Coatings containing multiple drugs

• US 8,852,625 B2
• Filed: 04/26/2007
• Issued: 10/07/2014
• Est. Priority Date: 04/26/2006
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Micell Technologies Inc.
• Inventors: DeYoung, James, Taylor, Doug, McClain, Jim, Smoke, Clint, Cole, Mike
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US12/298,459
• Publication Number:
  US 20090186069A1
• Time in Patent Office: 2,721 Days
• Field of Search: None
• US Class Current: 424/426
• CPC Class Codes: A61F 2/90 characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2300/20 containing or releasing organic materials
• CPC Class Codes: A61L 2300/216 with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• 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 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2300/61 containing two or more active agents in different layers
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• 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

A method for depositing a coating comprising a polymer and at least two pharmaceutical agents on a substrate, comprising the following steps: providing a stent framework; depositing on said stent framework a first layer comprising a first pharmaceutical agent; depositing a second layer comprising a second pharmaceutical agent; Wherein said first and second pharmaceutical agents are selected from two different classes of pharmaceutical agents.

Claims

1. A method of preparing a multi-drug eluting coronary stent comprising:

a. providing a stent framework;

b. depositing on said stent framework a first layer comprising a first pharmaceutical agent in dry powder form without use of a solvent;

c. depositing a second layer in dry powder form without use of a solvent, the second layer comprising a second pharmaceutical agent;

d. depositing one or more polymer layers thereby forming a coating; and

then

e. sintering said coating under conditions that do not substantially modify a morphology of said pharmaceutical agents, wherein said sintering comprises treating the coated stent framework with a compressed gas, compressed liquid, or super critical fluid that is a non-solvent for both the polymer and pharmaceutical agents;

wherein said first and second pharmaceutical agents are selected from two different classes of pharmaceutical agents and at least one of said first and second pharmaceutical agents comprises the morphology that is crystalline or semi-crystalline.

2. The method of claim 1, wherein at least one of said polymer layers comprises a bioabsorbable polymer.

3. The method of claim 1 wherein said polymer is selected from PLA, PLGA, PGA and Poly(dioxanone).

4. The method of claim 1 comprising depositing 5 or more layers as follows:

a first polymer layer

the first layer comprising said first pharmaceutical agent

a second polymer layer

the second layer comprising said second pharmaceutical agent; and

a third polymer layer.

5. The method of claim 1 comprising depositing 4 or more layers as follows:

a first polymer layer

the first layer comprising said first pharmaceutical agent

a second polymer layer; and

the second layer comprising said second pharmaceutical agent.

6. The method of claim 1 comprising depositing 4 or more layers as follows:

the first layer comprising said first pharmaceutical agent

a first polymer layer

the second layer comprising said second pharmaceutical agent; and

a second polymer layer.

7. The method of Claim 1 comprising depositing 3 or more layers as follows:

the first layer comprising said first pharmaceutical agent

a polymer layer; and

the second layer comprising said second pharmaceutical agent.

8. The method of claim 1 wherein said layers comprise alternate layers of pharmaceutical agent, or pharmaceutical agent and polymer, and layers of polymer without pharmaceutical agent.

9. The method of claim 8, wherein the pharmaceutical agent layers are substantially free of polymer and the polymer layers are substantially free of pharmaceutical agent.

10. The method of claim 1 comprising depositing 5, 10, 20, 50, or 100 layers.

11. The method of claim 1 wherein said first pharmaceutical agent has an elution profile that is slower than the elution profile of the second pharmaceutical agent.

12. The method of claim 11 wherein the second pharmaceutical agent achieves 100% elution in about 5 days to about 20 days and the first pharmaceutical agent achieves 100% elution in about 120 days to about 180 days.

13. The method of claim 1, wherein said first pharmaceutical agent is anti-thrombogenic agent and said second pharmaceutical agent is an anti-restenotic agent.

14. The method of claim 1, wherein said first pharmaceutical agent is heparin and said second pharmaceutical agent is taxol or a macrolide immunosuppressive (limus) drug.

15. The method of claim 2, wherein said bioabsorbable polymer is selected from PGA poly(glycolide), LPLA poly(l-lactide), DLPLA poly(dl-lactide), PCL poly(e-caprolactone)PDO, poly(dioxolane) PGA-TMC, 85/15 DLPLG p(dl-lactide-co-glycolide), 75/25 DLPLG, 65/35 DLPLG, 50/50 DLPLG, TMC poly(trimethylcarbonate), p(CPP:

SA) poly (1,3-bis-p-(carboxyphenoxy)propane-co-sebacic acid).

16. The method of claim 1, wherein at least one of said pharmaceutical agents comprise a macrolide immunosuppressive (limus) drug.

17. The method of claim 16, wherein the macrolide immunosuppressive drug comprises one or more of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′

-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′

-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′

-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′

-en-1′

-yl]-rapamycin, (2′

;

E,4′

S)-40-O-(4′

,5′

-Dihydroxypent-2′

-en-1′

-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin, 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′

-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′

,5′

-Dicarboethoxy-1′

,2′

,3′

-triazol-1′

-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), and 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus).

18. The method of claim 16, wherein said macrolide immunosuppressive drug is at least 50% crystalline.

19. The method of claim 1, comprising depositing polymer particles on said framework by an RESS process.

20. The method of claim 1, comprising depositing pharmaceutical agent particles on said framework in dry powder form.

21. A multi-drug eluting coronary stent prepared by the method of claim 1.

22. A multi-drug coronary stent comprising

a. a stent framework;

b. a first layer comprising a first pharmaceutical agent;

c. a second layer comprising a second pharmaceutical agent; and

d. one or more polymer layers thereby forming a coating;

wherein said coating is sintered under conditions that do not substantially modify the morphology of said pharmaceutical agents, wherein said sintering comprises treating the coated stent framework with a compressed gas, compressed liquid, or super critical fluid that is a non-solvent for both the polymer and pharmaceutical agents;

wherein said first and second pharmaceutical agents are selected from two different classes of pharmaceutical agents and at least one of said first and second pharmaceutical agents are crystalline or semi-crystalline; and

wherein the stent has no residual solvent.

23. The stent of claim 22, wherein at least one of said polymer layers comprises a bioabsorbable polymer.

24. The stent of claim 22 wherein said polymer is selected from PLA, PLGA, PGA and Poly(dioxanone).

25. The stent of claim 22 comprising 5 or more layers as follows:

a first polymer layer

the first layer comprising said first pharmaceutical agent

a second polymer layer

the second layer comprising said second pharmaceutical agent; and

a third polymer layer.

26. The stent of claim 22 comprising 4 or more layers as follows:

a first polymer layer

the first layer comprising said first pharmaceutical agent

a second polymer layer; and

the second layer comprising said second pharmaceutical agent.

27. The stent of claim 22 comprising 4 or more layers as follows:

the first layer comprising said first pharmaceutical agent

a first polymer layer

the second layer comprising said second pharmaceutical agent; and

a second polymer layer.

28. The stent of claim 22 comprising 3 or more layers as follows:

the first layer comprising said first pharmaceutical agent

a polymer layer; and

the second layer comprising said second pharmaceutical agent.

29. The stent of claim 22 wherein said layers comprise alternate layers of pharmaceutical agent, or pharmaceutical agent and polymer, and layers of polymer without pharmaceutical agent.

30. The stent of claim 28, wherein the pharmaceutical agent layers are substantially free of polymer and the polymer layers are substantially free of pharmaceutical agent.

31. The stent of claim 22 comprising depositing 5, 10, 20, 50, or 100 layers.

32. The stent of claim 22 wherein said first pharmaceutical agent has an elution profile that is slower than the elution profile of the second pharmaceutical agent.

33. The stent of claim 32 wherein the second pharmaceutical agent achieves 100% elution in about 5 days to about 20 days and the first pharmaceutical agent achieves 100% elution in about 120 days to about 180 days.

34. The stent of claim 22, wherein said first pharmaceutical agent is anti-thrombogenic agent and said second pharmaceutical agent is an anti-restenotic agent.

35. The stent of claim 22, wherein said first pharmaceutical agent is heparin and said second agent is taxol or a macrolide immunosuppressive (limus) drug.

36. The stent of claim 23, wherein said bioabsorbable polymer is selected from PGA poly(glycolide), LPLA poly(l-lactide), DLPLA poly(dl-lactide), PCL poly(e-caprolactone) PDO, poly(dioxolane) PGA-TMC, 85/15 DLPLG p(dl-lactide-co-glycolide), 75/25 DLPLG, 65/35 DLPLG, 50/50 DLPLG, TMC poly(trimethylcarbonate), p(CPP:

SA) poly(1,3-bis-p-(carboxyphenoxy)propane-co-sebacic acid).

37. The stent of claim 22, wherein at least one of said pharmaceutical agents comprise a macrolide immunosuppressive (limus) drug.

38. The method of claim 37, wherein the macrolide immunosuppressive drug comprises one or more of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′

-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′

-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′

-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′

-en-1′

-yl]-rapamycin, (2′

;

E,4′

S)-40-O-(4′

,5′

-Dihydroxypent-2′

-en-1′

-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin, 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-(2-(N-Methyl-N′

-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R) -26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′

,5′

-Dicarboethoxy-1′

,2′

,3′

-triazol-1′

-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), and 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus).