Therapeutic inhibitor of vascular smooth muscle cells

• US 6,171,609 B1
• Filed: 10/23/1995
• Issued: 01/09/2001
• Est. Priority Date: 02/15/1995
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: NeoRx Corporation
• Inventors: Kunz, Lawrence L.
• Primary Examiner(s): Barts, Samuel
• Application Number:
  US08/546,794
• Time in Patent Office: 1,905 Days
• Field of Search: 424/490, 424/422, 424/484, 623/1, 623/12, 606/194, 606/195
• US Class Current: 424/422
• 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 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/51 the non-active ingredient being a modifying agent
• 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 47/6923 : 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 47/6957 : the form being a device or a kit, e.g. stents or microdevices
• 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 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 : Biodegradation
• CPC Class Codes: A61L 2300/606 : 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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 9/08 : Vasodilators for multiple indications
• 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: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: Y10S 977/775 : Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/808 : Exterior attachment for targeting, e.g. drug targeting
• CPC Class Codes: Y10S 977/905 : Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/916 : Gene therapy

Abstract

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.

Claims

1. An intravascular stent comprising an amount of a cytoskeletal inhibitor effective to inhibit stenosis or reduce restenosis following placement of the stent.

2. The intravascular stent of claim 1 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

3. The intravascular stent of claim 1 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

4. The intravascular stent of claim 1 which comprises metal or plastic.

5. The intravascular stent of claim 1 which comprises a biodegradable material.

6. The intravascular stent of claim 4 which consists essentially of a biodegradable material.

7. The intravascular stent of claim 1 which comprises the cytoskeletal inhibitor in a sustained release form.

8. The intravascular stent of claim 7 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

9. The intravascular stent of claim 7 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

10. The intravascular stent of claim 7 wherein the sustained release form of the cytoskeletal inhibitor comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

11. The intravascular stent of claim 1 wherein the stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the cytoskeletal inhibitor.

12. The intravascular stent of claim 1 which further comprises an inhibitor of smooth muscle cell proliferation.

13. The intravascular stent of claim 11 herein the coating is biodegradable.

14. The intravascular stent of claim 11 herein the coating is porous.

15. The intravascular stent of claim 11 wherein the coating comprises a sustained release dosage form of the cytoskeletal inhibitor.

16. The intravascular stent of claim 15 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

17. The intravascular stent of claim 15 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

35. The intravascular stent of claim 2, 8, 16, 20, 23 or 30 wherein the cytochalasin is cytochalasin B or an analog thereof.

18. An intravascular stent comprising an amount of a cytostatic therapeutic agent which does not exhibit substantial cytotoxicity, which agent is effective to inhibit stenosis or reduce restenosis following placement of the stent, wherein the therapeutic agent is not heparin or a radioisotope.

19. The intravascular stent of claim 18 wherein the stent further comprises a cytoskeletal inhibitor.

20. The intravascular stent of claim 19 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

21. The intravascular stent of claim 19 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

22. The intravascular stent of claim 19 which comprises the cytoskeletal inhibitor in a sustained release form.

23. The intravascular stent of claim 22 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

24. The intravascular stent of claim 22 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

25. The intravascular stent of claim 22 wherein the sustained release form of the cytoskeletal inhibitor comprises a binding peptide or protein which specifically binds to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

26. The intravascular stent of claim 19 wherein the stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the cytoskeletal inhibitor.

27. The intravascular stent of claim 26 wherein the coating is biodegradable.

28. The intravascular stent of claim 26 wherein the coating is porous.

29. The intravascular stent of claim 26 wherein the coating comprises a sustained release dosage form of the cytoskeletal inhibitor.

30. The intravascular stent of claim 29 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

31. The intravascular stent of claim 29 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

32. The intravascular stent of claim 18 which comprises metal or plastic.

33. The intravascular stent of claim 18 which comprises a biodegradable material.

34. The intravascular stent of claim 33 which consists essentially of a biodegradable material.

36. An intravascular stent comprising a matrix and a coating on said matrix, wherein the coating and the matrix together comprise an amount of a cytoskeletal inhibitor effective to inhibit stenosis or reduce restenosis following placement of the therapeutic stent.

37. The intravascular stent of claim 36 wherein the coating comprises a cytochalasin or an analog thereof.

38. The intravascular stent of claim 36 wherein the coating comprises taxol or an analog thereof.

39. The intravascular stent of claim 36 wherein the matrix is impregnated with a cytochalasin or an analog thereof.

40. The intravascular stent of claim 36 wherein the matrix is impregnated with taxol or an analog thereof.

41. The intravascular stent of claim 37 or 39 wherein the cytochalasin comprises cytochalasin B.

42. The intravascular stent of claim 37 or 39 wherein the cytochalasin or an analog thereof is in sustained release dosage form.

43. The intravascular stent of claim 38 or 36 wherein taxol or an analog thereof is in sustained release dosage form.

64. The intravascular stent of claim 36, 46, 50, 52, 57 or 58 wherein the coating is formed from a biodegradable material.

65. The intravascular stent of claim 36, 44 or 55 wherein the stent is formed from a porous or permeable non-biodegradable material.

66. The intravascular stent of claim 36, 44 or 55 in which the intravascular stent comprises metal or plastic.

67. The intravascular stent of claim 36, 44 or 55 wherein the stent is formed from a biodegradable material.

69. The intravascular stent of claim 42 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

70. The intravascular stent of claim 43 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

44. An intravascular stent comprising an amount of a cytochalasin or an analog thereof effective to inhibit stenosis or reduce restenosis following placement of the therapeutic stent.

45. The intravascular stent of claim 44 wherein the matrix of the stent is impregnated with the cytochalasin or an analog thereof.

46. The intravascular stent of claim 44 which comprises a coating comprising the cytochalasin or an analog thereof.

47. The intravascular stent of claim 45 or 46 wherein the cytochalasin comprises cytochalasin B.

48. The intravascular stent of claim 45 or 46 wherein the cytochalasin or an analog thereof is in sustained release dosage form.

49. The intravascular stent of claim 46 wherein the matrix is impregnated with an amount of an inhibitor of smooth muscle cell proliferation.

50. The intravascular stent of claim 45 which further comprises a coating comprising a cytostatic amount of an inhibitor of smooth muscle cell proliferation.

51. The intravascular stent of claim 46 wherein the matrix is impregnated with taxol or an analog thereof.

52. The intravascular stent of claim 45 which further comprises a coating comprising taxol or an analog thereof.

53. The intravascular stent of claim 49 or 50 wherein the inhibitor of smooth muscle cell proliferation is in sustained release dosage form.

54. The intravascular stent of claim 51 or 52 wherein the taxol or analog thereof is in sustained release dosage form.

68. The intravascular stent of claim 53 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

71. The intravascular stent of claim 48 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

72. The intravascular stent of claim 54 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.

55. An intravascular stent comprising a cytostatic amount of an inhibitor of smooth muscle cell proliferation effective to inhibit stenosis or reduce restenosis following placement of the therapeutic stent, wherein the inhibitor is in sustained release dosage form.

56. The intravascular stent of claim 55 wherein the matrix is impregnated with the inhibitor of smooth muscle cell proliferation.

57. The intravascular stent of claim 56 which further comprises a coating comprising a cytoskeletal inhibitor.

58. The intravascular stent of claim 55 which comprises a coating comprising the inhibitor of smooth muscle cell proliferation.

59. The intravascular stent of claim 58 wherein the matrix is impregnated with a cytoskeletal inhibitor.

60. The intravascular stent of claim 57 or 59 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

61. The intravascular stent of claim 60 wherein the cytochalasin comprises cytochalasin B.

62. The intravascular stent of claim 57 or 59 wherein the cytoskeletal inhibitor comprises taxol or an analog thereof.

63. The intravascular stent of claim 57 or 59 wherein the cytoskeletal inhibitor is in sustained release dosage form.

73. The intravascular stent of claim 63 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to smooth muscle cells, stromal cells or interstitial matrix surrounding smooth muscle cells.