Anti-angiogenic compositions and methods of use

• US 20030004209A1
• Filed: 03/28/2002
• Published: 01/02/2003
• Est. Priority Date: 07/19/1993
• Status: Active Grant

• Current Assignee: Surgical Specialties Corporation Limited (Ssc Holdco Ltd)
• Original Assignee: Angiotech Pharmaceuticals Incorporated
• Inventors: Hunter, William L., Machan, Lindsay S., Arsenault, A. Larry
• Granted Patent: US 6,846,841 B2
• Time in Patent Office: Days
• US Class Current: 514/449
• 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 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• 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 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/5153 : Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/7007 : Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 2300/416 : Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 2300/622 : Microcapsules
• CPC Class Codes: A61L 2430/36 : for embolization or occlusion, e.g. vaso-occlusive compositions or devices
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/145 : Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C07K 14/811 : Serine protease (E.C. 3.4.21) inhibitors
• CPC Class Codes: C08L 2203/02 : for biomedical use
• CPC Class Codes: C08L 23/08 : Copolymers of ethene C08L23/16 takes precedence
• CPC Class Codes: C08L 23/0815 : Copolymers of ethene with aliphatic 1-olefins
• CPC Class Codes: C08L 23/0853 : Vinylacetate
• CPC Class Codes: C08L 2312/00 : Crosslinking
• CPC Class Codes: C08L 2666/06 : Homopolymers or copolymers of unsaturated hydrocarbons; Derivatives thereof
• CPC Class Codes: C08L 2666/18 : Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

The present invention provides compositions comprising an anti-angiogenic factor, and a polymeric carrier. Representative examples of anti-angiogenic factors include Anti-Invasive Factor, Retinoic acids and derivatives thereof, and paclitaxel. Also provided are methods for embolizing blood vessels, and eliminating biliary, urethral, esophageal, and tracheal/bronchial obstructions.

Claims

1. A composition, comprising:

(a) a compound which disrupts microtubule function; and

(b) a polymeric carrier, with the proviso that said polymeric carrier is not a capsule.

2. The composition according to claim 1 wherein said composition is formed into microspheres having an average size of between 0.5 and 200 μ

m.

3. The composition according to claim 1 wherein said composition is formed into a film with a thickness of between 100 μ

m and 2 mm.

4. The composition according to claim 1 wherein said composition is liquid above 45°

C., and solid or semi-solid at 37°

C.

5. The composition according to claim 1 wherein said polymeric carrier is poly(ethylene-vinyl acetate) (40% crosslinked).

6. The composition according to claim 1 wherein said polymeric carrier is copolymer of lactic acid and glycolic acid.

7. The composition according to claim 1 wherein said polymeric carrier is poly (caprolactone).

8. The composition according to claim 1 wherein said polymeric carrier is poly (lactic acid).

9. The composition according to claim 1 wherein said polymeric carrier is a copolymer of poly (lactic acid) and poly (caprolactone).

10. The composition according to claim 1 wherein said compound which disrupts microtubule function is paclitaxel.

11. The composition according to claim 1 wherein said compound which disrupts microtubule function is selected from the group consisting of estramustine, colchicine, methotrexate, curacin-A, epothilone, vinblastine and tBCEU.

13. The composition of claim 10 wherein said anti-angiogenic factor is selected from the group consisting of paclitaxel, suramin, methotrexate and lighter d group transition metals.

15. The composition according to claim 14 wherein said lighter d group is selected from the group consisting of species of vanadium, molybdenum, tungsten, titanium, niobium and tantalum.

16. A method for embolizing a blood vessel, comprising delivering into said vessel a therapeutically effective amount of composition according to any one of claims 1-15, such that said blood vessel is effectively occluded.

17. The method according to claim 16 wherein said blood vessel nourishes a tumor.

12. A composition, comprising:

(a) an anti-angiogenic factor; and

(b) hyaluronic acid.

14. A composition comprising:

(a) a lighter d group transition metal which inhibits the formation of new blood vessels; and

(b) a polymeric carrier.

18. A stent, comprising a generally tubular structure, the surface of which is coated with a composition comprising an anti-angiogenic factor and a polymeric carrier.

19. A method for expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said passageway is expanded.

20. A method for eliminating vascular obstructions, comprising inserting a vascular stent into a vascular passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said vascular obstruction is eliminated.

21. A method for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said biliary obstruction is eliminated.

22. A method for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said urethral obstruction is eliminated.

26. The method according to claim 25 wherein said composition is liquid above 45°

C. and solid or semi-solid at 37°

C.

27. The method according to claim 26 wherein the step of administering comprises spraying microspheres composed of said composition into the resection margin of the tumor.

30. The method according to claim 28 or 29 wherein said method further comprises the administration of a topical corticosteroid.

23. A method for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said esophageal obstruction is eliminated.

24. A method for eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into the trachea or bronchi, the stent having a generally tubular structure, the surface of which is coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, such that said tracheal/bronchial obstruction is eliminated.

25. A method for treating a tumor excision site, comprising administering a composition comprising an anti-angiogenic factor and a polymeric carrier to the resection margin of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at said site is inhibited.

28. A method for treating corneal neovascularization, comprising administering to a patient a therapeutically effective amount of a composition comprising an anti-angiogenic factor and a polymeric carrier to the cornea, such that the formation of blood vessels is inhibited.

29. A method for treating corneal neovascularization, comprising administering to a patient a therapeutically effective amount of paclitaxel to the cornea, such that the formation of blood vessels is inhibited.

31. A method for inhibiting angiogenesis in patients with non-tumorigenic, angiogenesis-dependent diseases, comprising administering to a patient a therapeutically effective amount of a composition comprising paclitaxel to a patient with a non-tumorigenic angiogenesis-dependent disease, such that the formation of new blood vessels is inhibited.

32. A method for embolizing a blood vessel in a non-tumorigenic, angiogenesis-dependent diseases, comprising delivering to said vessel a therapeutically effective amount of a composition comprising paclitaxel, such that said blood vessel is effectively occluded.

33. A method for expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said passageway is expanded.

34. A method for eliminating vascular obstructions, comprising inserting a vascular stent into a vascular passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said vascular obstruction is eliminated.

35. A method for eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said biliary obstruction is eliminated.

36. A method for eliminating urethral obstructions, comprising inserting a urethral stent into a urethra, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said urethral obstruction is eliminated.

37. A method for eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said esophageal obstruction is eliminated.

38. A method for eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into the trachea or bronchi, the stent having a generally tubular structure, the surface of said structure being coated with a composition comprising paclitaxel, such that said tracheal/bronchial obstruction is eliminated.

39. A method for treating a tumor excision site, comprising administering to a patient a composition comprising paclitaxel to the resection margin of a tumor subsequent to excision, such that the local recurrence of cancer and the formation of new blood vessels at said site is inhibited.

40. A method for treating neovascular disease of the eye, comprising administering to a patient a therapeutically effective amount of a compound which disrupts microtubule function to the cornea, such that the formation of new vessels is inhibited.

41. The method according to claim 40 wherein said compound which disrupts microtubule function is paclitaxel.

42. The method according to claim 40 wherein said compound which disrupts microtubule function is selected from the group consisting of estramustine, colchicine, methotrexate, curacin-A, epothilone, vinblastine and tBCEU.

43. The method according to claim 40 wherein said neovascular disease is selected from the group consisting of corneal neovascularization and macular degeneration.

44. A method for treating inflammatory arthritis, comprising administering to a patient a therapeutically effective amount of a composition comprising an anti-angiogenic factor and a polymeric carrier to a joint, such that the formation of blood vessels is inhibited, with the proviso that said anti-angiogenic factor is not methotrexate.

45. The method according to claim 44 wherein said anti-angiogenic factor is a compound which disrupts microtubule function.

46. The method according to claim 44 wherein said compound which disrupts microtubule function is selected from the group consisting of estramustine, colchicine, curacin-A, epothilone, vinblastine and tBCEU.

47. The method according to claim 44 wherein said compound which disrupts microtubule function is paclitaxel.

49. The method according to claim 48 wherein said anti-angiogenic factor is a compound which disrupts microtubule function.

50. The method according to claim 48 wherein said compound which disrupts microtubule function is selected from the group consisting of estramustine, colchicine, curacin-A, epothilone, vinblastine and tBCEU.

51. The method according to claim 48 wherein said compound which disrupts microtubule function is paclitaxel.

48. A method for inflammatory arthritis, comprising administering to a patient a therapeutically effective amount of an anti-angiogenic factor to a joint, such that the formation of blood vessels is inhibited, with the proviso that said anti-angiogenic factor is not methotrexate.

52. A composition comprising a polymeric carrier adapted to contain and release a hydrophobic compound, said carrier containing a hydrophobic compound in combination with a carbohydrate, protein or polypeptide.

53. The composition of claim 52 wherein said polymeric carrier is poly(ethylene-vinyl acetate) (40% crosslinked).

54. The composition of claim 52 wherein said polymeric carrier is copolymer of lactic acid and glycolic acid.

55. The composition of claim 52 wherein said polymeric carrier is poly (caprolactone).

56. The composition of claim 52 wherein said polymeric carrier is poly (lactic acid).

57. The composition according to claim 52 wherein said hydrophobic compound is a compound which disrupts microtubule function.

58. The composition according to claim 57 wherein said compound which disrupts microtubule function is paclitaxel.

59. The composition according to claim 57 wherein said compound which disrupts microtubule function is selected from the group consisting of estramustine, colchicine, methotrexate, curacin-A, epothilone, vinblastine and tBCEU.

60. A pharmaceutical product, comprising:

(a) a compound which disrupts microtubule function, in a container; and

(b) a notice associated with said container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by said agency of said paclitaxel, for human or veterinary administration to treat non-tumorigenic angiogenesis-dependent diseases.

61. The pharmaceutical product according to claim 60 wherein said compound which disrupts microtubule function is paclitaxel.