Heparin prodrugs and drug delivery stents formed therefrom

• US 7,396,541 B2
• Filed: 09/15/2005
• Issued: 07/08/2008
• Est. Priority Date: 06/18/2004
• Status: Expired due to Fees

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Ding, Ni, Hossainy, Syed Faiyaz Ahmed
• Primary Examiner(s): Kennedy; Sharon E.
• Application Number:
  US11/228,420
• Publication Number:
  US 20060014720A1
• Time in Patent Office: 1,027 Days
• Field of Search: 424/422, 424/423
• US Class Current: 424/423
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/80 characterised by a special chemical form
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C09D 105/10 Heparin; Derivatives thereof

Abstract

A prodrug comprising a heparin and a drug is provided. The prodrug can be used to form a coating on a medical device. The prodrug can also be used with a polymeric material to form a coating on a medical device. The polymeric material can be a hydrophobic polymer, a hydrophilic polymer, a non-fouling polymer, or combinations thereof. The medical device can be implanted in a human being for the treatment of a disease such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

Claims

1. A medical device comprising as a coating a prodrug, the prodrug comprising a drug, heparin, and a polymer,

wherein the heparin is linked to the polymer;

wherein the drug is linked to the heparin or the polymer; and

wherein the polymer is poly(L-lysine-co-ethylene glycol) (PLL-co-PEG), poly(L-lysine-co-hyaluronic acid) (PLL-co-HA), poly(L-lysine-co-phosphoryl choline) (PLL-co-PC), poly(L-lysine-co-PVP), poly(ethylimine-co-ethylene glycol) (PEI-co-PEG), poly(ethylimine-co-hyaluronic acid) (PEI-co-HA), poly(ethylimine-co-phosphoryl choline) (PEI-co-PC), poly(ethylimine-co-vinylpyrrolidone) (PEI-co-PVP), poly(L-lysine-g-ethylene glycol) (PLL-g-PEG), poly(L-lysine-g-hyaluronic acid) (PLL-g-HA), poly(L-lysine-g-phosphoryl choline) (PLL-g-PC), poly(L-lysine-g-PVP), poly(ethylimine-g-ethylene glycol) (PEI-g-PEG), poly(ethylimine-g-hyaluronic acid) (PEI-g-HA), poly(ethylimine-g-phosphoryl choline) (PEI-g-PC), and poly(ethylimine-g-vinylpyrrolidone) (PEI-g-PVP).

2. The medical device of claim 1, wherein the drug is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant substances, super oxide dismutases, super oxide dismutases mimics, nitric oxide donors, cytostatic agents, antibodies, progenitor cell capturing antibody, enzymes, prohealing drugs and combinations thereof.

3. The medical device of claim 1, wherein the drug is selected from the group consisting of paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, ABT-578, clobetasol, aspirin, and a combination thereof.

4. The medical device of claim 1, wherein the heparin is a molecular heparin, a heparin fragment, a heparin derivative or a heparin complex.

5. The medical device of claim 1, wherein the heparin is a pentasaccharide.

6. A medical device comprising as a coating a prodrug, the prodrug comprising:

a drug, heparin, and a polymer,

wherein the heparin is linked to the polymer; and

wherein the drug is linked to the heparin.

7. The medical device of claim 6, wherein the drug is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant substances, super oxide dismutases, super oxide dismutases mimics, nitric oxide donors, cytostatic agents, antibodies, progenitor cell capturing antibody, enzymes, prohealing drugs and combinations thereof.

8. The medical device of claim 6, wherein the drug is selected from the group consisting of paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, ABT-578, clobetasol, aspirin, and a combination thereof.

9. The medical device of claim 6, wherein the heparin is a molecular heparin, a heparin fragment, a heparin derivative or a heparin complex.

10. The medical device of claim 6, wherein the heparin is a pentasaccharide.

11. A medical device comprising as a coating a prodrug, the prodrug comprising a drug, heparin, and a polymer,

wherein the heparin is linked to the polymer;

wherein the drug is linked to the heparin or the polymer; and

wherein the heparin is modified by a hydrophobic counter-ion.

12. The medical device of claim 11, wherein the drug is selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant substances, super oxide dismutases, super oxide dismutases mimics, nitric oxide donors, cytostatic agents, antibodies, progenitor cell capturing antibody, enzymes, prohealing drugs and combinations thereof.

13. The medical device of claim 11, wherein the drug is selected from the group consisting of paclitaxel, docetaxel, estradiol, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin, ABT-578, clobetasol, aspirin, and a combination thereof.

14. The medical device of claim 11, wherein the heparin is a molecular heparin, a heparin fragment, a heparin derivative or a heparin complex.

15. The medical device of claim 11, wherein the heparin is a pentasaccharide.