Biocompatible controlled release coatings for medical devices and related methods

• US 8,088,404 B2
• Filed: 12/06/2004
• Issued: 01/03/2012
• Est. Priority Date: 03/20/2003
• Status: Active Grant

• Current Assignee: Medtronic Vascular, Inc. (Medtronic Plc)
• Original Assignee: Medtronic Vascular (Medtronic Plc)
• Inventors: Udipi, Kishore, Cheng, Peiwen, Chen, Mingfei, Lyu, Su-Ping
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Gulledge, Brian
• Application Number:
  US11/005,463
• Publication Number:
  US 20050084515A1
• Time in Patent Office: 2,584 Days
• Field of Search: None
• US Class Current: 424/426
• CPC Class Codes: A61L 2300/406 Antibiotics
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• 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

Abstract

Biocompatible coatings for medical devices are disclosed. Specifically, polymer coatings designed to control the release of bioactive agents from medical devices in vivo are disclosed wherein the solubility parameters of polymers and drugs are closely matched to control elute rate profiles. The present application also discloses providing vascular stents with controlled release coatings and related methods for making these coatings.

Claims

1. A medical device comprising a controlled release coating comprising:

a polymer component comprising a terpolymer-co-polymer-homopolymer polymer blend and a drug, wherein the δ

_T for the drug is within ±

10 J^1/2/cm^3/2 of the total solubility parameter δ

_T, for the polymer component; and

wherein said terpolymer comprises monomer subunits consisting essentially of vinyl acetate (VAc), alkyl methacrylate (AMA) and n-vinyl pyrrolidone (NVP), said co-polymer comprises monomer subunits consisting essentially of VAc and AMA, and said homopolymer is polyvinyl pyrrolidone, wherein;

the terpolymer has a Tg of 15°

C. to 20°

C.;

the co-polymer has a Tg of 32°

C. to 35°

C.;

the homopolymer has a Tg of 174°

C.; and

the polymer blend comprises 20-30% co-polymer, 60-70% terpolymer, and 5-15% homopolymer.

2. The medical device according to claim 1 wherein said relative mole percent concentrations of said monomer subunits in said terpolymer comprises 5-30% (VAc), 40-77% (AMA) and 18-30% (NVP).

3. The medical device according to claim 1 wherein said relative mole percent concentrations of said monomer subunits in said co-polymer comprises 5-70% VAc and 30-95% AMA.

4. The medical device according to claim 1 wherein said alkyl methacrylate is selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, and hexyl methacrylate.

5. The medical device according to any one of claim 1 through 4 wherein said δ

_T for the polymer component is approximately 15 to 21.

6. The medical device according to claim 1 wherein said drug is rapamycin, everolimus or ABT-578.

7. The medical device of claim 1 wherein the coating is biocompatible, non-thrombogenic, non-inflammatory, lubricious, and non-bioerodable.

8. A medical device comprising a controlled release coating comprising:

a polymer component comprising a terpolymer-co-polymer-homopolymer polymer blend, wherein;

the terpolymer and co-polymer each include vinyl acetate;

the terpolymer has a low Tg relative to the Tg of the co-polymer and homopolymer;

the co-polymer has an intermediate Tg relative to the Tg of the terpolymer and homopolymer;

the homopolymer has a high Tg relative to the Tg of the co-polymer and terpolymer;

wherein the terpolymer has a Tg of 15°

C. to 25°

C.; and

the polymer blend comprises 20-30% co-polymer, 60-70% terpolymer, and 5-15% homopolymer; and

a drug, wherein the δ

_T for the drug is within ±

10 J^1/2/cm^3/2 of the total solubility parameter δ

_T for the polymer component.

9. The medical device of claim 8 wherein the co-polymer has a Tg of 30°

C. to 40°

C.

10. The medical device of claim 8 wherein the homopolymer has a Tg of 170°

C. to 180°

C.

11. The medical device according to claim 8 wherein said coating has a glass transition point (Tg) from approximately −

20°

C. to 50°

C.

12. The medical device according to claim 8 wherein said terpolymer comprises monomer subunits consisting essentially of vinyl acetate (VAc), alkyl methacrylate (AMA) and n-vinyl pyrrolidone (NVP), said co-polymer comprises monomer subunits consisting essentially of VAc and AMA, and said homopolymer is polyvinyl pyrrolidone.

13. The medical device according to claim 12 wherein said relative mole percent concentrations of said monomer subunits in said terpolymer comprises 5-30% (VAc), 40-77% (AMA) and 18-30% (NVP).

14. The medical device according to claim 12 wherein said relative mole percent concentrations of said monomer subunits in said co-polymer comprises 5-70% VAc and 30-95% AMA.

15. The medical device according to claim 12 wherein said alkyl methacrylate is selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, and hexyl methacrylate.

16. The medical device according to any one of claim 11 through 15 and claim 8 wherein said δ

_T, for the polymer component is approximately 15 to 21.

17. The medical device according to claim 8 wherein said drug is selected from the group consisting of macrolide antibiotics, FKBP 12 binding compounds, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, peroxisome proliferator-activated receptor gamma ligands (PPARγ

), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, antibiotics, proteasome inhibitors anti-sense nucleotides and transforming nucleic acids.

18. The medical device according to claim 17 wherein said antibiotic is a FKBP 12 binding compound.

19. The medical device according to claim 18 wherein said FKBP 12 binding compound is a macrolide antibiotic.

20. The medical device according to claim 19 wherein said macrolide antibiotic is rapamycin, everolimus or ABT-578.

21. The medical device of claim 8 wherein the coating is biocompatible, non-thrombogenic, non-inflammatory, lubricious, and non-bioerodable.

22. A vascular stent comprising a structure:

said structure comprising a material having a hydrophobic polymer disposed thereon;

a controlled release coating over said hydrophobic polymer wherein said controlled release coating comprises a polymer component comprising a terpolymer-co-polymer-homopolymer polymer blend, wherein;

the terpolymer and co-polymer each include vinyl acetate;

the terpolymer has a low Tg relative to the Tg of the co-polymer and homopolymer;

the co-polymer has an intermediate Tg relative to the Tg of the terpolymer and homopolymer;

the homopolymer has a high Tg relative to the Tg of the co-polymer and terpolymer;

wherein the terpolymer has a Tg of 15°

C. to 25°

C.; and

the polymer blend comprises 20-30% co-polymer, 60-70% terpolymer, and 5-15% homopolymer; and

a bioactive agent, wherein the δ

_T for the bioactive agent is within ±

10 J^1/2/cm^3/2 of the total solubility parameter δ

_T for the polymer component.

23. The vascular stent of claim 22 wherein the co-polymer has a Tg of 30°

C. to 40°

C.

24. The vascular stent of claim 22 wherein the homopolymer has a Tg of 170°

C. to 180°

C.

25. The vascular stent according to claim 22 wherein said hydrophobic polymer is parylene.

26. The vascular stent according to claim 22 wherein said terpolymer comprises monomer subunits consisting essentially of vinyl acetate (VAc), alkyl methacrylate (AMA) and n-vinyl pyrrolidone (NVP), said co-polymer comprises monomer subunits consisting essentially of VAc and AMA, and said homopolymer is polyvinyl pyrrolidone.

27. The vascular stent according to claim 26 wherein said relative mole percent concentrations of said monomer subunits in said terpolymer comprises 5-30% (VAc), 40-77% (AMA) and 18-30% (NVP).

28. The vascular stent according to claim 26 wherein said relative mole percent concentrations of said monomer subunits in said co-polymer comprises 5-70% VAc and 30-95% AMA.

29. The vascular stent according to claim 26 wherein said alkyl methacrylate is selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, and hexyl methacrylate.

30. The vascular stent according to any one of claim 25 though 29 and claim 22 wherein said δ

_T for the polymer component is approximately 15 to 21.

31. The vascular stent according to claim 22 wherein said bioactive agent is selected from the group consisting of anti-proliferatives including, but not limited to, macrolide antibiotics, FKBP 12 binding compounds, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, peroxisome proliferator-activated receptor gamma ligands (PPARγ

), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, antibiotics, proteasome inhibitors anti-sense nucleotides and transforming nucleic acids.

32. The vascular stent according to claim 31 wherein said antibiotic is a FKBP 12 binding compound.

33. The vascular stent according to claim 32 wherein said FKBP 12 binding compound is a macrolide antibiotic.

34. The vascular stent according to claim 33 wherein said macrolide antibiotic is rapamycin, everolimus or ABT-578.

35. The vascular stent of claim 22 wherein the coating is biocompatible, non-thrombogenic, non-inflammatory, lubricious, and non-bioerodable.

36. A vascular stent comprising a structure:

said structure comprising a material having a hydrophobic polymer disposed thereon;

a controlled release coating over said hydrophobic polymer wherein said controlled release coating comprises a polymer component comprising a terpolymer-co-polymer-homopolymer polymer blend, wherein;

the terpolymer and co-polymer each include vinyl acetate;

wherein the terpolymer has a Tg of 15°

C. to 20°

C., the co-polymer has a Tg of 32°

C. to 35°

C., and the homopolymer has a Tg of 174°

C.; and

the polymer blend comprises 20-30% co-polymer, 60-70% terpolymer, and 5-15% homopolymer; and

a bioactive agent, wherein the δ

_T for the bioactive agent is within ±

10 J^1/2/cm^3/2 of the total solubility parameter δ

_T for the polymer component.

37. A vascular stent comprising a structure:

said structure comprising a material having a controlled release coating disposed thereon, said controlled release coating consisting essentially of ABT-578 dispersed in a polymer blend, said polymer blend consisting essentially of a terpolymer, a co-polymer and a homopolymer, wherein;

said terpolymer comprises approximately 5 mole-% of vinyl acetate, approximately 77 mole-% of n-hexyl methacrylate, and approximately 18 mole-% of n-vinyl pyrrolidone,

said co-polymer consisting essentially of approximately 5 mole-% of vinyl acetate and approximately 95 mole-% of n-butyl methacrylate, and

said homopolymer consisting essentially of polyvinyl pyrrolidone, and

the polymer blend comprises 20-30% co-polymer, 60-70% terpolymer, and 5-15% homopolymer, and

wherein said controlled release coating comprises approximately 35% by weight ABT-578 and approximately 65% by weight of said polymer blend.

38. The vascular stent according to claim 37 wherein said structure is composed of a material selected from the group consisting of metals, polymers and biodegradable polymers.