Therapeutic agent delivery device with protective separating layer

• US 20030068355A1
• Filed: 09/23/2002
• Published: 04/10/2003
• Est. Priority Date: 08/20/2001
• Status: Active Grant

• Current Assignee: Conor Medsystems Incorporated
• Original Assignee: Conor Medsystems Incorporated
• Inventors: Shanley, John F., Parker, Theodore L.
• Granted Patent: US 7,208,011 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61F 2/2493 Transmyocardial revascularisation [TMR] devices
• 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 2002/91558 connected peak to peak
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2250/003 differing in adsorbability or resorbability, i.e. in adsorption or resorption time
• CPC Class Codes: A61F 2250/0031 made from both resorbable and non-resorbable prosthetic parts, e.g. adjacent parts
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• 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 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 31/10 Macromolecular 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

Abstract

The present invention relates to implantable medical devices for delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having therapeutic agents protected by a protective layer that prevents or retards processes that deactivate or degrade the active agents.

Claims

1. An implantable medical device comprising:

an implantable device body having a plurality of holes therein;

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

a protective layer of material provided in the plurality of holes and arranged to protect the therapeutic agent from compounds or conditions in the body which would degrade the agent.

2. The implantable medical device of claim 1, wherein said protective layer is a pharmaceutically acceptable bioerodible matrix that allows said therapeutic agent to be released as the matrix erodes.

3. The implantable medical device of claim 2, wherein said bioerodible matrix substantially prevents the ingress of water.

4. The implantable medical device of claim 2, wherein said bioerodible matrix substantially prevents the ingress of enzymes.

5. The implantable medical device of claim 2, wherein said bioerodible matrix substantially protects the therapeutic agent from deactivation due to pH changes.

6. The implantable medical device of claim 2, wherein said bioerodible matrix comprises pharmaceutically acceptable polymers.

7. The implantable medical device of claim 6, wherein said pharmaceutically acceptable polymers are selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, cellulose, hydroxyehtylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, and polyphosphate esters.

8. The implantable medical device of claim 2, wherein said bioerodible matrix is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine, dipalmitoyl phosphatidylserine, fatty acids, and fatty acid esters.

9. The implantable medical device of claim 2, wherein the bioerodible matrix erodes by hydrolysis, dissolution, or enzymatic degradation.

10. The implantable medical device of claim 2, wherein the bioerodible matrix further comprises additives for controlling the rate of erosion.

11. The implantable medical device of claim 2, wherein said therapeutic agent is homogeneously dispersed in said bioerodible matrix.

12. The implantable medical device of claim 2, wherein said therapeutic agent is heterogeneously disposed in said bioerodible matrix.

13. The implantable medical device of claim 12, wherein said therapeutic agent is heterogeneously disposed in said bioerodible matrix 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 1, wherein the therapeutic agent is a first therapeutic agent provided in a first therapeutic agent layer adjacent said protective layer and said protective layer is a bioerodible matrix that prevents the therapeutic agent from being released until the protective layer has substantially eroded.

15. The implantable medical device of claim 14, further comprising a second therapeutic agent provided in a second therapeutic agent layer, wherein said protective layer separates the first therapeutic agent layer from a second therapeutic agent layer, and said first and second therapeutic agent layers each comprising a therapeutic agent disposed in a pharmaceutically acceptable bioerodible matrix.

16. The implantable medical device of claim 15, wherein said protective layer retards the ingress of water to one of the first and second therapeutic agent layers.

17. The implantable medical device of claim 15, wherein said protective layer retards the ingress of enzymes to one of the first and second therapeutic agent layers.

18. The implantable medical device of claim 15, wherein said protective layer substantially protects one of the first and second therapeutic agent layers from deactivation due to pH changes.

19. The implantable medical device of claim 15, wherein said bioerodible matrix comprises pharmaceutically acceptable polymers.

20. The implantable medical device of claim 19, wherein said pharmaceutically acceptable polymers are selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, cellulose, hydroxyehtylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, and polyphosphate esters.

21. The implantable medical device of claim 15, wherein said bioerodible matrix comprises a material selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine, dipalmitoyl phosphatidylserine, fatty acids, and fatty acid esters.

22. The implantable medical device of claim 15, wherein the bioerodible matrix erodes by hydrolysis, dissolution, or enzymatic degradation.

23. The implantable medical device of claim 15, wherein the protective layer erodes by physically breaking apart when the first therapeutic agent layer is substantially eroded.

24. The implantable medical device of claim 15, wherein the bioerodible matrix further comprises additives for controlling the rate of erosion.

25. The implantable medical device of claim 15, wherein said first and second therapeutic agents are homogeneously dispersed in each of said first and second therapeutic agent layers.

26. The implantable medical device of claim 15, wherein said first and second therapeutic agents are heterogeneously disposed in each of said first and second therapeutic agent layers.

27. The implantable medical device of claim 26, wherein said therapeutic agent is heterogeneously disposed in of said first and second therapeutic agent layers as a solid particle dispersion, encapsulated agent dispersion, and emulsion, a suspension, a liposome or a microparticle, wherein said liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

28. The implantable medical device of claim 15, wherein said protective layer further comprises an activating or a deactivating agent, wherein the activating or deactivating agent prevents the loss of biological function of the first or second therapeutic agents.

29. The implantable medical device of claim 28, wherein said activating or deactivating agents are selected from the group consisting of antacids, buffers, enzyme inhibitors, hydrophobic additives, and adjuvants.

30. The implantable medical device of claim 28, wherein said activating or deactivating agents is an antacid that protects one of said first and second therapeutic agents from a deactivating decrease in pH.

31. The implantable medical device of claim 29, wherein said protective layer comprises an agent that prevents deactivating interactions between said first and second therapeutic agents.

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

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

34. A method for delivering a drug to a patient which method comprises placement within the patient'"'"'s artery or vein of an implantable medical device comprising:

an implantable device body having a plurality of holes therein;

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

a protective layer of material provided in the plurality of holes and arranged to protect the therapeutic agent from compounds or conditions in the body which would degrade the agent.

35. The method for delivering a drug to a patient of claim 34, wherein said drug delivery method is used to treat restenosis in the patient after the patient has received percutaneous transluminal coronary angioplasty and intraluminal stent placement.

36. The method for delivering a drug to a patient of claim 34, wherein the therapeutic agent is a first therapeutic agent provided in a first therapeutic agent layer adjacent said protective layer and said protective layer is a bioerodible matrix that prevents the therapeutic agent from being released until the protective layer has substantially eroded.

37. The method for delivering a drug to a patient of claim 36, further comprising a second therapeutic agent provided in a second therapeutic agent layer, wherein said protective layer separates the first therapeutic agent layer from a second therapeutic agent layer, and said first and second therapeutic agent layers each comprising a therapeutic agent disposed in a pharmaceutically acceptable polymer.

38. The method for delivering a drug to a patient of claim 37, wherein said protective layer retards the ingress of water to one of the first and second therapeutic agent layers.

39. The method for delivering a drug to a patient of claim 37, wherein said protective layer retards the ingress of enzymes to one of the first and second therapeutic agent layers.

40. The method for delivering a drug to a patient of claim 37, wherein said protective layer substantially protects the therapeutic agent from deactivation due to pH changes.

41. The method for delivering a drug to a patient of claim 37, wherein said bioerodible matrix comprises pharmaceutically acceptable polymers.

42. The method for delivering a drug to a patient of claim 41, wherein said pharmaceutically acceptable polymers are selected from the group consisting of polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, cellulose, hydroxyehtylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, and polyphosphate esters.

43. The method for delivering a drug to a patient of claim 37, wherein said bioerodible matrix comprises a material selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine, dipalmitoyl phosphatidylserine, fatty acids, and fatty acid esters.

44. The method for delivering a drug to a patient of claim 37, wherein the bioerodible matrix erodes by hydrolysis, dissolution, or enzymatic degradation.

45. The method for delivering a drug to a patient of claim 37, wherein the protective layer erodes by physically breaking apart when the first therapeutic agent layer is substantially eroded.

46. The method for delivering a drug to a patient of claim 37, wherein the bioerodible matrix further comprises additives for controlling the rate of erosion.

47. The method for delivering a drug to a patient of claim 37, wherein said first and second therapeutic agents are homogeneously dispersed in each of said first and second therapeutic agent layers.

48. The method for delivering a drug to a patient of claim 37, wherein said first and second therapeutic agents are heterogeneously disposed in each of said first and second therapeutic agent layers.

49. The method for delivering a drug to a patient of claim 48, wherein said therapeutic agent is heterogeneously disposed in of said first and second therapeutic agent layers as a solid particle dispersion, encapsulated agent dispersion, and emulsion, a suspension, a liposome or a microparticle, wherein said liposome or microparticle comprise a homogeneous or heterogeneous mixture of the therapeutic agent.

50. The method for delivering a drug to a patient of claim 37, wherein said protective layer further comprises an activating or a deactivating agent, wherein the activating or deactivating agent prevents the loss of biological function of the first or second therapeutic agents.

51. The method for delivering a drug to a patient of claim 50, wherein said activating or deactivating agents are selected from the group consisting of antacids, buffers, enzyme inhibitors, hydrophobic additives, and adjuvants.

52. The method for delivering a drug to a patient of claim 50, wherein said activating or deactivating agents is an antacid that protects one of said first and second therapeutic agents from a deactivating decrease in pH.

53. The method for delivering a drug to a patient of claim 51, wherein said protective layer comprises an agent that prevents deactivating interactions between said first and second therapeutic agents.

54. The method for delivering a drug to a patient of claim 34, wherein the therapeutic agent is selected from the group consisting of antineoplastic agents, neoplastic agents, antiproliferative agents, antisense compounds, immunosuppresants, angiogenic agents, angiogenic factors, antiangiogenic agents, and anti-inflammatory agents, or combinations thereof.