Coatings of acrylamide-based copolymers

• US 20080146992A1
• Filed: 12/15/2006
• Published: 06/19/2008
• Est. Priority Date: 12/15/2006
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Glauser, Thierry, Hossainy, Syed F. A., Trollsas, Mikael O.
• Granted Patent: US 8,017,141 B2
• Time in Patent Office: Days
• US Class Current: 604/48
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• 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 33/26 Homopolymers or copolymers of acrylamide or methacrylamide

Abstract

An implantable device including conjugate formed of an acrylamide-based copolymer and a bioactive agent is provided.

Claims

1. An implantable device comprising a coating, the coating comprising a conjugate of a bioactive agent and a copolymer that comprises units derived from at least one acrylamide monomer.

2. The implantable device of claim 1, wherein the conjugate comprises covalent bonding between the bioactive agent and the copolymer.

3. The implantable device of claim 2, wherein the conjugate comprises a linker.

4. The implantable device of claim 2, wherein the conjugate comprises poly(ethylene glycol) (PEG), an alkyl chain, or a peptide sequence.

5. The implantable device of claim 4, wherein the peptide sequence comprises glycine-phenylalinine-leucine-glycine.

6. The implantable device of claim 2, wherein the copolymer comprises

wherein R₁ and R₃ are independently CH₃ or H;

wherein R₂ comprises a group having at least one hydroxyl, thiol, amino or carboxyl group;

wherein R₄ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl, or heterocyclic group;

wherein n and m are independently from about 0.01 to about 0.99, with a proviso that n+m=1; and

wherein Z is O or NH.

7. The implantable device of claim 6, wherein R₂ comprises PEG, a short alkyl chain or a peptide sequence.

8. The implantable device of claim 7, wherein the peptide sequence comprises glycine-phenylalinine-leucine-glycine.

9. The implantable device of claim 6, wherein the copolymer has a formula of

wherein R₅ and R₆ are independently CH₃ or H;

wherein R₇ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl, or heterocyclic group; and

wherein n and m are independently from about 0.01 to about 0.99, with a proviso that n+m=1.

10. The implantable device of claim 9, wherein the copolymer is poly[N-(2-hydroxypropyl)methacrylamide-co-methoxyethyl methacrylate] (HPMA-co-MOEMA).

11. The implantable device of claim 1, wherein the copolymer is a random or block copolymer.

12. The implantable device of claim 6, wherein the copolymer is a random or block copolymer.

13. The implantable device of claim 9, wherein the copolymer is a random or block copolymer.

14. The implantable device of claim 1, which is a stent.

15. The implantable device of claim 6, which is a stent.

16. The implantable device of claim 9, which is a stent.

17. The implantable device of claim 1, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

18. The implantable device of claim 6, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

19. The implantable device of claim 9, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

20. The implantable device of claim 14, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

21. The implantable device of claim 15, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

22. The implantable device of claim 16, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 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, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-1-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs, or combinations of these.

23. The implantable device of claim 1, wherein the coating comprises a layer of matrix comprising the copolymer and the bioactive agent.

24. The implantable device of claim 1, wherein the coating comprises a topcoat comprising the copolymer and the bioactive agent.

34. A method of treating, preventing or ameliorating a medical condition, comprising applying to a human being the composition of claim 17.

35. A method of treating, preventing or ameliorating a medical condition, comprising applying to a human being the composition of claim 18.

25. A method of forming a coating on an implantable device, comprising

providing a copolymer that comprises units derived from at least one acrylamide monomer,

providing a bioactive agent,

forming a conjugate of the bioactive agent and the copolymer, and

forming a coating comprising the conjugate on the implantable device.

26. The method of claim 25, wherein the conjugate comprises covalent bonding between the bioactive agent and the copolymer.

27. The method of claim 26, wherein the conjugate comprises a linker.

28. The method of claim 26, wherein the conjugate comprises poly(ethylene glycol) (PEG), an alkyl chain, or a peptide sequence.

29. The method of claim 28, wherein the peptide sequence comprises glycine-phenylalinine-leucine-glycine.

30. The method of claim 26, wherein the copolymer comprises

wherein R₁ and R₃ are independently CH₃ or H;

wherein R₂ comprises a group having at least one hydroxyl, thiol, amino or carboxyl group;

wherein R₄ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl, or heterocyclic group;

wherein n and m are independently from about 0.01 to about 0.99, with a proviso that n+m=1; and

wherein Z is O or NH.

31. The method of claim 30, wherein R₂ comprises PEG, a short alkyl chain or a peptide sequence.

32. The method of claim 31, wherein the peptide sequence comprises glycine-phenylalinine-leucine-glycine.

33. The method of claim 30, wherein the copolymer has a formula of

wherein R₅ and R₆ are independently CH₃ or H;

wherein R₇ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl, or heterocyclic group; and

wherein n and m are independently from about 0.01 to about 0.99, with a proviso that n+m=1.