TREATMENT OF RESTENOSIS USING TEMSIROLIMUS

• US 20180169075A1
• Filed: 02/07/2018
• Published: 06/21/2018
• Est. Priority Date: 09/22/2016
• Status: Active Grant

• Current Assignee: Mercator MedSystems, Inc.
• Original Assignee: Mercator MedSystems, Inc.
• Inventors: SEWARD, Kirk Patrick
• Granted Patent: US 10,617,678 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• 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 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

Described herein are methods for distributing temsirolimus to a tissue surrounding a blood vessel for treating vascular diseases. Also disclosed are injectable compositions of temsirolimus for delivery into the tissue surrounding a blood vessel for treating vascular diseases.

Claims

1. A method of treating a vascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising temsirolimus or its pharmaceutically acceptable salts thereof, wherein the composition is administered by direct injection to a disease site.

2. The method of claim 1, wherein the composition is injected though a catheter with a needle.

3. The method of claim 1, wherein the composition is injected distal or proximal to the disease site.

4. The method of claim 1, wherein the composition is injected at least about 2 cm away from the disease site.

5. The method of claim 1, wherein the composition is injected at or adjacent to the disease site.

6. The method of claim 1, wherein the composition is administered by injection into a blood vessel.

7. The method of claim 1, wherein the composition is injected into an adventitial tissue surrounding a blood vessel.

8. The method of claim 1, wherein the composition is injected into a perivascular tissue surrounding a blood vessel.

9. The method of claim 8, wherein the blood vessel is an artery.

10. The method of claim 8, wherein the blood vessel is a vein.

11. The method of claim 9, wherein the artery is a coronary artery or a peripheral artery.

12. The method of claim 9, wherein the artery is selected from the group consisting of renal artery, cerebral artery, pulmonary artery, and artery in the leg.

13. The method of claim 9, wherein the artery is below the knee.

14. The method of claim 9, wherein the artery is in the leg above the knee.

15. The method of claim 9, wherein the blood vessel is below-knee popliteal vessel or tibial vessel.

16. The method of claim 1, wherein the composition is injected into a blood vessel wall.

17. The method of claim 1, wherein the composition is injected into a tissue surrounding the blood vessel wall.

18. The method of claim 1, wherein the therapeutically effective amount of temsirolimus is about 1 μ

g to 50 mg.

19. The method of claim 18, wherein the therapeutically effective amount of temsirolimus is about 10 μ

g to 20 mg.

20. The method of claim 19, wherein the therapeutically effective amount of temsirolimus is about 25 μ

g to 10 mg.

21. The method of claim 1, wherein the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the blood vessel.

22. The method of claim 21, wherein the therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the blood vessel.

23. The method of claim 1, wherein the injection volume of the composition is about 0.01 ml to about 50 ml.

24. The method of claim 23, wherein the injection volume of the composition is about 0.5 ml to about 20 ml.

25. The method of claim 1, wherein the injection concentration of temsirolimus is 0.1 mg/mL to 0.4 mg/mL.

26. The method of claim 25, wherein the injection concentration of temsirolimus is 0.01 mg/mL to 2.0 mg/mL.

27. The method of claim 26, wherein the injection concentration of temsirolimus is 0.1 mg/mL to 0.5 mg/mL.

28. The method of claim 1, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 60%, when compared to vessel cross-sectional area at the disease site at the time of administration.

29. The method of claim 28, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 50%, when compared to vessel cross-sectional area at the disease site at the time of administration.

30. The method of claim 29, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 30%, when compared to vessel cross-sectional area at the disease site at the time of administration.

31. The method of claim 1, wherein the composition further comprises a contrast medium for visualizing the injection.

32. The method of claim 1, wherein the subject is human.

33. The method of claim 1, wherein the vascular disease is angina, myocardial infarction, congestive heart failure, cardiac arrhythmia, peripheral artery disease, claudication, or critical limb ischemia.

34. The method of claim 1, wherein the vascular disease is atherosclerosis, bypass graft failure, transplant vasculopathy, vascular restenosis, or in-stent restenosis.

35-56. -56. (canceled)

57. A method of treating a peripheral artery disease in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising temsirolimus or its pharmaceutically acceptable salts thereof, wherein the composition is administered by direct injection to or near a disease site in a tissue surrounding a wall of a peripheral artery or in the wall of the peripheral artery via a laterally extending injection needle of a catheter advanced through vasculature of the human subject, wherein the amount of the pharmaceutical composition is therapeutically effective to cause patency at the disease site after administration to increase or minimally decrease when compared to patency at the disease site at the time of administration.

58. The method of claim 57, wherein the therapeutically effective amount of temsirolimus is about 1 μ

g to 50 mg

59. The method of claim 58, wherein the therapeutically effective amount of temsirolimus is about 10 μ

g to 20 mg.

60. The method of claim 59, wherein the therapeutically effective amount of temsirolimus is about 25 μ

g to 10 mg.

61. The method of claim 57, wherein the therapeutically effective amount of temsirolimus is about 0.005 mg to 5 mg per cm of longitudinal length of the disease site in the peripheral artery.

62. The method of claim 61, wherein the therapeutically effective amount of temsirolimus is about 0.025 mg to 1 mg per cm of longitudinal length of the disease site in the peripheral artery.

63. The method of claim 57, wherein the injection volume of the composition is about 0.01 ml to about 50 ml.

64. The method of claim 63, wherein the injection volume of the composition is about 0.5 ml to about 20 ml.

65. The method of claim 57, wherein the injection concentration of temsirolimus is 0.01 mg/mL to 2.0 mg/mL.

66. The method of claim 65, wherein the injection concentration of temsirolimus is 0.1 mg/mL to 0.5 mg/mL.

67. The method of claim 66, wherein the injection concentration of temsirolimus is 0.1 mg/mL to 0.4 mg/mL.

68. The method of claim 57, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 60%, when compared to vessel cross-sectional area at the disease site at the time of administration.

69. The method of claim 68, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 50%, when compared to vessel cross-sectional area at the disease site at the time of administration.

70. The method of claim 69, wherein 12 months after administration of the pharmaceutical composition, vessel cross-sectional area at the disease site has decreased no more than 30%, when compared to vessel cross-sectional area at the disease site at the time of administration.

71. The method of claim 57, wherein the composition further comprises a contrast medium for visualizing the injection.

72. The method of claim 57, wherein the artery is below the knee.

73. The method of claim 57, wherein the artery is in the leg above the knee.

74. The method of claim 57, wherein the blood vessel is below-knee popliteal vessel or tibial vessel.

75-90. -90. (canceled)