Drug delivery systems for the prevention and treatment of vascular diseases

• US 20030170287A1
• Filed: 01/10/2003
• Published: 09/11/2003
• Est. Priority Date: 01/10/2002
• Status: Abandoned Application

• Current Assignee: Margaret Forney Prescott
• Original Assignee: Margaret Forney Prescott
• Inventors: Prescott, Margaret Forney
• Application Number:
  US10/339,820
• Publication Number:
  US 20030170287A1
• Time in Patent Office: Days
• US Class Current: 424/423
• 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 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• 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 31/10 Macromolecular materials
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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

Abstract

Provided are drug delivery systems for the prevention and treatment of proliferative diseases, particularly vascular diseases, comprising rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents.

Claims

1. A drug delivery device or system comprising i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from an EDG-receptor agonist having lymphocyte depleting properties, a cox-2 inhibitor, pimecrolimus, a cytokine inhibitor, a chemokine inhibitor, an antiproliferative agent, a statin, a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, a somatostatin analogue, an aldosterone synthetase inhibitor or aldosterone receptor blocker and a compound inhibiting the renin-angiotensin system, each being releasably affixed to the medical device.

3. The drug delivery device or system according to claim 1 wherein the medical device is a stent or coated stent.

2. A drug delivery device or system comprising i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties, in conjunction with a therapeutic dosage of one or more active co-agents selected from a calcineurin inhibitor and mycophenolic acid or a salt thereof or prodrug thereof, each being releasably affixed to the medical device.

4. The drug delivery device or system according to claim 2 wherein the medical device is a stent or coated stent.

5. A combination of rapamycin or a rapamycin derivative having mTOR inhibiting properties with pimecrolimus, an aldosterone synthetase inhibitor or an aldosterone receptor blocker, or with a compound inhibiting the renin-angiotensin system.

6. A method for preventing or treating smooth muscle cell proliferation and migration in hollow tubes, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a subject in need thereof, comprising local administration of a therapeutically effective amount of an active ingredient comprising a rapamycin derivative having mTOR inhibiting properties or rapamycin in conjunction with one or more active co-agents selected from an EDG-receptor agonist having lymphocyte depleting properties;

a cox-2 inhibitor;

pimecrolimus;

a cytokine inhibitor;

a chemokine inhibitor;

an antiproliferative agent;

a statin, a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker; and

a compound inhibiting the renin-angiotensin system.

7. A method according to claim 6 wherein the local administration is the controlled delivery from a drug delivery device or system comprising i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) the active ingredient wherein the active ingredient is releasably affixed to the medical device.

8. A method according to claim 6 wherein the local administration is the controlled delivery from a drug delivery device or system comprising i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) the active ingredient wherein the active ingredient comprises a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties, in conjunction with a therapeutic dosage of one or more active co-agents selected from a calcineurin inhibitor and mycophenolic acid or a salt thereof or prodrug thereof, each being releasably affixed to the medical device.

9. A method for stabilizing vulnerable plaques in blood vessels of a subject in need of such a stabilization comprising administering to said patient a therapeutically effective amount of rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents and/or a controlled delivery from a drug delivery device or system of a therapeutically effective amount of rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents.

10. A method according to claim 9 wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from a different immunosuppressant;

an EDG-receptor agonist having lymphocyte depleting properties;

an anti-inflammatory agent;

an anti-thrombotic or anti-coagulant agent;

an antiproliferative agent;

a statin;

a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a modulator of kinases;

a compound stimulating the release of NO or a NO donor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker;

a compound inhibiting the renin-angiotensin system; and

mycophenolic acid or salt or prodrug thereof;

each being releasably affixed to the medical device.

11. A method according to claim 9 wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from an EDG-receptor agonist having lymphocyte depleting properties;

a cox-2 inhibitor;

pimecrolimus;

a cytokine inhibitor;

a chemokine inhibitor;

an antiproliferative agent;

a statin, a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker; and

a compound inhibiting the renin-angiotensin system;

each being releasably affixed to the medical device.

12. A method according to claim 9 wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties, in conjunction with a therapeutic dosage of one or more active co-agents selected from a calcineurin inhibitor and mycophenolic acid or a salt thereof or prodrug thereof, each being releasably affixed to the medical device.

13. A method for preventing or treating restenosis in a diabetic patient comprising administering to said patient a therapeutically effective amount of rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents, and/or a controlled delivery from a drug delivery device or system of a therapeutically effective amount of rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents.

14. A method according to claim 13 comprising the controlled delivery from a drug delivery device or system wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from a different immunosuppressant;

an EDG-receptor agonist having lymphocyte depleting properties;

an anti-inflammatory agent;

an anti-thrombotic or anti-coagulant agent;

an antiproliferative agent;

a statin;

a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a modulator of kinases;

a compound stimulating the release of NO or a NO donor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker;

a compound inhibiting the renin-angiotensin system; and

mycophenolic acid or salt or prodrug thereof;

each being releasably affixed to the medical device.

15. A method according to claim 13 comprising the controlled delivery from a drug delivery device or system wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from an EDG-receptor agonist having lymphocyte depleting properties;

a cox-2 inhibitor;

pimecrolimus;

a cytokine inhibitor;

a chemokine inhibitor;

an antiproliferative agent;

a statin;

a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker; and

a compound inhibiting the renin-angiotensin system;

each being releasably affixed to the medical device

16. A method according to claim 13 comprising the controlled delivery from a drug delivery device or system wherein sain drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties, in conjunction with a therapeutic dosage of one or more active co-agents selected from a calcineurin inhibitor and mycophenolic acid or a salt thereof or prodrug thereof, each being releasably affixed to the medical device.

17. A method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, or actual treatment, in a subject in need thereof, which comprises administering to the subject rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more active co-agents, and/or a controlled delivery from a drug delivery device or system of a therapeutically effective amount of rapamycin or a rapamycin derivative having mTOR inhibiting properties, optionally in conjunction with one or more other active co-agents.

18. A method according to claim 17 comprising the controlled delivery from a drug delivery device or system wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from a different immunosuppressant;

an EDG-receptor agonist having lymphocyte depleting properties;

an anti-inflammatory agent;

an anti-thrombotic or anti-coagulant agent;

an antiproliferative agent;

a statin;

a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a modulator of kinases;

a compound stimulating the release of NO or a NO donor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker;

a compound inhibiting the renin-angiotensin system; and

mycophenolic acid or salt or prodrug thereof;

each being releasably affixed to the medical device.

19. A method according to claim 17 comprising the controlled delivery from a drug delivery device or system wherein the drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties or rapamycin, in conjunction with a therapeutic dosage of one or more active co-agents selected from an EDG-receptor agonist having lymphocyte depleting properties;

a cox-2 inhibitor;

pimecrolimus;

a cytokine inhibitor;

a chemokine inhibitor;

an antiproliferative agent;

a statin, a protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium;

a matrix metalloproteinase inhibitor;

a somatostatin analogue;

an aldosterone synthetase inhibitor or aldosterone receptor blocker; and

a compound inhibiting the renin-angiotensin system;

each being releasably affixed to the medical device

20. A method according to claim 17 comprising the controlled delivery from a drug delivery device or system wherein sain drug delivery device or system comprises i) a medical device adapted for local application or administration of an active ingredient in hollow tubes and and ii) an active ingredient comprising a therapeutic dosage of a rapamycin derivative having mTOR inhibiting properties, in conjunction with a therapeutic dosage of one or more active co-agents selected from a calcineurin inhibitor and mycophenolic acid or a salt thereof or prodrug thereof, each being releasably affixed to the medical device.