Methacrylate copolymers for medical devices

• US 20060067908A1
• Filed: 09/30/2004
• Published: 03/30/2006
• Est. Priority Date: 09/30/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Ding, Ni
• Granted Patent: US 9,011,831 B2
• Time in Patent Office: Days
• US Class Current: 424/78.270
• CPC Class Codes: A61L 2300/114 Nitric oxide, i.e. NO
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/254 Enzymes, proenzymes
• 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 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• 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 33/12 Homopolymers or copolymers of methyl methacrylate

Abstract

A polymer of hydrophobic monomers and hydrophilic monomers is provided. It is also provided a polymer blend that contains the polymer and another biocompatible polymer. The polymer or polymer blend and optionally a biobeneficial material and/or a bioactive agent can form a coating on an implantable device such as a drug delivery stent. The implantable device can be used for treating or preventing a disorder such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

Claims

1. A biocompatible polymer comprising hydrophobic monomers and hydrophilic monomers, wherein the biocompatible polymer has a backbone structure comprising at least a tertiary carbon grouping.

2. The biocompatible polymer of claim 1, having a glass transition temperature (T_g) at 15°

C. or above.

3. The biocompatible polymer of claim 1 having at least two glass transition temperatures, one glass transition temperature being under about 37°

C. and the other glass transition temperature being above about 37°

C.

4. The biocompatible polymer of claim 2, wherein the hydrophilic monomer is selected from the group consisting of vinyl monomers that bear a pyrrolidone group(s), carboxylic acid group(s), sulfonic acid group(s), sulfone group(s), amino group(s), alkoxy group(s), amide group(s), ester group(s), acetate group(s), poly(ethylene glycol) group(s), poly(propylene glycol) group(s), poly(tetramethylene glycol) group(s), poly(alkylene oxide) group(s), hydroxyl group(s), or a substituent that contains a charge or one of pyrrolidone group(s), carboxylic acid group(s), sulfone group(s), sulfonic acid group(s), amino group(s), alkoxy group(s), amide group(s), ester group(s), acetate group(s), poly(ethylene glycol) group(s), poly(propylene glycol) group(s), poly(tetramethylene glycol) group(s), poly(alkylene oxide) group(s), hydroxyl group(s), and combinations thereof.

5. The biocompatible polymer of claim 2, having the structure of formula I:

-[-Hydrophobic monomer-]α

-[-Hydrophilic monomer-]_n- 

 

Formula I

wherein R₁ is

wherein R₂ is —

OCH₂CH₂SO₃H, —

OCH₂CH₂CH₂SO₃H, -(—

CH₂CH₂O—

)_nCH₃, —

OCH₂CH₂SO₄⁻

NH₄⁺, —

NHCH₂CH₂NHSO₃⁻

NH₄⁺, —

O(CH₂CH₂O)_n—

Heparin, —

O(CH₂CH₂O)_n-Hyaluronic acid, or —

OH.

6. The biocompatible polymer of claim 1, having the structure of formulae II or III:

-[-Hydrophobic monomer 1-]_m-[-Hydrophobic monomer 2-]α

-[-Hydrophilic monomer-]_p- 

 

Formula II
-[-Hydrophobic monomer-]_m-[-Hydrophilic monomer 1-]_n-[-Hydrophilic monomer 2-]_p- 

 

Formula III

wherein m, n, and p are independently positive integers ranging from 1 to 100,000, and

wherein the hydrophobic monomer can be a methacrylate or fluorinated methacrylate.

7. The biocompatible polymer of claim 1, wherein the hydrophilicity monomer is selected from the group consisting of vinyl pyrrolidone, hydroxyethyl methacrylate, hydroxypropyl methacrylate, methyl vinyl ether, alkyl vinyl ether, vinyl alcohol, methacrylic acid, acrylic acid, acrylamide, N-alkyl acrylamide, hydroxypropylmethacrylamide, vinyl acetate, 2-sulfoethyl methacrylate, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, PEG-methacrylate, 2-aminoethyl methacrylate hydrochloride, N-(3-aminopropyl)methacrylamide hydrochloride, 2-N-morpholinoethyl methacrylate, vinylbenzoic acid, vinyl sulfonic acid, styrene sulfonates, a monomer that bears a charge, and combinations thereof.

8. A biocompatible polymer blend comprising a biocompatible polymer of claim 1 and at least one other biocompatible polymer.

9. A biocompatible polymer blend comprising a biocompatible polymer of claim 6 and at least one other biocompatible polymer.

10. A biocompatible polymer blend comprising a biocompatible polymer of claim 7 and at least one other biocompatible polymer.

11. The polymer blend of claim 8, further comprising a biobeneficial material.

12. The polymer blend of claim 9, further comprising a biobeneficial material.

13. The polymer blend of claim 10, wherein the biobeneficial material is coupled to the polymer through chemical reaction.

14. The polymer blend of claim 10, further comprising a biobeneficial material.

15. The polymer blend of claim 8, wherein the other biocompatible polymer is selected from the group consisting of poly(ester amide), polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates), poly(4-hydroxyalknaotes), polymers and copolymers comprising a monomer selected from the group consisting of 3-hydroxypropanoate, 3-hydroxybutyrate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 4-hydroxybutyrate, 4-hydroxyvalerate, 4-hydroxyhexanote, 4-hydroxyheptanoate, and 4-hydroxyoctanoate, poly polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide), polycaprolactone, poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes, polyphosphazenes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides, poly(vinylidene fluoride-co-hexafluoropropylene), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl acetate, copolymers of vinyl monomers with each other and olefins, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers, 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), polyamides, Nylon 66 and polycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glyceryl sebacate), poly(propylene fumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, polyethers, poly(ether-esters), poly(ethylene oxide-co-lactic acid) (PEO/PLA), polyalkylene oxides, poly(propylene oxide), polyalkylene oxalates, polyphosphazenes, phosphoryl choline, poly(aspirin), polymers and co-polymers of hydroxyl bearing monomers, HEMA, hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers, methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and 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), PLURONIC™

surfactants (polypropylene oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), glycosamino glycan (GAG), GAG derivatives, silicones, and combinations thereof.

16. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 1.

17. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 5.

18. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 7.

19. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 8.

20. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 9.

21. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 10.

22. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the polymer blend of claim 11.

23. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the polymer blend of claim 12.

24. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the polymer blend of claim 14.

25. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the polymer blend of claim 15.

26. The implantable device of claim 16 which is a drug delivery stent, wherein the coating further comprises a bioactive agent.

27. The implantable device of claim 17 which is a drug delivery stent, wherein the coating further comprises a bioactive agent.

28. The implantable device of claim 18 which is a drug delivery stent, wherein the coating further comprises a bioactive agent.

29. The drug delivery stent of claim 27, wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases 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, ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, and a combination thereof.

30. The drug delivery stent of claim 28, wherein the bioactive agent is selected from the group consisting of paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutases 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, ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, and a combination thereof.

31. A method of treating a disorder in a patient comprising implanting in the patient the drug delivery stent of claim 29, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

32. A method of treating a disorder in a patient comprising implanting in the patient the drug delivery stent of claim 30, wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.