CZ20003164A3 - Sustained-release preparation for angiotensin II antagonists, its preparation and use - Google Patents

Abstract

The present invention relates to 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]imidazol[4,5-b]pyridine and its salts), its precursor or salts thereof, a biodegradable polymer and optionally also a polyvalent metal.

Description

Technical field

The present invention relates to a sustained-release composition for a compound having angiotensin II antagonistic activity, a method for its production, its use as a medicine, etc.

State of the art

The renin-angiotensin system, together with the aldosterone system, is part of the homeostasis controlling systemic blood pressure, body fluid volume, electrolyte balance, etc. The relationship between renin-angiotensin and hypertension has been clarified based on the fact that angiotensin II, which has a potent vasoconstrictor effect, increases blood pressure via angiotensin II receptors on the cell membrane. An angiotensin II antagonist is therefore used for the treatment of hypertension caused by angiotensin. Heretofore, drugs having antagonistic activity against angiotensin II have been administered orally. However, these drugs have been applied for symptomatic therapy requiring repeated administration over a long period of time. Due to the necessity of continuous administration, co-dosing with other drugs in oral administration, etc., the burden to which a patient receiving this type of drug orally is exposed cannot be ignored. In addition, there is a possibility that the patient's condition will change when the intake of this type of drug is discontinued. Therefore, from the point of view of safe and reliable treatment, oral administration of drugs having angiotensin II antagonistic activity may not necessarily be satisfactory.

There is an article (Pharmaceutical Research, 14, 887-891 (1997)) in which 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 angiotensin II antagonistic activity is described, said formulation comprising high molecular weight polylactide (weight average molar mass M _w = 82,000 g/mol) and polyethylene glycol 400 distearate. It is also stated therein that the initial burst release from a sustained release formulation containing about 10% of the drug is about 20%.

····

In the Japanese publication of the translation of International Patent Application No. 504017/1998, a composition is described, characterized in that a physiologically active protein together with a metal cation component is dispersed in a biocompatible polymer.

The essence of the invention

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

The inventors have carefully conducted extensive studies to solve the above problems, and finally found that a sustained-release composition containing a compound with angiotensin Π antagonistic activity can contain said compound in a large amount, that the release rate of said compound can be controlled by adding a polyvalent metal compound, and that by administering said composition to a spontaneously hypertensive rat (SHR), the concentration of the drug in the rat's blood can be maintained, while the blood pressure of the rat can be reduced while maintaining the circadian rhythm of blood pressure for a long time. The inventors have conducted further research based on this finding and have come to the present invention.

More specifically, the present invention relates to

1) a sustained-release preparation comprising a compound having angiotensin II antagonistic activity (excluding 2-ethyl-5,7-dimethyl-3-[[2’-(1Htetrazol-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 according to item 1), wherein the compound having angiotensin II antagonistic activity is a non-peptide compound,

3) a sustained-release preparation according to point 1), wherein the compound having angiotensin II antagonistic activity is a compound having an oxygen atom in the molecule,

4) the sustained-release preparation according to item 1), wherein the compound having angiotensin II antagonistic activity is a compound having an ether bond or a carboxyl group,

5) a sustained-release preparation according to point 1), wherein the compound having angiotensin II antagonistic activity is a compound of general formula (I):

9 99 99 ·

• · · ···· · · · · · · · · · · · · · · · ♦ 4 4

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

6) the sustained-release preparation according to point 1), wherein the compound having angiotensin II antagonist activity is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan or Tasosartan,

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

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

9) a sustained-release preparation according to point 1), wherein the compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or its salts,

10) a sustained-release composition according to point 1), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer,

11) a sustained-release composition according to item 10), wherein the α-hydroxycarboxylic acid polymer is a copolymer of lactic acid and glycolic acid, • · · · • fc ♦ ·

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

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

14) a prolonged-release preparation according to point 1), intended for injection,

15) a sustained-release preparation according to point 1), which further contains a polyvalent metal,

16) a sustained-release preparation according to point 15), where the polyvalent metal is zinc,

17) a sustained-release preparation comprising a compound having angiotensin II antagonistic activity, a precursor thereof or a salt thereof, a biodegradable polymer and a polyvalent metal,

18) a method for producing a sustained-release preparation according to item 1), which consists in removing the solvent from a solution containing a compound having angiotensin II antagonistic activity, its precursor or salt thereof, and a biodegradable polymer,

19) a method for producing a sustained-release preparation according to item 17), which consists in removing the solvent from a solution containing a compound having angiotensin II antagonistic activity, its precursor or salt thereof, a biodegradable polymer and a polyvalent metal,

20) the method according to point 19), where the polyvalent metal is zinc,

21) a pharmaceutical preparation containing a sustained-release preparation according to point 1),

22) a product according to point 21), intended for the prevention or treatment of circulatory disease,

23) a preparation according to point 21), intended for the prevention or treatment of hypertension,

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

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

According to this embodiment, the angiotensin II antagonist activity consists in competitively or non-competitively inhibiting the binding of angiotensin II to angiotensin II receptors on cell membranes so as to reduce the potent vasoconstrictive action or the proliferative action of smooth muscle of veins induced by angiotensin II and thus alleviate the symptom of hypertension.

The compound having angiotensin II antagonistic activity to be used in the present invention may be either a peptide compound or a non-peptide compound. In view of the advantage of long-term action, a non-peptide compound having angiotensin II antagonistic activity is preferred. As the compound having angiotensin II antagonistic activity, a compound having an oxygen atom in the molecule is preferably used, more preferably a compound having an ether bond or a carbonyl group (this carbonyl group can form a hydroxyl group by resonance), even more preferably a compound having an ether bond or a keto group, and most preferably a compound being an ether derivative.

Any non-peptide compound having angiotensin II antagonist activity can be used for the present invention. Examples of said compounds include imidazole derivatives disclosed in Japanese Unexamined Patent Application No. 71073/1981, Japanese Unexamined Patent Application No. 71074/1981, Japanese Unexamined Patent Application No. 98270/1982, Japanese Unexamined Patent Application No. 157768/1983, USP 4,355,040, USP 4,340,598, etc., 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 described in USP 5,183,899, in EP-323841, EP-409332, Japanese Unexamined Patent Application No. 287071/1989, etc., benzimidazole derivatives described in USP 4,880,804, EP-0392317, EP-0399732, EP-0400835, EP-425921, EP-459136, Japanese Unexamined 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., imidazole derivatives with condensed rings described in EP-434038 etc., pyrimidinedione derivatives described in EP-442473 etc., thienopyridone derivatives described in EP-443568 etc., 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 a work published in Journal of Medicinal Chemistry, Vol. 39, No. 3, pp. 625-656 (1996). As the non-peptide compound having angiotensin II antagonistic activity, in addition to those mentioned in the aforementioned references, any compound may be used as long as it has angiotensin II antagonistic activity. Preferably, among others, Losartan (DuP753), Eprosartan (SK&F108566), Candesartan cilexetil (TCV-116), Valsartan (CGP-48933), Telmisartan (BIBR277), Irbesartan (SR47436), Tasosartan (ANA-756) and their active metabolites (Candesartan etc.) are used.

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

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

The group R ¹ in formula (I) capable of forming an anion (a group having a hydrogen atom that can be split off in the form of a proton) may be, for example, 1) a carboxyl group, 2) a tetrazolyl group, 3) a group derived from trifluoromethanesulfonic acid amide (-NHSO2CF3), 4) a phosphonic group, 5) a sulfo group, 6) an optionally substituted residue of a five- to seven-membered (preferably five- to six-membered) monocyclic heterocyclic ring containing one or more N, S, O, etc. atoms.

• · · · « · • · and · ·

• ·

As an example of the above-mentioned "optionally substituted residue of a five- to seven-membered (preferably five- to six-membered) monocyclic heterocyclic ring containing one or more N, S, O atoms" can be mentioned:

I ···· ·· « 9 • ·

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

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

N<>=Z

Then the specific options are

=Z

HN or

IN

Z ^X N • 4 4 · * · • · • · 4 4 ·4 44

4 · · 4 4 9 9 9

9 9 9 99 9 9 9 9

4 9 9 9 9 9 9 9 9 9 9 9 9

4 4 4 4 4 4 · 4 · · 4

4 4 4 4 4 4 4 44

Other examples of the substituent R ¹ bonded via a nitrogen atom include:

r=\

In the preceding formulas, the symbol g represents -CH2-, -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 (for example S, S(O), S(O)2 etc.), preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group, and m is an integer of 0, 1 or 2.

Suitable examples of the heterocyclic ring residue designated as R ¹ are heterocyclic ring residues having an -NH- or -OH group as a proton donor and simultaneously a carbonyl group, a thiocarbonyl group, a sulfinyl group, etc. as a proton acceptor, such as an oxadiazolone ring, an oxadiazolothione ring, or a thiadiazolone ring, etc.

The heterocyclic ring residue designated by R ¹ may form a fused ring system by connecting substituents on the heterocyclic ring, preferably a five- to six-membered ring residue, more preferably a five-membered ring residue.

Suitable examples of the heterocyclic ring residue designated as R ¹ include a group of the following general formula:

φφφφ φφ φφ · · φφ φφ

Φ· φ φ φφ φ · · φ φ • ΦΦ φφφφ φφφφ

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

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

where Z is O and Z is also O, they are:

These three tautomeric isomers a’, b’ and c’ exist and the group formula

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 to C ₄ ) alkyl group, an acyl group (e.g., lower (C 2 to C 5 ) alkanoyl, benzoyl, etc.), etc.

9*99 99 99

9 9 9

9 9 9 • 9 9 9 9

9 9 9 9

99 99

99 99 • 9 · 9 9

9 9 9 9

9 9 9 9 9 • 9 9 9 9

9« 9999

Examples of optionally substituted lower (C1 to C4) alkyl groups include 1) a lower (C1 to C4) alkyl group optionally substituted with one to three phenyl groups which may bear a halogen atom, a nitro group, a lower (C1 to C4) alkyl group, a lower (C1 to C4) alkoxy group, etc. (e.g., methyl, triphenylmethyl, /?-methoxybenzyl, p-nitrobenzyl, etc.),

2) a lower (Ci to _C4 ) alkoxy-lower (Ci to C4) alkyl group (for example methoxymethyl, ethoxymethyl, etc.), 3) a group of the formula -CH( ^R4 ) ^-OCOR5 , where ^R4 is a) hydrogen, b) a linear or branched lower (Ci to C4) alkyl group (for example methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, /-butyl, «-pentyl, isopentyl, neopentyl, etc.), c) a linear or branched lower (C2 to C6) alkenyl group or d) a C3 to C6 cycloalkyl group (for example cyclopentyl, cyclohexyl, cycloheptyl, etc.), and ^R5 is a) a linear or branched lower (Ci to C6) alkyl group (for example methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, /-butyl, «-pentyl, isopentyl, neopentyl etc.), b) a linear or branched lower (C ₂ to C 4 ) alkenyl group, c) a lower (C 1 to C 3 ) alkyl group substituted with a C 3 to C 5 cycloalkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g. phenyl, naphthyl, etc., optionally carrying a halogen atom, nitro, lower (C 1 to C 4 ) alkyl, lower (C 1 to C ₄ ) alkoxy group, etc.), such as benzyl, 7-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc., d) a lower (C ₂ to C ₃ ) alkenyl group substituted with a C 3 to C 5 cycloalkyl or optionally substituted aryl group (e.g. phenyl, naphthyl, optionally carrying a halogen atom, nitro, lower (C 1 to C ₄ ) alkyl, lower (C 1 to C ₄ ) alkoxyl, etc.), such as cinnamyl, etc. bearing an alkenyl function, such as vinyl, propenyl, allyl, isopropenyl, etc.,

e) optionally substituted aryl group (for example, phenyl group, naphthyl group, etc., optionally carrying a halogen atom, nitro group, lower (Ci to _C4 ) alkyl, lower (Ci to _C4 ) alkoxyl), such as phenyl, p-tolyl, naphthyl, etc., f) linear or branched lower (Ci to C6) alkoxy group (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 5-ec-butoxy, /-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), g) linear or branched lower ( _C2 to _C8 ) alkenyloxy group (for example, allyloxy, isobutenyloxy, etc.), h) C3 to _C8 cycloalkyloxy group (for example, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), i) lower (Ci to _C3 ) alkoxy group substituted C3 to _C8 cycloalkyl (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 to _C4 ) alkyl, lower (C1 to _C4 ) alkoxy, etc.), such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc., bearing an alkoxy group such as methoxy, ethoxy,

44 44 44

4 4 · 4 4 4

49 4444

4 4 4 9 9 4 9 • · · · · · · ·

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

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

The group in formula (I) convertible into a group capable of forming an anion (a group carrying a hydrogen atom, cleavable as a proton) as R ^l may be a group convertible into a group capable of forming an anion under biological or physiological conditions (for example, by in vivo reaction, etc., such as oxidation, reduction, hydrolysis, etc. by in vivo enzymes) [so-called precursor], or the group convertible to a group capable of forming an anion designated as R ¹ may be a group chemically convertible to a group capable of forming an anion, such as a cyano group, a N-hydroxycarbamimidoyl group (-C(=N-OH)-NH ₂ ), a group selected from the class consisting of 1) a carboxyl group, 2) a tetrazolyl group, 3) a group derived from trifluoromethanesulfonic acid amide (-NHSO ₂ CF ₃ ), 4) a phosphonic group, 5) a sulfo group, and 6) an optionally substituted residue of a monocyclic, five- to 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 group or acyl group, etc. [so-called synthetic intermediate].

As the group R ¹ , 1) carboxyl, tetrazolyl or 4,5-dihydro-5-oxol,2,4-oxadiazol-3-yl (preferably tetrazolyl) can be preferably used, each of which can be optionally protected

99

9 9

9 9

9 9

9 9 9

99 • 9 · ··«· 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 with a lower (C 1 to C ₄ ) alkyl (e.g. methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or an acyl group (e.g. lower (C 1 to C ₄ ) alkanoyl, benzoyl, etc.) or 2) a cyano group or N-hydroxycarbamimidoyl (preferably cyano).

In formula (I), the symbol X indicates that the phenylene group is bonded to the adjacent phenyl group directly or through 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 divalent chain in which the number of atoms forming the straight chain is equal to one or two and which may have a side chain, specifically lower (C 1 to C ₄ ) alkylene in which the number of atoms forming the straight chain is equal to one or two, and -CO-, -O-, -S-, -NH-, -C0-NH-, -O-CH2-, -S-CH2-, -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 the group 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 4 ) alkyl, 5) lower (C 1 to C 4 ) alkoxy, 6) optionally substituted amino [for example amino, N -alkylamino with lower (C 1 to C 4 ) alkyl (for example methylamino, etc.), N -dialkylamino with lower (C 1 to C 4 ) alkyls (for example dimethylamino, etc.), N -arylamino (for example phenylamino, etc.), alicyclic amino (for example morpholino, piperidino, piperazino, N -phenylpiperazino, etc.) etc.], 7) a group of the formula -CO-D', where D' is a hydroxyl group or a lower (C 1 to C 4 ) alkoxy group, the alkyl residue of which may be substituted by a hydroxyl group, a lower (C1 to C4) alkoxy, lower (C2 to C4) alkanoyloxy (e.g. acetoxy, pivaloyloxy, etc.), lower (C1 to C4) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or lower (C3 to C4) cycloalkoxycarbonyloxy (e.g. cyclohexyloxycarbonyloxy, etc.) or 8) tetrazolyl, trifluoromethanesulfonic acid amide, phosphonic or sulfo, each of which may be protected by an optionally substituted lower (C1 to C4) alkyl (“optionally substituted lower (C1 to C4) alkyl” similar to that exemplified by the protecting group capable of forming an anion and designated as ^R1, etc.) or acyl (e.g. lower (C2 to C5) alkanoyl, benzoyl, etc.), etc.

Of these substituents, one or two - in addition to the group R - may be simultaneously present at any available position of the benzene ring, and preferred examples of these substituents of the benzene ring A include optionally substituted lower (C1 to _C4 ) alkyl (for example lower (C1 4* 4 4 4 4 44 4

444 44 44 «44*

4· · · 4 44 444 44 4

1Λ 4444 4444 4444 ^J ' 99 99 99 99 99 99 to C ₄ ) alkyl, etc., optionally substituted with hydroxyl group, carboxyl group, halogen, etc.), halogen, etc. As the ring A, a benzene ring which does not carry any other substituent besides the group R ² is preferred.

Examples of the R group in formula (I) capable of forming an anion (groups having a hydrogen atom, which can be split off as a proton) include 1) an optionally esterified or amidated carboxyl group, 2) a tetrazolyl group, 3) a group derived from trifluoromethanesulfonic acid amide (-NHSO2CF3), 4) a phosphonic 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 (Ci to C4) alkyl group, similar to the "optionally substituted lower (Ci to _C4 ) alkyl group" given as an example of a protecting group for the said group capable of forming anion as R ¹ ) or an acyl group (for example, a lower (C2 to C5) alkanoyl, benzoyl, etc.) or any of the groups capable of being converted into them under biological or physiological conditions (for example, by in vivo reaction, etc., such as oxidation, reduction, hydrolysis, etc. by enzyme action in vivo, etc.) or chemically.

Examples where R ² is an optionally esterified or amidated carboxyl include a group of the formula -CO-D, where D is 1) a hydroxyl group, 2) an optionally substituted amino group (e.g. amino, N-lower (C 1 -C 4 ) alkylamino, Λζ A-di alkyl amino with lower (C 1 -C 4 ) alkyls, etc.) 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 with a hydroxyl group, an optionally substituted amino group (e.g. amino, A-lower (C 1 -C ₄ ) alkylamino, 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 an optionally substituted dioxolenyl group (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl etc.) or ii) a group of the formula -O-CH(R ⁶ )-OCOR ⁷ , where R ⁶ is a) hydrogen, b) a linear or branched lower (C 1 to C 6 ) alkyl group (for example methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, /-butyl, «-pentyl, isopentyl, neopentyl etc.), c) a linear or branched lower (C 2 to C 6 ) alkenyl group or d) a C 3 to C 8 cycloalkyl group (for example cyclopentyl, cyclohexyl, cycloheptyl etc.) and R ⁷ is a) a linear or branched lower (C 1 to C 6 ) alkyl group (for example methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, eec-butyl, /-butyl, «-pentyl, isopentyl, neopentyl etc.), b) a linear or branched lower (C 2 to Ce) alkenyl group, c) lower (Ci to C3) alkyl group substituted with C3 to C8 cycloalkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or optionally substituted aryl group (e.g. phenyl, naphthyl, etc.), optionally carrying a halogen atom, nitro group, lower (Ci ··>» »w • 9

9« ·* »9 44 • 9 9 · · · » 4 · • · · 9 9 44 · · 9 9 • 9 999 99 9 9 » 9 9 9 _1C » · · 9 · · r ♦ 9 · * · lO 00 ·· 94 44 99 9» to C ₄ ) alkyl, lower (C 1 to C ₄ ) alkoxy, etc.), such as benzyl, /?-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc., d) a lower (C 2 to C 3 ) alkenyl group substituted with C 3 to C 8 cycloalkyl or optionally substituted with an aryl group (for example, a phenyl group, a naphthyl group, etc., optionally carrying a halogen atom, a nitro group, a lower (C 1 to C ₄ ) alkyl, lower (C 1 to C ₄ ) alkoxy, etc.), such as cinnamyl, etc. having as alkenyl moiety vinyl, propenyl, allyl, isopropenyl, etc., e) optionally substituted aryl group (for example, phenyl group, naphthyl group, etc., optionally carrying a halogen atom, nitro group, lower (Ci to _C4 ) alkyl, lower (Ci to _C4 ) alkoxy, etc.), such as phenyl, p-tolyl, naphthyl, etc., f) linear or branched lower (Ci to C6) alkoxy group (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, se-butoxy, f-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), g) linear or branched lower (C2 to C8) alkenyloxy group (for example, allyloxy, isobutenyloxy, etc.), h) C3 to C8 cycloalkyloxy group (for example, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), i) lower (Ci a) a C3 to _C8 alkoxy group substituted with a _C3 to C8 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., phenyl, naphthyl, etc., optionally carrying a halogen atom, nitro, lower (C1 to _C4 ) alkyl, lower (C1 to _C4 ) alkoxy, etc.), such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc., having as the alkoxy moiety methoxy, ethoxy, n-propoxy, isopropoxy, etc., etc.); j) a C2 to _C3 lower alkenyloxy group substituted with a _C3 to C8 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., phenyl or naphthyl, etc., optionally carrying a halogen atom, nitro, lower (C1 to C4) alkyl, lower (C1 to C4) alkoxy, etc.); to C ₄ ) alkyl, lower (C 1 to C ₄ ) alkoxy, etc.), such as cinnamyloxy, etc. having as the alkenyloxy moiety vinyloxy, propenyloxy, allyloxy isopropenyloxy, etc. or

k) an optionally substituted aryloxy group (for example, phenoxy, naphthoxy, etc., optionally carrying 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, an optionally esterified carboxyl is preferred, and specific examples thereof include -COOH and its salts, -COOMe, -COOEt, -COOtBU, -COOPr, pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4ylmethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl,

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

ΦΦΦΦ φφ φφ φφ φφ φφ φφφ φφφφ «φφφ φφφ φφφφ φφφφ φφ ·*φ φφ φφφ φφ φ

Φφφφ φφφφ φφφφ ΦΦ ΦΦ νΦ ΦΦ ΦΦ φφ benzoyloxymethoxycarbonyl, cinnamoyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, etc. The group R ² may be any of the groups capable of forming an anion under biological or physiological conditions (for example, by in vivo reaction, etc., such as oxidation, reduction, hydrolysis, etc. by the action of an enzyme in vivo, etc.), it may be groups capable of forming an anion chemically (for example, COO-, its derivatives, etc.) or groups capable of being converted into it. The group R ² may be a carboxyl group or its precursor.

Preferred examples of the R group include a group of the formula -CO-D, where D is 1) a hydroxyl group or 2) a lower (C1 to C4) alkoxy group, the alkyl residue of which is optionally substituted with a hydroxyl group, an amino group, a halogen, a lower (C2 to %) alkanoyloxy group (e.g. acetoxy, pivaloyloxy, etc.), a lower (C3 to C5) cycloalkanoyloxy group, a lower (C1 to C6) alkoxycarbonyloxy group (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, etc.), a lower (C3 to C6) cycloalkoxycarbonyloxy group (e.g. cyclohexyloxycarbonyloxy, etc.), a lower (C1 to _C4 ) alkoxy group or a lower ( _C3 to _C8 ) cycloalkoxy group. Among others, carboxyl esterified with a lower (C1 to C4) alkyl (preferably methyl or ethyl) is preferred.

Preferable examples of the “hydrocarbon residue” in the “optionally substituted hydrocarbon residue which may be bonded via heteroatoms” shown in formula (I) as R ³ are 1) an alkyl group, 2) an alkenyl group, 3) an alkynyl group, 4) a cycloalkyl group, 5) an aryl group, 6) an aralkyl group, etc. Among others, an alkyl group, an alkenyl group, and a cycloalkyl group are preferable.

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

Examples of the alkenyl group mentioned above under item 2) 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 item 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 item 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 by a hydroxyl group, optionally substituted by an amino group (for example, amino, lower (C1 to C4) alkyl)-alkylamino, lower (C1 to C4) alkyl)-dialkylamino, lower (C1 to C4) alkyl)-dialkylamino, and the like.

C ₄ ) alkyls, etc.), halogen, lower (C 1 to C ₄ ) alkoxy group, lower (C 1 to C 4 ) alkylthio group, etc.

Examples of the aralkyl group mentioned above under item 5) include phenylalkyl with a C1 to C4 alkyl moiety, such as benzyl, phenethyl, etc.

Examples of the aryl group mentioned above under item 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 - with halogen (e.g. F, Cl, Br, etc.), nitro, optionally substituted amino, optionally substituted amino (e.g. amino, N-alkylamino with lower (Ci to C4) alkyl, ΛζΝ-dialkylamino with lower (Ci to C4) alkyl, etc.), lower (Ci to C4) alkoxy (e.g. methoxy, ethoxy, etc.), lower (Ci to C4) alkylthio (e.g. methylthio, ethylthio, etc.), lower (Ci to C4) alkyl (e.g. methyl, ethyl, etc.), etc.

Preferred examples of the "optionally substituted hydrocarbon residue" in the "optionally substituted hydrocarbon residue which may be bonded via heteroatoms" shown in formula (I) as R ³ include an optionally substituted alkyl or alkenyl group (for example, a lower (C 1 to C 5 ) alkyl or lower (C ₂ to C 5 ) alkenyl group, each of which may be substituted by a hydroxyl group, an amino group, a halogen, a lower (C 1 to C 4 ) alkoxy group, etc.). Among others, lower (C 1 to C 5 ) alkyl (preferably ethyl) is preferred.

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

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

Of the non-peptide compounds having angiotensin II antagonistic 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 carrying - in addition to the group R ² - an optional substituent selected from the class consisting of optionally substituted lower (C 1 to C 4 ) alkyl (for example lower (C 1 to C 4 ) alkyl optionally substituted by hydroxyl, halogen, etc.) and halogen (preferably the benzene ring has no further substituent in addition to the group R ² ). R ² is a group of the formula -CO-D, where D is

1) a hydroxyl group or 2) a lower (C1 to C4) alkoxy group, the alkyl portion of which may be substituted by a hydroxyl group, an amino group, a halogen, a lower ( _C2 to C6) alkanoyloxy group (e.g. acetoxy, pivaloyloxy, etc.), a lower (C3 to C8) cycloalkanoyloxy group, a lower (C1 to C8) alkoxycarbonyloxy group (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, etc.), a lower ( _C3 to C8) cycloalkoxycarbonyloxy group (e.g. cyclohexyloxycarbonyloxy, etc.), a lower (C1 to C4) alkoxy group or a lower (C3 to C8) cycloalkoxy group. R is a lower (Ci to C5) alkyl or lower ( _C2 to C5) alkenyl group, each of which may be bonded via -O-, -S(0) _m- [m is an integer of 0 to 2], -NR'- [R' is a hydrogen atom or lower (Ci to C4) alkyl], and which may be substituted with a substituent selected from the class consisting of hydroxyl, amino, halogen and lower (Ci to C4) alkoxy (lower (Ci to C5) is preferred) • · · · » · · <

» · · <

» · · · · · • · 1 alkyl or lower (C1 to C5) 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 i 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-1,2,4oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid, etc. or their salts are preferred.

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

The compound having angiotensin II antagonist activity or a precursor thereof may be used either in free form or in the form of any of its pharmaceutically acceptable salts. Examples of these salts include salts with inorganic bases (e.g., 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 (e.g., organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Ν,Ν'-dibenzylethylenediamine, etc., basic amino acids such as arginine, lysine, omitine, etc., etc.), when said compound having angiotensin II antagonistic activity bears an acidic group such as a carboxyl group, etc., as well as salts with inorganic acids or organic acids (e.g., hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid in the form of normal carbonates and bicarbonates, formic acid, acetic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ;;-toluenesulfonic acid, etc.), acidic amino acids such as aspartic acid, glutamic acid, etc., etc., if said compound having angiotensin II antagonistic activity bears a basic group such as an amino group, etc.

A precursor of a compound having angiotensin II antagonist activity [hereinafter referred to as an AII antagonist] means a compound that can be converted into AII antagonists under physiological conditions or by a reaction induced by an enzyme, digestive tract acids, 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 acids, etc., etc.

Examples of the AII antagonist precursor include compounds in which the amino group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, etc. (for example, compounds in which 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.), compounds in which the hydroxyl group of the AII antagonist is substituted with acyl, alkyl, phosphoric acid, boronic acid, etc. (for example, compounds in which the hydroxyl group of the AII antagonist is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.), compounds in which the carboxyl group of the AII antagonist is modified with 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, italidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methylamide, etc.) etc. These precursors can be prepared in a known manner from the AII antagonist.

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

The AII antagonist may also be hydrated.

Examples of the biodegradable polymer for use in the present invention include polymers, copolymers, esters thereof, or mixtures thereof, which are 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 which bear a free carboxyl group, maleic anhydride copolymers (e.g., styrene-maleic acid copolymer, etc.), etc.

These copolymers may be random, block or graft copolymers. If the 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, a polymer of α-hydroxycarboxylic acid (preferably a copolymer of lactic acid and glycolic acid), its ester, poly(a-cyanoacrylic acid) esters, of which a copolymer of lactic acid and glycolic acid and its ester is more preferred.

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

50/50.

Generally, the weight average molar mass of said copolymers of lactic acid and glycolic acid 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 of 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 values of weight average molar mass, number average molar mass and polydispersity in the present document were determined by gel permeation chromatography (GPC) using 14 polystyrene samples as reference standards with weight average molar masses 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 determination was carried out using a GPC column KF804Lx2 (manufactured by Showa Denko K.K., Japan) and chloroform as the mobile phase.

To obtain the 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 solution of potassium hydroxide using phenolphthalein as an indicator to determine the content of terminal carboxyl groups. In the following text, this value is referred to as the number average molar mass from the determination of terminal groups. While the value of the number average molar mass from the determination of terminal groups is absolute, the value of the same quantity from the determination by GPC is relative and varies depending on the analysis conditions (for example, the type of mobile phase, the type of column, reference standards, the choice of cut width, the choice of baseline, 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 number average molar mass from GPC and the number average molar mass from the determination of terminal groups almost coincide. The statement that the number average molar mass from GPC and from the end group determination "almost agree" here means that the value from the second method lies in the interval from 0.2 times to 1.5 times, preferably from 0.3 times to 1.2 times, of the value from the first method.

A copolymer of lactic acid and glycolic acid can be prepared, for example, by catalyst-free polycondensation from lactic acid and glycolic acid (Japanese Patent No.

999 · 9 9

9 9

9 9

9 9 9 · ·

9 99 · · · • fc 9 · • fcfc 9

9 9 9

9 9 9 unexamined application No. 28521/1986) or by catalyzed ring-opening polymerization from cyclic lactide, glycolide, etc. (Encyclopedic Handbook of Biomaterials and Bioengineering, Part A: Materials, Vol. 2, edited by Marcel Dekker, hic. (1995)).

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

The above copolymer of lactic acid and glycolic acid having terminal carboxyl groups can be synthesized without any problems by general synthetic methods (for example, 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 (for example, WO94/15587).

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

Lactic acid-glycolic acid copolymer esters can be prepared, for example, by known methods from lactic acid-glycolic acid copolymers bearing a free carboxyl group (for example, Japanese Unexamined Patent Application No. 278018/1995).

These biodegradable polymers can be used alone or in combination with two or more types 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 have an adverse effect on a living organism. Examples of the metal include polyvalent metals such as divalent metals (e.g., iron, zinc, copper, calcium, magnesium, aluminum, tin, manganese, etc.), trivalent metals (e.g., iron, aluminum, manganese, etc.), tetravalent metals (e.g., tin, etc.), etc.

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

« *

• · · · 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 C1 to C9 aliphatic carboxylic acid (for example, an aliphatic mono-, di- or tricarboxylic acid, etc.), etc., wherein the aliphatic carboxylic acid may be either saturated or unsaturated.

Examples of aliphatic monocarboxylic acid include C1 to C9 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, etc.), _C2 to C9 unsaturated aliphatic monocarboxylic acid (e.g. acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.), etc.

Examples of aliphatic dicarboxylic acid include _C2 to C9 saturated aliphatic dicarboxylic acid (e.g., malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, etc.), _C2 to C8 unsaturated aliphatic dicarboxylic acid (e.g., maleic acid, fumaric acid, citraconic acid, mesaconic acid, etc.), etc.

Examples of aliphatic tricarboxylic acid include _C2 to C8 saturated aliphatic tricarboxylic acid (e.g., tricarballylic acid, 1,2,3-butanetricarboxylic acid, etc.), etc.

The above aliphatic carboxylic acid may bear 1 to 2 hydroxyl groups, and 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 is preferred, preferably a _C2 to C9 aliphatic carboxylic acid, especially acetic acid.

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

As the polyvalent metal compound, iron chloride, iron acetylacetonate, zinc acetate, zinc acetylacetonate, calcium acetate, calcium acetylacetonate, magnesium acetate, magnesium acetylacetonate, zinc oxide, etc. are preferable, 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 salt of a biodegradable polymer with one or more kinds of polyvalent metal. This salt of a biodegradable polymer with a polyvalent metal may be prepared by the method described

in Japanese Unexamined Patent Application No. 221420/1997 or in a manner similar thereto.

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

The polyvalent metal may become part of said solution by using as a starting material a complex of the 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, further adding the polyvalent metal compound to said solution, etc. All of the polyvalent metal compound (or part thereof) added to said solution may form a complex in said solution with both compounds having angiotensin II antagonistic activity and the biodegradable polymer, or with 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 the polyvalent metal compound vary depending on the type of the compound having AII antagonistic activity, the desired pharmaceutical effect, the duration of the effect, etc. For example, if the sustained-release composition of the present invention consists of a compound having AII antagonistic activity and a biodegradable polymer, the amount of the compound having AII antagonistic activity is usually 1 to 50 wt. %, preferably 5 to 45 wt. %, more preferably 10 to 40 wt. %, based on the sum of these two components, that is, the compound having AII antagonistic activity and the biodegradable polymer. If the sustained-release composition of the present invention consists of a compound having AII antagonistic activity, a polyvalent metal compound and a biodegradable polymer, the amount of the compound having AII antagonistic activity is usually 1 to 50 wt. %, preferably 15 to 45 wt. %, preferably 20 to 40 wt. %, based on the sum of these three components, and on the other hand, the amount of the polyvalent metal compound is usually 0 to 20 wt. %, preferably 2 to 15 wt. %, preferably 4 to 10 wt. %.

t· · • ·

The sustained release formulation of the present invention can be administered in any form, preferably in a formulation for non-oral administration. Examples of such formulations include subcutaneous formulations, implantable formulations, injectable microcapsules, etc. Among them, injectable microcapsules are preferred because they maintain the pharmaceutical effect for a long time and reduce the patient's burden.

Examples of methods for preparing a sustained-release composition according to the present invention, for example microcapsules (hereinafter also referred to as microspheres), which contains a compound having AII antagonistic activity and a biodegradable polymer, include:

I) Drying from water

i) O/V method

The compound having antagonistic activity towards AII and - if necessary - the polyvalent metal compound are added to the solution of the biodegradable polymer in the organic solvent in a weight ratio as defined in the above-mentioned "amount of the compound having antagonistic activity towards AII and the polyvalent metal compound", to form a solution of the biodegradable polymer in the organic solvent containing the compound having antagonistic activity towards AII and - if necessary - the polyvalent metal compound. One or both of the compounds having antagonistic activity towards AII and the polyvalent metal compound do not have to be dissolved in the solution of the biodegradable polymer in the organic solvent, they can only be dispersed in said solution. When one or both of these components are dispersed in said solution, it is preferable to disperse these components finely, by a conventional method such as homogenization, ultrasonic dispersion, etc.

Examples of said organic solvent include halogenated hydrocarbons (e.g., dichloromethane, chloroform, dichloroethane, 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, etc.), alcohols (e.g., ethanol, methanol, etc.), acetonitrile, etc. These solvents may be used singly or in combination.

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

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

In the case where the compound having antagonistic activity towards AII contains a tetrazolyl group, ethanol is preferred as the alcohol to be mixed with dichloromethane, while in the case where the compound having antagonistic activity towards AII contains a 4,5-dihydro-5-oxol,2,4-oxadiazol-3-yl group, it is methanol.

An additive may be added to the above organic solvent solution. Examples of the additives include a solubilizer that 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 their salts, etc. Further, as stabilizers of this drug, for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyols such as polyethylene glycol, etc., etc., and as preservatives, for example, conventional paraoxybenzoic acid esters (for example, methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc.

The concentration of the biodegradable polymer in the organic solvent solution varies depending on the molar mass 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 the organic solvent solution is generally selected in the range of 0.5 to 70 wt. %, preferably 1 to 60 wt. %, preferably 2 to 50 wt. %. Furthermore, when ethanol or methanol is used as the mixed organic solvent together with dichloromethane, the concentration of dichloromethane in the organic solvent solution is generally selected in the range of 10 to 99 wt. %, preferably 20 to 98 wt. %, preferably 30 to 95 wt. %.

The thus obtained solution of the biodegradable polymer, the organic solvent of which contains a compound with antagonistic activity against angiotensin II and - if necessary - also a polyvalent metal compound, is added to the aqueous phase (also referred to as the external aqueous phase) to form an O(oil phase)/V(water phase) emulsion, followed by evaporation of the solvent from the oil phase to form microcapsules. The volume of the aqueous phase is generally chosen to be in the range of one to ten thousand times the volume of the oil phase, preferably from five to five thousand times, preferably from ten to two thousand times.

Any emulsifier may be added to said external aqueous phase as long as it can contribute to the formation of a stable O/W 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

444 44 444 44 4

4444 4444 ·· 4 4 4 4 polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid, etc. These emulsifiers can be used individually 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 creates an osmotic pressure in its aqueous solution.

Examples of osmotic pressure regulators include polyfunctional alcohols, monovalent alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids or their derivatives, etc.

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, especially mannitol, are preferred.

Examples of said monohydric alcohols include methanol, ethanol, isopropyl alcohol, etc. Among others, methanol is preferred.

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

Examples of said oligosaccharides include trisaccharides such as maltotriose, raffinose, etc., tetrasaccharides such as stachyose, etc., 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 can be used individually or as a mixture of two or more of them.

These osmotic pressure regulators are usually used in a concentration that will produce an osmotic pressure of the external aqueous phase in the range of one fiftieth to five times, preferably one twenty-five to three times, that of physiological solution.

For removing the organic solvent, known methods or methods analogous thereto may be used. This may be done, for example, by evaporating the organic solvent while stirring with a propeller stirrer, a magnetic stirrer, etc., under 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. Then, the substances attached to the surface of the microcapsules, i.e. the compound having antagonistic activity towards AII, its carriers, »4 44

4 · 4 4 • 4 4 4 4

4*44 44 • 4

4

4

4 4 4 4 4 4

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

If desired, after lyophilization is complete, 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 fuse with each other. Preferably, the microcapsules are heated to a suitable temperature that is slightly higher than the average glass transition temperature (determined using 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 ranging from the average glass transition temperature to a temperature that is approximately 30 °C higher than the average glass transition temperature of the biodegradable polymer. Specifically, when a copolymer of lactic acid and glycolic acid is used as the biodegradable polymer, the microcapsules are preferably heated to temperatures ranging from the mean glass transition temperature to a temperature that is about 10°C higher than the mean glass transition temperature of the polymer, preferably from the mean glass transition temperature to a temperature that is about 5°C higher than the mean glass transition temperature of the polymer.

The heating time varies depending on the amount of microcapsules being processed, etc. It is generally in the range of 12 to 168 hours, preferably 24 to 120 hours, most preferably 48 to 96 hours from the moment the temperature of the microcapsules themselves reaches the desired value.

Heating 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 microcapsules include a constant temperature bath, a fluidized bed, a moving bath or oven, microwave heating, etc. Among others, a method for heating and drying microcapsules in a constant temperature bath is preferred.

ii) I/O/O method

The compound having antagonistic activity towards AII is dissolved in water and to the resulting solution is added - if necessary - its carrier, such as a polyvalent metal compound ··»· »· ·· ·· ·» ·· ··· · 9 * * ····

9 9 9 9 99 · · · J • · · 9 9 9 9 9 ·»··

·. .. ·· ·· ·* ·· (for example, zinc acetate), basic amino acid (for example, arginine, histidine, lysine), gelatin, agar, polyvinyl alcohol, etc., so as to form an internal aqueous phase.

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

As pH regulators maintaining the stability and solubility of the drug, 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. Furthermore, as stabilizers of the drug, for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyols such as polyethylene glycol, etc. can be added. As preservatives, for example, common esters of paraoxybenzoic acid (for example, methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. can be added.

The internal aqueous phase thus obtained is added to a solution of a 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, ultrasonic device, etc. to form a W/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, etc.), alcohols (e.g., ethanol, methanol, etc.), acetonitrile, etc. These solvents may be used in a mixture in an appropriate ratio. Among others, halogenated hydrocarbons, especially dichloromethane, are preferred.

The concentration of the biodegradable polymer in the organic solvent solution varies depending on the molar mass of the biodegradable polymer and the type of organic solvent. For example, if dichloromethane is used as the organic solvent, the concentration of the biodegradable polymer in the organic solvent solution is generally selected to be in the range of 0.5 to 70 wt. %, preferably 1 to 60 wt. %, preferably 2 to 50 wt. %.

The thus obtained W/O emulsion, containing a compound having antagonistic activity towards AII, a biodegradable polymer and - if necessary - a polyvalent metal compound, is added to the aqueous phase (external aqueous phase) to form an emulsion V(internal aqueous phase)/O(oil 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 chosen in the range of one to ·«·· φφ φφ φφ φφ ·· φφ · · φφ · •ΦΦ φφφφ φφφ φφφ φφφ φφ φφφ φφ · φφφφ φφφφ φφ φφ φφ ·· ·· ·· ten thousand times the volume of the oil phase, preferably five to five thousand times, preferably ten to two thousand times.

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

II) Phase separation

In the preparation of microcapsules by phase separation, a coacervating agent is gradually added to the said organic solution of biodegradable polymer containing a compound with antagonistic activity against AII and, if necessary, a polyvalent metal compound as described in section I) (drying from water) with stirring so that the microcapsules precipitate and solidify. The volume of the coacervating agent is generally selected in the range of one hundredth to one thousandth of the volume of the oil phase, preferably from five hundredths to five hundredths, preferably from one tenth to two hundredths.

Any coacervative agent is acceptable as long as it is a polymer, mineral oil, vegetable oil, etc., which is miscible with the organic solvent and does not dissolve either of the two compounds having antagonistic activity against AII, 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 can also be used in combination.

The microcapsules thus obtained are separated, repeatedly washed with heptane or the like to remove the coacervating agent and other substances except the compound having AII antagonistic activity 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 microcapsules in this manner, the above-mentioned organic solution of a biodegradable polymer containing a compound with antagonistic activity against AII and optionally containing a polyvalent metal compound, as described in section I) (drying from water), is sprayed through a nozzle into the drying chamber of a spray dryer so that the organic solvent evaporates from the small droplets formed in a very short time, thus forming microcapsules. Examples • ΦΦΦ Φ« «4 Φ· *·

Φ φ Φ ΦΦΦΦ · φΦΦ Φ Φ ΦΦ Φ φ φ Φ Φ * Φ Φ · · · · * · “ ** ........

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

In addition to processing into the above-described microcapsule dosage form, the organic solution of the biodegradable polymer containing the compound with AII antagonistic activity and, in addition, if necessary, a polyvalent metal compound as described in section I) (drying from water) may be subjected to evaporation of the organic solvent and water under controlled vacuum using a rotary evaporator, and the resulting residue may be pulverized with 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), lyophilized, and then heated and dried.

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

The sustained-release preparation of the present invention can be used for the manufacture of various preparations, either as such or as a raw material, and administered as intracutaneous injections or implants, subcutaneously, into organs, etc., as mucosal preparations into the nasal cavity, rectum, uterus, as oral preparations [e.g., capsules (e.g., hard capsules, soft capsules, etc.), solid preparations such as granules, powders, etc., liquid preparations such as syrups, emulsions, suspensions, etc., etc.], etc. The sustained-release preparation of the present invention can also be administered using a needle-free injector.

For example, when the sustained-release composition of the present invention is to be formulated into an injection, it is dispersed together with a dispersing agent (e.g., surfactant such as Tween 80, HCO-60, etc., polysaccharide such as sodium hyaluronate, carboxymethylcellulose, sodium alginate, 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 it is dispersed together with a vegetable oil such as sesame oil, corn oil, etc. to form an oily suspension, and the suspensions are actually used as sustained-release injections.

When the sustained-release composition of the present invention is used as a suspension, the particle size is selected within a range that meets the requirements for dispersibility and permeability.

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

For the preparation of a sterile preparation of the sustained-release composition according to the present invention, a method of sterilizing all production steps, a method of γ-ray sterilization, and a method of adding a preservative are used, and there is no limitation 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., humans, cattle, pigs, dogs, cats, mice, rabbits, etc.).

The dosage of the sustained-release composition of the present invention is within the range of an effective amount of the compound with AII antagonistic activity and depends on the type, content and dosage form of the compound with AII antagonistic activity as the active ingredient, the length of time for which the compound with AII antagonistic activity is released, the target disease, the animal to be treated, etc. For example, the dosage for administration of the active ingredient, i.e., the compound having AII antagonistic activity, is preferably selected within the range of 0.01 to 10 mg per kilogram of adult body weight, preferably 0.05 to 5 mg per kilogram of adult body weight, when the sustained-release period is 1 month. The dosage for administration of the sustained-release composition of the present invention is preferably selected within the range of 0.05 to 50 mg per kilogram of adult body weight, preferably 0.1 to 30 mg per kilogram of adult body weight.

The number of administrations (applications) may be suitably selected from once every few weeks, once every month, to once every several months (e.g. 3 months, 4 months, 6 months, etc.), etc., depending on the type, content and dosage form of the active ingredient, the release time of the compound having AII antagonistic activity, the disease to be treated, the species of animal to be treated, etc.

The compound having antagonistic activity against AII is highly safe, so that the increase in the concentration of this compound in the blood immediately after the administration of the sustained-release injection will not cause excessive lowering of blood pressure. The sustained-release preparation of the present invention can thus be used in the diseases listed below and is capable of maintaining a constant concentration of the drug in the blood throughout the day and night. The dosage and number of applications can be reduced compared with the administration of conventional oral preparations. In addition, the change in the concentration of the drug in the blood is not significant, and the patient's condition does not change when the drug is discontinued, etc. Therefore, it can be expected that the therapeutic effect of the drug will be clarified by administering the sustained-release preparation.

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

The sustained-release composition of the present invention is useful for the prevention or treatment of hypertension, hypercardia, heart failure, myocardial infarction, stroke, ischemic peripheral circulatory disorders, myocardial ischemia, venous insufficiency, progressive heart failure after myocardial infarction, diabetic complications, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, vascular hypertrophy or obstruction after surgery (for example, percutaneous transluminal coronary angioplasty, etc.), vascular reobstruction after bypass, hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, intraocular high pressure, hyperlipemia, angina pectoris, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, central nervous system diseases, Alzheimer's disease, memory disorders, depression, amnesia, senile dementia, sensory disorders, multiple organ system failure, endothelial dysfunction disease or scleroderma, as well as for the prevention or alleviation of anxiety neuroses, catatonia, nausea or dyspeptic symptoms.

As for the method of treating patients, it is assumed that the patient is first administered conventional oral preparations containing a compound with angiotensin II antagonist activity for a certain period of time so as to verify the response of the patient, and then the sustained-release preparation of the present invention is administered to the patient. The compounds with angiotensin II antagonist activity to be administered both orally and as part of the sustained-release preparation may be the same or different. In addition, antihypertensive agents other than the angiotensin II antagonist activity (for example, calcium antagonist, diuretic, β-blocker, etc.) may be administered to the patient in advance so as to verify the response of the patient before administering the sustained-release preparation. In addition, the sustained-release preparation may be used in combination with a diuretic (oral preparation) which is usually used in combination with an angiotensin II antagonist.

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Examples of embodiments of the invention

The present invention is further illustrated in detail by means of 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-oxadiazol-3-yl)biphenyl-4yl]methyl]benzimidazole-7-carboxylic acid (hereinafter referred to as compound A) and 2.25 g of a copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 10,700 g/mol, number average molar mass from end group determination 3770 g/mol, manufacturer Wako Pure Chemical) were dissolved and this solution was injected into 500 ml of a polyvinyl alcohol solution with a concentration of 0.1 wt. %, previously tempered to 18 °C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at laboratory temperature so that dichloromethane and methanol flowed out and the oil phase solidified, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 subjected to lyophilization to form powdered microcapsules.

The yield of microcapsules was 69%, the entrapment rate of compound A in microcapsules was 92%, and the content of compound A in 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 copolymer of lactic acid and glycolic acid (same as in working example 1) in 4 ml of dichloromethane. The mixture was mixed with a homogenizer to form a W/O emulsion. This W/O emulsion was sprayed into 500 ml of a 0.1 wt. % polyvinyl alcohol solution, previously tempered to 18 °C, and this mixture was then mixed in a turbine homomixer at 7000 rpm to form a W/O/W emulsion. This W/O/W emulsion was mixed for 3 hours at laboratory temperature to allow the dichloromethane to flow out and for the oil phase to solidify, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 subjected to lyophilization to form powdered microcapsules.

The yield of microcapsules was 50%, the entrapment rate of compound A in microcapsules was 37%, and the content of compound A in 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 lactic acid polymer (a biodegradable polymer whose terminal carboxyl group is esterified with ethyl, whose weight average molar mass is 10,200 g/mol and whose number average molar mass is 5,680 g/mol, and which is manufactured by Wako Pure Chemical) were dissolved, and this solution was sprayed into 800 ml of a 0.1 wt. % polyvinyl alcohol solution containing 5% mannitol and previously tempered to 18°C, and this mixture was then stirred in a turbine homomixer at 7,000 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at room temperature to allow dichloromethane and methanol to flow out and the oil phase to solidify, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 entrapment rate of compound A in microcapsules was 86%, and the content of compound A in 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 injected into the back of seven-week-old male SD rats using a 22G needle. At regular intervals after the injection, blood was collected from the abdominal aorta of these rats, after which the 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 Worked example 3 66% 42% 27% 17% 15%

Table 2

1 day 1 week 2 weeks 3 weeks 4 weeks Worked 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 copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 14,000 g/mol, number average molar mass 4200 g/mol, number average molar mass from end group determination 4090 g/mol, manufacturer Wako Pure Chemical) in 4.5 ml of dichloromethane and 1 ml of ethanol were added 0.6 g of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (hereinafter referred to as compound B) and 0.09 g of zinc oxide (particle size 0.02 pm) and this mixture was shaken and stirred at room temperature for 12 hours to form a slightly cloudy suspension. This suspension was sprayed into 400 ml of a 0.1 wt. % polyvinyl alcohol solution, previously tempered to 15 °C, and this mixture was then stirred in a turbine homomixer at 7000 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at laboratory temperature so that dichloromethane and ethanol flowed out and the oil phase solidified, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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 microcapsules were prepared in a manner similar to that described in Working Example 1.

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

The entrapment 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 microcapsules were prepared in a manner similar to that described in Working Example 3.

The entrapment 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 a copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 14,000 g/mol, number average molar mass 4200 g/mol, number average molar mass from end group determination 4090 g/mol, manufacturer Wako Pure Chemical) in 9 ml of dichloromethane and 1.5 ml of ethanol were added 1.8 g of compound B and 0.3 g of zinc oxide (particle size 0.02 pm). The resulting mixture was shaken and stirred for 12 hours at laboratory temperature to form a slightly turbid suspension. This suspension was injected into 800 ml of a polyvinyl alcohol solution with a concentration of 0.1 wt. %, previously tempered to 15 °C, and this mixture was then mixed in a turbine homomixer at 7000 rpm to form an O/W emulsion. The resulting emulsion • · * · · 4

τ)

The O/W was stirred for 3 hours at room temperature to allow dichloromethane and ethanol to flow out and the oil phase to solidify, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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 a copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 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 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 pm). The resulting mixture was shaken and stirred for 12 hours at laboratory temperature to form a slightly cloudy suspension. This suspension was injected into 300 ml of a polyvinyl alcohol solution with a concentration of 0.1 wt. %, previously warmed to 15 °C, and this mixture was then stirred in a turbine homomixer at 6500 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at laboratory temperature so that dichloromethane and methanol flowed out and the oil phase solidified, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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 copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 14,000 g/mol, • · « • · « » · · « ·· ·· • « · · • * · · · · · · · · · · · · · · · number average molar mass 4200 g/mol, number average molar mass from end group determination 4090 g/mol, manufacturer Wako Pure Chemical) in 5 ml of dichloromethane was added 1 g of compound B and 0.18 g of zinc oxide (particle size 0.02 pm). The resulting mixture was emulsified for 60 seconds in a small homogenizer to form a suspension. This suspension was injected into 300 ml of a polyvinyl alcohol solution with a concentration of 0.1 wt. %, previously warmed to 15 °C, and this mixture was then stirred in a turbine homomixer at 6500 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at laboratory temperature so that dichloromethane flowed out and the oil phase solidified, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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, microcapsules were prepared in a manner similar to that described in Working Example 7.

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

Working example 12

In a stirred mixture of 4.5 ml of dichloromethane and 0.7 ml of ethanol, 0.9 g of l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-l-[[2’-(lH-tetrazol-5-yl)biphenyl-4yl]methyl]benzimidazole-7-carboxylate (hereinafter referred to as compound C) and 2.1 g of a copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 14,000 g/mol, number average molar mass 4200 g/mol, number average molar mass from end group determination 4090 g/mol, manufacturer Wako Pure Chemical), were dissolved, and 0.15 g of zinc oxide (size 4 particles 0.02 pm). This mixture was shaken and stirred for 12 hours at room temperature to form a slightly cloudy suspension. This suspension was sprayed into 400 ml of a 0.1 wt. % polyvinyl alcohol solution, previously tempered to 15 °C, and this mixture was then stirred in a turbine homomixer at 7500 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at room temperature so that dichloromethane and ethanol flowed out and the oil phase solidified, which was then separated by centrifugation at 2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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 exception that zinc oxide was not added, microcapsules were prepared in a manner similar to that described in Working Example 12.

The entrapment 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 copolymer of lactic acid and glycolic acid (molar ratio lactic acid/glycolic acid 75/25, weight average molar mass 14,000 g/mol, number average molar mass 4200 g/mol, number average molar mass from end group determination 4090 g/mol, manufacturer Wako Pure Chemical) were dissolved in 5 ml of dichloromethane. 0.18 g of zinc oxide (particle size 0.02 pm) was added to the resulting solution. This mixture was shaken and stirred for 1 hour at room temperature to form a slightly cloudy suspension. This suspension was injected into 400 ml of a polyvinyl alcohol solution with a concentration of 0.1 wt. %, previously warmed to 15 °C, and this mixture was then mixed in a turbine homomixer at 8000 rpm to form an O/W emulsion. The resulting O/W emulsion was stirred for 3 hours at laboratory temperature so that dichloromethane and ethanol flowed out and the oil phase solidified, which was then separated by centrifugation at ·· ·· • · · « • · · » • · · · · · · · · · · · · · · · · · · · ► «

2000 rpm. The precipitate was redispersed 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 lyophilization to form powdered microcapsules.

The entrapment 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 exception that zinc oxide was not added, microcapsules were prepared in a manner similar to that described in Working Example 4.

The entrapment 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 exception that zinc oxide was not added, microcapsules were prepared in a manner similar to that described in Working Example 9.

The entrapment 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 microcapsules obtained in Working Examples 4-14 were dispersed in 0.2 ml of 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 injected into the neck of seven-week-old male SD rats using 22G needles. At regular intervals after injection, the rats were gradually sacrificed by abdominal exsanguination and the microcapsules remaining at the injection site were isolated.

The amount of the compound having antagonistic activity towards AII was determined in the microcapsules and the results are shown in Table 3. Table 4 further shows the concentrations of compound B in the blood upon application of the microcapsules from Working Examples 4, 6 and 8.

···· ·· • · « · ·· ·· *· • · · · · · ♦ ♦ · · • ··«· ♦ » · ·

Table 3

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

Working example No. 1 day 1 week 2 weeks 3 weeks 4 weeks 4 91 62 36 11 3 5 85 60 18 not done not done 6 88 63 33 11 3 7 94 78 55 43 26 8 86 62 38 18 7 9 87 58 21 1 not done 10 90 79 43 17 3 11 96 82 49 27 12 12 95 64 24 7 not done 13 76 29 not done not done not done 14 94 ⁶⁸ 16 2 not done

Table 4

Average concentration (in ng/ml) of compound B in blood after subcutaneous administration of microcapsules (n = 5)

Working example No. 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 microcapsules obtained in Working Example 8 were dispersed in 0.2 ml of 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 applied using 22G needles into the neck of 28-week-old male 12008SHR rats implanted with a blood pressure transmitter for telemetry. After this application, blood pressure was monitored. The same preparation was subcutaneously applied into the neck of 29-week-old male 12008SHR rats.

After application, blood was collected from the tail vein at regular intervals. Table 5 shows the concentration of compound B in the blood and the effect of compound B on lowering blood pressure.

Table 5

Average concentration of compound B in the blood and its effect on lowering blood pressure after subcutaneous application of microcapsules (n = 3)

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

Industrial applicability

In the sustained release composition of the present invention, which contains high amounts of a compound having AII antagonistic activity, the rate of drug release can be controlled. Thus, the composition has AII antagonistic activity while maintaining the circadian rhythm of blood pressure for a long time.

In addition, the sustained-release preparation of the present invention is able to maintain a constant blood concentration of the drug for a day and night. Therefore, compared with the situation when administering conventional oral preparations, the change in blood concentration of the drug is not significant, and the patient's condition cannot be changed due to the change in the administration time, interruption of drug intake, intentional omission of drug intake in patients suffering from subjective symptoms, etc. Therefore, it can be expected that the therapeutic effect of the drug on circulatory diseases such as hypertension, heart disease (hypercardia, heart failure, myocardial infarction, etc.), nephritis, stroke, etc. will be clarified by using the sustained-release preparation 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.