Coatings containing multiple drugs

• US 9,415,142 B2
• Filed: 08/29/2014
• Issued: 08/16/2016
• Est. Priority Date: 04/26/2006
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Micell Technologies Inc.
• Inventors: DeYoung, James, Taylor, Charles Douglas, McClain, James B., Smoke, Clint, Cole, Mike
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US14/473,741
• Publication Number:
  US 20150112424A1
• Time in Patent Office: 718 Days
• US Class Current: 1/1
• 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 depositing a coating on a substrate comprising:

a. providing a substrate;

b. depositing at least one polymer layer in dry powder form onto said substrate;

c. depositing at least one pharmaceutical layer comprising a first pharmaceutical agent in dry powder form onto said substrate without use of a solvent; and

d. sintering said at least one polymer layer so as to produce a polymer film fused and adhered to said substrate under conditions that do not substantially modify a morphology of said first pharmaceutical agent,

wherein said first pharmaceutical agent comprises a morphology that is crystalline or semi-crystalline.

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

3. The method of claim 1 wherein said polymer of said at least one polymer layer 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 a 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 a 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 a 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

a second layer comprising a second pharmaceutical agent.

8. The method of claim 1 wherein said first layer and said at least one polymer layer comprising 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 4 wherein said first pharmaceutical agent has an elution profile that is slower than the elution profile of said 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 4, wherein said first pharmaceutical agent is anti-thrombogenic agent and said second pharmaceutical agent is an anti-restenotic agent.

14. The method of claim 4, 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), and p(CPP:

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

16. The method of claim 1, wherein said pharmaceutical agent comprises 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 -(2Hydroxy)ethoxycarbonylmethyl-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, wherein said depositing of said at least one polymer layer comprises depositing polymer particles on said substrate by an RESS process.

20. The method of claim 1, wherein the substrate is a biomedical implant selected from the group consisting of a stent, electrode, catheter, lead, implantable pacemaker or cardioverter housing, joint, screw, rod, ophthalmic implant, prosthetic, and shunt.

40. The method of claim 1 wherein said depositing of said at least one polymer layer and said depositing of said at least one pharmaceutical layer are carried out simultaneously.

41. The method of claim 1 wherein said depositing of said at least one polymer layer and said depositing of said at least one pharmaceutical layer are carried out in succession.

21. A multi drug coated substrate comprising

a. a substrate;

and

b. at least one polymer layer;

c. a pharmaceutical layer comprising at least one pharmaceutical agent;

wherein said at least one polymer layer comprises a sintered layer in which the morphology of said pharmaceutical agent in said coating has not been substantially modified and said first pharmaceutical agent is crystalline or semi-crystalline,

and wherein the coated substrate is substantially free of residual solvent.

22. The substrate of claim 21, wherein said at least one polymer layer comprises a bioabsorbable polymer.

23. The substrate of claim 21 wherein said polymer of said at least one polymer layer is selected from PLA, PLGA, PGA and Poly(dioxanone).

24. The substrate of claim 21 comprising 5 or more layers as follows:

a first polymer layer

a first pharmaceutical layer comprising said at least one pharmaceutical agent

a second polymer layer

a second pharmaceutical layer comprising a second pharmaceutical agent; and

a third polymer layer.

25. The substrate of claim 21 comprising 4 or more layers as follows:

a first polymer layer

a first pharmaceutical layer comprising said at least one pharmaceutical agent

a second polymer layer; and

a second pharmaceutical layer comprising a second pharmaceutical agent.

26. The substrate of claim 21 comprising 4 or more layers as follows:

the first pharmaceutical layer comprising a first pharmaceutical agent

a first polymer layer

a second pharmaceutical layer comprising a second pharmaceutical agent; and

a second polymer layer.

27. The substrate of claim 21 comprising 3 or more layers as follows:

a first pharmaceutical layer comprising said first pharmaceutical agent

a polymer layer; and

a second pharmaceutical layer comprising a second pharmaceutical agent.

28. The substrate of claim 21 wherein said pharmaceutical layer and said at least one polymer layer comprises alternate layers of pharmaceutical agent, or pharmaceutical agent and polymer, and layers of polymer without pharmaceutical agent.

29. The substrate of claim 27, wherein pharmaceutical is substantially free of polymer and said at least one polymer layer is substantially free of pharmaceutical agent.

30. The substrate of claim 21 comprising depositing 5, 10, 20, 50, or 100 layers.

31. The substrate of claim 24 wherein said first pharmaceutical layer has an elution profile that is slower than the elution profile of said second pharmaceutical agent.

32. The substrate of claim 31 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.

33. The substrate of claim 24, wherein said first pharmaceutical agent is anti-thrombogenic agent and said second pharmaceutical agent is an anti-restenotic agent.

34. The substrate of claim 24, wherein said first pharmaceutical agent is heparin and said second agent is taxol or a macrolide immunosuppressive (limus) drug.

35. The substrate of claim 22, 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), and p(CPP:

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

36. The substrate of claim 24, wherein at least one of said pharmaceutical agents comprise a macrolide immunosuppressive (limus) drug.

37. The substrate of claim 36, 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)ethoxycarbonylmethyl-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).

38. The substrate of claim 36, wherein the macrolide immunosuppressive drug is at least 50% crystalline.

39. The substrate of claim 21, wherein the substrate is a biomedical implant selected from the group consisting of a stent, electrode, catheter, lead, implantable pacemaker or cardioverter housing, joint, screw, rod, ophthalmic implant, prosthetic, and shunt.