MXPA00008171A - Sustained-release preparation for aii antagonist, production and use thereof - Google Patents

Abstract

The present invention is to provide a sustained-release preparation which comprises a compound having angiotensin II antagonistic activity, its pro-drug or their salt, and a biodegradable polymer, and if necessary, a polyvalent metal, and which is highly stable and active and shows angiotensin II antagonistic activity with maintaining circadian rhythm of blood pressure for a long time.

Description

PREPARATION OF PROLONGED ANTAGONIST, PRODUCTION AND USE OF THE SAME Field of Invention The present invention relates to a prolonged release preparation for a compound having angiotensin II antagonist activity, its method of production and its use as a medicine, etc.

Background of the Invention The renin-angiotensin system is involved in homostasis to control systemic blood pressure, the amount of body fluid, the balance between electrolytes, etc., together with the aldoterone system. The relationship between renin-angiotensin and hypertension has been clarified based on the fact that angiotensin II has a potent vasoconstrictive action that raises blood pressure by means of angiotensin II receptors in the cell membrane, and therefore Therefore, angiotensin II antagonists are used for the treatment REF .: 121741 e to per ens n cause a by ang or ens na. Therefore, drugs that have angiotensin II antagonist activity have been applied clinically by oral administration, however, said drugs are applied for symptomatic therapy that requires repeated administrations for a long time. Therefore, due to the need for continuous administration, administration simultaneously with other drugs for oral administration, etc., a burden on the patient receiving oral administration of this type of drug can not be ignored. Furthermore, there is the possibility that the patient's condition changes due to interruptions in the taking of this type of drug, etc. Thus, the administration of drugs that have angiotensin II antagonist activity is not necessarily satisfactory in view of a safe and feasible treatment.

In Pharmaceutical Research, 1 _, 887-891 (1997), a prolonged release preparation is reported for 2 -et i 1-5, 7 -dimet il-3- [[2 '- (1H-tetra zol-5 il) bi phenyl-4-yl] methyl] imide z [4,5-b] pyridine having antagonistic activity of the The preparation of the prolonged-release preparation, whose drug content is about 10%, is described in the preparation of the molecules (Mw 82,000) of polylactide diestarate and polyethylene glycol 400. of around 20%.

In the Japanese publication of the translation of the International patent application No. 504017/1998, a composition is described which is characterized in that a physiologically active protein together with a metal cation component is dispersed in a bi-compatible polymer.

Description of the invention.

The present invention provides a sustained release preparation comprising a high amount of a compound having an angiotensin II antagonist activity, whose initial burst is lower and is capable of controlling the release ratio of said compound after the initial burst, and also its production and use.

We present an extensive research or an extensive study to solve the aforementioned problems and, as a result, have found that a prolonged release preparation comprising a compound having angiotensin II antagonistic activity and a biodegradable polymer can contain said compound in a high amount, that the release ratio of said compound can be controlled by the addition of a polyvalent metal compound and that by administering said preparation to rat spontaneous hypertension (SHR), the concentration of drug in the blood of the rat is maintained and the blood pressure of the rat can be reduced by maintaining a heart rate of blood pressure for a long time. The inventors have made additional investigations based on this finding, and have developed the present invention.

More specifically, the present invention relates to (1) a prolonged release preparation comprising a compound having an activity an agon saea ang or ens na exc uyen oe 2-ethyl-5, 7 -dimet il-3- [[2 '- (lH-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazo [4, 5 -b] pyridine and a salt thereof), their prodrugs or their salts, and a biodegradable polymer; (2) a prolonged release preparation as in the above (i), wherein the compound having angiotensin II antagonist activity is a non-peptide compound; (3) a prolonged release preparation as in the above (1), wherein the compound having angiotensin II antagonist activity is a compound having an oxygen atom in its molecules; (4) a prolonged release preparation as in the above (1), wherein the compound having angiotensin II antagonist activity is a compound having an ether linkage or a carbonyl group; (5) a prolonged release preparation as in the previous one (1), wherein the compound that has an agonis activi a to angio ensia is a compound of the formula (I): wherein R1 is a group capable of forming an anion or a group capable of being converted to this, X shows that the phenylene group and the femlo group are linked to each other directly or through a spacer having an atomic chain length of 2. or smaller, n is an integer of 1 or 2, ring A is a benzene ring that has an optional substitution, in addition to the group R2, R2 is a group capable of forming an anion or a group capable of converting to this, and R3 is an optionally substituted hydrocarbon residue that can be linked through a heteroatom, or a salt thereof; a prognostic preparation as in the previous one (1), wherein the compound having angiotensin II antagonist activity is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsarian, Telmisartan, Irbesartan or Tasosartan; (7) a prolonged release preparation as in the above (1), wherein the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '- (1H-tetra zol-5-yl ) bifenyl-4-y1] met il] bancimidazole-7-carboxylic acid or a salt thereof; (8) a prolonged release preparation as in the above (1), wherein the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl -4-yl] -met i 1] -benzimidazole-7-carboxylic acid 1- (cyclohexy loxycarbonyl) ethyl ester or a salt of the (9) a prolonged release preparation as in the previous (1), wherein the compound having angiotensin II antagonist activity is c-ox - - -, - - - -,, -oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof; (10) a prolonged release preparation as in the above (1), wherein the biodegradable polymer is a polymer of α-hydroxy carboxylic acid; (11) a prolonged release preparation as in the above (10), wherein the polymer of α-hydroxycarboxylic acid is a polymer of lactic acid-glycolic acid; (12) a prolonged release preparation as in the above (11), wherein the molar ratio of lactic acid and glycolic acid is 100 / 0-40 / 60; (13) a prolonged release preparation as in the above (1), wherein the molecular weight of the average weight of the polymer is 3,000-50,000; (14) a prolonged release preparation as in the previous (1), which is for injection; a pro-ractic preparation as in the previous one (1), which also includes a polyvalent metal; (16) a prolonged release preparation as in the previous one (15), wherein the polyvalent metal is zinc; (17) a sustained release preparation comprising a compound having angiotensin II antagonist activity, its prodrugs or its salts, a biodegradable polymer and a polyvalent metal; (18) a method for producing a sustained release preparation as in the above (1), which comprises removing the solvent from a solution containing a compound having angiotensin II antagonist activity, its prodrugs or its salts, and a polymer biodegradable; (19) a method for producing a sustained release preparation as in the previous one (17), which comprises removing the solvent from a solution containing a compound having activity antagonist of angiotensin II, its prodrugs or its salts, a biodegradable polymer and a polyvalent metal; (20) the method of the previous one (19), wherein the polyvalent metal is zinc; (21) a pharmaceutical composition, comprising a prolonged release preparation of the above (1); (22) the composition as in the previous one (21), which is for the prevention or treatment of circulatory diseases; (23) the composition of the previous one (21), which is for the prevention or treatment of hypertension; (24) the composition of the previous one (21), which is for the prevention or treatment of hypercardia, heart failure, myocardial infarction, cerebral apoplexy, disturbances of the ischemic peripheral circulation, myocardial ischemia, venal insufficiency, progressive heart failure after a myocardial infarction, Ophthalmology, nephritis, nephritis, glaomerulonephrosis, atherosclerosis, angiohypertide, vascular hypertrophy or obstron after an operation, vascular reobstron after deviation surgery, hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, high intraocular pressure, hyperlipidemia, angina pectoris, aneuphole, arteroesclerosis is coronary artery, cerebral arteriosclerosis, peripheral arteroesclerosis, thrombosis, central nervous system disease, Alzheimer's disease, memory deficiency, depression, amnesia , senile dementia, disturbances of the senses, organ failure of the multiple system, a disease due to endothelial dysfunction or scleroderma, or the prevention or relief of anxious neurosis, catatonia, indisposition or dyspeptic symptoms; etc .

In the present specification, the antagonist activity of angiotensin II is to competitively or non-competitively inhibit the binding of angiotensin II to angiotensin II receptors in the cell membrane for reduce vasoconstrictive action or potent vascular proliferation action induced by angiotensin II and relieve symptoms of hypertension.

The compound having angiotensin II antagonist activity that can be used by the present invention can be either a peptide compound or a non-peptide compound. In view of the long-term advantage, a non-peptide compound having angiotensin II antagonist activity is preferred. As the compound having angiotensin II antagonist activity, a compound having an oxygen atom in its molecules is preferable, a compound having an ether bond or a carbonyl group (said carbonyl group can form a hydroxy group by resonance) is more preferably, a compound having an ether linkage or a ketone derivative is further preferable, and in particular, an ether derivative is preferable.

Any non-peptide compound having angiotensin II antagonist activity can be used by the present invention. Examples of The compounds of the invention are disclosed in Japanese Patent Unexamined Publication No. 71073/1981, Unexamined Publication of Japanese Patent No. 71074/1981, Unexamined Publication of Japanese Patent No.98270 / 1982, Publication Unexamined Japanese Patent No. 157768/1983, USP 4,355,040, USP 4,340,598, etc .; Modified imidazole derivatives are described in EP-253310, EP-291969, EP-324377, EP-403158, WO-9100277, Japanese Patent Unexamined Publication No. 23868/1988, Japanese Patent Unexamined Publication No. 117876 / 1989, etc .; pyrrole, pyrazole and triazole derivatives are described in USP 5,183,899, EP-323841, EP-409332, Unexamined Publication of Japanese Patent No. 287071/1989, etc .; the benz 1 imide zol derivatives are described in USP 4,880,804, EP-0392317, EP-0399732, EP-0400835, EP-425921, EP-459136, Unexamined Publication of Japanese Patent No. 63264/1991, etc .; Azaindene derivatives are described in EP-399731, etc .; pyrimidone derivatives are described in EP-407342, etc .; Quinazoline derivatives are described in EP-411766, etc .; Xanthine derivatives are described in EP-430300, etc .; imidazole derivatives We are writing in a -, e c .; pyrimidinedione derivatives are described in EP-442473, etc .; Tietnopyridone derivatives are described in EP-443568, etc .; Heterocyclic compounds are described in EP-445811, EP-483683, EP-518033, EP-520423, EP-588299, EP-603712, etc. In addition, these representative compounds are described in the Journal of Medicinal Chemistry, Vol. 39, No. 3, pages 625-656 (1996). It can be used as the non-peptide compound having angiotensin II antagonist activity, any in addition to the compounds described in the aforementioned references for their angiotensin II antagonist activity. Among others, preferred are Losartan (DuP753), Eprosartan (SK &F108566), Candesartan cilexetil (TCV-116), Valsarian (CGP-48933), Telmisartan (BIBR277), Irbesartan (SR47436), Tasosartan (ANA-756). , its active metabolites (Candesartan, etc.), etc.

Preferred examples of non-peptide compounds having angiotensin II antagonist activity include, for example, a benzylimide zol derivative of the formula (I): wherein R1 is a group capable of forming an anion or a group capable of being converted to this, X shows that- the phenylene group and the phenyl group are attached to each other directly or through a spacer having an atomic chain length of 2 or less, n is an integer of 1 or 2, ring A is a benzene ring having an optional substitution, in addition to the group R2, R 2 is a group capable of forming an anion or a group capable of becoming this, and R3 is an optionally substituted hydrocarbon residue that can be attached through a heteroatom (preferably, an optionally substituted hydrocarbon residue that is bonded through an oxygen atom), etc., or a salt thereof.

In formula (I) above, the group capable of forming an anion (a group having a hydrogen atom capable of starting as a proton) as R1 includes, for example, (1) a carboxyl group, (2) a tetrazolyl group, (3) an ammonium phonyl trifluoromethoxide group (-NHSO2CF3), (4), a phosphono group, (5) a sulfo group, (6) an optionally substituted monocyclic heterocyclic ring residue of up to 7 members (preferably 5- to 6-members) containing one or more of N, S and O, etc.

Examples of the above "residue of the optionally substituted monocyclic heterocyclic ring of 5- to 7-membered members (preferably 5- to 6-membered) containing one or more of N, S and O "include etc. The chemical bond between the heterocyclic ring residue represented by R1 and the femlo group to which said het erocyclic ring residue is linked can be a carbon-carbon bond as shown above, or a nitrogen-carbon bond by means of several atoms of nitrogen when the symbol g is -NH-, etc., in the previous formulas.

For example, when R1 is represented by the formula • these preferred modalities are Other examples of R 1 linked through a nitrogen atom include In the above formula, g is -CH2-, -NH-, -0-, or -S (0) m-; > = Z, > = Z 'and > = Z "is independently a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (eg, S, S (0), S (0) 2, etc.) Preferably, a car bon group or a locarbonyl group, more preferably a carbonyl group); and m is an integer of 0, 1 or 2.

Preferred examples of the heterocyclic ring residue represented by R1 include a heterocyclic ring residue having simultaneously an -NH- or -OH- group such as a proton donor and a carbonyl group, a thiocarbonyl group, a sulfinyl group, etc. , as a proton acceptor, such as an oxadia zolone ring, an oxasia zolotone ring or a tiadia zolone ring, etc.

Although the residue of the heterocyclic ring represented by R 1 can form a fused ring connecting the susbt ituyent is in the heterocyclic ring, it is preferably a ring residue of 5 to 6 members, more preferably a 5 member residue.

Preferred examples of the heterocyclic ring residue represented by R1 include a group of the formula: Rj where i is -0- or -S-, is > = 0, > = S or > = S (0) m, and m is as defined above (preferably, 4,5-dihydro-5-oxo-l, 2,4-oxadiazol-3-yl, 4,5-dihydro-5-t? oxo-l, 2,4-oxadiazol-3-yl, 4,5-dihydro-5-oxo-l, 2,4-tadia zol-3-yl, more preferably 4,5-dihydro-5-oxo - 1, 2, 4-oxadiazol-3-yl).

The residue of the aforementioned heterocyclic ring (R1) has the following tautomeric isomers. For example in , when Z is O and g is O, the three tautomeric isomers a ', b' and c 'exist and a group of the formula: includes all the previous ones to ', b' and c ' The group capable of forming an anion such as R1 can be protected by a (C1-4) alkyl group n er or opc ona men e su u u o, u (for example alkanoyl (C2-5) inferior, benzoilo, etc.), etc., as their possible positions.

Examples of the optionally substituted lower alkyl (Ci-) group include (1) a lower alkyl group (C? - () optionally substituted with one to three phenyl groups which may have a halogen atom, nitro, alkyl (C? - () lower, lower (C 1-4) alkoxy, etc., (eg, methyl, triphenylmethyl, p-met oxybenzyl, p-nitrobenzyl, etc.); (2) an alkoxy group (Ci-,) lower- lower alkyl (CI-1) (eg, methoxymethyl, ethoxymethyl, etc.); (3) a group of the formula: -CH (R 4) -OCOR 5 wherein R 4 is (a) a hydrogen, (b) a group straight or branched lower alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (c) a group straight or branched lower C2_6 alkenyl or (d) a C3-8 cycloalkyl group (for example cyclopentyl, cyclohexyl, cycloheptyl, etc.), and R5 is (a) a straight or branched lower C6-6 alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, nb utilo, isobutyl, sec- uti or, - uio, n-pen io, isopen io, neopentilo, etc.), (b) a straight or branched lower C2-6 alkenyl group, (c) a lower alkyl group C -? - 3 substituted with a group C3-8 cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower alkyl (C? -t), a lower alkoxy (C? - <?), etc.) such as benzyl, p-chlorobenzyl, phenethyl, ci clopent 1 lmet 1 l, cyclohexylmethyl, etc., (d a lower C2-3 alkenyl group substituted with a C3-8 cycloalkyl group or substituted aryl (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, an alkyl (C. _4) lower, a lower alkoxy (C? _4), etc.) such as cmamyl, etc., having an alsuenyl portion such as vinyl, propenyl, aillo, isopropenyl, etc., (e) an aplo group optionally substit uido (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower (C 1-4) alkyl, a lower (C 1-4) alkoxy, etc.) such as phenyl, p-tolyl, naphthyl, etc. (f) a straight or branched coxi-6 straight group (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, and sopentyloxy, neopentloxy, etc.), (g) a straight or branched lower C 2-8 alkenyloxy group (eg, allyloxy, isobutenyloxy, etc.), (h) a C3_8 cycloalkyloxy group (eg, cyclopentyloxy, cyclohexylocyl, cycloheptyloxy, etc.), (1) a lower C.sub.1 -C.sub.3 alkoxy group substituted with a C3_8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a phenyl group) , a naphthyl group, etc., optionally having a halogen atom, a nitro, an alkyl (C.- <) lower, a lower alkoxy (C 1-4), etc.) such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc., having an alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy, etc., etc.), (j) a lower C2-3 alkenylcyclic group substituted with n a C3_8 cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aplo group (for example, a phenyl group or a naphthyl group, etc., optionally having a halogen atom, a no ro, a a qui o? _4 in erior, a a coxi. Bottom, etc.) such as cinnamyloxy, etc., having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyl, isopropeny loxy, etc., or (k) an optionally substituted aryloxy group (e.g., a phenoxy group, a naphthoxy group, etc., optionally having a halogen atom, a nitro, a lower (C 1-4) alkyl, a lower (C 1-4) alkoxy, etc.) such as phenoxy, p-nit rofenoxi, naphthoxy, etc.; etc.

The group capable of forming an anion such as R 1 can be substituted, in addition to the above protecting group such as an optionally substituted lower alkyl (C 4) group or an acyl group (eg, lower (C 2-5) alkanoyl, benzoyl, etc. ), etc., with an optionally substituted lower alkyl (C? _4) group (for example an optionally substituted lower (Ci 4) alkyl group similar to the optionally substituted lower (C? _4) alkyl group "exemplified as a protecting group for the above group capable of forming an anion such as R1), a halogen atom, a nitro, a cyano, a lower alkoxy (C? _4), an ammo optionally substituted with 1 to 2 groups to which (C1-4) n eror, etc. in a possible position.

In the above formula, the group convertible into the group capable of forming an anion (a group having a hydrogen atom capable of splitting as a proton) as R1 can be a group convertible into a group capable of forming an anion under biological or biological conditions. physiological (for example an in vivo reaction, etc., such as oxidation, reduction, hydrolysis, etc., by enzyme in vivo, etc.) [also called prodrug], or the group convertible into a group capable of forming an anion represented by R1 may be a group chemically convertible to a group capable of forming an anion, such as cyano, an N-hydroxycarbamimidoyl group (-C (= N-OH) -NH2), a group selected from the class consisting of (1) a carboxyl group, (2) a tetrazolyl group, (3) a trifluoromethanesulphonic amino acid group (-NHS02CF), (4) a phosphono group, (5) a sulfo group and (6) a monocyclic heterocyclic ring residue optionally substituted from 5 to 7 members (preferably 5 up to 6 members) that contains one or more of N,? and O, each of which is protected with an optionally substituted lower alkyl group (C.-4) or an acyl group, etc., [also called synthetic intermediate].

As the group R1, (1) carboxyl, tetrazolyl or 4,5-d? H? Dro-5-oxo-l, 2,4-oxad? Azole-3-? Lo (preferably, t et razol lio), each one of which can be protected with an optionally substituted lower alkyl (C &sub1; &sub4;) (e.g., methyl, trifluoride, methoxymethyl, ethoxymethyl, p-methoxybenzene, p-robencyl, etc.) or a acyl group (eg lower (C2-5) alkanoyl, benzoyl, etc.) or (2) cyano or N-hydroxycarbamomodoyl (preferably cyano) is preferable.

In the above formula, X shows that the phenylene group is linked to the adjacent phenyl group directly or through a spacer with an atomic chain of 2 or less (preferably directly). Examples of the spacer with an atomic chain of 2 or less include any divalent chain in which the number of atoms constituting the straight chain is 1 or 2 and which can be a side chain, and specifically alkylene (C? _4) inferor in which the number of atoms constituting the straight chain is 1 or 2, -CO, -0-, -S-, -NH-, -CO-NH-, -0 -CH2-, -S-CH2-, -CH = CH-, etc.

In the above formula, n is an integer of 1 or 2 (preferably 1).

In the above formula, the ring A can have, in addition to the group R2, another substituent, for example, (1) halogen (eg, F, Cl, Br, etc.), (2) cyano, (3) nitro, (4) an optionally substituted lower alkyl (C._4), (5) lower (C_4) alkoxy, (6) an optionally substituted amino group (eg, amino, N-lower alkylamino (C_4)) ( for example, methylamino, etc.), N, N-di-lower alkylamino (C 4 -4) (for example, dimethylamino, etc.), N-arylamino (for example, phenylamino, etc.), aminoalicyclic (for example, example, morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), etc.), (7) a group of the formula: -CO-D 'wherein D' is a hydroxy group or an alkoxy (C.-4) which lower alkyl portion can be substituted with a hydroxy group, a lower (C? -4)) alkoxy, a lower (C 2-6) alkanoyloxy (eg example, acetoxy, pivaloyloxy, etc.), a lower alkoxycarbonyloxy (C6-6) (e.g., methoxycarbonyl, oxycarbonyloxy, etc.), or a lower (C3-6) cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy, etc.). ), or (8) tetrazolyl, an amide group of tr 1 fluorometanesulonic acid, a phosphono group or a sulfo group, each of which can be protected with an optionally substituted lower alkyl (C 4) alkyl ("an alkyl group"). C1-4) optionally substituted lower "similar to that exemplified as a protective group for the above group capable of forming an anion represented by R1, etc.) or acyl (eg, lower (C2-5) alkanoyl, benzoyl, etc. .), etc.

Of these substituents, one or two may be present simultaneously in any possible position in the benzene ring, in addition to the group R2, and the preferred examples of the susbt ítuyent is for the benzene ring represented by A include an alkyl (C? _4) optionally substituted lower (e.g., a lower (C? -4) alkyl, etc., optionally substituted with a hydroxy group, a carboxyl group, a halogen, etc.), a halogen, etc. As aye, a benzene ring having no substituent in addition to the group R2 is preferred.

In the above formula, examples of the group capable of forming an anion (a group having a hydrogen atom capable of starting as a proton) as R2 include (1) an optionally esterified or amidated carboxyl group, (2), a tetrazolyl group , (3) an amidophonic trifluoromethoxide (-NHSO2CF3) amido group, (4) a phosphono group, (5) a sulfo group, etc., each of which can be protected with an optionally substituted lower alkyl group (for example an optionally substituted lower alkyl (C? _4) group similar to the "optionally substituted lower (C._4) alkyl group" exemplified as the protecting group for the group capable of forming an anion such as R1) or an acyl group (eg example, lower alkanoyl (C2-s), benzoyl, etc.), or any of the groups capable of converting therein under biological or physiological conditions (for example an in vi ve reaction, etc., such as oxidation, reduction, hydrolysis , etc., by enzyme in vivo, etc. .), or chemically.

Examples of the carboxyl optionally esterified or amidated as R2 include a group of the formula: -CO-D wherein D is (I) a hydroxy group, (2) an optionally substituted amino (eg, amino, N-alkylamino (C)) ?), N, Nd? -C 1-4 lower alkylamino, etc.) or (3) an optionally substituted alkoxy [e.g., (i) a lower (C? 6) alkoxy group whose alkyl portion is optionally substituted with a hydroxy group, an optionally substituted am (eg, amino, lower alkylammo (C? -4), lower N, N-di-alkylamino (C._4), piperid, morpholino, etc.), a halogen, a lower alkoxy (C? -6), lower alkylthio (C? _6), a lower (C_8) cycloalkoxy or an optionally substituted dioxyolenyl (for example, 5-met? l-2 -oxo-1, 3- d? oxolen-4-? lo, etc.), or (n) a group of the formula: -O-CH (R6) -OCOR7 wherein R6 is (a) a hydrogen, (b) a lower alkyl group C ? -6 straight or branched (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (c) a straight or branched C 2-6 lower alkenyl group or (d) a C 3-8 cycloalkyl group (eg e emp, cc open o, cco ex o, cco ep o, etc.), and R7 is (a) a straight or branched C?-6 lower alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (b) a straight or branched C 2-6 lower alkenyl group, (c) a C 1-3 alkyl group lower substituted with a C3-8 cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower (C 1-4) alkyl, a lower (C 1-4) alkoxy, etc.) such as benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc., (d) an alkenyl group C2-lower substituted with a C3_8 cycloalkyl or an optionally substituted aryl group (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower (C? -4) alkyl, a lower alkoxy (C.-4), etc.) such as cinnamyl, etc., having an alkenyl portion such as vinyl, propenyl, allyl, isopropenyl, etc., (e) an optionally substituted aryl group (by ii ^^^^^^ i example, a group eni or, a group na ti or, etc., optionally having a halogen atom, a nitro, a lower alkyl (C? -), a lower alkoxy (C._4), etc.), such as phenyl, p-tolyl, naphthyl, etc., (f) a straight or branched lower C6-lower alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t) -butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a lower C2-s alkenyloxy group (e.g., allyloxy, isobuteni loxi, etc.), (h) a C3-8 cycloalkyloxy group ( for example, cyclopentyl, cyclohexyloxy, cycloheptyloxy, etc.), (i) a lower C?--3 alkoxy group substituted with a C 3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or a optionally substituted group (for example, a phenyl group, a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower alkyl (C? -4), a lower alkoxy (C? -4) , etc.) such as benzyloxy, phenethyloxy, cyclopentyl lmetoxy, cyclohexymethoxy, etc., having an alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy, etc., etc.), (j) a lower C2_3 alkenyloxy group substituted with a C3_8 cycloalkyl (e.g. what, cic or exi o, cic or ept l, etc. or an ary or optionally substituted group (for example, a phenyl group or a naphthyl group, etc., optionally having a halogen atom, a nitro, a lower alkyl (C? -4), an alkoxy (C.-4) lower, etc.) such as cinnamyloxy, etc., having an alkenyloxy moiety such as vmiloxy, propenyloxy, allyloxy, isopropenyloxy, etc., or (k) an optionally substituted aryloxy group (e.g., a phenoxy group, a naphthoxy group, etc., optionally having a halogen atom, a nitro, a lower alkyl (C? _4), a lower alkoxy (C] .- 4), etc.) such as phenoxy, p-nor t rof enoxi, naphthoxy, etc. .], etc.

As R, a carboxyl optionally is preferred, and its specific examples include -COOH and a salt thereof, COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxy-carbonyl, 1- (cyclohex loxycarbonyloxy) ethoxycarbonyl, met.l-2-oxo-l, 3-d? oxolen-4-? lmethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxyet oxycarbonyl, n-butyl methoxymethoxycarbonyl, isobutyloxymethoxycarbon J.1O, 1- (ethoxycarbon? lox) ethoxycarbonyl, l- (acetox?) - ethoxycarbonyl, 1 (isobutyryloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzyloxymethoxycarbonyl, cinnami loxycarbomyl, cyclopentylcarbonyloxymethoxycarbonyl , etc. The group R2 can be any of the groups capable of forming a ba anion or biological or physiological conditions (eg, in vivo reaction, etc., such as oxidation, reduction, hydrolysis, etc., by in vivo enzyme, etc.) , groups capable of chemically forming an anion (eg, COO-, its derivatives, etc.) or groups capable of becoming this. The group R2 can be a carboxyl group or its prodrugs.

Preferred examples of the group R2 include a group of the formula -CO-D wherein D is (1) a hydroxy group or (2) a lower (C? -4) alkoxy whose alkyl portion is optionally substituted with a group hydroxy, an amino, a halogen, a lower alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), a lower (C3-8) cycloalkyloxy, a lower alkoxycarbonyl (Ci-e) (eg, methoxycarbonyloxy) , et oxycarboni loxi, etc.), a cycloalkox car on ox (C3-8) n er or (for example, cyclohexyloxycarbonyloxy, etc.), a lower alkoxy (C? -4) or a lower cycloalkoxy (C3-8). In others, a carboxyl esterified with a lower alkyl (C? _4) (preferably, methyl or ethyl) is preferred.

In the above formula, the examples of the "hydrocarbon residue" in the "optionally substituted hydrocarbon residue that can be linked through a heteroatom" represented by R3 includes (1) an alkyl group, (2) an alkenyl group, (3) ) an alkynyl group, (4) a cycloalkyl group, (5) an aryl group, (6) an aralkyl group, etc. Among others, an alkyl group, an alkenyl group and a cycloalkyl group are preferred.

Examples of the aforementioned alkyl group (1) include a straight or branched lower alkyl group having about 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl , pentyl, i-pentyl, hexyl, heptyl, octyl, etc.

Examples of the aforementioned alkenyl group (3) include a straight or branched alkenyl group having about 2-8 carbon atoms such as vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl, etc.

Examples of the aforementioned alkynyl group (3) include a straight or branched lower alkynyl group having about 2-8 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 2-pantynyl, 2-octynyl, etc.

Examples of the cycloalkyl group of the above (4) include a lower cycloalkyl having about 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Each of the aforementioned alkyl group, alkenyl group, alkenyl group and cycloalkyl group can be substituted with a hydroxy group, an optionally substituted amino group (eg, amino, N-lower alkylamino (C.-4), N, N-di) -alkylamino (C? -4) lower, etc.), a geno, group a cox? -4 er er, lower alkylthio group (C? -4), etc.

Examples of the aralkyl group of the above (5) include a lower alkyl (C? -) phenyl, etc., such as benzyl, phenethyl, etc.

Examples of the aryl group of the above (6) include phenyl, etc.

Each of the aralkyl group and aryl group mentioned above can be substituted, in any possible position in the benzene ring, with a halogen (for example, F, Cl, Br, etc.), a nitro, an optionally substituted amino group (e.g. , amino, N-lower alkylamino (C? -4), N, N-di-lower alkylamino (C? -), etc.), lower (C? -4) alkoxy (e.g., methoxy, ethoxy, etc.) ), a lower alkylthio (C? -) (for example, methylthio, ethylthio, etc.), a lower (C? -4) alkyl (for example, methyl, ethyl, etc.), etc.

Preferred examples of the "optionally substituted hydrocarbon residue" in the "optionally substituted hydrocarbon residue" which may be linked through the hetero atom "represented by R3 includes an optionally substituted alkyl or alkenyl group (eg, a lower alkyl group (Ci-s) or a lower (C 2-5) alkenyl, each of which may be substituted with a hydroxy group, an amino group, a halogen, a lower (C 4 -4) alkoxy group, etc.) Among others, lower (C 1 -5) alkyl (more preferably, ethyl) is preferable.

Preferred examples of the "heteroatom" in the "optionally substituted hydrocarbon residue that can be linked through a heteroatom" represented by R3 include -O-, -S (0) m- [is an integer of 0-2], -NR '- [R' is a hydrogen atom or a lower alkyl (C.-4)], etc. Among others, -O- is the preferred one.

Among others, such as R, a lower (C1-5) alkyl group or a lower (C2-5) alkenyl group is preferable, each of which can be substituted with a substituent selected from the class consisting of a hydroxy group, a amino group, a halogen and a lower alkoxy group (C? -4) and which can be linked through - O-, -S m- m is an integer e - or - - is a hydrogen atom or a lower alkyl (C? _4), etc., and a lower (C1-5) alkyl or alkoxy (Ci-5) ) lower (in particular, ethoxy) is more preferred.

Among the non-peptide compounds having angiotensin II antagonist activity and represented by the formula (I), a benzimide zol-7-carboxylic acid derivative of the formula (I '): wherein R1 is (1) a carboxyl group, (2) a tetrazolyl group or (3) a group of the formula: where i is -0- or -S-, j is > = 0, > = S or > = S (0) m, and m is as defined above; ring A is a benzene ring having an optional substituent selected from the class consisting of an optionally substituted lower alkyl (C? _4) (for example, a lower alkyl (C? _4) optionally substituted with a hydroxy group, an carboxy group, a halogen, etc.) and a halogen, in addition to the group R2 (preferably, a benzene ring that does not have a substituent in addition to the group R2); R2 is a group of the formula: -CO-D wherein D is (1) a hydroxy group or (2) a lower (C4_4) alkoxy whose alkyl portion can be substituted with a hydroxy group, an amino, a halogen, a lower (C 2-6) alkanoyloxy (for example, acetoxy, pivaloyloxy, etc.), a lower (C 3-8) cycloalkyloxy, a lower (C 1-6) alkoxycarbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), a lower cycloalkoxycarboni (C3_8) (by example, cyclohexyloxycarboni oxy, etc.), a lower alkoxy (C 4) or a lower cycloalkoxy (C 3 s); R3 is an alkyl group. { C1-5) lower or lower (C2-5) alkenyl group, each of which can be linked through -O-, -S (0) m- [m is an integer of 0-2] or -NR ' - R 'is a hydrogen atom or a lower alkyl (C? _4) and which can be substituted with a substituent selected from the class consisting of a hydroxy group, an amino group, a halogen and a lower alkoxy (C? -) group (preferably, a lower (C1-5) alkyl or lower (C1-5) alkoxy, more preferably, ethoxy), etc., a pharmaceutically acceptable salt thereof is preferred.

Among others, the acid 2-ethoxy? -l- [[2 '- (1H-tetrazol-5? L) b? Phen? L-4? L] met? L] benc? M? Dazol-7- carboxylic [Candesartan], 2-ethoxy? -l- [[2 '- (1H-tetrazol-5? l) b? phen? l-4? l] met? l] -benc? m? dazol- 7-carboxylic acid 1 - (cyclohexy loxycarbonyl loxy) ethyl [Candesartan cilexetil], 2-et 0x1- 1 - [[2 '- (1H-tetrazole-5? L) b? Phen? l-4-? 1] metí l] benc? M? Da zol -7-carboxylate of pi aloi loximet 1 lo, the acid 2-ethoxy? -1- [[2 '- (4, 5-d? H? Dro-5-oxo -l, 2, 4-oxad? azole-3-? l) b? phen? l-4-? l] met? l] benc? l? m? dazol-7- carboxyl, etc., or a salt thereof are preferred.

The aforementioned benzylimidazole derivatives can be produced by known methods described in, for example, EP-42592] /, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272, etc., or an analogous method to this. When Candesartan cilexetil is used by the present invention, it is preferred to use a stable C-type crystal described in EP-459136.

The compound having angiotensin II antagonist activity or a prodrug thereof may be in a distinct entity or in the form of any possible pharmaceutically acceptable salts thereof. Examples of such salts include a salt with inorganic bases (for example, alkali metals such as sodium, potassium, etc., alkaline earth metals such as calcium, magnesium, etc., transition metals such as zinc, iron, copper, etc.).; etc.); organic bases (for example, organic amines such as triemet ilamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, tnetanolamma, dicyclohexylamine, N, N'-dibencilet ilendiamma, etc .; basic amino acids such as arginine, lysine, ornithm, etc .; etc.); etc., when said compounds have angiotensin II antagonist activity they have an acidic group such as a carboxyl group, etc., and a salt with inorganic acids or organic acids (for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid , carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, t-fluoroacetic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulphonic acid, benzenesulonic acid, p toluenesulfonic, etc.); amino acids such as aspartic acid, glutamic acid, etc .; etc., when said compound has an antagonist activity of angiotensin II it has a basic group such as an amino group, etc.

The prodrug of the compound having angiotensin II antagonist activity [hereinafter referred to as an AII antagonist] means a compound that is converted to an AII antagonist under the physiological condition or with a reaction due to an enzyme, gastric acid, etc., living in the body, which is, a compound that is converted to an AII antagonist with oxidation, reduction, hydrolysis, etc., in accordance with an enzyme; a compound that becomes an AII antagonist with gastric acid, etc .; etc.

Examples of the prodrugs of the AII antagonist include a compound wherein an amino group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, etc., (e.g., a compound wherein an amino group of the AII antagonist is substituted with eicosanoyl, alamlo, pentiamlamcarboni, (5-met? l-2-oxo-l, 3-d? oxolen-4-? l) methox? carbon? lo, tetrahydrofuranyl, pi r rolidinilmet lio, pi titi loximet lio, tert- butyl, etc.); a compound wherein a hydroxy group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g., a compound wherein a hydroxy group of the AII antagonist is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumarole, alanyl, dimethylaminomethylcarbonyl, etc.); a compound in On a carboxy group an agon sa is modified with ether, amide, etc., (for example a compound wherein a carboxyl group of the AII antagonist is modified with ethyl ester, phenyl ester, carboxymethyl ester, ester of dimethyl ilaminomet ilo, pivaloyloxymethyl ester, ethoxycarbonyl loxietheyl ester, phthalidyl ether, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonyl ester ilo, methyl amide, etc.), etc. These prodrugs can be produced by methods known per se from the AII antagonist.

The prodrug of the AII antagonist may be a compound that is converted to the AII antagonist under physiological conditions as described in "Pharmaceutical Research and Development", Vol. 7 (Drug Design), pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).

Also, the AII antagonist may be hydrated.

Examples of the biodegradable polymer for use in the present invention include a polymer, a copolymer, their esters, or a mixture thereof which is synthesized from one or more of the hydroxycarboxylic acids (eg, glycolic acid, lactic acid, etc.), hydroxy-dicarboxylic acid (e.g. malic acid, etc.), carboxylic hydroxy acids (eg, citopic acid, etc.), etc., and having a free carboxyl group; esters of polycyanoacrylic acid; polyamino acids (e.g., pol-β-g-benzyl-1-L-glutamic acid, etc.); copolymer of maleic anhydride (eg, styrene-maleic acid copolymer, etc.), etc.

The copolymers can be any of the random, block and graft copolymers.

When the hydroxycarboxylic acids, hydroxydicarboxylic acids and above hydroxycarboxylic acids have optical activity in their molecules, any of the D isomers, L isomers and DL isomers can be used. Among others, the α-hydroxycarboxylic acid polymer (preferathe lactico acid-glycolic acid polymer), its esters, the poly-α-cyanoacrylic acid esters, etc., are preferred, and the lactic acid-polymer of glycolic acid, its esters are more preferred.

When the lactic acid polymer of glycolic acid is used as the biodegradable polymer, the molar ratio (% mole) is in the range preferafrom 100/0 to 40/60 and more preferafrom 100/0 to 50/50.

In general, the weight average molecular weight of the lactic acid-polymer of the above glycolic acid is in the range from about 3,000 to about 50,000, preferaabout 4,000 to about 40,000, more preferaabout 5,000 to about 30,000. The degree of dispersion (weight average molecular weight / number average molecular weight, hereinafter also referred to as the degree of dispersion) is usually usually in the range from about 1.2 to about 4.0, preferafrom about 1.5 to about of 3.5.

In the present specification, the weight average molecular weight, the molecular weight average in number and the degree of dispersion mean the molecular weights and the degree of dispersion determined by gel permeation chromatography (CPG) with polystyrene polymer as reference substances with weight average molecular weights of 1,110,000, 707,000, 354,000, 189,000, 156,000, 98,900, 66,437, 37,200, 17,100, 9,830, 5,870, 2,500, 1,303 and 500, respectively. The determination is carried out using column CPG KF804L X 2 (manufactured by Showa Denko K.K., Japan) and using chloroform as the mobile phase.

To calculate the number average molecular weight, the biodegradable polymer was dissolved in a solvent mixture of acetone and methanol and the solution was triturated with an alcoholic potassium hydroxide solution which used phenol phthalein as an indicator to determine the carboxyl group content terminal. This value hereinafter referred to as the number average molecular weight by the determination of the final group. Although the molecular weight average in number by the determination of the final group is an absolute value, by the determination of the CPG it is a It is important to vary the analytical conditions (for example, type of the mobile phase, type of the column, reference substance, select the cutting width, selection of the baseline, etc.). ). Therefore it is difficult to have an absolute numerical representation of the latter. However, for example, in the case of a polymer having a terminal carboxyl group and produced from lactic acid and glycolic acid by catalyst-free polycondensation, the number average molecular weight per CPG and the number average molecular weight per the determination of the final group almost always adds to one another. The description that the number average molecular weight per CPG and by determination of the final group "almost always adds" detonates here that the latter falls within the range from about 0.2 to about 1.5 times, preferably about 0.3 to about 1.2 times of the trainer.

The lactic acid-glycolic acid polymer can be produced by, for example, polycondensation free of lactic acid catalyst and glycolic acid (Publication of Japanese Patent No. Examine No. or open ring polymerization with cyclic lactide catalyst, glycolide, etc. (Encyclopedic Handbook of Biomaterials and Bioengineer ing Part A: Materials, Volume 2, Marcel Dekker, Inc. (1995)).

The polymer produced by the ring-opening polymerization has a small carboxyl group or does not, however, have a polymer having a terminal carboxyl group obtained by chemical treatment of the forming polymer (J. Controlled Reléase, Vol. 41, pages 249-257 (1996)) can be used by the present invention.

The aforementioned lactic acid-polymer of the glycolic acid having a terminal carboxyl group can be synthesized by general synthetic methods (for example, the catalyst-free polycondensation described in JP-A-28521/1986), without any problem. However, the polymer having free carboxyl groups in an unspecified position can be synthesized by known methods (for example, in W094 / 15587).

Since co-pore and glycolic lactic acid has a terminal carboxyl group, the preparation by chemical treatment after the open ring polymerization, which is available from, for example, Boehringer Ingelheim KG, can be used.

The lactic acid-polymeric glycolic acid esters can be produced by, for example, known methods of the lactic acid-glycolic acid polymer having a free carboxyl group (eg, Japanese Unexamined Patent Publication No. 278018/1995).

These biodegradable polymer can be used alone or in combination with two or more types of polymers.

The polyvalent metal that can be incorporated in the sustained release preparation of the present invention can be any metal, as well as a metal that does not adversely affect the living body. Examples of the metal include polyvalent metals such as a divalent metal (e.g., iron, zinc, copper, calcium, magnesium, aluminum, tin, manganese, etc. , a trivalent target (for example, iron, aluminum, manganese, etc.), a tetravelent metal (for example, tin, etc.), etc.

In the prolonged release preparation of the present invention, these metals can be presented in the form of a compound with an inorganic substance, a compound with an organic compound, a metal oxide [hereinafter, these three types of compounds refer to as a polyvalent metal compound], etc .; in the form of a metal ion; or in the form of a complex with both of the compounds having angiotensin II antagonist activity, their prodrugs or their salts, and the biodegradable polymer or either one of them.

Preferred examples of the polyvalent metal include iron, aluminum, zinc, calcium, magnesium, etc., and in particular, zinc is preferred.

Among others, the zinc derivative of zinc oxide is preferred.

Examples of the usual substance include an inorganic acid, etc., such as hydrogen halide (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, etc.), sulfuric acid, nitric acid, thiocyanic acid , etc.

Examples of the organic substance include an organic acid, etc., such as, for example, an aliphatic carboxylic acid, an aromatic acid, and acetyl lacetone, etc.

Preferred examples of the aliphatic carboxylic acid include a C? -9 aliphatic carboxylic acid (eg, mono-, do- or tri-carboxylic aliphatic acid, etc.), etc., and the aliphatic carboxylic acid can be saturated or unsaturated .

Examples of the aliphatic monocarboxylic acid include a saturated C 1 -C 9 aliphatic monocarboxylic acid (eg, carbonic acid, acetic acid, propionic acid, butyric acid, valeric acid, capric acid, enantic acid, caprylic acid, pelargonic acid , ci or c ppco, etc. , an unsaturated aliphatic monocarboxylic acid or C2-C) (for example, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.), etc.

Examples of the aliphatic di-carboxylic acid include a C2-9 saturated aliphatic di-carboxylic acid (eg, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.), a di-carboxylic acid unsaturated aliphatic C2_g (for example, maleic acid, fumaric acid, citraconic acid, mesaconic acid, etc.), etc.

Examples of the aliphatic carboxylic acid include a saturated C2-9 aliphatic carboxylic acid (eg, t-carboxylic acid, 1,2-butane-carboxylic acid, et c.), Etc.

The aforementioned aliphatic carboxylic acid may have 1-2 hydroxy groups, and the examples of the aliphatic carboxylic acid have a hydroxy group which includes glycolic acid, lactic acid, citric acid, citric acid, malic acid, tartaric acid, citric acid, etc.

As the aliphatic carboxylic acid, an aliphatic monocarboxylic acid is preferable, a C2-9 aliphatic carboxylic acid is more preferable, and in particular, acetic acid is preferred.

Examples of the aromatic acid include benzoic acid, salicylic acid, phenolsulonic acid, et c.

Examples of the polyvalent metal compound include a salt of an inorganic acid with iron [e.g., iron halide (e.g., iron chloride, iron bromide, iron iodide, iron fluoride, etc.), iron sulfate, iron nitrate, iron thiocyanate, etc. ], a salt of an organic acid with iron [eg, aliphatic iron carboxylate (for example, iron carbonate, iron acetate, iron glycolate, iron tartrate, etc.), a salt of an aromatic acid with iron (for example, iron benzoate, iron salicylate, eno ona or e erro, e c. , ace ace ona or iron, etc .; a salt of an inorganic acid with zinc [for example zinc halide (for example, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate, etc.], a salt of an organic acid with zinc [e.g. zinc aliphatic carboxylate (for example, zinc carbonate, zinc acetate, zinc glycolate, zinc lactate, zinc tartarate, etc.), a salt of an aromatic acid with zinc (for example, zinc benzoate, zinc salicylate, zinc phenolsulfonate, etc.)], zinc acetylacetonate, etc .; a salt of an inorganic acid with calcium [for example calcium halide (for example calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, calcium thiocyanate, etc. .), a salt of an organic acid with calcium [eg, aliphatic calcium carboxylate (eg calcium carbonate, calcium acetate, calcium propionate, calcium oxalate, tartarate of calcium, calcium lactate, calcium carbonate, calcium carbonate, etc.), a salt of an aromatic acid with calcium (for example, calcium benzoate, calcium salicylic acid, etc.), acetylacetonate calcium, etc .; a salt of an inorganic acid with magnesium [e.g., magnesium halogenide (e.g., magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate ed , etc.], a salt of an organic acid with magnesium [e.g., magnesium aliphatic carboxylate (e.g., magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tararato, magnesium lactate, citrate of magnesium, magnesium gluconate, etc.), a salt of an aromatic acid with magnesium (for example, magnesium benzoate, magnesium salicylate, etc.), magnesium acetylacetonate, etc .; Y metal oxide (for example, iron oxide, zinc oxide, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, x or magnesium, etc.), etc.

As the polyvalent metal compound, iron chloride, iron acetylacetonate, zinc acetate, zinc acetylacetonate, calcium acetate, calcium acetylacetonate, magnesium acetate, magnesium acetylacetonate, zinc oxide, etc., they are preferred , and zinc oxide is the most preferred.

In the present invention, all or a portion of the polyvalent metal that can be incorporated in the sustained release preparation of the present invention can be used in the form of a biodegradable polymer salt with one or more types of polyvalent metals. Said salt of the biodegradable polymer with the polyvalent metal can be produced in accordance with a method described in Japanese Unexamined Patent Publication No. 221420/1997 or a method similar to this.

Examples of the preferred embodiments of the sustained release preparation of the present invention include a preparation of Liberac n pro onga to buy and one compues or having antagonistic activity of angiotensin II, prodrugs thereof or salts thereof [hereinafter, these compounds are referred to as a compound having antagonistic activity AII], a biodegradable polymer and a polyvalent metal, and examples of the production method of said preparation include a method for producing said sustained-release preparation, comprising removing solvent from a solution containing a compound having antagonist activity AII, a biodegradable polymer and a polyvalent metal, etc.

The polyvalent metal can be incorporated into said solution using, as a starting material, a metal complex polyvalent with both of the compound having AII antagonist activity, its prodrugs or its salts, and the biodegradable polymer or either one of them; adding the polyvalent metal compound to said solution; etc. All or a portion of the polyvalent metal compound that is added to said solution can form a complex with both of the compounds having AII antagonist activity. and the polymer iodegra to either one or e in that solution.

In the extended release preparation of the present invention, an amount of the compound having AII antagonist activity and a polyvalent metal compound varies depending on the type of compound having AII antagonist activity, the desired pharmaceutical effect, the duration to maintain said effect, etc. For example, when the sustained release preparation of the present invention consists of the compound having AII antagonist activity and the biodegradable polymer, the amount of the compound having AII antagonist activity is usually from about 1 to about 50% by weight, preferably from about 5 to about 45% by weight, more preferably from about 10 to about 40% by weight relative to the addition of said two compounds, the compound having AII antagonist activity and the biodegradable polymer. When the sustained release preparation of the present invention consists of the compound having AII antagonist activity, the polyvalent metal compound and the polymer or egra ae, at a compound level or having an AII antagonist activity is usually from about 1 to about 50% by weight, preferably from about 15 to about 45% by weight, more preferably from about 20 to about 40% by weight relative to the addition of said three compounds, and on the other hand, the amount of the polyvalent metal compound is usually from about 0 to about 20% by weight, preferably from about 2 to about 15% by weight. weight, more preferably from about 4 to about 10% by weight.

The sustained release preparation of the present invention can be administered in any form, and formulations for non-oral administration are preferable. Examples of such formulations include percutaneous formulations, resident formulations, injectable microcapsules, etc. Among these, injectable microcapsules are preferred, since they are long lasting to maintain a pharmaceutical effect and reduce the burden on the patient.

The production methods of the sustained release preparation of the present invention, for example, microcapsules (hereinafter referred to as microspheres), which comprise a compound having AII antagonist activity and a biodegradable polymer are exemplified as follows: (I) drying in water (i) O / W method The compound having AII antagonist activity and, in addition, the polyvalent metal compound when needed are added to an organic solvent solution of the biodegradable polymer in a weight ratio as defined above of the "amount of the compound having antagonist activity AII and the polyvalent metal compound ", to give an organic solvent solution of the biodegradable polymer containing the compound having AII antagonist activity and, if necessary, the polyvalent metal compound. Either or both of the compound having AII antagonist activity and the compound of The target can not be seen in the organic solvent solution of the biodegradable polymer and can be dispersed in said solution. When either or both of the components are dispersed in said solution, it is preferable to finely disperse said components in accordance with a conventional method such as homogenization, ultrasonication, etc.

Examples of said organic solvent include halogenated hydrocarbons (for example, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (e.g., ethyl ether, isopropyl ether, etc.), fatty acid esters (e.g. , ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), acetonitrile, etc. These solvents can be used in simple form or in combination.

Among others, such as the halogenated hydrocarbon, dichloromethane is preferable and, like alcohol, ethanol, methanol, etc., are preferable. These Solvents can be used as a solution to mix appropriate relationships. The preferred example of the alcohol to be mixed with dichloromethane is ethanol when the compound having AII antagonist activity contains a tetrazolyl group; and methanol when the compound having antagonist activity AII contains a group, 5-d? h? dro-5-oxo-1,2,4-oxad? azole-3? lo.

For the aforementioned organic solvent solution, an additive can be added. Examples of additives include a solubilizer which maintains the stability and solubility of the active ingredient such as carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, argmin, lysine and its salts etc. In addition, as stabilizers of the drug, for example, albumin, gelatin, citric acid, and sodium Ilendiammoetraacetic acid, dextpna, sodium hydrogen sulfide, polyols such as polyethylene glycol, etc., etc. can be added, and as preservatives they can be added, example, conventional para-oxybenzoic acid esters (eg, met i lparaben, propilparaben, etc.), enci a co o, c gold or ano, thimerosal, etc.

The concentration of the biodegradable polymer in the solution of the organic solvent varies depending on the molecular weight of the biodegradable polymer and the type of the organic solvent. For example, when dichloromethane is used as an organic solvent, the concentration of the biodegradable polymer in the organic solvent solution is generally selected from the range of from about 0.5 to about 40% by weight, more preferably from about 1 to about 60. % by weight, and in particular from about 2 to about 50% by weight. Further, when ethanol or methanol and dichloromethane are used as a mixture of organic solvent, the concentration of dichloromethane in the organic solvent solution is generally selected from the range of from about 10 to about 99% by volume, more preferably about 20 to about about 98% by volume, and in particular from about 30 to about 95% by volume.

The organic solvent solution is thus obtained from the biodegradable polymer, said solvent containing the compound having AII antagonist activity and, in addition, the polyvalent metal compound when necessary, are added to the aqueous phase (or referred to as aqueous outer phase) to form emulsion 0 (oily phase) / (aqueous phase), followed by evaporation of the solvent in the oily phase to yield microcapsules. The volume of the aqueous phase is generally selected from the range of from about 1 to about 10,000 times the volume of the oily phase, more preferably from about 5 to about 5,000 times, and in particular from about 10 up to about 2,000 times Any emulsifier can be added to the above exterior aqueous phase, to contribute to the formation of a stable 0 / W emulsion. Examples of emulsifiers include anionic surfactants (sodium oleate, sodium stearate, lauryl sodium sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan grade acid esters [Tween 80, Tween 60; Atlas Powder, Poxium and Endo-er and Beaver Oil [HCO-60, HCO-50; Nikko Chemicals], etc.), polyvinylpyrrolidone, polyvinylalcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid, etc. These emulsifiers can be used independently or in combination. The concentration can be selected from about 0.01 to about 10% by weight, preferably from about 0.05 to about 5% by weight.

To the exterior aqueous phase, an osmotic pressure adjuster can be added. Any osmotic pressure adjuster can be used in this by producing osmotic pressure in an aqueous solution thereof.

Examples of the osmotic pressure adjuster include polyhydric alcohols, monovalent alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids or their derivatives, etc.

Examples of the above polyhydric alcohols include dihydric alcohols such as glycerin, etc., pentahydric alcohols such as arabitol, x to, a on to, etc., hexahydric alcohols such as mannitol, sorbitol, dulcitol, etc., etc. Among others, hexahydric alcohols are preferable, and in particular, mannitol is preferred.

Examples of the above monovalent alcohols include methanol, ethanol, isopropyl alcohol, etc. Among others, methanol is preferred.

Examples of the above monosaccharides include pentoses such as arabinose, xylose, ribose, 2-deoxyribose, etc., hexoses such as glucose, fructose, galactose, mannose, sorbose, rhamnose, fucose, etc. Among others, hexoses are preferred.

Examples of the above oligosaccharides include trisaccharides such as maltotriose, raffinose, etc., tetrasaccharides such as stachyose, etc., etc. Among others, trisaccharides are preferred.

Examples of the above-mentioned monosaccharides, disaccharides and oligosaccharides include glucosamine, galactosamine, glucuronic acid, galacturon acid, etc.

Examples of the amino acids include any of the L-isomers and preferred examples include glycine, leucine, arginine, etc. Among others, L-arginine is preferable.

These osmotic pressure adjusters can be used alone or as a mixture of two or more of them.

These osmotic pressure adjusters are usually used at the concentration that makes the osmotic pressure of the outer aqueous phase from about 1/50 to about 5 times, preferably from about 1/25 to about 3 times of the physiological salt. .

To remove the organic solvent, methods known per se or methods analogous to these are employed. For example, this is carried out by evaporation of the organic solvent by stirring with a impeller type stirrer, magnetic stirrer, etc., under atmospheric pressure or gradually reducing the pressure or while controlling the degree of vacuum using a rotary evaporator, etc. , etc .

The microcapsules thus obtained are collected by centrifugation or filtration. Then, the compound having AII antagonist activity, the carriers thereof, emulsifiers, etc., attached at the surface of the microcapsules are washed with distilled water repeatedly several times, dispersing in distilled water, etc., and subjecting to drying by freezing In freeze drying, the addition of inhibitors can be done to prevent particles from being added. Examples of such aggregation inhibitors include water-soluble polysaccharides such as mannitol, lactose, glucose, starch (e.g., corn starch, etc.), etc., amino acids such as glycine, etc., proteins such as fibrin. , collagen, etc., etc. Among others, mannitol is preferred.

After drying or freezing, further removal of water and an organic solvent can be carried out by warming the microcapsules under reduced pressure and under conditions where the microcapsules do not attach to each other, if desired. Preferably, the microcapsules are warmed at an appropriate temperature that is less but greater than the average glass transition temperature (determined using a random calorimeter difference at increased temperatures of 10 or 20 ° C per minute) of the biodegradable polymer. More preferably, the microcapsules are cooled to temperatures in the range from the average glass transition temperature to about 30 ° C higher than the average glass transition temperature of the biodegradable polymer. In particular, when lactic acid-glycolic acid polymer is used as the biodegradable polymer, the microcapsules are preferably warmed at temperatures in the range from the average glass transition temperature to about 10 ° C higher than the transition temperature of middle glass of the polymer, more preferably from the average glass transition temperature to about C m s arr e e a tem e ura e trans c n n the average glass of the polymer.

The warming several times depends on the quantity of microcapsules to be treated, etc. In general, from about 12 hours to about 168 hours, preferably from about 24 hours to about 120 hours, and in particular, from about 48 hours to about 96 hours after the temperature of the microcapsules is reached by they themselves up to the desired temperature, are preferred.

A method for warming the microcapsules is not limited to a specific method, and any method can be employed so that the microcapsules are uniformly warmed.

Examples of the method for warming and drying the microcapsules include the one in a constant temperature bath, fluidized bath, moving bath or oven, whichever is by micro waves, etc. Among others, the method to warm or dry the microcapsules in a constant temperature bath is preferable. m o o The compound having AII antagonist activity is dissolved in water, and if necessary, a carrier thereof such as a polyvalent metal compound (e.g. zinc acetate), basic amino acid (e.g., arginine, histidine, lysine), gelatin , agar, polyvinylalcohol, etc., are added to the solution, to give an internal aqueous phase.

The concentration of the drug in the internal aqueous phase is generally selected from the range of about 0.1-80% by weight, more preferably from about 1-70% by weight, and in particular from about 2-60% by weight.

To the internal aqueous phase, as pH regulators to maintain the stability and solubility of the drug, can be added carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and its salts, etc. In addition, as stabilizers of the drug, there may be added, for example, albumin, gelatin, citric acid, et i lendiaminotet racet ato of so o, extr, rogensu uro e so o, polyols such as polyethylene glycol, etc., etc., and as preservatives can be added, for example, conventional a-oxibenzoic acid esters (for example met ilparaben, propilparaben, etc.), benzylalcohol, chlorobutanol, thimerosal, etc.

The internal aqueous phase thus obtained is added to a solution of the organic solvent of the biodegradable polymer (oily phase) optionally containing the polyvalent metal compound, and the mixture is emulsified by known methods using a homogenizer, ultra-sonicator, etc. , to form the emulsion / O.

Examples of the organic solvent include halogenated hydrocarbon (e.g., dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (e.g., ethyl ether, soproyl ether, etc.), fatty acid esters (e.g. , ethyl acetate, butyl acetate, etc.), aromatic hydrocarbon (for example, benzene, toluene, xylene, etc.), alcohols (for example, ethanol, methanol, etc.), acetonitrol, etc. These solvents can be used as a mixed solution at an appropriate ratio. Among others, halogenated hydrocarbons are preferable, and in particular, dichloromethane is preferred.

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 an organic solvent, the cocdentation of the biodegradable polymer in the organic solvent solution is generally selected from the range of about 0.5 to about 70% by weight, preferably from about 1 to about 60. % by weight, more preferably from about 2 to about 50% by weight.

The W / O emulsion thus obtained containing the compound having AII antagonist activity, the biodegradable polymer and, if necessary, the polyvalent metal compound is added to an aqueous phase (external aqueous phase) to give emulsion W (phase internal watery) (oily phase)! (external aqueous water), and to which the solvent in the oily phase evaporates to give microcapsules. The volume of the external aqueous phase is generally selected from the range of about 1 to about 10,000 times the volume of the oily phase, more preferably from about 5 to about 5,000 times, and in particular, from about 10 to about of 2,000 times.

Examples of the emulsifiers and osmotic pressure adjusters that can be added to the aforementioned external aqueous phase, and the preparation methods after the addition of these additives, are similar to those described in the preceding items (I) / (i) ).

(II) Phase Separation.

In the production of microcapsules by the phase separation method, a coacervating agent is gradually added to the aforementioned solvent solution of the biodegradable polymer containing the compound having AII antagonist activity and, in addition, the polyvalent metal compound when necessary as it is described in point (I) above, in water drying, during agitation to precipitate and solidify the microcapsules. The volume of the coacervation agent is generally selected from the range of about 0.01 to about 1,000 times the volume of the oily phase, more preferably about 0.05 to about 500 times, and in particular, about 0.1 to about 200 times. .

Any coacervating agent is acceptable, so long as it is a polymer, mineral oil, vegetable oil, etc., which is miscible in the organic solvent and does not dissolve both the compound having AII antagonist activity and the biodegradable polymer. For example, silicon oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane, etc., are used. These can be used in combination.

The microcapsules thus obtained are separated, repeatedly washed with heptane, etc., to remove the coacervating agent apart from the compound having AII antagonist activity and the biodegradable polymer, and then dried at reduced pressure. Alternatively, the microcapsules are washed with methods similar to those described in the above item (I) (i), dried in water, subjected to freeze drying, and then warming and drying.

(III) Drying by Atomized.

In the production of microcapsules by this method, the aforementioned organic solvent solution of the biodegradable polymer containing the compound having antagonist activity AII and optionally containing the polyvalent metal compound as described in the previous point (I), when drying in water, an injector is atomized in the drying chamber of an atomizing dryer to volatilize the organic solvent in fine droplets in a very short time to yield the microcapsule. Examples of injectors include dual fluid injectors, pressure injectors, rotary disk injectors, etc. Then, if necessary, the microcapsules are washed by means of methods similar to those described in the previous point (I), in drying in water, subjecting to freeze drying, and then warming and drying.

In addition to the dosage forms described above of the microcapsules, the solution of the organic solvent of the biodegradable polymer containing the compound having AII antagonist activity and, in addition, the polyvalent metal compound when necessary as described in (I) , in drying in water, can be subjected to the evaporation of organic solvent and water while controlling the degree of vacuum using a rotary evaporator, etc., and the residue can be crushed with a jet grinder, etc., to yield powders thin.

The fine powders thus obtained can be washed with the methods similar to those described in the previous point (I), in drying with water, subjecting to freeze drying, and then warming and drying.

The release of the compound having AII antagonist activity from the microcapsules or fine powders thus obtained can be controlled by the degradation ratio of the biodegradable polymer employed and the type and / or amount of the added polyvalent metal compound.

The sustained release preparation of the present invention can be used for the production of various preparations, such as a pure material and administered as injections or implants intramuscularly, subcutaneously, in organs, etc .; as transmucosal preparations in the nasal cavities, rectum, uterus, etc .; oral preparations (e.g., capsules (e.g., hard gelatin capsules, soft gelatin capsules, etc.), solid preparations such as granules, powders, etc., liquid preparations such as syrups, emulsions, suspensions, etc., etc.); etc. Also, the sustained release preparation of the present invention can be administered using a needleless injector.

For example, when the sustained release preparation according to the present invention is processed in injectors, they are dispersed together with a dispersing agent (for example, surfactants such as Tween 80, HCO-60, etc., poly saccharides such as hyaluronate sodium, carboxymethylcellulose, sodium alginate, etc., etc.), a preservative (eg, metilparaben, propylparaben, etc.), an isotonizing agent (eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.), etc., to form an aqueous suspension, or to disperse it together with a vegetable oil such as sesame oil, corn oil, etc., to form an oily suspension, said suspensions being currently used as prolonged release injections.

The particle size of the sustained release preparation of the present invention is selected from the range that satisfies the dispersibility and the requirements of the injector step when used as a suspension. For example, the average diameter ranges are from about 0.1 to about 300 μm, preferably from about 0.5 to about 150 μm, more preferably from about 1 to about 100 μm.

In order to prepare a sterile preparation of the sustained-release preparation of the present invention, a method for sterilizing all production steps, a method for sterilizing with? Rays, a method for adding a preservative, etc., are employed, and It is not limited to a specific method.

With low toxicity, the sustained release preparation of the present invention can be used in mammals (eg, humans, cattle, pig, dog, cat, mouse, rat, rabbit, etc.) as a safe medicine, etc.

With variation depending on the type, content and dosage form of the compound having AII antagonist activity as the active ingredient; duration of the release of the compound having AII antagonist activity; target disease; animal submitted; etc., the dose of the sustained release preparation of the present invention is within the range of an effective amount of the compound having AII antagonist activity. For example, the dose per administration of the active ingredient, the compound having AII antagonist activity, is preferably chosen within the range of from about 0.01 mg to about 10 mg / kg of body weight per adult, more preferably from about 0.05 mg. up to about 5 mg / kg of body weight per adult, when the prolonged-release preparation is a 1-month preparation. The dose per administration of the sustained release preparation of the present invention is preferably chosen within the range of from about 0.05 mg to about 50 mg / kg of body weight per adult, more preferably from about 0.1 mg to about 30 mg / kg of body weight per adult.

The number of modules can be selected appropriately from once to several times a week, once a month, or once a few months (for example, 3 months, 4 months, 6 months, etc.), etc. , depending on the type, content and dosage form of the active ingredient, the compound having AII antagonist activity, the duration of the release of the compound having AII antagonist activity, the target diseases, the animals subjected, etc.

The compound having AII antagonist activity has a high safety and therefore an increase in the concentration of said compound in the blood just after the administration of the prolonged release injection does not cause a reduction in excess blood pressure. In this manner, the sustained release preparation of the present invention can be used for the diseases described below and can maintain a constant concentration of the drug in the blood during the day and night. Therefore, the dose and the number of administrations can be reduced, compared with the administration of oral preparations Conventional is. However, the concentration of the drug in the blood is not marked and the patient's condition does not change due to the interruption of the drug intake, etc. Therefore, it is expected that the effect of the drug treatment will be clearly converted by the administration of the sustained release preparation of the present invention.

Examples of the diseases include circulatory diseases, etc., such as hypertension, heart disease (hypercardia, heart failure, myocardial infarction, etc.), nephritis, cerebral stroke, etc., which are caused by vasoconstriction expressed by means of the angiotensin II receptors.

The prolonged release preparation of the present invention is useful for the prevention or treatment of hypertension, hypercardia, heart failure, myocardial infarction, cerebral stroke, disturbances of the ischemic peripheral circulation, myocardial ischemia, venal insufficiency, progressive heart failure after a myocardial infarction, complication of diabetes, retinopathy ethics, diabetic nephropathy, nephritis, glomerulonephritis, atherosclerosis, angiohypert rofía, vascular hypertrophy or obstruction after the intervention (for example, percutaneous transluminal coronary angioplasty, etc.), vascular reobstraction after of deviation surgery, hyperaldosteronism, glomerulosclerosis, renal failure, glaucoma, high intraocular pressure, hyperlipidemia, angina pectoris, aneupuncture, art coronary eosclerosis, cerebral atherosclerosis, peripheral atherosclerosis, thrombosis, central nervous system disease, Alzheimer's disease, deficiency of memory, depression, amnesia, senile dementia, disturbances of sensibility, organ failure of the multiple system, a disease due to endothelial dysfunction or scleroderma; or the prevention or relief of anxious neurosis, catatonia, indisposition or dyspeptic symptoms.

As the method for the treatment of patients, it is considered to administer to the patient conventional oral preparations containing the compound having AII antagonist activity for a certain period to review the reaction of said patient and then to administer the prolonged-release preparation of the present invention to the patient. The angiotensin II antagonist can be administered orally and contained in the prolonged release preparation, and it can be the same or different. In addition, the ant? -h? Pertenso agent (eg, calcium antagonist, diuretic, β-blocker, etc.), other than the angiotensin II antagonist can be previously administered to the patient to review the reaction of said patient and then the The sustained release preparation of the present invention can be administered to the patient. Furthermore, the present prolonged release preparation can be used in combination with a diuretic (oral preparation) which is usually used in combination with the angiotensin II antagonist.

Best Way to Carry Out the Invention The present invention is hereinafter described in more detail by means of the following Working Examples and Examples Experience is that they are limiting.

Work Example 1 2-ethoxy? -l - [[2 '- (4,5-dihydro-5-oxo-l, 2,4-oxadia-zol-) acid was dissolved in a solution mixture of 3.5 ml of dichloromethane and 1.5 ml of methanol. 3-yl) bi-phenyl-1-4-yl] methyl] benzimide zol-7-carboxylic acid (hereinafter referred to as Compound A) 0.25 g lactic acid ico-copolymer glycolic acid (lactic acid / glycolic acid: 75/25 (mol%), weight average molecular weight: 10,700, number average molecular weight: 6,100, number average molecular weight by determination of the final group: 3.770, Wako Puré Chemical) 2.25 g, and the solution is Injected 500 ml of a 0.1 wt% polyvinylalcohol solution, previously adjusted to 18 ° C, followed by stirring in a homomixer turbine at 7,000 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and methanol and solidify the oily phase, which was then collected by e rn ation, rpm. precip dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collecting the microcapsules they were again dispersed in a small amount of distilled water, the dispersion was subjected to freeze drying to give powdered microcapsules.

The performance of the microcapsules was 69%, the trapped ratio of Compound A in the microcapsules was 92%, and the content of Compound A in the microcapsules was 9.2%.

Work Example 2 The disodium salt of Compound A 0.25 g, was dissolved in distilled water, 0.4 ml, and the solution was mixed with a solution of lactic acid-glycolic acid copolymer (the same as described in Working Example 1), 2.25 g, in dichloromethane, 4 ml. The mixture was stirred with a homogenizer to form the W / O emulsion. The W / O emulsion was injected up to 0.1% by weight of a polyvinyl alcohol solution, 500 ml, previously adjusted to 18 C, followed by stirring in a homomixer turbine at 7,000 rpm to yield the W / O / W emulsion. The W / O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collecting, the microcapsules were redispersed in small amounts of distilled water, the dispersion was subjected to freeze drying to give powdered microcapsules.

The performance of the microcapsules was 50%, the trapped ratio of Compound A in the microcapsules was 37%, and the content of Compound A in the microcapsules was 3.7%.

Work Example 3 In a mixed solution of dichloromethane, 3.5 ml, and methanol, 2.5 ml, Compound A was dissolved, 0. 4 g, and ethyl ester of the lactic acid polymer (a biodegradable polymer, where a group car on or term na po mero e c o c co esterifies with ethyl; weight average molecular weight: 10,200; number average molecular weight: 5,680; Wako Puré Chemical), 1.6 g, and the solution was injected at 0.1% by weight of a solution of polyvinylalcohol, 80 ml, containing 5% mannitol, previously adjusted to 18 ° C, followed by stirring in a homomixer turbine 7,000 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and methanol and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged to remove the free drug, etc. After collecting the microcapsules they were again dispersed in a small amount of distilled water, the dispersion was subjected to freeze drying to give powdered microcapsules.

The yield of the microcapsules was 83%, the trapped ratio of Compound A in the microcapsules was 86%, and the content of Compound A in the microcapsules was 17.1%. emp or xper men a.

The microcapsule of about 35 mg obtained in Work Example 3 was dispersed in a solvent, 0.3 ml, (distilled water in which carboxymethylcellulose, 0.25 mg, polysorbate 80, 0.5 mg, and mannitol, 25 mg) were dissolved, and the mixture was administered subcutaneously to the back of 7-week-old male SD rats using 22G needles. At regular intervals after administration, the blood was collected from the abdominal aortas of the rats, and the rats were sacrificed to collect the remaining microcapsules at the site of administration.

The amount of Compound A in the microcapsules was determined, and the results are shown in Table 1. In addition, the concentration of Compound A in the blood was determined, and the results are shown in Table 2.

Table 1 day week weeks week weeks E j us of Labor 3 66% 42% 27% 17% 15% Table 2? ? 2 3 4 day week weeks weeks weeks Work hours 3 4.4 0.6 0.3 0.2 0.1 (unit; μg / ml) Work Example 4 To a solution of lactic acid ico-copolymer of glycolic acid (lactic acid / glycolic acid: 75/25 (mol%), weight average molecular weight: 14,000, number average molecular weight: 4,200, number average molecular weight per the determination of the final group: 4.090, Wako Puré Chemical), 2.4 g, dissolved in dichloromethane, 4.5 m, ye ano, m, aci or -e ox? - - [[2 '- (lH-tetrazol-5-? l) b? phen? l-4- 11] metl] benzimide zol-7 was added -carbox? l ico (from here to below, referred to as Compound B), 0.6 g, and zinc oxide, 0.09 g, (particle size: 0.02 μm), and the mixture was stirred and stirred for 12 hours at room temperature to give a slightly cloudy suspension. The suspension was injected into a solution of polyvinylalcohol of 0.1% by weight, 400 ml, previously adjusted to 15 ° C, followed by stirring in a homomixer turbine at 7,000 rpm to yield an O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours until volatilized dichloromethane and ethanol, and solidified the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed until the free drug was removed, etc. After collecting, the microcapsules were dispersed in a small amount of distilled water in which mannitol was dissolved, the dispersion was subjected to freeze-drying to give powdered microcapsules.

The re-capture traps and the microcapsules were 97%, and the content of Compound B in the microcapsules was 18.8%.

Work Example 5 The amount of zinc oxide was changed to 0.057 g, and the microcapsules were produced according to a method similar to that described in Working Example 1.

The trapped ratio of Compound B in the microcapsules was 97%, and the content of Compound B in the microcapsules was 19.0%.

Work Example 6.

The amount of Compound B, zinc oxide and glycolic acid ico-copolymer lactic acid was changed to 0.9 g, 2.1 g and 0.12 g, respectively, and the microcapsules were produced according to a method similar to that described in the Example of Work 1.

The trapped ratio of Compound B in the microcapsules was 96%, and the content of Compound B in the microcapsules was 27.8%.

Working Example 7.

The amount of zinc oxide was changed to 0.18 g, and the microcapsules were produced according to a method similar to that described in Work Example 3.

The trapped ratio of Compound B in the microcapsules was 92%, and the content of Compound B in the microcapsules was 26.2%.

Working Example 8 To a solution of 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 per determination of the final group: 4.090; Wako Puré Chemical), 4.2 g, dissolved in dichloromethane, 9 ml, and ethanol, 1.5 ml, was added and ompues or,. g, and,. , (particle size: 0.02 μm), and the mixture was stirred and stirred for 12 hours at room temperature to give a slightly cloudy suspension. The suspension was injected into a solution of 0.1 wt% polyvinyl alcohol, 800 ml, previously adjusted to 15 ° C, followed by stirring in a homomixer turbine at 7,000 rpm to yield an O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collection, the microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the dispersion was subjected to freeze drying to give powdered microcapsules.

The trapped ratio of Compound B in the microcapsules was 94%, and the content of Compound B in the microcapsules was 26.8%.

E n e r To a solution of 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 per determination from the final group: 4.090; Wako Puré Chemical), 0.7 g, dissolved in dichloromethane, 1.5 ml, and methanol, 1 ml, Compound A, 0.3 g, and zinc oxide, 0.05 g, (particle size: 0.02) were added. μm), and the mixture was stirred and stirred for 12 hours at room temperature to give a slightly cloudy suspension. The suspension was injected into a 0.1 wt% polyvinyl alcohol solution, 300 ml, previously adjusted to 15 ° C, followed by stirring in a homomixer turbine at 6,500 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize the dichloromethane and methanol and the oily phase solidified, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the rmaco re, e c. When the microcapsules were dispersed again in a small amount of distilled water in which mannitol was dissolved, the dispersion was subjected to drying by freezing to give powdered microcapsules.

The trapped ratio of Compound A in the microcapsules was 91%, and the content of Compound A in the microcapsules was 25.9%.

Working Example 1 ( To a solution of 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 per determination from the final group: 4.090; Wako Puré Chemical), 1.8 g, dissolved in dichloromethane, 5 ml, was added Compound B, 1 g, and zinc oxide, 0.18 g, (particle size: 0. 02 μm), and the mixture was emulsified for 60 seconds with a small homogenizer to give a suspension. The suspension was injected to a so u n e po v a n o co n , ml, previously adjusted to 15 ° C, followed by stirring in a homomixer turbine at 8,000 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize the dichloromethane and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collection, the microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the dispersion was subjected to freeze drying to give powdered microcapsules.

The trapped ratio of Compound B in the microcapsules was 96%, and the content of Compound B in the microcapsules was 32.0%.

Working Example 11 Except that ethanol was added to dichloromethane and that the slightly turbid suspension given by stirring and stirring for 12 hours at ambient temperature, as c croc psu as occurred in accordance with a method similar to that described in Working Example 7.

The trapped ratio of Compound B in the microcapsules was 95%, and the content of Compound B in the microcapsules was 32.0% Work Example 12.

In a mixed solution of dichloromethane, 4.5 ml, and ethanol, 0.7 ml, 2-ethoxy-1 - [[2 '- (lH-tetrazol-5-yl) biphenyl-4-yl] methyla] benzylidazole was dissolved. -7-carboxylate of 1- (cyclohexy loxycarbonyl-oxy) eti lo (hereinafter referred to as Compound C), 0.9 g, and lactic acid-glycolic acid copolymer (lactic acid / glycolic acid: 75/25 ( % in mol), weight average molecular weight: 14,000, number average molecular weight: 4,200, number average molecular weight by determination of the final group: 4,900, Wako Puré Chemical), 2.1 g, and oxide was added to the solution of zinc 0.15 g (particle size: 0.2 μm). The mixture was stirred and stirred for 12 hours at room temperature. am in e for a geramen e turbid suspension. The suspension was injected to a solution of polyvinyl alcohol at 0.1% by weight, 400 ml, previously adjusted to 15 ° C, followed by agitation in a turbine-homomixer at 7,500 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize the dichloromethane and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collecting, the microcapsules were redispersed in a small amount of distilled water in which the mannitol was dissolved, the dispersion was subjected to freeze drying to give powdered microcapsules.

The trapped ratio of Compound C in the microcapsules was 96%, and the content of Compound C in the microcapsules was 27.4%.

E p o p e ra garlic.

Except that no zinc oxide was added, the microcapsules were produced according to a method similar to that described in Work Example 12.

The trapped ratio of Compound C in the microcapsules was 98%, and the content of Compound C in the microcapsules was 30.0%.

Working Example 14.

It was dissolved in dichloromethane, 5 ml, Compound C, 1.2 g, and lactic acid-copolymer or glycolic acid (lactic acid / glycolic acid: 75/25 (mol%); Weight average molecular weight: 14,000; number average molecular weight: 4,200; average molecular weight in number by the determination of the final group: 4,900; Wako Puré Chemical), 1.8 g, and zinc oxide 0.18 g (particle size: 0.02 μm) was added to the solution. The mixture was stirred and stirred for 1 hour at room temperature to give a slightly cloudy suspension. The suspension was injected to a so u n e po v e n a co. by weight, ml, previously adjusted to 15 ° C, followed by agitation in a homomixer turbine at 8,000 rpm to yield the O / W emulsion. The O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane and ethanol and solidify the oily phase, which was then collected by means of centrifugation at 2,000 rpm. The precipitate was dispersed again in distilled water, centrifuged and washed to remove the free drug, etc. After collecting, the microcapsules were redispersed in a small amount of distilled water in which the mannitol was dissolved, the dispersion was subjected to freeze drying to give powdered microcapsules.

The trapped ratio of Compound C in the microcapsules was 95%, and the content of Compound C in the microcapsules was 35.9%.

Working Example 15.

Except that zinc oxide was not added, the microcapsules were produced in accordance with a similar method to be written in the Work 4.

The trapped ratio of Compound B in the microcapsules was 99%, and the content of Compound B in the microcapsules was 19.8%.

Working Example 16.

Except that the zinc oxide was not added, the microcapsules were produced according to a method similar to that described in the Working Example 9.

The trapped ratio of Compound A in the microcapsules was 95%, and the content of Compound A in the microcapsules was 28.4%.

Experimental Example 2 The 25 mg microcapsule obtained in the Working Examples 4-14 was dispersed in 0.2 ml of a dispersant (distilled water, 1 ml, in which 5 mg of sodium carboxymethylcellulose, 1 mg of polysorbate 80 and 50 mg of mannitol was dissolved), and The mixture was admired by the cut neamen e in a back of the neck of SD male rats of 7 weeks of age using 22G needles. At regular intervals after administration, the rats were sacrificed by abdominal bleeding and the remaining microcapsules at the site of administration were collected.

The amount of the compound having AII antagonist activity in the microcapsules was determined, and the results are shown in e 3, in addition, the concentration of Compound B in the blood when the microcapsules of Working Examples 4, 6 and 8 were administered. , is shown in e 4. e 3 Average ratio of the compound having excess AII antagonist activity after subcutaneous administration of the microcapsules (n = 3-5) ND: not given e 4 Average concentration of Compound B in the blood after subcutaneous administration of the microcapsules (n = 5) Experimental Example 3 The 2.5 mg microcapsule obtained in Work Example 8 was dispersed in 0.2 ml of a dispersant (distilled water, 1 ml, in which 5 mg of sodium carboxymethylcellulose, 1 mg of polysorbate 80 and 50 mg of mannitol was dissolved) , and to the mixture was administered subcutaneously in the back of the neck of rats 12008SHR males of 28 weeks of age in which the blood pressure transmitted by telemetry was implanted, using 22G needles. After the administration, the blood pressure was checked. The same preparation was administered subcutaneously to the back of the neck of male rats 1208SHR of 29 weeks of age. At regular intervals after administration, blood was collected from the vein of the tail. The concentration of Compound B in the blood and the hypotensive action of Compound B are shown in e 5. a a Average concentration of Compound B in the blood and hypotensive action after subcutaneous administration of the microcapsules (n = 3) Industrial Application The sustained release preparation of the present invention contains a high amount of the compound having AII antagonist activity and can control the release rate of the drug. Therefore, it is shown that the antagonist activity of angiotensin II maintains a circadian rhythm of blood pressure for a long time.

Moreover, the prolonged preparation of the present invention can maintain the constant concentration of the drug in the blood during the day and night. Therefore, compared to the administration of conventional oral preparations, the change in concentration of the drug in the blood is not noticeable and the patient's condition does not change due to the change in administration time, interruption of the drug intake, intentionally avoided taking the medication in patients who have some subjective symptoms, etc. Consequently, it is expected that the effect of the treatment of the drug to the circulatory disease, etc., such as hypertension, heart diseases (hypercardia, heart failure, myocardial infarction, etc.), nephritis, cerebral apoplexy, etc., become clearly by the administration of the sustained release preparation of the present invention.

It should be noted that with reference to this principle, the best method known to the applicant for carrying out said invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (24)

Reiv n cations.

1. A prolonged release preparation, characterized in that it comprises a compound having angiotensin II antagonist activity (excluding 2-yl-5, 7-dimethyl-3 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazo [4, 5-b] pyridine and a salt thereof), their prodrugs or their salts, and a biodegradable polymer.

2. The prolonged release preparation according to claim 1, characterized in that the compound having angitensin II antagonist activity is a non-peptide compound.

3. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is a compound having an oxygen atom in its molecules.

4. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is a compound having an ether linkage or a carbonyl group.

5. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is a compound of the formula: wherein R1 is a group capable of forming an anion or a group capable of being converted to this, X shows that the phenylene group and the phenyl group are linked to each other directly or through a spacer having an atomic chain length of 2. or less, n is an integer of 1 or 2, ring A is a benzene ring that has a optional substitution, in addition to the group R, R is a group capable of forming an anion or a group capable of being converted to this, and R3 is an optionally substituted hydrocarbon residue that can be attached through a heteroatom, or a salt thereof.

6. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsarian, Telmisartan, Irbesartan or Tasosartan.

7. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is 2-ethoxy-l- [[2 '- (1H-tet ra zol-5-yl) bifen] L-4-y1] methyl] benzylimidazole-7-carboxylic acid or a salt thereof.

8. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] met yl] -benzimidazole-carboxylate of 1- (cyclohexyloxycarbonyloxy) ethyl or a salt of the

9. The prolonged release preparation according to claim 1, characterized in that the compound having angiotensin II antagonist activity is 2-ethoxy? -l- [[2 '- (4,5-dihydro-5-oxo- 1, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzylimidazole-7-carboxylic acid or a salt thereof.

10. The prolonged release preparation according to claim 1, characterized in that the biodegradable polymer is a polymer of a-hydroxycarboxylic acid.

11. The prolonged release preparation according to claim 10, characterized in that the polymer of the α-hydroxycarboxylic acid is lectic acid-glycolic acid polymer.

1 . The preparation of pro bono liq eration according to claim 11, characterized in that the molar ratio of lactic acid and glycolic acid is 100 / 0-40 / 60.

13. The prolonged release preparation according to claim 10, characterized in that the weight average molecular weight of the polymer is 3,000-50,000.

14. The prolonged release preparation as claimed in claim 1, characterized in that it is for injection.

15. The prolonged release preparation according to claim 1, characterized in that they also comprise a metal pol i valent e.

16. The prolonged release preparation according to claim 15, characterized in that the polyvalent metal is zinc.

17. The prolonged release preparation, characterized in that they comprise a compound that it has angiotensin II antagonist activity, its prodrugs or its salts, biodegradable polymers and a polyvalent metal.

18. A method for producing the sustained release preparation as claimed in claim 1, characterized in that it comprises removing the solvent from a solution containing a compound having angiotensin II antagonist activity, its prodrugs or its salts, and a biodegradbale polymer.

19. The method for producing the sustained release preparation as claimed in claim 17, characterized in that it comprises removing the solvent from a solution containing a compound having angiotensin II antagonist activity, its prodrugs or its salts, a biodegradable polymer and a polyvalent metal.

20. The method according to claim 19, characterized in that the polyvalent metal is zinc.

21. A pharmaceutical composition, characterized in that it comprises a prolonged release preparation as claimed in claim 1.

22. The composition as claimed in claim 21, characterized in that it is for the prevention or treatment of circulatory diseases.

The composition as claimed in claim 21, characterized in that it is for the prevention or treatment of hypertension.

24. The composition as claimed in claim 21, characterized in that it is for the prevention or treatment of hypercardia, heart failure, myocardial infarction, cerebral apoplexy, disturbances of the ischemic peripheral circulation, myocardial ischemia, venal insufficiency, progressive heart failure after a myocardial infarction, diabetic complication, diabetic retinopathy, nephropathy, nephritis, glaomerulonephritis, arthrosclerosis, angiohypertis, hypertrophy vascular or obstruction after an intervention, vascular reobstruction after deviation surgery, hyperaldoses, thromboembolism, glomerulosclerosis, renal insufficiency, glaucoma, high intraocular pressure, hyperlipidaemia, angina pectoris, aneurysm, art coronary eosclerosis, cerebral atherosclerosis, arteroesclerosis is peripheral, thrombosis, central nervous system disease, Alzheimer's disease, memory deficiency, depression, amnesia, senile dementia, disturbances of the senses, failure of the organ of the multiple system, a disease due to endothelial dysfunction or scleroderma, or prevention or relief of anxious neurosis, catatonia, indisposition or dyspeptic symptoms