Coatings for implantable medical devices for controlled release of a hydrophilic drug and a hydrophobic drug

• US 8,703,167 B2
• Filed: 06/05/2006
• Issued: 04/22/2014
• Est. Priority Date: 06/05/2006
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Glauser, Thierry, Astafieva, Irina, Hossainy, Syed Faiyaz Ahmed
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US11/447,551
• Publication Number:
  US 20070280991A1
• Time in Patent Office: 2,878 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/25 Peptides having up to 20 amino acids in a defined sequence
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• 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: C08L 33/14 of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
• CPC Class Codes: C08L 75/04 Polyurethanes

Abstract

Provided herein is a coating that includes cRGD for endothelial cells and methods of making and using the same.

Claims

1. A medical device comprising a coating, the coating comprising

a first layer comprising a hydrophilic drug and a polymer, the polymer having a polar block(s) or a polar segment(s);

and

a second layer comprising a hydrophobic drug and a hydrophobic polymer;

wherein the coating includes the hydrophilic drug and the hydrophobic drug in different layers and provides a concurrent release profile of the hydrophilic drug and the hydrophobic drug;

wherein the hydrophilic drug is a cRGD peptide;

wherein the hydrophobic drug is sirolimus, everolimus, zotarolimus, or a combination thereof;

wherein the polymer with a polar block(s) or segment(s) is selected from the group consisting of polyurethanes, poly(hydroxyethyl methacrylate-block-methyl methacrylate) (poly(HEMA-block-MMA)), poly(hydroxyethyl methacrylate-block-methyl methacrylate) (poly(HEMA-block-HPMA)), poly(hydroxypropyl methacrylate) terminated with glycine-pheylaniline-leucine-glycine (poly(HPMA-GFLG), poly(butyl methacrylate-block-poly(ethylene glycol) acrylate) (poly(BMA-block-PEGA)), poly(methoxyethyl methacrylate-block-hydroxyethyl methacrylate) (poly(MOEMA-block-HEMA)), and combinations of these;

and

wherein the hydrophobic polymer is a copolymer of MOEMA with PEGA or HEMA having a percentage of PEGA or HEMA below 10 mol %.

2. The medical device of claim 1, wherein the hydrophilic drug is attached to a polymer included in the coating.

3. The medical device of claim 2 wherein a linker attaches the hydrophilic drug to the polymer.

4. The medical device of claim 3 wherein the linker is a hydrolytically degradable linker or a proteolytically degradable linker.

5. The medical device of claim 3 wherein the linker is an enzymatically degradable linker.

6. The medical device of claim 3 wherein the linker comprises poly(ethylene glycol) (PEG) or an alkyl chain.

7. The medical device of claim 4, wherein the hydrolytically degradable linker is selected from the group consisting of an amide linkage, a thiol linkage, an ester linkage, a thiourea linkage, an alkylamine linkage, a urethane linkage, a thioether linkage and combinations thereof.

8. The medical device of claim 4, wherein the hydrolytically degradable linker comprises a cysteine unit, an aspartate unit, a glutamate unit, or a combination thereof.

9. The medical device of claim 3 wherein the linker is a biodegradable polymer.

10. The medical device of claim 5 wherein the enzymatically degradable linker comprises a dipeptide sequence.

13. The medical device of claim 1 wherein the release profile of the hydrophilic drug of the first coating layer includes an initial burst release followed by sustained release.

14. The medical device of claim 1 wherein the release profile of the hydrophilic drug of the first coating layer is zero-order sustained release.

15. The medical device of claim 1, wherein the layer comprising the cRGD peptide is a base coat, and

wherein the layer comprising everolimus, sirolimus, zotarolimus, or a combination thereof is a topcoat.

16. The medical device of claim 1,

wherein the hydrophobic drug is everolimus,

wherein the layer comprising the hydrophilic drug is a topcoat,

wherein the layer comprising the hydrophobic drug is a base coat, and

wherein the topcoat and the base coat are separated by a sealant layer comprising a hydrophobic polymer.

17. The medical device of claim 16, wherein the hydrophobic polymer of the sealant layer comprises a hydrophobic acrylate polymer or fluoropolymer.

18. The medical device of claim 1, further comprising another bioactive agent.

19. The medical device of claim 1 which is a stent.

20. The medical device of claim 2, which is a stent.

21. The medical device of claim 3, which is a stent.

22. The medical device of claim 1 which is a bioabsorbable stent.

23. The medical device of claim 2, which is a bioabsorbable stent.

24. The medical device of claim 3, which is a bioabsorbable stent.

25. A method of forming the medical device of claim 1, comprising forming a coating on the medical device comprising

a first layer comprising a hydrophilic drug and a polymer, the polymer having a polar block(s) or a polar segment(s);

and

a second layer comprising a hydrophobic drug and a hydrophobic polymer;

wherein the coating includes the hydrophilic drug and the hydrophobic drug in different layers and provides a concurrent release profile of the hydrophilic drug and the hydrophobic drug;

wherein the hydrophilic drug is a cRGD peptide;

wherein the hydrophobic drug is sirolimus, everolimus, zotarolimus, or a combination thereof;

wherein the polymer with a polar block(s) or segment(s) is selected from the group consisting of polyurethanes, poly(hydroxyethyl methacrylate-block-methyl methacrylate) (poly(HEMA-block-MMA)), poly(hydroxyethyl methacrylate-block-methyl methacrylate) (poly(HEMA-block-HPMA)), poly(hydroxypropyl methacrylate) terminated with glycine-pheylaniline-leucine-glycine (poly(HPMA-GFLG), poly(butyl methacrylate-block-poly(ethylene glycol) acrylate) (poly(BMA-block-PEGA)), poly(methoxyethyl methacrylate-block-hydroxyethyl methacrylate) (poly(MOEMA-block-HEMA)), and combinations of these;

and

wherein the hydrophobic polymer is a copolymer of MOEMA with PEGA or HEMA having a percentage of PEGA or HEMA below 10 mol %.

26. A method of treating, or ameliorating a medical condition, comprising implanting in a human being the medical device of claim 1, wherein the medical condition is selected from the group consisting of 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, and combinations of these.

27. The medical device of claim 1, wherein the hydrophobic polymer is a copolymer of MOEMA with PEGA having a percentage of PEGA below 10 mol %.

28. The method of claim 25, wherein the hydrophobic polymer is a copolymer of MOEMA with PEGA having a percentage of PEGA below 10 mol %.

11. The medical device of 10 wherein the enzymatically degradable linker comprises a spacer.

12. The medical device of claim 11 wherein the spacer is selected from the group consisting of p-aminobenzyloxycarbonyl (PABC), a dipeptide, PEG, and combinations thereof, and

wherein the dipeptide is selected from the group consisting of phenylaniline-lysine, valine-cysteine, alanyl-valine, alanyl-proline, glycyl-proline and combinations thereof.