Therapeutic agent delivery device with controlled therapeutic agent release rates

• US 20060008503A1
• Filed: 09/13/2005
• Published: 01/12/2006
• Est. Priority Date: 03/28/2003
• Status: Abandoned Application

• Current Assignee: Innovational Holdings, LLC
• Original Assignee: Conor Medsystems Incorporated
• Inventors: Shanley, John F., Parker, Theodore L.
• Application Number:
  US11/226,523
• Publication Number:
  US 20060008503A1
• Time in Patent Office: Days
• US Class Current: 424/425
• 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;

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

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; and

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 therapeutic agent when a portion of one of said therapeutic agent layer and said at least one mixing layer is in a liquid state.

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 5, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer.

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

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

12. 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.

13. 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.

14. 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.

15. 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 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.

18. 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.

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

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

16. 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.

21. 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, the mixing layer including said therapeutic agent;

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 one of the therapeutic agent layer and the mixing layer with the other of the therapeutic layer and the mixing layer material, whereby the mixing layer has a smaller amount concentration of therapeutic agent contained therein than the therapeutic agent layer.

22. The implantable medical device of claim 21, 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.

23. The implantable medical device of claim 22, wherein said bioresorbable matrix comprises at least one pharmaceutically acceptable polymer.

24. The implantable medical device of claim 23, 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.

25. The implantable medical device of claim 23, wherein the therapeutic agent layer comprises at least one pharmaceutically acceptable polymer different from the pharmaceutically acceptable polymer of the mixing layer.

26. The implantable medical device of claim 21, wherein the therapeutic agent layer comprises the therapeutic agent and a water soluble binding agent.

27. The implantable medical device of claim 26, 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.

28. The implantable medical device of claim 26, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer.

29. The implantable medical device of claim 26, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer.

30. The implantable medical device of claim 26, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer.

31. The implantable medical device of claim 30, 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.

32. The implantable medical device of claim 26, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as a solid solution in said mixing layer.

33. The implantable medical device of claim 26, wherein said therapeutic agent from the therapeutic agent layer is homogeneously dispersed as multi-phase mixture in said mixing layer.

34. The implantable medical device of claim 26, wherein said therapeutic agent from the therapeutic agent layer is heterogeneously disposed in said mixing layer.

35. The implantable medical device of claim 34, 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.

36. The implantable medical device of claim 21, 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.

37. The implantable medical device of claim 21, wherein the therapeutic agent is selected from the group consisting of 2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide.

38. The implantable medical device of claim 21, wherein said therapeutic agent is an agent selected for treatment of restenosis or inflammation.

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

40. 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, the at least one mixing layer including said therapeutic agent;

wherein the first 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; and

wherein the concentration gradient of the therapeutic agent in the holes has a highest concentration of therapeutic agent at an interior of the holes and a lowest concentration of therapeutic agent at an exterior of the holes.

41. The implantable medical device of claim 40, wherein said therapeutic agent is an agent selected for treatment of restenosis or inflammation.

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

43. The implantable medical device of claim 40, wherein said therapeutic agent is homogeneously dispersed as a solid solution in said therapeutic agent layer.

44. The implantable medical device of claim 40, wherein said therapeutic agent is homogeneously dispersed as multi-phase mixture in said therapeutic agent layer.

45. The implantable medical device of claim 40, wherein said therapeutic agent is heterogeneously disposed in said therapeutic agent layer.

46. An implantable medical device comprising:

an implantable device body having a plurality of holes;

a barrier layer of PLGA formed in the plurality of holes;

a therapeutic agent layer formed in the plurality of holes adjacent the barrier layer, the therapeutic agent layer comprising a therapeutic agent and PLGA; and

a mixing layer formed in the plurality of holes adjacent the therapeutic agent layer, wherein the mixing layer comprises PLGA and a concentration gradient of the therapeutic agent.