CZ20003164A3 - Preparation with prolonged release for angiotensin II antagonist, process of its preparation and use - Google Patents

Abstract

The present invention relates to an extended formulation a release comprising a compound having angiotensin II antagonistic activity (excluding 2- ethyl 5,7-dimethyl-3 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4- yl] methyl] imidazole [4,5-b] pyridine and its salts), its precursor or salts thereof, a biodegradable polymer and optionally also polyvalent metal.

Description

Technical field

The present invention relates to a sustained release composition for a compound having angiotensin II antagonist activity, a process for its manufacture, its use as a medicament, etc.

BACKGROUND OF THE INVENTION

The renin-angiotensin system, along with the aldosterone system, is part of homeostasis controlling systemic blood pressure, body fluid levels, electrolyte balance, etc. The relationship between renin-angiotensin and hypertension has been clarified on the basis that angiotensin II, having a potent vasoconstrictive effect, increases blood pressure via angiotensin II receptors on the cell membrane. The angiotensin II antagonist is therefore used to treat angiotensin-induced hypertension. To date, drugs having angiotensin II antagonist activity have been administered orally. However, these drugs have been administered for symptomatic therapy that requires repeated administration over a long period of time. Due to the necessity of continuous administration, co-dosing with other drugs when administered orally, etc., the burden on the patient receiving this type of drug orally cannot be ignored. In addition, there is a possibility that the patient's condition will change upon discontinuation of this type of drug. Thus, for safe and reliable treatment, oral administration of drugs having angiotensin II antagonist activity may not necessarily be satisfactory.

There is an article (Pharmaceutical Research, 14, 887-891 (1997)) describing a sustained release formulation for 2-ethyl-5,7-dimethyl-3 - [[2 '- (1H-tetrazol-5yl) biphenyl] -4-yl] methyl] imidazo [4,5-b] pyridine having antagonistic activity against angiotensin II, wherein the composition comprises a high molecular weight polylactide (weight-average molar mass M _w = 82,000 g / mole) and polyethylene glycol 400 distearate. It is also stated that the initial rapid release from the sustained release formulation, which contains about 10% of the drug, is about 20%.

····

A Japanese translation publication of International Patent Application No. 504017/1998 discloses a composition wherein the physiologically active protein together with a metal cation component is dispersed in a biocompatible polymer.

SUMMARY OF THE INVENTION

The present invention relates to a sustained release composition comprising large amounts of a compound having angiotensin II antagonistic activity and whose initial rapid release is small, which composition is capable of controlling the release rate of said compound after an initial rapid release.

The inventors have carefully conducted extensive studies to solve the above problems, and have finally found that the sustained release composition comprising a compound having angiotensin Π antagonist activity may contain said compound in large quantities, that the release rate of said compound may be controlled by the addition of a polyvalent metal and that by administering said composition to a rat with spontaneous hypertension (SHR), the drug concentration in the rat's blood is maintained, while the blood pressure of the rat can be reduced while maintaining circadian rhythm of blood pressure. The inventors have carried out further investigations based on this finding and have come to the present invention.

More particularly, the present invention relates

1) a sustained release formulation comprising a compound having angiotensin II antagonist activity (excluding 2-ethyl-5,7-dimethyl-3 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl) imidazo [4,5-b] pyridine and its salts), a precursor thereof or a salt thereof, and a biodegradable polymer,

(2) the sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is a non-peptide compound;

(3) the sustained release composition of (1), wherein the compound having angiotensin antagonist activity is a compound having an oxygen atom in the molecule;

(4) the sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is a compound having an ether bond or a carboxyl group;

(5) The sustained release composition according to (1), wherein the compound having angiotensin II antagonist activity is a compound of formula (I):

9 99 99 ·

• 4 4. 4 4

where R ¹ is a group capable of forming an anion or a group capable of converting therein, X means that the phenylene and phenyl groups are bonded to each other either directly or through a spacer having two or fewer atoms, n is an integer equal to 1 or 2 , ring A is a benzene ring having - in addition to the group R ² - an optional substitution, R ² is a group capable of forming an anion or a group capable of converting therein, and R ³ is an optionally substituted hydrocarbon radical which may be attached via heteroatoms or a salt thereof,

(6) the sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan, or Tasosartan;

(7) the sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7 -carboxylic acid or a salt thereof,

(8) The sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4- yl] methyl] benzimidazole-7-carboxylate or its salts,

(9) The sustained release composition of (1), wherein the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazole-3) acid]. -yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or its salts,

(10) the sustained release composition of (1), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer;

(11) The sustained release composition of (10), wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid copolymer.

(12) the sustained release composition of (11), wherein the lactic acid to glycolic acid molar ratio is 100/0 to 40/60;

(13) the sustained release composition of (10), wherein the weight average molecular weight of the polymer is 3000 to 50,000 g / mol;

(14) the sustained-release preparation of (1) for injection;

(15) the sustained release composition of (1) further comprising a polyvalent metal;

(16) the sustained release formulation of (15), wherein the polyvalent metal is zinc;

(17) a sustained release composition comprising a compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof, a biodegradable polymer, and a polyvalent metal;

(18) the method of producing the sustained release composition of (1), comprising removing the solvent from a solution comprising a compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof, and a biodegradable polymer;

(19) the method of producing the sustained release composition of (17), comprising removing the solvent from a solution comprising a compound having angiotensin II antagonist activity, a precursor thereof or a salt thereof, a biodegradable polymer, and a polyvalent metal;

(20) the method of (19), wherein the polyvalent metal is zinc,

(21) a pharmaceutical preparation containing the sustained release preparation of (1);

(22) the preparation referred to in (21), intended for the prevention or treatment of circulatory diseases;

(23) the preparation of (21) intended for the prevention or treatment of hypertension;

(24) the preparation according to (21), intended for the prevention or treatment of hypercardia, cardiac insufficiency, myocardial infarction, cerebral apoplexy, ischemic peripheral circulatory disorders, myocardial ischemia, venous insufficiency, progressive cardiac insufficiency after myocardial infarction, diabetic complications, diabetic retinopathy, , nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, vascular hypertrophy or obstruction after intervention, vascular reobstruction after bypass surgery, hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, high intraocular pressure, hyperlipemia, arteriosclerosis, arteriosclerosis, angina pectoris, angina pectoris arteriosclerosis, thrombosis, central nervous diseases • frfr ·

- Alzheimer's disease, impaired memory, depression, amnesia, senile dementia, sensory disorders, multiple system organ failure, diseases from endothelial dysfunction or scleroderm, or for the prevention or amelioration of anxiety neuroses, catatonia, indisposition or dyspeptic symptoms, etc.

According to this concretization, angiotensin II antagonist activity consists in competitive or non-competitive inhibition of angiotensin II binding to angiotensin II receptors on cell membranes so as to reduce the angiotensin II-induced vasoconstrictive action or proliferative action of the delicate venous muscles, thereby alleviating the symptom of hypertension.

The compound having angiotensin II antagonist activity to be used for the present invention may be either a peptide compound or a non-peptide compound. In the light of the advantage of long-term action, a non-peptide compound having angiotensin II antagonist activity is preferred. Preferably, the compound having an angiotensin II antagonist activity is a compound having an oxygen atom in the molecule, more preferably a compound having an ether bond or a carbonyl group (the carbonyl group may be a hydroxyl group by resonance), more preferably a compound having an ether bond or keto group. then a compound that is an ether derivative.

Any non-peptide compound having angiotensin II antagonist activity may be used in the present invention. Examples of such compounds include imidazole derivatives disclosed in Japanese Unexamined Patent Application No. 71073/1981, Japanese Unexplored Japanese Patent Application No. 71074/1981, Japanese Unexplored Japanese Patent Application No. 98270/1982, Japanese Unexplored Japanese Patent Application No. 157768 (1983), USP 4,355,040, USP 4,340,598, etc., the modified imidazole derivatives disclosed in EP-253310, EP-291969, EP-324377, EP-403158, WO-9100277, Japanese Unexamined Patent Application No. 23868/1988, Japanese Unexamined Patent Application No. 117876/1989 etc., pyrrole, pyrazole and triazole derivatives disclosed in USP 5,183,899, EP-323841, EP-409332, Japanese Unexplored Patent Application No. 287071/1989 etc., benzimidazole derivatives disclosed in U.S. Pat. USP 4,880,804, EP-0392317, EP-0399732, EP-0400835, EP-425921, EP-459136, Japanese patent application no. 63264/1991 etc., azaindene derivatives described in EP-399731 etc., pyrimidone derivatives described in EP-407342 etc., quinazoline derivatives described in EP-411766 etc., xanthine derivatives described in EP-430300 etc., condensed imidazole derivatives the rings described in EP-434038 etc., the pyrimidinedione derivatives described in EP-442473 etc., the thienopyridone derivatives described in EP-443568 etc., the heterocyclic compounds described in EP-445811, EP-483683, EP-518033, EP-520423, EP-588299, EP-603712 etc. In addition, typical compounds of this kind are described in the work published in the Journal of Medicinal Chemistry, Vol. 39, no. 3, pp. 625-656 (1996). As a non-peptide compound having angiotensin II antagonist activity, in addition to those mentioned in the above references, any compound can be used as long as it has angiotensin II antagonist activity. Preferably, among others, Losartan (DuP753), Eprosartan (SK & F108566), Candesartan cilexetil (TCV-116), Valsartan (CGP-48933), Telmisartan (BIBR277), Irbesartan (SR47436), Tasosartan (active ANA-756) and their active are used. metabolites (Candesartan etc.).

Preferred non-peptide compounds having angiotensin II antagonist activity include, for example, the benzimidazole derivatives of formula (I):

wherein R ¹ is a group capable of forming an anion or a group capable of converting therein, X means that the phenylene and phenyl groups are bonded to each other either directly or through a spacer having a chain of two atoms or less, n being an integer equal to 1 or 2, ring A is a benzene nucleus having - in addition to the group R ² - an optional substitution, R ² is a group capable of forming an anion or a group capable of converting therein and R ³ is an optionally substituted hydrocarbon radical which can be attached via heteroatoms, or a salt thereof.

The R ¹ group in formula (I) capable of forming an anion (a group having a proton-leaving hydrogen atom) may be, for example, 1) a carboxyl group, 2) a tetrazolyl group, 3) a trifluoromethanesulfonic acid amide (-NHSO2CF3) group, 4) phosphonic acid 5) a sulfo group; 6) an optionally substituted radical of a 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic ring containing one or more N, S, O and the like.

• · · · · · · · · · · · · · · · · · · · · · · · · · · ·

• ·

As an example of the above "optionally substituted radical of a 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic ring containing one or more N, S, O atoms"

I ······ 9 · ·

etc. The chemical bond between the R ¹ heterocyclic ring moiety and the phenyl group to which the heterocyclic ring moiety is attached may be a carbon-carbon bond as described above, or a nitrogen-carbon bond through one of several nitrogen atoms, where g is -NH- etc. in the above formulas.

For example, R ¹ can be represented by the formula. hA

N <> = Z

N then particular variants are

= Z

HN or

IN

Z ^X N • 4 4 4 44

4 · · 4

9 9 9 99

4 9 9 9 9 9 9 9 9 9 9

4 4 4 4 4 · 4 · 4

4 4 4 4 4 4 44

As further examples of the substituent R ¹ bound through a nitrogen atom include:

r = \

In the preceding formulas, g is -CH 2 -, -NH-, -O- or -S (O) _m -. Furthermore,> = Z,> = Z 'and> = Z "independently represent a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (e.g. S, S (O), S (O) 2 etc.), preferably it is carbonyl or a thiocarbonyl group, preferably a carbonyl group, and m is an integer of 0.1, or 2.

Suitable examples of the heterocyclic ring radical R ¹ are heterocyclic ring radicals having an -NH- or -OH group as a proton donor and at the same time a carbonyl group, a thiocarbonyl group, a sulfinyl group and the like as a proton acceptor such as an oxadiazolone ring, an oxadiazolothion ring or a thiadiazolone ring and the like.

The radical of the heterocyclic ring designated R ¹ may form a fused ring system by linking substituents on the heterocyclic ring, preferably a radical of a five to six membered ring, preferably a radical of a five membered ring.

Suitable examples of the heterocyclic ring residue denoted as R ¹ include a group of the formula:

φφφφ φφ φφ · · φφ φφ

Φ φ · · φ φ

Φφ φφφ φφ φφφ «« φ φφφφ φφφφ φφφφ • Φ φφ φφ φφ φφ φφ where ί is -Ο- or -S-, j is> = Ο,> = S or> = S (O) _m wherein m is as defined as above (preferably 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, _{4,5-dihydro-5-oxo)} 2,4-thiadiazol-3-yl, preferably 4,5-dihydro-5-oxo-l, 2,4-oxadiazol-3-yl).

The above-mentioned heterocyclic ring residue (R ¹ ) has the following tautomeric isomers. For example, in a structure

where ZjeOag is also O, they are:

The three tautomeric isomers a ', b' and c 'exist and a group of formulas

includes all three.

A group capable of forming an anion such as R ¹ may be protected at the appropriate position by an optionally substituted lower (C 1 -C ₄ ) alkyl group, an acyl group (e.g. lower (C 2 -C 5) alkanoyl, benzoyl, etc.), etc.

9 * 99 99 99

9 9 9

9 9 9 •

9

99 99

98 99 • 9 · 9 9

9

9 9 9 9 • 9 9 9 9

9 «9999

Examples of optionally substituted lower (C 1 to C 4) alkyl include 1) lower (C 1 to C 4) alkyl optionally substituted with one to three phenyl groups that may carry a halogen atom, nitro, lower (C 1 to C 4) alkyl, lower (C) to C4) alkoxy and the like (e.g. methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.),

2) a lower (C 1 -C ₄ ) alkoxy-lower (C 1 -C 4) alkyl group (for example methoxymethyl, ethoxymethyl and the like), 3) a group of the formula -CH (R ⁴ ) -OCOR ⁵ wherein R ⁴ is a) hydrogen, b) a linear or branched lower (C 1 -C 4) alkyl group (for example methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec-butyl, n -butyl, n -pentyl, isopentyl, neopentyl etc.), c) a linear or branched lower (C 2 -C 6) alkenyl group; or d) a C 3 -C 8 cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl etc.), and R ⁵ is a) a linear or branched lower (C 1 -C 6) alkyl group ( for example methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec-butyl, n -butyl, n -pentyl, isopentyl, neopentyl, etc.), b) linear or branched lower (C ₂ -C ₆ ) alkenyl c) a lower (C 1 -C 3) alkyl group substituted with a C 3 -C 8 cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or optionally substituted an aryl group (e.g., a phenyl group, a naphthyl group, and the like, optionally bearing a halogen atom, a nitro group, a lower (C 1-6) C4) alkyl, lower (Cl to _C4) alkoxy, etc.) such as benzyl, a 77-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc., d) lower _(C2 to _C3) alkenyl, substituted C3 to Cg cycloalkyl or an optionally substituted aryl group (e.g., phenyl, naphthyl, optionally bearing a halogen atom, nitro, lower (C 1 -C ₄ ) alkyl, lower (C 1 -C ₄ ) alkoxy, etc.) such as cinnamyl and the like bearing an alkenyl function, such as vinyl, propenyl, allyl, isopropenyl, etc.,

e) optionally substituted aryl (e.g. phenyl, naphthyl, etc.) optionally bearing a halogen atom, nitro, lower (C 1 -C ₄ ) alkyl, lower (C ₁ -C ₄ ) alkoxy) such as phenyl, p-tolyl, naphthyl, etc., f) a linear or branched lower (C 1 -C 6) alkoxy group (for example methoxy, ethoxy, n -propoxy, isopropoxy, n -butoxy, isobutoxy, 5-butoxy, n -butoxy, n -pentyloxy, isopentyloxy, neopentyloxy etc. g) linear or branched lower (C ₂ to C ₈ ) alkenyloxy (for example allyloxy, isobutenyloxy, etc.), h) C 3 to C ₈ cycloalkyloxy (for example cyclopentyloxy, cyclohexyloxy, cycloheptyloxy etc.), i) lower (C 1 - 8) to C ₃ ) alkoxy substituted with C 3 to C ₈ cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl etc.) or optionally substituted aryl (e.g. phenyl, naphthyl, etc.) optionally bearing a halogen atom, nitro, lower (C 1 to C 3) from C ₄₎ alkyl, lower (Cl to _C4) alkoxy, etc.), such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy etc., carrying an alkoxy group such as methoxy, ethoxy,

44 44 44

4 4 4

49 4444

4 4 4 9 9 4 9 •

94 49 49 n-propoxy, isopropoxy and the like), j) lower (C ₂ to C ₃ ) alkenyloxy substituted with C ₃ to C 8 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or optionally substituted aryl (e.g., phenyl or naphthyl, etc.), optionally bearing a halogen atom, nitro, lower (C 1 -C 4) alkyl, lower (C 1 -C 4) alkoxy, etc.) such as cinnamyloxy and the like bearing an alkenyloxy group such as vinyloxy, propenyloxy, allyoxy, isopropenyloxy etc., or k) optionally substituted aryloxy (e.g. phenoxy, naphthoxy, etc.) optionally bearing a halogen atom, nitro, lower (C 1 to C 4) alkyl, lower (C 1 to C 4) to C4) alkoxy and the like) such as phenoxy, p-nitrophenoxy, naphthoxy, etc., etc.

The R ¹ group capable of forming an anion may be substituted at the appropriate position - in addition to the aforementioned protecting groups, such as an optionally substituted lower (C 1 -C 4) alkyl or acyl group (e.g. lower (C ₂ -C 5) alkanoyl, benzoyl etc.). ) and the like - also optionally substituted lower (C1 to C4) alkyl (for example, optionally substituted lower (C1 to C4) alkyl similar to an "optionally substituted lower (C1 to C4) alkyl" exemplified as a protecting group for the above mentioned group) capable of forming an anion such as R ¹ ), halogen atom, nitro, cyano, lower (C 1 -C 4) alkoxy, amino optionally substituted with one to two lower (C 1 -C 4) alkyl groups, etc.

The group in formula (I) convertible to an anion-forming group such as R ¹ , can be a convertible to anion-forming group under biological or physiological conditions (e.g., in vivo reactions and the like) such as oxidation, reduction, hydrolysis, etc. using in vivo enzymes) or a group convertible to a group capable of forming an anion designated R ¹ may be chemically convertible to a group capable of forming an anion such as a cyano group, a N-hydroxycarbamimidoyl (-C (= N-OH) -NH ₂ ) group selected from from the class consisting of 1) a carboxyl group, 2) a tetrazolyl group, 3) a trifluoromethanesulfonic acid amide (-NHSO ₂ CF ₃ ) group, 4) a phosphonic group, 5) a sulfo group and 6) an optionally substituted monocyclic radical, five to five a seven-membered (preferably five to six-membered) heterocyclic ring containing one or more N, S and O atoms each protected by an optionally substituted lower (C 1 to C 4) alkyl or acyl group and the like. Synthetic intermediate].

As R ¹ , preferably 1) carboxyl, tetrazolyl or 4,5-dihydro-5-oxole, 2,4-oxadiazol-3-yl (preferably tetrazolyl), each of which may be optionally protected, may be used.

99

9 9

9 9

9 9

9 9 9

99 • 9 · 99 · 99

9 9

9 9

9 9 9

9 9 9

99

9 · 99

9 9

9 9 9

9 9

9 9 9

99 substituted lower (C 1 -C ₄ ) alkyl (e.g. methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl etc.) or acyl group (e.g. lower (C 1 -C ₄ ) alkanoyl, benzoyl etc.) or 2 cyano or N-hydroxycarbamimidoyl (preferably cyano).

In formula (I), the symbol X indicates that the phenylene group is attached to the adjacent phenyl group directly or via a spacer represented by a chain of two or fewer atoms (preferably directly). An example of a spacer represented by a chain of two or fewer atoms is any bivalent chain in which the number of atoms forming the straight chain is one or two and which may have a side chain, in particular lower (C 1 -C ₄ ) alkylene in which the number of atoms forming a straight chain is equal to one or two, further -CO-, -O-, -S-, -NH-, -CO-NH-, -O-CH 2 -, -S-CH 2 -, -CH = CH- and the like .

In formula (I), n is an integer equal to one or two (preferably one).

In formula (I), ring A may carry, in addition to R ² , another substituent, for example 1) halogen (for example F, Cl, Br etc.), 2) cyano, 3) nitro, 4) optionally substituted lower (C 1 to C 1) C4) alkyl, 5) lower (C1-C4) alkoxy, 6) optionally substituted amino [e.g., amino, N-alkylamino with lower (C1-C4) alkyl (e.g. methylamino, etc.), N-dialkylamino with lower (C1-C4) alkyls (e.g. dimethylamino and the like), N-arylamino (e.g. phenylamino and the like), alicyclic amino (e.g. morpholino, piperidino, piperazino, N-phenylpiperazino etc.) and the like], 7) a group of the formula -CO-D ', wherein D 'is a hydroxyl group or a lower (C 1 -C 4) alkoxy group whose alkyl residue may be substituted by a hydroxyl group, a lower (C 1 -C 4) alkoxy group, a lower (C 2 -C 6) alkanoyloxy group (e.g. acetoxy, pivaloyloxy and the like), lower ( C1-C6) alkoxycarbonyloxy (e.g. methoxy) (bonyloxy, ethoxycarbonyloxy, etc.) or lower (C 3 to C 6) cycloalkoxycarbonyloxy (e.g., cyclohexyloxycarbonyloxy, etc.); or 8) a tetrazolyl, trifluoromethanesulfonic amide, phosphonic or sulfo group, each of which may be protected with an optionally substituted lower ( to C4) alkyl ("optionally substituted by a lower (C1 to C4) alkyl group" similar to that exemplified by anionic protecting groups designated as R ¹ and the like) or by acyl (e.g. lower (C2 to C5) alkanoyl) , benzoyl, etc.), etc.

Of these substituents, one or two - in addition to the R group - may be simultaneously present at any available position of the benzene ring, and preferred examples of such substituents of the benzene ring A include optionally substituted lower (C 1 -C ₄ ) alkyl (e.g. lower (C 1 -C ₄ )). ·· · 4 * · · · 4 4 4

445 44 44 «44 *

4 · · · 44 444 44

1Λ 4444 4444 4444 ^J '99 99 99 99 99 99 to C ₄₎ alkyl, etc., Optionally substituted hydroxyl group, carboxyl group, halogen etc.), halogen and the like. A ring is preferably a benzene ring which in addition to the groups R ² assumes no other substituent.

Examples of the group R in formula (I) capable of forming an anion (groups having a hydrogen atom cleavable as a proton) include 1) an optionally esterified or amidated carboxyl group, 2) a tetrazolyl group, 3) a trifluoromethanesulfonic acid amide (-NHSO2CF3) group , 4) a phosphone group, 5) a sulfo group, etc., each of which may be protected by an optionally substituted lower alkyl group (for example, an optionally substituted lower (C 1 -C 4) alkyl group similar to an "optionally substituted lower (C 1 -C ₄ ) alkyl group") exemplified by a protecting group for said anion-forming group such as R ¹ ) or an acyl group (e.g. lower (C 2 to C 5) alkanoyl, benzoyl etc.) or any of the groups capable of being converted under biological or physiological conditions (e.g. in vivo etc., such as oxidation, reduction, hydrolysis, etc. by the action of an enzyme i n vivo and the like) or chemically.

Examples wherein R ² is optionally esterified or amidated carboxyl include a group of the formula -CO-D, wherein D is 1) a hydroxyl group, 2) an optionally substituted amino group (e.g., amino, N-alkylamino with lower (C 1 -C 4) alkyl) Λζ Or (3) an optionally substituted alkoxy group [e.g. i) a lower (C 1 -C 6) alkoxy group, the alkyl portion of which is optionally substituted by a hydroxyl group, an optionally substituted amino group (for example, amino, A-alkylamino with lower (C 1 -C ₄ ) alkyl, N, A-dialkylamino with lower (C 1 -C 4) alkyls, piperidino, morpholino etc.), halogen, lower (C 1 -C 6) alkoxy, lower (C 1 -C 6) alkylthio, lower (C 3 -C 8) cycloalkoxy or optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl and the like) or ii) -O-CH (R ⁶ ) -OCOR ⁷ , wherein R ⁶ is a) hydrogen, b) linear or branched lower a (C 1 -C 6) alkyl group (e.g., methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, n -butyl, n -pentyl, isopentyl, neopentyl, etc.), c) linear or branched lower (C 2 to C 6) (C 6) alkenyl; or (d) a C 3 -C 8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) and R ⁷ is a) a linear or branched lower (C 1 -C 6) alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl) , N -butyl, isobutyl, tert -butyl, n -butyl, n -butyl, isopentyl, neopentyl, etc.), b) linear or branched lower (C 2 -C 6) alkenyl group, c) lower (C 1 -C 3) alkyl group substituted with a C3 to C8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., phenyl, naphthyl, etc.) optionally bearing a halogen atom, nitro, lower (C1-4);

9 9 9 9 9 9 9 9 9 99 99 9 9 9 9 9 _1C 9 9 9 9 9 9 00 44 94 44 99 9 to C ₄ ) alkyl, lower (C 1 to C ₄ ) alkoxy, etc.) such as benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl etc., d) lower (C 2 to C 3) alkenyl group substituted with C 3 -C 8 cycloalkyl or optionally substituted aryl (for example phenyl, naphthyl, etc., optionally bearing a halogen atom, nitro, lower (C 1 -C ₄ ) alkyl, lower (C 1 -C ₄ ) alkoxy, etc.) such as cinnamyl etc. having as alkenyl moiety vinyl, propenyl, allyl, isopropenyl etc., e) optionally substituted aryl (e.g. phenyl, naphthyl, etc.) optionally bearing a halogen atom, nitro, lower (C 1 to C ₄ ) alkyl, lower (C 1 -C ₄ ) alkoxy, etc.) such as phenyl, p-tolyl, naphthyl, etc., f) linear or branched lower (C 1 -C 4); (C 6) an alkoxy group (for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, see-butoxy, n-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), g) linear or branched lower (C2) to Cg) alkenyloxy (e.g., allyloxy, isobutenyloxy etc.), h) a C3 to Cg cycloalkyloxy group (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy etc.), i) a lower (Ci-C ₃₎ alkoxy substituted C ₃ to Cg cycloalkyl (e.g. cyclopentyl , cyclohexyl, cycloheptyl, etc.) or optionally substituted aryl (e.g., phenyl, naphthyl, etc.) optionally bearing a halogen atom, nitro, lower (C 1 -C ₄ ) alkyl, lower (C 1 -C ₄ ) alkoxy, etc.), such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy etc. having an alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. etc.), j) lower (C2 to _C3) alkenyloxy substituted with _C3 to Cg cycloalkyl (n and, for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., a phenyl or naphthyl group, etc. optionally bearing a halogen atom, a nitro group, a lower (C 1 -C ₄ ) alkyl, a lower (C 1 -C ₄ ) alkoxy etc.) , such as cinnamyloxy and the like having as alkenyloxy moiety vinyloxy, propenyloxy, allyloxy isopropenyloxy etc. or

k) optionally substituted aryloxy (e.g., phenoxy, naphthoxy, etc., optionally bearing a halogen atom, nitro, lower (C 1 -C ₄ ) alkyl, lower (C 1 -C ₄ ) alkoxy, etc.) such as phenoxy, p-nitrophenoxy, naphthoxy etc.] etc.

As R ² is preferably an optionally esterified carboxyl group, and among specific examples thereof include -COOH and its salts, -COOMe, -COOEt, COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, l- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo- 1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl,

- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutyryloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl,

ΦΦΦΦ φ φ φ φ φ φ φ φ φ «φ φ φ φ φ φ φ φ φ φ φ φ

The group R ² may be any of the groups capable of forming an anion under biological or physiological conditions (e.g., by in vivo oxidation, reductions, etc., etc.). enzyme in vivo and the like), the groups may be capable of forming an anion chemically (e.g., COO-, derivatives thereof, etc.) or groups capable of converting into it. ^R2 may be carboxyl group or a precursor thereof.

Preferred examples of R include the group -CO-D wherein D is 1) a hydroxyl group or 2) a lower (C 1 -C 4) alkoxy group whose alkyl residue is optionally substituted by a hydroxyl group, amino group, halogen, lower (C 2 to%) alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.), lower (C 3 -C 8) cycloalkanoyloxy, lower (C 1 -C 6) alkoxycarbonyloxy (eg methoxycarbonyloxy, ethoxycarbonyloxy etc.), lower (C 3 to C 8) cycloalkoxycarbonyloxy (lower alkoxy) carbonyloxy, e.g. _(C-C4) alkoxy or lower (C ₃ to C ₈₎ cycloalkoxy. Among others, a carboxyl esterified with a lower (C1-C4) alkyl (preferably methyl or ethyl) is preferred.

Preferred examples of the "hydrocarbon radical" in the "optionally substituted hydrocarbon radical which may be bonded via heteroatoms" shown in formula (I) as R ³ are 1) alkyl, 2) alkenyl, 3) alkynyl, 4) cycloalkyl, 5) aryl, 6) aralkyl, etc. Among others, alkyl, alkenyl and cycloalkyl are preferred.

Examples of the alkyl group mentioned under 1) above include a linear or branched lower alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl etc.

Examples of the alkenyl group mentioned under 2) above include a linear or branched lower alkenyl group having 2 to 8 carbon atoms such as vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl, etc.

Examples of the alkynyl group mentioned above under 3) include a linear or branched lower alkynyl group having 2 to 8 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl, etc.

Examples of the cycloalkyl group mentioned above under 4) include lower cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Each of the above alkyl, alkenyl, alkynyl, and cycloalkyl groups may be substituted with a hydroxyl group, optionally substituted with an amino group (e.g., amino, N-alkylamino with lower (C 1 to C 4) alkyl, ,Α-dialkylamino with lower (C 1 to C). Β · · · β β β β β β β β β β β β β β β β β β β β β β β β β β · * ··

C ₄ ) alkyls and the like, halogen, lower (C 1 to C ₄ ) alkoxy, lower (C 1 to C 4) alkylthio, etc.

Examples of the aralkyl group mentioned above under 5) include phenylalkyl having a C 1 -C 4 alkyl moiety such as benzyl, phenethyl, etc.

Examples of the aryl group mentioned above under 6) include phenyl and the like.

Each of the above aralkyl and aryl groups may be substituted at any possible position of the benzene ring by halogen (e.g. F, Cl, Br, etc.), nitro, optionally substituted amino, optionally substituted amino (e.g. amino, N-alkylamino with lower (C 1 - C1-C4 alkyl, dial-dialkylamino with lower (C1-C4) alkyl and the like), lower (C1-C4) alkoxy (e.g. methoxy, ethoxy, etc.), lower (C1-C4) alkylthio (e.g. methylthio, ethylthio etc.). ), lower (C 1 -C 4) alkyl (e.g., methyl, ethyl, etc.), etc.

Preferable examples of the "optionally substituted hydrocarbon radical" in the "optionally substituted hydrocarbon radical which may be attached via heteroatoms" shown in formula (I) as R ³ include an optionally substituted alkyl or alkenyl group (e.g. lower (C 1 to C 5) alkyl or lower ( C ₂ to C 5) alkenyl, each of which may be substituted with hydroxyl, amino, halogen, lower (C 1 to C 4) alkoxy, etc.). Among others, lower (C 1 to C 5) alkyl (preferably ethyl) is preferred.

Preferable examples of the "heteroatoms" in the "optionally substituted hydrocarbon radical which may be attached via the heteroatoms" shown in formula (I) as R ³ include -O-, -S (O) _m - [m is an integer of 0 to 2], -NR'- [R 'is a hydrogen atom or lower (C 1 -C ₄ ) alkyl] etc. Among others, -O- is preferred.

As R ³ , inter alia, a lower (C 1 -C ₄ ) alkyl or lower (C ₂ -C ₅ ) alkenyl group, each of which may be substituted with a substituent selected from the group consisting of hydroxyl, amino, halogen and lower (Cf), is preferred. to C ₄ ) alkoxy and which may be attached via -O-, -S (O) _m - [m is an integer of 0 to 2] or -NR'- [R 'is a hydrogen atom or lower (C 1 to C 2) ₄ ) alkyl] etc., more preferably a lower (C 1 to C ₅ ) alkyl or a lower (C 1 to C 5) alkoxy (especially ethoxy) group.

Of the non-peptide compounds having angiotensin II antagonist activity represented by formula (I), a benzimidazole-7-carboxylic acid derivative of formula (Γ) is preferred:

• ·

wherein R ¹ is 1) a carboxyl group, 2) a tetrazolyl group, or 3) a group of the formula:

N - j H where i is -O- or -S-, j is> = O,> = S or> = S (O) _m , and _m is as defined above. Ring A is a benzene ring bearing - in addition to the R ² group - an optional substituent selected from the group consisting of optionally substituted lower (C 1 -C 4) alkyl (e.g. lower (C 1 -C 4) alkyl optionally substituted with hydroxyl, halogen, etc.) and halogen ( preferably a benzene ring having in addition to the group R ^{2 has} no further substituent). R ² is a group of the formula -CO-D, wherein D is

1) a hydroxyl group or 2) a lower (C 1 -C 4) alkoxy group whose alkyl moiety may be substituted by a hydroxyl group, an amino group, a halogen, a lower (C ₂ -C 6) alkanoyloxy group (e.g. acetoxy, pivaloyloxy etc.), lower (C 3 -C 4) Cg) cycloalkanoyloxy, lower (C 1 to C 8) alkoxycarbonyloxy (for example methoxycarbonyloxy, ethoxycarbonyloxy etc.), lower (C ₃ to C 8) cycloalkoxycarbonyloxy (for example cyclohexyloxycarbonyloxy etc.), lower (C 1 to C 4) alkoxy cycloalkoxy. R is lower (C 1 to C 5) alkyl or lower (C ₂ to C 5) alkenyl, each of which may be attached via -O-, -S (O) _m - [m is an integer of 0 to 2], -NR '- [R' is a hydrogen atom or lower (C1 to C4) alkyl], and which may be substituted with a substituent selected from the group consisting of hydroxyl, amino, halogen and lower (C1 to C4) alkoxy (lower is preferred ( Ci to C5)

»· · <

An alkyl or lower (C 1 to C 5) alkoxy group, preferably ethoxy, etc., or a pharmaceutically acceptable salt thereof.

Among others, 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy- 1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate [Candesartan cil ex et 1], pivaloyloxymethyl 2-ethoxy-1 - [[2' - (1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate, 2-ethoxy-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazole)] -3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, etc., or a salt thereof.

The above benzimidazole derivatives can be prepared by known methods described, for example, in EP-425921, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272 etc. or in a manner analogous thereto. When Candesartan cilexetil is used for the present invention, the stable type C crystal described in EP-459136 can be advantageously used.

A compound having angiotensin II antagonist activity or a prodrug thereof can be used either in the free form or in the form of any pharmaceutically acceptable salt 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 trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine, etc., basic amino acids such as arginine, lysine, omithine etc.). if said compound having angiotensin II antagonist activity carries an acid group such as a carboxyl group etc. as well as a salt with inorganic acids or organic acids (e.g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonate in the form of normal carbonates hydrogen carbonate, formic acid, acetic acid, propionic acid, acid other trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid ,; toluenesulfonic acid, etc.), acidic amino acids such as aspartic acid, glutamic acid etc. etc., when said compound having angiotensin II antagonist activity carries a basic group such as an amino group and the like.

A precursor of a compound having angiotensin II antagonist activity [hereinafter referred to as AII antagonist] is a compound that can be converted into AII antagonists under physiological conditions or by a reaction induced by an enzyme, digestive acids, · · 0 • 0 tract etc. in a living organism, that is, a compound convertible into AII antagonists by oxidation, reduction, hydrolysis, etc. by the action of an enzyme, a compound convertible into AII antagonists by the action of digestive tract, etc., etc.

Examples of the AII antagonist precursor include compounds wherein the amino group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, etc. (e.g., compounds wherein the amino group of the AII antagonist is substituted with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.), wherein the hydroxyl group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g., compounds in which the hydroxyl group of the AII antagonist is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.), wherein the carboxyl group of the AII antagonist is modified by ester, amide, etc. (compounds in which the carboxyl group of the AII antagonist is modified with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester, methylamide, etc.).

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

The AII antagonist can also be hydrated.

Examples of a biodegradable polymer to be used in the present invention include polymers, copolymers, esters or mixtures thereof synthesized from one or more α-hydroxycarboxylic acids (e.g., glycolic acid, lactic acid, etc.), hydroxydicarboxylic acids (e.g., lactic acid) etc.), hydroxytricarboxylic acids (e.g., citric acid, etc.), etc., and having a free carboxyl group, maleic anhydride copolymers (e.g., styrene-maleic acid copolymer, etc.), etc.

These copolymers can be random, block or graft copolymers. If said α-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity, both the D-isomer and the L-isomer and the D, L-isomer can be used. Among others, an α-hydroxycarboxylic acid polymer (preferably a lactic acid copolymer and a lactic acid copolymer and preferably a lactic acid copolymer and a lactic acid copolymer and a lactic acid copolymer and a lactic acid copolymer is preferred). esters of poly (α-cyanoacrylic acid), of which a copolymer of lactic acid and glycolic acid and its ester is more preferred.

If a lactic-glycolic acid copolymer is used as the biodegradable polymer, their molar ratio (mol%) is preferably in the range 100/0 to 40/60, preferably 100/0 to

50/50.

Generally, the weight average molar mass of said lactic-glycolic acid copolymers is in the range of about 3000 to 50,000 g / mol, preferably about 4000 to 40,000 g / mol, preferably about 5000 to 30,000 g / mol. The degree of polydispersity (i.e. the ratio by weight to number average molar mass, hereinafter also referred to as polydispersity) is usually in the range of about 1.2 to 4.0, preferably 1.5 to 3.5.

The molar mass average, molar mass number and polydispersity values in the present document were determined by gel permeation chromatography (GPC) using 14 samples of polystyrene as reference standards with molar mass weights of 1 110 000, 707 000, 354 000, 189 000, 156 000, 98 900, 66 437, 37 200, 17 100, 9830, 5870, 2500, 1303 and 500 g / mol. The assay was performed using a GPC column KF804Lx2 (manufactured by Showa Denko K.K., Japan) and chloroform as the mobile phase.

To obtain a number average molar mass, the biodegradable polymer was dissolved in a mixed solvent of acetone / methanol and the resulting solution was titrated with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator to determine the carboxyl end group content. Hereinafter, this value is referred to as the number average molar mass of the end group determinations. While the molar mass numerical value of the end group assays is absolute, the same GPC value is relative and varies depending on the conditions of the analysis (e.g., mobile phase type, column type, reference standards, section width selection, baseline selection) etc.). It is therefore difficult to obtain an absolute numerical expression of this quantity. However, in the case of a polymer bearing terminal carboxyl groups and prepared from lactic acid and glycolic acid by polycondensation without a catalyst, the values of the molar mass number average from GPC and the molar mass number from end group determination are almost identical. The statement that the number average molar mass of the GPC and the end group determination is "almost identical" here means that the value of the second method lies in the interval of 0.2 to 1.5 times, preferably 0.3 to 1 times, 2 times the value of the first method.

The lactic acid-glycolic acid copolymer can be prepared, for example, by a catalyst-free polycondensation of lactic acid and glycolic acid (Japanese patent application no.

999 · 9 9

9 9

9 9

9 9 9 ·

9 99 · fc 9 · fcfc 9

9 9 9

No. 9 9 9, or by catalysed ring-opening polymerization of cyclic lactide, glycolide, etc. (Encyclopedic Handbook of Biomaterials and Bioengineering, Part A: Materials, Vol. 2, published by Marcel Dekker, hic. (1995) )).

The polymer produced by ring-opening polymerization has few or no carboxyl groups, but can be chemically produced to produce a polymer with carboxyl groups (J. Controlled Release, Vol. 41, 249-257 (1996)), which can be used for the present invention. invention.

Said lactic acid-glycolic acid copolymer having carboxylic end groups can be readily synthesized by general synthetic procedures (for example, without the catalyst-free polycondensation described in JP-A-28542/1986). In addition, a polymer carrying free carboxyl groups at an unspecified position can be synthesized by known methods (e.g. WO94 / 15587).

As the lactic acid-glycolic acid copolymer bearing the carboxyl end group and prepared by chemical treatment after ring-opening polymerization, the copolymer available, for example, from Boehringer Ingelheim KG can be used.

Esters of lactic acid-glycolic acid copolymers can be prepared, for example, from known lactic acid-glycolic acid copolymers bearing a free carboxyl group (for example, Japanese Patent Application Laid-Open No. 278018/1995).

These biodegradable polymers can be used alone or in combination with two or more kinds of these polymers.

The polyvalent metal to be included in the sustained release composition of the present invention may be any metal as long as it is a metal that does not adversely affect the living organism. Examples of this metal include polyvalent metals such as divalent metal (e.g. iron, zinc, copper, calcium, magnesium, aluminum, tin, manganese, etc.), trivalent metal (e.g. iron, aluminum, manganese, etc.), tetravalent metal (e.g. tin) etc.) etc.

In the sustained release composition of the present invention, these metals may be present in the form of an inorganic compound, an organic compound, a metal oxide [hereinafter referred to as polyvalent metal compounds] etc., in the form of a metal ion, or in the form of a complex of a polyvalent metal with both compounds having angiotensin II antagonistic activity, their precursors or salts thereof and a biodegradable polymer, or with either of them separately.

«*

• · · fr · * · · · · · ·

9 · ητ · · · ·

9 9 9

Preferred examples of the polyvalent metal include iron, aluminum, zinc, calcium, magnesium, etc. Zinc is particularly preferred. Among others, zinc present in zinc oxide is preferred.

Examples of inorganic substances include inorganic acids and the like, such as hydrogen halide (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, etc.), sulfuric acid, nitric acid, thiocyanic acid, etc.

Examples of organic substances include organic acid and the like, such as aliphatic carboxylic acid, aromatic acid, acetylacetone, etc.

Preferable examples of the aliphatic carboxylic acid include a C 1 to C 9 aliphatic carboxylic acid (e.g. aliphatic mono-, di- or tricarboxylic acid and the like) etc., wherein the aliphatic carboxylic acid may be either saturated or unsaturated.

Examples of the aliphatic monocarboxylic acid include a C 1 -C 9 saturated aliphatic monocarboxylic acid (e.g., carbonic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid and the like), C ₂ to C9. C9 unsaturated aliphatic monocarboxylic acid (e.g. acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.) etc.

Examples of the aliphatic dicarboxylic acid include a C ₂ to C 9 saturated aliphatic dicarboxylic acid (e.g. malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.), a C ₂ to C 8 unsaturated aliphatic dicarboxylic acid (e.g. maleic acid, fumaric acid, fumaric acid) citraconic, mesaconic acid, etc.) etc.

Examples of the aliphatic tricarboxylic acid include a C ₂ to C 8 saturated aliphatic tricarboxylic acid (e.g. tricarballylic acid, 1,2,3-butanetricarboxylic acid, etc.), etc.

The above aliphatic carboxylic acid may carry 1 to 2 hydroxyl groups, examples of the aliphatic carboxylic acid bearing one hydroxyl group include glycolic acid, lactic acid, glyceric acid, tartronic acid, malic acid, tartaric acid, citric acid, etc.

Of the aliphatic carboxylic acids, an aliphatic monocarboxylic acid, preferably a C ₂ to C 9 aliphatic carboxylic acid, in particular acetic acid, is preferred.

Examples of aromatic acids include benzoic acid, salicylic acid, phenolsulfonic acid, etc.

• · · 4

4

4 »44 • 4

4 4

Examples of polyvalent metal compounds include an iron inorganic acid salt [e.g., an iron halide (e.g., iron chloride, iron bromide, iron iodide, iron fluoride, etc.), iron sulfate, iron nitrate, iron thiocyanate, etc.], an iron organic acid salt [e.g. aliphatic iron carboxylate (e.g. iron carbonate, iron acetate, iron glycolate, iron lactate, iron tartrate, etc.), iron aromatic acid salt (e.g. iron benzoate, iron salicylate, iron phenolsulfonate etc.)], iron acetylacetonate etc., inorganic salt zinc acids [e.g., zinc halide (e.g., zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate, etc.], zinc organic acid salt [e.g. zinc aliphatic carboxylate (e.g. , zinc acetate , zinc glycolate, zinc lactate, zinc tartrate, etc.), zinc aromatic acid salt (e.g. zinc benzoate, zinc salicylate, zinc phenolsulfonate, etc.)], zinc acetylacetonate etc., inorganic calcium salt [e.g. calcium halide (e.g. calcium chloride) calcium, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, calcium nitrate, calcium thiocyanate, etc.], a calcium organic acid salt [e.g., aliphatic calcium carboxylate (e.g., calcium carbonate, calcium acetate, calcium propionate, calcium oxalate, calcium tartrate, calcium lactate, calcium citrate, calcium gluconate, etc.), an aromatic acid salt of calcium (e.g. calcium benzoate, calcium salicylate, etc.)], calcium acetylacetonate etc., an inorganic acid salt of magnesium [e.g. magnesium halide (e.g. magnesium chloride) , magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate and the like], an organic salt of magnesium [e.g., aliphatic magnesium carboxylate (e.g. magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, tartrate) , magnesium lactate, magnesium citrate, magnesium gluconate, etc.), the aromatic acid salt of magnesium (e.g., magnesium benzoate, magnesium salicylate, etc.), magnesium acetylacetonate, etc., and a metal oxide (e.g., iron oxide, zinc oxide, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide, etc.) etc.

Preferred as the polyvalent metal compound are iron chloride, iron acetylacetonate, zinc acetate, zinc acetylacetonate, calcium acetate, calcium acetylacetonate, magnesium acetate, magnesium acetylacetonate, zinc oxide and the like, preferably zinc oxide.

In the present invention, all or part of the polyvalent metal to be included in the sustained release composition of the present invention may be used in the form of a biodegradable polymer salt with one or more types of polyvalent metal. The polyvalent metal biodegradable polymer salt may be prepared as described

Japanese Patent Application Unexamined No. 221420/1997 or a similar method.

Examples of preferred embodiments of the sustained release composition of the present invention include a sustained release composition comprising a compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof [hereinafter referred to as AII antagonist compounds], a biodegradable polymer and a polyvalent metal, and methods of preparing said composition comprising a method of preparing said sustained release composition comprising removing a solvent from a solution comprising a compound having AII antagonist activity, a biodegradable polymer and a polyvalent metal, etc.

The polyvalent metal may become part of said solution by using a polyvalent metal complex with both the compounds having angiotensin II antagonist activity, their precursors or their salts and a biodegradable polymer, or with either of them separately, as the starting material, further comprising a polyvalent compound All or part of the polyvalent metal compound added to said solution may complex with said solution having both angiotensin II antagonist activity and a biodegradable polymer or any of these components.

In the sustained release composition of the present invention, the amount of the compound having AII antagonistic activity and the amount of polyvalent metal compound varies depending on the type of compound having AII antagonistic activity, the desired pharmaceutical effect, the duration of the effect, etc. of the present invention consisting of a compound having AII antagonist activity and a biodegradable polymer, then the amount of the compound having AII antagonist activity is usually 1 to 50 wt. %, preferably 5 to 45 wt. %, preferably 10 to 40 wt. %, based on the sum of the two components, i.e., compounds having AII antagonist activity and biodegradable polymer. If the sustained release composition of the present invention consists of a compound having AII antagonist activity, a polyvalent metal compound and a biodegradable polymer, then the amount of the compound having AII antagonist activity is usually 1 to 50 wt. %, preferably 15 to 45 wt. %, preferably 20 to 40 wt. %, based on the sum of the three components, and on the other hand, the amount of polyvalent metal compound is usually 0 to 20 wt. %, preferably 2 to 15 wt. %, preferably 4 to 10 wt. %.

tl · · · ·

The sustained release composition of the present invention may be administered in any form, preferably it is part of a formulation for non-oral administration. Examples of such formulations include subcutaneous formulations, implantable formulations, injectable microcapsules, etc. Of these, injectable microcapsules are preferred because they maintain a long-term pharmaceutical effect and reduce the patient's burden.

Examples of methods for preparing the sustained release composition of the present invention, for example microcapsules (also referred to herein as microspheres) comprising a compound having AII antagonist activity and a biodegradable polymer include:

I) Water drying

i) O / V method

A compound having AII antagonist activity and, if desired, a polyvalent metal compound are added to a solution of the biodegradable polymer in an organic solvent in a weight ratio as defined in the above-mentioned "amount of AII antagonist compound and polyvalent metal compound" to forming a solution of the biodegradable polymer in an organic solvent comprising a compound having AII antagonist activity and, if necessary, a polyvalent metal compound. One or both of the compounds having AII antagonistic activity and the polyvalent metal compound need not be dissolved in the solution of the biodegradable polymer in the organic solvent, they can only be dispersed in the solution. When one or both of these components are dispersed in said solution, it is preferable to disperse these components finely in a conventional manner such as homogenization, ultrasonic dispersion and the like.

Examples of said organic solvent include halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like), ethers (e.g. diethyl ether, isopropyl ether and the like), fatty acid esters (e.g. ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (e.g. benzene, toluene) , xylene and the like), alcohols (e.g., ethanol, methanol, etc.), acetonitrile, etc. These solvents may be used singly or in combination.

Among others, the halogenated hydrocarbon is dichloromethane, the preferred alcohol is ethanol, methanol, and the like. These solvents can be used in a mixture in a suitable solvent.

............

ratio. When the compound having AII antagonist activity contains a tetrazolyl group, ethanol is preferred as a mixture with dichloromethane, while when the compound having AII antagonist activity contains 4,5-dihydro-5-oxole, 2,4- oxadiazol-3-yl group, it is methanol.

An additive may be added to the above solution in the organic solvent. Examples of additives include a solubilizer which maintains the stability and solubility of the active ingredient, which may be carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine, and salts thereof. for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyols such as polyethylene glycol, etc., and, for example, conventional paraoxybenzoic acid esters (e.g. methylparaben, propylparaben, etc.), benzyl alcohol may be added as preservatives. , chlorobutanol, thimerosal, etc.

The concentration of the biodegradable polymer in solution in the organic solvent varies depending on the molecular weight of the biodegradable polymer and the type of organic solvent. For example, when dichloromethane is used as the organic solvent, the concentration of the biodegradable polymer in solution in the organic solvent is generally chosen in the range of 0.5 to 70 wt. %, preferably 1 to 60 wt. %, preferably 2 to 50 wt. %. Further, when ethanol or methanol is used as a mixed organic solvent together with dichloromethane, the concentration of dichloromethane in solution in the organic solvent is generally chosen in the range of 10 to 99 wt. %, preferably 20 to 98 wt. %, preferably 30 to 95 wt. %.

The biodegradable polymer solution thus obtained, the organic solvent of which contains a compound having angiotensin II antagonistic activity and, if necessary, a polyvalent metal compound, is added to the aqueous phase (also referred to as the external aqueous phase) to form an O (oil phase) emulsion. V / v (aqueous phase) followed by evaporation of the solvent from the oil phase to form microcapsules. The volume of the aqueous phase is generally selected in the range of from 1 to 10 times the volume of the oil phase, preferably from 5 to 5 times, preferably from 10 to 2 times.

Any emulsifier may be added to said external aqueous phase as long as it can contribute to the formation of a stable O / V emulsion. Examples of emulsifiers include anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid esters [Tween 80, Tween 60, Atlas Powder], polyoxyethylene castor oil derivatives [CHO-60, HCO- 50, Nikko Chemicals], etc.),

4 «44 44» 4

4

44 ·· ··

4 4 4 4444

44 44 4444

443 44 443 44 4

4444 4444 ·· 4 4 4 4 polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid and the like. These emulsifiers can be used singly or in combination. The concentration can be selected from 0.01 to 10 wt. %, preferably from 0.05 to 5 wt. %.

An osmotic pressure regulator may be added to the external aqueous phase. Any osmotic pressure regulator may be added as long as it produces an osmotic pressure in its aqueous solution.

Exemplary osmotic pressure regulators include polyfunctional alcohols, monovalent alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids or derivatives thereof, and the like.

Examples of said polyfunctional alcohols include difunctional alcohols such as glycerin and the like, pentafunctional alcohols such as arabitol, xylitol, adonitol and the like, hexafunctional alcohols such as mannitol, sorbitol, dulcitol, etc. etc. Among others, hexafunctional alcohols are particularly preferred. mannitol.

Examples of said monovalent alcohols include methanol, ethanol, isopropyl alcohol and the like. Among others, methanol is preferred.

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

Examples of said oligosaccharides are trisaccharides such as maltotriose, raffinose and the like, tetrasaccharides such as stachyose and the like, etc. Among others, trisaccharides are preferred.

Examples of derivatives of said monosaccharides, disaccharides and oligosaccharides include glucosamine, galactosamine, glucuronic acid, galacturonic acid, etc.

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

These osmotic pressure regulators may be used singly or as a mixture of two or more thereof.

These osmotic pressure regulators are generally used at a concentration that exerts an osmotic pressure of the external aqueous phase in the range of from one fifth to five times, preferably from one twenty fifth to three times the saline value.

Known or analogous methods can be used to remove the organic solvent. This can be done, for example, by evaporating the organic solvent while stirring with a propeller stirrer, magnetic stirrer, etc. at atmospheric pressure or gradually reduced pressure or controlled vacuum using a rotary evaporator, etc., etc.

The microcapsules thus obtained are isolated by centrifugation or filtration. Subsequently, the substances attached to the surface of the microcapsules, i.e. the compound having AII antagonistic activity, its carriers, »4 44

4 · 4 4 4

4 * 44 44 4

4

4

4 4 4 4 4 5

44 44 44 emulsifiers, etc., washed several times with distilled water, dispersed in distilled water and the like, and subjected to lyophilization. Aggregation inhibitors may be added for lyophilization to prevent particle aggregation. Examples of such aggregation inhibitors include water-soluble polysaccharides such as mannitol, lactose, glucose, starch (e.g. corn starch, etc.) and the like, amino acids such as glycine and the like, proteins such as fibrin, collagen etc. etc. Among others, it is preferred mannitol.

If desired, after completion of the lyophilization, further removal of water and organic solvent can be accomplished by heating the microcapsules under reduced pressure and under conditions where the microcapsules do not associate with each other. Preferably, the microcapsules are heated to a suitable temperature that is slightly higher than the mean glass transition temperature (determined by a differential scanning calorimeter at a temperature increment of 10 or 20 ° C per minute) of the biodegradable polymer. Preferably, the microcapsules are heated to a temperature in the range of the mean glass transition temperature to a temperature that is about 30 ° C higher than the mean glass transition temperature of the biodegradable polymer. In particular, when a lactic acid-glycolic acid copolymer is used as the biodegradable polymer, the microcapsules are preferably heated to temperatures ranging from a mean glass transition temperature to about 10 ° C higher than the average glass transition temperature of the polymer, preferably from the average glass transition temperature to a temperature that is approximately 5 ° C higher than the average glass transition temperature of the polymer.

The heating time varies depending on the amount of microcapsules to be treated and the like. Generally it is in the range of 12 to 168 hours, preferably 24 to 120 hours, preferably 48 to 96 hours from the time the temperature of the microcapsules alone reaches the desired value.

The heating of the microcapsules is not limited to any particular method. Any method in which the microcapsule sample is heated uniformly may be used.

Examples of methods for heating and drying the microcapsules include a constant temperature bath, a fluid bath, a moving bath or an oven, microwave heating, etc. Among others, a method of heating and drying the microcapsules in a constant temperature bath is preferred.

ii) I / O / V method

The compound having AII antagonist activity is dissolved in water and, if necessary, a carrier thereof, such as a polyvalent metal compound, is added to the resulting solution. * ····

9 9 9 9 99 · · · J · · 9 9 9 9 · · ···

·. (E.g. zinc acetate), a basic amino acid (e.g. arginine, histidine, lysine), gelatin, agar, polyvinyl alcohol and the like to form an internal aqueous phase.

The concentration of drug in the internal aqueous phase is generally selected in the range of 0.1 to 80 wt. %, preferably 1 to 70 wt. %, preferably 2 to 60 wt. %.

As pH regulators to maintain drug stability and solubility, carbonic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and their salts, etc. can be added to the internal aqueous phase. albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyols such as polyethylene glycol, etc., etc., for example, conventional paraoxybenzoic acid esters (e.g. methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal may be added as preservatives. etc.

The internal aqueous phase thus obtained is added to a solution of the biodegradable polymer in an organic solvent (oil phase) optionally containing a polyvalent metal compound, and the resulting mixture is emulsified by known methods using a homogenizer, an ultrasonic device or the like to form an I / O emulsion.

Examples of this organic solvent include halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (e.g. diethyl ether, isopropyl ether, etc.), fatty acid esters (e.g. ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (e.g. benzene , toluene, xylene and the like), alcohols (e.g. ethanol, methanol, etc.), acetonitrile, etc. These solvents may be used in a mixture in a suitable ratio. Among others, halogenated hydrocarbons, especially dichloromethane, are preferred.

The concentration of the biodegradable polymer in solution in the organic solvent varies depending on the molecular weight of the biodegradable polymer and the type of organic solvent. For example, when dichloromethane is used as the organic solvent, the concentration of the biodegradable polymer in solution in the organic solvent is generally chosen in the range of 0.5 to 70 wt. %, preferably 1 to 60 wt. %, preferably 2 to 50 wt. %.

The thus obtained I / O emulsion, comprising a compound having AII antagonist activity, a biodegradable polymer and, if necessary, a polyvalent metal compound, is added to the aqueous phase (outer aqueous phase) to form the V (inner aqueous phase) / O (oily) emulsion. phase) / V (external aqueous phase) from which the solvent in the oil phase is evaporated to form microcapsules. The volume of the external aqueous phase is usually selected within the range of one to one. · Ten thousand times the volume of the oil phase, preferably five times to five thousand times, preferably ten times to two thousand times.

Examples of emulsifiers and osmotic pressure regulators that can be added to said external aqueous phase as well as the preparation methods after addition of these additives are similar to those described in section I) i).

II) Phase separation

To prepare the microcapsules by phase separation, a coacervating agent is added sequentially with stirring to said organic solution of the biodegradable polymer containing the compound having AII antagonist activity and, if necessary, the polyvalent metal compound as described in section I) (water drying), the microcapsules precipitated and solidified. The volume of the coacervating agent is generally selected in the range of from one hundredth to a thousand times the volume of the oil phase, preferably from five hundredths to five hundred times, preferably from one tenth to two hundred times.

Any coacervating agent is acceptable, as long as it is a polymer, a mineral oil, a vegetable oil, etc., which is miscible with an organic solvent and does not dissolve either of the compounds having AII antagonist activity or the biodegradable polymer. For example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane etc. are used. They may also be used in combination.

The microcapsules so obtained are separated, washed repeatedly with heptane and the like to remove the coacervating agent and other substances besides the compound having antagonistic activity against AII and the biodegradable polymer, and then dried under reduced pressure. Alternatively, the microcapsules are washed by methods similar to those described in section I) (i) (drying from water), subjected to lyophilization, and then heated and dried.

III) Spray drying

In preparing the microcapsules in this manner, the above-mentioned organic solution of the biodegradable polymer containing the compound having AII antagonistic activity and optionally containing the polyvalent metal compound as described in section I) (water drying) is sprayed into the spray chamber of the spray dryer. the formed small droplets vaporized the organic solvent within a very short time, forming microcapsules. Examples • ΦΦΦ Φ «« 4 Φ · * ·

Φ φ ΦΦΦΦ φ φ φ φ Φ Φ · Φ Φ · · · · * · “** ........

The nozzles include a dual-fluid nozzle, a pressure nozzle, a rotating disk nozzle, and the like. Then, if necessary, the microcapsules are washed by methods similar to those described above in section I) (water drying), subjected to lyophilization, and then heat and dry.

In addition to processing into the above-described microcapsule dosage form, the organic solution of the biodegradable polymer containing the compound having AII antagonistic activity and, if necessary, the polyvalent metal compound as described in section I) (water drying) may be subjected to evaporation of the organic solvent and water under controlled vacuum by means of a rotary evaporator, and the resulting residue is crushed by a jet mill or the like to form a fine powder.

The fine powders thus obtained can be washed by methods similar to those described above in section I) (drying from water), subjected to lyophilization, and then heated and dried.

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

The sustained release composition of the present invention can be used for the manufacture of various preparations, either as such or as a raw material, and administered as a iiinusinustile injection or implant, subcutaneously, into organs, etc., as mucosal preparations into the nasal cavity, rectum, uterus, as oral preparations [e.g. capsules (e.g. solid capsules, soft capsules, etc.), solid preparations such as granules, powders, etc., liquid preparations such as syrups, emulsions, suspensions, etc., etc., etc. The sustained release formulation according to the present invention can also be administered by means of a needleless injector.

For example, if the sustained release composition of the present invention is to be injected, it is dispersed together with a dispersing agent (for example a surfactant such as Tween 80, HCO-60 et al.), A polysaccharide such as sodium hyaluronate, carboxymethylcellulose, sodium alginate and the like. etc.), a preservative (e.g. methylparaben, propylparaben, etc.), an isotonizing agent (e.g. sodium chloride, mannitol, sorbitol, glucose, proline, etc.) etc. to form an aqueous suspension, or dispersed with a vegetable oil such as sesame oil, corn oil and the like to form an oily suspension, said suspensions being actually used as sustained release injections.

When the sustained release formulation of the present invention is used as a suspension, the particle size is selected to the extent that it meets the requirements of dispersibility and patency.

»Fr frfr fr · · 1k ··· ··· · 1k ·« «· ♦ ♦ · ··· · c · frfr ·· needle. The average particle diameter is, for example, in the range of 0.1 to 300 µm, preferably 0.5 to 150 µm, preferably 1 to 100 µm.

For the preparation of a sterile preparation from the extended release formulation of the present invention, a method of sterilizing all the manufacturing steps, a method of sterilizing by means of γ-rays and a method of adding a preservative is used, without being limited to any particular method.

Due to its low toxicity, the sustained release formulation of the present invention can be used as a safe drug for mammals (e.g., human, bovine, pig, dog, cat, mouse, rabbit, etc.).

The dose of the sustained release composition of the present invention is in the range of an effective amount of an AII antagonist compound and depends on the type, content and dosage form of the AII antagonist compound as active ingredient, the length of time the AII antagonist compound is administered. for example, the dose for the administration of the active ingredient, i.e. the compound having AII antagonistic activity, is preferably selected in the range of 0.01 to 10 mg per kilogram of body weight of the adult, preferably 0.05 to 5 mg. mg per kilogram body weight of an adult if the extended release period is 1 month. The dosage for administration of the sustained release composition of the present invention is preferably selected in the range of 0.05 to 50 mg per kilogram of body weight of an adult, preferably 0.1 to 30 mg per kilogram of body weight of an adult.

The number of administrations (applications) may suitably be selected from one in several weeks, one in a month, up to one in several months (eg 3 months, 4 months, 6 months, etc.), etc., depending on the type, content and dosage form. the active ingredient, the time of release of the compound having AII antagonist activity, the disease being treated, the species of animal being treated, etc.

A compound having AII antagonist activity is highly safe, so increasing the blood concentration of this compound just after sustained-release injection does not cause excessive blood pressure reduction. Thus, the sustained release composition of the present invention can be used in the diseases listed below and is able to maintain a constant concentration of the drug in the blood during the day and night. The dose and number of applications may be reduced compared to the administration of conventional oral preparations. In addition, the change in blood concentration of the drug is not significant and the patient's condition does not change upon discontinuation of the drug, etc. Therefore, it can be expected that the administration of the sustained release formulation will elucidate the therapeutic effect of the drug.

995 · 99 «

e 99 99 99 • ···· 9 9 9 9 • 9 9 9 9999 9999 9 999 9 9 99 99

Examples of diseases include circulatory diseases and the like, such as hypertension, heart disease (hypercardia, cardiac insufficiency, myocardial infarction, etc.), nephritis, stroke, etc., which are caused by vasoconstriction induced by angiotensin II receptors.

The sustained release composition of the present invention is useful for the prevention or treatment of hypertension, hypercardia, cardiac insufficiency, myocardial infarction, stroke, ischemic disorders of peripheral circulation, myocardial ischemia, venous insufficiency, progressive cardiac insufficiency after myocardial infarction, diabetic complications, diabetic retinopathia diabetic nephropathy, nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, vascular hypertrophy or obstruction after surgery (e.g., percutaneous transluminal coronary angioplasty, etc.), vascular reobstruction after bypass, hyperaldosteronism, glomerulosclerosis, glomerulosclerosis, glomerulosclerosis, glomerulosclerosis aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, central nervous system diseases, Alzheimer's disease, disorders memory, depression, amnesia, senile dementia, sensory disorders, multiple system organ failure, endothelial dysfunction disease or scleroderma, as well as preventing or ameliorating anxiety neuroses, catatonia, nausea or dyspeptic symptoms.

Regarding the method of treating patients, it is contemplated that for some time, the patient is first administered conventional oral preparations containing a compound having angiotensin II antagonist activity to verify the patient's response before the patient is administered the sustained release formulation according to the invention. of the present invention. Compounds with angiotensin II antagonist activity to be administered orally or as part of a sustained release formulation may be the same or different. In addition, other antihypertensive agents (such as a calcium antagonist, diuretics, a β-blocker, etc.) may be pre-administered to the patient other than the agent having angiotensin II antagonist activity to verify the patient's response prior to administration of the sustained release formulation. In addition, the sustained release composition may be used in combination with a diuretic (oral composition), which is usually used in combination with an angiotensin II antagonist.

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DETAILED DESCRIPTION OF THE INVENTION

The present invention is illustrated in detail by the following working examples and experimental examples, which are not intended to be limiting.

Working example 1

In a mixed solvent consisting of 3.5 ml of dichloromethane and 1.5 ml of methanol, 0.25 g of 2-ethoxy-1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4) acid was dissolved. -oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid (hereinafter referred to as Compound A) and 2.25 g of a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid molar ratio of 75/25, weight average molar mass 10,700 g / mol, number average molar mass from end group determination 3770 g / mol, manufactured by Wako Pure Chemical) and this solution was injected into 500 ml of 0.1 wt.% polyvinyl alcohol solution. % pre-equilibrated to 18 ° C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred at room temperature for 3 hours to allow dichloromethane and methanol to flow out and to solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water, the resulting dispersion was lyophilized to form powdered microcapsules.

The yield of microcapsules was 69%, the capture rate of compound A in the microcapsules was 92% and the content of compound A in the microcapsules was 9.2%.

Working Example 2

0.25 g of the disodium salt of Compound A was dissolved in 0.4 ml of distilled water, and the resulting solution was mixed with a solution of 2.25 g of a lactic acid-glycolic acid copolymer (same as in Working Example 1) in 4 ml of dichloromethane. The mixture was stirred with a homogenizer to form an I / O emulsion. This I / O emulsion was injected into 500 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 18 ° C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an I / O / V emulsion. This I / O / V emulsion was stirred at room temperature for 3 hours to flow out of dichloromethane and solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water, the resulting dispersion was lyophilized to form powdered microcapsules.

The yield of microcapsules was 50%, the capture rate of Compound A in the microcapsules was 37% and the content of Compound A in the microcapsules was 3.7%.

Working example 3

In a mixture of 3.5 ml of dichloromethane and 2.5 ml of methanol, 0.4 g of compound A and 1.6 g of ethyl ester of a lactic acid polymer (a biodegradable polymer having a carboxyl end group esterified with ethyl having a weight average molecular weight of 10,200) were dissolved. g / mol and the number average molar mass is 5680 g / mol, manufactured by Wako Pure Chemical), and this solution was injected into 800 ml of a 0.1 wt.% polyvinyl alcohol solution. % containing 5% mannitol and pre-equilibrated to 18 ° C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred at room temperature for 3 hours to allow dichloromethane and methanol to flow out and to solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water, the resulting dispersion was lyophilized to form powdered microcapsules.

The yield of microcapsules was 83%, the capture rate of Compound A in the microcapsules was 86% and the content of Compound A in the microcapsules was 17.1%.

Experimental Example 1

Approximately 35 mg of the microcapsules obtained in Working Example 3 were dispersed in 0.3 ml of solvent (distilled water in which 0.25 mg of carboxymethylcellulose, 0.5 mg of polysorbate 80 and 25 mg of mannitol were dissolved) and the resulting mixture was subcutaneously applied to the spine. seven week old male SD rats using a 22G needle. Blood was drawn from the abdominal aorta of these rats at regular intervals after administration, and rats were sacrificed to isolate the microcapsules remaining at the injection site.

• «·« «

The determined amounts of Compound A in these microcapsules are shown in Table 1. In addition, the amounts of Compound A in the blood were determined, and the results are shown in Table 2.

Table 1

1 day 1 week 2 weeks 3 weeks 4 weeks Working example 3 66% 42% 27% 17% 15%

Table 2

1 day 1 week 2 weeks 3 weeks 4 weeks Working example 3 4.4 0.6 0.3 0.2 0.1

(unit: pg / ml)

Working example 4

To a solution of 2.4 g of a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid ratio 75/25, weight average molar mass 14,000 g / mol, number average molar mass 4200 g / mol, number average molar mass from end-point determination of 4090 g / mol, manufactured by Wako Pure Chemical) in 4.5 ml of dichloromethane and 1 ml of ethanol was added 0.6 g of 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl] -4-yl] methyl] benzimidazole-7-carboxylic acid (hereafter referred to as compound B) and 0.09 g of zinc oxide (particle size 0.02 µm) and this mixture was shaken and stirred at room temperature for 12 hours to give slightly turbid suspensions. This suspension was injected into 400 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred for 3 hours at room temperature to flow out of dichloromethane and ethanol and solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was lyophilized to form powdered microcapsules.

The capture rate of Compound B in the microcapsules was 97% and the content of Compound B in the microcapsules was 18.8%.

• · »<9 <

• · · *

The amount of zinc oxide was changed to 0.057 g and the microcapsules were prepared in a manner similar to that described in Working Example 1.

The capture rate of Compound B in the microcapsules was 97% and the content of Compound B in the microcapsules was 19.0%.

Working example 5

Working example 6

The amount of compound B, zinc oxide, respectively. the lactic acid-glycolic acid copolymer was changed to 0.9 g, 2.1 g, respectively. 0.12 g and microcapsules were prepared in a manner similar to that described in Working Example 1.

The capture rate 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 prepared in a manner similar to that described in Working Example 3.

The capture rate 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 4.2 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid molar ratio of 75/25, molar mass average weight of 14,000 g / mol, molar mass number average of 4200 g / mol, molar mass number from endpoint determination of 4090 g / mol, manufactured by Wako Pure Chemical) in 9 ml of dichloromethane and 1.5 ml of ethanol, 1.8 g of compound B and 0.3 g of zinc oxide (particle size 0.02 µm) were added. The resulting mixture was shaken and stirred at room temperature for 12 hours to give a slightly cloudy suspension. This suspension was injected into 800 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O / V emulsion. The resulting emulsion • · * · · 4

τ)

The O / V was stirred for 3 hours at room temperature so that dichloromethane and ethanol flowed out and solidified the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was subjected to freeze-drying to form powder microcapsules.

The capture rate of Compound B in the microcapsules was 94% and the content of Compound B in the microcapsules was 26.8%.

Working example 9

To a solution of 0.7 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid 75/25 molar ratio, molar mass average 14000 g / mol, number molar mass 4200 g / mol, number average molar mass from end-point determination of 4090 g / mol, manufactured by Wako Pure Chemical) in 1.5 ml of dichloromethane and 1 ml of methanol were added 0.3 g of compound A and 0.05 g of zinc oxide (particle size 0.02 µm). The resulting mixture was shaken and stirred at room temperature for 12 hours to give a slightly cloudy suspension. This suspension was injected into 300 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 6500 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred at room temperature for 3 hours to allow dichloromethane and methanol to flow out and to solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was lyophilized to form powdered microcapsules.

The capture rate of Compound A in the microcapsules was 91% and the content of Compound A in the microcapsules was 25.9%.

Working example 10

To a solution of 1.8 g of a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid molar ratio of 75/25, weight average molar mass of 14,000 g / mol), Number average molar mass 4200 g / mol, number average molar mass from end group determination 4090 g / mol, manufactured by Wako Pure Chemical) in 5 ml 1 g of compound B and 0.18 g of zinc oxide (particle size 0.02 µm) were added to dichloromethane. The resulting mixture was emulsified in a small homogenizer for 60 seconds to form a suspension. This suspension was injected into 300 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 6500 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred at room temperature for 3 hours to allow the dichloromethane to escape and solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was lyophilized to form powdered microcapsules.

The capture rate of compound B in the microcapsules was 96% and the content of compound B in the microcapsules was 32.0%.

Working example 11

With the change that 0.8 ml of ethanol was added to the dichloromethane and that a slightly cloudy suspension was obtained by shaking and stirring for 12 hours at room temperature, the microcapsules were prepared in a manner similar to that described in Working Example 7.

The capture rate of compound B in the microcapsules was 95% and the content of compound B in the microcapsules was 32.0%.

Working example 12

0.9 g of 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl]] was dissolved in a stirred mixture of 4.5 ml of dichloromethane and 0.7 ml of ethanol. methyl] benzimidazole-7-carboxylate (hereinafter referred to as Compound C) and 2.1 g of a lactic acid-glycolic acid copolymer (lactic acid / glycolic acid molar ratio of 75/25, molar mass average weight of 14,000 g / mol, numerical) molar mass average 4200 g / mol, number average molar mass from end group determination 4090 g / mol, manufactured by Wako Pure Chemical), and 0.15 g was added to the resulting solution. Zinc oxide (particle size 0.02 µm). The mixture was shaken and stirred at room temperature for 12 hours to give a slightly cloudy suspension. This suspension was injected into 400 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 7500 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred for 3 hours at room temperature to flow out of dichloromethane and ethanol and solidify the oil phase, which was then separated by centrifugation at 2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was lyophilized to form powdered microcapsules.

The capture rate of Compound C in the microcapsules was 96% and the content of Compound C in the microcapsules was 27.4%.

Working example 13

With the change that no zinc oxide was added, the microcapsules were prepared in a manner similar to that described in Working Example 12.

The capture rate of Compound C in the microcapsules was 98% and the content of Compound C in the microcapsules was 30.0%.

Working example 14

1.2 g of compound C and 1.8 g of a lactic acid-glycolic acid copolymer were dissolved in 5 ml of dichloromethane (lactic acid / glycolic acid molar ratio of 75/25, molar mass average weight of 14,000 g / mol, molar mass number average of 4200). g / mol, number average molar mass from end group determination 4090 g / mol, manufactured by Wako Pure Chemical). To this solution was added 0.18 g of zinc oxide (particle size 0.02 µm). The mixture was shaken and stirred at room temperature for 1 hour to give a slightly cloudy suspension. This suspension was injected into 400 ml of 0.1 wt.% Polyvinyl alcohol solution. % pre-equilibrated to 15 ° C, and this mixture was then stirred in a turbine homomixer at 8,000 rpm to form an O / V emulsion. The resulting O / V emulsion was stirred at room temperature for 3 hours to release dichloromethane and ethanol and solidify the oily phase, which was then separated by centrifugation at <RTIgt;% </RTI>. · · · · · ·

2000 rpm. The precipitate was re-dispersed in distilled water, centrifuged and washed to remove free drug, etc. After the isolated microcapsules were redispersed in a small amount of distilled water in which mannitol was dissolved, the resulting dispersion was lyophilized to form powdered microcapsules.

The capture rate of Compound C in the microcapsules was 95% and the content of Compound C in the microcapsules was 35.9%.

Working example 15

With the change that no zinc oxide was added, the microcapsules were prepared in a manner similar to that described in Working Example 4.

The capture rate of Compound B in the microcapsules was 99% and the content of Compound B in the microcapsules was 19.8%.

Working Example 16

With the change that no zinc oxide was added, microcapsules were prepared in a manner similar to that described in Working Example 9.

The capture rate of Compound A in the microcapsules was 95% and the content of Compound A in the microcapsules was 28.4%.

Experimental Example 2 mg of the microcapsules obtained in Working Examples 4-14 were dispersed in 0.2 ml of a dispersant (1 ml of distilled water in which 5 mg of carboxymethylcellulose sodium, 1 mg of polysorbate 80 and 50 mg of mannitol were dissolved), and this mixture was injected subcutaneously into the neck of seven-week-old male SD rats using 22G needles. At regular intervals after administration, rats were gradually sacrificed by abdominal bleeding and the microcapsules remaining at the injection site were isolated.

The amount of compound having AII antagonist activity was determined in the microcapsules and the results are shown in Table 3. Table 4 below shows the blood concentrations of Compound B when microcapsules of Working Examples 4, 6 and 8 were administered.

··························

Table 3

Mean percentage of compound having AII antagonist activity remaining after subcutaneous administration of microcapsules (n = 3 to 5)

Working example C. 1 day 1 week 2 weeks 3 weeks 4 weeks 4 91 62 36 11 3 5 85 60 18 not performed not performed 6 88 63 33 11 3 7 94 78 55 43 26 8 86 62 38 18 7 9 87 58 21 1 not performed 10 90 79 43 17 3 11 96 82 49 27 Mar: 12 12 95 64 24 7 not performed 13 76 29 not performed not performed not performed 14 94 ⁶⁸ 16 2 not performed

Table 4

Mean concentration (ng / ml) of Compound B in the blood following subcutaneous administration of microcapsules (n = 5)

Working example C. 1 day 1 week 2 weeks 3 weeks 4 weeks 4 125 92 126 90 32 6 335 247 351 169 95 8 ¹³⁴ 158 166 168 101

Experimental Example 3

2.5 mg of the microcapsules obtained in Working Example 8 were dispersed in 0.2 ml of a dispersant (1 ml of distilled water in which 5 mg of sodium carboxymethylcellulose, 1 mg of polysorbate 80 and 50 mg of mannitol were dissolved) and this mixture was subcutaneously using 22G needles - applied to the neck of 28-week-old male 12008SHR rats implanted with a blood pressure transmitter for telemetry. Blood pressure was monitored after this application. The same preparation was administered subcutaneously in the nape of 29 weeks old male 12008SHR rats.

After application, blood was drawn from the tail vein at regular intervals. Table 5 shows the blood concentration of Compound B and the blood pressure lowering effect of Compound B.

Table 5

Mean blood concentration of Compound B and its effect on lowering blood pressure after subcutaneous administration of microcapsules (n = 3)

1 day 1 week 2 weeks 3 weeks 4 weeks Concentration (ng / ml) 41 27 Mar: 27 Mar: 55 45 Change in blood pressure (mm Hg) -21.4 -14.4 -17.4 -22.7 -20.9

Industrial applicability

The sustained release composition of the present invention containing high amounts of a compound having AII antagonist activity can influence the rate of drug release. Thus, the composition has AII antagonistic activity while maintaining circadian rhythm of blood pressure over the long term.

In addition, the sustained release formulation of the present invention is capable of maintaining a constant concentration of the drug in the blood for one day and night. Thus, the change in blood concentration of the drug is not significant compared to the situation with conventional oral agents and the patient's condition cannot change due to a change in time of administration, discontinuation of drug intake, deliberate omission of drug intake in patients suffering from subjective symptoms, etc. the effect of the drug on circulatory diseases such as hypertension, heart disease (hypercardia, cardiac insufficiency, myocardial infarction, etc.), kidney inflammation, stroke and the like will be clarified by the use of the sustained release composition of the present invention.

Claims (9)

PATENT CLAIMS A sustained release composition comprising a compound having angiotensin II antagonist activity (excluding 2-ethyl-5,7-dimethyl-3 - [[2 '- (1H-tetrazol-5-yl) biphenyl) 4-yl] methyl] imidazo [4,5-b] pyridine and its salts), a prodrug thereof, or a salt thereof, and a biodegradable polymer. The sustained release composition of claim 1, wherein the compound having angiotensin antagonist activity is a non-peptide compound. 3. The sustained release composition of claim 1, wherein the compound having angiotensin antagonist activity is a compound bearing an oxygen atom in its molecule. The sustained release composition of claim 1, wherein the compound having angiotensin II antagonist activity is an ether bond or carbonyl group containing compound. The sustained release composition of claim 1, wherein the compound having angiotensin II antagonist activity is a compound of the formula wherein R ¹ is a group capable of forming an anion or a group capable of converting into it, X is that phenylene and the phenyl group is bound to each other either directly or through a spacer whose chain is two atoms or less, n is an integer equal to 1 or 2, ring A is a benzene ring having - besides R - an optional substitution, R is a group capable of forming an anion or a group capable of converting therein and R ³ is an optionally substituted hydrocarbon radical which may be attached via heteroatoms, or a salt thereof. Frfr frfr fr fr fr fr fr fr 6. The sustained release composition of claim 1, wherein the compound having angiotensin II antagonist activity is Losartan, Eprosartan, Eandesartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan or Tasosartan. The sustained release composition of claim 1, wherein the compound having angiotensin II antagonist activity is 2-ethoxy-1 - [[2 '(1H-tetrazol-5-yl) biphenyl-4-yl] acid. methyl] benzimidazole-7-carboxylic acid or a salt thereof. The sustained release composition of claim 1, wherein the compound having angiotensin II antagonist activity is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl)]. ) biphenyl-4H. yl] methyl] benzimidazole-7-carboxylate or salts thereof. The sustained release composition of claim 1, wherein the compound having angiotensin antagonist activity is 2-ethoxy-1 - [[2 '(4,5-dihydro-5-oxo-1,2), 4-Oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof. The sustained release composition of claim 1, wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. The sustained release composition of claim 10, wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid copolymer. The sustained release composition of claim 11, wherein the lactic acid to glycolic acid molar ratio is 100/0 to 40/60. The sustained release composition of claim 10, wherein the weight average molecular weight of the polymer is 3000 to 50,000 g / mol. The sustained release composition of claim 1, wherein the composition is for injection. 15. The sustained release composition of claim 1, further comprising a polyvalent metal. The sustained release composition of claim 15, wherein the polyvalent metal is zinc 17. A sustained release composition comprising a compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof, a biodegradable polymer, and a polyvalent metal. • lit ** • * · lit lit lit lit lit 9 9 9 9 9 · · · 9 · · 9 4 9 4 99 99 99 99 99 99 18. The method of claim 1 wherein the solvent is removed from the solution containing the compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof, and a biodegradable polymer. 19. A method of preparing a sustained release formulation according to claim 17, comprising removing the solvent from a solution comprising a compound having angiotensin II antagonist activity, a prodrug thereof, or a salt thereof, a biodegradable polymer, and a polyvalent metal. The method of claim 19, wherein the polyvalent metal is zinc. 99 99 · * * · 9 9 9 9 9 9 I 99 99 9 9 9 9 99 99 99 9 9 98 9 9 9 «9 99 99 99 99 9999 · * 9 9 «• · · 4 99 99 21. A pharmaceutical composition comprising the sustained release composition of claim 1. 22. A composition according to claim 21, for the prevention or treatment of circulatory diseases. 23. A composition according to claim 21 for the prevention or treatment of hypertension. 24. A composition according to claim 21 for the prevention or treatment of hypercardia, cardiac insufficiency, myocardial infarction, stroke, peripheral ischemic disorders, myocardial ischemia, venous insufficiency, progressive cardiac insufficiency after myocardial infarction. , diabetic complications, diabetic retinopathy, diabetic nephropathy, glomerulonephritis, arteriosclerosis, angiohypertrophy, vascular hypertrophy or obstruction after intervention, vascular re-obstruction after bypass surgery, hyperaldosteronism, glomerulosclerosis, renal insufficiency, hyperlipse, glaucoma, high glaucoma, high glaucoma, high glaucoma, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, central nervous system diseases, Alzheimer's disease, impaired memory, depression, amnesia, senile dementia, sensory disorders, multiple failure of systemic organs, diseases of endothelial dysfunction or scleroderma, or for the prevention or amelioration of anxiety neuroses, catatonia, indisposition or dyspeptic symptoms, nephritis.