Coatings of acrylamide-based copolymers

• US 8,591,934 B2
• Filed: 11/14/2012
• Issued: 11/26/2013
• Est. Priority Date: 12/15/2006
• Status: Expired due to Fees

• Current Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories)
• Original Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories)
• Inventors: Hossainy, Syed Faiyaz Ahmed, Glauser, Thierry, Trollsas, Mikael O.
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US13/677,115
• Publication Number:
  US 20130071449A1
• Time in Patent Office: 377 Days
• Field of Search: None
• US Class Current: 424/423
• 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 a 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;

a linker comprising poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl, C3-C12 cycloalkyl, C3-12 aryl, a peptide, a peptide sequence, a protein, an oligomer of amino acids, succinic anhydride, glutaric anhydride, dimethyl succinic anhydride, methyl glutaric anhydride, a thioester, a disulfide bond, a polylactic acid oligomer, a poly(lactic-co-glycolic acid) oligomer, Polycaprolactone oligomer, an ester linkage, or an anhydride linkage; and

a copolymer of Formula II;

2. The implantable device of claim 1, wherein the linker comprises succinic anhydride, glutaric anhydride, dimethyl succinic anhydride, methyl glutaric anhydride, a thioester, a disulfide bond, a polylactic acid oligomer, a poly(lactic-co-glycolic acid) oligomer, a Polycaprolactone oligomer, an ester linkage, or an anhydride linkage.

3. The implantable device of claim 1, wherein the linker comprises succinic anhydride, glutaric anhydride, dimethyl succinic anhydride, or methyl glutaric anhydride.

4. The implantable device of claim 1, wherein the linker comprises poly(ethylene glycol) (PEG), a C1-C12 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 1, wherein the linker comprises poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl, C3-C12 cycloalkyl, or C3-C12 aryl.

7. The implantable device of claim 1, wherein the copolymer is poly[N-(2-hydroxypropyl)methacrylamide-co-methoxyethyl methacrylate] (HPMA-co-MOEMA).

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

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

10. The implantable device of claim 1, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, a nitric oxide donor, super oxide dismutase, a super oxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, a rapamycin derivative, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or a prodrug, co-drug, or combination of these.

11. The implantable device of claim 9, wherein the bioactive agent is selected from the group consisting of halofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, a nitric oxide donor, super oxide dismutase, a super oxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, a rapamycin derivative, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ

-hiridun, clobetasol, mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or a prodrug, co-drug, or combination of these.

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

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

14. The implantable device of claim 1, wherein the coating further comprises one or more biocompatible polymers selected from the group consisting of poly(ester amide), polyhydroxyalkanoates (PHA), poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(tyrosine carbonates), poly(tyrosine ester), polyphosphoester, polyphosphoester urethane, polycyanoacrylates, poly(iminocarbonate), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, polyvinyl chloride, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides, polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl esters, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, polyamides, polycaprolactam, polycarbonates, polyimides, poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butyl methacrylate), poly(sec-butyl methacrylate), poly(isobutyl methacrylate), poly(tert-butyl methacrylate), poly(n-propyl methacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, poly(propylene oxide), poly(aspirin), 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), polypropylene oxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin, fragments and derivatives of hyaluronic acid, heparin, fragments and derivatives of heparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin, chitosan, and alginate.

15. The implantable device of claim 14, wherein the one or more biocompatible polymers are selected from the group consisting of poly(3-hydroxyalkanoates), poly(4-hydroxyalkanaotes), vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidene halides, polyvinyl ketones, polyvinyl aromatics, polyamides and polyvinyl esters.

16. The implantable device of claim 14, wherein the one or more biocompatible polymers are selected from the group consisting of poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG-methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone (VP), polyvinyl chloride, polyvinyl methyl ether, polyvinylidene chloride, polyacrylonitrile, polystyrene, polycaprolactam and polyvinyl acetate.

17. A method of treating or ameliorating a medical condition, comprising implanting into a blood vessel the implantable device of claim 9.

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

providing a copolymer of Formula II;

19. The method of claim 18, wherein the linker comprises succinic anhydride, glutaric anhydride, dimethyl succinic anhydride, methyl glutaric anhydride, a thioester, a disulfide bond, a polylactic acid oligomer, a poly(lactic-co-glycolic acid) oligomer, a Polycaprolactone oligomer, an ester linkage, or an anhydride linkage.

20. The method of claim 18, wherein the linker comprises succinic anhydride, glutaric anhydride, dimethyl succinic anhydride, or methyl glutaric anhydride.

21. The method of claim 18, wherein the linker comprises poly(ethylene glycol) (PEG), an alkyl chain, or a peptide sequence.

22. The method of claim 21, wherein the peptide sequence comprises glycine-phenylalinine-leucine-glycine.

23. The method of claim 18, wherein the linker comprises poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12 alkyl, C3-C12 cycloalkyl, or C3-C12 aryl.

24. The method of claim 18, wherein the coating further comprises one or more biocompatible polymers selected from the group consisting of poly(ester amide), polyhydroxyalkanoates (PHA), poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(tyrosine carbonates), poly(tyrosine ester), polyphosphoester, polyphosphoester urethane, polycyanoacrylates, poly(iminocarbonate), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, polyvinyl chloride, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides, polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl esters, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, polyamides, polycaprolactam, polycarbonates, polyimides, poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butyl methacrylate), poly(sec-butyl methacrylate), poly(isobutyl methacrylate), poly(tert-butyl methacrylate), poly(n-propyl methacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, poly(propylene oxide), poly(aspirin), 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), polypropylene oxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin, fragments and derivatives of hyaluronic acid, heparin, fragments and derivatives of heparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin, chitosan, and alginate.

25. The method of claim 24, wherein the one or more biocompatible polymers are selected from the group consisting of poly(3-hydroxyalkanoates), poly(4-hydroxyalkanaotes), vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidene halides, polyvinyl ketones, polyvinyl aromatics, polyamides and polyvinyl esters.

26. The method of claim 24, wherein the one or more biocompatible polymers are selected from the group consisting of poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG-methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone (VP), polyvinyl chloride, polyvinyl methyl ether, polyvinylidene chloride, polyacrylonitrile, polystyrene, polycaprolactam and polyvinyl acetate.