Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-08-09
2003-07-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S501000, C424S489000, C424S499000, C424S451000, C424S457000, C514S964000, C514S965000
Reexamination Certificate
active
06589547
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP99/01011, filed Mar. 3, 1999.
TECHNICAL FIELD
The present invention relates to a sustained-release preparation for a compound having angiotensin II antagonistic activity, its production method and its use as a medicine, etc.
BACKGROUND ART
The renin-angiotensin system is involved in the homeostasis to control systemic blood pressure, body fluid amount, balance among the electrolytes, etc. together with aldosterone system. The relation between the angiotensin and hypertension has been clarified based on the fact that angiotensin II having potent vasoconstrictive action elevates blood pressure via the angiotensin II receptors on the cellular membrane, and therefore, the antagonist of angiotensin II has been used for the treatment of hypertension caused by angiotensin. So far, drugs having angiotensin II antagonistic activity have been clinically applied by oral administration, however, said drugs are applied for symptomatic therapy which needs repeated administration. Therefore, due to the necessity for continuous administration, simultaneous administration with other drugs for oral administration, etc., the burden on the patient receiving oral administration of this kind of drug can not be ignored. Moreover, there is a possibility that the condition of the patient could change due to interruption of taking this kind of drug, etc. Thus, oral administration of drugs having angiotensin II antagonistic activity is not necessarily satisfactory in view of safe and reliable treatment.
In Pharmaceutical Research, 14, 887-891 (1997), there is reported a sustained-release preparation for 2-ethyl-5,7-dimethyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine having angiotensin II antagonistic activity, said preparation containing high molecular weight (Mw 82,000) polylactide and polyethylene glycol 400 distearate and it is described that the initial burst from the sustained-release preparation, whose drug content is about 10%, is about 20%.
In the Japanese publication translation of International patent application No. 504017/1998, a composition characterized in that a physiologically active protein together with a metal cation component is dispersed in a biocompatible polymer is disclosed.
DISCLOSURE OF INVENTION
The present invention is to provide a sustained-release preparation which comprises a high amount of a compound having angiotensin II antagonistic activity, whose initial burst is low and is capable of controlling the release rate of said compound after initial burst, and also its production and use.
The present inventors diligently made extensive studies to solve the above-mentioned problems and, as a result, they found that a sustained-release preparation comprising a compound having angiotensin II antagonistic activity and a biodegradable polymer can contain said compound in high amount, that the release rate of said compound can be controlled by the addition of a polyvalent metal compound and that by administering said preparation to spontaneous hypertension rat (SHR), the drug concentration in blood of the rat is maintained and the blood pressure of the rat can be lowered while maintaining circadian rhythm of blood pressure for a long time. The inventors made further investigations based on this finding, and developed the present invention.
More specifically, the present invention relates to
(1) a sustained-release preparation which comprises a compound having angiotensin II antagonistic activity (excluding 2-ethyl-5,7-dimethyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazo[4,5-b]pyridine and a salt thereof), its pro-drug or their salt, and a biodegradable polymer;
(2) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is a non-peptide compound;
(3) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is a compound having an oxygen atom in its molecule;
(4) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is a compound having an ether linkage or a carbonyl group;
(5) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is a compound of the formula (I):
wherein R
1
is a group capable of forming an anion or a group capable of converting thereinto, X shows that the phenylene group and the phenyl group bind to each other directly or through a spacer having an atomic chain length of 2 or less, n is an integer of 1 or 2, the ring A is a benzene ring having an optional substitution, in addition to the group R
2
, R
2
is a group capable of forming an anion or a group capable of converting thereinto, and R
3
is an optionally substituted hydrocarbon residue which may bind through a hetero-atom, or a salt thereof;
(6) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is Losartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsartan, Telmisartan, Irbesartan or Tasosartan;
(7) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic activity is 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or a salt thereof;
(8) a sustained-release preparation of the above (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 a salt thereof;
(9) a sustained-release preparation of the above (1), wherein the compound having angiotensin II antagonistic 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;
(10) a sustained-release preparation of the above (1), wherein the biodegradable polymer is &agr;-hydroxycarboxylic acid polymer;
(11) a sustained-release preparation of the above (10), wherein the &agr;-hydroxycarboxylic acid polymer is lactic acid-glycolic acid polymer;
(12) a sustained-release preparation of the above (11), wherein the molar ratio of lactic acid and glycolic acid is 100/0-40/60;
(13) a sustained-release preparation of the above (10), wherein the weight-average molecular weight of the polymer is 3,000-50,000;
(14) a sustained-release preparation of the above (1), which is for injection;
(15) a sustained-release preparation of the above (1), which further comprises a polyvalent metal;
(16) a sustained-release preparation of the above (15), wherein the polyvalent metal is zinc;
(17) a sustained-release preparation which comprises a compound having angiotensin II antagonistic activity, its pro-drug or their salt, biodegradable polymer and a polyvalent metal;
(18) a method for producing a sustained-release preparation of the above (1), which comprises removing the solvent from a solution containing a compound having angiotensin II antagonistic activity, its pro-drug or their salt, and a biodegradable polymer;
(19) a method for producing a sustained-release preparation of the above (17), which comprises removing the solvent from a solution containing a compound having angiotensin II antagonistic activity, its pro-drug or their salt, a biodegradable polymer and a polyvalent metal;
(20) a method of the above (19), wherein the polyvalent metal is zinc;
(21) a pharmaceutical composition, which comprises a sustained-release preparation of the above (1);
(22) a composition of the above (21), which is for the prevention or treatment of circulatory disease;
(23) a composition of the above (21), which is for the prevention or treatment of hypertension;
(24) a composition of the above (21), which is for the prevention or treatment of hypercardia, cardiac insufficiency, myocardial infarction, cerebral apoplexy, ischemic
Igari Yasutaka
Inada Yoshiyuki
Kamei Shigeru
Saikawa Akira
Bennett Rachel M.
Chao Mark
Page Thurman K.
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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