JP2003212758A - Method for producing sustained release preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sustained release preparation having a uniform distribution of a sparingly water-soluble nonpeptidic physiologically active compound and capable of achieving stable sustained release effects of the sparingly water- soluble nonpeptidic physiologically active compound and further a pharmaceutical composition with effectively suppressed initial release of the physiologically active substance in a sustained release preparation containing the sparingly water-soluble nonpeptidic physiologically active compound and to provide a method, etc., for producing the same. <P>SOLUTION: This method for producing the sustained release preparation comprises removing a solvent from a solution containing the sparingly water-soluble nonpeptidic physiologically active compound in an amount exceeding the solubility of a biodegradable polymer in the absence of a polyvalent metal compound in the organic solvent, the polyvalent metal compound and the biodegradable polymer. The sustained release solid pharmaceutical composition comprises a polyvalent metal in an amount of about ≥0.05 wt.% based on the weight of the composition present on the surface of the composition in the composition containing the sparingly water-soluble nonpeptidic physiologically active substance and the biodegradable polymer. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a sustained-release preparation of a poorly water-soluble non-peptide bioactive compound. Furthermore, the present invention relates to a sustained-release solid pharmaceutical composition in which the initial release of a non-peptide bioactive substance is effectively suppressed, and a method for producing the same.

[0002]

2. Description of the Related Art A bioactive compound is added to a solution in which a biodegradable polymer is dissolved in the process of producing a sustained release agent using the biodegradable polymer. At this time, if the physiologically active compound is dissolved in the solution, the homogeneity (uniform distribution) of the physiologically active compound in the preparation is guaranteed, and if the preparation is for injection, aseptic treatment by filtering the solution with a filter. There are advantages such as Regarding water-soluble physiologically active compounds, JP-A-04-046115 and JP-A-04-046116 disclose methods for producing microspheres by an O / W type in-liquid drying method. Regarding the poorly water-soluble physiologically active compound, for example, USP 5,656,299 discloses a method for producing bromperidol-containing microspheres. In addition, a sustained-release agent for a physiologically active substance using a biodegradable polymer has a problem that a large amount of the physiologically active substance is often released at the initial stage of administration. Journal of Controlled Release (Journalo)
fControlled Release), 52, 311-320 (1998), it is disclosed that the initial release of ovalbumin is suppressed by changing the surfactant in the outer aqueous phase from polyvinyl alcohol to polyvinylpyrrolidone. On the other hand, regarding non-peptide bioactive substances, USP
Although a method for producing microspheres containing bromperidol is reported in 5,656,299, no method for suppressing the initial release of the drug is disclosed.

[0003]

Although there is the above-mentioned method, there is still no method for dissolving a poorly water-soluble physiologically active compound in a biodegradable polymer solution in which the drug is dissolved more than the solubility of the physiologically active compound. When the solubility is very low, if you want to increase the drug concentration beyond the industrially producible concentration, you have to use the S / O / W type in-liquid drying method in which a fine powder of the drug is dispersed. It is the actual situation. Especially S / O
When preparing an injectable preparation via a type emulsion, it is necessary to use a sterile bulk of the physiologically active compound. From these backgrounds, there is a demand for a method of dissolving a poorly water-soluble non-peptidic physiologically active compound in an organic solvent solution of a biodegradable polymer to a degree higher than its solubility. Also,
Although it has been reported that the initial release of the peptide ovalbumin is suppressed under extremely limited conditions, a method for sufficiently suppressing the initial release of a non-peptidic physiologically active substance having greatly different properties is not known. In particular, there is a need for a method of effectively suppressing the initial release of the physiologically active substance in a sustained-release agent containing the non-peptide physiologically active substance.

[0004]

Means for Solving the Problems As a result of various investigations for solving the above-mentioned problems, the present inventors have found that addition of a polyvalent metal compound causes a poorly water-soluble non-peptidic physiologically active compound to be incorporated into a biodegradable polymer. It has been found that it can be dissolved in an organic solvent solution above its solubility. Furthermore, in a composition comprising a non-peptide bioactive substance and a biodegradable polymer, if a polyvalent metal of about 0.05% by weight or more of the composition weight is present on the surface of the composition, Unexpectedly, the initial release of the non-peptidic physiologically active substance can be suppressed, and an organic solvent solution or suspension containing the non-peptidic physiologically active substance and the biodegradable polymer,
When the method for removing the organic solvent from the emulsion obtained by mixing with the aqueous phase in which the polyvalent metal ion is about 0.1 to about 80 mM is carried out for the first time, it is surprisingly suitable as a method for producing the composition. The present invention has been completed based on these findings.

That is, the present invention provides (1) a biodegradable polymer in the absence of a polyvalent metal compound, a sparingly water-soluble non-peptidic physiologically active compound, a polyvalent metal compound and A method for producing a sustained-release preparation, which comprises removing the solvent from an organic solvent solution containing a biodegradable polymer, and (2) the sparingly water-soluble non-peptidic physiologically active compound has a molecular weight of about 2000 or less ( 1)
(3) The method according to (1) above, wherein the poorly water-soluble non-peptidic physiologically active compound has a functional group capable of forming a complex salt with a polyvalent metal compound, and (4) the functional group is a shared electron pair. The production method according to the above (3), which is a group capable of donating
The production method according to (3) above, wherein the functional group is a group having one or more hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom, (6) the functional group is (1) a carboxyl group, ( 2) imidazolyl group, (3) mercapto group, (4) amino group, (5) tetrazolyl group, (6) trifluoromethanesulfonamide group, (7) phosphoric acid group, (8) sulfonic acid group and
(9) 1 selected from oxygen atom, nitrogen atom and sulfur atom
(7) The method according to the above (3), which is a group selected from an optionally substituted 5 to 7-membered monocyclic heterocyclic residue having 1 or 2 or more heteroatoms, The production method according to (1) above, wherein the peptidic physiologically active compound has a functional group having a pKa of about 2.5 to about 6, and (8) a sparingly water-soluble non-peptidic physiologically active compound having an angiotensin II antagonistic activity. The production method according to (1) above, which is a prodrug or a salt thereof, (9) the production method according to (8), wherein the compound having an angiotensin II antagonistic action is a compound having an oxygen atom in its molecule. ) The production method according to the above (8), wherein the compound having angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group, and (11) the compound having angiotensin II antagonistic activity is represented by the formula (I

[Chemical 3] (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents a spacer having 2 or less atoms in a bond or a straight chain portion, n represents 1 or 2, and a 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 which can be converted into an anion, and R ³ represents a hydrocarbon residue which may have a substituent. Group, wherein the hydrocarbon residue may be bound via a heteroatom), the production method according to the above (8), (12) a compound having angiotensin II antagonistic activity, The prodrug or salt thereof is losartan, losartan potassium, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomi Or wherein a tasosartan (8) The process according (13) a compound having angiotensin II antagonistic activity is 2-ethoxy-1 - [[2'-
(1) H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, (14) Angiotensin.
II The compound having an antagonistic effect is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-
The production method according to the above (8), which is [[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate, (15).
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]. The production method according to (8) above, which is methyl] benzimidazole-7-carboxylic acid, (16) the production method according to (1) above, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer, (17) The production method according to (16) above, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer, and (18) the lactic acid-glycolic acid polymer has a composition molar ratio of lactic acid to glycolic acid of 100/0 to 100/0.
The production method according to (17) above, which is 40/60,
The production method according to the above (16), wherein the polymer has a weight average molecular weight of 3,000 to 50,000, (20) the production method according to the above (1), wherein the sustained release preparation is for injection, (21) many. The method according to (1) above, wherein the valent metal is zinc, and (22) the polyvalent metal compound is one or two of zinc acetate and zinc oxide.
(21) The production method according to the above (21), wherein the molar ratio of the polyvalent metal compound in the organic solvent solution to the sparingly water-soluble non-peptidic physiologically active compound is 1/10 to 10/1.
(24) The method according to (1) above, wherein the concentration of the poorly water-soluble non-peptidic physiologically active compound in the organic solvent solution is about 0.5 to about 70% by weight. (25) The concentration of the biodegradable polymer in the organic solvent solution is about 0.5 to about 70% by weight, (1)
(26) A sustained-release preparation obtained by the production method according to (1) above, (27) a compound in which a poorly water-soluble non-peptidic physiologically active compound has angiotensin II antagonistic action, a prodrug thereof or Said salt (26)
The sustained-release preparation described in (28), a medicine containing the sustained-release preparation described in (26) above, (29) the medicine described in (28) above which is a preventive / therapeutic agent for cardiovascular disease, ( 30) The drug according to the above (28), which is a preventive / therapeutic agent for hypertension, abnormal blood pressure circadian rhythm or organ disorder, (31) Solubility in an organic solvent solution of a biodegradable polymer in the absence of a polyvalent metal compound. Water-soluble non-peptidic physiologically active compound, polyvalent metal compound and biodegradable polymer in organic solvent solution containing (32) biodegradable polymer in organic solvent solution Of a polyvalent metal compound for increasing the solubility of a physiologically active compound, (33) sparingly water-soluble in an organic solvent solution containing a biodegradable polymer, an organic solvent and a sparingly water-soluble non-peptidic physiologically active compound sex Method of the solubility of the peptide physiologically active compound is increased by using a polyvalent metal compound, (34)
In a composition comprising a non-peptide bioactive substance and a biodegradable polymer, the composition weight is about 0.05
A sustained-release solid pharmaceutical composition in which a polyvalent metal is present on the surface of the composition in an amount of not less than wt%, (35) The initial release of the non-peptide bioactive substance is about The sustained-release solid pharmaceutical composition according to (34), which is suppressed to 60% or less, and (36) the sustained-release solid pharmaceutical composition according to (34), wherein the non-peptide bioactive substance has a molecular weight of about 2000 or less. (37) The sustained-release solid pharmaceutical composition according to (34), wherein the non-peptidic physiologically active substance is a poorly water-soluble compound, (38) a compound wherein the non-peptidic physiologically active substance has an angiotensin II antagonistic effect, The sustained-release solid pharmaceutical composition according to (34) above, which is a prodrug or a salt thereof, (39) The sustained release according to (38) above, wherein the compound having angiotensin II antagonistic activity is a compound having an oxygen atom in its molecule. sex Form pharmaceutical composition, (40) the compound having angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group (38) controlled release solid pharmaceutical composition according, (41) angiotensin
The compound having II antagonism is represented by the formula (I)

[Chemical 4] (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents a spacer having 2 or less atoms in a bond or a straight chain portion, n represents 1 or 2, and a 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 which can be converted into an anion, and R ³ represents a hydrocarbon residue which may have a substituent. A group represented by the formula (38), wherein the hydrocarbon residue may be bonded via a heteroatom) (38)
The sustained-release solid pharmaceutical composition described in (42), a compound having angiotensin II antagonistic activity, its prodrug or a salt thereof is losartan, losartan potassium, eprosartan, candesartan cilexetil, candesartan,
Valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomil or tasosartan, The sustained-release solid pharmaceutical composition according to the above (38), (43) The compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2'- (1) H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, The sustained-release solid pharmaceutical composition according to the above (38), (44) Angiotensin II.
The compound having an antagonistic action is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-
The sustained-release solid pharmaceutical composition according to (38), which is [[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate, and (45) angiotensin II antagonism. The compound having an action is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benz. The sustained-release solid pharmaceutical composition according to the above (38), which is imidazole-7-carboxylic acid, (46) The sustained-release solid according to the above (34), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. The pharmaceutical composition, (47) above, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer (4)
6) The sustained-release solid pharmaceutical composition according to 6), wherein the composition molar ratio of lactic acid to glycolic acid of the (48) lactic acid-glycolic acid polymer is 1
The sustained-release solid pharmaceutical composition according to (47) above, which is 00/0 to 40/60, (49) above, wherein the polymer has a weight average molecular weight of about 3,000 to about 50,000. (50) The sustained-release solid pharmaceutical composition, (50) The sustained-release solid pharmaceutical composition according to the above (34), wherein the polyvalent metal is a divalent metal.
1) The sustained-release solid pharmaceutical composition according to (50) above, wherein the divalent metal is zinc, (52) the sustained-release solid pharmaceutical composition according to (34), which is for injection, (53) microcapsules. The sustained-release solid pharmaceutical composition according to the above (34),
4) From an emulsion obtained by mixing an organic solvent solution or suspension containing a non-peptide bioactive substance and a biodegradable polymer with an aqueous phase having a polyvalent metal ion concentration of about 0.1 to about 80 mM The method for producing a sustained-release solid pharmaceutical composition according to (34) above, which comprises removing an organic solvent, and (55) determining the solubility of a biodegradable polymer containing no polyvalent metal in an organic solvent solution. An organic solvent solution containing an excess amount of a non-peptide bioactive substance, a polyvalent metal and a biodegradable polymer, and a polyvalent metal ion concentration of about 0.
The organic solvent is removed from the emulsion obtained by mixing with an aqueous phase of 1 to about 80 mM (3)
(4) The method for producing a sustained-release solid pharmaceutical composition according to (4), wherein the polyvalent metal ion is zinc (54) or (55).
(57) The production method described in (55) above, wherein the polyvalent metal is used as one or two polyvalent metal compounds selected from zinc acetate and zinc oxide. The sustained-release solid pharmaceutical composition obtained by the production method according to (55), (59) the sustained-release solid pharmaceutical composition according to (38), which is a prophylactic / therapeutic agent for cardiovascular diseases.
(60) The sustained-release solid pharmaceutical composition according to (38), which is a prophylactic / therapeutic agent for hypertension, abnormal blood pressure circadian rhythm, or organ disorder, (61) a non-peptide bioactive substance and a biodegradable polymer In a solid pharmaceutical composition containing the method, a method for suppressing the initial release of a non-peptide physiologically active substance, characterized in that about 0.05% or more by weight of the composition is allowed to exist on the surface of the composition, etc. Regarding

A. Non-peptidic physiologically active substance The physiologically active compound in the present invention is a physiological substance effective for the prevention / treatment of pathological conditions / disease in mammals (eg, human, cow, pig, dog, cat, mouse, rat, rabbit, etc.). Non-peptidic active compounds are preferred, of which the molecular weight is about 2
The physiologically active compound having a molecular weight of 0 to about 3000 is preferable, the physiologically active compound having a molecular weight of about 2000 or less is more preferable, and the physiologically active compound having a molecular weight of about 300 to about 2000 is particularly preferable. In addition, the physiologically active compound in the present invention is preferably a “poorly water-soluble non-peptidic physiologically active compound”. Here, in the present specification, “poorly water-soluble” means water or physiological saline necessary to dissolve 1 g of solute within 30 minutes when shaken vigorously for 5 seconds at 20 ± 5 ° C. every 30 minutes. Is 100 mL or more, preferably 1000 mL or more, more preferably 10000
It means more than mL. The "non-peptidic physiologically active compound" used in the present invention may be any one that is pharmacologically useful, and is preferably a synthetic organic compound. Examples of the “non-peptidic physiologically active compound” include compounds having a receptor agonizing action or an antagonizing action, an enzyme inhibiting action, a carrier promoting or inhibiting action, and the like. The receptor to which the “non-peptidic physiologically active compound” exerts an agonistic action or an antagonistic action may be on the cell surface or inside the cell.
The cell surface receptor includes ion channel-linked type, G protein-linked type and enzyme-linked type. The types of ligands of the receptor include small peptides, proteins, amino acids, nucleotides, steroids, fatty acid derivatives, nitric oxide, carbon monoxide and the like. Examples of the receptor include luteinizing hormone releasing hormone (LH-RH) receptor,
Thyroid-stimulating hormone-secreting hormone (TRH) receptor, corticotropin-secreting hormone (CRF) receptor, endorphin receptor, substance P receptor, neurotensin receptor, thyroid-stimulating hormone (TSH) receptor, lactating hormone (PRL) receptor , Follicle-stimulating hormone (FS
H) receptor, luteinizing hormone (LH) receptor, adrenocorticotropic hormone (ACTH) receptor, PPAR-α receptor,
Examples thereof include PPAR-γ receptor and testosterone receptor.

Examples of the enzyme which the "non-peptidic physiologically active compound" exhibits an inhibitory action include blood coagulation enzyme, fibrinolytic enzyme, digestive enzyme, phosphorylase, metabolic enzyme, antioxidant enzyme and the like. Examples of the enzyme include monoamine oxidase (MAO), angiotensin converting enzyme, HMG-
CoA reductase, cholesterol esterifying enzyme (AC
AT), cyclooxygenase (COX), trypsin, α-chymotrypsin, kallikrein, β-galactosidase, elastase, thrombomodulin, thrombin, blood coagulation factors (factor I-factor X), protein C, protein S, plasmin, plus Minogen activator, urokinase, protein kinase C, tyrosine kinase, cytochrome p450s (3
A4, 1A, 2C, 2D, etc.), superoxide dismutase (SOD) and the like. Examples of the enzyme having an inhibitory action by the "non-peptidic physiologically active compound" include:
Those derived from human cells, bacteria, phages, viruses and the like can be mentioned. The non-peptide bioactive compound that exhibits the inhibitory action is expected to have an antibacterial or antiviral action. Examples of the enzyme include cross-linking enzyme transpeptidase, penicillin-binding protein (PBP-1
A, PBP-1B, PBP-2, PBP-3, PBP-
4, PBP-5, PBP-6), neuraminidase, aminopeptidase A, aminopeptidase B, α-amylase, β-camdase, reverse transcriptase inhibitor and the like. Examples of the carrier that the “non-peptide physiologically active compound” promotes or suppresses include passive or active ion channels, glucose transporters, peptide transporters, p-glycoprotein, and the like. Examples of the carrier include voltage-dependent sodium channel,
Calcium-dependent sodium channel, potassium-dependent calcium channel, potassium channel, chlorine ion channel, gastric mucosal proton pump (H ⁺ , K ⁺ -ATPa
se), glucose transporters (GLUT1,
GLUT2, GLUT3, GLUT4), PEPT1,
Examples thereof include MDR1, MDR2, MRP, cMOAT, ACT1 and the like. The “non-peptidic physiologically active compound” used in the present invention has a functional group capable of forming a complex salt with a polyvalent metal compound (polyvalent metal ion). The reaction between polyvalent metal compounds and organic compounds has been investigated in detail in the field of protein purification, for example, Purification of proteins by IMCA.
(Eugene Sulkowski, Ternds in Biotechnology, Vol
3, No. 1, pages 1-7 (1985)). According to it, it is described that a functional group capable of donating a shared electron pair to a polyvalent metal ion such as zinc, copper, cobalt and nickel can form a coordinate bond with the polyvalent metal. Examples of the atom that constitutes the functional group that donates the shared electron pair include a nitrogen atom, a sulfur atom, and an oxygen atom. That is, the functional group is preferably a group having one or more (preferably 1 to 5) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. As the functional group capable of donating a shared electron pair, (1) carboxyl group, (2) imidazolyl group, (3) mercapto group (-SH), (4) amino group, (5) tetrazolyl group, (6) trifluoromethane sulfonamide group (-NHSO ₂ CF _3), (7) a phosphate group, (8) a sulfonic acid group and (9) an oxygen atom, one or more selected from a nitrogen atom and a sulfur atom (preferably 1 to And optionally substituted 5- to 7-membered (preferably 5 to 6-membered) monocyclic heterocyclic residues having 5) heteroatoms. As the "optionally substituted 5 to 7-membered monocyclic heterocyclic residue having one or two or more hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom",
5 containing one or more of N, S, and O defined in R ¹ of the compound represented by the formula (I) described below.
The same as the "7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue" can be mentioned. The pKa of the functional group possessed by the “non-peptidic physiologically active compound” is preferably about 2.5 to about 6, and more preferably about 3 to about 5.
Is. The “non-peptidic physiologically active compound” used in the present invention is preferably a compound having angiotensin II antagonistic action (a compound having angiotensin II receptor antagonistic action), a prodrug thereof or a salt thereof. The angiotensin II antagonism in the present invention means competitively or non-competitively inhibiting the binding of angiotensin II to the angiotensin II receptor on the cell membrane, and angiotensin II-induced strong vasoconstrictor action and vascular smooth muscle proliferation. It refers to the effect of diminishing the effects and relieving the symptoms of hypertension. The compound having an angiotensin II antagonism used in the present invention is preferably a compound having a non-peptidic antagonism, which is advantageous in that the action time is long. The compound having an angiotensin II antagonistic action is preferably a compound having an oxygen atom in the molecule, among which a compound having an ether bond or a carbonyl group (the carbonyl group may form a hydroxyl group by resonance). The compound having an ether bond or a ketone derivative is more preferable, and an ether derivative is particularly preferable. Further, the compound having an angiotensin II antagonistic action is preferably a compound having a group capable of forming an anion or a group capable of changing to it. The compound having a non-peptide angiotensin II antagonistic action 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. 58-157768, USP 4,3
55,040 and USP 4,340,598, etc., and also EP-253310, EP-291969,
EP-324377, EP-403158, WO-91
00277, JP-A-63-23868 and JP-A-1-117876 disclose improved imidazole derivatives, and USP 5,183,89.
9, EP-323841, EP-409332 and JP-A-1-287071 disclose pyrrole, pyrazole and triazole derivatives, and USP.
4,880,804, EP-0392317, EP-0
399732, EP-0400835, EP-4259.
21, EP-459136 and JP-A-3-63264.
Benzimidazole derivatives are disclosed in Japanese Patent Publication No.
P-399731 and the like disclose azaindene derivatives, EP-407342 and the like pyrimidone derivatives, EP-411766 and the like quinazoline derivatives, EP-430300 and the like xanthine derivatives, and EP- 434038 and the like disclose fused imidazole derivatives, EP-442473 and the like disclose pyrimidinedione derivatives, EP-443568 and the like disclose thienopyridone derivatives, and EP-44
5811, EP-483683, EP-518033,
EP-520423, EP-588299, EP-60
Heterocyclic compounds are disclosed in 3712 and the like. Also,
Journal of Medicinal Chemistry (Jour
nalof Medicinal Chemistry, Volume 39, Issue 3, 625-
(Pp. 656, 1996), representative compounds among them are described. The non-peptidic angiotensin II antagonistic compound or salt thereof,
In addition to the compounds described in the above-mentioned publicly known documents, any non-peptidic compound having angiotensin II antagonistic action may be used, and among them, losartan (Losartan (DuP
753)), losartan potassium, eprosartan (Eprosa
rtan (SK & F108566)), candesartan cilexetil (TCV-116), valsartan (Valsartan (CGP-48933)), telmisartan (Telmisa
rtan (BIBR277)), Irbesartan (SR47
436)), tasosartan (ANA-756), olmesartan medoxomil and their metabolically active substances (candesartan, olmesartan, etc.) and the like are preferably used.

The non-peptidic compound having angiotensin II antagonistic activity is, for example, the compound of formula (I)

[Chemical 5] (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents a spacer having 2 or less atoms in a bond or a straight chain portion, n represents 1 or 2, and a 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 which can be converted into an anion, and R ³ represents a hydrocarbon residue which may have a substituent. Represents a group, and the hydrocarbon residue may be bonded via a heteroatom (may be bonded via a heteroatom and has a substituent, a hydrocarbon residue; preferably a substituent And a benzimidazole derivative represented by a hydrocarbon residue which is bonded via an oxygen atom)) or a salt thereof is preferably used. In the above formula (I), R
Examples of the group capable of forming an anion as ¹ (group having a hydrogen atom capable of being released as a proton) include, 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 including one or more of N, S and O 5
And a 7-membered (preferably 5-6 membered) monocyclic optionally substituted heterocyclic residue and the like. The above-mentioned “N,
Examples of the 5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or two or more of S and O include, for example,

[Chemical 6]

[Chemical 7] 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 is —NH— or the like. Na carbon-
Not only the carbon bond but also one may be bonded through one of a plurality of nitrogen atoms. For example, R ¹ is

[Chemical 8] In the above formula, g is _{-CH 2 -, - NH -,} - O- or -
S (O) m-, where> = Z,> = Z 'and> =
Z ″ represents a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (eg, S, S (O),
S (O) ₂ etc.) (preferably carbonyl or thiocarbonyl group, more preferably carbonyl group), m
Represents an integer of 0, 1 or 2.

R¹For example, the heterocyclic residue represented by
For example, oxadiazolone ring, oxadiazolothione ring,
As a proton donor such as the thiadiazolone ring
NH- and -OH groups and cal as a proton acceptor
Bonyl group, thiocarbonyl group, sulfinyl group, etc.
Groups having at the same time are preferred. Also, R¹Indicated by
A heterocyclic residue is a condensed ring formed by combining cyclic substituents.
R may ¹As a heterocyclic residue represented by
Is preferably a 5- to 6-membered ring, more preferably a 5-membered ring residue. R¹
The heterocyclic residue represented by

[Chemical 9] [In formula, i shows -O- or -S-, j is> = O,
> = S or> = S (O) m, and m has the same meaning as above] (in particular, 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.

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

[Chemical 10] There are three tautomers of a ', b'and c', such as

[Chemical 11] The heterocyclic residue represented by includes 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 by an optionally substituted lower (C _1-4 ) alkyl group or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl etc.). The optionally substituted lower (C _1-4 ) alkyl group has, for example, (1) halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like. Optionally lower phenyl group optionally substituted with 1 to 3 lower (C _1-4 ) alkyl groups (eg, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl etc.), (2) lower (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. ), (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 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 straight-chain 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, halogen atom, nitro, lower (C _1-4 ) alkyl, phenyl optionally having lower (C _1-4 ) alkoxy, etc. Or a carbon number 1 substituted with a naphthyl group)
-3 lower alkyl group (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) C3-8 cycloalkyl 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 which may have alkoxy or the like (eg, vinyl such as cinnamyl, propenyl,
(Eg, those having an alkenyl moiety such as allyl and isopropenyl), and (e) an optionally substituted aryl group (eg,
A halogen atom such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4 ) alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc.), (f) carbon A straight-chain or branched lower alkoxy group of the number 1-6 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec
-Butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a straight-chain or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, aryloxy, isobutenyloxy, etc.), (H) C3-8 cycloalkyloxy group (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) C3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) Or substituted with an optionally substituted aryl group (eg, a phenyl or naphthyl group which may have a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) Carbon number 1
-3 lower alkoxy group (eg, those having an alkoxy moiety such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, etc.),
(J) C3-C8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom,
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with nitro, lower (C _1-4 ) alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. (eg, cinnamyloxy) Such as those having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) or (k) an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, etc. , Phenoxy or naphthoxy group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like)]. The group capable of forming an anion as R ¹ is 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 above protecting groups, optionally substituted lower (C _1-4 ) alkyl groups (R ¹
The same examples as the "optionally substituted lower (C _1-4 ) alkyl group" exemplified as the protective group for the group capable of forming an anion as described above), a halogen atom, nitro, cyano, lower It may have a substituent such as (C _1-4 ) alkoxy and amino optionally substituted with 1 to 2 lower (C _1-4 ) alkyl.

In the above formula, a group capable of forming an anion as R ¹ (group having a hydrogen atom capable of being released as a proton) is a group which can be converted under biological or physiological conditions (for example, in vivo enzyme). It may be a group (so-called prodrug) capable of being converted into a group capable of forming an anion by an in-vivo reaction such as oxidation, reduction or hydrolysis by the like (so-called prodrug), or a cyano or N-hydroxycarbamimidoyl group. (-C (= N-OH) -NH 2), or an optionally substituted lower (C _1-4) protected respectively with an alkyl group or an acyl group (1) carboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5)
Sulfonic acid group, one or two of (6) N, S, O
A 5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue to form an anion represented by R ¹ by a chemical reaction. It may be a group that can be converted into a possible group (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.)
Carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl) or cyano, N-hydroxycarbamimidoyl which may be protected with (Preferably cyano) is preferable, and especially tetrazolyl is preferably used.

In the above formula, X represents a bond or a spacer having 2 or less atoms in the straight chain portion (preferably a bond), and as a spacer having 2 or less atoms in the straight chain portion,
Any divalent chain in which the number of atoms constituting the straight chain portion is 1 or 2 may be used, and may have a side chain. Specifically, lower (C _1-4 ) alkylene having 1 or 2 atoms constituting the straight chain portion, —CO—, —O—, —S
-, - NH -, - CO -NH -, - O-CH 2 -, - S
-CH ₂ -, - CH = CH-, and the like. In the above formula, n represents 1 or 2 (preferably 1).

In the above formula, ring A represents a benzene ring which may have a substituent in addition to the substituent R ² , and the substituent may be, for example, (1) halogen (eg, F, Cl, Br
Etc.), (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, piperidino, piperazino, N-phenylpiperazino, etc.), (7) formula -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.)
Or (8) an optionally substituted lower (C _1-4 ) alkoxy group] or (8) optionally substituted lower (C _1-4 ) alkyl (an anion as R ¹ described above. Examples of the protecting group for the group capable of forming a group include the same "optionally substituted lower (C _1-4 ) alkyl group" or acyl (eg, lower (C _2-5 ) alkanoyl). , Benzoyl, etc.), tetrazolyl, trifluoromethanesulfonic acid amide group, phosphoric acid group or sulfonic acid group which may be protected.
These substituents have 1 at the substitutable position on the benzene ring.
~ 2 may be substituted at the same time, but the substituent which the ring A further has in addition to the substituent R ² is an optionally substituted lower (C _1-4 ) alkyl (eg, a hydroxyl group, a carboxyl group, Lower optionally substituted with halogen etc. (C
_1-4 ) Alkyl etc.), halogen and the like are preferable, and it is more preferable that ring A has no substituent other than the substituent R ² .

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

Examples of the esterified or amidated carboxyl as R ² include, for example, the formula —CO
-D [wherein D is (1) hydroxyl group, (2) optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _{1- 4} ) Alkylamino etc.) or (3) optionally substituted alkoxy {eg, (i) alkyl moiety is hydroxyl group, optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkyl) Amino, N, N-dilower (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-
1,3-dioxolen-4-yl etc.) optionally substituted lower (C _1-6 ) alkoxy group, 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, etc.), (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 straight-chain 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 straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms, and (c) a cycloalkyl group 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 ) alkyl, phenyl optionally having lower (C _1-4 ) alkoxy, etc. Or a carbon number 1 substituted with a naphthyl group)
-3 lower alkyl group (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) C3-8 cycloalkyl 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 which may have alkoxy or the like (eg, vinyl such as cinnamyl, propenyl,
(Eg, those having an alkenyl moiety such as allyl and isopropenyl), and (e) an optionally substituted aryl group (eg,
A halogen atom such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4 ) alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc.), (f) carbon A straight-chain or branched lower alkoxy group of the number 1-6 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec
-Butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a straight-chain or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, aryloxy, isobutenyloxy, etc.), (H) C3-8 cycloalkyloxy group (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) C3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) Or substituted with an optionally substituted aryl group (eg, a phenyl or naphthyl group which may have a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) Carbon number 1
-3 lower alkoxy group (eg, those having an alkoxy moiety such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, etc.),
(J) C3-C8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom,
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with nitro, lower (C _1-4 ) alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. (eg, cinnamyloxy) Such as those having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) or (k) an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, etc. , Lower (C _1-4 ) alkyl, phenoxy or naphthoxy group which may have lower (C _1-4 ) alkoxy, etc.]], etc.] And so on.

R ² is preferably an optionally esterified carboxyl, and specific examples thereof include —COOH and salts thereof, —COOMe and —COOE.
t, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, Propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutyryloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxy Carbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, etc. 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 ⁻ , its derivative, etc.) or a group capable of being converted into it, a carboxyl group, or a prodrug thereof. Good.

R ² is represented by the formula —CO—D [in the formula,
D is (1) hydroxyl group or (2) alkyl moiety is hydroxyl group,
Amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, Ethoxycarbonyloxy, etc.), lower (C _3-8 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.), lower (C _1-
4 ) Alkoxy or lower (C _1-4 ) alkoxy optionally substituted with lower (C _3-8 ) cycloalkoxy] is preferred, and carboxyl is particularly preferred.

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

The above-mentioned aralkyl group or aryl group
At any position on the benzene ring, for example halogen
(Eg, F, Cl, Br, etc.), nitro, substituted
Amino group (eg, amino, N-lower (C_1-4) Al
Kiramino, N, N-di-lower (C _1-4) Alkylamino
Do), low grade (C_1-4) Alkoxy (eg methoxy, eth
Kish, etc.), low grade (C_1-4) Alkylthio (eg, methyl
Thio, ethylthio, etc.), lower (C_1-4) Alkyl
(Eg, methyl, ethyl, etc.) and the like.
Among the above, R³Represented by "via a heteroatom
Hydrocarbon residue having a substituent "
As the "hydrocarbon residue" in, even if substituted
Good alkyl or alkenyl groups (eg hydroxyl, amino
Group, halogen or lower (C_1-4) Substitute with an alkoxy group
Optionally lower (C_1-5) Alkyl or lower
(C_2-5) Alkenyl groups etc.) are preferred, among others:
Lower (C_1-5) Alkyl (more preferably ethyl) is
preferable. R³Represented by "bonded through a heteroatom
Which may have a substituent and is a hydrocarbon residue "
As the "hetero atom", -O-, -S (O) m- [m
Represents an integer of 0 to 2], -NR '-[R' is hydrogen
Atom or lower (C_1-4) Represents alkyl] and the like.
Among them, -O- is preferably used. Above
Among them, R³Are as follows: -O-, -S (O) m- [m
Represents an integer of 0 to 2] or -NR '-[R' is
Hydrogen atom or lower (C_1-4) Indicates alkyl]
May be combined with each other to form a hydroxyl group, amino group, halogen or
And lower (C_1-4) With a substituent selected from alkoxy groups
Optionally substituted lower (C_{1 -Five}) Alkyl or low
Grade (C_2-5) Alkenyl groups and the like are preferable, and among others,
Lower (C_1-5) Alkyl or lower (C_1-5) Alkoxy
(More preferably ethoxy) is preferred.

Among the non-peptidic compounds having angiotensin II antagonism represented by the formula (I), the formula (I ′)

[Chemical 12] (In the formula, R ¹ is (1) carboxyl group, (2) tetrazolyl group or (3) formula

[Chemical 13] [In formula, i shows -O- or -S-, j is> = O,
> = S or> = S (O) indicates a m, m is a group represented by indicating] as defined above, Ring A may be substituted in addition to the substituent R ² a lower (C _{1 -4} ) Alkyl (eg, hydroxyl group, carboxyl group, lower (C _1-4 ) alkyl optionally substituted with halogen etc.) or benzene ring optionally substituted with halogen (preferably substituent R ² represents a benzene ring) having no substituent in addition, R ² is wherein -CO-D [wherein, D is (1) hydroxy group or (2) alkyl moiety by hydroxyl, amino, halogen, lower (C _{2- 6} ) Alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy), 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 ] The group represented by these, R < ³ > is -O-, -S (O) m- [m shows the integer of 0 to 2] or -NR '-[R' is a hydrogen atom or lower ( _{C1- 4} ) represents an alkyl group], a hydroxyl group, an amino group, a halogen and a lower group (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). ] The benzimidazole-7-carboxylic acid derivative represented by these or its pharmacologically acceptable salt etc. are preferable, Especially 2-ethoxy-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Iyl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7-carboxylate [Candesartancilexetil], 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
Preferred is -yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof. The above-mentioned benzimidazole derivatives are, for example, EP-425921, EP-4.
59136, EP-553879, EP-57812.
5, it can be synthesized by a known method described in EP-520423, EP-668272, or a method similar thereto. When Candesartancilexetil is used, it is preferable to use the stable C-type crystal described in EP-459136.

The compound having angiotensin II antagonistic activity or its prodrug used in the present invention may be itself or a pharmacologically acceptable salt. As such salts, when the compound having an angiotensin II antagonistic action has an acidic group such as a carboxyl group, an inorganic base (eg, alkali metal such as sodium and potassium, alkaline earth metal such as calcium and magnesium, zinc , Transition metals such as iron and copper) and organic bases (eg,
Trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-
Examples thereof include salts with organic amines such as dibenzylethylenediamine and basic amino acids such as arginine, lysine and ornithine). The compound having an angiotensin II antagonistic activity used in the present invention [hereinafter, referred to as AII
Sometimes called an antagonist compound. ] Prodrugs are
A compound that is converted into an AII antagonist compound by a reaction with an enzyme or gastric acid under physiological conditions in the living body, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, or the like to be converted into an AII antagonist compound, or hydrolyzed by gastric acid, etc. A compound that causes a change to an AII antagonist compound. AII
As a prodrug of an antagonist compound, a compound in which the amino group of the AII antagonist compound is acylated, alkylated or phosphorylated (eg, the amino group of the AII antagonist compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation,
Pyrrolidylmethylation, pivaloyloxymethylation, te
rt-butylated compound, etc.); AII antagonistic compound whose hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, AII antagonistic compound's hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated) , Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); AII
The carboxyl group of the antagonist compound is esterified or amidated (eg, AII antagonist compound), the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified,
Pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound, etc.); and the like. These compounds can be produced from an AII antagonist compound by a method known per se. Prodrugs of AII antagonist compounds are described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design 163.
It may be changed to an AII antagonist compound under physiological conditions as described in pages 198 to 198. The AII antagonist compound may be either a hydrate or a non-hydrate.

B. Polyvalent metals (1) Biodegradable polymers in the absence of polyvalent metal compounds Amounts of poorly water-soluble non-peptidic physiologically active compounds, polyvalent metal compounds and biodegradable polymers that exceed the solubility in organic solvents The polyvalent metal used in the production method of the present invention using an organic solvent solution containing is described in detail below.
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, and examples of the metal species include divalent (eg, zinc, calcium, magnesium, iron, copper, aluminum, tin, A polyvalent metal (preferably zinc or the like) such as trivalent (eg, iron, aluminum, manganese, etc.), tetravalent (eg, tin, etc.) is used. The polyvalent metal used in the present invention may be used as a compound with an inorganic substance or an organic substance, a complex compound, or a “polyvalent metal compound” such as a metal oxide. The "polyvalent metal compound" may have bound water or crystal water. Specific preferred examples of the polyvalent metal include zinc,
Examples include calcium and magnesium. A particularly preferable example of the polyvalent metal is zinc. As the organic substance, for example, organic acids such as aliphatic carboxylic acids and aromatic acids, and acetylacetone are used. As the aliphatic carboxylic acid, an aliphatic carboxylic acid having 1 to 9 carbon atoms (eg, aliphatic monocarboxylic acid, aliphatic dicarboxylic acid, aliphatic tricarboxylic acid, etc.) is preferably used. The aliphatic carboxylic acid may be either saturated or unsaturated. Examples of the aliphatic monocarboxylic acid include saturated aliphatic monocarboxylic acid having 1 to 9 carbon atoms (eg, carbonic acid,
Formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid) and unsaturated aliphatic monocarboxylic acids having 2 to 9 carbon atoms (eg acrylic acid, propiolic acid) , Methacrylic acid, crotonic acid, isocrotonic acid, etc.) are used. Examples of the aliphatic dicarboxylic acid include saturated aliphatic dicarboxylic acid having 2 to 9 carbon atoms (eg, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.) and unsaturated aliphatic dicarboxylic acid 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.) is used. The above aliphatic carboxylic acid has a hydroxyl group of 1
Or two may be provided, and as an example of this,
Examples thereof include glycolic acid, lactic acid, glyceric acid, tartronic acid, malic acid, tartaric acid, citric acid and the like. The aliphatic carboxylic acid is preferably an aliphatic monocarboxylic acid. More preferably, it is an aliphatic monocarboxylic acid having 2 to 9 carbon atoms. A particularly preferred specific example of the aliphatic carboxylic acid is acetic acid. As the aromatic acid, for example, benzoic acid, salicylic acid, phenolsulfonic acid, etc. are used. Specific examples of the metal compound include salts of zinc and an inorganic acid [eg, zinc halide (eg, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate] Etc.], a salt of zinc and an organic acid [eg,
Zinc aliphatic carboxylic acid salts (eg, zinc carbonate, zinc acetate, zinc glycolate, zinc lactate, zinc tartrate, etc.), aromatic zinc salts (eg, zinc benzoate, zinc salicylate, zinc phenolsulfonate, etc.), zinc Acetylacetonate and other salts of calcium and inorganic acids (eg, calcium halides (eg, calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, calcium thiocyanate, etc.), Salts of calcium and organic acids [eg, aliphatic carboxylic acid calcium salts (eg, calcium carbonate, calcium acetate, calcium propionate, calcium oxalate, calcium tartrate,
Calcium lactate, calcium citrate, calcium gluconate, etc.), aromatic calcium salts (eg, calcium benzoate, calcium salicylate, etc.)], calcium acetylacetonate, etc., salts of magnesium with an inorganic acid [eg, magnesium halide ( Examples, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate, etc.], salts of magnesium with an organic acid [eg, aliphatic carboxylic acid magnesium salt (eg, Magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tartrate, magnesium lactate, magnesium citrate,
Magnesium gluconate, etc.), aromatic magnesium salts (eg, magnesium benzoate, magnesium salicylate, etc.), magnesium acetylacetonate, and other salts of iron with inorganic acids [eg, iron halides (eg, iron chloride, bromide)] Iron, iron iodide, iron fluoride, etc.), iron sulfate, iron nitrate, iron thiocyanate, etc.], salts of iron and organic acids [eg, aliphatic carboxylic acid iron salts (eg, iron carbonate, iron acetate, glycol) Iron acid, iron lactate, iron tartrate, etc.), aromatic iron salts (eg, iron benzoate, iron salicylate, iron phenolsulfonate, etc.)], iron acetylacetonate, etc., and metal oxides (eg, zinc oxide, oxidation) Iron, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide, etc.). The polyvalent metal compound is preferably zinc acetate, zinc oxide, calcium acetate, magnesium acetate, iron chloride, iron acetylacetonate, zinc acetylacetonate, calcium acetylacetonate, magnesium acetylacetonate and the like, more preferably Zinc acetate or / and zinc oxide are used, ie one or a combination of zinc acetate and zinc oxide. When zinc acetate and zinc oxide are used as the polyvalent metal compound, they may be used alone or as a mixture, and the ratio thereof is preferably a zinc acetate / zinc oxide (molar ratio) ratio of 0/100 to 10.
It is 0/0, preferably 10/90 to 70/30, and most preferably 25/75 to 55/45. In the present invention, a part of the polyvalent metal contained in the sustained-release preparation may form a metal salt (for example, a zinc salt or a different metal salt) with the biodegradable polymer. The metal salt of this biodegradable polymer is disclosed in, for example, Japanese Patent Laid-Open No.
It can be manufactured by the method described in JP-A-212420 or a method similar thereto. In addition, a part of the polyvalent metal contained in the sustained-release preparation may form a complex with the poorly water-soluble non-peptidic physiologically active compound. The mixing ratio of the metal compound used in the present invention to the sparingly water-soluble non-peptidic physiologically active compound is different depending on the metal compound and the sparingly water-soluble non-peptidic physiologically active compound. When it is divalent and the sparingly water-soluble non-peptidic physiologically active compound is an AII antagonist compound, the metal compound / poorly water-soluble non-peptidic physiologically active compound (molar ratio) ratio is preferably from 1/10 to 10/1. , More preferably 1/5 to 5/1, most preferably 1/2 to 2
It is / 1.

C. Biodegradable Polymer Examples of the biodegradable polymer used in the present invention include α-hydroxycarboxylic acids (eg, glycolic acid, lactic acid, etc.), hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxytricarboxylic acid. (Eg citric acid, etc.)
A polymer, a copolymer or a mixture thereof having a free carboxyl group, which is synthesized from one or more kinds of poly-α.
-Cyanoacrylic acid ester; polyamino acid (eg, poly-g-benzyl-L-glutamic acid, etc.); maleic anhydride copolymer (eg, styrene-maleic acid copolymer, etc.)
Are 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, D
Any of-, L-, and DL-forms can be used. Among these, α-hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), its ester,
Poly-α-cyanoacrylic acid ester and the like are preferable.
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 100/0 to 4
0/60 is preferable, and 100/0 to 50/50 is particularly preferable. The weight average molecular weight of the lactic acid-glycolic acid polymer is usually about 3,000 to about 50,000, preferably about 4,000 to about 40,000, more preferably about 5,000 to about 30, It is 000. The dispersity (weight average molecular weight / number average molecular weight) is usually about 1.2 to
About 4.0 is preferable and about 1.5 to 3.5 is more preferable. The weight average molecular weight, the number average molecular weight and the polydispersity in the present specification mean that the weight average molecular weight is 1,110,00.
0, 707,000, 354,000, 189,00
0, 156,000, 98, 900, 66, 437, 3
7,200,17,100,9,830,5,870,
It refers to the polystyrene-equivalent molecular weight measured by gel permeation chromatography (GPC) using 14 types of polystyrene of 2,500, 1,303, and 500 as reference substances, and the calculated dispersity. For the measurement, a GPC column KF804L × 2 (manufactured by Showa Denko) was used, and chloroform was used as a mobile phase. Further, the biodegradable polymer was dissolved in an acetone-methanol mixed solvent, the carboxyl group was titrated with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator, and the number average molecular weight was calculated by quantifying the end group. Hereinafter, this will be referred to as the number average molecular weight by quantitative determination of the end groups. The number average molecular weight determined by end group quantification is an absolute value, while the number average molecular weight determined by GPC measurement is determined by analysis or analysis conditions (for example, mobile phase type, column type, reference substance, slice width selection,
Since it is a relative value that fluctuates depending on the selection of the baseline, etc.), it is difficult to make a unique numerical value. In the polymer having, the number average molecular weight measured by GPC and the number average molecular weight measured by end group determination are almost the same. In the case of this lactic acid-glycolic acid polymer, it is said that the number average molecular weight determined by quantitative determination of the end groups is about 0.2 to about 1.5 of the number average molecular weight determined by GPC.
It is within the range of double, and preferably within the range of about 0.3 to about 1.2. The lactic acid-glycolic acid polymer is, for example, a catalyst-free dehydration polycondensation of lactic acid and glycolic acid (Japanese Patent Laid-Open No. 61-28521) or a ring-opening polymerization (Encyclopedic Handbook) using a catalyst of a cyclic substance such as lactide and glycolide. of Biomaterials and Bi
oengineering PartA: Materials, Volume 2, MarcelDe
kker, Inc., 1995). The polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but the polymer is chemically treated to give a free carboxyl group at the end (Journal of Control Release (J Controlled Release), Volume 41, 2
49-257, 1996) can also be used.
The lactic acid-glycolic acid polymer having a free carboxyl group at the terminal can be produced without problems by a known production method (for example, a catalyst-free dehydration polycondensation method, see JP-A-61-28521), and further, a terminal Polymers having a free carboxyl group not specified in US Pat.
94/15587). As the lactic acid-glycolic acid polymer in which the terminal is made into a free carboxyl group by a chemical treatment after ring-opening polymerization, for example, a commercially available product from Boehringer Ingelheim KG may be used. These biodegradable polymers may be used alone or in combination of two or more.

D. Embodiment (1) Biodegradable polymer in the absence of polyvalent metal compound An amount of sparingly water-soluble non-peptidic physiologically active compound, polyvalent metal compound and biodegradable polymer which exceeds the solubility in an organic solvent is used. The production method of the present invention using the contained organic solvent solution and the embodiment thereof will be described in detail below. The production method of the present invention includes a biodegradable polymer in the absence of a polyvalent metal compound, a poorly water-soluble non-peptidic physiologically active compound, a polyvalent metal compound and a biodegradable biodegradable polymer which exceeds the solubility in an organic solvent. An organic solvent solution containing a polymer is used, and even when the biodegradable polymer is not contained in the organic solvent solution, the water-soluble non-peptidic physiology is more difficult than the solubility in the absence of a polyvalent metal compound. It is characterized in that the active compound is dissolved in an organic solvent solution. That is, the solubility of the poorly water-soluble non-peptidic physiologically active compound in the organic solvent solution in the absence of the polyvalent metal compound increases due to the presence of the polyvalent metal compound, and the poorly water-soluble property in the absence of the polyvalent metal compound. The solubility of the non-peptidic physiologically active compound in the organic solvent solution of the biodegradable polymer is increased by the presence of the polyvalent metal compound. Here, the term "amount exceeding the solubility" means about 110% or more, preferably about about 10% of the solubility of the poorly water-soluble non-peptidic physiologically active compound in the biodegradable polymer organic solvent in the absence of the polyvalent metal compound. 300% or more, more preferably about 500% or more. Examples of the organic solvent include halogenated hydrocarbons (eg, dichloromethane, 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 benzene, toluene, xylene etc.), alcohols (eg ethanol, methanol etc.), acetonitrile etc. are used. You may mix and use these at an appropriate ratio. Among them, dichloromethane is the halogenated hydrocarbon.
Ethanol and methanol are preferable as the alcohol. You may mix and use these at an appropriate ratio. Additives may be added to the above organic solvent solution. Examples of the additive include carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and salts thereof as a solubilizing agent for maintaining drug stability. May be. Further, as a drug stabilizer, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium hydrogen sulfite, polyol compounds such as polyethylene glycol, or the like, or as a preservative, generally used paraoxybenzoic acid esters. (Eg, methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added. The concentration of the sparingly water-soluble non-peptidic physiologically active compound in an organic solvent solution varies depending on the kind of the sparingly water-soluble non-peptidic physiologically active compound and the kind of organic solvent, but is generally about 0.5 to about 70. %, For example, when the poorly water-soluble non-peptidic physiologically active compound is an AII antagonist compound and a mixture of dichloromethane and methanol is used as an organic solvent, it is generally about 0.5 to about 70% by weight. , More preferably about 1 to about 6
0% by weight, particularly preferably from about 2 to about 50% by weight. The concentration of the biodegradable polymer in the organic solvent solution varies depending on the molecular weight of the biodegradable polymer and the type of organic solvent, but is generally about 0.5 to about 70% by weight. When used as an organic solvent, it is generally about 0.5 to about 70% by weight, more preferably about 1 to about 60% by weight, and particularly preferably about 2 to about 50% by weight.
It is selected from weight%. When ethanol or methanol is used as a mixed organic solvent with dichloromethane, the ratio of dichloromethane in the mixed organic solvent is generally about 10 to about 90% by volume, more preferably about 15 to about 85% by volume, Particularly preferably, it is selected from about 20 to about 80% by volume. The poorly water-soluble non-peptidic physiologically active compound, the polyvalent metal compound and the biodegradable polymer may be added to the organic solvent in any order, or may be added at the same time. You may mix the organic solvent solution of a non-peptide bioactive compound and a polyvalent metal compound with the organic solvent solution of a biodegradable polymer. To dissolve the poorly water-soluble non-peptidic physiologically active compound, the polyvalent metal compound and the biodegradable polymer in an organic solvent, they may be allowed to stand still, or they may be mixed by appropriately using energy. The energy includes ultrasonic waves, physical shaking, stirring and the like. The melting temperature may be any temperature as long as it is lower than the boiling point of the solvent used, but is preferably 0 ° C to 30 ° C.
The time required for dissolution varies depending on the kind, compounding ratio, dissolution temperature, vibration, etc. of the poorly water-soluble non-peptidic physiologically active compound, polyvalent metal compound and biodegradable polymer, but preferably from 1 second at room temperature. It is within 7 days, more preferably within 5 seconds to 3 days, and most preferably within 30 seconds to 1 day. The poorly water-soluble non-peptidic physiologically active compound which is a feature of the present invention, the organic solvent solution of the polyvalent metal compound and the biodegradable polymer is preferably a sterile solution, more preferably a solution prepared by filtration sterilization, When used as an injection, there is an advantage that a sterile bulk of the poorly water-soluble non-peptide bioactive compound is not required.

The amount of the poorly water-soluble non-peptidic physiologically active compound and the polyvalent metal compound in the sustained-release preparation obtained by the production method of the present invention depends on the kind of the physiologically active compound, desired pharmacological effect, and sustained effect. Depending on the period etc.,
When the physiologically active compound, polyvalent metal compound and biodegradable polymer are used as starting materials, the amount of the physiologically active compound is usually about 1 to about 50% by weight, more preferably about 15% by weight based on the sum of the three factors. ~ 45% by weight, particularly preferably about 20 ~
40% by weight, while the polyvalent metal compound is usually about 0.5
To about 20% by weight, more preferably about 1 to about 15% by weight,
Particularly preferably, it is about 2 to about 10% by weight. The form of the sustained release preparation of the present invention is not particularly limited, but parenteral administration preparations are preferable, and transdermal administration agents, transmucosal agents, implants, microcapsule injections and the like are conceivable, but the sustained release period is long, Further, an injection preparation using microcapsules, which is less burdensome on the patient, is preferable.

In the absence of the polyvalent metal compound of the present invention
Biodegradable polymer Amount exceeding solubility in organic solvent
Sparingly water-soluble non-peptidic bioactive compounds, polyvalent metal compounds
Solvent solution containing substances and biodegradable polymers
Of a sustained-release preparation characterized by removing solvent from the
For example, if the formulation is microcapsules
It is sometimes referred to as "Fear"). (I) Underwater drying method Poorly water-soluble non-peptidic physiologically active compound obtained by the above method
Of organic substances, polyvalent metal compounds and biodegradable polymers
Add the solvent solution to the water phase and add O (oil phase) / W (water phase)
Solution, the solvent in the oil phase is evaporated and the
Prepare black capsules. The water phase volume at this time is generally
The volume of the oil phase is about 1 to about 10,000 times, more preferably
It is preferably about 5 times to about 5,000 times, particularly preferably about 10 times.
Double to about 2,000 times. During the above external water phase
You may add an emulsifier. The emulsifier is generally stable O /
Any material that can form a W emulsion
Yes. Specifically, for example, an anionic surfactant (ole
Sodium innate, sodium stearate, lauryl
Sodium sulfate, etc., nonionic surfactants (polio
Xyethylene sorbitan fatty acid ester (Tween
en) 80, Tween60, Atlas Powder Co., Ltd.,
Rioxyethylene castor oil derivative [HCO-60, HCO-50, JP
Photochemicals] etc.), polyvinylpyrrolidone, polyvinyl chloride
Nyl alcohol, carboxymethyl cellulose, lecithin
And gelatin, hyaluronic acid, etc. are used. these
One of the above or a combination of two or more
You may. The concentration at the time of use is preferably about 0.01
-10% by weight, more preferably about 0.05-
Used in the range of about 5% by weight. Immersion in the above external water phase
A permeability control agent may be added. As the osmotic pressure adjusting agent,
Any solution that exhibits an osmotic pressure when used as an aqueous solution may be used. The
Examples of the osmotic pressure adjusting agent include polyhydric alcohols and monohydric alcohols.
Polyhydric alcohols, monosaccharides, disaccharides, oligosaccharides and amines
Examples thereof include noic acids and their derivatives. above
Examples of polyhydric alcohols are dihydric alcohols such as glycerin.
Alcohols, arabitol, xylitol, adoni
Pentahydric alcohols such as tall, mannitol, sorbit
Hexahydric alcohols such as sugar and dulcitol are used.
Be done. Of these, hexahydric alcohols are preferable, and
Nnitol is preferred. As the above monohydric alcohols
For example, methanol, ethanol, isopropyl
Alcohol, etc. are mentioned, of which methanol is preferred.
Good Examples of the above monosaccharides include arabinose,
Five carbons such as xylose, ribose, 2-deoxyribose
Sugars, glucose, fructose, galactose, manose, sauce
Hexasaccharides such as levoose, rhamnose and fucose are used.
Of these, hexoses are preferred. As the oligosaccharide above
For example, maltotriose, raffinose sugar, etc.
Trisaccharides such as trisaccharides and stachyose are used.
Of these, trisaccharides are preferable. The above monosaccharides, disaccharides and
Examples of the derivatives of ribo-sugar include glucosamine and guar.
Used with ctosamine, glucuronic acid, galacturonic acid, etc.
To be The above-mentioned amino acids are L-forms.
Any of them can be used.
Examples include isine and arginine. Of these, L-a
Luginine is preferred. These osmolytes are used alone.
They may be used or mixed and used. These osmotic pressure regulation
As for the agent, the osmotic pressure of the external water phase is about 1 / the osmotic pressure of physiological saline.
50 to about 5 times, preferably about 1/25 to about 3 times the concentration
Used in degrees. As a method of removing the organic solvent,
A publicly known method or a method similar thereto is used.
For example, propeller stirrer or magnetic stirrer
With or without stirring, reduce the pressure to normal pressure or gradually reduce the pressure.
Method for Evaporating Machine Solvent, Rotary Evaporator
Evaporate the organic solvent while adjusting the degree of vacuum using
There is a method of doing so. My obtained in this way
Black capsules are separated by centrifugation or filtration, and then
Bioactive compound attached to the surface of the black capsule,
Washing drug-holding substances, emulsifiers, etc. repeatedly with distilled water several times
Then, it is dispersed again in distilled water and lyophilized. Manufacturing process
Medium, even if you add an anti-aggregation agent to prevent the aggregation of particles
Good. Examples of the aggregation preventing agent include mannitol,
Lactose, glucose, starches (eg corn star)
Water-soluble polysaccharides such as
Proteins such as fibrils and collagen are used
It Of these, mannitol is preferred. Also frozen
After drying, if necessary, place microcapsules under reduced pressure.
Moisture in microcapsules when heated under conditions that do not cause fusion
And the organic solvent may be removed. Preferably every
Differential scanning calorimeter under the condition of the heating rate of 10 to 20 ° C per minute.
Glass transition temperature of biodegradable polymer determined by
Heat at a temperature slightly higher than. More preferably, living body
From the midpoint glass transition temperature of the internally degradable polymer
Warm within a temperature range about 30 ° C higher. Especially in vivo
Lactic acid-glycolic acid polymer is used as degradable polymer
In the case of
Temperature range 10 ℃ higher than the glass transition temperature
More preferably, the glass transition temperature is above the midpoint glass transition temperature.
Heat in the temperature range 5 ° C higher than the temperature. My heating time is my
Generally depends on the amount of black capsules, etc.
Is about 1 after the microcapsules themselves reach a certain temperature.
2 hours to about 168 hours, preferably about 24 hours to about 12
0 hours, particularly preferably about 48 hours to about 96 hours
It As for the heating method, the assembly of microcapsules is heated uniformly.
The method is not particularly limited as long as it can be performed. The heating and drying method
For example, a constant temperature tank, a fluidized tank, a moving tank or a kill tank
Method of heating and drying in a microwave oven, method of heating and drying by microwave
The method is used. In this, heat dry in a constant temperature bath
Method is preferred. Also, the water content in the microcapsules
And the removal of the organic solvent are carried out by supercritical fluid (CO ₂Etc.)
Should be done by using carbon dioxide in high pressure gas state
You can also Preferably, use carbon dioxide in high pressure gas state
Method is adopted. Below, high-pressure gas carbon dioxide
The desolvation method using a substance or the like will be described in detail. In the present invention
A high-pressure gas is a certain temperature whose pressure is higher than atmospheric pressure and
A gas that is below the liquefaction pressure in degrees. Used in the present invention
Examples of high-pressure gas include carbon dioxide, nitrous oxide,
Nitrogen, helium, argon, alkanes (eg ethane,
Such as lopain) and alkenes (eg ethylene)
You can These may be mixed and used at an appropriate ratio.
However, it is preferable to use carbon dioxide alone.
Yes. The temperature of the high-pressure gas that comes into contact with the drug is used as the drug base.
Beyond the glass transition temperature of biodegradable polymers used
If it is too high, fusion of the preparation, deformation, decomposition of bioactive substances,
The risk of commodification increases. Glass transition temperature in the present invention
Degree is measured with a differential scanning calorimeter (DSC) at each heating rate.
Midpoint glass obtained when the temperature is raised at 10 or 20 ° C per minute
The transition temperature. Also, the temperature of the high pressure gas is too low.
Then, the removal of the organic solvent becomes insufficient. The organic solvent is 1,
Less than 000 ppm, preferably less than 500 ppm, more
It is preferable to remove to less than about 100 ppm. Shi
Therefore, in the present invention, carbon dioxide is used as the high-pressure gas.
The advantageous temperature for use is the gas of the biodegradable polymer.
Based on the lath transition temperature (usually about 20-60 ° C)
+20 to -60 ° C, preferably +10 to -50 ° C, more
Preferably 0 to -40 ° C, more preferably -5 to -3.
0 ° C, most preferably in the temperature range of -10 to -25 ° C.
It Depending on the selected high pressure gas, the range of pressure during use is
Although different, in general, if the pressure of the high-pressure gas is too high, the micro
Capsule fusion, deformation, increased initial release immediately after administration, etc.
The risk increases, and if the pressure is too low, the removal of the organic solvent will be incomplete.
Will be enough. In the present invention, carbon dioxide is used as a high pressure gas.
The advantageous pressure when used as a product is about 1 to 7 MPa, preferably
Is about 1 to 4 MPa, more preferably about 2 to 4 MPa. High
The pressure, temperature, and treatment of the high-pressure gas also affect the time of contact with the pressure gas.
Depending on the amount of microcapsules used, etc., carbon dioxide
About 5 minutes to about 24:00 when using hydrogen as high-pressure gas
Is preferred. Furthermore, about 10 minutes to about 12 hours is preferable.
Yes. Below, a micro using carbon dioxide in a high-pressure gas state
Further explanation of high pressure gas treatment process for capsules
To do. Such a high-pressure gas treatment device is, for example, a liquefied carbon dioxide
Battery, carbon dioxide delivery pump, heat exchanger, extraction container,
Consists of a temperature tank, detector, fully automatic pressure control valve and recovery container
Has been done. The microcapsules to be processed are placed in extraction containers
After being put in and sealing the device, it is warmed to the specified temperature.
It Next, liquefied carbon dioxide is sent from the liquefied carbon dioxide cylinder to carbon dioxide.
It is sent to a heat exchanger by a pump and heated to a predetermined temperature.
And converted into a high pressure gas state. Then this high pressure gas
The carbon dioxide in the state is blown into the extraction container,
The solvent in the capsule is dissolved / extracted in the high-pressure gas. Extraction
The collected solvent passes through the detector and the automatic pressure control valve and is stored once.
Collected in a container. The pressure applied to the whole system is connected to the most downstream.
It is controlled by a fully automatic pressure control valve. Predetermined time,
The residual organic solvent is removed by contacting with the high-pressure gas.
You can leave.

(II) Phase Separation Method In the case of producing microcapsules by this method, the poorly water-soluble non-peptidic physiologically active compound, polyvalent metal compound and biodegradable polymer organic solvent obtained by the above method are used. The coacervation agent is gradually added to the solution with stirring to precipitate and solidify the microcapsules. The coacervation agent is about 0.01 to 1,000 times the volume of the oil phase, preferably about 0.05 to 500 times, and particularly preferably about 0.
It is selected from 1 to 200 times. The coacervation agent is not particularly limited as long as it is a high molecular compound, a mineral oil compound or a vegetable oil compound that is 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. You may use these in mixture of 2 or more types. The microcapsules thus obtained are separated, washed repeatedly with heptane or the like to remove the coacervation agent other than the physiologically active compound and the biodegradable polymer, and dried under reduced pressure. Alternatively, after washing by the same method as described in the in-water drying method of (I) above, freeze-drying, further warm drying, desolvation with supercritical fluid or carbon dioxide in a high-pressure gas state is performed. Good. For the desolvation treatment, a method using carbon dioxide in a high-pressure gas state as described above is preferably adopted.

(III) Spray Drying Method In the case of producing microcapsules by this method, the poorly water-soluble non-peptidic physiologically active compound, polyvalent metal compound and organic solvent for biodegradable polymer obtained by the above method are used. The solution is sprayed into the drying chamber of a spray dryer (spray dryer) using a nozzle, and the organic solvent in the atomized droplets is volatilized within an extremely short time 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 above-mentioned (I) in-water drying method, and then freeze-drying, further heat-drying, and desorption with supercritical fluid or carbon dioxide in a high-pressure gas state. A solvent may be used. (IV) Gas Grinding Method As a dosage form other than the above-mentioned microcapsules, the biodegradable polymer in the absence of a polyvalent metal compound described in the in-water drying method of the manufacturing method (I) of the microcapsules has a solubility in an organic solvent. An organic solvent solution containing an amount of a poorly water-soluble non-peptidic physiologically active compound, a polyvalent metal compound and a biodegradable polymer, for example, an organic solvent while adjusting the degree of vacuum using a rotary evaporator or the like. After evaporating to dryness, a fine powder may be obtained by pulverizing with a jet mill or the like. Furthermore, the pulverized fine powder is washed in the same manner as described in the in-water drying method of the microcapsule production method (I), and then freeze-dried, further heated and dried, in a supercritical fluid or high-pressure gas state. Desolvation with carbon dioxide or the like may be performed. With the microcapsules or fine powders obtained here, drug release can be controlled according to the decomposition rate of the biodegradable polymer used and the type and amount of the polyvalent metal compound. The sustained-release preparation obtained by the production method of the present invention may be formulated into various dosage forms as it is or using these as raw materials, and injections or implants for intramuscular, subcutaneous, organ, etc., nasal cavity, rectum, uterus Liquid preparations such as transmucosal agents, inhalants, oral agents (eg, capsules (eg, hard capsules, soft capsules, etc.), granules, solid preparations such as powders, syrups, emulsions, suspensions, etc. Etc.) and the like. It can also be administered by a needleless syringe. For example, in order to prepare sustained-release preparations obtained by the production method of the present invention as injections, these are used as dispersants (eg, Tween 80, surfactants such as HCO-60, sodium hyaluronate, carboxymethylcellulose). , Polysaccharides such as sodium alginate), preservatives (eg, methylparaben, propylparaben, etc.), isotonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.) , A sesame oil, a corn oil, or the like, and a sustained-release injection that can be actually used as an oily suspension by dispersing with a vegetable oil. The particle size of the sustained-release preparation obtained by the production method of the present invention, when used as a suspension injection, may be in a range that satisfies the degree of dispersion and needle penetration, for example, as an average particle size. In the range of about 0.1 to 300 μm, preferably about 0.5 to 150 μm, more preferably about 1
To 100 μm. Examples of the aseptic preparation of the sustained-release preparation obtained by the production method of the present invention include a method of sterilizing the production process, a method of sterilizing with gamma rays, and a method of combining these or a method of adding a preservative. However, it is not particularly limited.

Since the sustained-release preparation obtained by the production method of the present invention has low toxicity, it can be administered to mammals (eg, humans, cattle,
Pigs, dogs, cats, mice, rats, rabbits, etc.) can be used as a safe medicine. The dose of the sustained-release preparation obtained by the production method of the present invention varies depending on the type and content of the physiologically active compound which is the main drug, the dosage form, the duration of the physiologically active compound release, the target disease, the target animal, etc. Any effective amount of the physiologically active compound may be used. The dose of the physiologically active compound as the main drug per dose is, for example, preferably in the range of about 0.01 mg to 10 mg / kg body weight per adult when the sustained-release preparation is a one-month preparation. Preferably about 0.05 mg-5 mg /
It can be appropriately selected from the range of kg body weight. The dose of the sustained-release preparation per dose is preferably per adult,
It can be appropriately 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. Administration frequency is once every few weeks, 1
Once a month, or once every few months (eg, 3 months, 4 months, 6 months, etc.), type and content of bioactive compound, dosage form, duration of release of bioactive compound It can be appropriately selected depending on the target disease, the target animal, and the like. In addition, the sustained-release preparation of the present invention is bedridden, dementia, throat / esophageal disease,
It can also be advantageously used for patients with digestive disorders, dysphagia, patients who are difficult or unable to be treated with an internal drug such as during surgery. When the physiologically active compound is a compound having an angiotensin II antagonistic action, these 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 or night. It is expected that the therapeutic effect will be more clear because the dose and frequency can be reduced and the blood drug concentration does not fluctuate and the medical condition does not change due to discontinuation of administration. Regarding safety, under normal use conditions, the risk of excessive blood pressure is less than for internal use due to the above reasons, but even if an excessive blood pressure is generated due to a situation involving a large amount of body fluid loss such as a traffic accident, Angiotensin
In addition to II, immediate boosting of pressure can be achieved by intravenous administration of drugs (catecholamine preparations, etc.) that are usually used in emergency medical settings, and further sustained pressure can be obtained by oral administration of antihypertensive drugs. Not only acute response in case of emergency but also long-term response is possible. The diseases targeted by compounds having angiotensin II antagonistic activity as physiologically active compounds include contraction and proliferation of blood vessels expressed via angiotensin II receptor and organ damage, the presence of angiotensin II, or the presence of angiotensin II. Then, a disease or the like that is caused or promoted by the factors that are induced is included. Examples of such diseases include hypertension, abnormal blood pressure circadian rhythm, heart disease (cardiac hypertrophy, chronic heart failure including acute heart failure and congestiveness, cardiomyopathy, angina, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc. ), Cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.),
Cerebral edema, cerebral circulatory disorders, recurrent and sequelae of cerebrovascular disorders (neurological symptoms, psychotic 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.), renal disease (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombosis) Microangiopathy, complications of dialysis, organ damage including nephropathy due to irradiation), arteriosclerosis including atherosclerosis (aneurysm, coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy , Vascular thickening or obstruction and organ damage after intervention (percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolytic therapy, etc.), revascularization / reocclusion after bypass surgery Stenosis, erythrocytosis after transplantation, hypertension, organ damage, blood vessel thickening, rejection after transplantation, eye diseases (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, etc. Cardiovascular system Patients (deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, obstructive thrombotic vasculitis, ischemic cerebral circulation disorder, Raynaud's disease, Buerger's disease, etc.), metabolic / nutrient disorders (obesity, high fat) , Hypercholesterolemia, diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia, hypernatremia, etc., 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 aftereffects / complications, head injury, spinal cord injury, cerebral edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, Multiple sclerosis, etc.),
Dementia, memory disorders, consciousness disorders, amnesia, anxiety symptoms, tension symptoms, unpleasant mental states, mental disorders (depression, epilepsy, alcoholism, etc.), inflammatory diseases (retinopathy, nephropathy, neuropathy, major) Diabetic complications such as vascular disorders; arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, and periosteitis; inflammation after surgery / trauma; remission of swelling; pharyngitis; cystitis; pneumonia; atopic skin Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; Meningitis; Inflammatory eye diseases; Inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc., Allergic diseases (allergic rhinitis, conjunctivitis) , Gastrointestinal allergy, hay fever, anaphylaxis, etc.), chronic obstructive pulmonary disease, interstitial pneumonia, carini 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, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, cholelithiasis, hemorrhoids, etc.), blood / hematopoietic organs Disease (erythrocytosis,
Vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelopathy, etc., bone disease (eg, bone fracture, re-fracture, osteoporosis, osteomalacia, bone Pecet's disease, ankylosing myelitis) , Rheumatoid arthritis, Destruction of joint tissues in knee osteoarthritis and similar diseases, Solid tumors, Tumors (melanoma, malignant lymphoma, digestive organs (eg,
(Stomach, intestine, etc.), cancer and associated cachexia, cancer metastasis, endocrine disease (Addison's disease, Cushing's syndrome,
Pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urogenital and male genital diseases (cystitis,
Prostatic hypertrophy, prostate cancer, sexually transmitted diseases, etc., gynecological diseases (menopausal disorders, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, mammary gland diseases, sexually transmitted diseases, etc.), diseases caused by environmental / occupational factors (Radiation disorders, disorders due to 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,
Herpesviruses and other viral infections, Rickettsia infections, bacterial infections, etc., Toxemia (sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.), otolaryngological disease (Menuel syndrome, Tinnitus, taste disorders, dizziness, imbalance, dysphagia, etc.), skin diseases (keloids, hemangiomas, psoriasis, etc.), dialysis hypotension, myasthenia gravis, chronic fatigue syndrome, and other systemic diseases. When a physiologically active compound is a compound having an angiotensin II antagonistic action, by inhibiting the action of angiotensin II for a long period of time, a disorder or abnormality in biological functions and physiological actions that causes various diseases associated with adult diseases and aging Can be improved or suppressed, and primary or secondary prevention or progress of diseases or conditions caused by these can be suppressed. Examples of such disorders or abnormalities in biological functions and physiological actions include disorders or abnormalities in cerebral circulation / renal circulation autoregulation ability, circulatory disorders (peripheral, brain, microcirculation, etc.), disorders of the blood-brain barrier, insulin sensitivity. Decrease, salt sensitivity, coagulation / fibrinolysis system abnormalities, abnormal properties of blood / hemocyte components (enhanced platelet aggregation, abnormal red blood cell deformability, increased leukocyte adhesion, increased blood viscosity, etc.), growth factors and cytokines (PDGF) , VEGF, FGF, interlokin, TN
F-α, MCP-1, etc.), increased production and action, increased production and infiltration of inflammatory cells, increased free radical production, accelerated fat deposition, endothelial dysfunction, endothelium, cell and organ disorders, edema, smooth muscle, etc. Cell morphological changes (morphological changes to proliferative type), production and dysfunction of vasoactive substances and thrombus-inducing substances (endothelin, thromboxane A ₂ etc.), abnormal contraction of blood vessels, abnormal glucose tolerance, metabolic abnormality (Abnormal serum lipids, abnormal blood sugar, etc.), abnormal proliferation of cells, etc., angiogenesis (including abnormal angiogenesis in abnormal capillartic network formation of atherosclerotic adventitia), among others, among others,
Organ disorders associated with various diseases (eg, cerebrovascular disorders and associated organ disorders, organ disorders associated with cardiovascular disease, organ disorders associated with diabetes, organ disorders associated with intervention, etc.)
It can be advantageously used as a primary or secondary preventive / therapeutic agent. In the sustained-release preparation obtained by the production method of the present invention, when the physiologically active compound is a compound having angiotensin II antagonistic activity (especially candesartan cilexetil, candesartan etc.), it is advantageous as a preventive / therapeutic agent for hypertension of portal vein. It is possible to use.
Rupture of esophageal varices occurs frequently at night (Hepatology 1994; 19:
595-601), and because this drug can maintain a constant blood concentration day and night, it is possible to reduce the dose and frequency compared to when administered orally. Not only is this possible, but a stable decrease in portal vein pressure can be expected because there is little fluctuation in blood drug concentration. The above features of this drug indicate its usefulness as a preventive agent for rupture of varicose veins in the esophagus and stomach. In addition, it is expected that the therapeutic effect will be more clear because the medical condition will not change due to discontinuation of administration. Furthermore, compounds having angiotensin II antagonism as physiologically active compounds (in particular, candesartan cilexetil, candesartan, etc.) are
It is expected to be effective in promoting the production of patocyte growth factor (hepatic cell growth factor), and can be expected to contribute to liver regeneration and liver brain recovery. In addition, by maintaining a constant blood concentration of compounds having angiotensin II antagonism as a physiologically active compound (in particular, candesartan cilexetil, candesartan, etc.) day and night, the prevention and treatment of cerebrovascular disorders such as cerebral infarction. It is also expected that the effect will become clearer. When the physiologically active compound is a compound having an angiotensin II antagonistic action, a method for treating a patient is to administer an orally administered angiotensin II antagonist 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 sex preparation. The orally administered angiotensin II antagonist and the angiotensin II antagonist contained in the sustained-release preparation may be the same or different. In addition, antihypertensive agents other than angiotensin II antagonists (calcium antagonists, diuretics, beta blockers, etc.) are orally administered in advance, and after confirming the patient's reactivity, the sustained release preparation of the present invention is administered. You may. Further, the sustained-release preparation of the present invention may be used in combination with a diuretic antihypertensive agent (oral preparation) which is usually used in combination with an angiotensin II antagonist. Also, other lipid-lowering or cholesterol-lowering drugs,
HMG-Co A reductase (3-hydroxy-3-methylglutar
ylcoenzyme A reductase) inhibitor, insulin sensitizer, bone disease therapeutic agent, myocardial protective agent, coronary artery disease therapeutic agent, other hypertension therapeutic agent, chronic heart failure therapeutic agent, diabetes therapeutic agent, liver disease therapeutic agent, gastric / duodenal ulcer Therapeutic drug therapeutic drug,
Used with other medicinal ingredients including biliary tract disease therapeutic agents, hypothyroidism therapeutic agents, nephrotic syndrome therapeutic agents, chronic renal failure therapeutic agents, gynecological disease therapeutic agents, urogenital and male genital disease therapeutic agents or infectious disease therapeutic agents In this case, these compounds may be administered as an oral preparation, or may be optionally administered as a rectal preparation in the form of suppositories.
Possible combination components in this case are, for example, fibrates [eg, clofibrate, benzafibrate, gemfiprozil, etc.], nicotinic acid, its derivatives and analogs [eg, acipimox and probucol], bile acid-binding resins. [Eg, cholestyramine, colestipol, etc.], compounds that suppress cholesterol absorption [eg, sitosterol, neomycin, etc.], squalene epoxidase inhibitors [eg, NB-598 and related compounds]. Further possible combination components are oxidosqualene-lanosterol cyclases, such as decalin derivatives, azadecalin derivatives and indane derivatives. Further, combinations with the following various therapeutic agents are also possible. Antihypertensive: Diuretics [eg, Furosemide (Lasix), Bumetanide (Renetron), Azosemide (Diart)], Antihypertensives [eg, ACE inhibitors, (enalapril maleate (renibase), etc.) and Ca antagonists (Manidipine, etc.) Amlodipine, etc., α or β receptor blockers, etc.); Chronic heart failure therapeutic agents: Cardiotonic drugs [eg, cardiac glycosides (such as digoxin), β receptor stimulants (catecholamines such as denopamine and dobutamine) and PDEs] Inhibitors, etc., diuretics [eg, furosemide (Lasix), spironolactone (aldactone), etc.], ACE inhibitors,
[Eg, enalapril maleate (renibase), etc.],
Ca antagonists (eg, amlodipine, etc.) and β receptor blockers; Antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride, β blockers, Ca antagonists, etc .; Bone disease treatment Drugs: calcium preparations (eg calcium carbonate etc.), calcitonin preparations, active vitamin D ₃ preparations (eg alfacalcidol (alpha roll etc.),
Calcitriol (locartrol), etc., sex hormones (eg, estrogen, estradiol, etc.), hormone preparations (eg, conjugated estrogen (premarin), etc.), ibriflavone preparations (such as Osten), vitamin K ₂ , vitamins K ₂ preparations [eg, menatetrenone (Graquette)], bisphosphonic acid preparations (etidronate, etc.), prostaglandin E2, fluorine compounds (eg, 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 factor-1 and 2 (IGF-1,
-2), parathyroid hormone (PTH), European Patent Publication EP-A1-376197, EP-A1-4.
Compounds described in JP-A-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
ide etc); Antidiabetic: Actos, Rogiglidason, Kinedac, Benfil, Humarin, Euglucon, Glymicron, Daoneyl, Novolin, Monotard, Insulin, Glucobay, Dimerin, Rastinone, Basilcon, Deamerin S, Isdirin, etc .; Liver Disease therapeutic agents: glycyrrhizin preparations [eg, strong minophagen, etc.], liver hydrolysates, SH compounds [eg, glutathione, etc.], special amino acid preparations [eg, aminolevane, etc.], phospholipids [eg, polyenphosphatidylcholine, etc.], vitamins [ Examples, vitamins B1, B2, B6, B12, C, etc.], adrenocortical hormones (eg, dexamethasone, betamethasone, etc.), interferons (eg, interferon α, β, etc.), hepatic encephalopathy therapeutic agents (eg, lactulose, etc.), Hemostatic agents used when the esophagus or gastric varices are ruptured (eg, Vasopressin, somatostatin, etc.]; Gastric / duodenal ulcer therapeutic drug Therapeutic agent: antacid [eg, histamine H2 antagonist (cimetidine etc.), proton pump inhibitor (lansoprazole etc.)]; [Eg, dehydrocholic acid, etc.],
Bile-removing agents [eg, magnesium sulfate, etc.]; Hypothyroid drug: Dry thyroid (threoid),
Levothyroxine sodium (tyrazine S), liothyronidine sodium (thyronine, thyromine), etc .; Nephrotic syndrome drug: Usually, prednisolone (predonin), prednisolone sodium succinate (predonin) is used as the first-choice steroid therapy. , Sodium methylprednisolone succinate (sol medrol), betamethasone (linderone), etc. are used. For anticoagulant therapy, antiplatelet agents such as dipyridamole (versantine), dilazep hydrochloride (comelian), ticlopidine, clovidogrel, and FXa inhibitors and anticoagulants are used; HMG-Co A 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, etc .; Remedies for chronic renal failure: diuretics [eg, Furosemide (Lasix), Bumetanide (Runetron), Azosemide (Diart)], antihypertensive drug (eg, ACE inhibitor, (enalapril maleate (renibase)) and Ca antagonist (manidipine), α receptor blocker in combination When administered, it can be used preferably orally. Thrombosis preventive and therapeutic agents: anticoagulants [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), blood coagulation factor Xa inhibitors and coagulation fibrinolytic system] Drugs with balance correction function], thrombolytic drugs [eg, tPA, urokinase], antiplatelet drugs [eg. ,
Aspirin, Sulfinpyrazolo (Anturan), Dipyridamole (Persanthin), Ticlopidine (Panaldine), Cilostazol (Pletal), GPIIb / IIIa
Antagonists (Leopro)] and other coronary vasodilators: Nifedipine, diltiazem, nicorazil, nitrite, etc. Myocardial protective agents: Cardiac ATP-K openers, Na-H exchange inhibitors, endothelin antagonists, urotensin antagonists, etc. Inflammatory drugs: aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (eg, indomethacin, etc.), steroid drugs (eg, dexamethasone, etc.) Antiallergic drugs: antihistamines (eg, chlorpheniramine maleate, etc.), stimulation therapy Agents (eg, bucillamine, etc.), other azelastine hydrochloride, seratrodast, tranilast, oxatomide, potent neominophagen C, tranexamic acid, ketotifen fumarate, etc. antitumor agents: alkylating agents, antimetabolites, antitumor antibiotic preparations, antitumors Tumorous botanical components and other anti-tumor drugs, etc. CNS agonists: anti-anxiety agents, hypnotic sedatives, anesthetics, anticonvulsants, autonomic nerve agents, anti-Parkinson's agents and other neuropsychiatric agents, etc. Gynecological disease therapeutic agents: [eg, menopausal agents ( Conjugated estrogens, estradiol, testosterone enanthate, valerate estradiol, etc.), breast cancer therapeutic agents (tamoxifen citrate, etc.), endometriosis / uterine fibroid treatment agents (leuprorelin acetate, danazol, etc.)], etc. Disease treatment: [eg, prostatic hypertrophy treatment (tamsulosin hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.), prostate cancer (leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.), etc. Infectious disease treatment drug: [eg, Antibiotics (cefatium hydrochloride, cefozopran hydrochloride, ampicillin, etc.), chemotherapeutic agents (sulfa drugs, Synthetic antibacterial agents, antiviral agents, etc.),
Biological agents (vaccines, blood products such as immunoglobulins), etc.] and other anti-obesity agents (such as mazindol), anti-rheumatic agents, etc., and treatment by various factors derived from the living body or gene transfer thereof (eg, HGF, angiogenesis-promoting factors such as VEGF or ischemic disease treatment by gene transfer thereof) or decoy nucleic acid treatment and the like, when using these agents in combination with the sustained-release preparation obtained by the production method of the present invention, Each drug may be mixed in one sustained-release preparation, but the above-mentioned drugs are mixed with a pharmacologically acceptable carrier, excipient, binder, diluent, etc. to prepare a formulation, It can be administered separately or simultaneously with the sustained-release preparation. When drugs are formulated separately, they can be administered separately by mixing them with a diluent or the like at the time of use, but individual formulations formulated separately can be administered simultaneously or with a time lag. Alternatively, they may be separately administered to the same subject.

E. Regarding polyvalent metal (2) In the composition containing the “non-peptide bioactive substance and biodegradable polymer” of the present invention, about 0.05 wt% or more of the polyvalent metal is contained in the composition. The polyvalent metal used in the "sustained release solid pharmaceutical composition present on the surface of" is described in detail below. The polyvalent metal present on the surface of the sustained-release solid pharmaceutical composition of the present invention is not particularly limited as long as it is a compound that does not adversely affect the living body, and examples of the metal species include divalent (eg, zinc, calcium, A polyvalent metal (preferably zinc or the like) such as magnesium, iron, copper, aluminum, tin, manganese, etc., trivalent (eg, iron, aluminum, manganese, etc.), tetravalent (eg, tin, etc.) is used. . The polyvalent metal present on the surface of the sustained-release solid pharmaceutical composition of the present invention may be used as a compound with an inorganic substance or an organic substance, a complex compound, or a “polyvalent metal compound” such as a metal oxide. The "polyvalent metal compound" may have bound water or crystal water. Preferable specific examples of the polyvalent metal include zinc, calcium, magnesium and the like. A particularly preferable example of the polyvalent metal is zinc. As the organic substance, for example, organic acids such as aliphatic carboxylic acids and aromatic acids, and acetylacetone are used. As the aliphatic carboxylic acid, an aliphatic carboxylic acid having 1 to 9 carbon atoms (eg, aliphatic monocarboxylic acid, aliphatic dicarboxylic acid, aliphatic tricarboxylic acid, etc.) is preferably used. The aliphatic carboxylic acid may be either saturated or unsaturated. Examples of the aliphatic monocarboxylic acid include saturated aliphatic monocarboxylic acid having 1 to 9 carbon atoms (eg, carbonic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, Capric acid and the like and unsaturated aliphatic monocarboxylic acid having 2 to 9 carbon atoms (eg acrylic acid,
Propiol acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.) are used. Examples of the aliphatic dicarboxylic acid include saturated aliphatic dicarboxylic acid having 2 to 9 carbon atoms (eg, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.) and unsaturated aliphatic dicarboxylic acid 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.) is used. The aliphatic carboxylic acid may have 1 or 2 hydroxyl groups, and examples thereof include glycolic acid, lactic acid, glyceric acid, tartronic acid, malic acid, tartaric acid,
Examples include citric acid and the like. The aliphatic carboxylic acid is preferably an aliphatic monocarboxylic acid. More preferably, it is an aliphatic monocarboxylic acid having 2 to 9 carbon atoms. A particularly preferred specific example of the aliphatic carboxylic acid is acetic acid. As the aromatic acid, for example, benzoic acid, salicylic acid, phenolsulfonic acid, etc. are used. Examples of the inorganic substance include halogen (eg, fluorine, chlorine, bromine, iodine), inorganic acid (eg, sulfuric acid, nitric acid, thiocyanic acid), oxygen and the like. Specific examples of the polyvalent metal compound include:
Salt of zinc and inorganic acid [eg, zinc halide (eg, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate], zinc and organic acid [Eg, zinc salt of aliphatic carboxylic acid (eg, zinc carbonate, zinc acetate, zinc glycolate, zinc lactate, zinc tartrate, etc.), aromatic zinc salt (eg, zinc benzoate, zinc salicylate, zinc phenolsulfonate) Etc.)], a salt of calcium and an inorganic acid such as zinc acetylacetonate [eg, calcium halide (eg, calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, thiocyan] Calcium salts, etc.), salts of calcium and organic acids [eg, aliphatic carboxylic acid calcium salts (eg, calcium carbonate, calcium acetate, calcium propionate Calcium oxalate, calcium tartrate, calcium lactate, calcium citrate, calcium gluconate, etc.), aromatic calcium salts (eg, calcium benzoate, calcium salicylate, etc.)], salts of magnesium and inorganic acids such as calcium acetylacetonate [Eg, magnesium halide (eg, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate, etc.], a salt of magnesium and an organic acid [eg, aliphatic Carboxylic acid magnesium salt (eg, magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tartrate, magnesium lactate, magnesium citrate, magnesium gluconate, etc.), aromatic mag Salts of iron and inorganic acids such as sium salts (eg, magnesium benzoate, magnesium salicylate, etc.), magnesium acetylacetonate, etc. [eg, iron halides (eg, iron chloride, iron bromide, iron iodide, fluorinated) Iron, etc.), iron sulfate, iron nitrate, iron thiocyanate, etc.), salts of iron and organic acids [eg, aliphatic carboxylic acid iron salts (eg, iron carbonate, iron acetate, iron glycolate, iron lactate, iron tartrate] Etc.), aromatic iron salts (eg, iron benzoate, iron salicylate, iron phenolsulfonate, etc.)], iron acetylacetonate, and the like. Alternatively, a metal oxide (eg, zinc oxide, iron oxide, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide, or the like) may be used. The polyvalent metal compound is preferably zinc acetate, zinc sulfate, calcium acetate,
Magnesium acetate or the like is used, and more preferably zinc acetate and / or zinc sulfate is used. The polyvalent metal present on the surface of the sustained-release solid pharmaceutical composition of the present invention may be the polyvalent metal compound itself used, or the polyvalent metal ion may be present as the polyvalent metal ion (for example, the composition The non-peptide bioactive substance or biodegradable polymer therein, other additives, etc. In particular, a salt may be formed with a functional group such as a carboxyl group existing at the end of the biodegradable polymer). Here, "existing on the surface" may be coated in the form of a film, may exist in the form of a mesh, and may be scattered or localized. As an aspect of "presence", a salt may be formed with the solid pharmaceutical composition as described above, or may be fixed, attached or coexistent with the components of the solid pharmaceutical composition. In the present invention, the term "surface" means, for example, not only the outermost layer surface of the solid pharmaceutical composition,
The average diameter from the outermost surface is about 10% or less, preferably about 5
% Means a portion having a thickness of not more than%.

As a method for allowing the polyvalent metal to be present on the surface of the sustained-release solid pharmaceutical composition, physical, chemical, electrical or thermodynamic external force can be used. That is, spraying a solution containing the polyvalent metal (compound), plating the polyvalent metal (compound), adsorbing the polyvalent metal (compound) fine particles, heating the polyvalent metal (compound) fine particles There are methods such as welding. Of these methods,
The presence of the polyvalent metal on the surface of the sustained-release solid pharmaceutical composition without degrading the quality of the sustained-release solid pharmaceutical composition is preferable in the solution containing the polyvalent metal (compound). It is a method of coating the surface of a sustained-release solid pharmaceutical composition. The solvent used for dissolving the polyvalent metal is preferably a poor solvent for the biodegradable polymer that constitutes the sustained-release solid pharmaceutical composition. Preferred solvents include distilled water, alcohol (methanol or ethanol), acetone, acetonitrile, ethyl acetate and the like, and more preferred are distilled water and alcohol. You may use these solvents in mixture of 2 or more types. The concentration of the polyvalent metal (compound) in the solution is preferably about 0.1 to about 80 mM,
More preferably about 0.5 to about 60 mM, most preferably about 1 to
It is about 40 mM. Immersion of the sustained-release solid pharmaceutical composition in the solution of the polyvalent metal (compound) may be during the production of the sustained-release solid pharmaceutical composition or after molding, but is preferably This is a process in the manufacturing process. In particular, when the sustained-release solid pharmaceutical composition is produced as microcapsules using the in-water drying method described below, the polyvalent metal (compound)
The polyvalent metal can be effectively present on the surface of the microcapsule by the step of emulsifying the non-peptide bioactive substance, the biodegradable polymer and the organic solvent in the aqueous phase (outer aqueous phase) in which the microcapsules are dissolved. It will be possible. The amount of the polyvalent metal present on the surface of the sustained-release solid pharmaceutical composition produced by the above method is about 0.05% by weight based on the total weight of the sustained-release solid pharmaceutical composition.
% Or more, preferably about 0.05% to about 5% by weight, and more preferably about 0.1% to about 2% by weight. The initial drug release rate when the sustained-release solid pharmaceutical composition having a polyvalent metal present on the surface produced by the above method is administered to a living body is the same as that of the sustained-release solid pharmaceutical composition having no polyvalent metal present. It is preferably suppressed to about 60% or less, more preferably about 50% or less, and most preferably about 40% or less. The polyvalent metal "is not present" means that the amount of the polyvalent metal is less than 0.05% by weight based on the total weight of the sustained-release solid pharmaceutical composition,
It is preferably 0.03% by weight or less, more preferably 0.01% by weight or less. "Initial release rate" means the amount of drug released in "a certain period after administration" with respect to the total amount of drug released in "sustained release period" after administering the sustained-release solid pharmaceutical composition to a living body. The ratio of The "certain period after administration" depends on the sustained-release period of the sustained-release solid pharmaceutical composition. For example, when the "sustained-release period" is 24 hours, it is 4 hours, and when the "sustained-release period" is 7 days, it is 0. 5 days, 1 day, etc. when the "sustained release period" is 30 days or more. Methods for determining the initial drug release rate of the sustained-release solid pharmaceutical composition include in vivo and in vitro treatments.
There is a calculation method in o. The method for calculating the initial release rate in vivo is the drug concentration during the whole sustained release period obtained by measuring the drug concentration in blood after administration of the sustained release solid pharmaceutical composition to a living body-area under the time curve (AUC). To A for a certain period after administration
There is a method to obtain the ratio of UC. There is also a method of calculating from the amount of drug remaining in the sustained-release solid pharmaceutical composition after administration of the drug for a certain period of time and the amount of administered drug. Invitro
The initial release rate calculation method in (1) can also be calculated by dividing the amount of drug released in the release test solution within a predetermined time by the amount of drug contained in the sustained-release solid pharmaceutical composition used for evaluation. . As the release test solution, various buffer solutions (for example,
Phosphate buffer, carbonate buffer, HEPES, citrate buffer, etc.) are preferably used. Further, various surfactants (Tween 20, Tween 80, Pluronics, SDS, etc.) may be added to the release test solution. The predetermined time depends on the release test period. For example, when the release period is 24 hours, it is within 1 hour, when the release period is 1 week, about 0.2-0.5 days, and when the release period is 1 month. It's about a day.

F. Intrinsic metal In the sustained-release solid pharmaceutical composition of the present invention, a polyvalent metal may be blended in addition to the surface. The polyvalent metal is not particularly limited as long as it is a compound that does not adversely affect the living body, and examples of the metal species include divalent (eg, zinc, calcium, magnesium, iron, copper, aluminum, tin, manganese, etc.), 3
Valency (eg, iron, aluminum, manganese, etc.), 4 valency (eg,
A polyvalent metal (preferably zinc or the like) such as tin) is used. The polyvalent metal that may be blended on the surface other than the surface may be used as a compound with an inorganic substance or an organic substance, a complex compound, or a “polyvalent metal compound” such as a metal oxide. The "polyvalent metal compound" may have bound water or crystal water. Preferable specific examples of the polyvalent metal include zinc, calcium, magnesium and the like. A particularly preferable example of the polyvalent metal is zinc. 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.
The aliphatic carboxylic acids (eg, aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, aliphatic tricarboxylic acids, etc.) are used. 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, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid) and 2 carbon atoms To 9 unsaturated aliphatic monocarboxylic acids (eg, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.) are used. Examples of the aliphatic dicarboxylic acid include saturated aliphatic dicarboxylic acid having 2 to 9 carbon atoms (eg, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.) and unsaturated aliphatic dicarboxylic acid 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.) is used. The aliphatic carboxylic acid may have 1 or 2 hydroxyl groups, and examples thereof include glycolic acid, lactic acid, glyceric acid, tartronic acid, malic acid, tartaric acid, citric acid and the like. To be The aliphatic carboxylic acid is preferably an aliphatic monocarboxylic acid. More preferably, it has 2 to 9 carbon atoms.
Is an aliphatic monocarboxylic acid. A particularly preferred specific example of the aliphatic carboxylic acid is acetic acid. As the aromatic acid, for example, benzoic acid, salicylic acid, phenolsulfonic acid, etc. are used. Examples of the inorganic substance include halogen (eg, fluorine, chlorine, bromine, iodine), inorganic acid (eg, sulfuric acid, nitric acid, thiocyanic acid), oxygen and the like. Specific examples of the polyvalent metal compound that may be blended in addition to the surface include salts of zinc and an inorganic acid [eg, zinc halide (eg, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), Zinc sulfate, zinc nitrate, zinc thiocyanate, etc.], a salt of zinc and an organic acid [eg, aliphatic carboxylic acid zinc salt (eg, zinc carbonate,
Zinc acetate, zinc glycolate, zinc lactate, zinc tartrate, etc.), aromatic zinc salts (eg, zinc benzoate, zinc salicylate, zinc phenolsulfonate, etc.)], zinc acetylacetonate and other salts of calcium and inorganic acids [Eg, calcium halide (eg, calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, calcium thiocyanate, etc.], salt of calcium and organic acid [eg, aliphatic Carboxylic acid calcium salt (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.)], calcium acetylacetate A salt of magnesium with an inorganic acid such as nato [eg, magnesium halide (eg, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate], magnesium and Salts with organic acids (eg, aliphatic carboxylic acid magnesium salts (eg, magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tartrate, magnesium lactate, magnesium citrate, magnesium gluconate, etc.), aromatic magnesium Salts (eg, magnesium benzoate, magnesium salicylate, etc.), magnesium acetylacetonate, etc., salts of iron and inorganic acids [eg, iron halides (eg, iron chloride, iron bromide, iron iodide, iron fluoride) Etc.), iron sulfate, glass Iron, iron thiocyanate, etc.], salts of iron with organic acids [eg, aliphatic carboxylic acid iron salts (eg, iron carbonate, iron acetate, iron glycolate, iron lactate, iron tartrate, etc.), aromatic iron salts ( Examples, iron benzoate, iron salicylate, iron phenolsulfonate, etc.), iron acetylacetonate, etc., and metal oxides (eg, zinc oxide, iron oxide, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide). Etc.) and the like. The polyvalent metal (compound) that may be compounded other than on the surface is preferably zinc acetate, zinc oxide, calcium acetate, magnesium acetate, iron chloride, iron acetylacetonate, zinc acetylacetonate, calcium acetylacetonate, magnesium acetylacetonate. Nart and the like are used, and more preferably zinc acetate and / or zinc oxide (that is, one kind or a combination of two kinds selected from zinc acetate and zinc oxide) is used.
In the present invention, a part of the polyvalent metal contained in the sustained-release solid pharmaceutical composition forms a metal salt with a biodegradable polymer (for example, a zinc salt or a different metal salt). Good. The metal salt of this biodegradable polymer is
For example, it can be produced by the method described in JP-A No. 09-212420 or a method similar thereto. Further, a part of the polyvalent metal contained in the sustained-release solid pharmaceutical composition may form a complex with the non-peptide bioactive substance. The mixing ratio of the polyvalent metal (compound) existing outside the surface to the non-peptidic physiologically active substance is different depending on the kind of the polyvalent metal (compound) and the non-peptidic physiologically active substance. The polyvalent metal (compound) is divalent and the non-peptide bioactive substance is A
In the case of the II antagonist compound, the ratio of polyvalent metal (compound) / non-peptidic physiologically active substance (molar ratio) is preferably about 1 /.
10 to about 10/1, more preferably about 1/5 to about 5/1, most preferably about 1/2 to about 2/1.

G. Embodiment (2) In the "composition comprising a non-peptidic physiologically active substance and a biodegradable polymer of the present invention, about 0.05% by weight or more of the weight of the composition is a polyvalent metal of the composition. The method for producing the "released solid pharmaceutical composition on the surface" and its embodiment are described in detail below. The sustained-release solid pharmaceutical composition of the present invention comprises, for example, an organic solvent solution or suspension containing a non-peptide bioactive substance and a biodegradable polymer at a polyvalent metal ion concentration of about 0.1 to about 80 mM. It can be produced by removing an organic solvent from an emulsion obtained by mixing with a certain aqueous phase. Here, the solubility of a non-peptidic physiologically active substance in an organic solvent solution in the absence of a polyvalent metal (compound) increases due to the presence of the polyvalent metal (compound), and
The solubility of a non-peptide bioactive substance in an organic solvent solution of a biodegradable polymer in the absence thereof increases due to the presence of a polyvalent metal (compound). Therefore, for example, as a method for producing the sustained-release solid pharmaceutical composition of the present invention, a biodegradable polymer containing no polyvalent metal (compound) in an amount exceeding the solubility in an organic solvent of a non-peptide bioactive substance, An organic solvent solution containing a polyvalent metal (compound) and a biodegradable polymer may be used, and even when the biodegradable polymer is not contained in the organic solvent solution,
The non-peptidic physiologically active substance may be dissolved in the organic solvent solution more than the solubility in the absence of the polyvalent metal (compound). Examples of the organic solvent include halogenated hydrocarbons (eg, dichloromethane, 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 benzene, toluene, xylene etc.), alcohols (eg ethanol, methanol etc.), acetonitrile etc. are used. These may be used as a mixture of two or more kinds at an appropriate ratio. Of these, dichloromethane is preferable as the halogenated hydrocarbon, and ethanol and methanol are preferable as the alcohol. You may mix and use these at an appropriate ratio. Additives may be added to the above organic solvent solution. Examples of the additive include acetic acid, a solubilizer for maintaining the stability of the drug,
Carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, etc., sodium hydroxide, arginine, lysine and salts thereof may be added. Further, as a drug stabilizer, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite,
Paraoxybenzoic acid esters (eg, methylparaben, propylparaben, etc.) generally used, benzyl alcohol, chlorobutanol, thimerosal, etc. may be added as a preservative such as a polyol compound such as polyethylene glycol. Although the concentration of the non-peptidic physiologically active substance in the organic solvent solution varies depending on the type of the non-peptidic physiologically active substance and the type of organic solvent, for example, the non-peptidic physiologically active substance is an AII antagonist compound, such as dichloromethane and When a mixed solution of methanol is used as an organic solvent, it is generally selected from about 0.5 to about 70% by weight, more preferably about 1 to about 60% by weight, particularly preferably about 2 to about 50% by weight. The concentration of the biodegradable polymer in the organic solvent solution varies depending on the molecular weight of the biodegradable polymer and the type of the organic solvent. For example, when dichloromethane is used as the organic solvent, it is generally about 0.5 to About 70% by weight, more preferably about 1 to
It is selected from about 60% by weight, particularly preferably from about 2 to about 50% by weight. When ethanol or methanol is used as a mixed organic solvent with dichloromethane, the ratio of dichloromethane in the mixed organic solvent is generally about 10
To about 98% by volume, more preferably about 20 to about 95% by volume, and particularly preferably about 30 to about 90% by volume. The non-peptide bioactive substance, polyvalent metal (compound)
The biodegradable polymer may be added to the organic solvent in any order, or may be added at the same time, and a non-peptidic physiologically active substance and a polyvalent metal (compound) in an organic solvent solution may be added. You may mix the organic solvent solution of a biodegradable polymer. The non-peptide bioactive substance,
In order to dissolve the polyvalent metal (compound) and the biodegradable polymer in the organic solvent, they may be allowed to stand still, or may be appropriately mixed by using external energy. The energy includes ultrasonic waves, physical shaking, stirring and the like. The dissolution temperature may be any temperature below the boiling point of the solvent used, but is preferably about 0 ° C to about 30 ° C. The time required for dissolution varies depending on the types of the non-peptide bioactive substance, the polyvalent metal (compound) and the biodegradable polymer, the compounding ratio, the dissolution temperature, the strength of vibration, etc., but preferably about 1 second at room temperature. To about 7 days, more preferably about 5 seconds to about 3 days, most preferably about 30 seconds to about 1 day. As a method for removing the organic solvent, a method known per se or a method similar thereto is used. For example, a method of evaporating the organic solvent by stirring at a propeller stirrer or a magnetic stirrer at atmospheric pressure or gradually reducing the pressure, a method of evaporating the organic solvent while adjusting the degree of vacuum using a rotary evaporator, etc. And so on. The processing time for removing the solvent is 0.1
~ 20 hours, preferably 0.5-10 hours. The organic solvent solution of the non-peptide bioactive substance, polyvalent metal (compound) and biodegradable polymer is preferably a sterile solution, more preferably a solution prepared by filtration sterilization,
When used as an injection, there is an advantage that a sterile bulk of non-peptide bioactive substance is not required.

The amount of the non-peptidic physiologically active substance and the polyvalent metal (compound) to be mixed in the sustained-release solid pharmaceutical composition of the present invention depends on the kind of the physiologically active substance, the desired pharmacological effect and the duration of the effect. Although different, when the physiologically active substance, polyvalent metal (compound) and biodegradable polymer are used as starting materials, the physiologically active substance is usually about 1 to about 50% by weight based on the sum of the three factors. More preferably about 1
5 to about 45% by weight, particularly preferably about 20 to about 40% by weight, while the polyvalent metal (compound) is usually about 0.5 to about 20% by weight, more preferably about 1 to about 15% by weight. And particularly preferably about 2 to about 10% by weight. The form of the sustained-release solid pharmaceutical composition of the present invention is not particularly limited, but parenterally-administered preparations are preferable, and transdermal administration agents, transmucosal agents, implants, microcapsule injections and the like are conceivable. It is preferable to use an injectable preparation using microcapsules, which has a long period of time and has a small burden on the patient.

The present invention relates to a method for producing a sustained-release pharmaceutical composition.
However, if the formulation is microcapsules (hereinafter referred to as
In some cases, it is also referred to as
You (I) Underwater drying method Non-peptide bioactive substance obtained by the above method, polyvalent gold
Solvents (compounds) and biodegradable polymers dissolved in organic solvents
Liquid or suspension and polyvalent metal (compound) are dissolved in advance
Aqueous solution or water phase (hereinafter sometimes referred to as the external water phase)
It ) Is mixed with O (oil phase) / W (water phase) or S
(Solid phase) / O (oil phase) / W (water phase) Emulsion formation
After that, the solvent in the oil phase is evaporated and the microcapsules are removed.
To prepare. The polyvalent metal (compound) used here is described above.
Selected from among the following: zinc acetate, sulfite
Lead, calcium acetate, magnesium acetate and those
The mixture of two or more selected from
Dissolve to 0.1 to about 80 mM. Volume of water phase at this time
Is generally about 1 to about 10,000 times the volume of the oil phase,
More preferably about 5 times to about 5,000 times, particularly preferably
Is selected from about 10 times to about 2,000 times. Again in the water phase
Is an alcohol (eg methanol or ethanol
Water), acetone, acetonitrile, etc.
You may match. An emulsifier may be added to the above external water phase.
Yes. The emulsifier generally forms a stable O / W emulsion.
Any of them can be used. Specifically, an example
For example, anionic surfactants (eg, sodium oleate)
Gum, sodium stearate, sodium lauryl sulfate
Etc.), nonionic surfactants (eg polyoxyethylene)
N-sorbitan fatty acid ester (Tween 80,
Tween 60, Atlas Powder Co., Ltd., Polyoxy
Ethylene castor oil derivative [HCO-60, HCO-50, Nikko Chemica
]), Polyvinylpyrrolidone, polyvinylalcohol
Cole, carboxymethylcellulose, lecithin, zera
Chin, hyaluronic acid, etc. are used. One of these
You can use one type or a combination of two or more types
Yes. The concentration at the time of use is preferably about 0.01 to
In the range of about 10% by weight, more preferably about 0.05 to.
Used in the range of about 5% by weight. Immersion in the above external water phase
A permeability control agent may be added. As the osmotic pressure adjusting agent,
Any solution that exhibits an osmotic pressure when made into an aqueous solution may be used.
For example, polyhydric alcohols, monohydric alcohols, monosaccharides,
Disaccharides, oligosaccharides and amino acids or their derivatives
The body etc. are mentioned. As the above polyhydric alcohols
Are, for example, dihydric alcohols such as glycerin, arabic
Pentavalent alcohol such as tall, xylitol, adonitol
Such as lees, mannitol, sorbitol, dulcitol, etc.
Hexahydric alcohols are used. Among them, hexavalent
Rucols are preferable, and mannitol is particularly preferable.
It Examples of the above monohydric alcohols include methano
Alcohol, ethanol, isopropyl alcohol, etc.
Of these, methanol is preferred. With the above monosaccharides
For example, arabinose, xylose, ribose
Pentose, 2-deoxyribose and other pentose sugars, glucose, fruits
Sugar, galactose, manose, sorbose, rhamno
Hexasaccharides such as sugar and fucose are used.
Classes are preferred. Examples of the above oligosaccharides include maltose.
Totriose, trisaccharides such as raffinose sugar, stachyose
Tetrasaccharides such as sugar are used, of which trisaccharides are preferred.
Yes. As derivatives of the above monosaccharides, disaccharides and oligosaccharides
For example, glucosamine, galactosamine, gluc
Ronic acid and galacturonic acid are used. Ami above
Any of the L-forms can be used as the no acids.
Can be, for example, glycine, leucine, arginine
And so on. Of these, L-arginine is preferred
Yes. These osmotic pressure regulators may be used alone or in combination of two or more.
You may mix and use the above. These osmotic pressure regulators
Is the osmotic pressure of the external water phase is about 1/50 of the osmotic pressure of physiological saline.
At a concentration of about 5 times, preferably about 1/25 to about 3 times
Used. As a method of removing the organic solvent,
A known method or a method similar thereto is used. example
A propeller-type stirrer or a magnetic stirrer.
While stirring at a normal pressure or gradually reducing the pressure to dissolve the organic solvent
Method to evaporate the medium, rotary evaporator, etc.
To evaporate an organic solvent while adjusting the degree of vacuum using
Law, etc. Micro obtained in this way
Centrifuge or filter the capsules to collect and then
The physiologically active substances and drug
Wash retained substances, emulsifiers, etc. several times with distilled water and
And disperse in distilled water and freeze-dry. Grain during the manufacturing process
A coagulation inhibitor may be added to prevent the coagulation of the particles.
Examples of the aggregation inhibitor include mannitol and lacto.
Glucose, starch, starches (eg, corn starch, etc.)
Water soluble polysaccharides such as, amino acids such as glycine, fibri
Proteins such as collagen and collagen are used. Na
Of these, mannitol is preferred. Also freeze-dried
Later, if necessary, the microcapsules are fused together under reduced pressure.
Water in microcapsules and
The organic solvent may be removed. Preferably 1 per minute
Obtained with a differential scanning calorimeter under the condition of a heating rate of 0 to 20 ° C.
From 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, it is about 3
Warm in the temperature range 0 ° C higher. In particular, biodegradation
When lactic acid-glycolic acid polymer is used as the water-soluble polymer
In the case of
Temperature range about 10 ℃ higher than glass transition temperature, more preferred
Specifically, the glass transition temperature above the midpoint glass transition temperature
Heat in a temperature range about 5 ° C higher than the temperature. My heating time is my
Generally depends on the amount of black capsules, etc.
Is about 1 after the microcapsules themselves reach a certain temperature.
2 hours to about 168 hours, preferably about 24 hours to about 12
0 hours, particularly preferably about 48 hours to about 96 hours
It As for the heating method, the assembly of microcapsules is heated uniformly.
The method is not particularly limited as long as it can be performed. The heating and drying method
For example, a constant temperature tank, a fluidized tank, a moving tank or a kill tank
Method of heating and drying in a microwave oven, method of heating and drying by microwave
The method is used. In this, heat dry in a constant temperature bath
Method is preferred. Also, the water content in the microcapsules
And the removal of the organic solvent are carried out by supercritical fluid (CO ₂Etc.)
Can also be performed by the method using carbon dioxide in high pressure gas state
it can. The desolvation treatment is performed under the high pressure gas state as described above.
A method using carbon oxide or the like is preferably adopted.

(II) Phase Separation Method When producing microcapsules by this method, a solution of the non-peptide bioactive substance, polyvalent metal (compound) and biodegradable polymer obtained in the above method in an organic solvent is used. Alternatively, a coacervation agent in which one kind or two or more kinds of polyvalent metals are dissolved is gradually added to the suspension with stirring to precipitate and solidify the microcapsules. The polyvalent metal is selected from those described above, for example, zinc caprylate,
One or a mixture of two or more selected from zinc enanthate, zinc caprylate, zinc caprate, zinc benzoate and zinc salicylate is preferable, and it is used after being dissolved in a concentration of about 0.1 to about 80 mM. The coacervation agent is about 0.01 to about 1,000 times the volume of the oil phase, preferably about 0.05.
To about 500 times, particularly preferably about 0.1 to about 200 times. The coacervation agent is not particularly limited as long as it is a high molecular compound, a mineral oil compound or a vegetable oil compound that is miscible with an organic solvent and does not dissolve both the physiologically active substance and the biodegradable polymer. In particular,
For example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-
Heptane or the like is used. You may use these in mixture of 2 or more types. The microcapsules thus obtained are separated, washed repeatedly with heptane or the like to remove coacervation agents other than the physiologically active substance and the biodegradable polymer, and dried under reduced pressure. Alternatively, after washing by the same method as the method described in the in-water drying method of (I) above, freeze-drying, further warm drying, desolvation with carbon dioxide or the like in a supercritical fluid or high-pressure gas state is performed. Good.

With the microcapsules or fine powders obtained here, the degradation rate of the biodegradable polymer used,
Drug release can be controlled according to the type and amount of polyvalent metal (compound). The sustained-release solid pharmaceutical composition of the present invention may be formulated into various dosage forms as it is or as a raw material, and may be injected into or injected into intramuscular, subcutaneous, organ, nasal cavity, rectum, uterus, etc. Transmucosal agents, inhalants, oral agents (eg, capsules (eg, hard capsules, soft capsules, etc.), granules, solid preparations such as powders, syrups, emulsions, etc.
It can be administered as a liquid such as a suspension).
It can also be administered by a needleless syringe.
For example, in order to prepare a sustained-release solid preparation obtained by the production method of the present invention as an injection, this is a dispersant (eg, Tween 80, a surfactant such as HCO-60, sodium hyaluronate, carboxy). Aqueous suspension with methylcellulose, polysaccharides such as sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, etc.), isotonicity agent (eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.) Alternatively, it can be dispersed with a vegetable oil such as sesame oil or corn oil to give a sustained-release injection that can be actually used as an oily suspension. The particle size of the sustained-release solid pharmaceutical composition of the present invention, when used as a suspension injection, may be within the range that satisfies its dispersity and needle-passing property, for example, an average particle size of about 0. .1 to 3
00 μm, preferably about 0.5 to 150 μm, and more preferably about 1 to 100 μm. Aseptic preparations of the sustained-release solid preparations obtained by the production method of the present invention include a method of sterilizing the production process, a method of sterilizing with gamma rays, and a method of combining these or a method of adding a preservative. However, it is not particularly limited.

Since the sustained-release solid preparation obtained by the production method of the present invention has low toxicity, it can be administered to mammals (eg, humans,
(Cattle, pigs, dogs, cats, mice, rats, rabbits, etc.) can be used as a safe medicine. The dose of the sustained-release solid pharmaceutical composition of the present invention depends on the type and content of the non-peptide bioactive substance which is the main drug, the dosage form, the release duration of the non-peptide bioactive substance, the target disease, the target animal, etc. Although it is different, an effective amount of the non-peptidic physiologically active substance may be used. The dose of the non-peptide physiologically active substance which is the main drug is, for example, preferably about 0.01 mg to about 10 mg / kg per adult when the sustained-release solid preparation is a one-month preparation. It can be appropriately selected from the range of body weight, more preferably from about 0.05 mg to about 5 mg / kg body weight. The dose of the sustained-release solid preparation per dose is preferably about 0.0 per adult.
It can be appropriately selected from the range of 5 mg to 50 mg / kg body weight, more preferably the range of about 0.1 mg to 30 mg / kg body weight.

The frequency of administration is once every several weeks and once per month.
Once or several months (eg, 3 months, 4 months, 6 months, etc.)
Once, etc., and can be appropriately selected depending on the type and content of the non-peptide bioactive substance, the dosage form, the duration of release of the non-peptide bioactive substance, the target disease, the target animal and the like. Further, the sustained-release solid preparation of the present invention can be applied to patients who are bedridden, dementia, throat / esophageal disease, digestive system diseases, patients with eating / swallowing disorders, and patients who are difficult or unable to treat with oral medication during surgery. It can be used advantageously. When the non-peptidic physiologically active substance is a compound having angiotensin II antagonistic action,
These are highly safe, and even if the blood concentration increases immediately after administration, the blood pressure does not fall too low. The sustained-release solid pharmaceutical composition of the present invention can be used as a therapeutic agent for the following diseases, and can maintain a certain blood concentration day and night, and therefore, when administered as an oral agent It is expected that the therapeutic effect will be more clear because the dose and frequency can be reduced compared to the above, the fluctuation of the drug concentration in blood is small, and there is no change in the medical condition due to discontinuation of administration. . Regarding safety, under normal use conditions, the risk of excessive blood pressure is less than for internal use due to the above reasons, but even if an excessive blood pressure is generated due to a situation involving a large amount of body fluid loss such as a traffic accident, Not only angiotensin II but also intravenous administration of drugs (catecholamines, etc.) usually used in emergency medical settings can immediately increase the blood pressure, and oral administration of hypotensive drugs can also continuously increase the blood pressure. Therefore, not only acute response in case of emergency but also long-term response is possible. The diseases targeted by the compound having angiotensin II antagonistic activity as a non-peptide bioactive substance include contraction and proliferation of blood vessels expressed through angiotensin II receptor and organ damage, the presence of angiotensin II, or angiotensin II. Diseases whose onset or onset is promoted by factors that are induced by the presence of II are mentioned. Examples of such diseases include hypertension, abnormal blood pressure circadian rhythm, heart disease (cardiac hypertrophy, chronic heart failure including acute heart failure and congestiveness, cardiomyopathy, angina, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc. ),
Cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient ischemic attack,
Stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), cerebral edema,
Cerebral circulatory disorders, recurrence of cerebrovascular disorders and sequelae (neurologic symptoms, psychotic symptoms, subjective symptoms, impairment of 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.), renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis , Organ damage including nephropathy due to irradiation), arteriosclerosis including atherosclerosis (aneurysm, coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular thickening, intervention (percutaneous coronary artery) Thickening or occlusion and organ damage after plastic surgery, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolysis, etc., reocclusion / restenosis after bypass surgery, polycythemia after transplantation・ High blood・ Organ damage / vascular thickening, rejection after transplantation, eye diseases (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, and other cardiovascular diseases (deep vein thrombosis) , Obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic vasculitis, ischemic cerebral circulation disorder, Raynaud's disease, Buerger's disease, etc., metabolic / nutrient disorders (obesity, hyperlipidemia, hypercholesterolemia) , Diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia, hypernatremia, etc.), 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 its sequelae / complications, head trauma, spinal cord injury, brain edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction,
Autonomic dysfunction, multiple sclerosis, etc.), dementia, memory disorder, consciousness disorder, amnesia, anxiety symptoms, tension symptoms, unpleasant mental states, mental disorders (depression, epilepsy, alcoholism, etc.), inflammatory Diseases (diabetic complications such as retinopathy, nephropathy, neuropathy, macroangiopathy; arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, and periosteitis);
Inflammation after trauma; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye disease; pneumonia, silicosis, lung Sarcoidosis, inflammatory lung diseases such as pulmonary tuberculosis, etc.), 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 (hepatitis including chronic, cirrhosis, etc.), portal hypertension, gastrointestinal disease (gastritis, gastric ulcer, gastric cancer, post gastric surgery disorder, dyspepsia) , Esophageal ulcer, pancreatitis, colorectal polyps, cholelithiasis, hemorrhoids, etc.),
Hematological / hematopoietic disorders (erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelopathy, etc.), bone disorders (eg, bone fracture, re-bone fracture, osteoporosis, osteomalacia) Disease, bone Pettet's disease, ankylosing myelitis, rheumatoid arthritis, joint tissue destruction in osteoarthritis of the knee and similar diseases, solid tumors, tumors (melanoma, malignant lymphoma, digestive organs (eg, stomach) , Intestine, etc.), cancer and associated cachexia, cancer metastasis, endocrine disease (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and male genitals Diseases (cystitis, benign prostatic hyperplasia, prostate cancer, sexually transmitted diseases, etc.), gynecological diseases (menopausal disorders, gestational poisoning, endometriosis, uterine fibroids, ovarian diseases, mammary gland diseases,
Sexually transmitted diseases), diseases caused by environmental / occupational factors (radiation damage, ultraviolet / infrared / laser ray damage, altitude sickness, etc.), respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis / pulmonary embolism) Etc.), infectious diseases (virus infections such as cytomegal virus, influenza virus, herpes virus, rickettsia infection, bacterial infection, etc.), toxicemia (sepsis, septic shock, endotoxic shock, gram-negative sepsis) , Toxin shock syndrome, etc.), ENT disease (Menuel syndrome, tinnitus, taste disorder, dizziness, imbalance, dysphagia, etc.), skin disease (keloid, hemangiomas, psoriasis, etc.), dialysis hypotension, myasthenia gravis, Systemic diseases such as chronic fatigue syndrome are mentioned. When the non-peptidic physiologically active substance is a compound having angiotensin II antagonism, by suppressing the action of angiotensin II for a long period of time, the biological functions and physiological actions that cause various diseases associated with adult diseases and aging are suppressed. The disorder or abnormality can be improved or suppressed, and primary or secondary prevention or progress of a disease or condition caused by these disorders can be suppressed. Examples of such disorders or abnormalities in biological functions and physiological actions include disorders or abnormalities in cerebral circulation / renal circulation autoregulation ability, circulatory disorders (peripheral, brain, microcirculation, etc.), disorders of the blood-brain barrier, insulin sensitivity. Decrease, salt sensitivity, coagulation / fibrinolysis system abnormalities, abnormal properties of blood / hemocyte components (enhanced platelet aggregation, abnormal red blood cell deformability, increased leukocyte adhesion, increased blood viscosity, etc.), growth factors and cytokines (PDGF) , VEGF, FGF, interlokin, TNF-α,
MCP-1) and inflammatory cell production and infiltration, free radical production, fat deposition promotion, endothelial dysfunction, endothelium, cell and organ disorders, edema, cell morphology such as smooth muscle Changes (morphological changes to proliferative type), production and hyperactivity of vasoactive substances and thrombus-inducing substances (endothelin, thromboxane A _2, etc.), abnormal contraction of blood vessels, abnormal glucose tolerance, abnormal metabolism (abnormal serum lipids) , Abnormal blood glucose, etc.), abnormal proliferation of cells, etc., angiogenesis (including abnormal angiogenesis in abnormal atherosclerotic adventitial adventitia network formation), among others, associated with various diseases Primary and secondary preventive / therapeutic agents for organ disorders (eg, cerebrovascular disorders and organ disorders associated therewith, organ disorders associated with cardiovascular disease, organ disorders associated with diabetes mellitus, organ disorders associated with intervention, etc.) To, it can be advantageously used. In the sustained-release solid pharmaceutical composition of the present invention, the non-peptidic physiologically active compound is a compound having an angiotensin II antagonistic action (particularly, candesartan cilexetil,
Candesartan), prevent portal hypertension
It can be advantageously used as a therapeutic agent. Rupture of esophageal varices occurs frequently at night (Hepatology 1994; 19: 595-60)
It is known that 1), and because this drug can maintain a constant blood concentration day and night, it is possible to reduce the dose and frequency compared to when administered orally. Not only that, but there is little fluctuation in blood drug concentration, so a stable reduction in portal vein pressure can be expected. The above features of this drug indicate its usefulness as a preventive agent for rupture of varicose veins in the esophagus and stomach. In addition, it is expected that the therapeutic effect will be more clear because the medical condition will not change due to discontinuation of administration. Furthermore, angiotensin as a physiologically active compound
Compounds having II antagonism (in particular, candesartan cilexetil, candesartan, etc.) can be treated with HGF (Hepatocy
teGrowth Factor: Hepatocyte growth factor) is expected to be effective in promoting production, and can be expected to contribute to liver regeneration and liver brain recovery. In addition, a compound having an angiotensin II antagonistic action as a non-peptide bioactive substance (particularly,
Candesartan cilexetil, candesartan, etc.)
It is also expected that the effect of preventing / treating cerebral vascular disorders such as cerebral infarction will be more clarified by maintaining the blood concentration of A. When the non-peptidic physiologically active substance is a compound having an angiotensin II antagonism, the method for treating a patient is to administer an oral administration agent of an angiotensin II antagonist for a certain period of time, and after confirming the reactivity of the patient, the present invention It is also conceivable to administer a sustained release preparation of
The orally administered angiotensin II antagonist and the angiotensin II antagonist contained in the sustained-release preparation may be the same or different. In addition, antihypertensive agents other than angiotensin II antagonists (calcium antagonists, diuretics,
Beta blocker or the like) may be orally administered in advance to confirm the reactivity of the patient, and then the sustained release preparation of the present invention may be administered. Further, a diuretic antihypertensive agent (oral preparation) which is usually used in combination with the sustained-release solid pharmaceutical composition of the present invention and an angiotensin II antagonist
You may use together.

In addition, other lipid-lowering drugs or cholesterol-lowering drugs, HMG-Co A reductase (3-hydroxy-
3-methylglutarylcoenzyme A reductase) inhibitor, insulin sensitizer, bone disease therapeutic agent, myocardial protective agent, coronary artery disease therapeutic agent, other hypertension therapeutic agent, chronic heart failure therapeutic agent, diabetes therapeutic agent, liver disease therapeutic agent, stomach / Others including therapeutic agent for duodenal ulcer, therapeutic agent for biliary tract disease, therapeutic agent for hypothyroidism, therapeutic agent for nephrotic syndrome, therapeutic agent for chronic renal failure, therapeutic agent for gynecological disease, therapeutic agent for urinary and male genital diseases, or therapeutic agent for infectious diseases May be used with any of the pharmaceutical ingredients of
In this case, these compounds may be administered as an oral preparation, or may be optionally administered as a rectal preparation in the form of suppositories. Possible combination components in this case are:
For example, fibrates [eg, clofibrate, benzafibrate, gemfiprozil, etc.], nicotinic acid,
Derivatives and analogs thereof (eg, acipimox and probucol), bile acid-binding resins [eg, cholestyramine,
Cholestipol, etc.], compounds that suppress cholesterol absorption [eg, sitosterol, neomycin, etc.], squalene epoxidase inhibitors [eg, NB-598 and related compounds]. Further possible combination components are oxidosqualene-lanosterol cyclases, such as decalin derivatives, azadecalin derivatives and indane derivatives. Further, combinations with the following various therapeutic agents are also possible. Antihypertensive: Diuretics [eg, Furosemide (Lasix), Bumetanide (Renetron), Azosemide (Diart)], Antihypertensives [eg, ACE inhibitors, (enalapril maleate (renibase), etc.) and Ca antagonists (Manidipine, etc.) Amlodipine, etc., α or β receptor blockers, etc.); Chronic heart failure therapeutic agents: Cardiotonic drugs [eg, cardiac glycosides (such as digoxin), β receptor stimulants (catecholamines such as denopamine and dobutamine) and PDEs] Inhibitors, etc., diuretics [eg, furosemide (Lasix), spironolactone (aldactone), etc.], ACE inhibitors,
[Eg, enalapril maleate (renibase), etc.],
Ca antagonists (eg, amlodipine, etc.) and β receptor blockers; Antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride, β blockers, Ca antagonists, etc .; Bone disease treatment Drugs: calcium preparations (eg calcium carbonate etc.), calcitonin preparations, active vitamin D ₃ preparations (eg alfacalcidol (alpha roll etc.),
Calcitriol (locartrol), etc., sex hormones (eg, estrogen, estradiol, etc.), hormone preparations (eg, conjugated estrogen (premarin), etc.), ibriflavone preparations (such as Osten), vitamin K ₂ , vitamins K ₂ preparations [eg, menatetrenone (Graquette)], bisphosphonic acid preparations (etidronate, etc.), prostaglandin E2, fluorine compounds (eg, 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 factor-1 and 2 (IGF-1,
-2), parathyroid hormone (PTH), European Patent Publication EP-A1-376197, EP-A1-4.
Compounds described in JP-A-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
ide etc); Antidiabetic: Actos, Rogiglidason, Kinedac, Benfil, Humarin, Euglucon, Glymicron, Daoneyl, Novolin, Monotard, Insulin, Glucobay, Dimerin, Rastinone, Basilcon, Deamerin S, Isdirin, etc .; Liver Disease therapeutic agents: glycyrrhizin preparations [eg, strong minophagen, etc.], liver hydrolysates, SH compounds [eg, glutathione, etc.], special amino acid preparations [eg, aminolevane, etc.], phospholipids [eg, polyenphosphatidylcholine, etc.], vitamins [ Examples, vitamins B1, B2, B6, B12, C, etc.], adrenocortical hormones (eg, dexamethasone, betamethasone, etc.), interferons (eg, interferon α, β, etc.), hepatic encephalopathy therapeutic agents (eg, lactulose, etc.), Hemostatic agents used when the esophagus or gastric varices are ruptured (eg, Vasopressin, somatostatin, etc.]; Gastric / duodenal ulcer therapeutic drug Therapeutic agent: antacid [eg, histamine H2 antagonist (cimetidine etc.), proton pump inhibitor (lansoprazole etc.)]; [Eg, dehydrocholic acid, etc.],
Bile-removing agents [eg, magnesium sulfate, etc.]; Hypothyroid drug: Dry thyroid (threoid),
Levothyroxine sodium (tyrazine S), liothyronidine sodium (thyronine, thyromine), etc .; Nephrotic syndrome drug: Usually, prednisolone (predonin), prednisolone sodium succinate (predonin) is used as the first-choice steroid therapy. , Sodium methylprednisolone succinate (sol medrol), betamethasone (linderone), etc. are used. For anticoagulant therapy, antiplatelet agents such as dipyridamole (versantine), dilazep hydrochloride (comelian), ticlopidine, clovidogrel, and FXa inhibitors and anticoagulants are used; HMG-Co A 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, etc .; Remedies for chronic renal failure: diuretics [eg, Furosemide (Lasix), Bumetanide (Runetron), Azosemide (Diart)], antihypertensive drug (eg, ACE inhibitor, (enalapril maleate (renibase)) and Ca antagonist (manidipine), α receptor blocker in combination When administered, it can be used preferably orally. Thrombosis preventive and therapeutic agents: anticoagulants [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), blood coagulation factor Xa inhibitors and coagulation fibrinolytic system] Drugs with balance correction function], thrombolytic drugs [eg, tPA, urokinase], antiplatelet drugs [eg. ,
Aspirin, Sulfinpyrazolo (Anturan), Dipyridamole (Persanthin), Ticlopidine (Panaldine), Cilostazol (Pletal), GPIIb / IIIa
Antagonists (Leopro)] and other coronary vasodilators: Nifedipine, diltiazem, nicorazil, nitrite, etc. Myocardial protective agents: Cardiac ATP-K openers, Na-H exchange inhibitors, endothelin antagonists, urotensin antagonists, etc. Inflammatory drugs: aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (eg, indomethacin, etc.), steroid drugs (eg, dexamethasone, etc.) Antiallergic drugs: antihistamines (eg, chlorpheniramine maleate, etc.), stimulation therapy Agents (eg, bucillamine, etc.), other azelastine hydrochloride, seratrodast, tranilast, oxatomide, potent neominophagen C, tranexamic acid, ketotifen fumarate, etc. antitumor agents: alkylating agents, antimetabolites, antitumor antibiotic preparations, antitumors Tumorous botanical components and other anti-tumor drugs, etc. CNS agonists: anti-anxiety agents, hypnotic sedatives, anesthetics, anticonvulsants, autonomic nerve agents, anti-Parkinson's agents and other neuropsychiatric agents, etc. Gynecological disease therapeutic agents: [eg, menopausal agents ( Conjugated estrogens, estradiol, testosterone enanthate, valerate estradiol, etc.), breast cancer therapeutic agents (tamoxifen citrate, etc.), endometriosis / uterine fibroid treatment agents (leuprorelin acetate, danazol, etc.)], etc. Disease treatment: [eg, prostatic hypertrophy treatment (tamsulosin hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.), prostate cancer (leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.), etc. Infectious disease treatment drug: [eg, Antibiotics (cefatium hydrochloride, cefozopran hydrochloride, ampicillin, etc.), chemotherapeutic agents (sulfa drugs, Synthetic antibacterial agents, antiviral agents, etc.),
Biological agents (vaccines, blood products such as immunoglobulins), etc.] and other anti-obesity agents (such as mazindol), anti-rheumatic agents, etc., and treatment by various factors derived from the living body or gene transfer thereof (eg, HGF, angiogenesis-promoting factors such as VEGF, ischemic disease treatment by gene transfer thereof, etc.) or treatment with decoy nucleic acid, etc. When these agents are used in combination with the sustained-release solid pharmaceutical composition of the present invention, each drug May be blended in one sustained release formulation, but the above drug is formulated by mixing with a pharmacologically acceptable carrier, excipient, binder, diluent, etc.
The sustained-release solid pharmaceutical composition of the present invention can be administered separately or simultaneously. If the drugs were formulated separately,
Separately formulated products can be mixed and administered using a diluent etc. at the time of use, but individual formulations formulated separately can be administered to the same subject simultaneously or separately with a time lag. May be.

[0043]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Reference Examples, Examples, Comparative Examples and Experimental Examples, but these do not limit the present invention.

[0044]

EXAMPLES Reference Example 1 Increase in solubility of sparingly water-soluble non-peptidic physiologically active compound by addition of metal compound
Table 1 shows the amount of a solvent (dichloromethane / methanol = 7/3) capable of dissolving 0.1 g of 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (hereinafter abbreviated as compound A). .

[Table 1]

Example 1 Compound A 2 g and zinc acetate dihydrate (manufactured by Wako Pure Chemical Industries)
0.996 g and polylactic acid (weight average molecular weight 14,500, manufactured by Wako Pure Chemical Industries, Ltd.) 3.67 g were added to a solution prepared by dissolving 7.5 ml of dichloromethane and 3.5 ml of methanol, and the mixture was shaken and stirred at room temperature for 2 hours to obtain a uniform solution. Obtained. Pre-mix this solution 15
The mixture was poured into 800 ml of a 0.1% by weight polyvinyl alcohol aqueous solution adjusted to 0 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O
The / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and methanol to solidify the oil phase, and then collected at 2,000 rpm using a centrifuge. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were obtained as a powder by adding distilled water in which a small amount of mannitol was dissolved and redispersing, and then freeze-drying. The encapsulation rate of Compound A in microcapsules was 101.6%, and the content of Compound A in microcapsules was 2
It was 6.6%.

Example 2 Compound A 2 g and zinc acetate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.)
757 g and zinc oxide (TYPE V Wako Pure Chemical Industries, Ltd.) 0.277 g polylactic acid (weight average molecular weight 14,500, Wako Pure Chemical Industries Ltd.)
3.64 g of dichloromethane 7.5 ml and methanol 3.5 ml
Microcapsules were obtained in the same manner as in Example 1 except that the homogeneous solution obtained by adding to the solution dissolved in was added.
The encapsulation rate of Compound A in the microcapsules was 101.9%,
The content of Compound A in the microcapsules was 25.9%.

Example 3 Compound A (2 g) and zinc acetate (manufactured by Wako Pure Chemical Industries, Ltd.) 0.996 g were mixed with lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/2
3 (5 (mol%), weight average molecular weight 10,600, manufactured by Wako Pure Chemical Industries, Ltd.) was added to a solution dissolved in 7 ml of dichloromethane and 3 ml of methanol to obtain a uniform solution. This was cast on a flat plate in a circular shape having a radius of about 5 cm, and dried under reduced pressure at room temperature for 16 hours to obtain a dried product. Coarse pulverization of this dried product on a sieve having a pore size of 150 mm, 3.6 g of the dried product obtained by sieving and mannitol 0.
After mixing with 4 g, a jet mill device (A-OJET, manufactured by Seishin Enterprise Co., Ltd.) was used to perform gas pulverization at an air pressure of 2 kg / cm ² to obtain fine particles having an average particle diameter of 21 mm. The content of Compound A in the microparticles was 29.1%.

Experimental Example 1 25 mg of the microcapsules obtained in Examples 1 and 2 were added to 0.1
Disperse in 5 ml of dispersion medium (5 mg sodium carboxymethylcellulose, 1 mg polysorbate 80, 50 mg mannitol dissolved in 1 ml distilled water) and subcutaneously inject 20G needle into the back of the neck of 7-week-old male SD rats. Was administered.
After administration, blood was removed from the rat abdominal aorta over time and sacrificed, and then the microcapsules remaining at the administration site were taken out,
Table 2 shows the residual ratios of the compounds calculated by quantifying the compounds therein.

[0049]

[Table 2]

Comparative Example 1 2-Ethoxy-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (hereinafter abbreviated as compound A) 2.0 g and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%) , Weight average molecular weight 8,700,
Wako Pure Chemical Industries, Ltd.) 3.97 g of dichloromethane 12.75 ml
, 2.25 ml of methanol and 0.136 mL of acetic acid, and the mixture was shaken and stirred overnight at room temperature to obtain a suspension. This suspension was poured into 800 ml of a 0.1 wt% polyvinyl alcohol aqueous solution which had been adjusted to 18 ° C. in advance, and a S / O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. The S / O / W emulsion was stirred at room temperature for 3 hours to evaporate dichloromethane, methanol and acetic acid,
After solidifying the polymer, 3,000 rpm using a centrifuge
It was collected in. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 100%.

Comparative Example 2 Compound A 2.0 g, zinc oxide (manufactured by Shiramizu Chemical Industry Co., Ltd.) 0.37 g
And lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 8,700, manufactured by Wako Pure Chemical Industries) 3.6 g in a mixture of dichloromethane 12.75 ml, methanol 2.25 ml and acetic acid 0.136 mL. Add and stir overnight at room temperature with shaking to obtain a homogeneous solution. This solution in advance
The mixture was poured into 800 ml of a 0.1% by weight polyvinyl alcohol aqueous solution adjusted to 18 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the polymer and then collected at 3,000 rpm using a centrifuge.
This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 90.5%, and the content of Compound A in the microcapsule / mannitol powder was 26.4%.

Comparative Example 3 Compound A 1.5 g, zinc oxide (manufactured by Shiramizu Chemical Industry Co., Ltd.) 0.278 g
And 2.7 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 10,500, manufactured by Wako Pure Chemical Industries) were added to a mixed liquid of dichloromethane 11.25 ml, methanol 1.69 ml and acetic acid 0.102 mL. Then, the mixture was shaken and stirred at room temperature overnight to obtain a uniform solution. This solution in advance 1
The mixture was poured into 800 ml of a 0.1% by weight polyvinyl alcohol aqueous solution adjusted to 8 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O
The / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the polymer, which was then collected using a centrifuge at 3,000 rpm.
This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 93.1%, and the content of Compound A in the microcapsule / mannitol powder was 26.8%.

Example 4 2.0 g of Compound A and a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 8,7)
00, Wako Pure Chemical Industries, Ltd.) 3.97 g of dichloromethane 12.75
ml, 2.25 ml of methanol and 0.136 ml of acetic acid were added, and the mixture was shaken and stirred overnight at room temperature to obtain a suspension. Add 30 mM zinc acetate that had been adjusted to 18 ℃ to this suspension.
Pour into 800 ml of 0.1 wt% polyvinyl alcohol aqueous solution and use a turbine type homomixer at S / rpm at 7,000 rpm.
It was an O / W emulsion. This S / O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the polymer and then collected at 3,000 rpm using a centrifuge. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 94.9%.

Example 5 Compound A 2.0 g, zinc oxide (manufactured by Shiramizu Chemical Industry Co., Ltd.) 0.37 g
And lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 8,700, manufactured by Wako Pure Chemical Industries, Ltd.) 3.6 g in a mixture of dichloromethane 12.75 ml, methanol 2.25 ml and acetic acid 0.136 mL. Add and stir overnight at room temperature with shaking to obtain a homogeneous solution. This solution in advance
The mixture was poured into 800 ml of a 0.1% by weight aqueous polyvinyl alcohol solution containing 10 mM zinc acetate adjusted to 18 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the oil phase, and then use a centrifuge to spin at 3,000 rpm.
It was collected in. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 90.7%, and the content of Compound A in the microcapsule / mannitol powder was 26.4%.

Example 6 2.0 g of compound A, 0.37 g of zinc oxide (manufactured by Hakusui Chemical Co., Ltd.)
And lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 8,700, manufactured by Wako Pure Chemical Industries, Ltd.) 3.6 g of dichloromethane 12.75 ml, methanol
It was added to a mixed solution of 2.25 ml and 0.136 ml of acetic acid, and the mixture was shaken and stirred overnight at room temperature to obtain a uniform solution. This solution in advance 1
The mixture was poured into 800 ml of a 0.1% by weight aqueous polyvinyl alcohol solution containing 30 mM zinc acetate adjusted to 8 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the oil phase, and then use a centrifuge to spin at 3,000 rpm.
It was collected in. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 92.2%, and the content of Compound A in the microcapsule / mannitol powder was 26.6%.

Example 7 Compound A 1.5 g, zinc oxide (manufactured by Shiramizu Chemical Industry Co., Ltd.) 0.278 g
And 2.7 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 10,500, manufactured by Wako Pure Chemical Industries) were added to a mixed liquid of dichloromethane 11.25 ml, methanol 1.69 ml and acetic acid 0.102 mL. Then, the mixture was shaken and stirred at room temperature overnight to obtain a uniform solution. This solution in advance 1
The mixture was poured into 800 ml of a 0.1% by weight polyvinyl alcohol aqueous solution containing 30 mM zinc acetate adjusted to 8 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. The O / W emulsion was stirred at room temperature for 3 hours to strip off dichloromethane, methanol and acetic acid,
After solidifying the oil phase, it was collected at 3,000 rpm using a centrifuge. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 88.0%, and the content of Compound A in the microcapsule / mannitol powder was 25.4%.

Example 8 Compound A 2 g, zinc oxide (manufactured by Shiramizu Chemical Industry Co., Ltd.) 0.37 g
And 3.6 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 8,700, manufactured by Wako Pure Chemical Industries, Ltd.) in a mixed liquid of dichloromethane 12.75 ml, methanol 2.25 ml and acetic acid 0.136 mL. Add and stir overnight at room temperature with shaking to obtain a homogeneous solution. This solution in advance
The mixture was poured into 800 ml of a 0.1% by weight aqueous polyvinyl alcohol solution containing 10 mM zinc acetate adjusted to 18 ° C., and an O / W emulsion was prepared at 7,000 rpm using a turbine homomixer. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, methanol and acetic acid to solidify the oil phase, and then centrifuge to obtain 3,000 rp.
collected by m. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. The collected microcapsules were redispersed by adding distilled water in which 0.8 g of mannitol was dissolved, and then freeze-dried to obtain a powder. The encapsulation rate of Compound A in the microcapsules was 89.1%, and the content of Compound A in the microcapsule / mannitol powder was 26.2%.

Experimental Example 2 The zinc content in the microcapsules obtained in Comparative Examples 1, 2, 3 and Examples 4, 5, 6, 7 was measured by the following method. That is, the zinc concentration in the liquid obtained by heating and ashing each microcapsule and then dissolving in hydrochloric acid aqueous solution was measured with an atomic absorption spectrophotometer (Z-8000 polarized Zeeman atomic absorption spectrophotometer, Hitachi, Ltd.) and weighed with a micrometer. The zinc content in the microcapsules was calculated by correcting for the capsule weight. Table 3 shows the zinc content in the microcapsules.

[Table 3] As for the zinc content in the microcapsules produced by adding zinc acetate to the external water phase, an increase in zinc content of at least 0.1% or more was observed as compared with the one produced without addition of zinc acetate.

Experimental Example 3 About 5 mg of the microcapsules obtained in Comparative Example 1 and Example 4 was added to 10 mL of the release test solution (1 / 150M phosphate buffer solution), and the mixture was stirred and mixed at room temperature for 1 minute. 3000
Compound A in the supernatant obtained by centrifugation at 10 rpm for 10 minutes
The concentration was measured by liquid chromatography. The amount of Compound A released in the release test solution calculated from the concentration of Compound A in the supernatant was measured separately.
The in vitro initial release rate from each microcapsule was determined by dividing by the amount. The obtained in vitro initial release rate is shown in Table 4.

[0060]

[Table 4] The initial drug release from microcapsules prepared by adding zinc acetate to the external water phase is about the same as that prepared without addition.
It was reduced to 30% or less, which shows the characteristics of the composition of the present invention.

Experimental Example 4 Microcapsules 25 obtained in Comparative Example 2 and Example 5
mg to 0.2 ml dispersion medium (5 mg sodium carboxymethylcellulose, 1 mg polysorbate 80, 50 m
The mannitol (g) was dispersed in distilled water (1 ml) and the solution was administered subcutaneously to the back of the neck of 7-week-old male SD rats with a 22G injection needle. Blood was collected from the rat tail vein over time after administration, and the obtained drug concentration in plasma was measured. Microcapsule administration
The area under the drug-time curve up to 24 hours is shown in Table 5.

[0062]

[Table 5] The initial drug release from microcapsules prepared by adding zinc acetate to the external water phase is about the same as that prepared without addition.
It was reduced to 20% or less, which shows the characteristics of the composition of the present invention.

Experimental Example 5 Microcapsules 25 obtained in Comparative Example 3 and Example 7
mg to 0.2 ml dispersion medium (5 mg sodium carboxymethylcellulose, 1 mg polysorbate 80, 50 m
The mannitol (g) was dispersed in distilled water (1 ml) and the solution was administered subcutaneously to the back of the neck of 7-week-old male SD rats with a 22G injection needle. Blood was collected from the rat tail vein over time after administration, and the obtained drug concentration in plasma was measured. The area under the drug-time curve up to 24 hours after microcapsule administration is shown in Table 6.

[Table 6] The initial drug release from microcapsules prepared by adding zinc acetate to the external water phase was reduced to about 40% or less as compared with those prepared without addition, showing the characteristics of the composition of the present invention. It was

[0064]

EFFECTS OF THE INVENTION (1) Biodegradable polymer in the absence of a polyvalent metal compound, which is a feature of the present invention, an amount of a poorly water-soluble non-peptidic physiologically active compound or a polyvalent metal which exceeds the solubility in an organic solvent. The method of using an organic solvent solution containing a compound and a biodegradable polymer is suitable for the production of injectable preparations because it can be easily sterilized in the production process by filtration with a filter, Since the distribution of the sparingly water-soluble non-peptide bioactive compound is uniform,
A stable sustained release effect can be obtained. When a poorly water-soluble non-peptidic physiologically active compound is an angiotensin II antagonistic compound, the concentration in the blood can be maintained at a certain level, and therefore the drug concentration in blood is less fluctuated and stable compared to when it is administered orally. Continued pharmacological action can be expected. Therefore, aggravation of the medical condition due to intentional avoidance such as fluctuation of dosing time or discontinuation of dosing in a group of patients with few subjective symptoms is unlikely to occur, and hypertension, abnormal blood pressure circadian fluctuation, and heart disease (cardiac hypertrophy,
Heart failure, myocardial infarction, etc., cerebrovascular disorder (symptomatic cerebral infarction, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), ischemic peripheral circulation disorder, myocardial ischemia, cardiomyopathy , Venous insufficiency, progression of heart failure after myocardial infarction, sequela of cerebrovascular accidents, diabetic complications, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulonephritis, irradiation nephropathy, arteriosclerosis Disease, vascular thickening, vascular thickening or occlusion after intervention, revascularization after bypass surgery, erythrocytosis / hypertension / organ damage / vascular thickening after transplantation, rejection after transplantation, hyperaldosteronism, glomerulosclerosis , Renal failure, glaucoma, ocular hypertension, hyperlipidemia, angina,
Aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, central nervous system disease, Alzheimer's disease, memory deficiency, depression, amnesia, senile dementia, sensory dysfunction,
Multi-organ failure, endothelial dysfunction, hypertensive tinnitus, Menuel syndrome, dizziness or scleroderma, or anxiety symptoms,
It is expected that the therapeutic effects of tension symptom, unpleasant mental state, dyspepsia, autonomic dysfunction, myasthenia gravis or cancer and cancer-related diseases will become clearer. (2) In the composition containing the non-peptide bioactive substance and the biodegradable polymer of the present invention, about 0.05% by weight or more of the weight of the composition is present on the surface of the polyvalent metal. The sustained-release solid pharmaceutical composition can suppress the initial release to 60% or less compared to when the polyvalent metal is not present on the surface. Depending on the non-peptidic physiologically active substance used, when an excessively large amount is released in the initial stage, there are some effects which are inconvenient for the living body such as a decrease in blood glucose or a decrease in blood pressure, and the effect of suppressing the release is large. In particular,
When the non-peptidic physiologically active substance is a compound having an angiotensin II antagonistic action, there is a risk that blood pressure may be excessively lowered due to an initial excessive drug release, and the effect of inhibiting the initial release is significant in the sense that it suppresses it. To have. When the pharmaceutical composition of the present invention contains a compound having angiotensin II antagonism, the blood drug concentration is stable and stable as compared with the case where it is administered as an oral agent because a certain blood concentration can be maintained. Continued pharmacological action can be expected.
Therefore, it is difficult to cause deterioration of the condition due to intentional avoidance such as fluctuation of dosing time and interruption of dosing in a group of patients with few subjective symptoms, hypertension, abnormal blood pressure circadian fluctuation, heart disease (heart hypertrophy, heart failure, Myocardial infarction, etc., cerebrovascular disorder (asymptomatic cerebral infarction, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), ischemic peripheral circulation disorder, myocardial ischemia, cardiomyopathy, vein Dysfunction, progression of heart failure after myocardial infarction,
Not only cerebrovascular accident sequelae, diabetic complications, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulonephritis, irradiation-induced nephropathy, arteriosclerosis, vascular thickening, vascular thickening after intervention or Occlusion, re-occlusion of blood vessels after bypass surgery, polycythemia vera after transplantation, hypertension, organ damage,
Vascular hypertrophy, rejection after transplantation, hyperaldosteronism, glomerulosclerosis, renal failure, glaucoma, ocular hypertension, hyperlipidemia, angina, aneurysm, coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteries Sclerosis, thrombosis, central nervous system disease, Alzheimer's disease,
Memory deficiency, depression, amnesia, senile dementia, sensory dysfunction, multiple organ dysfunction, endothelial dysfunction, hypertensive tinnitus, Menuel syndrome, dizziness or scleroderma, or anxiety, tension, discomfort It is expected that the therapeutic effect on dyspepsia, autonomic dysfunction, myasthenia gravis or cancer and cancer-related diseases will become clearer.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 45/00 A61K 45/00 47/02 47/02 47/12 47/12 47/30 47/30 47 / 34 47/34 47/46 47/46 A61P 1/00 A61P 1/00 3/10 3/10 7/00 7/00 9/00 9/00 9/08 9/08 9/10 9/10 9 / 12 9/12 13/12 13/12 19/00 19/00 25/00 25/00 25/28 25/28 27/02 27/02 27/16 27/16 29/00 29/00 101 101 35 / 00 35/00 37/06 37/06 37/08 37/08 43/00 111 43/00 111 F term (reference) 4C076 AA61 AA94 BB11 CC01 CC11 CC21 CC27 DD21Q DD41Q EE01A EE24A FF16 FF33 GG21 4C084 AA17 MA22 MA38 MA66 NA12 ZA01 ZA02 ZA15 ZA33 ZA34 ZA36 ZA361 ZA362 ZA39 ZA42 ZA421 ZA422 ZA45 ZA51 ZA66 ZA81 ZA96 ZB08 ZB11 ZB13 ZB15 ZB26 ZC35 4C086 AA01 AA02 BC39 BC62 BC71 MA03 ZA45 ZA45 ZA45 ZA45 ZA45 MA22 MA38 ZB08 ZB11 ZB13 ZB15 ZB26 ZC35

Claims (61)

[Claims] 1. A biodegradable polymer in the absence of a polyvalent metal compound, which contains a poorly water-soluble non-peptidic bioactive compound, a polyvalent metal compound and a biodegradable polymer in an amount exceeding the solubility in an organic solvent. A method for producing a sustained-release preparation, which comprises removing the solvent from the organic solvent solution. 2. The method according to claim 1, wherein the poorly water-soluble non-peptidic physiologically active compound has a molecular weight of about 2000 or less. 3. The method according to claim 1, wherein the poorly water-soluble non-peptidic physiologically active compound has a functional group capable of forming a complex salt with a polyvalent metal compound. 4. The method according to claim 3, wherein the functional group is a group capable of donating a shared electron pair. 5. The method according to claim 3, wherein the functional group is a group having one or more hetero atoms selected from oxygen atom, nitrogen atom and sulfur atom. 6. The functional group is (1) carboxyl group, (2) imidazolyl group, (3) mercapto group, (4) amino group, (5) tetrazolyl group, (6) trifluoromethanesulfonamide group, (7)
An optionally substituted 5- to 7-membered monocycle having one or more heteroatoms selected from a phosphoric acid group, (8) sulfonic acid group and (9) oxygen atom, nitrogen atom and sulfur atom. The method according to claim 3, which is a group selected from heterocyclic residues. 7. The poorly water-soluble non-peptidic physiologically active compound has a functional group having a pKa of about 2.5 to about 6.
The manufacturing method described. 8. The method according to claim 1, wherein the poorly water-soluble non-peptidic physiologically active compound is a compound having angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. 9. The method according to claim 8, wherein the compound having angiotensin II antagonistic activity is a compound having an oxygen atom in its molecule. 10. The method according to claim 8, wherein the compound having angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group. 11. A compound having angiotensin II antagonistic activity is represented by the formula (I): (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents a spacer having 2 or less atoms in a bond or a straight chain portion, n represents 1 or 2, and a 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 which can be converted into an anion, and R ³ represents a hydrocarbon residue which may have a substituent. 9. The production method according to claim 8, wherein the hydrocarbon residue is a compound represented by the formula (3), wherein the hydrocarbon residue may be bonded via a heteroatom). 12. A compound having angiotensin II antagonistic activity, a prodrug thereof or a salt thereof is losartan, losartan potassium, eprosartan, candesartan.
The production method according to claim 8, which is cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomil or tasosartan. 13. A compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. The manufacturing method according to claim 8. 14. A compound having angiotensin II antagonistic activity is 1- (cyclohexyloxycarbonyloxy).
The production method according to claim 8, which is ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7-carboxylate. 15. A compound having an angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-
9. The process according to claim 8, which is yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. 16. The method according to claim 1, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. 17. The method according to claim 16, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer. 18. The method according to claim 17, wherein the lactic acid-glycolic acid polymer has a composition molar ratio of lactic acid to glycolic acid of 100/0 to 40/60. 19. A polymer having a weight average molecular weight of 3,000 to.
The production method according to claim 16, which is 50,000. 20. The method according to claim 1, wherein the sustained-release preparation is for injection. 21. The method according to claim 1, wherein the polyvalent metal is zinc. 22. The method according to claim 21, wherein the polyvalent metal compound is one or two of zinc acetate and zinc oxide. 23. The method according to claim 1, wherein the molar ratio of the polyvalent metal compound to the poorly water-soluble non-peptidic physiologically active compound in the organic solvent solution is 1/10 to 10/1. 24. The concentration of a poorly water-soluble non-peptidic physiologically active compound in an organic solvent solution is about 0.5 to about 70% by weight.
The method according to claim 1, wherein 25. The concentration of the biodegradable polymer in the organic solvent solution is about 0.5 to about 70% by weight.
The manufacturing method described. [26] A sustained-release preparation obtained by the production method according to [1]. 27. The sustained-release preparation according to claim 26, wherein the poorly water-soluble non-peptidic physiologically active compound is a compound having angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. 28. A medicine comprising the sustained release preparation according to claim 26. 29. The medicine according to claim 28, which is a prophylactic / therapeutic agent for cardiovascular diseases. 30. The medicine according to claim 28, which is a prophylactic / therapeutic agent for hypertension, abnormal circadian rhythm of blood pressure or organ disorder. 31. Biodegradable polymer in the absence of a polyvalent metal compound An amount of a sparingly water-soluble non-peptidic physiologically active compound, a polyvalent metal compound and a biodegradable polymer which exceeds the solubility in an organic solvent solution. An organic solvent solution containing. 32. Use of a polyvalent metal compound for increasing the solubility of a poorly water-soluble non-peptidic bioactive compound in an organic solvent solution of a biodegradable polymer. 33. The solubility of a poorly water-soluble non-peptidic physiologically active compound in an organic solvent solution containing a biodegradable polymer, an organic solvent and a poorly water-soluble non-peptidic physiologically active compound is determined by using a polyvalent metal compound. How to increase. 34. A composition comprising a non-peptidic physiologically active substance and a biodegradable polymer, wherein the polyvalent metal is present on the surface of the composition in an amount of about 0.05% by weight or more based on the weight of the composition. Releaseable solid pharmaceutical composition. 35. The sustained-release solid pharmaceutical composition according to claim 34, wherein the initial release of the non-peptidic physiologically active substance is suppressed to about 60% or less as compared with when the polyvalent metal is not present on the surface. 36. The sustained-release solid pharmaceutical composition according to claim 34, wherein the non-peptidic physiologically active substance has a molecular weight of about 2000 or less. 37. The sustained-release solid pharmaceutical composition according to claim 34, wherein the non-peptide bioactive substance is a poorly water-soluble compound. 38. The sustained-release solid pharmaceutical composition according to claim 34, wherein the non-peptidic physiologically active substance is a compound having angiotensin II antagonistic action, a prodrug thereof or a salt thereof. 39. The compound having an angiotensin II antagonistic action is a compound having an oxygen atom in the molecule.
8. The sustained-release solid pharmaceutical composition according to item 8. 40. The sustained-release solid pharmaceutical composition according to claim 38, wherein the compound having angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group. 41. A compound having angiotensin II antagonistic activity is represented by the formula (I): (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents a spacer having 2 or less atoms in a bond or a straight chain portion, n represents 1 or 2, and a 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 which can be converted into an anion, and R ³ represents a hydrocarbon residue which may have a substituent. 39. The sustained-release solid pharmaceutical composition according to claim 38, which is a compound represented by a group, wherein the hydrocarbon residue may be bound via a heteroatom). 42. A compound having angiotensin II antagonism, a prodrug thereof or a salt thereof is losartan, losartan potassium, eprosartan or candesartan.
39. The sustained-release solid pharmaceutical composition according to claim 38, which is cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomil or tasosartan. 43. The compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. 39. The sustained release solid pharmaceutical composition according to claim 38. 44. A compound having angiotensin II antagonistic activity is 1- (cyclohexyloxycarbonyloxy).
39. The sustained release solid pharmaceutical composition according to claim 38, which is ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate. . 45. A compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-
39. The sustained release solid pharmaceutical composition according to claim 38, which is yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. 46. The sustained-release solid pharmaceutical composition according to claim 34, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. 47. The sustained-release solid pharmaceutical composition according to claim 46, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer. 48. The sustained-release solid pharmaceutical composition according to claim 47, wherein the lactic acid-glycolic acid polymer has a composition molar ratio of lactic acid and glycolic acid of 100/0 to 40/60. 49. The weight average molecular weight of the polymer is about 3,000.
47. The sustained release solid pharmaceutical composition according to claim 46 which is about 50,000. 50. The sustained-release solid pharmaceutical composition according to claim 34, wherein the polyvalent metal is a divalent metal. 51. The sustained-release solid pharmaceutical composition according to claim 50, wherein the divalent metal is zinc. 52. The sustained-release solid pharmaceutical composition according to claim 34, which is for injection. 53. The sustained-release solid pharmaceutical composition according to claim 34, which is a microcapsule. 54. Obtained by mixing an organic solvent solution or suspension containing a non-peptide bioactive substance and a biodegradable polymer with an aqueous phase having a polyvalent metal ion concentration of about 0.1 to about 80 mM. 35. The method for producing a sustained-release solid pharmaceutical composition according to claim 34, wherein the organic solvent is removed from the obtained emulsion. 55. An organic solvent solution containing a non-peptide bioactive substance, a polyvalent metal and a biodegradable polymer in an amount exceeding the solubility of the biodegradable polymer containing no polyvalent metal in the organic solvent solution. And the polyvalent metal ion concentration is about
The organic solvent is removed from the emulsion obtained by mixing with an aqueous phase of 0.1 to about 80 mM.
4. The method for producing a sustained-release solid pharmaceutical composition according to 4. 56. The polyvalent metal ion is zinc.
Or the production method according to 55. 57. The method according to claim 55, wherein the polyvalent metal is used as one or two polyvalent metal compounds selected from zinc acetate and zinc oxide. 58. A sustained-release solid pharmaceutical composition obtained by the production method according to claim 54 or 55. 59. The sustained-release solid pharmaceutical composition according to claim 38, which is a prophylactic / therapeutic agent for cardiovascular diseases. 60. The sustained-release solid pharmaceutical composition according to claim 38, which is a prophylactic / therapeutic agent for hypertension, abnormal blood pressure circadian rhythm, or organ disorder. 61. A solid pharmaceutical composition comprising a non-peptide bioactive substance and a biodegradable polymer, wherein about 0.05% or more by weight of the composition is present on the surface of the polyvalent metal. A method for suppressing the initial release of a non-peptidic physiologically active substance, comprising: