Stable pharmaceutical composition of fumagillol derivatives

• US 5,422,363 A
• Filed: 12/15/1993
• Issued: 06/06/1995
• Est. Priority Date: 12/16/1992
• Status: Expired due to Term

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Yanai, Shigeo, Saito, Kazuhiro, Okada, Hiroaki
• Primary Examiner(s): LONE, WERREN
• Application Number:
  US08/167,479
• Time in Patent Office: 538 Days
• Field of Search: 514/410
• US Class Current: 514/410
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 9/1617 Organic compounds, e.g. phospholipids, fats

Abstract

A pharmaceutical composition having improved stability which comprises a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin is disclosed. The composition is useful for treating diseases associated with angiogenesis such as hepatoma, etc.

Claims

1. A pharmaceutical composition comprising a fumagillol derivative represented by the formula (I):

##STR2## wherein R¹ is hydrogen;

R² is halogen, N(O)_m R⁵ R⁶, N+R⁵ R⁶ R⁷.X^-, S(O)_n R⁵ or S+R⁵ R⁶.X^-, in which R⁵, R⁶ and R⁷ represent each independently a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterocyclic group;

X^- represents a counter anion;

m represents 0 or 1;

n represents an integer of 0 to 2;

or R⁵ and R⁶ together with the adjacent nitrogen or sulfur atom may form a nitrogen- or sulfur-containing heterocyclic group which is substituted or unsubstituted and may form a condensed ring;

or R¹ and R² together are a chemical bond;

R³ is a substituted or unsubstituted 2-methyl-1-propenyl group or a substituted or unsubstituted isobutyl group;

A is O or NR⁸, in which R⁸ represents hydrogen, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group; and

R⁴ is hydrogen, a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted acyl group;

or a salt thereof, and a fatty acid ester of glycerin or polyglycerin wherein the fatty acid constituting the fatty acid ester is a saturated fatty acid having 6 to 22 carbon atoms.

2. A pharmaceutical composition according to claim 1, wherein the fumagillol derivative is dissolved or dispersed in the fatty acid ester of glycerin or polyglycerin.

3. A pharmaceutical composition according to claim 1, wherein the fatty acid ester of glycerin is a fatty acid triglyceride.

4. A pharmaceutical composition according to claim 1, wherein the fumagillol derivative is dissolved in a fatty acid triglyceride.

5. A pharmaceutical composition according to claim 1, wherein the ratio of the fumagillol derivative based on the fatty acid ester of glycerin, or polyglycerin is about 0.001 to about 50% (w/v).

6. A pharmaceutical composition according to claim 1, wherein the degree of esterification of the glycerin or polyglycerin is at least about 60%.

7. A pharmaceutical composition according to claim 1, wherein the degree of polymerization of the polyglycerin is 2 to 10.

8. A pharmaceutical composition according to claim 1, which comprises an injectable composition.

9. A pharmaceutical composition according to claim 1, which is in a liquid form.

10. A pharmaceutical composition according to claim 1, which comprises a solid micro-particle composition having an particle diameter of about 10 to 1000 μ

m.

11. A pharmaceutical composition according to claim 1 wherein R¹ and R² together are a chemical bond, or R¹ is hydrogen and R² is N(O)_m R⁵ R⁶, N⁺ R⁵ R⁶ R⁷.X^-,S(O)_n R⁵ or S⁺ R⁵ R⁶.X^- ;

A is O or NH;

R³ is a substituted or unsubstituted 2-methyl-1-propenyl or isobutyl group; and

R⁴ is hydrogen or a substituted or unsubstituted carbamoyl group.

12. A pharmaceutical composition according to claim 1, wherein R¹ and R² together are a chemical bond.

13. A pharmaceutical composition according to claim 11, wherein A is O;

R³ is a 2-methyl-1-propenyl or isobutyl group which is unsubstituted or substituted with a hydroxyl or dialkylamino group;

R⁴ is a carbamoyl group which is substituted with a C_1-6 alkyl or halogeno-C_1-6 alkanoyl group.

14. A pharmaceutical composition according to claim 1, wherein the fumagillol derivative is 6-O-(N-chloroacetylcarbamoyl)fumagillol.

15. A pharmaceutical composition according to claim 1, wherein the fumagillol derivative is 4-(N'"'"'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl )-1-(1,3-dihydrobenzo[c]thiophen-2-ylio)methyl-3-methoxycyclohexanol chloride.

16. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is caprylic acid (C₈).

17. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is capric acid (C₁₀).

18. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is caprylic acid (C₈) and capric acid (C₁₀).

19. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is lauric acid (C₁₂).

20. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is myristic acid (C₁₄).

21. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is palmitic acid (C₁₆).

22. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is stearic acid (C₁₈).

23. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is arachidic acid (C₂₀).

24. A pharmaceutical composition according to claim 1, wherein the main component of the fatty acid which constitutes the fatty acid ester is behenic acid (C₂₂).

25. A pharmaceutical composition according to claim 1, which is an angiogenesis inhibitory composition.

26. A method of stabilizing a fumagillol derivative (I) or a salt thereof as defined in claim 1 which comprises dissolving or dispersing the fumagillol derivative in a fatty acid ester of glycerin or polyglycerin as defined in claim 1.

27. A method of treating a disease associated with angiogenesis in mammals which comprises administering the pharmaceutical composition according to claim 1 to a subject in need thereof.

28. A method according to claim 27, wherein the disease is a malignant tumor.

29. A method according to claim 28, wherein the malignant tumor is hepatoma.

30. A pharmaceutical composition for inhibiting angiogenesis comprising a fumagillol derivative (I) or a salt thereof as defined in claim 1 and a fatty acid ester of glycerin or polyglycerin as defined in claim 1.

31. A stable, sustained-release composition for inhibiting angiogenesis comprising a fumagillol derivative (I) or a salt thereof as defined in claim 1 and a fatty acid ester of glycerin or polyglycerin as defined in claim 1.