy group having 2-8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (H) a cycloalkyloxy group having 3-8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.); (i) a cycloalkyl having 3-8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) Or an optionally substituted aryl group (eg, a phenyl or naphthyl group optionally having a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) Carbon number 1
-3 lower alkoxy groups (eg, those having an alkoxy moiety such as methoxy such as benzyloxy, phenethyloxy, cyclopentylmethoxy, and cyclohexylmethoxy, ethoxy, n-propoxy, and isopropoxy);
(J) C 3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or an optionally substituted aryl group (eg, a halogen atom,
A lower alkenyloxy group having 2 to 3 carbon atoms substituted by nitro, lower (C _1-4 ) alkyl, phenyl or naphthyl group which may have lower (C _1-4 ) alkoxy, etc. (eg, cinnamiroxy) Such as those having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, and isopropenyloxy) or (k) an optionally substituted aryloxy group (eg, halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro A phenoxy or naphthoxy group which may have a lower (C _1-4 ) alkyl, a lower (C _1-4 ) alkoxy, etc.). And the like.

R ² is preferably carboxyl which may be esterified, and specific examples thereof include -COOH and its salts, -COOMe and -COOE.
t, -COOTBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, Propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxy Carbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like; Conditions (e.g., in vivo reaction such as oxidation-reduction or hydrolysis by in vivo enzymes)
Or a group capable of chemically forming an anion (eg, COO ⁻ , a derivative thereof, etc.) or a group capable of changing the same, or a carboxyl group or a prodrug thereof. Good.

The above R ² is represented by the formula —CO—D [wherein
D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group,
Amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, Ethoxycarbonyloxy, etc.), lower (C _3-8 ) cycloalkoxycarbonylyloxy (eg, cyclohexyloxycarbonyloxy, etc.), lower (C _1-
4 ) alkoxy or lower (C _1-4 ) alkoxy which may be substituted with lower (C _3-8 ) cycloalkoxy], and carboxyl is particularly preferable.

In the above formula, the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes, for example,
(1) alkyl group, (2) alkenyl group, (3) alkynyl group, (4) cycloalkyl group, (5) aryl group,
(6) An aralkyl group and the like are mentioned, and among them, an alkyl group, an alkenyl group and a cycloalkyl group are preferable. The alkyl group of the above (1) is a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like. As the alkenyl group of the above (2),
The lower alkenyl group having about 2 to 8 carbon atoms may be linear or branched and includes, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl and the like. The alkynyl group of the above (3) is a lower alkynyl group having about 2 to 8 carbon atoms and may be linear or branched. For example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-pentynyl, Octynyl and the like. Examples of the cycloalkyl group of the above (4) include lower cycloalkyl having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The above alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group, an amino group which may be substituted (eg,
Amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino, etc.), halogen, lower (C _1-4 ) alkoxy group, lower (C _1-4 ) It may be substituted with an alkylthio group or the like. Examples of the aralkyl group (5) include phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, and examples of the aryl group (6) include phenyl.

Aralkyl group or aryl group described above
Can be located at any position on the benzene ring, for example, halogen
(Eg, F, Cl, Br, etc.), nitro, substituted
Amino groups (eg, amino, N-lower (C_1-4) Al
Killamino, N, N-di-lower (C _1-4A) alkylamino
Etc.), low grade (C_1-4) Alkoxy (eg, methoxy, eth
Low-grade (C_1-4) Alkylthio (eg, methyl
Thio, ethylthio, etc.), lower (C_1-4) Alkyl
(Eg, methyl, ethyl, etc.).
Among the above, R^ThreeRepresented by "through a heteroatom
A hydrocarbon residue having a substituent "
In the "hydrocarbon residue" even if substituted
Good alkyl or alkenyl groups (eg, hydroxyl, amino
Group, halogen or lower (C_1-4) Substituted with alkoxy group
Low-grade (C_1-5) Alkyl or lower
(C_2-5Alkenyl, etc.) are preferred;
Low grade (C_1-5) Alkyl (more preferably, ethyl)
preferable. R^ThreeRepresented by a “bonded through a heteroatom
May have a substituent in the hydrocarbon residue "
As the “hetero atom”, -O-, -S (O) m- [m
Represents an integer of 0 to 2], -NR '-[R' is hydrogen
Atomic or lower (C_1-4) Represents alkyl]
In particular, -O- is preferably used. Above
Above all, R^ThreeAre -O-, -S (O) m- [m
Represents an integer of 0 to 2] or -NR '-[R' is
Hydrogen atom or lower (C_1-4) Represents an alkyl]
Hydroxyl, amino, halogen, etc.
And low (C_1-4) A substituent selected from an alkoxy group
Optionally substituted lower (C_{1 -Five}) Alkyl or low
Grade (C_2-5) Alkenyl groups and the like are preferred,
Low grade (C_1-5) Alkyl or lower (C_1-5) Alkoxy
(More preferably, ethoxy).

Among the non-peptidic compounds having angiotensin II antagonistic activity represented by the formula (I), the compounds represented by the formula (I ')

Embedded image (Wherein, R ¹ represents (1) a carboxyl group, (2) a tetrazolyl group, or (3)

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) m, wherein m has the same meaning as described above], and ring A is a lower (C ₁₎ which may be substituted other than the substituent R ^2. _-4 ) an alkyl (eg, a hydroxyl group, a carboxyl group, a lower (C _1-4 ) alkyl which may be substituted with a halogen or the like) or a benzene ring optionally substituted with a halogen (preferably a substituent R ² And R ² is a group represented by the formula —CO—D wherein D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _{2−). 6} ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), lower (C _3-8 ) Cycloalkoxy carboxymethyl Niro alkoxy (e.g., such as cyclohexyloxycarbonyloxy), a lower (C _1-4) alkoxy or lower (C _3-8) be substituted with a cycloalkoxy optionally substituted lower (C _1-4) alkoxy R ³ represents —O—, —S (O) m— [m represents an integer of 0 to 2] or —NR ′ — [R ′ represents a hydrogen atom or lower (C _{1- 4} ) represents alkyl]], a hydroxyl group, an amino group, a halogen and a lower (C
_1-4) which may lower substituted with a substituent selected from alkoxy groups (C _1-5) alkyl or lower (C _{2 -5)} alkenyl group (preferably a lower (C _1-5) alkyl or lower (C _1-5 ) alkoxy; more preferably ethoxy). A benzimidazole-7-carboxylic acid derivative or a pharmacologically acceptable salt thereof, and the like, and particularly, 2-ethoxy-1-[[2 ′
-(1H-tetrazol-5-yl) biphenyl-4-
Yl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate [Candesartan cilexetil], pivaloyloxymethyl 2-ethoxy-1-[[2 ′-(1H-tetrazole- 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate, 2-ethoxy-
1-[[2 ′-(2,5-dihydro-5-oxo-1,
2,4-oxadiazol-3-yl) biphenyl-4
-Yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof is preferred. The above-mentioned benzimidazole derivatives are described in, for example, EP-425921, EP-4.
59136, EP-553879, EP-57812
5, EP-520423, EP-668272 and the like, or a method analogous thereto. When Candesartan cilexetil is used, it is preferable to use a stable C-type crystal described in EP-59136.

The compound having an angiotensin II antagonistic activity or a prodrug thereof used in the present invention may be itself or a pharmacologically acceptable salt. Examples of such salts include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc, etc.) when the compound having an angiotensin II antagonistic activity has an acidic group such as a carboxyl group. , Iron, transition metals such as copper) and organic bases (eg,
Trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-
Salts with organic amines such as dibenzylethylenediamine, and basic amino acids such as arginine, lysine, and ornithine). When the compound having an angiotensin II antagonistic action has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), aspartic acid, glutamic acid and other acidic amino acids. No. Compound having an angiotensin II antagonism used in the present invention [hereinafter may be referred to as an AII antagonist compound. Is a compound which is converted into an AII antagonist compound by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, enzymatic oxidation, reduction,
It refers to a compound that undergoes hydrolysis or the like to change to an AII antagonistic compound, or a compound that undergoes hydrolysis or the like due to gastric acid or the like to change to an AII antagonistic compound. Examples of the prodrug of the AII antagonist compound include compounds in which the amino group of the AII antagonist compound is acylated, alkylated, or phosphorylated (eg, AII antagonist compound).
When the amino group of the antagonist compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-
Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.); the hydroxyl group of the AII antagonistic compound is acylated , Alkylated, phosphorylated, borated compounds (eg, compounds in which the hydroxyl group of an AII antagonist compound is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated) Etc.); a compound in which the carboxyl group of the AII antagonist compound is esterified or amidated (eg, the AII antagonist compound) has a carboxyl group of ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivalo Yloxymethyl esterification Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.); And the like. These compounds can be produced from AII antagonist compounds by a method known per se. Also, A
Prodrugs of II antagonist compounds are described in "Development of Pharmaceuticals", Hirokawa Shoten 1990, Vol. 7, Molecular Design, pp.163-198.
It may be one that changes to an AII antagonist compound under physiological conditions, as described on page. Further, the AII antagonist compound may be either a hydrate or a non-hydrate.

In the present invention, "a component obtained by treating a poorly water-soluble polyvalent metal compound with water" refers to a poorly water-soluble physiologically active compound or / and a poorly water-soluble polyvalent metal compound alone. And a component generated by water treatment in the presence of a biodegradable polymer, and easily achieves controlled release or stabilization of poorly water-soluble bioactive compounds by changing the treatment conditions and environment. It is possible.
The water treatment is a treatment for a short time, for example, within one hour, preferably within 30 minutes, more preferably within 10 minutes, still more preferably within 5 minutes, and particularly preferably within 3 minutes. The amount of water to be added depends on the amount of the polyvalent metal compound, the type and amount of the bioactive compound, the type and amount of the biodegradable polymer, and the type and amount of the organic solvent solution of the biodegradable polymer. It is generally 3-500%, more preferably 5-30% by weight of the polyvalent metal compound.
0%, particularly preferably in the range of 10-150%. The water to be added does not have to be partially dissolved in the organic solvent of the biodegradable polymer, and is preferably finely dispersed and emulsified by a known method such as a homogenizer or ultrasonic waves. If necessary, the added water may include a polyvalent metal compound (eg, zinc acetate or the like), a basic amino acid (eg, arginine, histidine, lysine, etc.), albumin, gelatin, agar, dextrin, polyvinyl alcohol, carbonic acid, Oxalic acid citric acid, phosphoric acid, hydrochloric acid, etc., sodium hydroxide, citric acid, sodium ethylenediaminetetraacetate, sodium bisulfite, polyol compounds (eg, polyethylene glycol), paraoxybenzoates (methylparaben, propylparaben, etc.),
Benzyl alcohol, chlorobutanol, thimerosal and the like may be added. Examples of the component obtained by treating a poorly water-soluble polyvalent metal compound with water include, for example, a poorly soluble polyvalent metal compound obtained by mixing a sparingly water-soluble polyvalent metal compound and water, Examples of the metal compound include a polyvalent metal compound that is hardly soluble in water that has been treated with water, and a part or all of the polyvalent metal compound may be a hardly soluble polyvalent metal compound (unchanged compound). Further, in the process for producing the sustained-release preparation of the present invention, the water-treated water-soluble polyvalent metal compound forms an emulsion with an organic solvent solution of a biodegradable polymer in the presence of water. Preferably, an emulsion containing a bioactive compound that is hardly soluble in water, a polyvalent metal compound that is hardly soluble in water and water in the internal phase, and an organic solvent solution of a biodegradable polymer in the external phase. It is preferable to produce the sustained-release preparation of the present invention via the above method. However, by forming an emulsion in the presence of water, it is possible to adjust a stable and uniform emulsification system in a short time.

The biodegradable polymer used in the present invention includes, for example, α-hydroxycarboxylic acids (eg,
Glycolic acid, lactic acid, etc.), hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxytricarboxylic acids (eg,
A polymer, copolymer or mixture thereof having at least one carboxyl group and synthesized from at least one compound such as citric acid); poly-α-cyanoacrylate; polyamino acids (eg, poly-g-benzyl- L-glutamic acid and the like);
A maleic anhydride copolymer (eg, a styrene-maleic acid copolymer, etc.) is used. The type of polymerization may be random, block, or graft. When the α-hydroxy acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have an optically active center in the molecule, any of D-, L-, and DL-forms can be used. Among these, an α-hydroxycarboxylic acid polymer (preferably a lactic acid-glycolic acid polymer), an ester thereof, and a poly-α-cyanoacrylate are preferred. More preferably, it is a lactic acid-glycolic acid polymer. When a lactic acid-glycolic acid polymer is used as the biodegradable polymer, its composition ratio (mol%) is 10
0/0 to 40/60 is preferable, and 100/0 to 50/5
0 is particularly preferred. The weight average molecular weight of the above lactic acid-glycolic acid polymer is usually about 3,000 to about 50,000.
0, preferably from about 4,000 to about 40,000, more preferably from about 5,000 to about 30,000. The dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, and more preferably about 1.5 to 3.0.
5 is preferred. The weight average molecular weight, number average molecular weight and dispersity in the present specification mean that the weight average molecular weight is 1,11.
0000, 707,000, 354,000, 18
9,000, 156,000, 98,900, 66,4
37, 37, 200, 17, 100, 9, 830, 5,
The molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC) using 14 types of polystyrene of 870, 2,500, 1,303, and 500 as a reference substance and the calculated degree of dispersion. For measurement, G
Using PC column KF804L × 2 (manufactured by Showa Denko)
Chloroform was used as a mobile phase. Further, the biodegradable polymer is dissolved in an acetone-methanol mixed solvent,
Using phenolphthalein as an indicator, this solution was titrated with an alcoholic potassium hydroxide solution for the carboxyl group, and the number average molecular weight was calculated by terminal group determination. Hereinafter, this is referred to as a number average molecular weight determined by terminal group quantification. Whereas the number average molecular weight determined by end group quantification is an absolute value, the number average molecular weight determined by GPC is determined by the analysis or analysis conditions (eg, mobile phase type, column type, reference material, selection of slice width, baseline, , Etc.), it is difficult to obtain a unique numerical value, but for example, a polymer having a free carboxyl group at the end synthesized from lactic acid and glycolic acid by a noncatalytic dehydration polycondensation method is difficult. In the coalescence, the number average molecular weight determined by GPC and the number average molecular weight determined by terminal group quantification are almost the same. The term "substantially the same as that of the lactic acid-glycolic acid polymer" means that the number average molecular weight determined by terminal group quantification is about 0.2% of the number average molecular weight determined by GPC measurement.
It refers to within a range of 2 to about 1.5 times, preferably within a range of about 0.3 to about 1.2 times. The lactic acid-glycolic acid polymer is, for example, a non-catalytic dehydration polycondensation of lactic acid and glycolic acid (Japanese Patent Application Laid-Open No. 61-28521)
Alternatively, ring-opening polymerization using a catalyst from a cyclic body such as lactide and glycolide (Encyclopedic Handbook of Bioma
terials and Bioengineering PartA: Materials, Volum
e 2, Marcel Dekker, Inc., 1995). The polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but a polymer obtained by chemically treating the polymer to form a free carboxyl group at the end (Journal
J. Controlled Rele
ase), 41, 249-257 (1996)). The lactic acid-glycolic acid polymer having a free carboxyl group at the terminal can be produced without any problem by a known production method (for example, a non-catalytic dehydration polycondensation method, see JP-A-61-28521). The polymer having a free carboxyl group which is not specified in the above can be produced by a known production method (for example, see WO94 / 15587). Further, a lactic acid-glycolic acid polymer having a free carboxyl group at the end by a chemical treatment after ring-opening polymerization is, for example, Boehringer Ingelheim (Boehring
erIngelheim KG) may be used. These biodegradable polymers may be used alone or as a mixture of two or more. The polyvalent metal used in the present invention is not particularly limited as long as it is a compound that does not adversely affect the living body. Examples of the metal species include divalent (eg, iron, zinc, copper, calcium, magnesium,
Polyvalent metals (preferably zinc, etc.) such as aluminum, tin, manganese, etc., trivalent (eg, iron, aluminum, manganese, etc.) and tetravalent (eg, tin, etc.) are used. The "polyvalent metal compound" used in the present invention may be used as a compound with an inorganic or organic substance or a metal oxide, or may be used as a metal ion. It is preferred to apply the resulting components. Preferred specific examples of the polyvalent metal include, for example, iron, aluminum, zinc, calcium, and magnesium. A particularly preferred specific example of the polyvalent metal includes zinc. As the inorganic substance, for example, hydrogen halide (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, etc.), inorganic acids such as sulfuric acid, nitric acid, thiocyanic acid and the like are used. As the organic substance, for example, organic acids such as aliphatic carboxylic acids and aromatic acids, and acetylacetone are used. The aliphatic carboxylic acid preferably has 1 to 9 carbon atoms.
(E.g., aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, aliphatic tricarboxylic acids, etc.). The aliphatic carboxylic acid may be either saturated or unsaturated. As the aliphatic monocarboxylic acid,
For example, a saturated aliphatic monocarboxylic acid having 1 to 9 carbon atoms (eg, carbonic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, etc.) and 2 to 9 carbon atoms (E.g., acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.). Examples of the aliphatic dicarboxylic acid include saturated aliphatic dicarboxylic acids having 2 to 9 carbon atoms (eg, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.) and unsaturated aliphatic dicarboxylic acids having 2 to 9 carbon atoms. Acids (eg, maleic acid, fumaric acid, citraconic acid, mesaconic acid, etc.) are used. As the aliphatic tricarboxylic acid, for example, a saturated aliphatic tricarboxylic acid having 2 to 9 carbon atoms (eg,
Tricarballylic acid, 1,2,3-butanetricarboxylic acid, etc.). The aliphatic carboxylic acid may have one or two hydroxyl groups, and examples thereof include glycolic acid, lactic acid, glyceric acid, tartronic acid, malic acid, tartaric acid, and citric acid. Can be
The aliphatic carboxylic acid is preferably an aliphatic monocarboxylic acid. More preferred are aliphatic monocarboxylic acids having 2 to 9 carbon atoms. A particularly preferred specific example of the aliphatic carboxylic acid is acetic acid. As aromatic acids,
For example, benzoic acid, salicylic acid, phenolsulfonic acid and the like are used. Specific examples of metal compounds include salts of iron and inorganic acids [eg, iron halides (eg, iron chloride, iron bromide,
Iron iodide, iron fluoride, etc.), iron sulfate, iron nitrate, iron thiocyanate etc.), salts of iron with organic acids [eg, iron salts of aliphatic carboxylic acids (eg, iron carbonate, iron acetate, iron glycolate) , Iron lactate, iron tartrate, etc.), aromatic iron salts (eg, iron benzoate, iron salicylate, iron phenolsulfonate, etc.), salts of zinc with inorganic acids such as iron acetylacetonate [eg, zinc halides] (Eg, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate, etc.), salts of zinc with organic acids [eg, zinc salts of aliphatic carboxylic acids (eg, ,
Calcium and inorganic acids such as zinc carbonate, zinc acetate, zinc glycolate, zinc lactate, zinc tartrate), aromatic zinc salts (eg, zinc benzoate, zinc salicylate, zinc phenolsulfonate), zinc acetylacetonate, etc. (Eg, calcium halides (eg, calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, calcium thiocyanate, etc.), salts of calcium with organic acids [eg, , Calcium aliphatic carboxylate (eg, calcium carbonate, calcium acetate, calcium propionate, calcium oxalate, calcium tartrate, calcium lactate, calcium citrate, calcium gluconate, etc.), aromatic calcium salt (eg, calcium benzoate) , Calcium salicylate, etc.) Salts of magnesium and inorganic acids such as tilacetonate [eg, magnesium halides (eg, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate, etc.], Salts of magnesium and organic acids [eg, magnesium aliphatic carboxylate (eg, magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tartrate, magnesium lactate, magnesium citrate, magnesium gluconate, etc.), aroma Group magnesium salts (eg, magnesium benzoate, magnesium salicylate, etc.)], magnesium acetylacetonate and the like, and metal oxides (eg, zinc oxide, iron oxide,
Calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide, etc.). The polyvalent metal compound is preferably zinc oxide, iron chloride, iron acetylacetonate, zinc acetate, zinc acetylacetonate, calcium acetate, calcium acetylacetonate, magnesium acetate, magnesium acetylacetonate, and more preferably used. Zinc oxide is used. In the "component obtained by treating a poorly water-soluble polyvalent metal compound with water" of the present invention, a polyvalent metal which is the same as or different from the polyvalent metal used as a raw material (a polyvalent metal compound not treated with water) ) May be present in the sustained release formulation of the present invention,
Such a polyvalent metal may be present as a polyvalent metal compound (such as a compound with an inorganic or organic substance or a metal oxide) or may be present as a metal ion.
A complex may be formed with one or both of the bioactive compound, its prodrug or its salt, and the biodegradable polymer. In the present invention, a part of the polyvalent metal which may be contained may be used as a biodegradable polymer in which zinc or a different metal salt is used. The metal salt of the biodegradable polymer can be produced, for example, by the method described in JP-A-09-221420 or a method similar thereto. A preferred method for producing the sustained-release preparation of the present invention is a solution containing a bioactive compound that is hardly soluble in water, a component obtained by treating a sparingly water-soluble polyvalent metal compound with water, and a biodegradable polymer. From water and a solvent. By using a complex of one or both of a bioactive compound and a biodegradable polymer and a polyvalent metal as a raw material, the liquid can be used as a component obtained by treating a poorly water-soluble polyvalent metal compound with water. ) May be added to a polyvalent metal other than the polyvalent metal derived from the water-soluble polyvalent metal compound at the time of the preparation of the "component obtained by treating the water-insoluble polyvalent metal compound with water". At this time, by adding to water, the liquid may contain a polyvalent metal other than the polyvalent metal derived from “a component obtained by treating a sparingly water-soluble polyvalent metal compound with water”. A part or all of the polyvalent metal other than the polyvalent metal derived from the “component obtained by treating a poorly water-soluble polyvalent metal compound with water” is a bioactive compound and a biodegradable polymer in the liquid. A complex may be formed with one or both of the above.

In the sustained-release preparation of the present invention, the amounts of the physiologically active compound and the “component obtained by treating the poorly water-soluble polyvalent metal compound with water” depend on the kind of the physiologically active compound, the desired pharmacological effect and When the starting material is a bioactive compound, a component obtained by treating a water-insoluble polyvalent metal compound with water, and a biodegradable polymer, the sum of the three On the other hand, the physiologically active compound is usually about 1 to about 50% by weight, more preferably about 1 to about 50% by weight.
5 to 45% by weight, particularly preferably about 20 to 40% by weight
On the other hand, "a polyvalent metal compound which is hardly soluble in water to be treated with water"
Is usually about 0.5 to about 20% by weight, more preferably about 1% by weight.
To about 15% by weight, particularly preferably about 2 to about 10% by weight. The form of the sustained release preparation of the present invention is not particularly limited, but a parenteral administration preparation is preferable, and a transdermal preparation, a transmucosal preparation, an implant, a microcapsule injection, and the like can be considered. Injectable preparations using microcapsules, which place little burden on patients, are preferred.

[0027]

DETAILED DESCRIPTION OF THE INVENTION The physiologically active compound of the present invention, for a short time
Components generated from zinc oxide during treatment and biodegradable
Sustained-release preparations containing limers, such as microcapsules
Manufacturing (hereinafter sometimes referred to as microspheres)
The method will be exemplified. (I) Underwater drying method The amount of the above compounded in the organic solvent solution of the biodegradable polymer.
The bioactivity that is hardly soluble in water so that the weight ratio shown in
Compounds, one or more polyvalent metallizations poorly soluble in water
Compound and water, and water, a poorly soluble bioactive compound
And "Polymerized compounds that are hardly soluble in water
Of biodegradable polymers containing organic components in organic solvents
Make the liquid. At this time, a bioactive compound that is hardly soluble in water,
One or more water-insoluble polyvalent metal compounds and
And water are each converted into a biodegradable polymer organic solvent solution.
Some may not be dissolved and may be dispersed.
Or disperse finer in a short time with a known method such as ultrasonic wave
Preferably. Addition of water is polyvalent, which is hardly soluble in water
Metal compounds are present and can be mixed well by known methods
Conditions, bioactive compounds that are poorly soluble in water and bioactive compounds
Either or both of biodegradable polymers do not coexist
It may be performed under conditions. For example, polyvalent, which is hardly soluble in water
Organic solvent of biodegradable polymer with water
Add to the solution and mix well, then add the bioactive compound
Multi-stage bioactivation such as adding and redispersing
Of organic solvent solution of biodegradable polymer containing compound
It may be one process during the manufacturing method. As the organic solvent
Is, for example, a halogenated hydrocarbon (eg, dichlorometa
, Chloroform, dichloroethane, trichloroethane
, Carbon tetrachloride, etc.), ethers (eg, ethyl ether
Isopropyl ether, etc.), fatty acid esters (eg,
Ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (eg,
Alcohol, toluene, xylene, etc.)
For example, ethanol, methanol, etc.), acetonitrile, etc.
Is used. These may be used by mixing at an appropriate ratio.
Good. Among them, dichloro is the halogenated hydrocarbon.
Methane is ethanol, methanol as alcohol
Is preferred. These may be used by mixing at an appropriate ratio.
Good. An additive may be added to the above organic solvent solution.
Such additives include, for example, drug stability and solubility.
Carbonic acid, oxalic acid, citric acid,
Phosphoric acid, hydrochloric acid, etc., sodium hydroxide, arginine, lysine
And salts thereof. Also,
Albumin, gelatin, citric acid
Acid, sodium ethylenediaminetetraacetate, dextrin
, Sodium bisulfite, polyethylene glycol, etc.
Polyol compounds, etc., or as a preservative,
Paraoxybenzoic acid esters (eg, methyl
Leparaben, propylparaben, etc.), benzyl alcohol
Chlorobutanol, thimerosal, etc.
No. The concentration of the biodegradable polymer in the organic solvent solution is
Depending on the molecular weight of the biodegradable polymer and the type of organic solvent
For example, using dichloromethane as an organic solvent
When used, generally from about 0.5 to about 70% by weight, more
Preferably about 1 to about 60% by weight, particularly preferably about 2 to about 60% by weight.
It is selected from about 50% by weight. Also, with dichloromethane
Use ethanol or methanol as mixed organic solvent
The ratio of dichloromethane in the mixed organic solvent is
Generally, about 10 to about 99% by volume, more preferably about 2
0 to about 98% by volume, particularly preferably about 30 to about 95% by volume
%. Then, the obtained water, a water-insoluble
Physiologically active compounds and water-insoluble polyvalent metal compounds
Biodegradable polymer containing "components obtained by processing"
Is added to the aqueous phase, and O (oil phase) / W (water
Phase) After the emulsion is formed, the water and
Evaporate the medium to prepare microcapsules. At this time
The volume of the aqueous phase is generally about 1 time to about 10.0 times the volume of the oil phase.
00 times, more preferably about 5 times to about 5,000 times, especially
Preferably, it is selected from about 10 times to about 2,000 times. Up
An emulsifier may be added to the above external aqueous phase. The emulsifier,
Generally, a stable O / W emulsion can be formed.
Any may be used. Specifically, for example, anionic
Surfactants (sodium oleate, sodium stearate
Lium, sodium lauryl sulfate, etc.), non-ionic field
Surfactant (polyoxyethylene sorbitan fatty acid ester
Le (Tween 80, Tween 60, Atlas
Powder), polyoxyethylene castor oil derivative [HC
O-60, HCO-50, Nikko Chemicals, etc.)
Lolidone, polyvinyl alcohol, carboxymethylse
For use with lulose, lecithin, gelatin, hyaluronic acid, etc.
Can be. One or two or more of these
They may be used in combination. The concentration at the time of use is
More preferably in the range of about 0.01 to 10% by weight.
Or about 0.05 to about 5% by weight. the above
An osmotic pressure adjusting agent may be added to the outer aqueous phase of the above. The osmotic pressure
Modifiers that exhibit osmotic pressure when used in aqueous solution
Should be fine. As the osmotic pressure adjusting agent, for example, polyvalent
Alcohols, monohydric alcohols, monosaccharides, disaccharides,
Rigosaccharides and amino acids or their derivatives are listed.
I can do it. As the above polyhydric alcohols, for example,
Dihydric alcohols such as glycerin, arabitol, xy
Pentahydric alcohols such as litol and adonitol, mannini
Hexavalent alcohols such as tall, sorbitol and dulcitol
And the like are used. Among them, hexahydric alcohols
Preferably, mannitol is particularly preferred. Above value
Examples of alcohols include methanol, ethanol
And isopropyl alcohol.
Methanol is preferred. Examples of the above monosaccharides include
For example, arabinose, xylose, ribose, 2-deoxy
Pentoses such as siribose, glucose, fructose, galactose
, Manose, sorbose, rhamnose, fucose, etc.
Hexoses are used, and among them, hexoses are preferable.
Examples of the above oligosaccharide include maltotriose,
Trisaccharides such as raffinose sugars and tetrasaccharides such as stachyose
Etc., of which trisaccharides are preferred. The above simple sugar
, Disaccharides and oligosaccharide derivatives include, for example,
Glucosamine, galactosamine, glucuronic acid, galact
Tulonic acid or the like is used. As the above amino acids
Can be any L-form,
Examples include glycine, leucine, arginine and the like.
It is. Of these, L-arginine is preferred. These dipping
The pressure regulator may be used alone or in combination.
No. These osmotic pressure regulators increase the osmotic pressure of
About 1/50 to about 5 times the osmotic pressure of salt water, preferably about 1/50
It is used at a concentration of 25 to about 3 times. Water and organic solvents
As a method for removing the medium, a method known per se or a method known in the art.
A method according to this is used. For example, propeller type stirring
While stirring with a machine or magnetic stirrer.
Water or organic solvent
Using a rotary evaporator, etc.
Method of evaporating water and organic solvent while adjusting the airness
And the like. The microcapsules thus obtained
The cells are collected by centrifugation or filtration, and then
Bioactive compounds and drug deposits on the surface of the capsule
Wash the carrier substance, emulsifier, etc. several times with distilled water
And freeze-dried. During the manufacturing process, grains
An anticoagulant may be added to prevent coagulation of the children.
Examples of the aggregation inhibitor include mannitol, lactolactide
Sauce, glucose, starches (eg, corn starch, etc.)
Such as water-soluble polysaccharides, amino acids such as glycine, fibrils
And proteins such as collagen and collagen. What
Nevertheless, mannitol is preferred. Also freeze-dried
After that, if necessary, the microcapsules are fused under reduced pressure
Heating under conditions that do not
And the removal of the organic solvent. Preferably 1 per minute
Under the condition of a heating rate of 0 to 20 ° C., a differential scanning calorimeter
The midpoint glass transition temperature of biodegradable polymers
Is also heated at a slightly higher temperature. More preferably, in vivo
From the midpoint glass transition temperature of the degradable polymer,
Heat within 0 ° C higher temperature range. Above all, biodegradation
Of using lactic acid-glycolic acid polymer as the conductive polymer
In this case, it is preferable that
Temperature range 10 ° C higher than glass transition temperature, more preferred
Or above the midpoint glass transition temperature
Heat in a temperature range 5 ° C. higher. Heating time is micro
Although it depends on the amount of capsules, etc.
After the microcapsule itself reaches the specified temperature,
Between about 168 hours, preferably about 24 hours to about 120 hours
And especially preferably from about 48 hours to about 96 hours. Addition
The heating method can uniformly heat the microcapsule aggregate
There is no particular limitation as long as it is a method. As the heating drying method
For example, in a constant temperature bath, fluidized bath, moving bath or kiln
Heat drying method, microwave heating method, etc.
Is used. Heating and drying in a constant temperature bath
Is preferred. In addition, the moisture and
Removal of the organic solvent is performed using a supercritical fluid (CO _TwoEtc.), pressurized gas
(CO_Two, Etc.).

(II) Phase Separation Method In the case of producing microcapsules by this method, water, a physiologically active compound which is hardly soluble in water and a water-soluble compound which is described in the above-mentioned (I) method for drying in water are used. A microcapsule is precipitated and solidified by gradually adding a coacervation agent to an organic solvent solution of a biodegradable polymer containing a component obtained by treating a valent metal compound with water. The coacervation agent has an oil phase volume of about 0.01 to 1,000
Fold, preferably about 0.05 to 500 times, particularly preferably about 0.1 to 200 times. The coacervation agent is not particularly limited as long as it is a polymer, mineral oil or vegetable oil compound miscible with an organic solvent and does not dissolve both the physiologically active compound and the biodegradable polymer. Specifically, for example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more. After fractionating the microcapsules thus obtained, they are repeatedly washed with heptane or the like to remove the bioactive compound and the coacervation agent other than the biodegradable polymer, and dried under reduced pressure. Alternatively, after washing by the same method as described in the underwater drying method (I), freeze-drying, heat drying, desolvation with a supercritical fluid, a pressurized gas, or the like may be performed.

(III) Spray drying method In the case of producing microcapsules by this method, water, a poorly water-soluble bioactive compound and a water-insoluble water-soluble compound described in the above (I) in-water drying method are used. The organic solvent solution of the biodegradable polymer containing the component obtained by treating the valent metal compound with water is sprayed into the drying chamber of a spray dryer using a nozzle, and atomized in an extremely short time. The water and organic solvent in the droplets are volatilized to prepare microcapsules. Examples of the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type. Thereafter, if necessary, washing is carried out in the same manner as described in the underwater drying method (I), followed by freeze-drying, heating drying, desolvation with a supercritical fluid, pressurized gas and the like. You may. Water described in the underwater drying method of the microcapsule production method (I) as a dosage form other than the microcapsules described above;
An organic solvent solution of a biodegradable polymer containing a poorly water-soluble bioactive compound and "a component obtained by treating a poorly water-soluble polyvalent metal compound with water", for example, a rotary evaporator or the like. The organic solvent and water may be evaporated and evaporated to dryness while controlling the degree of vacuum to obtain a fine powder by pulverizing with a jet mill or the like. Further, the pulverized fine powder is washed in the same manner as described in the underwater drying method of the microcapsule production method (I), and then freeze-dried, and further heated, dried by a supercritical fluid, a pressurized gas, or the like. Desolvation may be performed. In the microcapsules or fine powder obtained here, the decomposition rate of the biodegradable polymer to be used, the "component obtained by treating a poorly water-soluble polyvalent metal compound with water", the amount of water added, the polyvalent metal Drug release can be controlled according to the type and amount of the compound. The sustained-release preparation of the present invention may be formulated as it is or as a raw material into various dosage forms, and injected or implanted into intramuscular, subcutaneous, organs, etc., transmucosally into nasal cavity, rectum, uterus, etc. Or inhalants, oral preparations (eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as syrups, emulsions, suspensions, etc.) can do. It can also be administered with a needleless syringe. For example, in order to make the sustained-release preparations of the present invention into injections, they are used as dispersants (eg, Tween 80, HCO
Surfactants such as -60, polysaccharides such as sodium hyaluronate, carboxymethylcellulose, and sodium alginate), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, (E.g., glucose, proline, etc.) or an aqueous suspension, or dispersed with vegetable oils such as sesame oil and corn oil to give sustained-release injections that can actually be used as oil suspensions. The particle size of the sustained-release preparation of the present invention, when used as a suspension injection, may be within a range that satisfies the degree of dispersion and needle penetration. 300 μm, preferably about 0.
5 to 150 μm, more preferably about 1 to 10
The range is 0 μm. The sustained-release preparation of the present invention can be made into a sterile preparation by, for example, a method of sterilizing the production process, a method of sterilizing with gamma ray, a method of combining these methods, or a method of adding a preservative, and the like. Not done.

Since the sustained-release preparation of the present invention has low toxicity, it can be used in mammals (eg, humans, cows, pigs, dogs, cats, mice,
(Rats, rabbits, etc.). The dosage of the sustained-release preparation of the present invention varies depending on the type and content of the bioactive compound as the main drug, dosage form, duration of bioactive compound release, target disease, target animal, etc. Any quantity is sufficient.
For example, when the sustained-release preparation is a one-month preparation, the dose of the physiologically active compound as the main drug is preferably about 0.01 mg to 10 mg / k per adult.
g weight range, more preferably about 0.05mg-5m
It can be appropriately selected from the range of g / kg body weight. The dose of the sustained-release preparation per dose is preferably selected from the range of about 0.05 mg to 50 mg / kg body weight, more preferably the range of about 0.1 mg to 30 mg / kg body weight per adult. it can. The frequency of administration is once every few weeks.
Type, content, dosage form, release of bioactive compound, such as once every month, once every month, or once every few months (eg, every 3 months, 4 months, 6 months, etc.) Can be appropriately selected depending on the duration of the disease, the target disease, the target animal, and the like. Further, the sustained-release preparation of the present invention can be used for bedridden, dementia, throat,
It can also be used advantageously for patients with esophageal disease, digestive tract disease, eating and dysphagia patients, patients who have difficulty or cannot treat with internal medicine such as during surgery. When the bioactive compounds are compounds having angiotensin II antagonistic activity, they are highly safe, and even if the blood concentration increases immediately after administration, the blood pressure does not drop too much. The sustained-release preparation of the present invention can be used as a therapeutic agent for the following diseases, and can maintain a constant blood concentration regardless of day and night. Therefore, it is expected that the treatment effect can be further clarified because the dose and the number of doses can be reduced, and there is little change in the blood drug concentration, and no change in the disease state occurs due to discontinuation of taking the drug. Regarding safety, in normal use conditions, the danger of excessive blood pressure etc. is smaller than for internal use etc. for the above reasons, but even if excessive blood pressure occurs due to the occurrence of a situation involving a large amount of fluid loss such as a traffic accident, Immediate intravenous administration of not only angiotensin II but also drugs commonly used in emergency medical settings (such as catecholamines) can immediately increase blood pressure, and continuous oral hypertension can be achieved by oral administration of antihypertensive drugs Therefore, not only acute emergency response but also long-term response is possible. The target disease of a compound having angiotensin II antagonistic activity as a physiologically active compound is the presence of angiotensin II or the presence of angiotensin II due to contraction and proliferation of blood vessels and organ damage expressed through angiotensin II receptor. Then, depending on the induced factor, a disease or the like in which the onset or the onset is promoted may be mentioned. Such diseases include, for example, hypertension, abnormal circadian blood pressure, heart diseases (cardiac hypertrophy, chronic heart failure including acute heart failure and congestion, cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia,
Myocardial infarction, etc.), cerebrovascular disorders (asymptomatic cerebral vascular disorders, transient cerebral ischemic attacks, stroke, cerebral vascular dementia, hypertensive encephalopathy, etc.), cerebral edema, cerebral circulation disorder, cerebrovascular disorder recurrence and Sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, impaired activities of daily living, etc.), ischemic peripheral circulatory disorders, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, diabetes, diabetic complications (diabetic retinopathy) , Diabetic nephropathy, diabetic neuropathy, etc.), kidney diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, organ damage including radiation-induced nephropathy) ), Arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hyperplasia, intervention (percutaneous coronary angioplasty, stent placement, coronary artery endoscopy) , Intravascular ultrasound, coronary infusion Vascular hyperplasia or occlusion and organ damage after lysis therapy, revascularization / restenosis after bypass surgery, erythrocytosis / hypertension / organ damage / vascular hypertrophy after transplantation, rejection after transplantation, eye disease (glaucoma) , Ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (deep vein thrombosis, obstructive peripheral circulation disorder, obstructive atherosclerosis, obstructive thrombotic Vasculitis, ischemic cerebral circulatory disorder, Raynaud's disease, Burger's disease, etc., metabolic and nutritional disorders (obesity, hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia) , Hypernatremia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system disorders (disorders such as cerebral hemorrhage and cerebral infarction and their sequelae and complications, Outside wound, spinal cord injury, cerebral edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, such as multiple sclerosis),
Dementia, memory impairment, consciousness impairment, amnesia, anxiety symptoms, tension symptoms, discomfort mental state, mental illness (depression, epilepsy, alcoholism, etc.), inflammatory diseases (retinopathy, nephropathy, neuropathy, Diabetic complications such as vascular disorders; arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periosteitis; inflammation after surgery and trauma; remission of swelling; pharyngitis; cystitis; pneumonia; atopic skin Inflammation; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye diseases; inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis, and tuberculosis; allergic diseases (allergic rhinitis, conjunctivitis) , Gastrointestinal allergy, hay fever, anaphylaxis, etc.), chronic obstructive pulmonary disease, interstitial pneumonia, carinii pneumonia, collagen disease (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver disease (chronic) Including Hepatitis, cirrhosis, etc.), portal hypertension, gastrointestinal disorders (gastritis, gastric ulcer, gastric cancer, post-gastric surgery disorders, indigestion, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, etc.) Diseases (erythrocytosis,
Vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelosis, etc., bone disease (eg, fracture, refracture, osteoporosis, osteomalacia, bone Petchet disease, ankylosing myelitis) , Rheumatoid arthritis, destruction of joint tissue in osteoarthritis and similar diseases, solid tumors, tumors (melanoma, malignant lymphoma, gastrointestinal tract (eg,
Stomach, intestines, etc.), cancer and associated cachexia, cancer metastasis, endocrine disorders (Addison's disease, Cushing's syndrome,
Brown cell types, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and male genital diseases (cystitis,
Prostatic hyperplasia, prostate cancer, sexually transmitted diseases, etc.), gynecological diseases (such as menopause, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, breast disease, sexually transmitted diseases, etc.), and diseases caused by environmental or occupational factors (Radiation damage, damage caused by ultraviolet rays, infrared rays, laser beams, altitude sickness, etc.), respiratory diseases (cold syndrome,
Pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis / pulmonary embolism, etc., infectious diseases (cytomegal virus, influenza virus,
Viral infections such as herpes virus, rickettsial infections, bacterial infections, etc., toxicemia (sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxin shock syndrome, etc.), otolaryngology (Mennell syndrome, Examples include systemic diseases such as tinnitus, taste disorder, dizziness, imbalance, and dysphagia, skin diseases (such as keloids, hemangiomas, and psoriasis), dialysis hypotension, myasthenia gravis, and chronic fatigue syndrome. If the bioactive compound is a compound having angiotensin II antagonistic activity, by inhibiting the action of angiotensin II in the long term, impaired or abnormal biological functions and physiological effects that cause various diseases associated with adult diseases and aging Can be ameliorated or suppressed, and primary and secondary prevention or progress of a disease or condition resulting therefrom can be suppressed. Such disorders or abnormalities in biological functions and physiological functions include, for example, disorders or abnormalities in the ability to automatically regulate cerebral circulation and renal circulation, circulatory disorders (peripheral, brain, microcirculation, etc.), disorders in the blood-brain barrier, insulin sensitivity Blood loss, salt sensitivity, coagulation / fibrinolytic system abnormalities, abnormalities in blood and blood cell components (such as increased platelet aggregation, abnormal red blood cell deformability, increased white blood cell adhesion, increased blood viscosity, etc.), growth factors and cytokines (PDGF , VEGF, FGF, Interlokin, T
NF-α, MCP-1 etc.) production and action, inflammatory cell production and invasion, free radical production,
Acceleration of fat deposition, endothelial dysfunction, endothelial, cell and organ damage, edema, morphological change of cells such as smooth muscle (morphological change to proliferative type, etc.), vasoactive substances and thrombotic substances (endothelin, thromboxane A ₂ Production and hyperactivity, abnormal contraction of blood vessels, abnormal glucose tolerance, abnormal metabolism (abnormal serum lipids, abnormal blood glucose, etc.), abnormal proliferation of cells, etc., angiogenesis (abnormal capillaries in the outer membrane of atherosclerotic lesions) Abnormal angiogenesis in reticular formation), among others,
Organ disorders due to various diseases (eg, cerebrovascular disorders and related organ disorders, organ disorders due to circulatory diseases, organ disorders due to diabetes, organ disorders after intervention, etc.)
Can be advantageously used as primary and secondary preventive / therapeutic agents. In the sustained-release preparation of the present invention, when the physiologically active compound is a compound having an angiotensin II antagonistic activity (particularly, candesartan cilexetil, candesartan, etc.), it can be advantageously used as an agent for preventing or treating portal hypertension. It is. It is known that rupture of the esophageal varices occurs frequently at night (Hepatology 1994; 19: 595-601), and this drug can maintain a constant blood concentration regardless of day and night. Compared with the case of administration, not only can the dose and frequency be reduced, but also a stable decrease in portal vein pressure can be expected because the blood drug concentration does not fluctuate much. The above features of this drug demonstrate its usefulness as a preventive for rupture of varices in the esophagus and stomach. Also,
It is expected that the treatment effect will be clearer because no change in the medical condition occurs due to discontinuation of taking the drug. Furthermore, compounds having an angiotensin II antagonistic activity as physiologically active compounds (especially candesartan cilexetil, candesartan, etc.) can be obtained from HGF (Hepatocyte Growth Fact).
or: hepatocyte growth factor) is expected to be effective in promoting production, and can be expected to contribute to liver regeneration and liver brain recovery.
Prevention and treatment of cerebrovascular disorders such as cerebral infarction by maintaining the blood concentration of compounds having angiotensin II antagonism as physiologically active compounds (especially candesartan cilexetil, candesartan, etc.) regardless of day and night. It is expected that the effect will be more clear.
When the physiologically active compound is a compound having an angiotensin II antagonistic action, as a method of treating a patient, an orally administered angiotensin II antagonist is administered for a certain period of time, and after confirming the reactivity of the patient, the sustained release of the present invention is performed. It is also conceivable to administer a sexual preparation. The angiotensin II antagonist administered orally and the angiotensin II antagonist contained in the sustained-release preparation may be the same or different. In addition, antihypertensive agents (calcium antagonists, diuretics, beta-blockers, etc.) other than angiotensin II antagonists are orally administered in advance, and after confirming the reactivity of the patient, the sustained-release preparation of the present invention is administered. May be. Also, a diuretic antihypertensive agent used in combination with the sustained-release preparation of the present invention and usually an angiotensin II antagonist
(Oral formulation) may be used in combination. In addition, other lipid-lowering drugs or cholesterol-lowering drugs, HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reduct)
ase) Inhibitor, insulin sensitizer, bone disease treatment, cardioprotective, coronary artery disease treatment, other hypertension treatment, chronic heart failure treatment, diabetes treatment, liver disease treatment, gastric / duodenal ulcer treatment Remedies, biliary tract remedies,
It may be used together with other pharmaceutical ingredients including a therapeutic agent for hypothyroidism, a therapeutic agent for nephrotic syndrome, a therapeutic agent for chronic renal failure, a therapeutic agent for gynecological diseases, a therapeutic agent for urinary and male genital diseases or a therapeutic agent for infectious diseases, in this case. These compounds may be administered as an oral preparation or, if necessary, as a rectal preparation in the form of suppositories. Possible combinations in this case include, for example, fibrates (eg, clofibrate, benzafibrate, gemfiprodil, etc.), nicotinic acid, derivatives and analogs thereof (eg, acipimox and probucol), bile acid binding resins [Eg, cholestyramine, colestipol, etc.], compounds which suppress cholesterol absorption [eg, sitosterol and neomycin, etc.], squalene epoxidase inhibitors [eg, NB-598 and related compounds, etc.]. Yet another possible combination component is an oxide squalene-lanosterol cyclase, such as a decalin derivative, an azadecalin derivative and an indane derivative. Also, combinations with the following various therapeutic agents are possible. Antihypertensives: diuretics (eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diate)), antihypertensives (eg, ACE inhibitors, (enalapril maleate (Lenibase), etc.)) and Ca antagonists (Manidipine, Amlodipine, etc.), α or β receptor blockers, etc.) Chronic heart failure drugs: inotropic drugs (eg, cardiac glycosides (digoxin, etc.), β receptor stimulants (catecholamine preparations such as denopamine and dobutamine) and PDE inhibition Drugs, etc.), diuretics [eg, furosemide (Lasix), spironolactone (aldactone), etc.], ACE inhibitors,
[Examples, enalapril maleate (Lenibase), etc.],
Ca antagonists (eg, amlodipine, etc.) and β receptor blockers, etc. Antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride, β blockers, Ca antagonists, etc. calcium preparations (e.g., calcium carbonate, etc.), calcitonin preparations, the active vitamin D ₃ preparations (e.g., such as alfacalcidol (alpha roll),
Calcitriol (locartrol), etc., sex hormones (eg, estrogen, estradiol, etc.), hormone preparations (eg, conjugated estrogen (premarin), etc.), ibriflavone preparations (osten, etc.), vitamin K ₂ , vitamin K ₂ formulation [eg, menatetrenone (Glakay), etc.], (such as etidronate) bisphosphonic acid preparations, prostaglandin E2, fluorine compounds (e.g., sodium fluoride, etc.), bone morphogenetic protein (BMP), fibroblast growth factor (FGF), platelet-derived growth factor (PD
GF), transforming growth factor (TGF-
β), insulin-like growth factors-1 and 2 (IGF-1,
-2), parathyroid hormone (PTH), EP-A1-376197, EP-A1-4
Nos. 60488 and EP-A1-719782 (eg, (2R.4S)-(-)-N- [4- (diethoxyphos
phorylmethyl) phenyl] -1,2,4,5-tetrahydro-4-methyl-
7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxam
Drugs for treating diabetes: Actos, rosiglitazone, kinedak, benfil, humulin, oigurcon, glimicron, daoneil, novolin, monotard, insulins, glucoby, dimerin, rustinone, basilcon, deamelin S, isgilin, etc .; Drugs for treating liver diseases: glycyrrhizin preparations (eg, strong minophagen, etc.), liver hydrolyzate, SH compounds (eg, glutathione, etc.), special amino acid preparations (eg, aminolevan, etc.), phospholipids (eg, polyenphosphatidylcholine, etc.), vitamins (E.g., vitamins B1, B2, B6, B12, C, etc.), corticosteroids (e.g., dexamethasone, betamethasone, etc.), interferons (e.g., interferon alpha, beta, etc.), drugs for treating hepatic encephalopathy (e.g., lactulose, etc.) , Esophagus, hemostatic used when gastric varices rupture [eg, Vasopressin, somatostatin, etc.); gastric / duodenal ulcer therapeutic agent: antacid (eg, histamine H2 antagonist (cimetidine, etc.), proton pump inhibitor (lansoprazole, etc.)); biliary disease therapeutic agent: bile agent [Examples, such as dehydrocholic acid],
Bile suppressants (eg, magnesium sulfate, etc.); Hypothyroidism drugs: dry thyroid (thyreoid),
Levothyroxine sodium (Tyrazine S), liothyronidine sodium (thyronine, thyromin), etc .; Nephrotic syndrome drug: Prednisolone (prednin), prednisolone sodium succinate (prednin) for steroid therapy usually adopted as the first choice , Methylprednisolone sodium succinate (Sol Medrol), betamethasone (Rinderone) and the like are used. Anticoagulant therapy includes antiplatelet drugs and anticoagulants such as dipyridamole (versantin), dilazep hydrochloride (comerian), ticlopidine, clopidogrel, and FXa inhibitor; HMG-CoA reductase inhibitors: cerivastatin, atorvastatin , Pravastatin, simvastatin, itavastatin, lovastatin, fluvastatin, (+)
-3R, 5S-7- [4- (4-fluorophenyl)-
6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid; therapeutic agent for chronic renal failure: diuretic [eg, Furosemide (Lasix), Bumetanide (Lunetron), Azosemide (Diart)], Antihypertensives (eg, ACE inhibitors, (Enalapril maleate (Lenibase)) and Ca antagonists (Manidipine), alpha receptor blockers, etc. When administered, it can preferably be used orally.Thrombosis-preventing and treating drugs: anticoagulants [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), blood coagulation factor Xa inhibitors, and coagulation-fibrinolytic drugs] Drugs with balance correction function], thrombolytic drugs [eg, tPA, urokinase], antiplatelet drugs [eg ,
Aspirin, sulfinpyrazolo (anturane), dipyridamole (persantin), ticlopidine (panaldine), cilostazol (pletal), GPIIb / IIIa
Antagonists (Leopro)] Coronary vasodilators: nifedipine, diltiazem, nicorazil, nitrite, etc. Cardioprotective drugs: Cardiac ATP-K openers, Na-H exchange inhibitors, endothelin antagonists, urotensin antagonists, etc. Inflammatory drugs: aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (eg, indomethacin, etc.), steroid drugs (eg, dexamethasone, etc.) Antiallergic drugs: antihistamine drugs (eg, chlorpheniramine maleate, etc.), stimulation therapy Agents (eg, bucillamine), azelastine hydrochloride, seratrodast, tranilast, oxatomide, potent neominophagency, tranexamic acid, ketotifen fumarate, etc. Antineoplastic agents: alkylating agents, antimetabolites, antitumor antibiotics, antitumor agents Oncology plant ingredients and other antitumor agents Drugs acting on the central nervous system: anxiolytics, hypnotics, anesthetics, analgesics, autonomic nervous drugs, antiparkinson drugs and other psychiatric drugs, etc. Gynecological diseases drugs: [eg, menopause drugs (Bound estrogen, estradiol, testosterone enanthate / estradiol valerate, etc.), breast cancer drug (tamoxifen citrate, etc.), endometriosis / uterine fibroid treatment drug (leuprorelin acetate, danazol, etc.) etc. Drugs for genital diseases: [eg, drugs for prostatic hypertrophy (tamsulosin hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.), prostate cancer (leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.)] Infectious disease drugs: [examples , Antibiotics (cefatiam hydrochloride, cefozopran hydrochloride, ampicillin, etc.), Agents, synthetic antibacterial agents, antiviral agents, etc.),
Biological products (vaccines, blood products such as immunoglobulins), etc.] In addition, anti-obesity drugs (such as mazindol), anti-rheumatic drugs, etc. In addition, treatment by introducing various biological factors or their genes (eg, When these drugs are used in combination with the sustained-release preparation of the present invention, such as angiogenesis promoting factors such as HGF and VEGF, or the ischemic disease treatment by gene transfer thereof, each drug is used in one sustained-release preparation. It may be blended, but the above drug is formulated by mixing with a pharmacologically acceptable carrier, excipient, binder, diluent and the like, and administered separately or simultaneously with the sustained-release preparation of the present invention. can do. When the drugs are separately formulated, the separately formulated ones can be mixed and administered using a diluent or the like at the time of use.
Alternatively, they may be separately administered to the same subject at different times.

[0031]

The present invention will be described in more detail with reference to the following Examples and Experimental Examples, which do not limit the present invention. Reference Example 1 2-ethoxy-1-[[2 ′-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (hereinafter abbreviated as compound A) 2
g and zinc oxide (TYPE V, Wako Pure Chemical Industries, Ltd.) 0.36 g with lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 7
5/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight 4,090 by terminal group quantification, manufactured by Wako Pure Chemical Industries) 3.6 g was added to a solution of 11 ml of dichloromethane and 0.4 ml of ethanol The mixture was shaken and stirred at room temperature for 14 hours to obtain a cloudy solution. This solution in advance
The mixture was poured into 800 ml of a 0.1% by weight aqueous solution of polyvinyl alcohol adjusted to 15 ° C., and an O / W emulsion was formed at 8,500 rpm using a turbine-type homomixer. The O / W emulsion was stirred at room temperature for 3 hours to evaporate dichloromethane and ethanol and solidify the oil phase.
Collection was performed at 2,000 rpm using a centrifuge. This was dispersed again in distilled water and then centrifuged to wash free drugs and the like. The collected microcapsules were redispersed by adding distilled water in which a small amount of mannitol was dissolved, and then freeze-dried to obtain a powder. Compound in microcapsules
The encapsulation rate of A was 98%, and the content of compound A in the microcapsules was 33.0%.

Comparative Example 1 Microcapsules were obtained in the same manner as in Reference Example 1, except that the shaking and stirring for 14 hours was changed to the dispersion and mixing for 1 minute using a homogenizer. The encapsulation rate of compound A in the microcapsules is 100%, and the content of compound A in the microcapsules is 3
3.5%.

Example 1 A microparticle was prepared in the same manner as in Comparative Example 1 except that 0.4 ml of distilled water was added and dispersed (emulsified) and mixed with a solid (compound A and zinc oxide) using a homogenizer at the same rotation speed for 1 minute. Capsules were obtained. Compound in microcapsules
The encapsulation rate of A was 97%, and the content of compound A in the microcapsules was 32.6%.

Example 2 Microcapsules were obtained in the same manner as in Example 1 except that the amount of distilled water added was changed to 0.08 ml. The encapsulation rate of compound A in the microcapsules was 97%, and the content of compound A in the microcapsules was 32.5%.

Experimental Example 1 25 mg of the microcapsules obtained in Reference Example 1, Comparative Example 1, and Examples 1 and 2 were combined with 0.1 ml of a dispersion medium (5 mg of sodium carboxymethylcellulose, 1 mg of polysorbate 80, and 50 mg of a dispersion medium). Mannitol in 1 ml of distilled water) and subcutaneously on the back of the neck of a 7-week-old male SD rat.
Administered with a 23G needle. After the administration, blood was removed from the abdominal aorta of the rat over time and sacrificed. The microcapsules remaining at the administration site were taken out, and the residual ratio of the compounds calculated by quantifying the compounds therein was shown in Table 1.

[0036]

[Table 1] In the preparations of Examples 1 and 2 containing a component generated from zinc oxide in a short-time water treatment, a reference example in which a formulation component containing zinc oxide was mixed for a long time to form an interaction between the components. Similar to Comparative Example 1, the initial release of the physiologically active compound was remarkably suppressed, unlike the preparation of Comparative Example 1 which was treated for a short time without adding water. In the preparation of Comparative Example 1, which was prepared by treating for a short time without adding water, a marked excess initial release of the physiologically active compound was observed. The subsequent release rate of the physiologically active compound in the preparations of Examples 1 and 2 in which the initial release was suppressed changed depending on the amount of water added during the short-time treatment, and the release in Example 1 where the amount of added water was large. It was confirmed that the release rate of the physiologically active compound could be controlled by adjusting the rate faster than in Example 2 with a small amount of added water, and by the amount of added water.

Example 3 Compound A (4 g) and zinc oxide (TYPE V, manufactured by Wako Pure Chemical Industries) 0.7
2 g and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 10,600) 7.2 g
Was added to a solution of 22 ml of dichloromethane and 0.8 ml of ethanol, and 0.16 ml of distilled water was added thereto.
Immediately under the same conditions as in Comparative Example 1, the mixture was dispersed (emulsified) and mixed with a homogenizer to obtain a cloudy solution. This was cast into a circle having a radius of about 5 cm on a flat plate, and dried under reduced pressure at room temperature for 15 hours to obtain a dried product. The dried product was coarsely pulverized on a sieve having a pore size of 250 μm, 5 g of the dried product obtained by sieving was mixed with 0.4 g of mannitol, and then mixed with a jet mill (A-OJE
(T, manufactured by Seishin Enterprise Co., Ltd.) and pulverized at an air pressure of 2 kg / cm ² to obtain fine particles having an average particle diameter of 21 μm. The content of compound A in the fine particles was 31.0%.

Example 4 A cloudy solution obtained by dispersing (emulsifying) and mixing the same formulation and operation as in Example 3 was spray-dried (Mobile Min) under the following conditions.
or Niro Japan) to obtain fine particles having an average particle diameter of 32 μm as a dried product under a cyclone. Spraying method: Two-fluid nozzle (nozzle diameter 1.2 mm) Air pressure: 1 kg / cm ² Drying room inlet temperature: 90 ° C Drying room outlet temperature: 40-43 ° C The content of compound A in the obtained fine particles was 28.1%. Was.

Experimental Example 2 About 5 mg of the microcapsules and fine particles obtained in Comparative Example 1 and Examples 2 to 4 were added to 12 ml of a glycine buffer solution (pH 10, 25 mM) containing 1% CTAB in a 17P vial, and the rubber was added. After closing the stopper,
The mixture was shaken and stirred at 42 ° C. at 120 times / minute. With time, 0.1 ml was withdrawn through a rubber stopper, and after a 0.25 μm filter, the concentration of Compound A was measured to calculate the release rate. Table 2 shows the results.

[0040]

[Table 2] It was confirmed that the sample of Comparative Example 1 in which the release was fast in vivo in Experimental Example 1 was fast even in the set in vitro test system. Since the release of Examples 3 and 4 was almost the same as that of Example 2 in which sustained release over 4 weeks was confirmed in vivo, the samples of Examples 3 and 4 were in vivo.
It was suggested that ivo has a sustained release of about 4 weeks in ivo.

[0041]

Industrial Applicability The sustained-release preparation of the present invention is a preparation containing a component obtained by treating a poorly water-soluble polyvalent metal compound with water. Since the compound is contained in a high content and its release rate can be controlled, the desired pharmacological action of the physiologically active compound can be expected for a long period of time. In the case of a compound having angiotensin II antagonistic activity, a poorly water-soluble physiologically active compound can maintain a constant blood concentration, so that the blood drug concentration fluctuates less than when administered orally, and is stable. Continued pharmacological action can be expected. Therefore, it is unlikely that the patient's condition deteriorates due to intentional repulsion such as fluctuation of the taking time or interruption of taking in a patient group with a small number of subjective symptoms, hypertension,
Circadian blood pressure fluctuation, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.), cerebrovascular disorder (asymptomatic cerebral infarction, transient cerebral ischemic attack, stroke, cerebral vascular dementia, hypertensive encephalopathy, etc.) Blood peripheral circulatory disorders, obstructive atherosclerosis, obstructive thrombotic vasculitis, myocardial ischemia, cardiomyopathy, venous dysfunction, progression of heart failure after myocardial infarction, sequelae of cerebrovascular disease, etc., as well as diabetic complications, Diabetic retinopathy, diabetic nephropathy, nephritis, glomerulonephritis, radiation nephropathy, atherosclerosis, arteriosclerosis, vascular hypertrophy, vascular hypertrophy or occlusion after intervention, vascular revascularization after bypass surgery Obstruction, post-transplant erythrocytosis / hypertension / organ damage / vascular hypertrophy, transplant rejection, hyperaldosteronism, glomerulosclerosis, renal failure, portal hypertension, glaucoma, ocular hypertension, hyperlipidemia Disease, angina, aneurysm, coronary atherosclerosis Cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, central nervous system disease, Alzheimer's disease, memory deficiency, depression, amnesia, senile dementia, sensory dysfunction, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, More clear treatment effects for Menuel syndrome, scleroderma, or anxiety, tension and discomfort associated with vertigo, as well as dyspepsia, autonomic dysfunction, myasthenia gravis or cancer and cancer-related diseases. There is expected. The sustained-release preparation of the present invention is also used for bedridden patients, dementia, throat / esophageal diseases, digestive disorders, eating / dysphagia patients, patients who are difficult or impossible to treat with internal medicine such as at the time of surgery. An excellent drug that can be.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4184 A61K 31/4184 31/4245 31/4245 31/519 31/519 47/02 47/02 A61P 9/00 A61P 9/00 9/12 9/12 (72) Inventor Yasutaka Ikari 5-4-25-503, Motoyamaminami-cho, Higashinada-ku, Kobe-shi, Hyogo F-term (reference) 4C076 AA29 AA61 BB11 CC11 DD21 DD29 DD38 DD43 EE06 EE24 FF16 FF32 GG05 GG06 GG21 4C086 AA01 AA02 BC38 BC39 BC62 CB09 GA07 MA03 MA05 MA38 MA66 NA12 ZA36 ZA42

Claims (39)

[Claims] A sustained-release preparation comprising a physiologically active compound that is hardly soluble in water, a component obtained by treating a water-soluble polyvalent metal compound with water, and a biodegradable polymer. 2. The sustained-release preparation according to claim 1, wherein the physiologically active compound is a non-peptidic compound. 3. The sustained-release preparation according to claim 1, wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. 4. The sustained-release preparation according to claim 3, wherein the compound having an angiotensin II antagonistic action is a non-peptidic compound. 5. The sustained-release preparation according to claim 3, wherein the compound having an angiotensin II antagonistic action is a compound having an oxygen atom in the molecule. 6. The sustained-release preparation according to claim 3, wherein the compound having an angiotensin II antagonistic action is a compound having an ether bond or a carbonyl group. 7. A compound having an angiotensin II antagonistic activity is represented by the formula (I): (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. Or a salt thereof, or a salt thereof. 8. The sustained-release preparation according to claim 3, wherein the compound having an angiotensin II antagonistic activity is losartan, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, or tasosartan. 9. The compound having an angiotensin II antagonistic activity is 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a compound thereof. The sustained-release preparation according to claim 3, which is a salt. 10. The compound having an angiotensin II antagonistic activity is 1- (cyclohexyloxycarbonyloxy)
The sustained-release preparation according to claim 3, which is ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof. . 11. A compound having an angiotensin II antagonistic action, wherein the compound is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-).
4. The sustained-release preparation according to claim 3, which is yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof. 12. The sustained-release preparation according to claim 1, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. 13. The sustained-release preparation according to claim 12, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer. 14. The composition molar ratio of lactic acid to glycolic acid is 10
The sustained-release preparation according to claim 13, wherein the ratio is 0/0 to 40/60. 15. A polymer having a weight average molecular weight of 3,000 to 3,000.
13. The sustained-release preparation according to claim 12, which has a molecular weight of 50,000. 16. The sustained-release preparation according to claim 1, which is for injection. 17. The sustained-release preparation according to claim 1, wherein the polyvalent metal is zinc. 18. The sustained-release preparation according to claim 17, wherein the polyvalent metal compound is zinc oxide. 19. The method according to claim 1, further comprising a polyvalent metal.
The sustained-release preparation according to the above. 20. The sustained-release preparation according to claim 19, wherein the polyvalent metal is zinc. 21. A method for removing water and a solvent from a solution containing a bioactive compound that is hardly soluble in water, a component obtained by treating a water-soluble polyvalent metal compound with water and a biodegradable polymer. The method for producing the sustained-release preparation according to claim 1, wherein 22. The method for producing a sustained-release preparation according to claim 21, wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. 23. Water and a solvent are prepared from a solution containing a bioactive compound which is hardly soluble in water, a component obtained by treating a water-soluble polyvalent metal compound with water, a biodegradable polymer and a polyvalent metal. The method for producing a sustained-release preparation according to claim 19, wherein the preparation is removed. 24. The method for producing a sustained-release preparation according to claim 23, wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. (25) A pharmaceutical composition comprising the sustained-release preparation according to (1). (26) the composition according to the above (25), which is an agent for preventing or treating a circulatory disease; (27) the agent which is a prophylactic / therapeutic agent for hypertension;
5. The composition according to 5. 28. The composition according to claim 25, which is a prophylactic / therapeutic agent for circadian blood pressure abnormalities. (29) the agent which is a prophylactic / therapeutic agent for organ damage;
5. The composition according to 5. 30. The component according to claim 1, wherein the component obtained by treating the water-insoluble polyvalent metal compound with water is a component obtained by mixing a water-insoluble polyvalent metal compound with water. Sustained-release preparation. 31. Removal of water and a solvent from an emulsion obtained by mixing a water-insoluble physiologically active compound, a water-insoluble polyvalent metal compound and water with an organic solvent solution of a biodegradable polymer. A method for producing a sustained-release preparation of a physiologically active compound which is hardly soluble in water, characterized by comprising: 32. A water-soluble physiologically active compound is dispersed in an emulsion obtained by mixing a water-insoluble polyvalent metal compound and water with an organic solvent solution of a biodegradable polymer; A method for producing a sustained-release preparation of a physiologically active compound which is hardly soluble in water, characterized by removing water. 33. A bioactive compound which is hardly soluble in water,
An emulsion comprising a water-insoluble polyvalent metal compound and water, and an organic solvent solution of a biodegradable polymer in an external phase. 34. A sustained-release preparation obtained by the production method according to claim 31. (35) A sustained-release preparation obtained by the production method according to (32). 36. Water and a solvent are dissolved from a liquid containing a water-insoluble bioactive compound and a biodegradable polymer in the presence of a component obtained by treating a water-insoluble polyvalent metal compound with water. A method for controlling the release rate of a sustained-release preparation of a poorly water-soluble physiologically active compound, characterized by removing the compound. 37. The method according to claim 35, wherein the amount of water to be treated is adjusted. 38. An emulsion obtained by mixing a poorly water-soluble bioactive compound and a poorly water-soluble polyvalent metal compound with a solution of a biodegradable polymer in an organic solvent in the presence of water. 36. The method of claim 35, wherein is removed. 39. A water-insoluble bioactive compound is dispersed in an emulsion obtained by mixing a poorly water-soluble polyvalent metal compound with an organic solvent solution of a biodegradable polymer in the presence of water. 36. The method according to claim 35, wherein water, solvent and solvent are removed.