Stable emulsion compositions

• US 20030212114A1
• Filed: 07/30/2002
• Published: 11/13/2003
• Est. Priority Date: 02/04/2000
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Sato, Jun
• Granted Patent: US 7,105,572 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 311/14 : Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07D 275/06 : with hetero atoms directly attached to the ring sulfur atom

Abstract

An emulsion composition containing a compound represented by the formula:

wherein R is an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR¹ (wherein R¹ is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula:

wherein R^1b is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R^1c is the same as or different from R^1b and is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R⁰ is a hydrogen atom or an aliphatic hydrocarbon group, or R and R⁰ in combination represent a bond, Ar is an aromatic hydrocarbon group optionally having substituents

and the like, and n is an integer of 1 to 4, a salt thereof or a prodrug thereof, wherein the composition is adjusted to have a pH of not more than about 6, shows improved stability of the compound, a salt thereof or a prodrug thereof, and realizes expression of superior efficacy.

Claims

1. An emulsion composition comprising a compound (I) represented by the formula:

2. The composition according to claim 1, wherein R is (1) (A) a linear or branched C_1-20 alkyl group, (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, all of which optionally having 1 to 4 substituents selected from the group (hereinafter substituent group A) consisting of (i) a 5- to 8-membered ring group or its condensed ring group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (ii) an oxo group, (iii) a hydroxyl group, (iv) a C_1-6 alkoxy group, (v) a C_3-10 cycloalkyloxy group, (vi) a C_6-10 aryloxy group, (vii) a C_7-19 aralkyloxy group, (viii) a 5- to 8-membered ring group or its condensed ring-oxy group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (ix) a C_1-6 alkylthio group (sulfur atom may be oxidized), (x) a C_3-10 cycloalkylthio group (sulfur atom may be oxidized), (xi) a C_6-10 arylthio group (sulfur atom may be oxidized), (xii) a C_7-19 aralkylthio group (sulfur atom may be oxidized), (xiii) a 5- to 8-membered ring group or its condensed ring thereof-thio group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (xiv) a 5- to 8-membered ring group or its condensed ring-sulfinyl group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (xv) a 5- to 8-membered ring group or its condensed ring-sulfonyl group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (xvi) a nitro group, (xvii) a halogen atom, (xviii) a cyano group, (xix) a carboxyl group, (xx) a C_1-10 alkoxy-carbonyl group, (xxi) a C_3-6 cycloalkyloxy-carbonyl group, (xxii) a C_6-10 aryloxy-carbonyl group, (xxiii) a C_7-19 aralkyloxy-carbonyl group, (xxiv) a 5- to 8-membered ring group or its condensed ring-oxycarbonyl group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which is optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy, (xxv) a C_6-10 aryl-carbonyl group, (xxvi) a C_1-6 alkanoyl group, (xxvii) a C_3-5 alkenoyl group, (xxviii) a C_6-10 aryl-carbonyloxy group, (xxix) a C_2-6 alkanoyloxy group, (xxx) a C_3-5 alkenoyloxy group, (xxxi) a carbamoyl group or a cyclic aminocarbonyl group, which is optionally substituted by 1 or 2 substituents selected from a C_1-4 alkyl, a phenyl, a C_1-7 acyl and a C_1-4 alkoxy-phenyl, (xxxii) a thiocarbamoyl group optionally substituted by 1 or 2 substituents selected from a C_1-4 alkyl and a phenyl, (xxxiii) a carbamoyloxy group optionally substituted by 1 or 2 substituents selected from a C_1-4 alkyl and a phenyl, (xxxiv) a C_1-6 alkanoylamino group, (xxxv) a C_6-10 aryl-carbonylamino group, (xxxvi) a C_1-10 alkoxy-carboxamide group, (xxxvii) a C_6-10 aryloxy-carboxamide group, (xxxviii) a C_7-19 aralkyloxy-carboxamide group, (xxxix) a C_1-10 alkoxy-carbonyloxy group, (xxxx) a C_6-10 aryloxy-carbonyloxy group, (xxxxi) a C_7-19 aralkyloxy-carbonyloxy group, (xxxxii) a C_3-10 cycloalkyloxy-carbonyloxy group, (xxxxiii) a ureido group optionally substituted by 1 to 3 substituents selected from a C_1-4 alkyl group and a phenyl group, and (xxxxiv) a C_6-10 aryl group optionally having 1 to 4 substituents selected from the group consisting of the above-mentioned (i) to (xxxxiii), wherein the substituent selected from substituent group A may form, together with (A) a linear or branched C_1-20 alkyl group, (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, an indanyl group or a 1,2,3,4-tetrahydronaphthyl group, all of which optionally having 1 to 4 substituents selected from the substituent group A,

(2) a C_6-14 aromatic hydrocarbon group optionally having 1 to 5 substituents selected from the group consisting of a halogen atom, a C_1-4 alkyl group, a C_1-4 alkoxy group, a C_1-4 alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, a C_1-4 alkanoylamino group, a C_3-6 cycloalkyl group, a C_6-10 aryl group, a halogeno C_1-4 alkyl group, a halogeno C_1-4 alkoxy group, a C_1-4 alkylthio group, a C_1-4 alkylsulfonyl group, a C_1-4 alkanoyl group, a 5-membered aromatic heterocyclic group, a carbamoyl group, a C_1-4 alkyl-carbamoyl group, a C_1-4 alkoxy-carbonyl-C_1-4 alkyl-carbamoyl group and a 1,3-diacylguanidino-C_1-4 alkyl group,

(3) a 5- to 8-membered ring group or its condensed ring group, which contains 1 to 4 hetero atoms selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, and which optionally has 1 to 3 substituents selected from the group consisting of a C_1-4 alkyl, a hydroxy, an oxo and a C_1-4 alkoxy,

(4) a group represented by the formula —

OR¹ (wherein R¹ is (i) a hydrogen atom or (ii) (A) a linear or branched C_1-20 alkyl group, (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, all of which optionally having 1 to 4 substituents selected from the substituent group A), wherein the substituent selected from the substituent group A may form, together with (A) the linear or branched C_1-20 alkyl group, (B) the C_3-10 cycloalkyl group, (C) the C_4-12 cycloalkylalkyl group, (D) the lower (C_3-6) alkenyl group or (E) the lower (C_3-6) alkynyl group, an indanyl group or 1,2,3,4-tetrahydronaphthyl group, which optionally has 1 to 4 substituents selected from the substituent group A, or

(5) a group represented by the formula

wherein R^1b is (i) a hydrogen atom or (ii) (A) a linear or branched C_1-20 alkyl group, (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, all of which optionally having 1 to 4 substituents selected from the substituent group A, (wherein the substituent selected from the substituent group A may form, together with (A) the linear or branched C_1-20 alkyl group, (B) the C_3-10 cycloalkyl group, (C) the C_4-12 cycloalkylalkyl group, (D) the lower (C_3-6) alkenyl group or (E) the lower (C_3-6) alkynyl group, an indanyl group or a 1,2,3,4-tetrahydronaphthyl group, which optionally has 1 to 4 substituents selected from the substituent group A), and R^1c is the same as or different from R^1b and is (i) a hydrogen atom or (ii) (A) a linear or branched C_1-20 alkyl group, (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, all of which optionally having 1 to 4 substituents selected from the substituent group A (wherein the substituent selected from the substituent group A may form, together with (A) the linear or branched C_1-20 alkyl group, (B) the C_3-10 cycloalkyl group, (C) the C_4-12 cycloalkylalkyl group, (D) the lower (C_3-6) alkenyl group or (E) the lower (C_3-6) alkynyl group, an indanyl group or a 1,2,3,4-tetrahydronaphthyl group, which optionally has 1 to 4 substituents selected from the substituent group A) or an aliphatic hydrocarbon group optionally having a substituent,

R⁰ is a hydrogen atom, a linear or branched C_1-20 alkyl group, a C_3-10 cycloalkyl group, a C_4-12 cycloalkylalkyl group, a lower (C_3-6) alkenyl group or a lower (C_3-6) alkynyl group,

or R and R⁰ in combination represent a bond,

ring A¹ is

(1) (A) a linear or branched C_1-20 alkyl group (B) a C_3-10 cycloalkyl group, (C) a C_4-12 cycloalkylalkyl group, (D) a lower (C_3-6) alkenyl group or (E) a lower (C_3-6) alkynyl group, all of which optionally having 1 to 4 substituents selected from the substituent group A (wherein the substituents selected from the substituent group A may form, together with (A) the linear or branched C_1-20 alkyl group, (B) the C_3-10 cycloalkyl group, (C) the C_4-12 cycloalkylalkyl group, (D) the lower (C_3-6) alkenyl group or (E) the lower (C_3-6) alkynyl group, an indanyl group or a 1,2,3,4-tetrahydronaphthyl group, which optionally has 1 to 4 substituents selected from the substituent group A),

(2) a C_6-14 aromatic hydrocarbon group optionally having 1 to 5 substituents selected from the group consisting of a halogen atom, a C_1-4 alkyl group, a C_1-4 alkoxy group, a C_1-4 alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, a C_1-4 alkanoylamino group, a C_3-6 cycloalkyl group, a C_6-10 aryl group, a halogeno C_1-4 alkyl group, a halogeno C_1-4 alkoxy group, a C_1-4 alkylthio group, a C_1-4 alkylsulfonyl group, a C_1-4 alkanoyl group, a 5-membered aromatic heterocyclic group, a carbamoyl group, a C_1-4 alkyl-carbamoyl group, a C_1-4 alkoxy-carbonyl-C_1-4 alkyl-carbamoyl group and a 1,3-diacylguanidino-C_1-4 alkyl group,

(3) a group represented by the formula —

OR¹ (wherein R¹ is as defined above) or

(4) a cycloalkene optionally substituted by 1 to 4 substituents selected from halogen atoms, and

Ar is a C_6-14 aromatic hydrocarbon group optionally having 1 to 5 substituents selected from the group consisting of a halogen atom, a C_1-4 alkyl group, a C_1-4 alkoxy group, a C_1-4 alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, a C_1-4 alkanoylamino group, a C_3-6 cycloalkyl group, a C_6-10 aryl group, a halogeno C_1-4 alkyl group, a halogeno C_1-4 alkoxy group, a C_1-4 alkylthio group, a C_1-4 alkylsulfonyl group, a C_1-4 alkanoyl group, a 5-membered aromatic heterocyclic group, a carbamoyl group, a C_1-4 alkyl-carbamoyl group, a C_1-4 alkoxy-carbonyl-C_1-4 alkyl-carbamoyl group and a 1,3-diacylguanidino-C_1-4 alkyl group.

3. The composition according to claim 1, wherein the compound is (A) d-ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (B) d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (C) ethyl 6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, (D) ethyl 6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, or a salt thereof.

4. The composition according to claim 1, which is an oil-in-water type.

5. The composition according to claim 1, which has a pH adjusted to about 3 to about 6.

6. The composition according to claim 1, which is used as an injection.

7. The composition according to claim 1, which comprises a disperse phase particle comprising an oil component, an emulsifier and compound (I), a salt thereof or a prodrug thereof, and water in which the disperse phase particle is dispersed.

8. The composition according to claim 7, wherein the oil component is selected from the group consisting of a vegetable oil, a partially hydrogenated vegetable oil, a simple glyceride, a mixed glyceride and a medium-size chain fatty acid glycerol ester.

9. The composition according to claim 7, wherein the oil component is a vegetable oil.

10. The composition according to claim 9, wherein the vegetable oil is a soybean oil, a cottonseed oil, a rapeseed oil, a peanut oil, a safflower oil, a sesame oil, a rice bran oil, a corn germ oil, a sunflower oil, a poppy oil or an olive oil.

11. The composition according to claim 10, wherein the vegetable oil is a soybean oil.

12. The composition according to claim 7, wherein the emulsifier is a phospholipid or a nonionic surfactant.

13. The composition according to claim 7, wherein the emulsifier is a phospholipid.

14. The composition according to claim 13, wherein the phospholipid is an egg yolk lecithin, a soybean lecithin, a hydrogenation product thereof, a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidic acid, a phosphatidylserine, a phosphatidylinositol or a phosphatidylglycerol.

15. The composition according to claim 14, wherein the phospholipid is an egg yolk lecithin.

16. The composition according to claim 7, wherein the oil component is used in a proportion of about 1-about 30 wt % of the whole composition.

17. The composition according to claim 7, wherein the emulsifier is used in a proportion of about 0.1-about 10 w/v %.

18. The composition according to claim 7, wherein the emulsifier is contained in a proportion of about 0.1-about 150 wt % of the oil component.

19. The composition according to claim 1, which comprises a vegetable oil and a phospholipid.

20. The composition according to claim 1, which comprises a soybean oil, an egg yolk lecithin, a glycerol and a purified water.

21. The composition according to claim 1 or 7, which comprises the compound (I), a salt thereof or a prodrug thereof in a proportion of about 0.001-about 95 wt % of the whole composition.

22. The composition according to claim 1 or 7, which comprises the compound (I), a salt thereof or a prodrug thereof in a proportion of about 0.01-about 30 wt % of the whole composition.

23. The composition according to claim 7, wherein the disperse phase particle has an average particle size of about 25-about 500 nm.

24. The composition according to claim 1, which is a nitric oxide and/or a cytokine production inhibitor.

25. The composition according to claim 1, which is an agent for the prophylaxis or treatment of a cardiac disease, an autoimmune disease, sepsis or septic shock.

28. A method for the prophylaxis or treatment of a cardiac disease, an autoimmune disease, sepsis or septic shock, which comprises administrating an effective amount of the composition of claim 1 to a mammal.

29. Use of the composition of claim 1 for manufacturing an agent for the prophylaxis or treatment of a cardiac disease, an autoimmune disease, sepsis or septic shock.

26. A method for stabilizing an emulsion composition comprising a compound represented by the formula:

27. The stabilizing method according to claim 26, which improves the stability during autoclave sterilization.