Delivery of highly lipophilic agents via medical devices

• US 8,257,725 B2
• Filed: 03/22/2006
• Issued: 09/04/2012
• Est. Priority Date: 09/26/1997
• Status: Expired due to Term

• Current Assignee: Abbott Laboratories Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Toner, John L., Burke, Sandra E., Krasula, Richard W., Schwartz, Lewis B., Cromack, Keith R.
• Primary Examiner(s): Packard, Benjamin
• Assistant Examiner(s): Milligan, Adam C
• Application Number:
  US11/386,498
• Publication Number:
  US 20060228453A1
• Time in Patent Office: 2,358 Days
• Field of Search: 424/423, 514/291, 514/449
• US Class Current: 424/423
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/22 Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
• 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 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• 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 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

An apparatus and system for delivering a lipophilic agent associated with a medical device including: a medical device, a first lipophilic agent capable of penetrating a body lumen, wherein the transfer coefficients of the first lipophilic agent is by an amount that is statistically significant of at least approximately 5,000, wherein the first lipophilic agent is associated with the medical device, wherein the first lipophilic agent/medical device is placed adjacent to said body lumen, and wherein a therapeutically effective amount of the first lipophilic agent is delivered to a desired area within a subject. Furthermore, the invention relates to a method for improving patency in a subject involving placement of a medical device in a body lumen for treating and/or preventing adjacent diseases or maintaining patency of the body lumen.

Claims

1. A method for improving patency in a subject involving placement of a medical device in a body lumen for treating diseases or maintaining patency of the body lumen, comprising:

providing a medical device to be placed in a body lumen, wherein the medical device comprises;

a first lipophilic agent capable of penetrating a body lumen, wherein the transfer coefficient of said first lipophilic agent is by an amount of at least 5,000 (ug/mL)<sup>−

1</sup>, wherein said first lipophilic agent comprises zotarolimus having one of the following structures;

2. The method according to claim 1, further comprising at least one pharmaceutically acceptable carrier or excipient, wherein said medical device further comprises said pharmaceutically acceptable carrier or excipient.

3. The method according to claim 2, wherein said pharmaceutically acceptable carrier or excipient is a polymer.

4. The method according to claim 2, wherein said pharmaceutically acceptable carrier or excipient is an agent.

5. The method according to claim 1, wherein said body lumen comprises at least one of a vessel wall, a coronary artery, an esophageal lumen, and a urethra.

6. The method according to claim 1, wherein said first lipophilic agent/medical device is placed in said body lumen including coronary arteries, wherein a therapeutically effective amount of said first lipophilic agent is delivered into said coronary arteries and diffused into the epicardium, myocardium, or pericardial sac.

7. The method according to claim 6, wherein said method provides substantially uniform drug delivery of said lipophilic agent to the myocardium.

8. The method according to claim 1, wherein said body lumen is a blood vessel.

9. The method according to claim 3, wherein said delivery mechanism of said first lipophilic agent includes polymer hydration followed by dissolution of said first lipophilic agent, and wherein said first lipophilic agent is thereafter delivered into said body lumen.

10. The method according to claim 3, wherein said delivery mechanism of said first lipophilic agent includes a lipophilic agent/polymer matrix which controls the elution rate of said first lipophilic agent to said body lumen.

11. The method according to claim 1, wherein the medical device further comprises at least one second lipophilic agent.

12. The method according to claim 1, further comprises at least one lipophilic prodrug.

13. The method according to claim 1, further comprises at least one lipophilic penetration enhancer.

14. The method according to claim 13, wherein said lipophilic penetration enhancer is a pharmaceutical agent.

15. The method according to claim 1, wherein the first lipophilic agent is delivered into said body lumen in a therapeutically effective amount.

16. The method according to claim 11, wherein the second lipophilic agent in combination with said first lipophilic agent is delivered into said body lumen in a therapeutically effective amount.

17. The method according to claim 1, wherein said first lipophilic agent is zotarolimus.

18. The method according to claim 1, wherein the medical device further comprises at least one beneficial agent.

19. The method according to claim 1, wherein the dosage delivery of said first lipophilic agent into said body lumen ranges from about 15 μ

g/g to about 150 μ

g/g over a period of up to about 5 days.

20. The method according to claim 1, wherein the dosage delivery of said first lipophilic agent into said body lumen ranges from about 15 μ

g/g to about 80 μ

g/g over a period from about 5 days to up to about 15 days.

21. The method according to claim 1, wherein the dosage delivery of said first lipophilic agent into said body lumen ranges from about 5 μ

g/g to about 60 μ

g/g over a period from 15 days up to about 28 days.

22. The method according to claim 1, wherein said first lipophilic agent reaches therapeutically significant concentrations in targeted areas in said subject,

wherein the targeted areas comprise at least one of the group consisting of the distal myocardium, the unstented myocardium, the subjacent myocardium, and the unstented and distal coronary arteries, and

wherein the targeted areas maintain those concentrations throughout a 28 day period.

23. The method according to claim 1, wherein said medical device is permanently or temporarily implanted into a subjects'"'"' body.

24. The method according to claim 1, wherein said first lipophilic agent is in amorphous form.

25. The method according to claim 1, further comprises a beneficial agent including at least one of antithrombotics, anticoagulants, antiplatelets agents, anti-lipid agents, thrombolytics, antiproliferatives, antiinflammatories, agents that inhibit hyperplasia, smooth muscle cell inhibitors, antibiotics, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, antimitotics, antifibrins, antioxidants, antineoplastics, agents that promote endothelial cell recovery, matrix metalloproteinase inhibitors, antineoplastics, antimetabolites, antiallergic substances, viral vectors, nucleic acids, monoclonal antibodies, inhibitors of tyrosine kinase, antisense compounds, oligionucleotides, cell permeation enhancers, and any combinations thereof.

26. The method according to claim 1, further comprises a beneficial agent including at least one of hypoglycemic agents, hypolipidemic agents, proteins, nucleic acids, agents useful for erythropoiesis stimulation, angiogenesis agents, antiulcer/antireflux,agents, and antinauseants/antiemetics, PPAR-alpha agonists, and any combinations thereof.

27. The method according to claim 1, further comprises a beneficial agent including at least one of sodium heparin, LMW heparins, heparoids, hirudin, argatroban, forskolin, vapriprost, prostacyclin and prostacylin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), glycoprotein Iib/Iia (platelet membrane receptor antagonist antibody), recombinant hirudin, thrombin inhibitors, indomethacin, phenyl salicylate, p-estradiol, vinblastine, ABT-627 (astrasentan), testosterone, progesterone, paclitaxel, methotrexate, fotemustine, RPR-101511A, cyclosporin A, vincristine, carvediol, vindesine, dipyridamole, methotrexate, folic acid, thrombospondin mimetics, estradiol, dexamethasone, metrizamide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan and pro-drugs, analogs, derivatives, and any combinations thereof.

28. The method according to claim 1, wherein said medical device is an endovascular medical device.

29. The method according to claim 1, wherein said medical device includes intracoronary medical devices selected from the group consisting of stents, drug delivery catheters, grafts, and drug delivery balloons utilized in a subject'"'"'s vasculature.

30. The method according to claim 1, wherein said medical device includes a stent selected from the group consisting of peripheral stents, peripheral coronary stents, degradable coronary stents, non-degradable coronary stents, self-expanding stents, balloon-expanded stents, and esophageal stents.

31. The method according to claim 1, wherein said medical device is selected from the group consisting of arterio-venous grafts, by-pass grafts, penile implants, vascular implants and grafts, intravenous catheters, small diameter grafts, artificial lung catheters, electrophysiology catheters, bone pins, suture anchors, blood pressure and stent graft catheters, breast implants, benign prostatic hyperplasia and prostate cancer implants, bone repair/augmentation devices, breast implants, orthopedic joint implants, dental implants, implanted drug infusion tubes, oncological implants, pain management implants, neurological catheters, central venous access catheters, catheter cuff, vascular access catheters, urological catheters/implants, atherectomy catheters, clot extraction catheters, PTA catheters, PICA catheters, stylets (vascular and non-vascular), drug infusion catheters, angiographic catheters, hemodialysis catheters, neurovascular balloon catheters, thoracic cavity suction drainage catheters, electrophysiology catheters, stroke therapy catheters, abscess drainage catheters, biliary drainage products, dialysis catheters, central venous access catheters, and parental feeding catheters.

32. The method according to claim 1, wherein said medical device is selected from the group consisting of pacemakers, vascular grafts, sphincter devices, urethral devices, bladder devices, renal devices, gastroenteral and anastomotic devices, vertebral disks, hemostatic barriers, clamps, surgical staples/sutures/screws/plates/wires/clips, glucose sensors, blood oxygenator tubing, blood oxygenator membranes, blood bags, birth control/IUDs and associated pregnancy control devices, cartilage repair devices, orthopedic fracture repairs, tissue adhesives, tissue sealants, tissue scaffolds, CSF shunts, dental fracture repair devices, intravitreal drug delivery devices, nerve regeneration conduits, electrostimulation leads, spinal/orthopedic repair devices, wound dressings, embolic protection filters, abdominal aortic aneurysm grafts and devices, neuro aneurysm treatment coils, hemodialysis devices, uterine bleeding patches, anastomotic closures, in vitro diagnostics, aneurysm exclusion devices, neuropatches, vena cava filters, urinary dilators, endoscopic surgical and wound drainings, surgical tissue extractors, transition sheaths and dialators, coronary and peripheral guidewires, circulatory support systems, tympanostomy vent tubes, cerebro-spinal fluid shunts, defibrillator leads, closure devices, drainage tubes, bronchial tubes, vascular coils, vascular protection devices, vascular intervention devices including vascular filters and distal support devices and emboli filter/entrapment aids, AV access grafts, surgical tampons, drug delivery capsule and cardiac valves.

33. The method according to claim 1, wherein said medical device is selected from the group consisting of atrial septal defect closures, electro-stimulation leads for cardiac rhythm management, tissue and mechanical prosthetic heart valves and rings, arterial-venous shunts, valve annuloplasty devices, mitral valve repair devices, left ventricle assist devices, left atrial appendage filters, cardiac sensors, pacemaker electrodes and leads.

34. The method according to claim 6, wherein the delivery of said lipophilic agent to the epicardium and/or pericardial sac is continuous.

35. The method according to claim 1, wherein said first lipophilic agent comprises zotarolimus of both structures in claim 1.

36. The method according to claim 1, wherein the desired area outside the body lumen where the medical device is placed is selected from the distal myocardium, the unstent myocardium, the subjacent myocardium, an unstented coronary artery, and a distal coronary artery.