Biocompatible controlled release coatings for medical devices and related methods

Patent metadata

Field	Value
Publication number	US-9687368-B2
Application number	US-59509504-A
Country	US
Kind code	B2
Filing date	Aug 12, 2004
Priority date	Aug 13, 2003
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

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.

First claim

We claim:

1. A medical device comprising a controlled release coating for an implantable medical device comprising:
a bioactive agent-containing terpolymer-bipolymer blend, wherein the terpolymer-bipolymer blend has a total solubility parameter (δ T ) approximately equal to said bioactive agent's solubility parameter (δ) and wherein δ T and δ is between 15 J 1/2 /cm 3/2 to 25 J 1/2 /cm 3/2 , wherein the terpolymer and bipolymer each include vinyl acetate and an alkyl methacrylate.

2. The medical device according to claim 1 wherein said coating has a glass transition point (Tg) between approximately −20° C. and 50° C.

3. The medical device according to claim 2 wherein said coating has a glass transition point (Tg) between approximately 10° C. and 35° C.

4. The medical device according to claim 1 wherein said terpolymer comprises monomer subunits consisting of vinyl acetate (VAc), alkyl methacrylate (AMA) and n-vinyl pyrrolidone (NVP) and said bipolymer comprises monomer subunits consisting of VAc and AMA.

5. The medical device according to claim 4 wherein said relative mole percent concentrations of said monomer subunits in said terpolymer comprises 7-30% (VAc), 40-75% (AMA) and 19-30% (NVP).

6. The medical device according to claim 4 wherein said relative mole percent concentrations of said monomer subunits in said bipolymer comprises 5-70% VAc and 30-95% AMA.

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

8. The medical device according to claim 1 wherein said δ T is approximately 15 to 21 and said polymer blend comprises from 25% to 80% bipolymer and from 20% to 75% terpolymer.

9. The medical device according to claim 1 wherein said terpolymer has a lower Tg than said bipolymer.

10. The medical device according to claim 1 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.

11. The medical device according to claim 10 wherein said antiproliferative is a FKBP 12 binding compound.

12. The medical device according to claim 11 wherein said FKBP 11 binding compound is a macrolide antibiotic.

13. The medical device according to claim 12 wherein said macrolide antibiotic is rapamycin, everolimus, or ABT-578.

14. A vascular stent comprising:
a structure comprising a material, said material having a coating thereon comprised of a hydrophobic polymer;
a bioactive agent-containing terpolymer-bipolymer blend over said hydrophobic polymer wherein the difference between the solubility parameters of said terpolymer-bipolymer blend and said bioactive agent is no greater than 10 J 1/2 /cm 3/2 and the total solubility parameter (δ T ) of said bioactive agent-containing terpolymer-bipolymer blend is no greater than 25 J 1/2 /cm 3/2 , wherein the terpolymer and bipolymer each include vinyl acetate and an alkyl methacrylate.

15. The vascular stent according to claim 14 wherein said hydrophobic polymer is parylene or a parylene derivative.

16. The vascular stent according to claim 14 wherein said terpolymer comprises monomer subunits consisting of vinyl acetate (VAc), alkyl methacrylate (AMA) and n-vinyl pyrrolidone (NVP) and said bipolymer comprises monomer subunits consisting of VAc and AMA.

17. The vascular stent according to claim 16 wherein said relative mole percent concentrations of said monomer subunits in said terpolymer comprises 7-30% (VAc), 40-75% (AMA) and 19-30% (NVP).

18. The vascular stent according to claim 14 wherein said relative mole percent concentrations of said monomer subunits in said bipolymer comprises 5-70% VAc and 30-95% AMA.

19. The vascular stent according to claim 16 wherein said alkyl of said alkyl methacrylate is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl methacrylate.

20. The vascular stent according to claim 14 wherein said δ T is approximately 15 to 21 and said polymer blend comprises from 25% to 80% bipolymer and from 20% to 75% terpolymer.

21. The vascular stent according to claim 14 wherein said terpolymer has a lower Tg than said bipolymer.

22. The vascular stent according to claim 14 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.

23. The vascular stent according to claim 22 wherein said antiproliferative is a FKBP 12 binding compound.

24. The vascular stent according to claim 23 wherein said FKBP 12 binding compound is a macrolide antibiotic.

25. The vascular stent according to claim 24 wherein said macrolide antibiotic is rapamycin, everolimus, or ABT-578.

26. A vascular stent device comprising a controlled release coating comprising:
a polymer component comprising a terpolymer-bipolymer polymer blend,
wherein
the terpolymer and bipolymer each include vinyl acetate; 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.

27. An implantable medical device comprising a controlled release, non-bioerodable coating comprising:
a terpolymer-bipolymer blend, wherein the terpolymer-bipolymer blend has a total solubility parameter (δ T ) approximately equal to a bioactive agent's solubility parameter (δ) and wherein δ T and δ is between 15 J 1/2 /cm 3/2 .

28. The medical device according to claim 27 wherein said coating has a glass transition point (Tg) between approximately −20° C. and 50° C.

29. The medical device according to claim 28 wherein said coating has a glass transition point (Tg) between approximately 10° C. and 35° C.

30. The medical device according to claim 27 wherein said δ T is approximately 15 to 21 and said polymer blend comprises from 25% to 80% bipolymer and from 20% to 75% terpolymer.

31. The medical device according to claim 27 wherein said terpolymer has a lower Tg than said bipolymer.

32. The medical device according to claim 27 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.

Assignees

• Udipi Kishore
• Cheng Peiwen
• Shalaby Shalaby W
• Campbell Todd
• Lyu Su Ping
• Medtronic Vascular Inc

Inventors

• Udipi Kishore
• Cheng Peiwen
• Shalaby Shalaby W
• Campbell Todd
• Lyu Su Ping

Classifications

• A61L31/06

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds {(A61L31/041 takes precedence)} · CPC title

• A61L2300/602

  Type of release, e.g. controlled, sustained, slow · CPC title

• A61F2/91 Primary

  made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes · CPC title

• A61L31/10

  Macromolecular materials · CPC title

• A61L2300/406

  Antibiotics · CPC title