Polymers of fluorinated monomers and hydrophilic monomers

• US 20060047095A1
• Filed: 08/31/2004
• Published: 03/02/2006
• Est. Priority Date: 08/31/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Pacetti, Stephen Dirk
• Granted Patent: US 7,244,443 B2
• Time in Patent Office: Days
• US Class Current: 526/242
• 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 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• 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: C08F 214/18 Monomers containing fluorine
• CPC Class Codes: C08F 214/22 Vinylidene fluoride
• CPC Class Codes: C08L 27/12 containing fluorine atoms
• CPC Class Codes: Y10T 428/31786 Of polyester [e.g., alkyd, etc.]

Abstract

A polymer of fluorinated monomers and hydrophilic monomers is provided. It is also provided a polymer blend that contains a polymer of fluorinated monomers and another biocompatible polymer. The polymer of fluorinated monomers or polymer blend described herein and optionally 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 fluorinated monomers and hydrophilic monomers.

2. The biocompatible polymer of claim 1, having the structure of formula I:

3. The biocompatible polymer of claim 2, wherein the flexibility monomer can be —

CF₂—

CRF—

, —

CHF—

CRF—

, and —

CF₂—

CRH—

, or combinations thereof in which R is selected from the group consisting of trifluoromethyl, F, Cl, Br, I, short chain alkyl groups from C₂ to C₁₂, fluorinated short chain alkyl groups from C₂ to C₁₂, and combinations thereof.

4. 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.

5. The biocompatible polymer of claim 2, 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.

6. The biocompatible polymer of claim 2 having a structure of any of formulae II-IV:

7. The biocompatible polymer of claim 2, wherein the strength fluoro monomer is in the range from about 60 mole % to about 90 mole %,

wherein the flexibility fluoro monomer is in the range from about 0 mole % to about 40 mole %, and

wherein the hydrophilic monomer is in the range from above 0 mole % to about 20 mole %.

11. A polymer blend, comprising the polymer of fluorinated monomers as defined according to claim 1, a biocompatible polymer, and optionally a biobeneficial material.

12. A polymer blend, comprising the polymer of fluorinated monomers as defined according to claim 2, a biocompatible polymer, and optionally a biobeneficial material.

13. A polymer blend, comprising the polymer of fluorinated monomers as defined according to claim 6, a biocompatible polymer, and optionally a biobeneficial material.

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

15. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 2.

16. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 3.

17. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 4.

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

19. An implantable device having a biocompatible coating thereon, wherein the biocompatible coating comprises the biocompatible polymer of claim 6.

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

24. The implantable device of claim 14 which is a drug-delivery stent, wherein the coating further comprises a bioactive agent.

25. The implantable device of claim 15 which is a drug-delivery stent, wherein the coating further comprises a bioactive agent.

26. The drug-delivery stent of claim 24, 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.

27. The drug-delivery stent of claim 25, 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.

28. A method of treating a disorder in a patient comprising implanting in the patient the drug-delivery stent of claim 24, 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.

29. A method of treating a disorder in a patient comprising implanting in the patient the drug-delivery stent of claim 25, 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. tetramethylpiperidine-

8. A biocompatible polymer blend comprising a biocompatible polymer that comprises fluorinated monomers and at least one other biocompatible polymer.

9. The polymer blend of claim 8, wherein the other biocompatible polymer is a hydrophilic polymer.

10. The polymer blend of claim 8, wherein the 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.

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

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

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