JP2003113120A - Sustained release medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sustained release medicine which exhibits remarkable effects as a reduced dose with reduced side effects. SOLUTION: This sustained release medicine comprises (A) an angiotensin II antagonist and (B) one or more medicines selected from an anti-hypertensive medicine, an anti-hypoglycemic medicine, an anti-hyperlipemic medicine, an anti-thrombotic medicine, an anti-climacteric medicine, and an anti-cancer medicine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to (A) angiotensin II antagonist (hereinafter sometimes abbreviated as “AII antagonist”), (B) antihypertensive drug, hypoglycemic drug, and hyperlipidemia. The present invention relates to a sustained-release drug or the like, which is a combination of one or more drugs selected from therapeutic agents, antithrombotic agents, menopausal agents, and anticancer agents.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II has a strong vasoconstrictor action, an aldosterone producing action and a cell proliferating action, and is considered to be one of the mediators of various cardiovascular diseases. Angiotensin II antagonists that antagonize this angiotensin II and angiotensin II receptor and suppress the action of angiotensin II are hypertension, heart disease (for example, heart failure, myocardial infarction, etc.), stroke, nephritis,
It is useful for prevention and treatment of cardiovascular diseases such as arteriosclerosis. On the other hand, in the treatment of diabetes, treatment with a diabetic postprandial hyperglycemia-improving drug, or treatment with an insulin-sensitizing enhancer for improving a decrease in insulin sensitivity to glucose uptake in peripheral tissues is used. Furthermore, in the treatment of hyperlipidemia, HMG-Co
A reductase (3-hydroxy-3-methylglutaryl coenzyme
A reductase) inhibitor, which is used to suppress cholesterol biosynthesis. Among them, hypertension, impaired glucose tolerance, and abnormal lipid metabolism are known to be easily combined with each other. Is believed to worsen.

[0003]

DISCLOSURE OF THE INVENTION The present invention is achieved by combining an AII antagonist and a drug having a mechanism of action other than that, and formulating it into a sustained release drug (eg, sustained release injection). , AII-mediated diseases, in particular, single diseases such as hypertension, hyperlipidemia, arteriosclerosis, diabetes or their complications (eg thrombosis, menopause, cancer, etc.) It is intended to compensate for various drawbacks that are observed when a drug is administered as a single agent.

[0004]

[Means for Solving the Problems] As a result of various investigations, the present inventors have found that (A) an AII antagonist,
Sustained-release preparations (eg sustained-release injections) in combination with one or more drugs selected from hypoglycemic agents, hyperlipidemia agents, antithrombotic agents, menopausal agents and anticancer agents As a result of being used for the first time as an actual drug, for example, in the properties required as pharmaceuticals such as pharmaceutical effect, safety, stability, dosage, dosage form, method of use, etc. The present invention was completed based on these findings.

That is, the present invention relates to [1] (A) angiotensin II antagonist and (B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, menopausal drug and anticancer drug. [2] Angiotensin II, which is a sustained-release medicine comprising a combination of one or more drugs selected from
The antagonist is of formula (I)

[Chemical 2] (In the formula, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, n Represents 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of changing to an anion, R ³
Is a compound represented by a hydrocarbon residue which may be bonded through a hetero atom and which may have a substituent) or a salt thereof, [3] Angiotensin II antagonists are losartan, eprosartan,
Candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, or tasosartan, wherein [4] the angiotensin II antagonist is 2-ethoxy-
1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7-
The drug according to the above [1], which is a carboxylic acid or a salt thereof,
[5] Angiotensin II antagonist is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1
-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof, the [6] angiotensin II antagonist. Is 2-ethoxy-
1-[[2 '-(2,5-dihydro-5-oxo-1,
2,4-oxadiazol-3-yl) biphenyl-4
-Yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof, the medicine according to the above [1], [7] a therapeutic agent for hypertension, an angiotensin converting enzyme inhibitor, a diuretic, a calcium antagonist, a vasopressin antagonist, The drug according to the above [1], which is a drug selected from angiotensin converting enzyme and neutral endopeptidase inhibitor, β blocker and aldosterone antagonist, and [8] the angiotensin converting enzyme inhibitor is enalapril, cilazapril, temocapril, trandolapril, The drug according to the above [7], which is a drug selected from lisinopril and ramipril,

[9] The drug according to the above [7], wherein the diuretic is a drug selected from indapamide, trichlormethiazide, bumetamide, hydrochlorothiazide and metolazone,
[10] The drug according to the above [7], wherein the calcium antagonist is a drug selected from amlodipine, nitrendipine and manidipine, and [11] the above [7] wherein the vasopressin antagonist is a drug selected from tolvaptan, conivaptan hydrochloride and lercobaptan. Medicine, [12]
The angiotensin converting enzyme and the neutral endopeptidase inhibitor are the drugs selected from omapatrilate, fasidotril and sanpatrilate, [7] the drug described above, and [13] the β blocker is a drug selected from carvedilol, metoprolol and propranolol. The pharmaceutical according to the above [7], [14] the pharmaceutical according to the above [7], wherein the aldosterone antagonist is spironolactone.
[15] The above-mentioned [1], wherein the hypoglycemic agent is an insulin sensitizer, an insulin secretagogue or an insulin preparation.
[16] The drug according to [15] above, wherein the insulin sensitizer is a drug selected from pioglitazone hydrochloride, troglitazone and rosiglitazone maleate, and [17] the insulin secretagogue is selected from glibenclamide, nateglinide and repaglinide. The drug according to [15] above which is a drug, [18] the drug according to [1] above, wherein the therapeutic drug for hyperlipidemia is a statin drug, fibrate drug or nicotinic acid derivative, [19] statin drug [18] which is a drug selected from cerivastatin sodium, pravastatin sodium, simvastatin and atorvastatin calcium hydrate
[20] The drug according to [18] above, wherein the fibrate drug is fenofibrate, fenofibric acid, bezafibrate or gemfibrozil.
[21] The drug according to the above [18], wherein the nicotinic acid derivative is niceritrol or cholexamine, and [22] the antithrombotic drug is a drug selected from a GPIIb / IIIa antagonist, a low molecular weight heparin, a thrombin inhibitor and an antiplatelet drug. The pharmaceutical according to [1] above, [23] the pharmaceutical according to [22] wherein the GPIIb / IIIa antagonist is abciximab, [24] the pharmaceutical according to [22], wherein the low molecular weight heparin is enoxaparin, [25] The drug according to the above [22], wherein the thrombin inhibitor is argatroban, and the above [22], wherein the antiplatelet drug is clopidogrel sulfate or aspirin.
[27] The drug according to [1] above, wherein the therapeutic drug for menopause is an estrogen selected from estradiol, estradiol valerate and a conjugated estrogen, and [28] the anticancer drug is a GnRH agonist or antagonist. 1] The medicine described in [29] GnR
[30] The medicament according to the above [28], wherein the H agonist is leuprorelin or a salt thereof, [30] (A) angiotensin II antagonist, and (B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, anti The drug according to the above [1], which comprises one or more drugs selected from thrombotic agents, menopausal agents and anticancer drugs, and [31] (A) sustained release containing angiotensin II antagonist Sustained release containing a sex preparation and one or more drugs selected from (B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, menopausal drug and anticancer drug [32] (A) Angiotensin II, which comprises a pharmaceutical preparation
A sustained-release preparation containing an antagonist, and (B) antihypertensive drug,
The above-mentioned [1], which is combined with a sustained-release preparation containing one or more drugs selected from hypoglycemic agents, hyperlipidemic agents, antithrombotic agents, menopausal agents and anticancer agents. [33] (C) The drug according to [1], which contains a biodegradable polymer, [34] The drug according to [33], wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. [35] The medicine according to the above [34], wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer, and [36] the composition molar ratio of lactic acid to glycolic acid is 100/0 to 40/60. [35]
The drug as described above, and the [37] polymer has a weight average molecular weight of 3,0.
The drug according to the above [34], which is from 00 to 50,000,
[38] The medicine according to the above [1], which is for injection, [39]
The drug according to the above [1], which is a preventive / therapeutic agent for cardiovascular disease, and [40] the above [1], which is a preventive / therapeutic agent for hypertension.
[41] The medicament according to [1], which is a preventive / therapeutic agent for abnormal blood pressure circadian fluctuations, [42] the medicament according to [1], which is a preventive / therapeutic agent for organ disorders, and [43] cancer. The drug according to the above [1], which is a preventive / therapeutic agent for the above, [44] the drug according to [1], which is an organ protecting agent, and [45] the drug according to the above [1], to a mammal. For the treatment of cardiovascular diseases, hypertension, abnormal blood pressure circadian fluctuations, organ disorders or cancer, [46] therapeutic agent for cardiovascular diseases, hypertension, abnormal blood pressure circadian fluctuations, organ disorders or cancer The use of the drug according to the above [1], and [47] a sustained release comprising a combination of two or three drugs selected from angiotensin II antagonists, antihypertensive agents, hypoglycemic agents and antihyperlipidemic agents Related to medicine, etc.

[0006] The angiotensin II antagonism possessed by the AII antagonist in the present invention means that angiotensin II binding to the angiotensin II receptor on the cell membrane is competitively or non-competitively inhibited and is strongly induced by angiotensin II. It refers to the action of reducing the vasoconstrictor action and vascular smooth muscle proliferation action, and alleviating the symptoms of hypertension. The AII antagonist used in the present invention may be peptidic or non-peptidic, but a compound having a non-peptidic antagonism, which has an advantage of long action time, is preferable. 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. The compound having a non-peptidic angiotensin II antagonistic action is not particularly limited, but it is disclosed in JP-A-56-
71073, JP-A-56-71074, JP-A-57-98270, and JP-A-58-15776.
No. 8, USP 4,355,040 and USP 4,
340,598 and other imidazole derivatives, and EP-253310, EP-291969, EP-3
24377, EP-403158, WO-910027.
7, JP-A-63-23868 and JP-A-1-1-1
Imidazole derivatives disclosed in Japanese Patent No. 17876,
Also, USP 5,183,899, EP-32384.
1, EP-409332 and JP-A-1-287071.
Pyrrole, pyrazole and triazole derivatives disclosed in Japanese Unexamined Patent Publication (Kokai) No. 4,880,804, E
P-0392317, EP-0399732, EP-0
400835, EP-425921, EP-45913
6 and the benzimidazole derivatives disclosed in JP-A-3-63264, the azaindene derivatives disclosed in EP-399731, the pyrimidone derivatives disclosed in EP-407342, and the quinazoline derivatives disclosed in EP-411766. , A xanthine derivative disclosed in EP-430300 and the like, a condensed imidazole derivative disclosed in EP-434038 and the like, EP-442473.
EP-443, a pyrimidinedione derivative disclosed in US Pat.
And the thienopyridone derivatives disclosed in 568, and
EP-445811, EP-483683, EP-51
8033, EP-520423, EP-588299,
Heterocyclic compounds disclosed in EP-603712, and also Journal of Medicinal Chemistry, Vol. 39, No. 3, 6.
25-656, 1996) and the like. As the non-peptidic compound having angiotensin II antagonistic action, in addition to the compounds described in the above-mentioned known documents, any non-peptidic compound having angiotensin II antagonistic action may be used, among which losartan ( Losartan (DuP753)), Losartan potassium, Eprosartan (SK & F10856
6)), Candesartan cilexetil
lexetil (TCV−116)), Valsartan (CGP
−48933)), Telmisartan (BIBR27
7)), irbesartan (Irbesartan (SR47436)), tasosartan (ANA-756), olmesartan medoxomil and their metabolically active substances (candesartan, olmesartan, etc.) are preferably used.

The non-peptidic compound having angiotensin II antagonism includes, for example, compounds of 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 that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, n Represents 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of changing to an anion, R ³
Is a hydrocarbon residue which may be bonded via a hetero atom and which may have a substituent (preferably a hydrocarbon residue which may have a substituent and is bonded via an oxygen atom). A benzimidazole derivative represented by the formula (1) or a salt thereof is preferably used. In the above formula (I),
Examples of the group capable of forming an anion as R ¹ (group having a hydrogen atom that can be 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.

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

[Chemical 4]

[Chemical 5] 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 6] 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 a carbonyl or thiocarbonyl group, more preferably a 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 7] [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 8] There are three tautomers of a ', b'and c', such as

[Chemical 9] 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, an optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _1-4 ))
_2-5 ) Alkanoyl, benzoyl, etc.) and the like. 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 by 1 to 3 (C
_1-4 ) alkyl group (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 —CH (R ⁴ ) —OCOR ⁵ [In the formula, R ⁴ is (a) hydrogen, and (b) has 1 to 6 carbon atoms. A linear or branched lower alkyl group (eg, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl, t
-Butyl, n-pentyl, isopentyl, neopentyl, etc.), (c) a straight-chain 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., and R ⁵ 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) 3 carbon atoms.
8 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy Such as a phenyl or naphthyl group which may have)
A lower alkyl group having 1 to 3 carbon atoms substituted with (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) cycloalkyl having 3 to 8 carbon atoms or substituted Good aryl groups (eg halogen atoms, nitro, lower (C
_1-4 ) lower alkenyl group having 2-3 carbon atoms substituted with alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. (eg vinyl such as cinnamyl, propenyl) , Those having an alkenyl moiety such as allyl and isopropenyl), (e) an optionally substituted aryl group (eg, phenyl, p-tolyl,
Halogen atom such as naphthyl, nitro, lower (C _1-4 )
Alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc.), (f) straight or branched lower alkoxy group having 1 to 6 carbon atoms (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 2-8 carbon atoms (eg, aryloxy, isobutenyloxy, etc.), (h) Carbon number 3-8
Cycloalkyloxy group (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) C3-C8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or optionally substituted aryl Group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C
_1-4 ) a lower alkoxy group having 1 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy and other methoxy, ethoxy, such as those having an alkoxy part such as n-propoxy and isopropoxy), (j) 3 carbon atoms
-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy Such as a phenyl or naphthyl group which may have)
A lower alkenyloxy group having 2 to 3 carbon atoms (eg, a vinyloxy group such as cinnamyloxy, a propenyloxy group, an aryloxy group, an alkenyloxy group such as isopropenyloxy group, etc.) or an (k) optionally substituted aryloxy group. (Eg, phenoxy, p-nitrophenoxy, phenoxy or naphthoxy group optionally having nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc., such as phenoxy, p-nitrophenoxy, naphthoxy, etc.) Group] and the like. Also, R
^The group capable of forming an anion as ¹ is protected by 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 group, in the substitutable position,
Optionally substituted lower (C _1-4 ) alkyl group (“optionally substituted lower (C _1-4 )” exemplified as the protecting group for the group capable of forming an anion as R ¹ described above. The same as "an alkyl group", a halogen atom, nitro, cyano, lower (C _1-4 ) alkoxy, amino optionally substituted with 1 to 2 lower (C _1-4 ) alkyl, etc. It may have a substituent.

In the above formula, the 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 protected, respectively optionally substituted lower _{(C 1-4)} 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, (6) 5 to 7 membered (preferably 5 to 6 membered) monocyclic optionally substituted heterocycle containing one or more of N, S and O It may be a group such as a residue that can be converted into a group capable of forming an anion represented by R ¹ by a chemical reaction (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 Carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4 optionally protected with a group (eg lower (C _2-5 ) alkanoyl, benzoyl etc.)
-Oxadiazol-3-yl (preferably tetrazolyl) or cyano, N-hydroxycarbamimidoyl (preferably cyano) are preferable, and tetrazolyl is particularly preferably used.

In the above formula, X represents that the adjacent phenylene group and phenyl group are bonded directly or via a spacer having an atom chain of 2 or less (preferably direct bond). 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 ( _C1-4 ) alkylene having 1 or 2 atoms constituting the straight chain portion, -CO-, -O-, -S-, -NH-, -C.
_{O-NH -, - O-} CH 2 -, - S-CH 2 -, - CH
= CH- and the like. In the above formula, n is 1 or 2
An integer of (preferably 1) is shown.

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) 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' represents a hydroxyl group or an alkyl moiety is a hydroxyl group, a lower _{(C 1-4)} alkoxy, lower _{(C 2-6)} alkanoyloxy (e.g., acetoxy, etc. pivaloyloxy), lower _{(C 1-6} ) Alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or lower (C _3-6 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.) which may be substituted with lower (C
_1-4 ) represents an alkoxy group] or (8) optionally substituted lower (C _1-4 ) alkyl (exemplified as a protecting group for a group capable of forming an anion as R ¹ described above). "A lower optionally substituted (C
_1-4 ) Alkyl group "and the like, or tetrazolyl optionally protected by acyl (eg, lower ( _C2-5 ) alkanoyl, benzoyl, etc.), trifluoromethanesulfonic acid amide group, phosphoric acid Group or sulfonic acid group. These substituents are
1 to 2 may be simultaneously substituted at substitutable positions on the benzene ring, and as the substituent which the ring A further has in addition to the substituent R ² , an optionally substituted lower (C
_1-4 ) Alkyl (eg, hydroxyl group, carboxyl group, lower (C _1-4 ) alkyl _optionally substituted with halogen, etc.), halogen and the like are preferable, and ring A has a substituent other than substituent R ^2. It is more preferable not to have it.

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.) and may be protected under biological or physiological conditions (eg, in vivo enzyme). It may be any group capable of forming an anion or a group capable of being converted into an anion by an in-vivo reaction such as oxidation, reduction or hydrolysis.

R^TwoEsterified or amidated as
Examples of the optionally substituted carboxyl include, for example, the formula —CO
-D [wherein D is (1) hydroxyl group, (2) substituted
May also be amino (eg, amino, N-lower (C_1-4)
Alkylamino, N, N-di-lower (C_1-4) Alkyl
Amino etc.) or (3) optionally substituted alco
Xy {eg, (i) alkyl part is hydroxyl group, substituted
Optionally amino (eg, amino, N-lower (C_1-4)
Lucylamino, N, N-di-lower (C_1-4) Alkyla
Mino, piperidino, morpholino, etc.), halogen, lower
(C_1-6) Alkoxy, lower (C_1-6) Alkyl
Oh, low (C_3-8) Cycloalkoxy or substituted
Optionally dioxolenyl (eg, 5-methyl-2-
Oxo-1,3-dioxolen-4-yl etc.)
Optionally lower (C_1-6) Alkoxy group, also
Is (ii) formula -O-CH (R⁶) -OCOR⁷[In the formula,
R ⁶Is (a) hydrogen, (b) a straight chain having 1 to 6 carbon atoms, or
Branched lower alkyl groups (eg, methyl, ethyl, n-propyl
Ropyr, isopropyl, n-butyl, isobutyl, t-bu
Chill, n-pentyl, isopentyl, neopentyl
Etc.), (c) a straight-chain or branched lower one having 2-6 carbon atoms
Alkenyl group or (d) cycloalkyl having 3 to 8 carbon atoms
Group (eg, cyclopentyl, cyclohexyl, cyclohexyl
), And R⁷Is (a) a straight chain having 1 to 6 carbon atoms
Or a branched lower alkyl group (eg, methyl, ethyl
, N-propyl, isopropyl, n-butyl, isobuty
, Sec-butyl, t-butyl, n-pentyl, isopene
Chill, neopentyl, etc.), (b) straight chain having 2-6 carbon atoms
Or, a branched lower alkenyl group, (c) 3-carbon atoms
8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl)
Xyl, cycloheptyl, etc.) or substituted
Good aryl groups (eg halogen atom, nitro, lower)
(C_1-4) Alkyl, lower (C_1-4) Alkoxy
Which may have phenyl or naphthyl groups, etc.)
A lower alkyl group having 1 to 3 carbon atoms substituted with
Zil, p-chlorobenzyl, phenethyl, cyclopentyl
(Methyl, cyclohexylmethyl, etc.), (d) carbon number
3-8 cycloalkyl or optionally substituted
Aryl group (eg, halogen atom, nitro, lower (C
_1-4) Alkyl, lower (C_1-4) Alkoxy etc.
Phenyl or naphthyl groups which may have)
A substituted lower alkenyl group having 2 to 3 carbon atoms (eg, cinna
Vinyl such as mill, propenyl, allyl, isopropenyl
Such as those having an alkenyl moiety), (e) substituted
Optionally an aryl group (eg, phenyl, p-tolyl,
Halogen atom such as naphthyl, nitro, lower (C_1-4)
Alkyl, lower (C_1-4) Has alkoxy etc.
Optionally phenyl or naphthyl group), (f) carbon
Number 1-6 linear or branched lower alkoxy group
(Eg methoxy, ethoxy, n-propoxy, isoprop
Poxy, n-butoxy, isobutoxy, sec-butoxy,
t-butoxy, n-pentyloxy, isopentyloxy
Ci, neopentyloxy, etc.), (g) C2-8
A straight-chain or branched lower alkenyloxy group (eg, ants
Roxy, isobutenyloxy, etc.), (h) C3-8
Cycloalkyloxy groups (eg, cyclopentyloxy)
Si, cyclohexyloxy, cycloheptyloxy
Etc., (i) cycloalkyl having 3 to 8 carbon atoms (eg, cycl
(Lopentyl, cyclohexyl, cycloheptyl, etc.)
Optionally substituted aryl groups (eg halogens
Atom, nitro, lower (C_1-4) Alkyl, lower (C
_1-4) Phenyl, which may have alkoxy, etc.
Or a naphthyl group, etc.) substituted lower one having 1-3 carbon atoms
Alkoxy groups (eg benzyloxy, phenethyloxy, silane
Such as clopentyl methoxy and cyclohexyl methoxy
Methoxy, ethoxy, n-propoxy, isopropoxy
Such as those having an alkoxy moiety), (j) 3 carbon atoms
-8 cycloalkyl (eg, cyclopentyl, cyclohexyl
Xyl, cycloheptyl, etc.) or substituted
Good aryl groups (eg halogen atom, nitro, lower)
(C_1-4) Alkyl, lower (C_1-4) Alkoxy
Which may have phenyl or naphthyl groups, etc.)
C3-C3 lower alkenyloxy group substituted with
(Eg, vinyloxy such as cinnamyloxy, propenyloxy
Alkeniro such as Ci, allyloxy, and isopropenyloxy
(Eg, having a xy moiety) or (k) even if substituted
Good aryloxy groups (eg, phenoxy, p-nitrophenyl)
Halogen atom such as enoxy and naphthoxy, nitro, lower
(C_1-4) Alkyl, lower (C_1-4) Alkoxy
A phenoxy or naphthoxy group which may have any
Etc.]], etc.]
And so on.

R ² is preferably an optionally esterified carboxyl, and specific examples thereof include —COOH and salts thereof, —COOMe, —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 _3-8 ) alkoxy optionally substituted with lower (C _1-4 ) alkoxy]. Of these, carboxyl is 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
-Di-lower (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 is, for example, halogen (eg, F, Cl, Br etc.), nitro, optionally substituted amino group (eg, amino, etc.) at any position on the benzene ring. N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino and the like), lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy and the like), lower (C _{1 -4} ) Alkylthio (eg, methylthio, ethylthio, etc.), Lower (C _1-4 ) alkyl (eg, methyl, ethyl, etc.) and the like may be included. Among the above, the “hydrocarbon residue” in “hydrocarbon residue having a substituent, which may be bonded via a hetero atom represented by R ³ ” may be substituted. A good alkyl or alkenyl group (eg hydroxyl, amino, halogen or lower (C
_1-4 ) lower optionally substituted by an alkoxy group (C
_1-5 ) Alkyl or lower ( _C2-5 ) alkenyl group) is preferable, and lower ( _C1-5 ) alkyl (more preferably ethyl) is particularly preferable. The "hetero atom" which may be bonded via a hetero atom and has a substituent and which is represented by R ³ and is a hydrocarbon residue, is -O-, -S (O) m- [. m represents an integer of 0 to 2], -NR '-[R' represents a hydrogen atom or lower (C
_1-4 ) represents alkyl] and the like.
O- is preferably used. Among the above, R ³ is -O-, -S (O) m- [m represents an integer of 0 to 2] or -NR '-[R' is a hydrogen atom or a lower (C _1-4 ) Represents an alkyl group], a hydroxyl group, an amino group, a halogen and a lower group (C
_1-4 ) Lower (C _1-5 ) alkyl which may be substituted with a substituent selected from an alkoxy group or lower (C ₁ ).
_2-5 ) alkenyl groups and the like are preferable, and lower (C _1-5 ) alkyl or lower (C _1-5 ) alkoxy (more preferably ethoxy) is particularly preferable.

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

[Chemical 10] (In the formula, R ¹ is a (1) carboxyl group, (2) tetrazolyl group or (3) formula

[Chemical 11] [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,
A hydroxyl group, a carboxyl group, a lower (C _1-4 ) alkyl which may be substituted with a halogen or the like) or a benzene ring which may be substituted with a halogen (preferably having a substituent other than the substituent R ²⁾ No benzene ring)
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 (e.g., 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 _3-8 ) alkoxy, which may be substituted with lower (C _1-4 ) alkoxy] are shown, ^{R 3} is -O -, - indicating the - '[R' is a hydrogen atom or a lower _{(C 1-4)} alkyl S (O) m- [m denotes an integer of 0 to 2] or -NR ] And is substituted with a substituent selected from a hydroxyl group, an amino group, a halogen and a lower (C _1-4 ) alkoxy group. Also optionally substituted lower _{(C 1 -5)} alkyl or lower _{(C 2-5)} alkenyl group (preferably, a lower _{(C 1
-5} ) alkyl or lower ( _C1-5 ) alkoxy; more preferably ethoxy). ] The benzimidazole-7-carboxylic acid derivative represented by these or its pharmacologically acceptable salt etc. are preferable, and especially 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl] -4-yl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4 -Yl] methyl] benzimidazole-7
-Carboxylate [Candesartan cilexetil], pivaloyloxymethyl 2-ethoxy-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazol-7-carboxylate, 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2. , 4-Oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof is preferable. The above-mentioned benzimidazole derivative is, for example, EP-42.
5921, EP-459136, EP-535879,
EP-578125, EP-520423, EP-66
It can be synthesized by a known method described in 8272 or the like or a method similar thereto. Also Candesar
When using tan cilexetil, EP-459136
It is preferable to use the stable C-type crystal described in 1.

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). When the compound having angiotensin II antagonistic action has a basic group such as an amino group, an inorganic acid or organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
Carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Examples thereof include salts with acidic amino acids such as citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid and glutamic acid. Angiotensin II used in the present invention
A compound having an antagonistic action [hereinafter, sometimes referred to as an AII antagonistic compound. ] Prodrug is a compound that is converted into an AII antagonist compound by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, or the like to be an AII antagonist compound, A compound that is converted to an AII antagonist compound by being hydrolyzed by gastric acid or the like. Prodrugs of AII antagonist compounds include compounds in which the amino group of the AII antagonist compound is acylated, alkylated, or phosphorylated (eg, A
The amino group of the II antagonist compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); , Alkylated, phosphorylated, and borated compounds (eg, hydroxyl groups of AII antagonist compounds were acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated) Compound etc.); Carboxyl group of AII antagonist compound is esterified or amidated Compound (eg, AII antagonist compound) carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, Baroyloxymethyl ester , Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) And the like. These compounds can be produced from an AII antagonist compound by a method known per se. Also, A
The prodrugs of II antagonist compounds are described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, pages 163 to 198.
It may be converted to an AII antagonist compound under physiological conditions as described on page. The AII antagonist compound may be either a hydrate or a non-hydrate. Further, the AI used in the present invention, which will be described in detail below,
Active ingredients other than I antagonists include salts, educts, prodrugs,
It may be either a hydrate or a non-hydrate. Examples of such salts or prodrugs include the same as those exemplified for the above-mentioned AII antagonist compound.

The antihypertensive drug used in the present invention includes angiotensin converting enzyme (ACE) inhibitor, diuretic, calcium antagonist, vasopressin antagonist, angiotensin converting enzyme and neutral endopeptidase (AC).
E / NEP) inhibitors, β blockers, aldosterone antagonists and the like. Examples of the ACE inhibitor include enalapril, cilazapril, temocapril, trandolapril, lisinopril, ramipril and the like. Examples of diuretics include indapamide, trichlormethiazide, bumetamide, hydrochlorothiazide, metrazone and the like. As calcium antagonists, amlodipine,
Examples include nitrendipine and manidipine. Examples of vasopressin antagonists include tolvaptan, conivaptan hydrochloride, lercobaptan and the like. ACE / NEP
The inhibitor is a protease inhibitor that has both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitory effects. It inhibits the production of angiotensin II and at the same time inhibits the degradation of atrial Na diuretic peptide to prevent hypertension. Agents to be treated include omapatrilate, fasidotril and sampatrilat. β
Blockers include carvedilol, metoprolol, propranolol and the like. Examples of the aldosterone antagonist include spironolactone and eplerenone. Here, as another aspect of the present invention, for example, as an aspect of using an aldosterone antagonist such as eplerenone (epoxymexrenone), WO 9
According to 6/40257, it may be a medicine which is a combination of an AII antagonist and an aldosterone antagonist. Specifically, the present invention relates to [1] 2-ethoxy-1-[[2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
[2] A drug comprising a combination of methyl] benzimidazole-7-carboxylic acid or a salt thereof and eplerenone.
1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof and eplerenone [3] 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-
1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazol-7-carboxylic acid or a salt thereof in combination with eplerenone or a drug or [4] losartan, eprosartan, valsartan , Telmisartan, irbesartan, olmesartan medoxomil, olmesartan, and tasosartan, and one or more kinds of AII antagonists and eplerenone in combination are included. When the specific AII antagonist and the aldosterone antagonist are used in combination as described above, these drugs may be used separately or simultaneously, and a pharmacologically acceptable carrier,
It can be orally or parenterally administered as a pharmaceutical composition by mixing it with an excipient, a binder, a diluent and the like to formulate. 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. A kit product for administering separately formulated products by mixing with a diluent at the time of use (for example,
Ampoules containing individual drugs in powder form and injection kits containing diluents for mixing and dissolving two or more drugs at the time of use), individual preparations prepared separately, simultaneously, Alternatively, a kit product for administration to the same subject separately with a time difference (for example, tablets containing the individual drugs are put in the same or different bags, and if necessary,
A tablet kit for administering two or more tablets at the same time or separately with a time lag, which includes a column for describing the time of drug administration, and the like are also included in the medicament of the present invention. AI
The medicine which is a combination of I antagonist and aldosterone antagonist is, for example, granule, powder, powder, tablet, capsule, syrup, emulsion, suppository (eg, rectal suppository, vaginal suppository), injection Agents (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), drops, external preparations (eg, nasal preparations, transdermal preparations, ointments, etc.), emulsions,
It can be orally or parenterally administered as an elixir, a suspension, a solution and the like, and these preparations can be prepared according to a method known per se generally used in the preparation process. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution and the like. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. To this end, any non-volatile oil or fatty acid may be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Furthermore, additives such as preservatives, isotonicity agents, solubilizers, stabilizers, soothing agents and the like may be appropriately used. A suppository for rectal administration is a drug and a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract and melt in the rectum. It can be manufactured by mixing with a substance that emits. Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like described above. In such dosage forms, the active ingredient is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins. , Tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms can also, as usual, contain further additives such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, Antioxidants such as α-tocopherol and cysteine, excipients, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfume agents,
Examples thereof include coating agents. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which contain an inert diluent commonly used in the art, such as water. You can stay. A medicine comprising a combination of an AII antagonist and an aldosterone antagonist has the following characteristics:
0.6-39% by weight of antagonists (0.7-27% by weight in particular), 0.06-35% by weight of aldosterone antagonists
(Among others, 0.6 to 23% by weight) is preferably contained. This composition may be a composition in which two or more drugs are separately or simultaneously formulated. AI
The dose of the drug comprising the combination of the I antagonist and the aldosterone antagonist is based on the minimum recommended clinical dose of each drug, and the administration subject, age and weight of the administration subject, symptoms,
It can be appropriately selected depending on the administration time, administration method, dosage form, combination of drugs and the like. The dosage for a particular patient will depend on age, weight, general health, sex, diet, time of administration, mode of administration, excretion rate, drug combination, and the extent of the condition being treated by the patient at that time. , And these or other factors. Typically, the individual daily doses will be about 1/50 of the minimum recommended clinical dose or more and below the maximum recommended level (preferably below the minimum recommended clinical dose; (Preferably the minimum recommended clinical dose is 1/2 or less)
Is the range. For example, in the treatment of hypertension or heart failure in adults (body weight about 60 kg), candesartan cilexetil in the range of about 1 to 50 mg / human / day (preferably about 1 to 35 mg / human / day) and, for example, about 0. 1 to
30 mg / human / day (preferably about 2 to 30 mg / human /
It can be effectively combined with eplerenone in the (day) range. Of course, these dosage ranges can be adjusted on the basis of the units required to divide the daily dose, but as noted above, the dosage will vary according to the nature and extent of the disease, age of the patient, weight, general health status, It is determined in consideration of sex, diet, administration time, administration method, excretion rate, drug combination, and other factors. Unit dose is 1 to 1 a day
It is administered three times (preferably once). A diuretic (eg, hydrochlorothiazide) or the like which is usually used in combination with the AII antagonist may also be used in combination with the above-mentioned drug in which the AII antagonist and the aldosterone antagonist are combined.

As hypoglycemic agents (antidiabetic agents), insulin preparations (eg, animal insulin preparations extracted from the pancreas of cattle and pigs; human insulin preparations genetically synthesized using Escherichia coli and yeast; insulin zinc; Protamine insulin zinc; fragments or derivatives of insulin (eg, INS-1 etc.), insulin sensitizers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate salt, GI-2)
62570, JTT-501, MCC-555, YM-
440, KRP-297, CS-011, FK-614
Etc.), α-glucosidase inhibitors (eg, voglibose,
Acarbose, miglitol, emiglitate, etc.), biguanide agents (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylurea agents (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, trazamide, acetohexamide, glycrolide) Pyramide, glimepiride, glipizide,
Glibzole, etc.), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1
Etc. Glibenclamide and nateglinide are particularly preferable. ], Other, dipeptidyl peptidase IV inhibitor (eg, NVP-DPP-278, PT-100, etc.), β
3 agonists (eg CL-316243, SR-586
11-A, UL-TG-307, SB-226552.
AJ-9677, BMS-196085, AZ-401
40, etc.), amylin agonist (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.) , SGLUT (sodium-glucose
se cotransporter) inhibitors (eg, T-1095 etc.) and the like. Of these, insulin sensitizers, insulin secretagogues, insulin preparations and the like are preferable. Preferred insulin sensitizers are pioglitazone hydrochloride, troglitazone, rosiglitazone and the like. As the insulin secretagogue, glibenclamide, nateglinide, repaglinide and the like are preferable.

Statins are used as therapeutic agents for hyperlipidemia,
Examples include fibrate drugs and nicotinic acid derivatives. Examples of statins include cerivastatin or its sodium salt, pravastatin or its sodium salt, simvastatin, atorvastatin or its calcium hydrate, and the like. Examples of the fibrate drug include fenofibrate, fenofibric acid, bezafibrate, gemfibrozil and the like. Examples of the nicotinic acid derivative include niceritrol and cholexamine.

Examples of antithrombotic agents include GPIIb / IIIa antagonists, low molecular weight heparin, thrombin inhibitors, antiplatelet agents and the like. Examples of GPIIb / IIIa antagonists include abciximab. Examples of the low molecular weight heparin include enoxaparin. Examples of thrombin inhibitors include argatroban. Examples of the antiplatelet agent include clopidogrel sulfate, aspirin and the like.

Examples of the drug for treating climacteric disorder include estrogen (eg, estradiol, estradiol valerate, conjugated estrogen, etc.) and the like.

Examples of the anticancer drug include the following hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors. Examples of the “hormone therapeutic agent” include phosfestrol, diethylstilbestrol, chlorotrianiserine, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate,
Danazol, Allylestrenol, Gestrinone, Mepaltricin, Raloxifene, Olmeroxifene, Levormeroxifene, Antiestrogens (eg Tamoxifen citrate, Toremifene citrate, etc.), Pills, Mepithiostane, Testrolactone, Aminoglutetimide, LH -RH agonists (eg, goserelin acetate, buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, Formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), Renal cortex hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone etc.), androgen synthesis inhibitors (e.g., such as abiraterone), drugs (e.g., such as liarozole) to slow the metabolism of retinoids and retinoid like.

Examples of the "chemotherapeutic agent" include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like. Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, and the like.
Improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etogluside,
Carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temozolomide, threosulfan, trofosfamide, zinostatin stimalamer, carbocon system, adzelecin. Examples include stin and biselecin. Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, gallocitabine, emitefur, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folineate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, guadoxituridine, mitofuridone, mitofurin, mitofurin , Ambamustine and the like. Examples of the "anti-cancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride. , Neocarzinostatin, mithramycin, zarcomycin, carcinophylline, mitotan, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like. Examples of the “plant-derived anticancer agent” include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and the like.

Examples of the "immunotherapeutic agent (BRM)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin,
BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole and the like can be mentioned. The "cell growth factor" in the "drugs that inhibit the action of cell growth factor and its receptor" may be any substance as long as it is a substance that promotes cell growth, and usually has a molecular weight of 20,000. The following peptides include factors that exert their effects at low concentrations by binding to the receptor. Specifically, (1) EGF (epidermal gr)
owth factor) or a substance having substantially the same activity as that (eg, EGF, heregulin (HER2 ligand))
Etc.), (2) Insulin or a substance having substantially the same activity as that [eg, insulin, IGF (insul
in-like growth factor) -1, IGF-2, etc.], (3)
FGF (fibroblast growth factor) or a substance having substantially the same activity as that [eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), F
GF-10 etc.], (4) Other cell growth factors [eg C
SF (colony stimulating factor), EPO (erythro
poietin), IL-2 (interleukin-2), NGF (nerve
growth factor), PDGF (platelet-derived growth)
factor), TGFβ (transforming growth factor)
β), HGF (hepatocyte growth factor), VEGF
(Vascular endothelial growth factor)] and the like. The “cell growth factor receptor” may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor, and specifically, EGF receptor,
Hallegulin Receptor (HER2), Insulin Receptor-
1, insulin receptor-2, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the “drug that inhibits the action of cell growth factor” include Herceptin (HER2 receptor antibody) and the like. In addition to the above-mentioned agents, L-asparaginase, asegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topoisomerase 1I inhibitor (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitor (eg, sobuzoxane, etc.) ), Differentiation inducers (eg, retinoids, vitamin Ds, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.) and the like can also be used.

Particularly preferred anticancer agents include GnRH agonists and antagonists. GnRH agonists / antagonists include hormone-dependent diseases, particularly sex hormone-dependent cancers (eg, prostate cancer, uterine cancer,
Breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis,
Uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multihormonal ovary syndrome and other sex hormone-dependent diseases and contraception (or when using the rebound effect after withdrawal) Include infertility-effective GnRH agonists or antagonists. Further, GnRH agonists or antagonists effective for benign or malignant tumors that are sex hormone independent but GnRH sensitive are also included. Specific examples of GnRH agonists / antagonists include Treatment with GnRH analogs: Controversies and p.
erspectives) [Published by The Parthenon Publishing Group Ltd. 1
996], JP-A-3-503165, JP-A-3-
101695, 7-97334 and 8-25.
Examples thereof include peptides described in Japanese Patent No. 9460.

As the GnRH antagonist, for example, a compound represented by the general formula [I] X-D2Nal-D4ClPhe-D3Pal-Ser-AB-Leu-C-Pro-DAlaNH ₂ [wherein X is N (4H ₂ -furoyl) Gly or NAc, A is NMeTy
r, Tyr, Aph (Atz), the residue selected from NMeAph (Atz),
B is DLys (Nic), DCit, DLys (AzaglyNic), DLys (AzaglyF
ur), DhArg (Et ₂ ), DAph (Atz) and DhCi, where C is Lys (Nisp), Arg or hArg (Et ₂ )] or a salt thereof. To be Further, examples of non-peptide GnRH antagonists include WO 95/28405 (JP-A 8-295693), WO 97
/ 14697 (JP-A 9-169767), WO 97/14682 (JP-A 9-169735), WO 96/24597 (JP-A 9-169735)
-169768), thienopyridine compounds "Example, 3- (N-Benz
yl-N-methylaminomethyl) 4,7-dihydro-5-isobutyryl-7-
(2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) c
arbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine
Etc., WO 00/00493, a thienopyrimidine compound “eg, 5- (N-benzyl-N-methylaminomethyl) -1-
(2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl]
-3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione
Etc. ”, WO 00/56739 and the like.

Examples of the GnRH agonist include, for example, the general formula [II] 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [wherein Y is DLeu, DAla, DTrp, A residue selected from DSer (tBu), D2Nal and DHis (ImBzl), Z is NH-C ₂ H ₅ or
Gly-NH ₂ respectively] or a physiologically active peptide represented by the formula] is used. In particular, Y is DLeu,
A peptide or a salt thereof in which Z is NH-C ₂ H ₅ (ie 5-oxo)
-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C ₂ H ₅ or its salt, especially its acetate (leuprorelin acetate: manufactured by Takeda Pharmaceutical Company Limited) ) Etc. are suitable. The peptides exemplified as the GnRH agonist / antagonist may be pharmacologically acceptable salts. Examples of such salts include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.), organic acids (eg, carbonic acid, bicarbonate, succinic acid) when the peptide has a basic group such as an amino group. Examples thereof include salts with acetic acid, propionic acid, trifluoroacetic acid, etc.). When the peptide has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium) or an organic base (eg, an organic amine such as triethylamine, And basic amino acids such as arginine). Further, the peptide may form a metal complex compound (eg, copper complex, zinc complex, etc.). These peptides or salts thereof can be produced by the methods described in the above-mentioned documents or gazettes or methods equivalent thereto.

Specific preferred examples of the GnRH agonist other than the above leuprorelin (leuprorelin acetate) include (1) goserelin

[Chemical 12] (U.S. Pat. No. 4,100,274, Japanese Patent Laid-Open No. 52-1361.
72), (2) Buserelin

[Chemical 13] (US Patent No. 4,024,248, German Patent No. 2
438352, JP-A-51-41359), (3) Triptorelin

[Chemical 14] (U.S. Pat. No. 4,010,125, Japanese Unexamined Patent Publication No. 52-3107)
No. 3), (4) Nafarelin

[Chemical 15] (U.S. Pat. No. 4,234,571, JP-A-55-1646)
No. 63, No. 63-264498, No. 64-257.
No.94), (5) Histrelin

[Chemical 16] (6) Deslorelin

[Chemical 17] (U.S. Pat. Nos. 4,569,967 and 4,218,439.
No.), (7) Meterelin

[Chemical 18] (PCT WO 91/18016), (8) Gonadrelin

[Chemical 19] (German Patent No. 2213737), or salts thereof.

Among the above, leuprine (leuprorelin acetate), 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6
-[4- (3-Methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione or a salt thereof, 3- (N-benzyl-N-
Methylaminomethyl) -4,7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4
-[(1-Hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine or a salt thereof is preferable. Examples of the salt include those similar to those exemplified for the above AII antagonist.

In the present invention, (A) an AII antagonist,
(B) One or two or more drugs selected from antihypertensive drugs, hypoglycemic drugs, antihyperlipidemic drugs, antithrombotic drugs, anti-menopausal drugs and anticancer drugs are used in combination. The drugs may be separately or simultaneously formulated into a sustained-release preparation and administered orally or parenterally as a pharmaceutical composition. When the drugs are separately formulated, they can be administered separately by mixing them with a diluent or the like at the time of use. You may administer to the same subject separately at time intervals. A kit product for administering separately formulated products by mixing them with a diluent at the time of use (for example, an ampoule containing each drug in powder form and two or more drugs are mixed and dissolved at the time of use) A kit product for administration to the same subject simultaneously or separately with a time lag, such as an injection kit containing a diluent etc. Put tablets containing individual drugs in the same or different bags, and if necessary, provide a column for describing the time of drug administration, to administer two or more tablets at the same time or separately with a time lag. Such as a tablet kit) are also included in the medicament of the present invention. Preferred embodiments of the sustained-release pharmaceutical preparation of the present invention include the following embodiments (1) to (3). (1) One or more selected from (A) AII antagonist and (B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug and anticancer drug ( A sustained-release medicine containing preferably 2 to 3 kinds of drugs. This is because "(A) AII antagonist" and "(B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug and anticancer drug in the minimum constituent unit of the preparation. A sustained-release preparation containing one or more (preferably two to three) drugs selected from the above, which are simultaneously formulated. (2) (A) A sustained-release preparation containing an AII antagonist,
(B) Contains one or more (preferably two to three) drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents A sustained-release medicine containing a sustained-release preparation. this is,
The minimum constituent unit of the preparation is "(A) sustained-release preparation containing AII antagonist" and "(B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, menopausal drug And a sustained-release preparation containing one or more (preferably two to three) drugs selected from anticancer drugs, and two or more separately-prepared sustained-release preparations before use. Alternatively, at the time of use, it is mixed in the same preparation with a diluent and the like, if desired, and used as a single preparation. Here, when the sustained-release preparation (B) contains two or more kinds of drugs, “hypertensive drug”, “hypoglycemic drug”, “hyperlipidemic drug”,
Two or more (preferably 2-3) drugs selected from "antithrombotic drug", "climacteric disorder remedy" and "anticancer drug" are simultaneously formulated and contained in the same sustained-release preparation. Alternatively, a plurality of drugs may be separately formulated, and may be formulated into two or more (preferably 2-3) separate sustained-release formulations.
When using, "(A) sustained-release preparation containing AII antagonist"
And "(B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug, and anticancer drug, sustained-release preparation containing one or more drugs selected" Are administered by the same route at the same time. (3) (A) A sustained-release preparation containing an AII antagonist,
(B) Contains one or more (preferably two to three) drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents A sustained-release medicine which is combined with a sustained-release preparation. The minimum constituent units of the preparation are "(A) sustained-release preparation containing AII antagonist" and "(B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, menopausal drug. A sustained-release preparation containing one or more (preferably 2-3) drugs selected from disorder therapeutic agents and anti-cancer agents, and two or more sustained-release preparations separately formulated. They are used separately in combination. Here, when the sustained-release preparation (B) contains two or more kinds of drugs, "a drug for treating hypertension",
"Hypoglycemic drug", "hyperlipidemia drug", "antithrombotic drug",
Two or more (preferably 2 to 3) drugs selected from “menopausal drug” and “anti-cancer drug” may be simultaneously formulated and contained in the same sustained-release preparation. May be formulated separately and may be formulated into two or more (preferably 2-3) separate sustained-release preparations. At the time of use, "(A) sustained release preparation containing AII antagonist" and "(B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug,
"A sustained-release preparation containing one or more (preferably 2-3) types of drugs selected from antithrombotic agents, menopausal agents and anticancer agents" may be administered via different routes at the same time or with a time lag. May be. Particularly preferred embodiments of the sustained release drug of the present invention are as follows. (i) A sustained-release drug comprising a combination of candesartan and actos. Specifically, a sustained-release drug containing candesartan and actos, a sustained-release drug containing candesartan and a sustained-release preparation containing candesartan, or a sustained-release drug containing candesartan A sustained-release medicine comprising a combination of a sex preparation and a sustained-release preparation containing Actos. Particularly preferred is a sustained release drug containing candesartan and actos. (ii) A sustained-release drug comprising a combination of candesartan cilexetil and actos. Specifically, a sustained-release drug containing candesartan cilexetil and actos, a sustained-release drug containing candesartan cilexetil and a sustained-release drug containing actos or candesartan A sustained-release medicine comprising a combination of a sustained-release preparation containing cilexetil and a sustained-release preparation containing Actos. Particularly preferred is a sustained release drug containing candesartan cilexetil and actos. (iii) A sustained-release drug comprising a combination of candesartan and atorvastatin. Specifically, it contains a sustained-release drug containing candesartan and atorvastatin, a sustained-release drug containing candesartan and a sustained-release drug containing candesartan or candesartan. A sustained-release medicine comprising a combination of a sustained-release preparation and a sustained-release preparation containing atorvastatin. Particularly preferred is a sustained-release drug containing candesartan and atorvastatin. (iv) A sustained-release drug comprising a combination of candesartan cilexetil and atorvastatin. Specifically, a sustained-release pharmaceutical preparation containing candesartan cilexetil and atorvastatin, a sustained-release pharmaceutical preparation containing a sustained-release preparation containing candesartan cilexetil and a sustained-release preparation containing atorvastatin, or A sustained-release medicine comprising a combination of a sustained-release preparation containing candesartan and cilexetil and a sustained-release preparation containing atorvastatin. Particularly preferred is a sustained-release drug containing candesartan cilexetil and atorvastatin. (v) A sustained-release drug comprising a combination of candesartan and enoxaparin. Specifically, a sustained-release medicine containing candesartan and enoxaparin, a sustained-release medicine containing a sustained-release preparation containing candesartan and a sustained-release preparation containing enoxaparin or a sustained-release preparation containing candesartan A sustained-release medicine comprising a combination of a sex preparation and a sustained-release preparation containing enoxaparin. Particularly preferred is a sustained-release drug containing candesartan and enoxaparin. (vi) A sustained-release drug comprising a combination of candesartan cilexetil and enoxaparin. Specifically, sustained release medicine containing candesartan cilexetil and enoxaparin, sustained release medicine containing candesartan cilexetil and sustained release preparation containing enoxaparin or candesartan. A sustained-release medicine comprising a combination of a sustained-release preparation containing cilexetil and a sustained-release preparation containing enoxaparin. Particularly preferred is a sustained-release drug containing candesartan cilexetil and enoxaparin. (vii) A sustained-release drug comprising a combination of candesartan and estradiol. Specifically, a sustained-release medicine containing candesartan and estradiol, a sustained-release medicine containing a sustained-release preparation containing candesartan and a sustained-release preparation containing estradiol, or a sustained-release preparation containing candesartan A sustained-release medicine comprising a combination of a sex preparation and a sustained-release preparation containing estradiol. Particularly preferred is a sustained release drug containing candesartan and estradiol. (viii) A sustained-release drug comprising a combination of candesartan cilexetil and estradiol. Specifically, a sustained-release drug containing candesartan cilexetil and estradiol, a sustained-release drug containing candesartan cilexetil and a sustained-release drug containing estradiol or candesartan A sustained-release medicine comprising a combination of a sustained-release preparation containing cilexetil and a sustained-release preparation containing estradiol.
Particularly preferred is a sustained-release drug containing candesartan cilexetil and estradiol. (ix) A sustained-release drug comprising a combination of candesartan and leuprin. Specifically, a sustained-release medicine containing candesartan and leuprin, a sustained-release medicine containing candesartan and a sustained-release preparation containing leuprin, or a sustained-release preparation containing candesartan A sustained-release medicine comprising a combination of a sex preparation and a sustained-release preparation containing leuprin. Particularly preferred is a sustained release drug containing candesartan and leuprin. (x) A sustained-release drug comprising a combination of candesartan cilexetil and leuprin. Specifically, a sustained-release drug containing candesartan cilexetil and leuprin, a sustained-release drug containing candesartan cilexetil and a sustained-release preparation containing leuprin or candesartan A sustained-release medicine comprising a combination of a sustained-release preparation containing cilexetil and a sustained-release preparation containing leuprin. Particularly preferred is a sustained-release drug containing candesartan cilexetil and leuprin. The sustained-release medicine of the present invention is a pharmaceutical composition containing each active ingredient, and usually contains 5 to 50% by weight of an AII antagonist.
(Preferably 5 to 40% by weight), and one kind selected from the group consisting of a therapeutic agent for hypertension, a hypoglycemic agent, a therapeutic agent for hyperlipidemia, an antithrombotic agent, a therapeutic agent for climacteric disorder, and an anticancer agent, which are used in combination or 1 to 5 drugs for treating hypertension are usually used as two or more drugs.
0% by weight (preferably 5-40% by weight), hypoglycemic agent 1-50% by weight (preferably 5-40% by weight), hyperlipidemia therapeutic agent 1-50% by weight (preferably 1-40%) % By weight), 1-50% by weight of antithrombotic drug (preferably 2-40%)
%), 0.1 to 50% by weight of menopausal disorder therapeutic agents (preferably 0.1 to 40% by weight), 0.1 to 50% of anticancer agents
% (Preferably 0.1 to 40% by weight) is blended.
For example, to describe in detail the above particularly preferred embodiment, in a sustained-release drug (composition) obtained by combining candesartan or candesartan cilexetil and actos, candesartan or candesartan cilexetil and actos are contained in the entire pharmaceutical composition. The amounts are 5 to 50% by weight and 1 to 50% by weight, respectively, preferably 5 to 40% by weight and 1 to 40% by weight. In a sustained-release drug (composition) obtained by combining candesartan or candesartan cilexetil and atorvastatin, the contents of candesartan or candesartan cilexetil and atorvastatin in the whole pharmaceutical composition are 5 to 50% by weight and 1 respectively. ~ 50
% By weight, preferably 5-40% by weight and 2-40% by weight. In the sustained-release medicine (composition) obtained by combining candesartan or candesartan cilexetil and enoxaparin, the contents of candesartan or candesartan cilexetil and enoxaparin in the whole pharmaceutical composition are 5 to 50% by weight and 1 to 50%, respectively. % By weight, preferably 5-40% by weight and 2-50% by weight. In a sustained-release medicine (composition) obtained by combining candesartan or candesartan cilexetil and estradiol, the contents of candesartan or candesartan cilexetil and estradiol in the whole pharmaceutical composition are 5 to 50% by weight and 0.1 to 0.1%, respectively.
50% by weight, preferably 5-40% and 0.2-40% by weight
Is. In a sustained-release medicine (composition) obtained by combining candesartan or candesartan cilexetil and leuprin, the contents of candesartan or candesartan cilexetil and leuprin in the whole pharmaceutical composition are 5 to 50% by weight and 0.1 to 50%, respectively. % By weight, preferably 5-40% by weight and 0.1-40% by weight. As described above, the administration form of the sustained-release medicine of the present invention is not particularly limited, and at the time of administration, an AII antagonist and an antihypertensive agent, a hypoglycemic agent, an antihyperlipidemic agent, an antithrombotic agent, and a menopausal treatment. One or more drugs selected from drugs and anticancer drugs (hereinafter, one selected from antihypertensive drug, hypoglycemic drug, hyperlipidemia drug, antithrombotic drug, menopausal drug and anticancer drug, or Two or more drugs may be abbreviated as a concomitant drug in some cases.) And each drug is controlled to be released gradually. Examples of such a dosage form include (1) administration of a single preparation obtained by simultaneously formulating an AII antagonist and a concomitant drug into a sustained release preparation, and (2) an AII antagonist and a concomitant drug. Simultaneous administration of two or more sustained-release preparations obtained by separately formulating into sustained-release preparations by the same administration route, (3) AII antagonist and concomitant drug are separately formulated into sustained-release preparations Administration of two or more types of sustained-release preparations obtained by the same administration route with a time difference, (4)
Simultaneous administration of two or more sustained-release preparations obtained by separately formulating an AII antagonist and a concomitant drug into sustained-release preparations by different administration routes (5) Separately the AII antagonist and concomitant drug Administration of two or more types of sustained-release preparations obtained by formulation into sustained-release preparations with different administration routes (eg, AII
Administration of a sustained-release preparation containing an antagonist and a sustained-release preparation containing a concomitant drug in this order, or in the reverse order).

Examples of the biodegradable polymer (C) 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.) and the like, which are synthesized from one or more kinds and have a free carboxyl group, a copolymer, an ester thereof, or a mixture thereof; poly-α-cyanoacrylic acid ester; polyamino acid (Eg, poly-g-benzyl-L-glutamic acid, etc.); Maleic anhydride type copolymers (eg, styrene-maleic acid copolymer, etc.) and the like are used. The type of polymerization may be random, block or graft. Further, the above α-hydroxy acids,
When the hydroxydicarboxylic acids and hydroxytricarboxylic acids have an optically active center in the molecule, D-, L-,
Any of the 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 or its ester. When a lactic acid-glycolic acid polymer is used as the biodegradable polymer, its composition ratio (mol%) is 100 /
0-40 / 60 is preferable, and 100 / 0-50 / 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,
It is preferably about 4,000 to about 40,000, more preferably about 5,000 to about 30,000. Also,
The dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5.
Is preferred. The weight average molecular weight, the number average molecular weight, and the dispersity in the present specification mean that the weight average molecular weight is 1,11.
50,000, 707,000, 354,000, 18
9,000, 156,000, 98,900, 66,4
37, 37, 200, 17, 100, 9, 830, 5,
The polystyrene-equivalent molecular weight measured by gel permeation chromatography (GPC) using 14 types of polystyrene of 870, 2,500, 1,303, and 500 as reference substances, and the calculated dispersity. For measurement, G
Using a PC column KF804L x 2 (manufactured by Showa Denko),
Chloroform was used as the mobile phase. Further, the biodegradable polymer is dissolved in an acetone-methanol mixed solvent,
Using phenolphthalein as an indicator, the carboxyl group of this solution was titrated with an alcoholic potassium hydroxide solution to calculate the number average molecular weight by quantitative determination of the end groups. Hereinafter, this will be referred to as the number average molecular weight by quantitative determination of the end groups. While the number average molecular weight determined by end group quantification is an absolute value, the number average molecular weight determined by GPC measurement is used for analysis or analysis conditions (for example, mobile phase type, column type, reference substance, slice width selection, baseline). It is difficult to make a unique numerical value because it is a relative value that fluctuates depending on (such as selection of In the combination, the number average molecular weight measured by GPC and the number average molecular weight measured by end group determination are almost the same. It is said that the case of this lactic acid-glycolic acid polymer is almost the same as that of the lactic acid-glycolic acid polymer because the number average molecular weight measured by the end group determination is about 0.
It means within a range of 2 to about 1.5 times, preferably within a range of about 0.3 to about 1.2 times. A lactic acid-glycolic acid polymer is, for example, a catalyst-free dehydration polycondensation of lactic acid and glycolic acid (JP-A-61-28521).
Alternatively, a ring-opening polymerization using a catalyst derived from a cyclic substance such as lactide and glycolide (Encyclopedic Handbook of Bioma
terials and Bioengineering PartA: Materials, Volum
e 2, Marcel Dekker, Inc., 1995). The polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but the polymer is chemically treated to give a free carboxyl group at the end (Journal
Of Controlled Rele
ase), 41, 249-257, 1996). The lactic acid-glycolic acid polymer having a free carboxyl group at the terminal can be produced without problems by a known production method (for example, catalyst-free dehydration polycondensation method, see JP-A-61-28521), and further, the terminal A polymer having a free carboxyl group, which is not specified in paragraph 1, can be produced by a known production method (see, for example, WO94 / 15587). In addition, a lactic acid-glycolic acid polymer in which a terminal is made into a free carboxyl group by a chemical treatment after ring-opening polymerization is, for example, Boehringer Ingelheim (Boehring
erIngelheim KG) may be used. The ester of a lactic acid-glycolic acid polymer is, for example, a known production method from a lactic acid-glycolic acid polymer having a free carboxyl group (for example, JP-A-7-2780).
It can be manufactured by the method described in Japanese Patent No. 18). These biodegradable polymers may be used alone or in combination of two or more. The sustained-release preparation of the present invention may contain (D) a polyvalent metal, and 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 metals. (Eg, iron, zinc, copper, calcium, magnesium, aluminum, tin, manganese, etc.), trivalent (eg, iron, aluminum, manganese, etc.), tetravalent (eg, tin, etc.) and other polyvalent metals are used. . In the sustained-release preparation of the present invention, these metals may be present as a compound with an inorganic substance or an organic substance, a metal oxide (hereinafter referred to as a polyvalent metal compound), or the like, and are present as a metal ion. Alternatively, a complex may be formed with one or both of the physiologically active substance and the biodegradable polymer. Specific preferred examples of the polyvalent metal include iron, aluminum, zinc, calcium,
Examples include magnesium. Zinc is mentioned as a particularly preferable example of the polyvalent metal, and among them, zinc derived from zinc oxide is preferably used. As the inorganic substance, for example, hydrogen halide (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, etc.), inorganic acid such as sulfuric acid, nitric acid, thiocyanic acid, etc. are used. 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, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid). Etc.) and unsaturated aliphatic monocarboxylic acids having 2 to 9 carbon atoms (eg acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.) and the like. 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. Examples of the aliphatic tricarboxylic acid include saturated aliphatic tricarboxylic acid having 2 to 9 carbon atoms (eg, tricarballylic acid, 1,2,3-
Butanetricarboxylic acid etc.) and the like are 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. Specific examples of the metal compound include a salt of iron and an inorganic acid [eg, iron halide (eg, iron chloride, iron bromide, iron iodide, iron fluoride, etc.),
Iron sulfate, iron nitrate, iron thiocyanate, etc.], a salt of iron and an organic acid [eg, aliphatic carboxylic acid iron salt (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, etc., salts of zinc with 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 salt (eg magnesium benzoate, magnesium salicylate etc.)], magnesium acetylacetonate etc., and metal oxides (eg iron oxide, zinc oxide, calcium oxide,
Magnesium oxide, aluminum oxide, copper oxide, manganese oxide, etc.). The polyvalent metal compound is preferably iron chloride, iron acetylacetonate, zinc acetate, zinc acetylacetonate, calcium acetate, calcium acetylacetonate, magnesium acetate, magnesium acetylacetonate, zinc oxide and the like, more preferably Zinc acetate or zinc oxide is used. In the present invention, all or part of the polyvalent metal that may be contained may be used as a biodegradable polymer in which the same or different metal salt is formed. The metal salt of the biodegradable polymer can be produced, for example, by the method described in JP-A No. 09-212420 or a method similar thereto.

The following three preferred embodiments are: (1) (A) AII antagonist and (B) antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug, and Sustained-release drug containing one or more drugs selected from anticancer drugs, (2) (A) Sustained-release preparation containing AII antagonist, (B) Antihypertensive drug, blood sugar Sustained-release drug containing a depressant, a hyperlipidemia therapeutic drug, an antithrombotic drug, a climacteric disorder therapeutic drug and a sustained-release preparation containing one or more drugs selected from anticancer drugs, (3)
(A) a sustained release preparation containing an AII antagonist, and (B) one selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents, and anticancer agents, or "Sustained release formulation containing AII antagonist", "Sustained release formulation containing AII antagonist", "Sustained release formulation containing a combination of sustained release formulation containing two or more drugs", "hypertension drug, hypoglycemic agent, hyperlipidemia treatment" Sustained-release preparation containing one or more drugs selected from drugs, antithrombotic drugs, menopausal drug and anticancer drug "
And "AII antagonist and one or more drugs selected from antihypertensive drug, hypoglycemic drug, hyperlipidemia drug, antithrombotic drug, menopausal drug and anticancer drug" The "sustained release drug" will be described in detail.

[Sustained Release Preparation Containing AII Antagonist] As a preferred embodiment of the sustained release preparation containing an AII antagonist, an AII antagonist [for example, a compound having angiotensin II antagonistic action as described above, or a prodrug thereof] Or a salt thereof (hereinafter, these may be collectively referred to as a compound having an AII antagonistic action)], a biodegradable polymer and, if desired, a sustained-release preparation containing a polyvalent metal. Examples of the production method include a compound having an AII antagonistic action, a biodegradable polymer, and a method of removing a solvent from a liquid containing a polyvalent metal, if desired. A polyvalent metal may be contained in the liquid by using a composite of a polyvalent metal with either or both of the polyvalent polymers as a raw material. By adding the group compound may contain a polyvalent metal in the solution. In addition, a part or all of the added polyvalent metal compound may form a complex with either or both of the compound having an AII antagonistic action and the biodegradable polymer in the liquid.

The compounding amount of the compound having an AII antagonistic action in the sustained-release preparation containing the AII antagonist is different depending on the kind of the compound having an AII antagonistic action, a desired pharmacological effect and the duration of the effect. When the sustained-release preparation containing a drug is composed of a compound having an AII antagonistic effect and a biodegradable polymer, the amount of the compound having an AII antagonistic effect and the biodegradable polymer is usually about 1 to about 50% by weight, more preferably about 5 to about 45% by weight. Further, in the case of being composed of a compound having an AII antagonism, a polyvalent metal compound and a biodegradable polymer, the sum of the three of the compound having an AII antagonism, the polyvalent metal compound and the biodegradable polymer The compound having an AII antagonism is usually about 1 to about 50.
%, More preferably about 15-45% by weight, while
The polyvalent metal compound is usually about 0 to about 20% by weight, more preferably about 2 to about 15% by weight.

The sustained-release preparation containing an AII antagonist may further contain (D ') a component obtained by treating a poorly water-soluble polyvalent metal compound with water. The "component obtained by water-treating a poorly water-soluble polyvalent metal compound" means a physiologically active compound (preferably a poorly water-soluble physiologically active compound) or a water-insoluble polyvalent metal compound alone. / And a component produced by water treatment in the presence of a biodegradable polymer,
It is possible to easily achieve controlled release or stabilization of a physiologically active compound (preferably a sparingly water-soluble physiologically active compound) by changing the treatment conditions and environment. The water treatment is a treatment for a short time, for example, within 1 hour, preferably within 30 minutes, more preferably within 10 minutes, particularly preferably. The amount of water added varies depending on the amount of the polyvalent metal compound, the type and amount of the physiologically active compound, the type and amount of the biodegradable polymer, and the type and amount of the organic solvent solution of the biodegradable polymer. It is generally selected from the range of 3-500%, more preferably 5-300%, based on the weight of the polyvalent metal compound. The water to be added does not have to be partially dissolved in the organic solvent of the biodegradable polymer, and it is preferable to finely disperse and emulsify it by a known method such as a homogenizer or ultrasonic waves. In the water to be added, if necessary, a polyvalent metal compound (eg, zinc acetate), a basic amino acid (eg, arginine, histidine, lysine, etc.), albumin, gelatin, agar,
Dextrin, polyvinyl alcohol, carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, citric acid, sodium ethylenediaminetetraacetate, sodium hydrogen sulfite, a polyol compound (for example, polyethylene glycol), paraoxybenzoic acid esters ( (Methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added. Examples of the component obtained by water-treating a sparingly water-soluble polyvalent metal compound include, for example, a mixture of water and a sparingly water-soluble polyvalent metal compound, and a polyvalent sparingly soluble in water-treated water. Examples thereof include metal compounds. Here, the water-treated poorly water-soluble polyvalent metal compound may be a part or all of the poorly water-soluble polyvalent metal compound (unmodified form). In the process for producing the sustained-release preparation of the present invention, the water-treated poorly soluble polyvalent metal compound forms an emulsion with the organic solvent solution of the biodegradable polymer in the coexistence of water. Preferably, the inner phase contains a physiologically active compound (preferably a poorly water-soluble physiologically active compound), a water-insoluble polyvalent metal compound and water, and an outer phase contains an organic solvent of a biodegradable polymer. The sustained-release preparation of the present invention is preferably produced via an emulsion containing a solution, but by forming the emulsion in the coexistence of water, a stable and uniform emulsion system can be prepared in a short time. It is possible to

In the "component obtained by treating a poorly water-soluble polyvalent metal compound with water" of the present invention, a polyvalent metal which is the same as or different from the polyvalent metal used as the raw material (a polyvalent metal which has not been treated with water) is used. (A valent metal compound) may be present in a sustained-release preparation containing an AII antagonist, and such a polyvalent metal is used as a polyvalent metal compound (a compound with an inorganic substance or an organic substance or a metal oxide). It may be present or may be present as a metal ion, and may form a complex with any one or both of a physiologically active compound, a prodrug thereof or a salt thereof and a biodegradable polymer. Good. A preferred method for producing a sustained-release preparation containing an AII antagonist is obtained by subjecting a physiologically active compound (preferably a sparingly water-soluble physiologically active compound) and a water-insoluble polyvalent metal compound to water treatment. Examples include a method of removing water and a solvent from a liquid containing the component and the biodegradable polymer. By using a complex of a polyvalent metal with either or both of a physiologically active compound and a biodegradable polymer as a raw material, the liquid is treated with a "component obtained by water treatment of a water-insoluble polyvalent metal compound". It may contain a polyvalent metal other than the polyvalent metal derived from, "of the water treatment of the polyvalent metal compound at the time of the preparation of the" component obtained by water treatment of a poorly soluble polyvalent metal compound " At this time, the liquid may contain a polyvalent metal other than the polyvalent metal derived from the “component obtained by water treatment of the sparingly water-soluble polyvalent metal compound” by being added to water. A part or all of the polyvalent metal other than the polyvalent metal derived from the “component obtained by water treatment of a poorly water-soluble polyvalent metal compound” is a physiologically active compound and a biodegradable polymer in the liquid. A complex with either one or both of them may be formed.

The compounding amounts of the physiologically active compound and the "component obtained by water treatment of a poorly water-soluble polyvalent metal compound" in the sustained-release preparation containing the AII antagonist are selected depending on the kind of the physiologically active compound and the desired amount. Depending on the pharmacological effect and the duration of the effect, etc., physiologically active compounds, "components obtained by water treatment of poorly water-soluble polyvalent metal compounds" and biodegradable polymers are used as starting materials. The physiologically active compound is generally about 1 to about 50% by weight, more preferably about 15 to 45% by weight, and particularly preferably about 20 to 10% by weight.
40% by weight, on the other hand, the "poorly water-soluble polyvalent metal compound to be treated with water" is usually about 0.5 to about 20% by weight, more preferably about 1 to about 15% by weight, particularly preferably about 2%. ~ About 1
It is 0% by weight.

The form of the sustained-release preparation containing the AII antagonist is
Although not particularly limited, parenteral preparations are preferable, and transdermal
Consideration of administration agents, implants, microcapsule injections, etc.
However, the sustained release period is long and the burden on the patient is small.
Injectable formulation using non-microcapsules is preferred
Yes. AII antagonistic compounds and biodegradability
Sustained release formulations containing polymers, eg microcaps
Made of cells (sometimes referred to as microspheres below)
The construction method will be illustrated. (I) Underwater drying method (I) O / W method Biodegradable polymer in organic solvent solution
AII antagonism to achieve the weight ratio shown
Compound, or even a polyvalent metal compound, “poorly soluble in water
Component obtained by treating polyvalent metal compound with water ", if desired
Further, water is added to contain a compound having an AII antagonistic effect.
An organic solvent solution of the biodegradable polymer is prepared. this
When a compound having an AII antagonistic effect, a polyvalent metal compound
Each of the substances is dissolved in an organic solvent solution of biodegradable polymer.
Part may not be dissolved and may be dispersed, with a homogenizer
Or disperse more finely by a known method such as ultrasonic wave.
Is preferred. Examples of the organic solvent include halogenated compounds.
Hydrocarbons (eg dichloromethane, chloroform, dichloromethane
Loethane, trichloroethane, carbon tetrachloride, etc.), ete
(Eg ethyl ether, isopropyl ether
Etc.), fatty acid ester (eg, ethyl acetate, butyl acetate)
Etc.), aromatic hydrocarbons (eg, benzene, toluene, xy
Ren, etc.), alcohols (eg, ethanol, methano)
Etc.), acetonitrile, etc. are used. They are
You may mix and use it in an appropriate ratio. Among them, halogen
Dichloromethane is a hydrocarbon
Ethanol and methanol are preferable. They are
You may mix and use it in an appropriate ratio. With dichloromethane
Alcohol to be combined has AII antagonism
When the compound to be treated has, for example, a tetrazolyl group,
Tanol is preferred, for example 4,5-dihydro-5-o.
Having a xo-1,2,4-oxadiazol-3-yl group
If so, methanol is preferred. Organic solvent above
Additives may be added to the solution. Examples of the additive include
For example, as a solubilizer to maintain the stability and solubility of the drug
Carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, etc.
Sodium chloride, arginine, lysine and their salts, etc.
May be added. In addition, as a drug stabilizer
Albumin, gelatin, citric acid, ethylene diami
Sodium tetraacetate, dextrin, sodium bisulfite
Polyol compounds such as um and polyethylene glycol
Or as a preservative
Cibenzoate (eg, methylparaben, propyl
Paraben, etc.), benzyl alcohol, chlorobutano
, Thimerosal, etc. may be added. Biodegradable
The concentration of the limer in the organic solvent solution depends on the biodegradable polymer.
Depending on the molecular weight of the solvent and the type of organic solvent,
For example, when dichloromethane is used as an organic solvent,
Typically about 0.5 to about 70% by weight, more preferably about 1 to
From about 60% by weight, particularly preferably from about 2 to about 50% by weight
To be elected. Also, as a mixed organic solvent with dichloromethane
Mixed with ethanol or methanol
The ratio of dichloromethane in the organic solvent is generally about 10
To about 99% by volume, more preferably about 20 to about 98% by volume
%, Particularly preferably about 30 to about 95% by volume.
It Then, the obtained compound having an AII antagonistic action,
Or even more polyvalent metal compounds, "polyvalent metal which is hardly soluble in water
Components obtained by treating a genus compound with water ", if desired
Aqueous solution of biodegradable polymer containing water in organic solvent
In addition, it forms an O (oil phase) / W (water phase) emulsion
After that, the solvent in the oil phase is evaporated and the microcapsules are removed.
To prepare. The volume of the water phase at this time is generally the volume of the oil phase.
To about 10,000 times, more preferably about 5 times
About 5,000 times, particularly preferably about 10 times to about 2,000 times.
It is selected from 0 times. Add an emulsifier to the above external water phase
Good. The emulsifier is generally a stable O / W emulsion
Any material can be used as long as it can form Specifically
Is, for example, an anionic surfactant (sodium oleate).
Um, sodium stearate, sodium lauryl sulfate
Etc.), nonionic surfactants (polyoxyethylene
Sorbitan fatty acid ester (Tween 80, Twi
(Tween 60, Atlas Powder Co., Ltd.), polyoxye
Tile castor oil derivative [HCO-60, HCO-50, Nikko Chemical
], Etc.), polyvinylpyrrolidone, polyvinylalco
, Carboxymethylcellulose, lecithin, gelatin
And hyaluronic acid are used. One of these
Or two or more types may be used in combination
Yes. The concentration at the time of use is preferably about 0.01 to 10 times.
% Range, more preferably about 0.05 to about 5 weight
Used in the range of%. Osmotic adjustment in the above external water phase
Agents may be added. As the osmotic pressure adjusting agent, an aqueous solution
If it does, it may be one that exhibits an osmotic pressure. The osmotic pressure adjustment
Examples of the agent include polyhydric alcohols and monohydric alcohols.
And monosaccharides, disaccharides, oligosaccharides and amino acids.
Or derivatives thereof. Polyvalent al above
Examples of the call include divalent alcohol such as glycerin.
, Arabitol, xylitol, adonitol, etc.
Pentahydric alcohols, mannitol, sorbitol, and
Hexahydric alcohols such as lucitol are used. Na
Of these, hexahydric alcohols are preferred, especially mannito.
Is preferred. Examples of the above monohydric alcohols include
For example, methanol, ethanol, isopropyl alcohol
And the like, of which methanol is preferred. Up
Examples of the above monosaccharides include arabinose and xylose.
Pentoses, ribose, 2-deoxyribose, etc.
Dough sugar, fructose, galactose, manose, sorbose
Hexacarbon sugars such as sucrose, rhamnose and fucose are used.
Of these, hexose sugars are preferred. As the above oligosaccharide,
For example, trisaccharides such as maltotriose and raffinose sugar
And tetrasaccharides such as stachyose are used.
Trisaccharides are preferred. Monosaccharides, disaccharides and oligos mentioned above
Examples of sugar derivatives include glucosamine and galacto
Such as samin, glucuronic acid, and galacturonic acid are used.
It As the above amino acids, if the L-form
Both can be used, for example, glycine and leucine.
And arginine. Of these, L-Argi
Nin is preferred. These osmolality regulators should be used alone
Alternatively, they may be mixed and used. 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. With a method to remove solvents such as organic solvents and water
For this, a method known per se or a method equivalent thereto is used.
Can be For example, a propeller stirrer or magnetic
Atmospheric pressure or gradually decrease while stirring with a stirrer, etc.
Method to evaporate the solvent by applying pressure, rotary evaporation
Evaporate the solvent while adjusting the vacuum level using a
There is a method of making it. Ma obtained in this way
Ikuro capsules are separated by centrifugation or filtration,
AII antagonism on the surface of microcapsules
Distilled water containing compounds, drug-holding substances, emulsifiers, etc.
Wash repeatedly several times, disperse again in distilled water and freeze-dry.
To dry. Aggregate to prevent particles from aggregating during the manufacturing process
Inhibitors may be added. As the anti-agglomeration agent, for example,
For example, mannitol, lactose, glucose, starches
Glycine, a water-soluble polysaccharide such as corn starch
Such as amino acids, fibrin, tamper such as collagen
Quality is used. Of these, mannitol is preferred
Is. In addition, after freeze-drying, if necessary,
Microphones are heated under conditions where the black capsules do not fuse together
The water and organic solvent in the capsule may be removed.
Yes. Preferably, under the condition of the heating rate of 10 to 20 ° C. per minute.
Of the biodegradable polymer determined by a differential scanning calorimeter
Heating is carried out at a temperature slightly higher than the glass transition temperature between points. Yo
More preferably, the midpoint glass transition of the biodegradable polymer
Warm up within the temperature range about 30 ℃ higher than the transfer temperature
It In particular, lactic acid-glycan as a biodegradable polymer
When using a cholic acid polymer, it is preferable that the midpoint thereof be used.
10 ° C higher than the midpoint glass transition temperature above the glass transition temperature
Temperature range, more preferably the midpoint glass transition temperature
Heating at a temperature range 5 ° C higher than the midpoint glass transition temperature
To do. The heating time depends on the amount of microcapsules, etc.
However, in general, the microcapsules themselves
After reaching the temperature, about 12 hours to about 168 hours, preferably
About 24 hours to about 120 hours, particularly preferably about 48 hours
It is between about 96 hours. The heating method is microcapsule
Is not particularly limited as long as it can uniformly heat the set of
Yes. Examples of the heating and drying method include a constant temperature bath and a flow
Method of heating and drying in a tank, moving tank or kiln, microphone
A method of heating and drying with a microwave is used. In this
A method of heating and drying in a constant temperature bath is preferable. Also microphone
The removal of water and organic solvent in the capsule
Body (CO _TwoEtc.) or carbon dioxide in high pressure gas state
It can also be done in any way.

(Ii) W / O / W Method A compound having an AII antagonistic action is dissolved in water, and if necessary, a polyvalent metal compound (eg zinc acetate), a basic amino acid (eg arginine, A drug holding substance such as histidine, lysine), gelatin, agar or polyvinyl alcohol is added and dissolved to obtain an inner aqueous phase. The concentration of the drug in the inner aqueous phase is generally selected from about 0.1 to 80% by weight, more preferably about 1 to 70% by weight, particularly preferably about 2 to 60% by weight. In the inner aqueous phase, carbonic acid, as a pH adjusting agent for maintaining the stability and solubility of the drug,
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, a polyol compound such as polyethylene glycol, or the like, or a preservative, commonly used paraoxybenzoic acid esters (Methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added. The internal water phase thus obtained is
In some cases, it is added to an organic solvent solution (oil phase) of a biodegradable polymer which may contain a polyvalent metal, and this mixture is emulsified by a known method such as a homogenizer or ultrasonic waves to obtain a W / O emulsion. Let it form. Examples of the above-mentioned 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. Of these, halogenated hydrocarbons are preferable, and dichloromethane is particularly preferable. Although 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 about 6%.
0% by weight, particularly preferably from about 2 to about 50% by weight. Then, the W / O emulsion containing the obtained compound having an AII antagonistic action and the biodegradable polymer is added to the aqueous phase (outer aqueous phase) to give W (internal aqueous phase) / O (oil phase) / W. (Outer water phase) After forming an emulsion, the solvent in the oil phase is evaporated to prepare microcapsules. The volume of the external water phase at this time is generally about 1 to 1 times the volume of the oil phase.
10,000 times, more preferably about 5 times to about 5,000 times.
Double, particularly preferably about 10 times to about 2,000 times. The emulsifiers and osmotic pressure regulators that may be added to the external water phase and the preparation method thereafter are the same as those described in the above item (I) (i).

(II) Phase Separation Method In the case of producing microcapsules by this method, the compound having an AII antagonistic action described in the above-mentioned (I) in-water drying method, or a polyvalent metal compound, “a water-resistant compound” is used. A component obtained by treating a soluble polyvalent metal compound with water ", and optionally a coacervation agent is gradually added to an organic solvent solution of a biodegradable polymer containing water with stirring to precipitate and solidify microcapsules. . The coacervation agent is about 0.01 to 1,000 times, preferably about 0.05 to 500 times, and particularly preferably about 0.1 to 2 times the volume of the oil phase.
It is selected from 00 times. As a coacervation agent,
There is no particular limitation as long as it is a polymer-based compound, a mineral oil-based compound, a vegetable oil-based compound or the like that is miscible with an organic solvent and does not dissolve both the compound having an AII antagonistic action 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, etc. are used. You may use these in mixture of 2 or more types. The microcapsules thus obtained are collected, and then repeatedly washed with heptane or the like to remove the compound having an AII antagonistic effect and the coacervation agent other than the biodegradable polymer, and dried under reduced pressure. Alternatively, the above (I)
After washing in the same manner as described in the underwater drying method (i), freeze-drying and further warm drying are performed.

(III) Spray Drying Method In the case of producing microcapsules by this method, a compound having an AII antagonistic action described in the above (I) in-water drying method, or a polyvalent metal compound, “a water-resistant compound” is used. A component obtained by treating a soluble polyvalent metal compound with water, further spraying an organic solvent solution of a biodegradable polymer containing water into a drying chamber of a spray dryer (spray dryer) using a nozzle, 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 may be carried out by the same method as described in the underwater drying method (I), followed by freeze-drying and further warm drying. As a dosage form other than the above-mentioned microcapsules, AII described in the in-water drying method of manufacturing method (I) of microcapsules
A compound having an antagonistic effect, or a polyvalent metal compound, “a component obtained by treating a poorly water-soluble polyvalent metal compound with water”, and further an organic solvent solution of a biodegradable polymer containing water, if desired, For example, the organic solvent and water may be evaporated to dryness while adjusting the degree of vacuum using a rotary evaporator or the like, and then pulverized by a jet mill or the like to obtain fine powder. Furthermore, the pulverized fine powder may be subjected to washing by the same method as described in the in-water drying method of the microcapsule production method (I), followed by freeze-drying and further heat-drying. With the microcapsules or fine powders obtained here, drug release can be controlled according to the decomposition rate of the biodegradable polymer used or the type and amount of the added polyvalent metal compound. Sustained-release preparations containing AII antagonists can be formulated into various dosage forms as they are or as raw materials, and injected or implanted into intramuscular, subcutaneous, organ, nasal cavity, rectum, uterus, etc. As a transmucosal agent, an oral agent (eg, capsules (eg, hard capsules, soft capsules, etc.), granules, solid preparations such as powders, syrups, emulsions, liquid preparations such as suspensions), etc. B) in combination with a sustained-release preparation containing one or more drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents, It can be administered as a single formulation or as separate formulations. It can also be administered by a needleless syringe. For example, in order to prepare sustained-release preparations containing an AII antagonist as injections, these are dispersed (eg, Tween (Twee
n) Surfactants such as 80, HCO-60, polysaccharides such as sodium hyaluronate, carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride) , Mannitol, sorbitol, glucose, proline, etc.) or an aqueous suspension, or 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. . When used as a suspension injection, the particle size of the sustained-release preparation containing the AII antagonist may be within a range satisfying the degree of dispersion and needle penetration, for example, an average particle size of about 0. 1 to 30
0 μm, preferably about 0.5 to 150 μm, more preferably about 1 to 100 μm. Examples of aseptic preparations of sustained-release preparations containing AII antagonists include, but are not limited to, a method of sterilizing all manufacturing steps, a method of sterilizing with gamma rays, and a method of adding a preservative.

Since the sustained-release preparation containing the AII antagonist has low toxicity, it is a safe drug for mammals (eg, human, cow, pig, dog, cat, mouse, rat, rabbit, etc.). Can be used as The dose of the sustained-release preparation containing the AII antagonist is the type and content of the main compound having AII antagonistic action, the type and content of the concomitant drug, the dosage form,
Although it varies depending on the duration of release of the compound having an AII antagonism, target disease, target animal, etc., an effective amount of the compound having an AII antagonism may be used. The dose per administration of the compound having an AII antagonistic action is preferably, for example, when the sustained-release preparation is a one-month preparation,
Range of about 0.01 mg to 10 mg / kg body weight per adult, more preferably about 0.05 mg to 5 mg / kg
It can be appropriately selected from the range of body weight. AI per session
The dose of the sustained release preparation containing the I antagonist is preferably in the range of about 0.05 mg to 50 mg / kg body weight per adult, more preferably about 0.1 mg to 30 mg / k.
It can be appropriately selected from the range of g body weight. The frequency of administration is
AI every few days, once every few weeks, once every month, or once every few months (eg, 3 months, 4 months, 6 months, etc.)
I Compound type and content having antagonistic activity, dosage form, AII
Duration of release of compound having antagonistic effect, target disease,
It can be appropriately selected depending on the target animal and the like.

[Sustained release preparation containing one or more drugs selected from antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug and anticancer drug] Hypertension One or two or more (preferably two to three) drugs selected from therapeutic agents, hypoglycemic agents, hyperlipidemia therapeutic agents, antithrombotic agents, climacteric disorder therapeutic agents and anticancer agents (hereinafter,
It may be abbreviated as a concomitant drug. The sustained-release preparation containing) contains the "AII antagonist" in the above-mentioned "sustained-release preparation containing an AII antagonist" (for example, the compound having angiotensin II antagonistic activity described above, a prodrug thereof, or a salt thereof). The same as in place of "one or more (preferably 2-3) drugs selected from antihypertensive drug, hypoglycemic drug, hyperlipidemia drug, antithrombotic drug, menopausal drug and anticancer drug" In addition, it can be formulated into a sustained-release preparation (eg, microcapsules, microcapsule injections, implants, etc.) and carried out.

Sustained-release preparations containing concomitant drugs may be formulated into various dosage forms as they are or as raw materials, and may be intramuscularly, subcutaneously, injected or implanted into organs, nasal cavity, rectum, uterus. Transmucosal agents, oral agents (eg,
Sustained release containing (A) AII antagonist as a capsule (eg, hard capsule, soft capsule, etc.), granule, solid preparation such as powder, syrup, emulsion, liquid such as suspension) It can be administered as a single formulation or as separate formulations in combination with a sex formulation.

Sustained-release preparations containing a concomitant drug have low toxicity, so that mammals (eg, humans, cows, pigs, dogs, cats,
It can be used as a safe drug for mice, rats, rabbits, etc.). The dose of the sustained-release preparation containing the concomitant drug varies depending on the type and content of the concomitant drug, dosage form, duration of concomitant drug release, target disease, target animal, etc. I wish I had it. As a single dose of the concomitant drug, for example, when the sustained-release preparation is a one-month preparation, it is preferably in the range of about 0.01 mg to 200 mg / kg body weight per adult, more preferably about 0.05 mg. It can be appropriately selected from the range of up to 150 mg / kg body weight. The dose of the sustained-release preparation containing the concomitant drug per administration is preferably about 0.05 mg to 5 per adult.
It can be appropriately selected from the range of 0 mg / kg body weight. Once a few days, once a few weeks, once a month,
Or every few months (eg, 3 months, 4 months, 6 months, etc.)
It can be appropriately selected depending on the dose, type and content of concomitant drug, dosage form, duration of release of concomitant drug, target disease, target animal, and the like.

An example of a specific formulation method and implementation method will be shown below by taking GnRH agonist / antagonist as an anticancer drug. A GnRH agonist or antagonist as described above (preferably of the formula 5-oxo-Pro-His-Trp-Ser-Tyr-
Peptide represented by DLeu-Leu-Arg-Pro-NH-C ₂ H ₅ or a salt thereof (hereinafter sometimes simply referred to as “leuprorelin or a salt thereof”), more preferably leuprorelin acetate Is preferably administered as a sustained release injection.
When the sustained-release preparation is a sustained-release microcapsule, it is preferably a long-term sustained-release microcapsule that releases a GnRH agonist or antagonist over 2 months or longer. Sustained-release preparations (particularly sustained-release microcapsules) containing the above GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) can be prepared by a method known per se, for example, JP-A-60-100516,
JP-A-62-201816, JP-A-4-321622
No. 6, JP-A-6-192068, JP-A No. 9-13252
4, JP-A-9-221417, and JP-A-11-279.
It can be produced according to the method described in No. 054, WO 99/36099, or the like. Among the above sustained-release preparations, "long-term sustained-release type microcapsules that release zero-order physiologically active substances over zero months" described in JP-A-4-321622 are particularly preferably used.

An example of the method for producing the above sustained release microcapsules will be described below. First, about 20% to 70% (W / W), preferably 25 to 65% of GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) is added to water.
(W / W), more preferably 35 to 60% (W / W), and if necessary, a drug-holding substance such as gelatin or basic amino acid is dissolved or suspended to obtain an internal aqueous phase liquid. . A GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) is contained in the inner aqueous phase liquid.
Carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and salts thereof may be added as a pH adjusting agent for maintaining the stability and solubility of the. Further, further as a stabilizer of GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate), albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, Paraoxybenzoic acid esters (methylparaben, etc.) commonly used as a polyol compound such as polyethylene glycol or as a preservative.
Propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added. The thus obtained inner aqueous phase liquid is added to a solution (oil phase) containing a polymer, and then an emulsification operation is performed to prepare a W / O type emulsion. As the emulsification operation, a known dispersion method is used, for example, a method using a mixer such as an intermittent shaking method, a propeller type stirrer or a turbine type stirrer, a colloid mill method, a homogenizer method, an ultrasonic irradiation method. And so on. Then, the W / O prepared in this way
Type emulsion is subjected to microencapsulation process,
An in-water drying method or a phase separation method can be applied as the step. When the microcapsules are produced by the in-water drying method, the W / O emulsion is further added to the aqueous phase of the third phase to form a W / O / W type three-phase emulsion, and then the oil phase in the oil phase is added. The solvent is evaporated and microcapsules are prepared. An emulsifier may be added to the aqueous phase of the outer phase, and examples thereof include any one that generally forms a stable O / W type emulsion. For example, an anionic surfactant (sodium oleate, Sodium stearate, sodium lauryl sulfate, etc., nonionic surfactant (polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween 60, Atlas Powder Co.],
Polyoxyethylene castor oil derivative [HCO-60, H
CO-50, Nikko Chemicals, etc.), or polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, etc., and one of these may be used, or some of them may be used in combination. When used, the concentration is about 0.01% to 2
It can be appropriately selected from the range of 0%, more preferably about 0.0
Used in the range of 5% to 10%. A commonly used method is adopted for evaporation of the solvent in the oil phase. As the method, the pressure is gradually reduced while stirring with a propeller stirrer, a magnetic stirrer, or the like, or while the degree of vacuum is adjusted using a rotary evaporator or the like. In this case, when the solidification of the high molecular weight polymer has progressed to a certain extent, W
The time required can be shortened by gradually heating the / O / W type emulsion. The microcapsules thus obtained are separated by centrifugation or filtration, and then the free GnRH adhering to the surface of the microcapsules is attached.
Agonists or antagonists (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate), drug-holding substances, emulsifiers, etc. are repeatedly washed several times with distilled water, and then dispersed again in distilled water or the like. Lyophilize. At this time, an anti-aggregation agent (eg, mannitol, sorbitol, lactose, glucose, etc.) may be added. If necessary, heating is performed, and the water and organic solvent in the microcapsules are desorbed more completely under reduced pressure. When producing microcapsules by the phase separation method,
A coacervation agent is gradually added to the W / O emulsion with stirring to precipitate and solidify a polymer. As the coacervation agent, a polymer system miscible with a solvent of a polymer, a mineral oil system or a vegetable oil system compound, as long as it does not dissolve the encapsulating polymer, for example, silicon oil, Sesame oil, soybean oil, corn oil,
Examples include cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like. You may use these in mixture of 2 or more types. The microcapsules thus obtained are filtered and separated, and then repeatedly washed with heptane or the like to remove the coacervation agent. Further, the free drug and the solvent are removed by the same method as the in-water drying method. To prevent the agglomeration of particles during washing,
An agglomeration inhibitor may be added. The microcapsules obtained above are lightly crushed if necessary, and then sieved to remove the oversized microcapsule portions. The average particle size of the microcapsules is about 0.5 to 1000 μm.
It is desirable to be in the range of about 2 to 500 μm. When used as a suspension injection, it may be in a range satisfying the dispersibility and needle penetration, and for example, it is preferably in the range of about 2 to 100 μm.

Examples of the above-mentioned polymer include biodegradable polymers such as α-hydroxymonocarboxylic acids (eg, glycolic acid, lactic acid), α-hydroxydicarboxylic acids (eg, malic acid), α-hydroxy. Polymers, copolymers, or mixtures thereof synthesized from one or more α-hydroxycarboxylic acids such as tricarboxylic acid (eg, citric acid) and having a free carboxyl group; poly (α
-Cyanoacrylic acid ester); polyamino acid (eg, poly (γ-benzyl-L-glutamic acid), etc.); maleic anhydride copolymer (eg, styrene-maleic acid copolymer, etc.) and the like are used. The monomer binding mode is
It may be random, block or graft. When the above α-hydroxymonocarboxylic acids, α-hydroxydicarboxylic acids and α-hydroxytricarboxylic acids have an optically active center in the molecule, D-, L-, D
Any of the L-form may be used. Among these, lactic acid-glycolic acid polymer (hereinafter referred to as poly (lactide-co-
Sometimes referred to as glycolide), poly (lactic acid-co-glycolic acid) or lactic acid-glycolic acid copolymer,
Unless otherwise specified, homopolymers (polymers) and copolymers of lactic acid and glycolic acid are collectively referred to.
Lactic acid homopolymer may be referred to as lactic acid polymer, polylactic acid, polylactide, etc., and glycolic acid homopolymer may be referred to as glycolic acid polymer, polyglycolic acid, polyglycolide, etc.), poly (α-cyanoacrylic acid). (Ester) and the like are preferable. More preferably, lactic acid-
It is a glycolic acid polymer, and more preferably a lactic acid-glycolic acid polymer having a free carboxyl group at the terminal. The biodegradable polymer may be a salt. Examples of the salt include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium) and organic bases (eg, organic amines such as triethylamine, basic amino acids such as arginine). Etc.) and the like, or salts with transition metals (eg, zinc, iron, copper, etc.) and complex salts. When a lactic acid-glycolic acid polymer is used as the biodegradable polymer, its composition ratio (mol%) is about 100/0 to about 40/6.
0 is preferable and about 100/0 to about 50/50 is more preferable. Further, in the case of long-term sustained release type microcapsules that release zero-order physiologically active substances over 2 months or more, lactic acid homopolymer having a composition ratio of 100/0 is also preferably used. The optical isomer ratio of lactic acid, which is one of the minimum repeating units of the “lactic acid-glycolic acid polymer”, is D-form / L-form.
Those having a body (mol / mol%) range of about 75/25 to about 25/75 are preferred. As the D-form / L-form (mol / mol%), those having a range of about 60/40 to about 30/70 are generally used. The weight average molecular weight of the "lactic acid-glycolic acid polymer" is usually about 3,000 to about 100,000.
0, preferably about 3,000 to about 60,000, more preferably about 3,000 to about 50,000 is used. In addition, the dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5. The amount of free carboxyl groups of the “lactic acid-glycolic acid polymer” is usually about 20 to about 1000 μmol per unit mass (gram) of the polymer.
(Micromolar) is preferable, and further about 40 to about 10
00 μmol (micromol) is particularly preferred. The above-mentioned weight average molecular weight, number average molecular weight and dispersity mean that the weight average molecular weight is 1,110,000, 707,000, 45.
5,645,354,000,189,000,15
6,055, 98,900, 66,437, 37,20
0, 17, 100, 9, 830, 5,870, 2,50
The molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC) using 15 kinds of monodisperse polystyrene of 0, 1, 303, and 504 as reference substances and the calculated dispersity. A high-speed GPC device (manufactured by Tosoh Corp., HLC-8120GPC, detection method depends on differential refractive index), GPC column KF804L × 2 (manufactured by Showa Denko KK) is used for measurement, and chloroform is used as a mobile phase. The flow rate is 1 ml / min. The amount of the above free carboxyl group was obtained by the labeling method (hereinafter,
It is referred to as "the amount of carboxyl groups by the labeling method"). Specifically, in the case of polylactic acid, polylactic acid Wmg was added to 5N hydrochloric acid / acetonitrile (v / v = 4 /
96) It was dissolved in a mixed solution of 2 ml, and 0.01M o-nitrophenylhydrazine hydrochloride (ONPH) solution (5N hydrochloric acid /
Acetonitrile / Ethanol = 1.02 / 35/15)
2 ml and 0.15 M 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride solution (pyridine / ethanol = 4v / 96v) 2 ml were added, and the temperature was 40 ° C.
After reacting for 30 minutes, the solvent is distilled off. Wash the residue with water (4
After 2 times), dissolve in 2 ml of acetonitrile, 0.5 m
1 ml of ethanolic potassium hydroxide solution of ol / l is added, and the mixture is reacted at 60 ° C. for 30 minutes. The reaction solution was diluted with a 1.5N sodium hydroxide aqueous solution to make Yml, and a 1.5N sodium hydroxide aqueous solution was used as a target to absorb at 544 nm.
(/ Cm) is measured. On the other hand, using the DL-lactic acid aqueous solution as a reference substance, the amount of free carboxyl groups Cmol / L
Is determined by alkali titration, and DL is also determined by the ONPH labeling method.
-Specify the absorbance at 544 nm when using lactic acid hydrazide as B
(/ Cm), the molar amount of the free carboxyl group per unit mass (gram) of the polymer is calculated by the following mathematical formula. [COOH] (mol / g) = (AYC) / (WB) Further, the "amount of carboxyl group" is obtained by dissolving the biodegradable polymer in a toluene-acetone-methanol mixed solvent,
It is also possible to titrate the carboxyl group of this solution with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator (hereinafter, the value obtained by this method is referred to as "the amount of carboxyl group by the alkali titration method"), As a result of competing with the hydrolysis reaction of the polyester main chain during titration, the end point of titration may become unclear, and it is desirable to quantify by the above labeling method. The "lactic acid-glycolic acid polymer" is, for example, a catalyst-free dehydration polycondensation from lactic acid and glycolic acid (JP-A-61-28521) or a ring-opening using a catalyst from a cyclic diester compound such as lactide and glycolide. Polymerization (Encyclopedic Handbook of Bi
omaterials and Bioengineering Part A: Materials, V
olume 2, Marcel Dekker, Inc. 1995).
The polymer obtained by the above known ring-opening polymerization method,
Although the obtained polymer does not always have a free carboxyl group at the end, for example, EP-A-083952
By subjecting it to the hydrolysis reaction described in No. 5, a polymer having a certain amount of carboxyl groups per unit mass can be modified, and this can also be used. The above-mentioned "lactic acid-glycolic acid polymer having a free carboxyl group at the end" is the same as a known production method (for example, non-catalyst dehydration polycondensation method, see JP-A-61-28521) or a method similar thereto. It can be manufactured by the method. To use the microcapsules as an injection, the microcapsules are a dispersant (eg, Tween 80, HCO-60, carboxymethyl cellulose, sodium alginate, etc.), a preservative.
(Eg, methylparaben, propylparaben, etc.), isotonicity agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. The drug is a sustained-release injection that can be actually used.

A sustained-release preparation (preferably leuprorelin or a salt thereof, preferably a leuprorelin acetate or a salt thereof, more preferably leuprorelin acetate) containing the above-mentioned GnRH agonist or antagonist (preferably leuprorelin acetate or a salt thereof). (Leuprorelin acetate) containing a sustained-release microcapsule), combined with a sustained-release preparation containing an AII antagonist, subcutaneously,
It can be easily administered intramuscularly, in blood vessels and the like (preferably subcutaneously and the like) as injections and implants (preferably injections and the like). In addition, it can be molded into various other formulations described above and administered, and can also be used as a raw material when producing such a formulation. Also, GnRH
The dose of the sustained-release preparation containing an agonist or antagonist is the content of GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate), and the combination of AII.
Dosage, dosage form, duration of GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) of a sustained-release preparation containing an antagonist, an animal to be administered [eg, temperature] Blood mammal
(E.g., human, mouse, rat, rabbit, sheep, pig,
The effective amount of the GnRH agonist or antagonist (preferably leuprorelin or its salt, more preferably leuprorelin acetate) as a prophylactic / therapeutic agent for prostate cancer, breast cancer, etc. If For example, a single dose for the warm-blooded mammal is in the range of about 0.01 mg to 100 mg / kg body weight, preferably about 0.02 mg to 50 mg / kg body weight, more preferably 0.05 mg to 20 mg / kg body weight. Can be selected as appropriate. When a sustained release preparation containing the GnRH agonist or antagonist is administered as an injection, for example, in an adult prostate cancer patient (with a body weight of 60 kg), a GnRH agonist or antagonist (preferably, once) Leuprorelin or a salt thereof, more preferably leuprorelin acetate) is usually about 0.01 to 50 mg, preferably about 0.1 to 20 mg, more preferably about 0.1 to 15 mg subcutaneously or intramuscularly. May be administered to. Further, for example, the above-mentioned GnRH agonist or antagonist (preferably leuprorelin or a salt thereof,
More preferably, when the prophylactic / therapeutic agent for prostate cancer containing sustained-release microcapsules containing leuprorelin acetate) is administered as an injection, administration is performed depending on the drug sustained-release period of the sustained-release microcapsules. When the doses are different and, for example, the administration is performed about once a month, for example, in an adult prostate cancer patient (relative to a body weight of 60 kg), the GnRH agonist or antagonist (preferably leuprorelin or the same) is administered once. A salt, more preferably leuprorelin acetate) is usually administered in an amount of about 0.01 to 20 mg, preferably about 0.1 to 10 mg, more preferably about 0.1 to 5 mg subcutaneously or intramuscularly. For example, when the administration is performed about once every 3 months, for example, in adult prostate cancer patients (weight 60 kg), GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) is usually about 0.1 to 30 mg, preferably about 0.1 to 20 m
About g, more preferably about 1 to 15 mg may be administered subcutaneously or intramuscularly. Also in the case of other animals, the dose converted per 60 kg of body weight can be administered. Further, a sustained-release preparation containing a GnRH agonist or antagonist (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) is AII.
In combination with a sustained release formulation containing an antagonist,
It can also be administered in combination with an anti-estrogen agent (eg, Tamoxifen, etc.) for the prevention / treatment of prostate cancer, breast cancer, etc.

[Containing an AII antagonist and one or more drugs selected from antihypertensive drugs, hypoglycemic drugs, antihyperlipidemic drugs, antithrombotic drugs, anti-menopausal drugs and anticancer drugs Sustained-release medicine] AII antagonist and antihypertensive drug,
One or more (preferably 2-3) drugs selected from hypoglycemic agents, hyperlipidemia agents, antithrombotic agents, menopausal agents, and anticancer agents (hereinafter referred to as AII antagonists and concomitant drugs) May be abbreviated.) Is a sustained-release preparation containing "AII antagonist" in the above-mentioned "sustained-release preparation containing AII antagonist" as well as "hypertension therapeutic agent, hypoglycemic agent,
Hyperlipidemia therapeutic agent, antithrombotic agent, climacteric disorder therapeutic agent and anticancer agent, selected from one or more kinds (preferably 2 to
It can be similarly formulated into a sustained-release preparation (eg, microcapsules, microcapsule injections, implants, etc.) by adding (mixing) “three kinds of drugs” and carrying out the same.

The compounding amount of the AII antagonist and the concomitant drug in the sustained-release preparation containing the AII antagonist and the concomitant drug is
The sustained-release preparation (pharmaceutical composition) containing the AII antagonist and the concomitant drug is different depending on the type of the AII antagonist and the concomitant drug, the desired pharmacological effect, the duration of the effect, and the like. In the case of the biodegradable polymer, the composition ratio of the AII antagonist, the concomitant drug and the biodegradable polymer to the whole preparation is about 5 to 5 respectively.
About 50% by weight (preferably about 5 to about 40% by weight), about 0.1
To about 50 wt% (preferably about 0.1 to about 40 wt%) and about 0.1 to about 95 wt% (preferably about 1 to about 90 wt%)
Is. The ratio of the physiologically active compound in which the AII antagonist and the concomitant drug are combined is usually about 1 to about 90% by weight, based on the sum of the three factors of the AII antagonist, the concomitant drug, and the biodegradable polymer.
More preferably, it is about 5 to about 80% by weight. Further, when the sustained-release preparation containing the AII antagonist and the concomitant drug consists of four members, the AII antagonist, the concomitant drug, the polyvalent metal compound and the biodegradable polymer, the AII antagonist and the concomitant drug for the whole preparation The composition ratio of the polyvalent metal compound and the biodegradable polymer is about 1 to about 50% by weight (preferably about 15 to 45% by weight), about 0.1 to about 50% by weight (preferably about 0.1 to about 45% by weight). %), About 0.1 to about 20% by weight
(Preferably about 2 to about 15% by weight), and about 1 to about 90
% By weight (preferably about 5 to about 80% by weight). AII
The ratio of the physiologically active compound in which the AII antagonist and the concomitant drug are combined is usually about 1 to about 90% by weight based on the sum of the four factors of the antagonist, the concomitant drug, the polyvalent metal compound and the biodegradable polymer. , And more preferably about 5 to about 80% by weight.

In the sustained-release preparation containing the AII antagonist and the concomitant drug as well, as in the case of the above-mentioned "sustained-release preparation containing the AII antagonist", (D ') a poorly water-soluble preparation is further added. It may contain a component obtained by treating a valent metal compound with water, and can be prepared and used in the same manner as in the case of the “sustained release preparation containing an AII antagonist”.

The compounding amounts of the physiologically active compound and the “component obtained by water treatment of a poorly water-soluble polyvalent metal compound” in a sustained-release preparation containing an AII antagonist and a concomitant drug are
The physiologically active compound (AII antagonist and concomitant drug) depends on the kind of the physiologically active compound (AII antagonist and concomitant drug), the desired pharmacological effect and the duration of the effect, and the like. In the case of using "a component obtained by treating water with water" and a biodegradable polymer as a starting material, the sum of the physiologically active compound, that is, the AII antagonist and the concomitant drug is usually about 0.1 to
About 90% by weight, more preferably about 1-80% by weight, while
The "poorly water-soluble polyvalent metal compound to be treated with water" 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 preparation containing the AII antagonist and the concomitant drug is not particularly limited, but parenterally-administered preparations are preferable, and transdermal preparations, implants, microcapsule injections, etc. are considered. An injectable preparation using microcapsules, which has a long release period and a small burden on the patient, is preferable. A sustained release preparation containing an AII antagonist (compound having an AII antagonistic action), a concomitant drug and a biodegradable polymer, for example, a method for producing a microcapsule, is described above in "Sustained release containing AII antagonist" It can be manufactured in the same manner as "Preparation". That is, it can be produced according to the following methods (I) to (III) depending on the properties of the concomitant drug. (I) In-water drying method (i) O / W method A compound and a concomitant drug having an AII antagonistic action in an organic solvent solution of a biodegradable polymer in an organic solvent solution so as to have the weight ratio shown in the above blending amount, or more Metal compounds,
"Component obtained by water-treating a sparingly water-soluble polyvalent metal compound", if desired, water is further added to prepare an organic solvent solution of a biodegradable polymer containing a compound having an AII antagonistic action and a concomitant drug. . At this time, the compound having an AII antagonistic action, the concomitant drug, and the polyvalent metal compound may not be partially dissolved in the organic solvent solution of the biodegradable polymer and may be dispersed, and may be dispersed by a known homogenizer or ultrasonic wave. It is preferable to disperse more finely by the method. Examples of the organic solvent include the same ones as those exemplified in the method for producing the “sustained release preparation containing an AII antagonist”. Additives may be added to the above organic solvent solution. Examples of the additive include the same ones as those exemplified in the method for producing the “sustained release preparation containing an AII antagonist”. 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 It is selected from about 70% by weight, more preferably about 1 to about 60% by weight, particularly preferably 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 99% by volume, more preferably about 20 to about 98% by volume, Particularly preferably, it is selected from about 30 to about 95% by volume. Then, the obtained compound having an AII antagonistic action and a concomitant drug, or a polyvalent metal compound, “a component obtained by subjecting a poorly water-soluble polyvalent metal compound to water treatment”, and optionally a living body further containing water A solution of a degradable polymer in an organic solvent is added to an aqueous phase to form an O (oil phase) / W (aqueous phase) emulsion, and then the solvent in the oil phase is evaporated to prepare microcapsules. In this case, the volume of the aqueous phase is generally about 1 to about 1 times the volume of the oil phase.
10,000 times, more preferably about 5 times to about 5,000 times.
Double, particularly preferably about 10 times to about 2,000 times. An emulsifier may be added to the above external water phase. Examples of the emulsifier and the concentration at the time of use include the same as those exemplified in the method for producing the "sustained release preparation containing an AII antagonist". An osmotic pressure adjusting agent may be added to the above-mentioned external water phase. The osmotic pressure regulator may be any agent that exhibits an osmotic pressure when made into an aqueous solution. Examples of the osmotic pressure adjusting agent include the same ones as exemplified in the method for producing the “sustained release preparation containing an AII antagonist”. The osmotic pressure adjusting agent is used at a concentration such that the osmotic pressure of the outer aqueous phase is about 1/50 to about 5 times, preferably about 1/25 to about 3 times the osmotic pressure of physiological saline. Examples of the method for removing the solvent such as the organic solvent and water include the same methods as those described in the method for producing the “sustained release preparation containing an AII antagonist”. The microcapsules thus obtained are separated by centrifugation or filtration, and then attached to the surface of the microcapsules, the compound having an AII antagonistic activity,
The concomitant drug, drug-holding substance, emulsifier, etc. are repeatedly washed several times with distilled water, dispersed again in distilled water, etc., and freeze-dried. During the manufacturing process, an anti-agglomeration agent may be added to prevent the particles from aggregating. Examples of the aggregation inhibitor include the above-mentioned "AI
The same as those exemplified in the production method of the "sustained release preparation containing an I antagonist" can be mentioned. In addition, as in the case of the method for producing the “sustained release preparation containing an AII antagonist” described above, after lyophilization, if necessary, heating is performed under reduced pressure under conditions where microcapsules do not fuse together. The water and organic solvent in the microcapsules may be removed by removing the water.

(Ii) W / O / W Method The W / O / W method can be used in consideration of the solubilities of the compound having an AII antagonistic action and the concomitant drug in the aqueous phase and the oil phase. That is, it is possible to dissolve a plurality of compounds contained in the same phase to prepare a microcapsule, but they do not necessarily have to be dissolved in the same phase,
Microcapsules can also be prepared by dissolving in separate phases. A compound having an AII antagonistic effect and a concomitant drug are dissolved in water, and if necessary, a polyvalent metal compound (eg, zinc acetate), a basic amino acid (eg, arginine, histidine, lysine), gelatin, agar or A drug-retaining substance such as polyvinyl alcohol is added and dissolved to obtain an inner aqueous phase. The concentration of the compound having an AII antagonistic action and the concomitant drug in the inner aqueous phase is generally about 0.1 to 80% by weight, more preferably about 1 to 70% by weight, particularly preferably about 2 to 60% by weight. It is selected from%. In order to maintain the stability and solubility of the drug in the internal aqueous phase, the above "AII
PH similar to that shown in "Sustained release formulation containing antagonist"
A regulator may be added. The internal aqueous phase thus obtained is added to an organic solvent solution (oil phase) of a biodegradable polymer which may contain a polyvalent metal, depending on the case,
This mixture is emulsified by a known method such as a homogenizer or ultrasonic waves to form a W / O emulsion. Examples of the above-mentioned organic solvent include the same ones as those exemplified in the above-mentioned method for producing the “sustained release preparation containing an AII antagonist”. 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,
It is more preferably selected from about 1 to about 60% by weight, particularly preferably about 2 to about 50% by weight. Then the obtained AI
A W / O emulsion containing a compound having an I antagonistic action, a concomitant drug, and a biodegradable polymer is added to the aqueous phase (outer aqueous phase), and W (internal aqueous phase) / O (oil phase) / W (external phase) Water phase)
After forming the emulsion, the solvent in the oil phase is evaporated to prepare microcapsules. In this case, the volume of the external water phase is generally about 1 to about 10,000 times, more preferably about 5 to about 5,000 times, particularly preferably about 10 to about 2,000 times the volume of the oil phase. Selected from double. The emulsifiers and osmotic pressure regulators that may be added to the external water phase and the preparation method thereafter are the same as those described in the above item (I) (i).

(II) Phase Separation Method In the case of producing microcapsules by this method, the compound having an AII antagonistic action, the concomitant drug or the polyvalent metal compound described in the above (I) in-water drying method,
"Components obtained by water-treating a sparingly water-soluble polyvalent metal compound" and, if desired, a coacervation agent is gradually added to an organic solvent solution of a biodegradable polymer containing water with stirring to form microcapsules. Precipitate and solidify. The coacervation agent has an oil phase volume of about 0.01 to 1,000.
Times, preferably about 0.05 to 500 times, particularly preferably about 0.1 to 200 times. As the coacervation agent, a compound that is miscible with an organic solvent, such as a polymer-based compound, a mineral oil-based compound, or a vegetable oil-based compound, which has an AII antagonistic action, and a concomitant drug and a biodegradable polymer are not dissolved. There is no particular limitation. Specifically, 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 collected and then repeatedly washed with heptane or the like to obtain A
II compounds having an antagonistic action, concomitant drugs, coacervation agents other than biodegradable polymers, etc. are removed,
Dry under reduced pressure. Alternatively, washing is carried out by the same method as described in the underwater drying method of (I) (i) above, followed by freeze drying and further warm drying.

(III) Spray drying method In the case of producing microcapsules by this method, the compound having an AII antagonistic action, the concomitant drug, or the polyvalent metal compound described in the above (I) in-water drying method,
"Ingredients obtained by water treatment of poorly water-soluble polyvalent metal compounds", and optionally an organic solvent solution of biodegradable polymer containing water using a nozzle, a drying chamber of a spray dryer (spray dryer) 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. After this,
If necessary, freeze-drying and further warm drying may be performed after washing by the same method as described in the above-mentioned (I) in-water drying method. As a dosage form other than the above-mentioned microcapsules, the compound having an AII antagonistic action described in the in-water drying method of the microcapsule production method (I), a concomitant drug, or a polyvalent metal compound, “a sparingly water-soluble polyvalent metal” A component obtained by treating a compound with water, and further, an organic solvent solution of a biodegradable polymer containing water if desired, for example, an organic solvent and water are evaporated while adjusting the degree of vacuum using a rotary evaporator or the like. After being dried and solidified, it may be pulverized by a jet mill or the like to obtain fine powder. Moreover,
The pulverized fine powder may be washed by the same method as described in the in-water drying method of the microcapsule production method (I), and then freeze-dried and further heated and dried. With the microcapsules or fine powders obtained here, drug release can be controlled according to the decomposition rate of the biodegradable polymer used or the type and amount of the added polyvalent metal compound. AII
Sustained-release preparations containing an antagonist and a concomitant drug may be formulated into various dosage forms as they are or as raw materials, and injections or implants for intramuscular, subcutaneous, organ, etc., nasal cavity, rectum, uterus Transmucosal agents, oral agents (eg,
Capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as syrups, emulsions, suspensions, etc.) and the like can be administered. It can also be administered by a needleless syringe. For example,
In order to prepare sustained-release preparations containing an AII antagonist and a concomitant drug as injections, these can be used as a dispersant (eg, Tween).
n) Surfactants such as 80, HCO-60, polysaccharides such as sodium hyaluronate, carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride) , Mannitol, sorbitol, glucose, proline, etc.) or an aqueous suspension, or 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 preparation containing the AII antagonist and the concomitant drug, when used as a suspension injection, may be in the range satisfying the dispersity and needle-penetration property, for example, the average particle size. About 0.1 to 300 μm, preferably about 0.5 to 150 μm
m, more preferably about 1 to 100 μm. Aseptic preparations of sustained-release preparations containing AII antagonists and concomitant drugs include, but are not limited to, a method of sterilizing all manufacturing steps, a method of sterilizing with gamma rays, a method of adding a preservative, and the like. Not done.

The release period of the AII antagonist contained in the sustained-release preparation and the release period of the concomitant drug may be adjusted to the same period, but they may be different and may be appropriately adjusted depending on the symptom. Not done.

Sustained-release preparations containing an AII antagonist and a concomitant drug have low toxicity, so that they can be used in mammals (eg, humans, cows,
Pigs, dogs, cats, mice, rats, rabbits, etc.) can be used as a safe medicine. The dose of the sustained-release preparation containing the AII antagonist and the concomitant drug depends on the type and content of the main drug, the compound having the AII antagonistic action, the dosage form, the release of the compound having the AII antagonistic action and the concomitant drug. Although it varies depending on the duration, target disease, target animal, etc., it may be an effective amount of a compound having an AII antagonistic action and a concomitant drug. The dose of the compound having an AII antagonism is, for example, when the sustained-release preparation is a one-month preparation, preferably in the range of about 0.01 mg to 200 mg / kg body weight per adult, and more preferably Can be appropriately selected from the range of about 0.05 mg to 150 mg / kg body weight. The dose of the concomitant drug per administration is preferably, for example, when the sustained-release preparation is a one-month preparation,
It can be appropriately selected from the range of about 0.05 mg to 200 mg / kg body weight per adult. The dose of the sustained-release preparation containing the AII antagonist and the concomitant drug per dose is preferably about 0.05 mg to 50 mg / kg body weight per adult, more preferably about 0.1 mg to 30 mg / kg. It can be appropriately selected from the range of kg body weight. The administration frequency is once every few days, once every few weeks, once every month, or once every few months (eg, 3 months, 4 months, 6 months, etc.), AII, etc.
It can be appropriately selected depending on the types and contents of the compound having an antagonistic effect and the concomitant drug, the dosage form, the duration of the release of the compound having an AII antagonistic effect and the concomitant drug, the target disease, the target animal and the like.

The sustained-release medicine of the present invention can be applied to patients who are bedridden, demented, throat / esophageal disease, digestive system diseases, eating / swallowing disorders, and patients who are difficult or unable to treat with oral medication during surgery. It can be used advantageously.

The sustained-release medicine of the present invention is an animal, especially a mammal (eg, human, dog, rabbit, rat, mouse, etc.).
, For example, as an agent for preventing or treating angiotensin II-mediated diseases or complications with the diseases. 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. As such angiotensin II-mediated diseases or complications with the diseases, hypertension, abnormal blood pressure circadian fluctuation, heart disease (cardiac hypertrophy, chronic heart failure including congestive heart failure, 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 circulation Disorder, recurrence of cerebrovascular disorder and its sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, activities of daily living, etc.), ischemic peripheral circulatory disorder, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, diabetes, diabetes Sexual complications (diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, etc.), renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, dialysis complications, radiation Irradiated organ damage including nephropathy Th), arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular thickening, intervention (percutaneous coronary angioplasty, stent placement, coronary endoscopy) , Intravascular ultrasound, coronary infusion thrombolytic therapy, etc.) vascular thickening or occlusion and organ damage, vascular re-occlusion / restenosis after bypass surgery, erythrocytosis after transplantation, hypertension, organ damage / vascular hypertrophy, transplantation Subsequent rejection, eye diseases (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (deep vein thrombosis, obstructive peripheral circulatory disturbance, obstruction) Arteriosclerosis, obstructive thrombotic vasculitis, ischemic cerebral circulation disorder, Raynaud's disease, Buerger's disease, etc., metabolic and nutritional 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 (cerebral hemorrhage and cerebral infarction, etc., and their sequelae) Complications, head injury, 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 state, mental illness (depression, epilepsy, alcoholism) ), Inflammatory diseases (retinopathy,
Diabetic complications such as nephropathy, neuropathy, macroangiopathy; arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, peritonitis; inflammation after surgery / trauma; remission of swelling; pharyngitis; bladder Inflammation; pneumonia; atopic dermatitis; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye disease;
Pneumonia, silicosis, pulmonary 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, carini 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, gastric surgery) Post-disorders, dyspepsia, esophageal ulcer, pancreatitis, colorectal polyps, cholelithiasis, hemorrhoids, etc., blood / hematopoietic disorders (erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome) , Bone marrow disease, etc.), bone disease (eg, fracture, re-fracture, osteoporosis, osteomalacia, bone Pecet's disease,
Ankylosing myelitis, rheumatoid arthritis, joint tissue destruction in knee osteoarthritis and similar diseases), solid tumors, tumors (melanoma, malignant lymphoma, gastrointestinal (eg, stomach, intestine, etc.) cancer, etc. ), Cancer and associated cachexia, cancer metastasis, endocrine diseases (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and male genital diseases (cystitis, prostate) 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.), urinary frequency, environmental / occupational factors Diseases (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.), infections Mega-le virus, influenza virus, viral infections such as herpes virus,
Rickettsia infection, bacterial infection, etc., Toxemia (sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.), ENT disease (Menuel syndrome, tinnitus, taste disorder, dizziness, balance) Disorders, dysphagia, etc.), skin diseases (keloids, hemangiomas, psoriasis, etc.), dialysis hypotension, myasthenia gravis, chronic fatigue syndrome and other systemic diseases. Among them, it is preferably used as a preventive or therapeutic agent for circulatory system diseases and an organ protective agent. The circulatory system diseases mentioned here also include central nervous system diseases caused by circulatory system disorders and the like. Among cardiovascular diseases, it is preferable to use the sustained-release pharmaceutical composition of the present invention for the prevention or treatment of arteriosclerosis, hyperlipidemia, etc., and particularly preferable for the prevention or treatment of arteriosclerosis. . Furthermore, the sustained-release medicine of the present invention can also be used for the therapeutic method used for lowering cholesterol. The sustained-release medicine of the present invention is prominent in the prevention or treatment of menopausal disorders and cancers associated with hypertension-related diseases such as diabetic, obese, hyperlipidemic, essential, and thrombotic. It is effective, and is preferably used for prevention or treatment of diabetes, hyperlipidemia, and arteriosclerosis, which are complications of hypertension. The sustained-release drug of the present invention is, in addition to angiotensin II-mediated diseases directly targeted by an AII antagonist or a complication with the diseases, an antihypertensive drug, a hypoglycemic drug, and hyperlipemia which are used in combination. It is also useful for the prevention and treatment of target diseases for therapeutic diseases, antithrombotic agents, menopausal agents, and anticancer agents. The diseases targeted by the antihypertensive drug as a concomitant drug include hypertension, abnormal blood pressure circadian rhythm, hypertensive encephalopathy, and hypertensive tinnitus. Examples of diseases targeted by hypoglycemic agents as concomitant drugs include diabetes and diabetic complications (diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, etc.) and the like. The diseases targeted by the therapeutic drug for hyperlipidemia as a concomitant drug include obesity, hyperlipidemia, hypercholesterolemia and the like. Diseases targeted by antithrombotic drugs as concomitant drugs include thrombosis, heart disease (cardiac hypertrophy, chronic heart failure including acute heart failure and congestive heart disease, cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia, myocardium Infarction, etc.), cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.),
Cerebral circulatory disorder, ischemic peripheral circulatory disorder, myocardial ischemia, venous insufficiency, other cardiovascular diseases (deep vein thrombosis, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thromboangiitis, void Blood cerebral circulation disorder, Raynaud's disease, Buerger's disease, etc.) and the like. Menopausal disorders and the like are mentioned as the diseases targeted by the therapeutic drug for menopausal disorder as a concomitant drug. The target diseases of anticancer drugs as concomitant drugs include breast cancer, uterine cancer, esophageal cancer, gastric cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, testicular cancer, liver cancer, kidney cancer, pancreatic cancer,
Examples include leukemia, skin cancer, malignant melanoma and malignant lymphoma. Such a target disease may have a causal relationship with the above-mentioned angiotensin II-mediated diseases such as hypertension and heart failure, and may independently coexist.

The sustained-release drug of the present invention may be the sustained-release preparation of the above-mentioned various embodiments as it is, or by using the sustained-release preparation, for example, granules, powders, powders, tablets, capsules, Syrup, emulsion, suppository (eg, rectal suppository, vaginal suppository, etc.), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), drip, external preparation (Eg,
Nasal administration preparations, transdermal preparations, ointments, etc.), emulsions, elixirs, suspensions, solutions, etc. can be further formulated and administered orally or parenterally. It can be formulated according to a method known per se generally used in the formulation step. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion and the like. The sustained release drug of the present invention is preferably formulated into an injectable preparation.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents. sell. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution and the like. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. To this end, any non-volatile oil or fatty acid may be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Furthermore, additives such as preservatives, isotonicity agents, solubilizers, stabilizers, soothing agents and the like may be appropriately used. A suppository for rectal administration is a drug and a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract and melt in the rectum. It can be manufactured by mixing with a substance that emits.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like described above. In such dosage forms, the active ingredient is at least one additive such as sucrose, lactose,
Cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers It can be mixed with the compounds or glycerides. Such dosage forms can also, as usual, contain further additives, for example inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, α
-Antioxidants such as tocopherol and cysteine, excipients, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfume agents, coating agents and the like. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which contain an inert diluent commonly used in the art, such as water. You can stay.

The dose of the sustained-release drug of the present invention is based on the minimum recommended clinical dose of each drug, and the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, drug Can be appropriately selected by a combination of the above. The dosage for a particular patient will depend on age, weight, general health, sex, diet, time of administration, mode of administration, excretion rate, drug combination, and the extent of the condition being treated by the patient at that time. , And these or other factors. Typically, when the AII antagonist is combined with at least one antihypertensive drug, antihyperglycemic drug, antihyperlipidemic drug, antithrombotic drug, anti-menopausal drug, and anticancer drug, individual daily administration The amount should be about 1 / th of the minimum recommended clinical dose with respect to the actual situation when they are administered alone.
50 or more and below the maximum recommended clinical dose (preferably below the minimum recommended clinical dose, more preferably below the minimum recommended clinical dose 1 /
2 or less). Although the dose range can be adjusted based on the unit required to divide the daily dose, as described above, the dose is determined by the nature and degree of the disease, the age of the patient, the body weight, the general health condition, the sex, the diet, the administration. It is decided in consideration of time, administration method, excretion rate, drug combination, and other factors. In the preventive or therapeutic agent of the present invention, the unit dose is administered once or twice a day to several months.

The compounds having the above AII antagonistic action are
The blood pressure is high even if the blood concentration is high immediately after administration
It doesn't fall too much. Do not combine AII antagonists
The sustained-release drug of the present invention is a therapeutic agent for the above-mentioned various diseases, etc.
It can be used for a certain blood concentration
Since it can be maintained at any time of the night, it should be administered orally.
It is possible to reduce the dose and frequency compared to
There is little fluctuation in blood drug concentration, and
The effect of treatment is clearer because no change in
Is expected to As for safety, normal usage
However, due to the above reasons, the risk of over-pressure reduction is
Although it is small, in a situation involving a large amount of fluid loss such as a traffic accident
Even if hypertension occurs due to occurrence, angiotensin
II as well as drugs (category) that are commonly used in emergency medical settings.
Immediate pressurization by intravenous administration of choleamine
Is possible, and even by oral administration of antihypertensive drugs
However, since it is possible to continuously increase the pressure, only emergency response in an emergency
It is also possible to deal with it for a long time. The sustained-release medicine of the present invention is
Having a compound with angiotensin II antagonism
To suppress the action of angiotensin II in the long term
Causes various diseases associated with adult diseases and aging.
A disorder or abnormality in biological functions and physiological functions
Or suppresses hyperactivity, resulting in diseases or conditions
The primary and secondary prevention or progression of can be suppressed. This
As an impairment or abnormality of such biological functions and physiological functions
Is, for example, an impaired or abnormal cerebral circulation / renal circulation autoregulation ability.
Circulatory disorders (peripheral, brain, microcirculation, etc.), blood-brain barrier
Disorders, decreased insulin sensitivity, salt sensitivity, coagulation /
Abnormal fibrinolytic system, abnormal properties of blood and blood cell components (platelet aggregation ability
Enhancement, abnormal erythrocyte deformability, enhanced leukocyte adhesion, blood
Viscosity increase, growth factors and cytokines (PDGF, VE
GF, FGF, interlokin, TNF-α, MCP-1 etc.)
Increased production and action, increased production and infiltration of inflammatory cells
Promotion, production of free radicals, promotion of fat deposition, endothelium
Disability, endothelial, cell and organ disorders, edema, smooth muscle, etc.
Morphological changes of cells (morphological changes to proliferative type), vascularization
Motile substances and thrombus-inducing substances (endothelin, thromboxa
N A₂  , Etc.) and abnormal function of blood vessels
Shrinkage, glucose intolerance, metabolic disorders (serum lipid abnormalities, blood glucose abnormalities
), Abnormal proliferation of cells, angiogenesis (atherosclerotic plaque)
Including abnormal angiogenesis in adventitial abnormal capillary network formation
, Etc., among which organs associated with various diseases
Disorders (eg, cerebrovascular disorders and associated organ disorders, circulation)
Organ disorders associated with organ diseases, organ disorders associated with diabetes,
Primary and secondary prevention)
-It can be advantageously used as a therapeutic agent. further,
It can be advantageously used as a preventive or therapeutic agent for portal hypertension.
It is possible. Rupture of esophageal varices occurs frequently at night (Hepato
logy 1994; 19: 595-601).
Is capable of maintaining a constant blood concentration day and night
Therefore, compared with the case of oral administration,
Not only is it possible to reduce the number of drugs, but
Since there is little movement, a stable reduction in portal pressure can be expected.
It The above features of this drug are preventive agents for rupture of varicose veins in the esophagus and stomach
It shows the usefulness as. Also, do not stop taking
The treatment effect is clearer because the condition does not change due to throat
It is also expected to be accurate. Furthermore, with bioactive compounds
Compounds with angiotensin II antagonism (
Candesartan cilexetil, candesartan
HGF (Hepatocyte Growth Factor)
Is expected to be effective in promoting production, and liver regeneration
And it can be expected to contribute to liver recovery. Also, physiological activity
Has angiotensin II antagonism as a volatile compound
Compounds (especially candesartan cilexetil, cande
The blood concentration of sultan etc.) is kept constant day and night
To prevent and treat cerebrovascular accidents such as cerebral infarction
It is also expected that the fruits will become clearer. How to treat patients
As an oral administration of angiotensin II antagonist
After administration for a fixed period of time and confirming the reactivity of the patient,
It is also possible to administer a sustained release formulation. Orally administered
Contained in angiotensin II antagonists and sustained release formulations
Angiotensin II antagonists can be the same or different
May be In addition, angiotensin II antagonists
External antihypertensive agents (calcium antagonists, diuretics, beta blockers)
, Etc., is orally administered in advance to confirm patient reactivity
Then, the sustained-release preparation of the present invention may be administered. Also,
The sustained-release preparation of the present invention and a normal angiotensin II antagonist
A diuretic antihypertensive agent (oral agent) to be used in combination may be used in combination. Well
, Other lipid-lowering or cholesterol-lowering drugs,
HMG-Co A reductase (3-hydroxy-3-methylglutar
yl coenzyme A reductase) inhibitor, insulin sensitive
Sex improver, bone disease therapeutic agent, myocardial protective agent, coronary artery disease therapeutic agent
Drugs, other antihypertensive drugs, chronic heart failure drugs, diabetes treatment
Medicine, liver disease therapeutic agent, gastric / duodenal ulcer therapeutic agent therapeutic agent,
Biliary tract disease drug, hypothyroid drug, nephrotic disease
Symptom group therapeutic agent, chronic renal failure therapeutic agent, gynecological disease therapeutic agent, lactation
Others including therapeutic agents for urinary and male genital diseases or infectious diseases
(However, the raw materials contained in the sustained-release preparation of the present invention
Physically active compounds are excluded. ) May be used with
In some cases, these compounds may be administered as an oral formulation.
If necessary, it may be administered as a rectal preparation in the form of suppositories.
You may Possible combination components in this case are
Fibrates (eg, clofibrate, benzafi
Blate, gemfiprozil, etc.], nicotinic acid,
Derivatives and analogs [eg acipimox and prob
Cole], bile acid binding resin [eg, cholestyramine, chole
Stypol, etc.], compounds that suppress cholesterol absorption
[Eg, sitosterol, neomycin, etc.], squalene
Epoxidase inhibitors [eg, NB-598 and related
Compound, etc.] can be mentioned. Further possible combination ingredients
Oxidosqualene-lanosterol cycler
Such as decalin derivatives, azadecalin derivatives and
It is an indane derivative. In addition, the following various therapeutic agents (however
However, the physiologically active compound contained in the sustained-release preparation of the present invention is
except. ) Is also possible. Antihypertensive drugs: diuretics [eg, furosemide (Lassic
B), bumetanide (Renetron), azosemide (diamond)
)), Antihypertensive drugs [eg, ACE inhibitors, (maleic acid
Narapril (Renibase) etc. and Ca antagonist (Manifold)
Dipine, amlodipine, etc.), α or β receptor blockers
etc Chronic heart failure drug: Cardiotonic drug [eg, cardiac glycoside (digoxi
, Β-receptor stimulants (denopamine and dobutami)
Catecholamine preparations) and PDE inhibitors
, Etc., diuretics [eg, furosemide (Lasix), spiro]
Nolactone (aldactone), etc., ACE inhibitor,
[Eg, enalapril maleate (renibase), etc.],
Ca antagonists (eg, amlodipine, etc.) and β-receptor blockade
Abstinence Antiarrhythmic drugs: disopyramide, lidocaine, quinidi sulfate
, Flecainide acetate, mexiletine hydrochloride, amio hydrochloride
Darons, β-blockers, Ca antagonists, etc. Bone disease remedies: Calcium preparations (eg, calcium carbonate
Etc.), calcitonin preparation, active vitamin D_ThreeFormulation
(Eg Alfacalcidol (Alpharoll, etc.),
Calcitriol (locartrol), etc., sex hormones
Type (eg, estrogen, estradiol, etc.)
Mon preparations [eg, conjugated estrogens (premarin)
Etc.], ibriflavone preparations (such as Osten), vitamins
K_Two, Vitamin K _TwoFormulations [eg, menatetrenone (Graquette
-), Etc.), bisphosphonic acid-based preparations (such as etidronate
, Etc., prostaglandin E2, fluorine compounds (eg, F
Sodium chloride, etc.), bone morphogenetic protein (BMP), fiber
Blast 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 application
Publication EP-A1-376197, EP-A1-4
No. 60488 and EP-A1-719782
Compounds described in the report (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.) and so on; Antidiabetic: Actos, Rosiglitazone, Kinedat
Ku, Benfil, Humarin, Euglecon, Grimi
Klong, Daonir, Novolin, Monotard, Insul
Phosphorus, glucobai, dimerin, rastinone, basilco
N, Deamelin S, Isudirins, etc .; Drugs for liver diseases: Glycyrrhizin preparations [eg, strong minof
Etc.], liver hydrolyzate, SH compound [eg, glutathione]
Etc.], special amino acid preparations [eg, aminolevane, etc.], phosphorus
Lipid [eg, polyenephosphatidylcholine, etc.], vitamin
(Eg, vitamins B1, B2, B6, B12, C, etc.), adrenal cortex hormone
Mon [eg, dexamethasone, betamethasone, etc.]
-Feron (eg, interferon α, β, etc.), hepatic brain
Disease treatment (eg, lactulose, etc.), esophagus, ruptured gastric varices
Hemostatic agents sometimes used (eg, vasopressin, somatos
Tachin, etc.] Stomach / duodenal ulcer remedies Remedies: antacids [eg, histamine
H2 antagonists (cimetidine, etc.), proton pump inhibitors
(Lansoprazole etc.)]; Biliary tract disease therapeutic agents: Bile-promoting agents (eg, dehydrocholic acid, etc.)
Bile-removing agents [eg magnesium sulfate, etc.]; Hypothyroid drug: dry thyroid (threoid),
Levothyroxine sodium (Tyrazine S), liotyro
Nisin sodium (thyronine, thyromine), etc .; Nephrotic Syndrome Remedy: Usually Adopted as the First Choice
Prednisolone (prednisolone)
), Prednisolone sodium succinate (prednisolone)
), Methylprednisolone sodium succinate (sol
・ Medrol), betamethasone (Linderon), etc. are used
To be For anticoagulant therapy, dipyridamole (Belsanthi
), Dilazep hydrochloride (comelian), ticlopidine, cucumber
Antiplatelet drugs such as ropidogrel and FXa inhibitors
Coagulants are used; HMG-Co A reductase inhibitors: cerivastatin, a
Trovastatin, pravastatin, simvastatin, a
Tabastatin, Lovastatin, Fluvastatin, (+)
-3R, 5S-7- [4- (4-fluorophenyl)-
6-isopropyl-2- (N-methyl-N-methanesulfate
Honylamino) pyrimidin-5-yl] -3,5-dihi
Droxy-6 (E) -heptenoic acid and the like; Drugs for treating chronic renal failure: diuretics [eg, furosemide (Lashik
B), bumetanide (Renetron), azosemide (diamond)
,), Antihypertensive drugs (eg, ACE inhibitors, (maleic acid
Narapril (Renibase) and Ca antagonist (Manidipi)
), Alpha receptor blockers, etc.
In this case, it can be preferably used by oral administration. Anti-thrombosis drug: Anticoagulant [eg, heparinna
Thorium, heparin calcium, warfarin calciu
Mu (warfarin), blood coagulation factor Xa inhibitor and
Drugs that have the function of correcting coagulation / fibrinolysis balance], thrombolysis
Dissolution [eg, tPA, urokinase], antiplatelet drug [eg,
Aspirin, Sulfinpyrazolo (Anturan), Ji
Pyridamole (Persanthin), Ticlopidine (Panal)
Gin), cilostazol (pletal), GPIIb / IIIa
Antagonist (Leopro)] etc. Coronary vasodilators: nifedipine, diltiazem, nicoradi
Lu, nitrite, etc. Myocardial protectant: Cardiac ATP-K opener, Na-H exchange blocker
Harmful drugs, endothelin antagonists, urotensin antagonists, etc. Anti-inflammatory: aspirin, acetaminophen, non-stero
Id anti-inflammatory drug (eg, indomethacin, etc.), steroid
Agents (eg, dexamethasone, etc.), etc. Antiallergic agents: antihistamines [eg, black maleate
Lupheniramine, etc.), stimulant therapy [eg, bucillamine, etc.
], Other azelastine hydrochloride, seratrodast, tiger
Nilast, oxatomide, strong neominophage
ー, tranexamic acid, ketotifen fumarate, etc. Antitumor agents: alkylating agents, antimetabolites, antitumor antibiotics
Preparations, antitumor plant component preparations and other antitumor agents
Such Central nervous system agents: anxiolytics, hypnotics, anesthetics, sedatives
Antispasmodic, autonomic, anti-Parkinsonian and other
Psychiatry and medicine Gynecological disease remedy: [eg, menopausal remedies
Trogen, estradiol, testosterone enanthate
・ Estradiol valerate, etc., breast cancer drug (quee)
(Tamoxifen acidate, etc.), endometriosis, fibroid treatment
Drugs (leuprorelin acetate, danazol, etc.)] etc. Drugs for urological and male genital diseases: [eg, treatment of benign prostatic hyperplasia
Drugs (tamsulosin hydrochloride, prazosin hydrochloride, chlorma acetate
Zinone, Prostate cancer (leuprorelin acetate, vinegar)
Acid goserelin, chlormadinone acetate, etc.)] etc. Infectious disease remedy: [eg, antibiotics (Cefatia hydrochloride
, Cefozopran hydrochloride, ampicillin, etc.), chemotherapy
Legal agents (sulfa drugs, synthetic antibacterial agents, antiviral agents, etc.),
Biological products (blood such as vaccines and immunoglobulins)
Formulations, etc.] etc. Other anti-obesity drugs (such as mazindol), anti-rheumatism
Medicine Furthermore, for the introduction of various factors derived from living organisms or their gene transfer
Treatment (eg, angiogenic factors such as HGF, VEGF, or
This is the treatment of ischemic diseases by gene transfer
Use of these drugs in combination with the sustained-release preparation of the present invention
In this case, each drug may be combined into one sustained-release preparation.
[(A) Compounded in sustained-release preparation containing AII antagonist
Case, and (B) antihypertensive drug, hypoglycemic drug, hyperlipidemia
Disease treatment, antithrombotic drug, menopausal drug and anticancer drug?
Sustained release containing one or more drugs selected from
Including the case of compounding in the formulation]
With an acceptable carrier, excipient, binder, diluent, etc.
Can be mixed and formulated separately from the sustained-release preparation of the present invention.
Can be administered simultaneously. Formulating the drug separately
In case of using
Can be mixed and administered, but formulated separately
Separated individual preparations at the same time or at different times
Each may be administered to the same subject.

As another embodiment of the present invention, there is provided a sustained-release medicine comprising a combination of two or three drugs selected from AII antagonists, antihypertensive agents, hypoglycemic agents and antihyperlipidemic agents. Examples of the AII antagonist, antihypertensive agent, hypoglycemic agent and antihyperlipidemic agent include the same ones as described above. The AII antagonist, the antihypertensive agent, the hypoglycemic agent and the antihyperlipidemic agent can be separately or simultaneously formulated into sustained-release preparations and administered orally or parenterally as a pharmaceutical composition. When the drugs are separately formulated, they can be administered separately by mixing them with a diluent or the like at the time of use. You may administer to the same subject separately at time intervals. A kit product for administering separately formulated products by mixing them with a diluent at the time of use (for example, an ampoule containing each drug in powder form and two or more drugs are mixed and dissolved at the time of use) A kit product for administration to the same subject simultaneously or separately with a time lag, such as an injection kit containing a diluent etc. Put tablets containing individual drugs in the same or different bags, and if necessary, provide a column for describing the time of drug administration, to administer two or more tablets at the same time or separately with a time lag. Such as a tablet kit) are also included in the medicament of the present invention. Such sustained-release pharmaceuticals include the above-mentioned "sustained-release preparation containing an AII antagonist", "antihypertensive drug, hypoglycemic drug, antihyperlipidemic drug,
It can be formulated and carried out in the same manner as the "sustained release preparation containing one or more kinds of drugs selected from antithrombotic agents, menopausal agents and anticancer agents".

The meanings of the abbreviations used in the present specification are as follows. Abbreviation Name N (4H ₂ -furoyl) Gly ： N-tetrahydrofuroylglycine residue NAc ： N-acetyl group D2Nal ： D-3- (2-naphthyl) alanine residue D4ClPhe ： D-3- (4-chloro) Phenylalanine residue D3Pal: D-3- (3-pyridyl) alanine residue NMeTyr: N-methyltyrosine residue Aph (Atz): N- [5 '-(3'-amino-1'H-1', 2 ', 4'-Triazolyl)] phenylalanine residue NMeAph (Atz): N-methyl- [5'-(3'-amino-1'H-1 ', 2', 4'-triazolyl)] phenylalanine residue Group DLys (Nic): D- (eN-nicotinoyl) lysine residue Dcit: D-citrulline residue DLys (AzaglyNic): D- (azaglycylnicotinoyl) lysine residue DLys (AzaglyFur): D- (azagly) Sylfuranyl) lysine residue DhArg (Et ₂ ): D- (N, N'-diethyl) homoarginine residue DAph (Atz): DN- [5 '-(3'-amino-1'H-1', 2 ', 4'-Triazolyl)] Phenylalanine residue DhCi: D-homocitrulline residue Lys (Nisp): (eN-isopropyl) lysine residue hAr g (Et ₂ ): (N, N′-diethyl) homoarginine residue D2Nal: D-3- (2-naphthyl) alanine residue DSer (tBu): O-tert-butyl-D-serine Dhis (ImBzl) : N ^im -benzyl-D-histidine and other amino acids, IUPAC-IU when indicated by abbreviations
B Commission of Biochemical Nomenclature
(European Journal of Biochemistry, Vol. 138, 9
~ 37 (1984)) or conventional abbreviations in the relevant field, and where amino acids may have optical isomers, L form is shown unless otherwise specified.

[0076]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited thereto.

EXAMPLES Reference Example 1 2-Ethoxy-1-[[2 '-(4,5-dihydro-5
-Oxo-1,2,4-oxadiazol-3-yl)
Biphenyl-4-yl] methyl] benzimidazole-
0.25 g of 7-carboxylic acid (hereinafter abbreviated as compound A) and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid = 75
/ 25 (mol%), weight average molecular weight 10,700, number average molecular weight
6,100, number average molecular weight 3,770 by quantitative determination of end groups, 2.25 g of Wako Pure Chemical Industries, Ltd., and 3.5 ml of dichloromethane and methanol 1.
Dissolve in a mixture with 5 ml and adjust the temperature to 18 ℃ in advance 0.1%
(w / w) Inject into 500 ml of polyvinyl alcohol aqueous solution,
Using a turbine homomixer, an O / W emulsion was prepared at 7,000 rpm. This O / 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 redispersed by adding a small amount of distilled water and then freeze-dried to obtain a powder. The recovery rate was 69%, the encapsulation rate of Compound A in the microcapsules was 92%, and the content of Compound A in the microcapsules was 9.2%.

Reference Example 2 A solution prepared by dissolving 0.25 g of the disodium salt of Compound A in 0.4 ml of distilled water was used as a solution prepared by dissolving 2.25 g of a lactic acid-glycolic acid copolymer (same as in Reference Example 1) in 4 ml of dichloromethane. The mixture was mixed and emulsified with a homogenizer to form a W / O emulsion. Next, this W / O emulsion was adjusted to 18 ° C in advance with a 0.1% (w / w) polyvinyl alcohol aqueous solution 5
Pour into 00 ml, and use a turbine homomixer for 7,00
A W / O / W emulsion was prepared at 0 rpm. This W / O / W
The emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase, and then using a centrifuge 2,
Collected at 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 a small amount of distilled water and then freeze-dried to obtain a powder. The recovery rate was 50%, the encapsulation rate of Compound A in the microcapsules was 37%, and the content of Compound A in the microcapsules was 3.7%.

Reference Example 3 0.4 g of Compound A and lactic acid polymer ethyl ester (a biodegradable polymer in which the terminal carboxy group of the lactic acid polymer was ethyl esterified, weight average molecular weight 10,200, number average molecular weight 5,
680, manufactured by Wako Pure Chemical Industries, Ltd.) 1.6 g was dissolved in a mixed liquid of 3.5 ml of dichloromethane and 2.5 ml of methanol, and 800 ml of a 0.1% (w / w) polyvinyl alcohol aqueous solution containing 5% mannitol which had been adjusted to 18 ° C. in advance. The mixture was poured into the mixture, and a turbine homomixer was used to prepare an O / W emulsion at 7,000 rpm. This O / 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 redispersed by adding a small amount of distilled water and then freeze-dried to obtain a powder. The recovery rate is 83%, and the encapsulation rate of Compound A in the microcapsules is 8
At 6%, the content of Compound A in the microcapsules was 17.1%.

Reference Example 4 2-Ethoxy-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (hereinafter abbreviated as compound B) 0.6 g and zinc oxide 0.09 g having a particle size of 0.02 μm were mixed with lactic acid-glycolic acid copolymer ( Lactic acid / glycolic acid 75/2
5 (mol%), weight average molecular weight 14,000, number average molecular weight
4,200, number average molecular weight by quantitative determination of end groups, 4,090, manufactured by Wako Pure Chemical Industries, Ltd.) 2.4 g was added to a solution dissolved in 4.5 ml of dichloromethane and 1 ml of ethanol, and shaken and stirred at room temperature for 12 hours to give a slightly cloudy solution. Got This solution was poured into 400 ml of a 0.1% by weight polyvinyl alcohol aqueous solution which had been adjusted to 15 ° C. in advance, and an O / W emulsion was made at 7,000 rpm using a turbine homomixer. After stirring this O / W emulsion at room temperature for 3 hours to vaporize dichloromethane and ethanol to solidify the oil phase,
It collected at 2,000 rpm using the 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 B in the microcapsules was 97%, and the content of Compound B in the microcapsules was 18.8%.

Reference Example 5 Microcapsules were obtained in the same manner as in Reference Example 1 except that the amount of zinc oxide was changed to 0.057 g. The encapsulation rate of Compound B in the microcapsules was 97%, and the content of Compound B in the microcapsules was 19.0%.

Reference Example 6 Microcapsules were obtained in the same manner as in Example 1 except that the amounts of compound B, zinc oxide and lactic acid-glycolic acid copolymer were changed to 0.9 g, 2.1 g and 0.12 g, respectively. . The encapsulation rate of Compound B in the microcapsules is 96%
Thus, the content of compound B in the microcapsules was 27.8%.

Reference Example 7 Microcapsules were obtained in the same manner as in Reference Example 3 except that the amount of zinc oxide was changed to 0.18 g. The encapsulation rate of Compound B in the microcapsules was 92%, and the content of Compound B in the microcapsules was 26.2%.

Reference Example 8 1.8 g of Compound B and 0.3 g of zinc oxide having a particle size of 0.02 μm were mixed with a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 7
5/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight 4,090 by end group quantification, manufactured by Wako Pure Chemical Industries, Ltd.) 4.2 g was added to a solution dissolved in 9 ml of dichloromethane and 1.5 ml of ethanol. Then, the mixture was shaken and stirred at room temperature for 12 hours to obtain a slightly cloudy solution. This solution was poured into 800 ml of a 0.1% by weight polyvinyl alcohol aqueous solution which had been adjusted to 15 ° C. in advance, and an O / W emulsion was made at 7,000 rpm using a turbine homomixer. After stirring this O / W emulsion at room temperature for 3 hours to vaporize dichloromethane and ethanol to solidify the oil phase,
It collected at 2,000 rpm using the 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 B in the microcapsules was 94%, and the content of Compound B in the microcapsules was 26.8%.

Reference Example 9 0.3 g of Compound A and 0.05 g of zinc oxide having a particle size of 0.02 μm were mixed with a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 7
5/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight by end group determination 4,090, manufactured by Wako Pure Chemical Industries, Ltd.) 0.7 g was added to a solution dissolved in 1.5 ml of dichloromethane and 1 ml of methanol. Then, the mixture was shaken and stirred at room temperature for 12 hours to obtain a slightly cloudy solution. This solution was poured into 300 ml of a 0.1 wt% aqueous polyvinyl alcohol solution which had been adjusted to 15 ° C. in advance, and an O / W emulsion was prepared at 6,500 rpm using a turbine homomixer.
This O / 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 the microcapsules was 91%, and the content of Compound A in the microcapsules was 25.9%.

Reference Example 10 Compound B 1 g and zinc oxide 0.18 g having a particle size of 0.02 μm were mixed with lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75
/ 25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight 4,090 by end group quantification, manufactured by Wako Pure Chemical Industries, Ltd.) The mixture was emulsified and mixed for 2 seconds to obtain a cloudy dispersion. This dispersion was adjusted to 15 ° C in advance, and a 0.1% by weight polyvinyl alcohol aqueous solution was prepared.
Pour into the tube and use a turbine homomixer for 8,000
An O / W emulsion was prepared at 0 rpm. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase and then use a centrifuge to remove 2,000 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 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 B in the microcapsules was 96%, and the content of Compound B in the microcapsules was 32.0%.

Reference Example 11 Microcapsules were obtained in the same manner as in Example 7 except that 0.8 ml of ethanol was added to dichloromethane and the solution was gently turbid for 12 hours at room temperature with shaking.
The encapsulation rate of Compound B in the microcapsules was 95%, and the content of Compound B in the microcapsules was 32.0%.

Reference Example 12 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (Hereinafter abbreviated as compound C) 0.9 g and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 1
4,000, a number average molecular weight of 4,200, a number average molecular weight of 4,090 by terminal group quantification, and 2.1 g of Wako Pure Chemical Industries, Ltd.) were dissolved in a mixed solvent of 4.5 ml of dichloromethane and 0.7 ml of ethanol. To this solution was added 0.15 g of zinc oxide having a particle size of 0.02 μm, and the mixture was shaken and stirred for 12 hours at room temperature to obtain a slightly cloudy solution. This solution was adjusted to 15 ° C in advance.
It was poured into 400 ml of a weight% polyvinyl alcohol aqueous solution, and O / at 7500 rpm using a turbine homomixer.
It was a W emulsion. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol to solidify the oil phase and then use a centrifuge to remove 2,000 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 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 C in the microcapsules was 96%, and the content of Compound C in the microcapsules was 27.4%.

Reference Example 13 Microcapsules were prepared in the same manner as in Reference Example 12 except that zinc oxide was not added. The encapsulation rate of Compound C in the microcapsules was 98%, and the content of Compound C in the microcapsules was 30.0%.

Reference Example 14 1.2 g of Compound C and a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 1
4,000, a number average molecular weight of 4,200, a number average molecular weight of 4,090 by end group quantification, manufactured by Wako Pure Chemical Industries, Ltd.) (1.8 g) were dissolved in 5 ml of dichloromethane. To this solution was added 0.18 g of zinc oxide having a particle size of 0.02 μm, and the mixture was shaken and stirred at room temperature for 1 hour to obtain a slightly cloudy solution. This solution was adjusted to 15 ℃ in advance, and 0.1 wt% polyvinyl alcohol aqueous solution 400
Pour into the tube and use a turbine homomixer for 8,000
An O / W emulsion was prepared at 0 rpm. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase and then use a centrifuge to remove 2,000 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 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 C in the microcapsules was 95%, and the content of Compound C in the microcapsules was 35.9%.

Reference Example 15 Microcapsules were prepared in the same manner as in Example 4 except that zinc oxide was not added. The encapsulation rate of Compound B in the microcapsules was 99%, and the content of Compound B in the microcapsules was 19.8%.

Reference Example 16 Microcapsules were prepared in the same manner as in Reference Example 9 except that zinc oxide was not added. The encapsulation rate of Compound A in the microcapsules was 95%, and the content of Compound A in the microcapsules was 28.4%.

Reference Example 17 2-Ethoxy-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (Compound B) 2 g and zinc oxide (TYPE V, manufactured by Wako Pure Chemical Industries, Ltd.) 0.36 g were added to a lactic acid-glycolic acid copolymer (lactic acid / Glycolic acid 75/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight 4,090 by end group determination, Wako Pure Chemical Industries, Ltd.)
3.6 g of dichloromethane 11 ml and ethanol 0.4 ml
It was added to the solution dissolved in and was stirred with shaking at room temperature for 14 hours to obtain a cloudy solution. This solution was adjusted to 15 ℃ in advance, and a 0.1% by weight polyvinyl alcohol aqueous solution 80
Pour into 0 ml and use a turbine homomixer for 8,5
An O / W emulsion was prepared at 00 rpm. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol 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 B in the microcapsules is
At 98%, the content of Compound B in the microcapsules was 33.0%.

Reference Example 18 Reference was made except that 0.4 ml of distilled water was added, and the stirring and stirring for 14 hours was changed to dispersion (emulsification) mixing with a solid (compound B and zinc oxide) at the same rotation speed for 1 minute by a homogenizer. Microcapsules were obtained in the same manner as in Example 17.
The encapsulation rate of Compound B in the microcapsules was 97%, and the content of Compound B in the microcapsules was 32.6%.

Reference Example 19 Reference Example 17 except that the amount of added distilled water was changed to 0.08 ml.
Microcapsules were obtained in the same manner as. The encapsulation rate of Compound B in the microcapsules was 97%, and the content of Compound B in the microcapsules was 32.5%.

Reference Example 20 Compound B 4 g and zinc oxide (TYPE V, manufactured by Wako Pure Chemical Industries, Ltd.)
72 g and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 (mol%), weight average molecular weight 10,600) 7.2
g was added to a solution dissolved in 22 ml of dichloromethane and 0.8 ml of ethanol, and 0.16 ml of distilled water was added thereto, and immediately after that, dispersion (emulsification) and mixing were performed with a homogenizer under the same conditions as in Reference Example 18, resulting in white turbidity. A solution was obtained. 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 15 hours to obtain a dried product. This dried product has a pore size of 250 μm
After roughly pulverizing on a sieve of No. 4 and mixing 5 g of dried matter obtained by sieving with 0.4 g of mannitol, jet mill device (A
-OJET, manufactured by Seishin Enterprise Co., Ltd.) was subjected to gas pulverization at an air pressure of 2 kg / cm ² to obtain fine particles having an average particle diameter of 21 μm. The content of compound B in the microparticles was 31.0%.

Reference Example 21 A cloudy solution obtained by dispersing (emulsifying) and mixing by the same formulation and operation as in Reference Example 20 was spray-dried (Mobile M
inor, manufactured by Niro Japan) to obtain fine particles having an average particle diameter of 32 μm as a dried product under a cyclone. Spraying method: Two-fluid nozzle (nozzle diameter 1.2 mm) Air pressure: 1 kg / cm ² Drying chamber inlet temperature: 90 ° C Drying chamber outlet temperature: 40-43 ° C The content of compound B in the obtained fine particles is 28.1%. It was

Reference Example 22 Compound B 2 g and zinc acetate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.)
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, which was 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 the microcapsules was 101.6%, and the content of compound B in the microcapsules was 26.6%.

Reference Example 23 Compound B 2 g and zinc acetate dihydrate (manufactured by Wako Pure Chemical Industries)
0.757 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 was added to dichloromethane 7.5 ml and methanol 3.
Microcapsules were obtained in the same manner as in Reference Example 22 except that a uniform solution obtained by adding to a solution dissolved in 5 ml was used. The encapsulation rate of Compound B in the microcapsules is 10
At 1.9%, the content of compound B in the microcapsules was 25.9%.

Reference Example 24 Compound B (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
5 (mol%), weight average molecular weight 10,600, manufactured by Wako Pure Chemical Industries, Ltd.) 3 g was added to a solution dissolved in dichloromethane 7 ml and methanol 3 ml 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. This dried product was roughly crushed on a sieve with a pore size of 150 mm, and 3.6 g of the dried product obtained by sieving and mannitol
After mixing with 0.4 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. Compound B in fine particles
The content was 29.1%.

Reference Example 25 Compound B 2.0 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.) 3.97 g of dichloromethane 12.7
The mixture was added to a mixed solution of 5 ml, 2.25 ml of methanol and 0.136 mL of acetic acid, and 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% by weight 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 B in the microcapsules was 94.9%.

Reference Example 26 Compound B 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
Addition of 10 mM zinc acetate adjusted to 18 ℃ 0.1% by weight
The mixture was poured into 800 ml of an aqueous polyvinyl alcohol solution, and a turbine type homomixer was used to prepare an O / W emulsion at 7,000 rpm. 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 remove 3,000
Collected at 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 B in microcapsules is 90.7%, and the content of Compound B in microcapsules / mannitol powder is 26.4%.
Met.

Reference Example 27 Compound B 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
Addition of 30 mM zinc acetate adjusted to 18 ℃ 0.1% by weight
The mixture was poured into 800 ml of an aqueous polyvinyl alcohol solution, and a turbine type homomixer was used to prepare an O / W emulsion at 7,000 rpm. 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 remove 3,000
Collected at 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 B in the microcapsules was 92.2%, and the content of Compound B in the microcapsules / mannitol powder was 26.6%.
Met.

Reference Example 28 Compound B 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 wt% 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. 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 B in the microcapsules was 88.0%, and the content of Compound B in the microcapsule / mannitol powder was 25.4%.

Reference Example 29 Compound B 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
Addition of 10 mM zinc acetate adjusted to 18 ℃ 0.1% by weight
The mixture was poured into 800 ml of an aqueous polyvinyl alcohol solution, and a turbine type homomixer was used to prepare an O / W emulsion at 7,000 rpm. 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 remove 3,000
Collected at 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 B in the microcapsules was 89.1%, and the content of Compound B in the microcapsules / mannitol powder was 26.2%.
Met.

Example 1 2-Ethoxy-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (Compound B) 0.2 g, zinc acetate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1 g and lactic acid-glycolic acid copolymer (lactic acid / Glycolic acid 75/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4,200, number average molecular weight 4,090 by end group determination, Wako Pure Chemical Industries, Ltd.)
1.5 g of dichloromethane 3 mL and methanol 0.9 mL
And were added to obtain a solution. The solution obtained by adding 0.2 g of Actos and dissolving it was adjusted to 15 ° C in advance.
Pour into 800 mL of 0.1 wt% polyvinyl alcohol aqueous solution and use a turbine homomixer at 0,200 rpm.
/ W emulsion. This O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and methanol to solidify the oil phase, and then use a centrifuge to remove 2,000.
Collected at rpm. 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 contents of Compound B and Actos in the microcapsules were 10% and 12%, respectively.

Experimental Example 1 0.1 mL of 25 mg of the microcapsules obtained in Example 1
9-week-old male
A 23 G needle was administered subcutaneously to the back of the neck of SD rats. The drug concentration in plasma obtained by collecting blood from the tail vein with time after administration was measured. The results are shown in Table 1.

[Table 1] As is clear from Table 1, the drug concentration in plasma was sustained, confirming the sustained release of both compounds from this preparation.

[0107]

EFFECTS OF THE INVENTION (A) Angiotensin II antagonist,
(B) Sustained release of the present invention in combination with one or more drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents The sex medicine can significantly reduce the dose when each active ingredient is used alone, and as a result, the occurrence of side effects of the drug can be suppressed as compared with the case where each active ingredient is used alone. Made possible, angiotensin
II Prophylactic or therapeutic agents for intervening diseases, especially arterial hypertension with diabetic arteriosclerosis or hypertension, diabetes,
It is advantageously used as a prophylactic or therapeutic agent for hyperlipidemia, thrombosis, climacteric disorder and the like. Furthermore, it is possible to enhance the actions of the drug used alone, such as antihypertensive action, hypoglycemic action, cholesterol lowering action, antithrombotic action, and anticancer action, and a synergistic effect of suppressing cardiovascular events can be expected. The sustained-release drug of the present invention contains a high content of a concomitant drug selected from AII antagonists and antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents. In addition, since its release rate can be controlled, it exhibits angiotensin II antagonistic action and hypoglycemic action, cholesterol lowering action, antithrombotic action, anticancer action, etc. while maintaining diurnal blood pressure fluctuations for a long period of time. In addition, since it is possible to maintain a constant blood concentration regardless of day or night, it is expected that a stable pharmacological action will be continued with less fluctuation in the blood drug concentration as compared with the case of oral administration. Therefore, it is difficult to cause deterioration of the medical condition due to intentional avoidance such as change in dosing time and interruption of dosing in a group of patients with few subjective symptoms, and hypertension, abnormal blood pressure circadian fluctuation, heart disease (heart hypertrophy, heart failure, Myocardial infarction, etc., cerebrovascular disorder (syndromic infarction, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), ischemic peripheral circulatory disorder, arteriosclerosis obliterans, obstructive Thrombotic vasculitis, myocardial ischemia, cardiomyopathy,
Not only venous insufficiency, progression of heart failure after myocardial infarction, sequela of cerebrovascular accidents, diabetic complications, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulonephritis, irradiation-induced nephropathy, atheromatous artery Sclerosis, arteriosclerosis, vascular thickening, vascular thickening or occlusion after intervention, vascular re-occlusion after bypass surgery, erythrocytosis / hypertension / organ damage / vascular thickening after transplantation, rejection after transplantation, high aldosterone Disease, glomerulosclerosis, renal failure, portal hypertension, glaucoma, ocular hypertension, hyperlipidemia, angina, aneurysm, coronary atherosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis , Central nervous system diseases, Alzheimer's disease, memory deficiency, depression, amnesia,
Senile dementia, sensory dysfunction, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, Menuel syndrome, scleroderma, or dizziness-related anxiety, tension and discomfort,
Furthermore, it is expected that the therapeutic effects of dyspepsia, autonomic dysfunction, myasthenia gravis or cancer and cancer-related diseases, and climacteric disorders will become clearer. Further, the sustained-release preparation of the present invention is also used for bedridden, dementia, throat / esophageal disease, digestive system diseases, patients with dysphagia / dysphagia, patients who are difficult or unable to treat with oral medication during surgery, etc. It is an excellent drug that can. Recently, dyslipidemia, hypertension, diabetes and the like are risk factors for cardiovascular disease, and it is known that the risk is significantly increased when these are accumulated, rather than alone. For example, it develops vascular endothelial dysfunction and arteriosclerosis, and destabilizes plaques, causing serious cardiovascular diseases such as coronary artery disease and stroke. AII used in the present invention is applied to a group having such a risk factor of arteriosclerosis / cardiovascular disease and a high cardiovascular risk.
Antagonists, antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, etc. bring about multifaceted risk reduction effects. The major goal of antihypertensive therapy with AII antagonists is to prevent the progression and prevention of cardiovascular complications, which greatly affect the prognosis of patients with hypertension and damage to important organs, and reduce the morbidity and mortality of cardiovascular disease. It is in. Most patients who are treated for antihypertensive need combination therapy, have multiple risk factors, and are often associated with organ damage and complications. Therefore, it is desirable to select a drug combination that has little effect on other risk factors such as glucose / lipid metabolism and also has organ-protecting effects (particularly renal / vascular protection, anti-atherogenic effects, etc.). From such a viewpoint, the combination preparation of the present invention, particularly the long-acting sustained-release preparation, is useful for the treatment according to the pathological condition of individual cases for the purpose of preventing / treating organ disorders and complications.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/403 A61K 31/403 31/404 31/404 31/4152 31/4152 31/4178 31/4178 31 / 4184 31/4184 31/4245 31/4245 31/4422 31/4422 31/4439 31/4439 31/455 31/455 31/4709 31/4709 31/496 31/496 31/519 31/519 31/55 31/55 31/551 31/551 31/554 31/554 31/565 31/565 31/585 31/585 31/60 31/60 31/727 31/727 38/00 39/395 V 39/395 47 / 30 47/30 47/34 47/34 A61P 3/06 A61P 3/06 3/10 3/10 5/00 5/00 7/02 7/02 9/00 9/00 9/12 9/12 35 / 00 35/00 A61K 37/02 (72) Inventor Tetsuo Hoshino 6F term at 5-13 Shinkofudai, Toyono-cho, Toyono-gun, Osaka Prefecture (reference) 4C076 AA11 BB11 CC09 CC11 CC12 CC14 CC21 CC27 CC30 EE24A FF32 4C084 AA02 AA03 AA20 AA24 BA01 BA08 BA17 BA23 MA02 MA05 MA66 NA05 NA12 ZA361 ZA421 ZA541 ZB261 ZC031 ZC331 ZC351 ZC751 4C085 AA35 EE03 GG01 4C086 AA01 AA02 BA07 BA13 BC16 BC19 BC26 BC28 BC38 BC50 BC62 BC71 BC82 BC91 CB09 CB11 DA09 DA13 DA17 EA27 GA04 GA07 GA09 GA11 MA26 Z75C33 A53 ZAZA4A53 A36 A75 ZAZA4 AA02 DB03 DB25 DB43 DB56 FA19 MA02 MA03 MA04 MA05 MA37 MA86 NA05 NA14 ZA36 ZA42 ZA54 ZB26 ZC03 ZC33 ZC35 ZC75

Claims (45)

[Claims] 1. An (A) angiotensin II antagonist,
(B) A sustained-release medicine which is a combination of one or more drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents. 2. An angiotensin II antagonist 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 that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, n Represents 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of changing to an anion, R ³
Is a hydrocarbon residue which may be bound via a hetero atom and which may have a substituent), or a salt thereof. 3. Angiotensin II antagonist is losartan,
The drug according to claim 1, which is eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan or tasosartan. 4. An angiotensin II antagonist is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7.
-Carboxylic acid, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or 2-ethoxy-1-[[2 '-(2,5-dihydro-
The pharmaceutical according to claim 1, which is 5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazol-7-carboxylic acid or a salt thereof. 5. The antihypertensive drug is a drug selected from angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists, vasopressin antagonists, angiotensin-converting enzymes and neutral endopeptidase inhibitors, β blockers and aldosterone antagonists. The medicine according to claim 1. 6. The medicine according to claim 5, wherein the angiotensin converting enzyme inhibitor is a drug selected from enalapril, cilazapril, temocapril, trandolapril, lisinopril and ramipril. 7. The medicine according to claim 5, wherein the diuretic is a drug selected from indapamide, trichlormethiazide, bumetamide, hydrochlorothiazide and metolazone. 8. The medicine according to claim 5, wherein the calcium antagonist is a drug selected from amlodipine, nitrendipine and manidipine. 9. The medicine according to claim 5, wherein the vasopressin antagonist is a drug selected from tolvaptan, conivaptan hydrochloride and lercobaptan. 10. The medicine according to claim 5, wherein the angiotensin converting enzyme and the neutral endopeptidase inhibitor are drugs selected from omapatrilate, fasidotril and sanpatrilate. 11. The medicine according to claim 5, wherein the β blocker is a drug selected from carvedilol, metoprolol and propranolol. 12. The medicine according to claim 5, wherein the aldosterone antagonist is spironolactone. 13. A hypoglycemic drug is an insulin sensitizer,
The medicine according to claim 1, which is an insulin secretagogue or an insulin preparation. 14. The medicine according to claim 13, wherein the insulin sensitizer is a drug selected from pioglitazone hydrochloride, troglitazone and rosiglitazone maleate. 15. The medicine according to claim 13, wherein the insulin secretagogue is a drug selected from glibenclamide, nateglinide and repaglinide. 16. The therapeutic agent for hyperlipidemia is a statin drug, a fibrate drug or a nicotinic acid derivative.
The described medicine. 17. The medicine according to claim 16, wherein the statin drug is a drug selected from cerivastatin sodium, pravastatin sodium, simvastatin and atorvastatin calcium hydrate. 18. The pharmaceutical according to claim 16, wherein the fibrate is fenofibrate, fenofibric acid, bezafibrate or gemfibrozil. 19. The pharmaceutical according to claim 16, wherein the nicotinic acid derivative is niceritrol or cholexamine. 20. The medicine according to claim 1, wherein the antithrombotic drug is a drug selected from GPIIb / IIIa antagonists, low molecular weight heparin, thrombin inhibitors and antiplatelet drugs. 21. The medicine according to claim 20, wherein the GPIIb / IIIa antagonist is abciximab. 22. The medicine according to claim 20, wherein the low molecular weight heparin is enoxaparin sodium. 23. The medicine according to claim 20, wherein the thrombin inhibitor is argatroban. 24. The medicine according to claim 20, wherein the antiplatelet drug is clopidogrel sulfate or aspirin. 25. A therapeutic agent for menopause is estradiol,
The pharmaceutical according to claim 1, which is an estrogen selected from estradiol valerate and a conjugated estrogen. 26. The medicine according to claim 1, wherein the anticancer drug is a GnRH agonist or antagonist. 27. The pharmaceutical agent according to claim 26, wherein the GnRH agonist is leuprorelin or a salt thereof. 28. (A) Angiotensin II antagonist;
(B) One or two or more drugs selected from antihypertensive agents, hypoglycemic agents, antihyperlipidemic agents, antithrombotic agents, anti-menopausal agents and anticancer agents. Medicine. 29. (A) A sustained-release preparation containing an angiotensin II antagonist, (B) an antihypertensive agent, a hypoglycemic agent,
The pharmaceutical according to claim 1, which comprises a sustained-release preparation containing one or more drugs selected from the group consisting of hyperlipidemia therapeutic agents, antithrombotic agents, climacteric disorder therapeutic agents and anticancer agents. 30. (A) A sustained-release preparation containing an angiotensin II antagonist, (B) an antihypertensive agent, a hypoglycemic agent,
The drug according to claim 1, which is combined with a sustained-release preparation containing one or more drugs selected from the drugs for treating hyperlipidemia, antithrombotic drugs, menopausal drugs and anticancer drugs. 31. The medicine according to claim 1, which comprises (C) a biodegradable polymer. 32. The medicine according to claim 31, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. 33. The medicine according to claim 32, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer. 34. The composition molar ratio of lactic acid and glycolic acid is 10.
34. The medicine according to claim 33, which is 0/0 to 40/60. 35. The weight average molecular weight of the polymer is 3,000 to.
33. The medicine according to claim 32, which is 50,000. 36. The medicine according to claim 1, which is for injection. 37. The medicine according to claim 1, which is a prophylactic / therapeutic agent for cardiovascular diseases. 38. A preventive / therapeutic agent for hypertension.
The described medicine. 39. The pharmaceutical composition according to claim 1, which is a prophylactic / therapeutic agent for abnormal blood pressure circadian rhythm. 40. A preventive / therapeutic agent for organ disorders.
The described medicine. 41. The pharmaceutical according to claim 1, which is a preventive / therapeutic agent for cancer. 42. The medicine according to claim 1, which is an organ protecting agent. 43. A method for treating cardiovascular disease, hypertension, abnormal circadian rhythm of blood pressure, organ disorder or cancer, which comprises administering the pharmaceutical according to claim 1 to a mammal. 44. Use of the medicament according to claim 1 for producing a therapeutic agent for cardiovascular disease, hypertension, abnormal blood pressure circadian rhythm, organ disorder or cancer. [45] A sustained-release medicine comprising a combination of two or three drugs selected from angiotensin II antagonists, antihypertensive agents, hypoglycemic agents and antihyperlipidemic agents.