Doxorubicin formulations for anti-cancer use

• US 20070196493A1
• Filed: 02/22/2006
• Published: 08/23/2007
• Est. Priority Date: 02/22/2006
• Status: Active Grant

• Current Assignee: Softkemo Pharma Corp.
• Original Assignee: Supratek Pharma, Inc.
• Inventors: Pietrzynski, Grzegorz, Klinski, Evgueni, Patel, Kishore, Alakhov, Valery
• Granted Patent: US 8,148,338 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: A61P 35/00 Antineoplastic agents

Abstract

Doxorubicin block copolymer formulations for use in preparing injectable compositions for treating cancer patients which contain lactose for solubilizing the doxorubicin and block copolymers in said formulations and methyl paraben for stabilizing these formulations, as well as a method of preparing and using these injectable compositions.

Claims

1. A composition comprising a) doxorubicin or a pharmaceutically acceptable salt thereof, b) a mixture of polyoxyethylene polyoxypropylene copolymers, wherein the copolymer mixture contains two block copolymers, one of which is a hydrophobic polymer having an ethylene oxide content of from about 10% to about 50% by weight of the copolymer mixture and the other being a hydrophilic copolymer having an ethylene oxide content of from about 50% by weight to about 90% by weight of the copolymer mixture, and c) lactose, wherein said lactose is present in said composition in an amount at least sufficient to solubilize said doxorubicin or its salt in an aqueous medium.

2. The composition of claim 1, wherein said lactose is present in the composition in an amount of from about 2.5 parts to about 25 parts by weight based upon the weight of doxorubicin or its salt in the composition.

3. The composition of claim 2, wherein said copolymer mixture in said composition is present in an amount of from about 4 parts to about 40 parts by weight of the doxorubicin or its salt in said composition.

4. The composition of claim 3, wherein a hydrophilic copolymer is present in an amount of from about 2 to about 20 per parts by weight of a hydrophobic copolymer.

5. The composition of claim 4, wherein the hydrophilic copolymer is present in an amount of 3 to 10 parts by weight per part by weight of the hydrophobic copolymer.

6. The composition of claim 4, wherein said composition contains from about 10 to about 15 parts by weight of the copolymer mixture based upon the weight of doxorubicin in the composition.

7. The composition of claim 6, wherein the block copolymers are selected from the compounds of the formula:

8. The composition of claim 7, wherein both block copolymers have the formula:

wherein z, y and z are as above.

9. The composition of claim 1, wherein said composition contains methyl paraben in an amount at least sufficient to stabilize the doxorubicin or its pharmaceutically acceptable salt in said composition.

10. The composition of claim 8, wherein said composition contains methyl paraben in an amount of from about 0.1 parts by weight to 2 parts by weight based upon the weight of doxorubicin or its pharmaceutically acceptable salts.

11. A composition for delivering a doxorubicin to a patient comprising a composition containing a) a therapeutically effective amount of doxorubicin or pharmaceutically acceptable salts thereof, b) a mixture of polyoxyethylene polyoxypropylene copolymers, wherein the copolymer mixture contains two block copolymers, one of which is a hydrophobic block copolymer having an ethylene oxide content of from about 10% to about 50% by weight of the copolymer mixture and the other being a hydrophilic block copolymer with an ethylene oxide content of from about 50% by weight to about 90% by weight of the copolymer mixture, and c) lactose, said lactose being present in said composition in an amount at least sufficient to solubilize the doxorubicin or its pharmaceutically acceptable salt in an aqueous medium.

12. The composition of claim 11, wherein said composition is in the form for injectable administration to a patient.

13. The composition of claim 12, wherein said lactose is present in the composition in an amount of from about 2.5 parts to about25 parts by weight based upon the weight of doxorubicin or its salt in the composition.

14. The composition of claim 13, wherein said copolymer mixture in said composition is present in an amount of from about 4 parts to about 40 parts by weight of the doxorubicin or its salt in said composition.

15. The composition of claim 14, wherein a hydrophilic copolymer is present in an amount of from about 2 to about 20 per parts by weight of a hydrophobic copolymer.

16. The composition of claim 15, wherein the hydrophilic copolymer is present in an amount of from about 3 to about 10 parts by weight per part by weight of the hydrophobic copolymer.

17. The composition of claim 14, wherein said composition contains from about 10 to about 15 parts by weight of the copolymer mixture based upon the weight of doxorubicin in the composition.

18. The composition of claim 11, wherein said composition contains methyl paraben in an amount at least sufficient to stabilize the doxorubicin or its pharmaceutically acceptable salt in said composition.

19. The composition of claim 18, wherein said composition contains methyl paraben in an amount of from about 0.1 parts by weight to about 2 parts by weight based upon the weight of doxorubicin or its pharmaceutically acceptable salts.

20. The composition of claim 14, wherein the block copolymers are selected from the compounds of the formula:

21. The composition of claim 20, wherein both block copolymers have the formula:

wherein z, y and z are as above.

22. An injectable liquid unit dosage form comprising a mixture containing a) from about 16 mg to about 200 mg of doxorubicin or pharmaceutically acceptable salts thereof, b) a mixture of polyoxyethylene polyoxypropylene copolymers, wherein the copolymer mixture contains two block copolymers, one of which is a hydrophobic copolymer having an ethylene oxide content of from about 10% to about 50% by weight of the copolymer mixture and the other being a hydrophilic copolymer with an ethylene oxide content of from about 50% by weight to about 90% by weight of the copolymer mixture, and c) lactose present in said composition in an amount of from about 2.5 parts by weight to about 25 parts by weight based upon the weight of the doxorubicin or pharmaceutically acceptable salt thereof wherein said mixture is dissolved in a suitable injectable aqueous medium.

23. The injectable unit dosage form of claim 22, wherein said copolymer mixture in said composition is present in an amount of from about 4 parts to about 40 parts by weight of the doxorubicin in said composition.

24. The injectable unit dosage form of claim 23, wherein said composition contains methyl paraben in an amount of from about 0.1 parts by weight to about 2 parts by weight based upon the weight of doxorubicin or its pharmaceutically acceptable salts.

25. The injectable unit dosage form of claim 24, wherein said composition contains from about 10 to about 15 parts by weight of the copolymer mixture based upon the weight of doxorubicin in the composition.

26. The injectable unit dosage form of claim 25, wherein said unit dosage form has a volume of from about 10 mL to about 500 mL.

27. The injectable unit dosage form of claim 26, wherein said dosage form is a vial or ampoule.

28. The injectable unit dosage form of claim 22, wherein the block copolymers are selected from the compounds of the formula:

29. The injectable unit dosage form of claim 28, wherein both block copolymers have the formula:

wherein z, y and z are as above.

30. A method of forming a doxorubicin composition comprising providing a first mixture containing a) a predetermined amount of doxorubicin or pharmaceutically acceptable salt thereof, b) polyoxyethylene polyoxypropylene copolymer mixture, wherein the copolymer mixture contains two block copolymers, one of which is a hydrophobic copolymer having an ethylene oxide content of from about 10% to about 50% by weight of the copolymer mixture and the other block copolymer being a hydrophilic copolymer having an ethylene oxide content of from about 50% by weight to about 90% by weight of the copolymer mixture, and c) lactose present in said composition in an amount at least sufficient to provide fast dissolution of said doxorubicin in an aqueous medium, dissolving said first mixture in an aqueous medium;

freeze drying said aqueous medium containing said first mixture to form first mixture as a dry solid.

31. The method of claim 30, wherein said dry solid is dissolved in an aqueous medium to form a second mixture and the resulting mixture is divided into separate injectable doses, each containing a therapeutically effective amount of said doxorubicin for injection into patients.

32. The method of claim 30, wherein said first mixture contains said copolymer mixture in an amount of from about 4 parts to about 40 parts by weight based upon the weight of the doxorubicin in said first mixture.

33. The method of claim 30, wherein said drying is carried out by freeze drying.

34. The method of claim 30, wherein said lactose is present in the composition in an amount of from about 2.5 parts to about 25 parts by weight based upon the weight of doxorubicin or its salt in the composition.

35. The method of claim 34, wherein a hydrophilic copolymer is present in an amount of from about 2 to about 20 per parts by weight of a hydrophobic copolymer.

36. The method of claim 30, wherein said composition contains methyl paraben in an amount of from about 0.1 parts by weight to about 2 parts by weight based upon the weight of doxorubicin or its pharmaceutically acceptable salts.

37. The method of claim 35, wherein said first mixture contains the copolymer mixture in an amount of from about 10 parts by weight to about 15 parts by weight based upon the weight of the doxorubicin in said first mixture.

38. The method of claim 37, wherein the block copolymers are selected from the compounds of the formula:

39. The method of claim 38, wherein both block copolymers have the formula:

wherein z, y and z are as above.

40. The method of treating tumors in cancer patients comprising injecting into said patients a liquid injectable aqueous composition containing an effective amount of doxorubicin, and a mixture of polyoxyethylene polyoxypropylene copolymer, wherein the copolymer mixture contains two block copolymers, one of which is a hydrophobic copolymer having an ethylene oxide content of from about 10% to about 50% by weight of the copolymer mixture and the other being a hydrophilic copolymer having an ethylene oxide content of from about 50% by weight to about 90% by weight of the copolymer mixture, and lactose, wherein said lactose is present in the composition in an amount at least sufficient to solubilize the doxorubicin or its pharmaceutically acceptable salt in said aqueous composition.

41. The method of claim 40, wherein the doxorubicin is administered to the patient in a dose of from about 30 mg to about 80 mg per square meter by means of said injection.

42. The method of claim 41, wherein the copolymer mixture is present in the composition in an amount of from about 4 parts to about 40 parts by weight based upon the weight of the doxorubicin in said composition.

43. The method of claim 42, wherein said lactose is present in the composition in an amount of from about 2.5 parts to about 25 parts per weight based upon the weight of said doxorubicin in the composition.

44. The method of claim 43, wherein a hydrophilic copolymer is present in an amount of from about 2 to about 20 per parts by weight of a hydrophobic copolymer.

45. The method of claim 40, wherein said composition contains methyl paraben in an amount at least sufficient to stabilize the doxorubicin or its pharmaceutically acceptable salt in said composition.

46. The method of claim 45 wherein said composition contains methyl paraben in an amount of from about 0.1 to about 2 parts by weight per part by weight of doxorubicin.