Therapeutic inhibitor of vascular smooth muscle cells

• US 5,981,568 A
• Filed: 03/31/1997
• Issued: 11/09/1999
• Est. Priority Date: 01/28/1993
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation), UAB Research Foundation (University of Alabama System)
• Original Assignee: NeoRx Corporation
• Inventors: Kunz, Lawrence L., Reno, John M., Klein, Richard A.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/829,685
• Time in Patent Office: 953 Days
• Field of Search: 514/499, 514/411, 514/319, 514/324, 514/422, 514/428
• US Class Current: 514/411
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/131 acyclic
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• 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 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6831 : Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
• CPC Class Codes: A61K 47/6843 : the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6849 : the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6923 : the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6927 : the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 9/0024 : Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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 2300/432 : Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 2300/622 : Microcapsules
• CPC Class Codes: A61L 31/08 : Materials for coatings
• CPC Class Codes: A61L 31/148 : Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/915 : Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/92 : Detection of biochemical

Abstract

Methods are provided for inhibiting stenosis or restenosis following vascular trauma in a mammalian host, comprising administering to the host a therapeutically effective dosage of a cytostatic agent and/or cytoskeletal inhibitor so as to biologically stent the traumatized vessel. Also provided is a method to inhibit or reduce vascular remodeling following vascular trauma, comprising administering an effective amount of a cytoskeletal inhibitor. Further provided are pharmaceutical compositions and kits comprising the therapeutic agents of the invention.

Claims

1. A therapeutic method comprising administering to a mammalian blood vessel a dosage form comprising a cytoskeletal inhibitor effective to inhibit or reduce diminution in vessel lumen area of the mammalian blood vessel, wherein the cytoskeletal inhibitor is in substantially crystalline form and wherein the crystals are of a size which results in sustained release of the cytoskeletal inhibitor.

2. The method of claim 1 wherein the crystals are microcrystals.

3. The method of claim 1 wherein the crystal size is about 0.1 micron to about 1 mm.

4. The method of claim 1 wherein the cytoskeletal inhibitor comprises taxol, cytochalasin, or an analog thereof.

5. The method of claim 4 wherein the cytoskeletal inhibitor comprises a n analog of cytochalasin B.

6. The method of claim 4 wherein the cytoskeletal inhibitor comprises cytochalasin B.

7. The method of claim 6 wherein the cytochalasin B comprises about 5 to about 40 weight percent of the dosage form.

8. The method of claim 4 wherein the cytoskeletal inhibitor comprises an analog of taxol.

9. The method of claim 4 wherein the cytoskeletal inhibitor comprises taxol.

10. The method of claim 9 wherein taxol comprises about 3 to about 50 weight percent of the dosage form.

11. The method of claim 1 wherein the cytoskeletal inhibitor is administered via an implantable device.

12. The method of claim 11 wherein the cytoskeletal inhibitor is releasably embedded in, coated on, or embedded in and coated on, the implantable device.

13. The method of claim 11 wherein the cytoskeletal inhibitor is releasably embedded in microparticles, nanoparticles, or a mixture thereof.

14. The method of claim 13 wherein the microparticles or nanoparticles are releasably embedded in, coated on, or embedded in and coated on, the implantable device.

15. The method of claim 12 or 14 wherein the device is an adventitial wrap.

16. The method of claim 12 or 14 wherein the device is artificial graft.

17. The method of claim 12 or 14 wherein the device is a stent.

18. The method of claim 12 or 14 wherein the device is a shunt.

19. The method of claim 1 wherein the cytoskeletal inhibitor is releasably embedded in, coated on, or embedded in and coated on, a non-liquid matrix.

20. The method of claim 1 wherein the crystalline form is dispersed in a liquid vehicle.

21. The method of claim 20 wherein the dispersed crystalline form is administered by a catheter.

22. The method of claim 1 wherein the administration is before, during or after procedural vascular trauma, or any combination thereof.

23. The method of claim 1 wherein the vessel is traumatized by angioplasty, placement of a stent, placement of a shunt, or natural grafting, or any combination thereof.

24. The method of claim 1 wherein the administration is local.

25. The method of claim 1 wherein the vessel is procedurally traumatized.

55. The method of claim 4 or 43 wherein the cytoskeletal inhibitor comprises cytochalasin D.

56. The method of claim 4 or 43 wherein the cytoskeletal inhibitor comprises cytochalasin A.

26. A therapeutic method comprising administering to a procedurally traumatized mammalian blood vessel a sustained release dosage form comprising microparticles or nanoparticles comprising taxol or an analog thereof effective to inhibit or reduce diminution in vessel lumen area of the mammalian blood vessel.

27. The method of claim 26 wherein sustained release dosage form comprises microparticles of about 2 to about 50 microns in size.

28. The method of claim 26 wherein sustained release dosage form comprises microparticles of about 0.5 to about 100 microns in size.

29. The method of claim 26 wherein the sustained release dosage form comprises nanoparticles of about 50 to about 200 nanometers in size.

30. The method of claim 26 wherein the sustained release dosage form comprises nanoparticles of about 0.1 to about 1000 nanometers in size.

31. The method of claim 26 wherein the sustained release dosage form is administered via an implantable device.

32. The method of claim 31 wherein the sustained release dosage form is releasably embedded in, coated on, or embedded in and coated on, the implantable device.

33. The method of claim 32 wherein the device is an adventitial wrap.

34. The method of claim 32 wherein the device is artificial graft.

35. The method of claim 32 wherein the device is a stent.

36. The method of claim 32 wherein the device is a shunt.

37. The method of claim 26 wherein the sustained release dosage form is releasably embedded in, coated on, or embedded in and coated on, a non-liquid matrix.

38. The method of claim 26 wherein the sustained release dosage form is biodegradable.

39. The method of claim 26 wherein the administration is before, during or after procedural vascular trauma, or any combination thereof.

40. The method of claim 26 wherein the vessel is traumatized by angioplasty, placement of a stent, placement of a shunt, or natural grafting, or any combination thereof.

41. The method of claim 26 wherein the microparticles or nanoparticles are administered in solution via the implantable device.

42. The method of claim 41 wherein the device is a catheter.

43. A therapeutic method comprising administering to a mammalian blood vessel a dosage form comprising a cytochalasin or an analog thereof in a non-liquid matrix effective to inhibit or reduce diminution in vessel lumen area of the mammalian blood vessel.

44. The method of claim 43 wherein the dosage form comprises microparticles or nanoparticles comprising the cytochalasin or analog thereof.

45. The method of claim 43 wherein dosage form comprises crystals or microcrystals of the cytochalasin or analog thereof.

46. The method of claim 43 wherein the matrix comprises a gel, membrane or paste.

47. The method of claim 43 wherein the cytochalasin comprises an analog of cytochalasin B.

48. The method of claim 43 wherein the cytochalasin comprises cytochalasin B.

49. The method of claim 43 wherein the cytochalasin or analog thereof is administered via an implantable device.

50. The method of claim 49 wherein the cytochalasin or analog thereof is releasably embedded in, coated on, or embedded in and coated on, the implantable device, the matrix, or both.

51. The method of claim 50 wherein the device is an adventitial wrap.

52. The method of claim 50 wherein the device is artificial graft.

53. The method of claim 50 wherein the device is a stent.

54. The method of claim 50 wherein the device is a shunt.