Medicament incorporation matrix

• US 7,794,751 B2
• Filed: 03/23/2006
• Issued: 09/14/2010
• Est. Priority Date: 08/15/2000
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Chudzik, Stephen J., Everson, Terrence P., Amos, Richard A.
• Primary Examiner(s): Henley, III; Raymond J
• Application Number:
  US11/387,508
• Publication Number:
  US 20060165751A1
• Time in Patent Office: 1,636 Days
• Field of Search: 424/487
• US Class Current: 424/487
• CPC Class Codes: A61L 2300/22 Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
• CPC Class Codes: A61L 2300/232 Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A coating composition, in both its uncrosslinked and crosslinked forms, for use in delivering a medicament from the surface of a medical device positioned in vivo. Once crosslinked, the coating composition provides a gel matrix adapted to contain the medicament in a form that permits the medicament to be released from the matrix in a prolonged, controlled, predictable and effective manner in vivo. A composition includes a polyether monomer, such as an alkoxy poly(alkylene glycol), a carboxylic acid-containing monomer, such as (meth)acrylic acid, a photoderivatized monomer, and a hydrophilic monomer such as acrylamide.

Claims

1. A coating composition for use in delivering a medicament from the surface of a medical device positioned in vivo, the composition comprising a polymeric reagent formed by the polymerization of the following monomers:

a) about 1 to about 20 mole % of a polyether monomer,

b) about 5 to about 75 mole % of a carboxylic acid-containing monomer, such that the effective ratio of ether groups to carboxylic acid groups in the resultant copolymer is between about 1 to 1 and about 10 to 1, and

c) an amount of a hydrophilic monomer suitable to bring the composition to 100%.

2. A composition according to claim 1 wherein the polyether monomer comprises an alkoxy (poly)alkyleneglycol (meth)acrylate.

3. A composition according to claim 2 wherein the alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, and butoxy.

4. A composition according to claim 2 wherein the (poly)alkylene glycol component of the alkoxy (poly)alkyleneglycol (meth)acrylate is selected from the group consisting of (poly)propylene glycol and (poly)ethylene glycol.

5. A composition according to claim 4 wherein the (poly)alkylene glycol has a nominal weight average molecular weight ranging from about 200 g/mole to about 2000 g/mole.

6. A composition according to claim 5 wherein the polyether monomer is selected from the group consisting essentially of methoxy (poly)ethylene glycol methacrylates, (poly)ethylene glycol methacrylates, and (poly)propylene glycol methacrylates.

7. A composition according to claim 1 wherein the polyether monomer is present in an amount of between about 5 and about 15 mole %.

8. A composition according to claim 1 wherein the carboxylic acid-containing monomer is selected from carboxyl substituted ethylene compounds.

9. A composition according to claim 8 wherein the carboxyl acid-containing monomer is selected from acrylic, methacrylic, maleic, crotonic, itaconic, and citraconic acid.

10. A composition according to claim 8 wherein the concentration of the carboxylic acid-containing monomer is between about 30 to about 50 mole %.

11. A composition according to claim 10 wherein the carboxylic-acid containing monomer comprises (meth)acrylic acid.

12. A composition according to claim 9 wherein the concentration of the carboxylic acid-containing monomer is between about 30 to about 50 mole % and the carboxylic acid containing monomer comprises (meth)acrylic acid.

13. A composition according to claim 1 wherein the photoderivatized monomer is selected from the group consisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide, 9-vinyl anthracene, and 9-anthracenylmethyl methacrylate.

14. A composition according to claim 13 wherein the photoderivatized monomer is present in an amount of between about 1 to about 7 mole %.

15. A composition according to claim 1 wherein the hydrophilic monomer comprises an alkenyl substituted amide.

16. A composition according to claim 15 wherein the hydrophilic monomer is selected from the group consisting of acrylamide, N-vinylpyrrolidone, methacrylamide, and acrylamido propanesulfonic acid (AMPS).

17. A composition according to claim 16 wherein the hydrophilic monomer is present in an amount of between about 30 and about 70 mole %.

18. A composition according to claim 1 wherein the medicament is selected from the group consisting of peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides and combinations thereof.

19. A composition according to claim 1 wherein the medicament is selected from the group consisting of gene therapy agents selected from therapeutic nucleic acids and nucleic acids encoding therapeutic gene products, antibiotics selected from penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin and cephalosporins and antiseptics selected from silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds.

20. A composition according to claim 1 wherein the device is selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs and filters adapted for deployment in a blood vessel in order to trap emboli.

41. A composition according to claim 1 wherein the polyether monomer comprises an alkoxy (poly)alkyleneglycol (meth)acrylate, the carboxylic acid-containing monomer is selected from carboxyl substituted ethylene compounds, the photoderivatized monomer is selected from the group consisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide, 9-vinyl anthracene, and 9-anthracenylmethyl methacrylate, and the hydrophilic monomer is selected from the group consisting of acrylamide, N-vinylpyrrolidone, methacrylamide, and acrylamido propanesulfonic acid (AMPS).

42. A composition according to claim 41 wherein the medicament is selected from the group consisting of gene therapy agents selected from therapeutic nucleic acids and nucleic acids encoding therapeutic gene products, antibiotics selected from penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin and cephalosporins and antiseptics selected from silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds and the device is selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs and filters adapted for deployment in a blood vessel in order to trap emboli.

43. A composition according to claim 41, wherein the device provides a polymeric surface selected from the group consisting of polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, and chitins.

44. A composition according to claim 41, wherein the device provides a surface selected from the group consisting of titanium/titanium alloys, TiNi, aluminum oxide, platinum/platinum alloys, stainless steels, pyrolytic carbon, silver, glassy carbon, polyurethanes, polycarbonates, silicone elastomers, polyolefins, polyvinyl chlorides, polyethers, polyesters, nylons, polyvinyl pyrrolidones, polyacrylates polymethacrylates, n-butyl cyanoacrylate, polyvinyl alcohols, polyisoprenes, rubber, cellulosics, polyvinylidene fluoride, polytetrafluoroethylene, ethylene tetrafluoroethylene copolymer, acrylonitrile butadiene ethylene, polyamide, polyimide, styrene acrylonitrile, hydroxyapatite, bone, skin, teeth, collagen, laminin, elastin, fibrin, wood, cellulose, compressed carbon and glass.

49. The coating composition of claim 1, further comprising about 0.1 to about 10 mole % of a photoderivatized monomer.

21. A crosslinked coating composition for use in delivering a medicament from the surface of a medical device positioned in vivo, the composition comprising a polymeric reagent in the form of a gel matrix, the polymeric reagent being formed by the polymerization of the following monomers:

a) about 1 to about 20 mole % of a polyether monomer,

b) about 5 to about 75 mole % of a carboxylic acid-containing monomer, such that the effective ratio of ether groups to carboxylic acid groups in the resultant copolymer is between about 1 to 1 and about 10 to 1,

c) about 0.1 to about 10 mole % of the residue of a photoderivatized monomer, and

d) an amount of a hydrophilic monomer suitable to bring the composition to 100%.

22. A crosslinked composition according to claim 21 wherein the polyether monomer comprises an alkoxy (poly)alkyleneglycol (meth)acrylate.

23. A crosslinked composition according to claim 22 wherein the alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, and butoxy.

24. A crosslinked composition according to claim 22 wherein the (poly)alkylene glycol component of the alkoxy (poly)alkyleneglycol (meth)acrylate is selected from the group consisting of (poly)propylene glycol and (poly)ethylene glycol.

25. A crosslinked composition according to claim 24 wherein the (poly)alkylene glycol component has a nominal weight average molecular weight ranging from about 200 g/mole to about 2000 g/mole.

26. A crosslinked composition according to claim 25 wherein the polyether monomer is selected from the group consisting essentially of methoxy (poly)ethylene glycol methacrylates, (poly)ethylene glycol methacrylates, and (poly)propylene glycol methacrylates.

27. A crosslinked composition according to claim 21 wherein the polyether monomer is present in an amount of between about 5 and about 15 mole %.

28. A crosslinked composition according to claim 21 wherein the carboxylic acid-containing monomer is selected from carboxyl substituted ethylene compounds.

29. A crosslinked composition according to claim 28 wherein the carboxyl acid-containing monomer is selected from acrylic, methacrylic, maleic, crotonic, itaconic, and citraconic acid.

30. A crosslinked composition according to claim 28 wherein the concentration of the carboxylic acid-containing monomer is between about 30 to about 50 mole %.

31. A crosslinked composition according to claim 30 wherein the carboxylic-acid containing monomer comprises (meth)acrylic acid.

32. A crosslinked composition according to claim 29 wherein the concentration of the carboxylic acid-containing monomer is between about 30 to about 50 mole % and the carboxylic acid containing monomer comprises (meth)acrylic acid.

33. A crosslinked composition according to claim 21 wherein the photoderivatized monomer is selected from the group consisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide (“

BBA-APMA”

), 9-vinyl anthracene, and 9-anthracenylmethyl methacrylate.

34. A crosslinked composition according to claim 33 wherein the photoderivatized monomer is present in an amount of between about 1 to about 7 mole %.

35. A crosslinked composition according to claim 21 wherein the hydrophilic monomer comprises an alkenyl substituted amide.

36. A crosslinked composition according to claim 35 wherein the hydrophilic monomer is selected from the group consisting of acrylamide, N-vinylpyrrolidone, methacrylamide, and acrylamido propanesulfonic acid (AMPS).

37. A crosslinked composition according to claim 36 wherein the hydrophilic monomer is present in an amount of between about 30 and about 70 mole %.

38. A crosslinked composition according to claim 21 wherein the medicament is selected from the group consisting of peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides and combinations thereof.

39. A crosslinked composition according to claim 21 wherein the medicament is selected from the group consisting of gene therapy agents selected from therapeutic nucleic acids and nucleic acids encoding therapeutic gene products, antibiotics selected from penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin and cephalosporins and antiseptics selected from silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds.

40. A crosslinked composition according to claim 21 wherein the device is selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs and filters adapted for deployment in a blood vessel in order to trap emboli.

45. A crosslinked composition according to claim 21 wherein the polyether monomer comprises an alkoxy (poly)alkyleneglycol (meth)acrylate, the carboxylic acid-containing monomer is selected from carboxyl substituted ethylene compounds, the photoderivatized monomer is selected from the group consisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide, 9-vinyl anthracene, and 9-anthracenylmethyl methacrylate, and the hydrophilic monomer is selected from the group consisting of acrylamide, N-vinylpyrrolidone, methacrylamide, and acrylamido propanesulfonic acid (AMPS).

46. A crosslinked composition according to claim 45 wherein the medicament is selected from the group consisting of gene therapy agents selected from therapeutic nucleic acids and nucleic acids encoding therapeutic gene products, antibiotics selected from penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erytliromycin and cephalosporins and antiseptics selected from silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds and the device is selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, total artificial hearts and ventricular assist pumps, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs and filters adapted for deployment in a blood vessel in order to trap emboli.

47. A crosslinked composition according to claim 45, wherein the device provides a polymeric surface selected from the group consisting of polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, and chitins.

48. A crosslinked composition according to claim 45, wherein the device provides a surface selected from the group consisting of titanium/titanium alloys, TiNi, aluminum oxide, platinum/platinum alloys, stainless steels, pyrolytic carbon, silver, glassy carbon, polyurethanes, polycarbonates, silicone elastomers, polyolefins, polyvinyl chlorides, polyethers, polyesters, nylons, polyvinyl pyrrolidones, polyacrylates polymethacrylates, n-butyl cyanoacrylate, polyvinyl alcohols, polyisoprenes, rubber, cellulosics, polyvinylidene fluoride, polytetrafluoroethylene, ethylene tetrafluoroethylene copolymer, acrylonitrile butadiene ethylene, polyamide, polyimide, styrene acrylonitrile, hydroxyapatite, bone, skin, teeth, collagen, laminin, elastin, fibrin, wood, cellulose, compressed carbon and glass.