Method and system of controlled temperature mixing and molding of polymers with active agents for implantable medical devices

• US 7,785,512 B1
• Filed: 05/25/2004
• Issued: 08/31/2010
• Est. Priority Date: 07/31/2003
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Pathak, Jaya
• Primary Examiner(s): HUSON, MONICA ANNE
• Application Number:
  US10/853,924
• Time in Patent Office: 2,289 Days
• Field of Search: None
• US Class Current: 264/211
• CPC Class Codes: A61L 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: B29C 2948/92019 Pressure
• CPC Class Codes: B29C 2948/92209 Temperature
• CPC Class Codes: B29C 2948/924 Barrel or housing
• CPC Class Codes: B29C 2948/926 Flow or feed rate
• CPC Class Codes: B29C 2948/92704 Temperature
• CPC Class Codes: B29C 2948/92828 Raw material handling or dosing, e.g. active hopper or feeding device
• CPC Class Codes: B29C 2948/92866 Inlet shaft or slot, e.g. passive hopper; Injector, e.g. injector nozzle on barrel
• CPC Class Codes: B29C 2948/92895 Barrel or housing
• CPC Class Codes: B29C 2948/92971 Fluids, e.g. for temperature control or of environment
• CPC Class Codes: B29C 48/04 Particle-shaped making granules B29B9/00
• CPC Class Codes: B29C 48/405 Intermeshing co-rotating screws
• CPC Class Codes: B29C 48/41 Intermeshing counter-rotating screws
• CPC Class Codes: B29C 48/92 Measuring, controlling or regulating
• CPC Class Codes: C08L 27/16 Homopolymers or copolymers or vinylidene fluoride
• CPC Class Codes: C08L 31/06 Homopolymers or copolymers of esters of polycarboxylic acids

Abstract

A method and system for making a composition for use in manufacturing an implantable medical device, such as a drug-eluting and/or delivery stent, is described. The method includes introducing a polymer, active agent, and a solvent into a mixing apparatus such as an extruder. The polymer, active agent, and solvent may be mixed in the apparatus to form a homogeneous or substantially homogeneous polymer mixture. The method may further include controlling a temperature of the polymer mixture in at least a portion of the apparatus. In an embodiment, the polymer mixture may be used as a coating for an implantable medical device, or fabricating an implantable medical device. The invention also includes a composition formed by the method described above.

Claims

1. A method of making a composition for use in manufacturing an implantable medical device, comprising:

introducing a polymer into a first segment of an extruder of a mixing apparatus allowing the polymer to flow out of an outlet of the extruder;

introducing an active agent into a second segment of the extruder, the second segment located between the first segment and the outlet;

removing impurities from the polymer while the polymer is in the apparatus;

mixing the active agent with the polymer in the apparatus to form a polymer mixture;

preventing degradation of at least some of the active agent, including controlling a temperature of the polymer mixture in at least a portion of the apparatus, wherein controlling the temperature is performed at least by either one or both of;

(1) cooling a solvent, without the active agent, to a temperature below an ambient room temperature followed by introducing the cooled solvent, without the active agent, into the extruder, and

(2) cooling a mixture of the solvent and the active agent to a temperature below an ambient room temperature followed by introducing the cooled mixture of the solvent and the active agent into the extruder; and

removing the polymer mixture from the apparatus, wherein the polymer mixture is for use as a coating for an implantable medical device, or fabricating an implantable medical device.

2. The method of claim 1, further comprising coating an implantable medical device with the polymer mixture, or fabricating an implantable medical device with the polymer mixture.

3. The method of claim 1, further comprising purifying the polymer prior to mixing the polymer with the active agent and the solvent.

4. The method of claim 1, wherein the polymer mixture is homogeneous or substantially homogeneous in at least a portion of the apparatus.

5. The method of claim 1, wherein the extruder is selected from the group consisting of a single screw extruder, an intermeshing co-rotating extruder, and a counter-rotating twin extruder.

6. The method of claim 1, further comprising mixing of the polymer with the solvent and the active agent in an inert or substantially inert atmosphere.

7. The method of claim 1, further comprising heating the polymer prior to the introduction of the polymer into the apparatus.

8. The method of claim 1, further comprising heating the polymer subsequent to the introduction of the polymer into the apparatus.

9. The method of claim 1, wherein the active agent and solvent are introduced contemporaneously as a mixture, and wherein the active agent and the solvent are mixed contemporaneously with the polymer.

10. The method of claim 9, wherein the introduction of the solvent-active agent mixture is controlled to obtain a desired active agent to polymer ratio in at least a portion of the apparatus, the ratio being in the range of about 1:

3 to about 1;

5.

11. The method of claim 9, wherein the introduction of the solvent-active agent mixture is controlled to obtain a desired viscosity of the polymer, the viscosity being no greater than about 20,000 poises at 1 atm.

12. The method of claim 1, wherein the active agent is introduced in a solid state.

13. The method of claim 12, wherein the introduction of the solid is controlled to obtain a desired active agent to polymer ratio in at least a portion of the apparatus, the ratio being in the range of about 1:

3 to about 1;

5.

14. The method of claim 1, wherein the introduction of the solvent is controlled to obtain a desired active agent to polymer ratio, the ratio being in the range of about 1:

3 to about 1;

5.

15. The method of claim 1, wherein the introduction of the solvent is controlled to obtain a desired viscosity of the polymer, the viscosity being no greater than about 20,000 poises at 1 atm.

16. The method of claim 1, wherein controlling the temperature of the polymer mixture comprises controlling the rate of introduction of the solvent into the extruder to achieve a desired temperature range of the polymer mixture in at least a portion of the apparatus.

17. The method of claim 1, wherein the active agent and solvent are introduced contemporaneously as a mixture, and wherein controlling the temperature of the polymer mixture comprises controlling the rate of introduction of the solvent-active agent mixture into the extruder to achieve a desired temperature range of the polymer mixture in at least a portion of the apparatus.

18. The method of claim 1, wherein the temperature of the polymer mixture is controlled to be below a degradation temperature of the active agent.

19. The method of claim 1, wherein the temperature of the polymer mixture is controlled with a heat exchanger in the apparatus.

20. The method of claim 1, wherein a residence time of the polymer mixture in the apparatus is less than a time that causes a minimum acceptable degradation of the active agent.

21. The method of claim 1, wherein a residence time of the polymer mixture in the apparatus is less than about 10 seconds.

22. The method of claim 1, further comprising removing at least a portion of the solvent from the polymer mixture in the apparatus prior to removal of the polymer mixture from the apparatus.

23. The method of claim 22, wherein removing at least a portion of the solvent from the polymer mixture comprises heating at least a portion of the polymer mixture in the apparatus and extracting solvent vapor from the apparatus.

24. The method of claim 2, wherein coating the implantable medical device with the polymer mixture comprises feeding the removed polymer mixture to an injection molding apparatus and forming a coating on the implantable medical device.

25. The method of claim 2, wherein coating the implantable medical device with the polymer mixture comprises spraying the polymer mixture onto the implantable medical device.

26. The method of claim 2, wherein fabricating the implantable medical device with the polymer mixture comprises feeding the removed polymer mixture to an injection molding apparatus, and forming a tube.

27. The method of claim 26, further comprising forming a pattern comprising a network of struts on the surface of the tube.

28. The method of claim 26, further comprising disposing the tube over an uncoated implantable medical device.

29. The method of claim 1, wherein the polymer is selected from the group consisting of an ethylene vinyl alcohol copolymer, poly(butyl methacrylate), poly(vinylidene fluoride-co-hexafluororpropene), polyvinylidene fluoride, poly(L-lactic acid), poly(caprolactone), an ethylene-vinyl acetate copolymer and polyethylene glycol.

30. The method of claim 1, wherein the solvent is selected from the group consisting of water, isopropyl alcohol, methanol, flux remover, acetone, ethanol, dimethyl acetamide, acetonitrile, dimethyl formamide, cyclohexane, dimethyl sulfoxide, and combinations thereof.

31. The method of claim 1, wherein removing the impurities includes extracting the solvent from a segment of the extruder located between the second segment and the outlet of the extruder.

32. The method of claim 1, wherein removing the impurities includes extracting the solvent from a segment of the extruder located between the first segment and the second segment.

33. The method of claim 1, wherein removing the impurities includes extracting the solvent from a segment of the extruder that is located between the second segment and the outlet of the extruder and from a segment of the extruder that is located between the first segment and the second segment.

34. The method of claim 1, wherein removing the impurities includes extracting a vapor of the solvent, the vapor extraction performed using a vacuum pump attached the extruder at a segment located between the first segment and the second segment or between the second segment and the outlet of the extruder.

35. The method of claim 1, further comprising allowing the polymer mixture in the apparatus to increase in temperature above the degradation temperature of the active agent, and preventing the degradation of the active agent includes limiting residence time of the active agent in the extruder to less than about 10 seconds.

36. The method of claim 1, wherein the solvent has an ambient pressure boiling point that is below the degradation temperature of the active agent.

37. The method of claim 1, wherein the mixing of the active agent with the polymer in the apparatus to form a polymer mixture results in a homogenous or substantially homogenous mixture at the molecular- or ionic-size level of the polymer, the active agent, and the solvent.

38. The method of claim 1, wherein the segments of the extruder form a chamber configured so that the volume of the chamber is in proportion to the volume of material introduced into the segments.

39. The method of claim 1, wherein preventing the degradation of the active agent further includes introducing an inert gas in the first segment and removing atmospheric oxygen from the apparatus.

40. A method of making a composition for use in manufacturing an implantable medical device, comprising:

introducing a polymer into a first segment of an extruder;

allowing the polymer to flow out of a die of the extruder;

introducing an active agent into a second segment of the extruder, the second segment located between the first segment and the die;

mixing the active agent with the polymer in the extruder to form a polymer mixture;

controlling the temperature of the polymer mixture in at least a portion of the extruder by introducing a solvent into the extruder, wherein controlling the temperature includes varying the temperature of the solvent being introduced into the extruder;

and

removing the polymer mixture from the apparatus, wherein the polymer mixture is for use as a coating for an implantable medical device or is for fabricating an implantable medical device.

41. The method of claim 40, wherein controlling the temperature includes varying the flow rate of the solvent into the extruder.

42. The method of claim 40, wherein the solvent is introduced into the extruder as a mixture of the solvent and the active agent.

43. The method of claim 40, further comprising removing impurities from the polymer by extracting from the extruder a vapor of the solvent.

44. The method of claim 43, wherein the extraction is performed at a segment of the extruder located between the second segment and the die and at a segment of the extruder located between the first segment and the second segment.

45. A method of making a composition for use in manufacturing an implantable medical device, comprising:

introducing a polymer into a first segment of an extruder;

allowing the polymer to flow out of a die of the extruder;

introducing an active agent into a second segment of the extruder, the second segment located between the first segment and the die;

mixing the active agent with the polymer in the extruder to form a polymer mixture;

controlling the temperature of the polymer mixture in at least a portion of the extruder by introducing a solvent into the extruder;

and

removing the polymer mixture from the apparatus, wherein the polymer mixture is for use as a coating for an implantable medical device or is for fabricating an implantable medical device.