Hyaluronan as a cytotoxic agent, drug pre-sensitizer and chemo-sensitizer in the treatment of disease

• US 20060178342A1
• Filed: 08/05/2005
• Published: 08/10/2006
• Est. Priority Date: 07/14/2000
• Status: Active Grant

• Current Assignee: Alchemia Oncology Limited
• Original Assignee: Alchemia Oncology Limited
• Inventors: Fox, Richard, Brown, Tracey
• Granted Patent: US 9,066,919 B2
• Time in Patent Office: Days
• US Class Current: 514/54
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/525 Isoalloxazines, e.g. riboflavins, vitamin B2
• 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 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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

Abstract

This application provides methods and compositions for the treatment of cancer. The application provides compositions comprising hyaluronic acid and a chemotherapeutic agent such as irinotecan that are useful in the treatment of cancer.

Claims

1. A method of preventing metastasis of a cellular proliferative disease comprising the step of administering to a subject in need thereof a therapeutically effective amount of a 750,000 to 1,500,000 dalton hyaluronan

2. The method of claim 1, wherein said hyaluronan is provided in combination with one or more of a pharmaceutical carrier, adjuvant or vehicle.

3. The method according to claim 1, wherein the cellular proliferative disorder is selected from the group consisting of cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, colon, intestinal, exocrine, endocrine, lymphatic, hematopoietic system or head and neck tissue.

4. The method according to claim 1, wherein the subject is a mammal.

5. The method according to claim 4, wherein the mammal is selected from the group consisting of bovine, canine, equine, feline, porcine and human.

6. The method according to claim 1, further comprising the step of administering a chemotherapeutic agent.

7. The method of claim 6, wherein the bioavailability of the chemotherapeutic agent is enhanced.

8. The method according to claim 6, wherein the administration of hyaluronan is prior to or subsequent to the administration of the chemotherapeutic agent.

9. The method according to claim 6, wherein the chemotherapeutic agent is selected from the group consisting of carmustine (BCNU), chlorambucil (Leukeran), cisplatin (Platinol), Cytarabine, doxorubicin (Adriamycin), fluorouracil (5-FU), methotrexate (mexate), CPT 11 (irinotecan), etoposide, pliamycin (Mithracin) and taxanes.

10. The method according to claim 9, wherein the chemotherapeutic agent is fluorouracil (5-FU).

11. The method according to claim 6, wherein the chemotherapeutic agent is CPT11.

12. The method according to claim 1, wherein the administration is orally, topically, or parenterally.

13. The method according to claim 12, wherein parenteral administration is by subcutaneous injection, aerosol, intravenous, intramuscular, intrathecal, intracranial, intrasternal injection or infusion techniques.

14. A method of treating a cellular proliferative disease comprising the step of orally or parenterally administering to a subject in need thereof a therapeutically effective amount of a composition comprising a 750,000 to 1,500,000 dalton hyaluronan and a chemotherapeutic agent.

15. The method of claim 14, wherein said hyaluron is provided in combination with one or more of a pharmaceutical carrier, adjuvant or vehicle.

16. The method according to claim 14, wherein the cellular proliferative disorder is selected from the group consisting of cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, colon, intestinal, exocrine, endocrine, lymphatic, hematopoietic system or head and neck tissue.

17. The method according to claim 14, wherein the subject is a mammal.

18. The method according to claim 17, wherein the mammal is selected from the group consisting of bovine, canine, equine, feline, porcine and human.

19. The method according to claim 14, wherein the bioavailability of the chemotherapeutic agent is enhanced.

20. The method according to claim 14, wherein the administration of hyaluronan is prior to or subsequent to the administration of the chemotherapeutic agent.

21. The method according to claim 14, wherein the chemotherapeutic agent is selected from the group consisting of carmustine (BCNU), chlorambucil (Leukeran), cisplatin (Platinol), Cytarabine, doxorubicin (Adriamycin), fluorouracil (5-FU), methotrexate (mexate), CPT 11 (irinotecan), etoposide, pliamycin (Mithracin) and taxanes.

22. The method according to claim 21, wherein the chemotherapeutic agent is fluorouracil (5-FU).

23. The method according to claim 14, wherein the administration is orally, topically, or parenterally.

24. The method according to claim 23, wherein parenteral administration is by subcutaneous injection, aerosol, intravenous, intramuscular, intrathecal, intracranial, intrasternal injection or infusion techniques.

25. A method of treating a drug resistant disease in a subject in need thereof comprising the step of orally or parenterally administering to said subject a therapeutically effective amount of a 750,000 to 1,500,000 dalton hyaluronan in conjunction with a chemotherapeutic agent.

26. The method of claim 25, wherein said hyaluron is provided in combination with one or more of a pharmaceutical carrier, adjuvant or vehicle.

27. The method according to claim 25, wherein the cellular proliferative disorder is selected from the group consisting of cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, hematopoietic system or head and neck tissue.

28. The method according to claim 25, wherein the subject is a mammal.

29. The method according to claim 28, wherein the mammal is, selected from the group consisting of bovine, canine, equine, feline, porcine and human.

30. The method according to claim 25, wherein the. administration of hyaluronan is prior to or subsequent to the administration of the chemotherapeutic agent.

31. The method according to claim 25, wherein the bioavailability of the chemotherapeutic agent is enhanced.

32. The method according to claim 25, wherein the chemotherapeutic agent is selected from the group consisting of carmustine (BCNU), chlorambucil (Leukeran), cisplatin (Platinol), Cytarabine, doxorubicin (Adriamycin), fluorouracil (5-FU), methotrexate (mexate), CPT 11 (irinotecan), etoposide, pliamycin (Mithracin) and taxanes.

33. The method according to claim 32, wherein the chemotherapeutic agent is fluorouracil (5-FU).

34. The method according to claim 25, wherein the administration is orally, topically, or parenterally.

35. The method according to claim 34, wherein parenteral administration is either by subcutaneous injection, aerosol, intravenous, intramuscular, intrathecal, intracranial, intrasternal injection or infusion techniques.

36. A pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent or a derivative thereof and hyaluronic acid.

37. The composition of claim 36, wherein said anticancer agent is irinotecan (CPT 11) or a derivative thereof.

38. The composition of claim 36, wherein the molecular weight of hyaluronic acid is 800,000 to 1,000,000 daltons.

39. The composition of claim 38, wherein the molecular weight of hyaluronic acid is about 825,000 to 850,000 daltons.

40. A method of treating a patient with cancer comprising the administration of a therapeutically effective amount of an anticancer agent, or a derivative thereof and hyaluronic acid to a patient in need of such treatment.

41. A method of treating a patient with cancer comprising the administration of a therapeutically effective amount of irinotecan (CPT 11) or a derivative thereof and hyaluronic acid to a patient in need of such treatment.

42. A method of claim 41, wherein the molecular weight of hyaluronic acid is about 800,000 to 1,000,000 daltons.

43. A method of claim 42, wherein the molecular weight of hyaluronic acid is about 825,000 to 850,000 daltons.

44. A method of claim 41, wherein the therapeutically effective amount of irinotecan (CPT 11) is about 100 to 500 mg/m2.

45. A method of claim 44, wherein the therapeutically effective amount of irinotecan (CPT 11) is about 100 to 150 mg/m2 administered every five to ten days for two or more cycles.

46. A method of claim 44, wherein the therapeutically effective amount of irinotecan (CPT11) is about 300 to 350 mg/m2 administered every 15 to 30 days for two or more cycles.

47. The method according to claim 41, wherein the administration is orally, topically, or parenterally.

48. The method according to claim 47, wherein parenteral administration is by subcutaneous injection, aerosol, intravenous, intramuscular, intrathecal, intracranial, intrasternal injection or infusion techniques.

49. The method according to claim 42, wherein one or both of the hyaluronan and irinotecan are administered by intravenous injection.

50. The method according to claim 42, wherein the cancer is lung cancer.

51. The method of claim 42, wherein the cancer is pancreatic cancer

52. A method of treating a subject having colorectal cancer comprising:

administering to said subject a composition comprising hyaluronic acid and an effective amount of irinotecan (CPT

     11) or a derivative thereof, thereby treating the subject.

53. The method of claim 52, wherein said hyaluronic acid has a molecular weight of about 825,000 to 850,000 daltons.

54. The method of claim 52, wherein said hyaluronic acid is administered at a concentration of about 500 to 1500 mg/m2.

55. The method of claim 52 where said hyaluronic acid is administered at a concentration of about 900 to 1100 mg/m2.

56. The method of claim 52, wherein said irinotecan is administered at a concentration of about 1000 mg/m2.

57. The method according to claim 56, wherein one or both of the hyaluronan and CPT11 is administered by intravenous injection.

58. A method of treating a subject having colorectal cancer comprising:

administering to said subject a composition comprising hyaluronic acid having a molecular weight of about 825,000 to 850,00 daltons at a concentration of about 25 mg/kg to about 100 mg/kg and an effective amount of irinotecan (CPT

     11) or a derivative thereof at a concentration of 50 mg/kg, thereby treating the subject.