Coatings for drug delivery devices comprising hydrolitically stable adducts of poly(ethylene-co-vinyl alcohol) and methods for fabricating the same

• US 20050070936A1
• Filed: 09/30/2003
• Published: 03/31/2005
• Est. Priority Date: 09/30/2003
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Pacetti, Stephen D.
• Granted Patent: US 7,318,932 B2
• Time in Patent Office: Days
• US Class Current: 606/153
• 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 2300/424 Anti-adhesion agents
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• 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 29/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids

Abstract

A polymer coating for medical devices based on a derivatized poly(ethylene-co-vinyl alcohol) is disclosed. A variety of polymers are described to make coatings for medical devices, particularly, for drug delivery stents. The polymers include poly(ethylene-co-vinyl alcohol) modified by alkylation, esterification, and introduction of fluorinated alkyl fragments, polysiloxane fragments and poly(ethylene glycol) fragments into the macromolecular chains of poly(ethylene-co-vinyl alcohol).

Claims

1. A medical article comprising an implantable substrate having a coating deposited on at least a portion of the substrate, the coating comprising a polymer having the formula:

2. The medical article of claim 1, wherein the non-fouling moiety comprises a derivative of a compound selected from a group consisting of a poly(alkylene glycol), heparin, poly(vinyl pyrrolidone), poly(2-hydroxyethylmethacrylate), poly(2-hydroxypropyl methacrylamide), poly(styrene sulfonate), hyaluronic acid, chondroitan sulfate, and chitosan.

3. The medical article of claim 2, wherein poly(alkylene glycol) is selected from a group consisting of poly(ethylene glycol), poly(1-propylene glycol), poly(2-propylene glycol) and poly(tetramethylene glycol).

4. The medical article of claim 1, wherein the implantable substrate is a stent.

5. The medical article of claim 1, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600;

the sum of m, n and p is within a range of between about 700 and about 7,600; and

x=0 or x=1.

6. The medical article of claim 1, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

7. A method for fabricating a medical article, including synthesizing a polymer having a formula:

8. The method of claim 7, wherein preparing the primary amino-functional poly(ethylene vinyl alcohol) further comprises:

(a) oxidizing poly(ethylene vinyl alcohol) to form a poly(ethylene vinyl alcohol) having ketone groups;

(b) reacting the poly(ethylene vinyl alcohol) having ketone groups with ammonia to form an imino derivative of poly(ethylene vinyl alcohol); and

(c) reducing the imino derivative of poly(ethylene vinyl alcohol).

9. The method of claim 7, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600;

the sum of m, n and p is within a range of between about 700 and about 7,600; and

x is an integer having a value between 0 and 10.

10. The method of claim 7, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

11. The method of claim 7, further comprising incorporating a drug into the polymer.

12. The method of claim 11, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

13. A method for fabricating a medical article, including synthesizing a polymer having a formula:

14. The method of claim 13, wherein preparing the primary amino-functional poly(ethylene vinyl alcohol) further comprises:

(a) oxidizing poly(ethylene vinyl alcohol) to form a poly(ethylene vinyl alcohol) having ketone groups;

(b) reacting the poly(ethylene vinyl alcohol) having ketone groups with ammonia to form an imino derivative of poly(ethylene vinyl alcohol); and

(c) reducing the an imino derivative of poly(ethylene vinyl alcohol).

15. The method of claim 13, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

16. The method of claim 13, wherein a ratio between n and p is between about 1:

19 andabout 1;

3.

17. The method of claim 13, further comprising incorporating a drug into the polymer.

18. The method of claim 17, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

19. A method for fabricating a medical article, including synthesizing a polymer having a formula:

20. The method of claim 19, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about I land about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

21. The method of claim 19, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

22. The method of claim 19, further comprising incorporating a drug into the polymer.

23. The method of claim 22, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

24. A method for fabricating a medical article, the method including synthesizing a polymer having a formula:

25. The method of claim 24, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

26. The method of claim 24, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

27. The method of claim 26, further comprising incorporating a drug into the polymer.

28. The method of claim 27, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

29. A method for fabricating a medical article, including synthesizing a polymer having a formula:

30. The method of claim 29, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

31. The method of claim 29, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

32. The method of claim 29, further comprising incorporating a drug into the polymer.

33. The method of claim 32, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

34. A method for fabricating a medical article, including synthesizing a polymer having a formula:

35. The method of claim 34, wherein preparing the dihydrazide derivative of hyaluronic acid further comprises reacting hyaluronic acid with dihydrazide of adipic acid.

36. The method of claim 34, wherein:

m and n, is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

37. The method of claim 34, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

38. The method of claim 37, further comprising incorporating a drug into the polymer.

39. The method of claim 38, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of rapamycin, clobetasol, or dexamethasone and derivatives thereof.

40. A method for fabricating a medical article, including synthesizing a polymer having a formula:

41. The method of claim 40, wherein preparing the primary amino-functional poly(ethylene vinyl alcohol) further comprises:

(a) oxidizing poly(ethylene vinyl alcohol) to form a poly(ethylene vinyl alcohol) having ketone groups;

(b) reacting the poly(ethylene vinyl alcohol) having ketone groups with ammonia to form an imino derivative of poly(ethylene vinyl alcohol); and

(c) reducing the an imino derivative of poly(ethylene vinyl alcohol).

42. The method of claim 40, wherein in the polymer:

m and n, is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of the sum of n and p is within a range of between about 30 and about 7,600; and

the sum of m, n and p is within a range of between about 700 and about 7,600.

43. The method of claim 40, wherein a ratio between n and p is between about 1:

19 and about 1;

3.

44. The method of claim 40, further comprising incorporating a drug into the polymer.

45. The method of claim 44, wherein the drug comprises actinomycin D, estradiol, paclitaxel, docetaxel, heparin, low molecular weight heparins, heparinoids, heparin derivatives containing hydrophobic counter-ions, rapamycin, derivatives and analogs of raparnycin, clobetasol, or dexamethasone and derivatives thereof.

46. A method for fabricating a medical article, including synthesizing a polymer having a formula:

47. The method of claim 46, wherein the non-fouling moiety comprises a derivative of a compound selected from a group consisting of a poly(alkylene glycol), heparin, poly(vinyl pyrrolidone), poly(2-hydroxyethylmethacrylate), poly(2-hydroxypropyl methacrylamide), poly(styrene sulfonate), hyaluronic acid, chondroitan sulfate, and chitosan.

48. The method of claim 47, wherein poly(alkylene glycol) is selected from a group consisting of poly(ethylene glycol), poly(1-propylene glycol), poly(2-propylene glycol) and poly(tetramethylene glycol).

49. The method of claim 46, wherein:

m, n, o is each, independently, a positive integer;

p is a positive integer or p=0;

the value of m is within a range of between about 30 and about 7,600;

the value of o is within a range of between about 11 and about 680;

the value of the sum of n and p is within a range of between about 30 and about 7,600;

the sum of m, n and p is within a range of between about 700 and about 7,600; and

x=0 or x=1.

50. The method of claim 61, wherein a ratio between n and p is between about 1:

19 and about 1;

3.