Therapeutic agent delivery device with controlled therapeutic agent release rates

• US 20040193255A1
• Filed: 03/28/2003
• Published: 09/30/2004
• Est. Priority Date: 03/28/2003
• Status: Active Grant

• Current Assignee: Innovational Holdings, LLC
• Original Assignee: Conor Medsystems Incorporated
• Inventors: Shanley, John F., Parker, Theodore L.
• Granted Patent: US 7,056,338 B2
• Time in Patent Office: Days
• US Class Current: 623/1.42
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2/915 with bands having a meander structure, adjacent bands being connected to each other
• CPC Class Codes: A61F 2002/91541 Adjacent bands are arranged out of phase
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• 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 2300/60 characterised by a special physical form
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: Y10S 623/92 Method or apparatus for preparing or treating prosthetic

Abstract

The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer that allows for controlled release of the therapeutic agents.

Claims

1. An implantable medical device comprising:

an implantable device body having a plurality of holes;

a therapeutic agent provided in a first therapeutic agent layer and contained within the plurality of holes in the device body; and

at least one mixing layer provided adjacent the first therapeutic agent layer in the plurality of holes;

wherein the therapeutic agent layer and the at least one mixing layer together contain a concentration gradient of said therapeutic agent and allow for the controlled release of the therapeutic agent contained within the therapeutic agent layer and the at least one mixing layer.

2. The implantable medical device of claim 1, wherein the at least one mixing layer is a pharmaceutically acceptable bioresorbable matrix that allows the therapeutic agent contained within the therapeutic agent layer and the at least one mixing layer to be released as the matrix resorbs.

3. The implantable medical device of claim 2, wherein said pharmaceutically acceptable bioresorbable matrix comprises at least one pharmaceutically acceptable polymer.

4. The implantable medical device of claim 3, wherein said pharmaceutically acceptable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, lipids, and mixtures thereof.

5. The implantable medical device of claim 1, wherein the therapeutic agent layer comprises the therapeutic agent and a water soluble binding agent.

6. The implantable medical device of claim 5, wherein the binding agent is a pharmaceutically acceptable polymer selected from the group consisting of poly ethylene glycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polysaccharides, polysaccharide derivatives, poly hyaluronic acid, poly alginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid, and proteins.

7. The implantable medical device of claim 5, wherein the at least one mixing layer includes a polymer different from the water soluble binding agent

8. The implantable medical device of claim 7, wherein the at least one mixing layer includes a plurality of mixing layers formed by sequential delivery of a substantially identical composition to the implantable medical device for each of the layers which take on the concentration gradient in the plurality of holes.

9. The implantable medical device of claim 1, wherein the at least one mixing layer is formed by delivery of a polymer without the therapeutic agent to the holes and further wherein the mixing layer acquires the therapeutic agent by liquefying a portion of the therapeutic agent layer.

10. The implantable medical device of claim 5, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer.

11. The implantable medical device of claim 5, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer.

12. The implantable medical device of claim 5, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer.

13. The implantable medical device of claim 5, wherein said therapeutic agent is homogeneously or heterogeneously disposed in said therapeutic agent layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

14. The implantable medical device of claim 4, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as a solid solution in said at least one mixing layer.

15. The implantable medical device of claim 4, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said at least one mixing layer.

16. The implantable medical device of claim 4, wherein said therapeutic agent from the therapeutic agent layer is heterogeneously disposed in said at least one mixing layer.

17. The implantable medical device of claim 16, wherein said therapeutic agent from the therapeutic agent layer is homogeneously or heterogeneously disposed in said at least one mixing layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

18. The implantable medical device of claim 1, wherein the therapeutic agent is selected from the group consisting of antithrombotic agents, antineoplastic agents, neoplastic agents, antiproliferative agents, antisense compounds, immunosuppresants, angiogenic agents, angiogenic factors, antiangiogenic agents, and anti-inflammatory agents, or combinations thereof.

19. The implantable medical device of claim 1, wherein the therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide.

20. The implantable medical device of claim 1, wherein said therapeutic agent is an agent selected for treatment of restensosis or inflammation.

21. The implantable medical device of claim 1, wherein the implantable medical device is a stent.

22. An implantable medical device comprising:

an implantable device body having a plurality of holes;

a therapeutic agent within the plurality of holes in the device body provided in a therapeutic agent layer; and

a mixing layer provided in the plurality of holes;

wherein the therapeutic agent layer and the mixing layer contain a concentration gradient of said therapeutic agent created by delivering a mixing layer material without the therapeutic agent and liquefying a portion of the therapeutic agent layer with the mixing layer material, whereby the mixing layer has a smaller amount of therapeutic agent contained therein than the therapeutic agent layer.

23. The implantable medical device of claim 22, wherein the mixing layer is a pharmaceutically acceptable bioresorbable matrix that allows the therapeutic agent contained within the therapeutic agent layer and the mixing layer to be released as the matrix resorbs.

24. The implantable medical device of claim 23, wherein said bioresorbable matrix comprises at least one pharmaceutically acceptable polymer.

25. The implantable medical device of claim 24, wherein said pharmaceutically acceptable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, lipids, and mixtures thereof.

26. The implantable medical device of claim 24, wherein the therapeutic agent layer comprises at least one pharmaceutically acceptable polymer different from the pharmaceutically acceptable polymer of the mixing layer.

27. The implantable medical device of claim 22, wherein the therapeutic agent layer comprises the therapeutic agent and a water soluble binding agent.

28. The implantable medical device of claim 27, wherein the binding agent is a pharmaceutically acceptable polymer selected from the group consisting of poly ethylene glycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan, polysaccharides, polysaccharide derivatives, poly hyaluronic acid, poly alginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid, and proteins.

29. The implantable medical device of claim 27, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer.

30. The implantable medical device of claim 27, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer.

31. The implantable medical device of claim 27, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer.

32. The implantable medical device of claim 31, wherein said therapeutic agent is homogeneously or heterogeneously disposed in said therapeutic agent layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

33. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as a solid solution in said mixing layer.

34. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as multi-phase mixture in said mixing layer.

35. The implantable medical device of claim 27, wherein said therapeutic agent from the therapeutic agent layer is heterogeneously disposed in said mixing layer.

36. The implantable medical device of claim 35, wherein said therapeutic agent from the therapeutic agent layer is homogeneously or heterogeneously disposed in said mixing layer as a solid particle dispersion, encapsulated agent dispersion, an emulsion, a suspension, a liposome, niosome, or a microparticle, wherein said niosome, liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

37. The implantable medical device of claim 22, wherein the therapeutic agent is selected from the group consisting of antithrombotic agents, antineoplastic agents, neoplastic agents, antiproliferative agents, antisense compounds, immunosuppresants, angiogenic agents, angiogenic factors, antiangiogenic agents, and anti-inflammatory agents, or combinations thereof.

38. The implantable medical device of claim 22, wherein the therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide.

39. The implantable medical device of claim 22, wherein said therapeutic agent is an agent selected for treatment of restensosis or inflammation.

40. The implantable medical device of claim 22, wherein the implantable medical device is a stent.

41. A method for preparing an implantable medical device, which method comprises:

a) providing an implantable medical device with a plurality of holes;

b) loading into the plurality of holes an amount of a liquified therapeutic agent, which amount is sufficient to form a therapeutic agent layer;

c) allowing said liquified therapeutic agent layer to at least partially solidify;

d) loading into the plurality of holes an amount of a liquified bioresorbable polymer which amount is sufficient to liquify a portion of the therapeutic agent layer, thereby allowing a portion of the therapeutic agent layer to be disposed within a mixing layer;

e) allowing said liquified bioresorbable polymer and said portion of the therapeutic agent layer to solidify;

wherein an amount of therapeutic agent contained within the mixing layer upon solidification is smaller than an amount of therapeutic agent contained in the therapeutic agent layer;

and further wherein steps d and e may optionally be repeated to form multiple mixing layers.

42. The method for preparing an implantable medical device of claim 41, wherein the liquified therapeutic agent is liquified by maintaining the therapeutic agent at a temperature that is higher than its melting point, or glass transition temperature.

43. The method for preparing an implantable medical device of claim 41, wherein the liquified therapeutic agent is formed by dissolving the therapeutic agent in a solvent.

44. The method for preparing an implantable medical device of claim 41, wherein the liquified bioresorbable polymer is liquified by maintaining the bioresorbable polymer at a temperature that is higher than its melting point, or glass transition temperature.

45. The method for preparing an implantable medical device of claim 41, wherein the liquified bioresorbable polymer is formed by dissolving the bioresorbable polymer in a solvent.

46. The method for preparing an implantable medical device of claim 41, further comprising the step of forming a barrier layer by loading into the plurality of holes an amount of a liquified biocompatible polymer, which amount is sufficient to form a barrier layer, wherein the barrier layer is located adjacent the therapeutic agent layer.

47. The method for preparing an implantable medical device of claim 46, wherein the liquified biocompatible polymer is liquified by maintaining the biocompatible polymer at a temperature that is higher than its melting point, or glass transition temperature.

48. The method for preparing an implantable medical device of claim 46, wherein the liquified biocompatible polymer is formed by dissolving the biocompatible polymer in a solvent.

49. The method for preparing an implantable medical device of claim 41, wherein the liquefied bioresorbable polymer loaded into the holes does not contain the therapeutic agent.

50. The method for preparing an implantable medical device of claim 41, wherein the liquefied therapeutic agent layer comprises the therapeutic agent and a pharmaceutically acceptable polymer.

51. The method for preparing an implantable medical device of claim 50, wherein the liquefied therapeutic agent layer comprises from about 50% to about 95% therapeutic agent and from about 5% to about 50% pharmaceutically acceptable polymer.