Polymer coatings containing drug powder of controlled morphology
A method for depositing a coating comprising a polymer and pharmaceutical agent on a substrate, comprising the following steps: discharging at least one pharmaceutical agent in a therapeutically desirable morphology in dry powder form through a first orifice; discharging at least one polymer in dry powder form through a second orifice; depositing the polymer and/or pharmaceutical particles onto said substrate, wherein an electrical potential is maintained between the substrate and the pharmaceutical and/or polymer particles, thereby forming said coating; and sintering said coating under conditions that do not substantially modify the morphology of said pharmaceutical agent.
1. A coated implantable medical device, comprising:
a substrate; and
a coating wherein said coating comprises at least one polymer and at least one pharmaceutical agent comprising a macrolide immunosuppressive (limus) drug in a therapeutically desirable morphology, and wherein said coating is disposed on said substrate by a coating process comprising:
a) discharging the at least one macrolide immunosuppressive (limus) drug in dry powder form through a first orifice; discharging the at least one polymer in dry powder form through a second orifice; depositing polymer and macrolide immunosuppressive (limus) drug particles onto said substrate, wherein an electrical potential is maintained between the substrate and the polymer and macrolide immunosuppressive (limus) drug particles, thereby forming said coating; and then
b) sintering said coating under conditions that do not substantially modify the morphology of said macrolide immunosuppressive (limus) drug, wherein said sintering comprises treating said coated substrate with a compressed gas, compressed liquid or supercritical fluid that is a non-solvent for both the polymer and the macrolide immunosuppressive (limus) drug, wherein the therapeutically desirable morphology of said macrolide immunosuppressive (limus) drug pharmaceutical agent is crystalline or semi-crystalline; 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-I′-yl]-rapamycin, (2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-I′-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-I-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, 40-0-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus).
2. The medical device of claim 1 , wherein said coating comprises at least two pharmaceutical agents and/or active biological agents.
3. The medical device of claim 1 , wherein said coating has a thickness of about 1 to about 30 microns.
4. The medical device of claim 1 , wherein said coating is substantially free of solvent residue.
5. The medical device of claim 1 , wherein the coating is sintered at a temperature below the phase transition temperature of the polymer.
6. The medical device of claim 1 , wherein said substrate is a biomedical implant selected from the group consisting of stents, electrodes, catheters, leads, implantable pacemaker, cardioverter or defibrillator housings, joints, screws, rods, ophthalmic implants, femoral pins, bone plates, grafts, anastomotic devices, perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable cardioverters and defibrillators, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, dressings, bone substitutes, intraluminal devices, and vascular supports.
7. The medical device of claim 1 , wherein said substrate further comprises a top layer disposed on said coating wherein said top layer is a polymer film.
8. The medical device of claim 7 , wherein said polymer film has a thickness of 0.5 to 10 microns.
9. The medical device of claim 1 , wherein the substrate is a vascular stent.
10. The medical device of claim 1 , wherein the substrate is a coronary stent.
11. The medical device of claim 1 , wherein coating covers substantially the entire surface of said stent.
12. The medical device of claim 1 , wherein said coating is substantially free of aggregated macrolide immunosuppressive (limus) drug particles.
13. The medical device of claim 1 , wherein said polymer is selected from poly(alkyl methacrylates), poly(methyl methacrylate), poly(butyl methacrylate) (PBMA), polyethylene-co-vinyl acetate (PEVA), Polyethylene, polybutylene and polybutylene copolymers, Polyurethanes, polyanhydrides, Aliphatic polycarbonates, poly(3-hydroxybutyrate), poly(hydroxyalkanoate)s, poly(alkyl siloxane)s, Poly(dimethyl siloxane) (PDMA), silicone polymers, aliphatic polyesters, Polyglycolide (PGA), Polylactide (PLA), Poly(lactide-co-glycolide) (PLGA), Poly(e-caprolactone) (PCL), Polytetrafluoroethylene, (PTFE) and PTFE copolymers, polystyrene and polystyrene copolymers, and poly(phosphasones).
14. The medical device of claim 1 , wherein said polymer is poly(butyl methacrylate) (PBMA), polyethylene-co-vinyl acetate (PEVA) or a mixture thereof.
15. The medical device of claim 1 , wherein said substrate is an orthopedic device.
16. The medical device of claim 1 , wherein the coating has improved bulk properties and adhesion of the coating to said substrate obtained by sintering said coating at a temperature below the phase transition temperature of the polymer without altering the quality of said macrolide immunosuppressive (limus) drug.
17. The medical device of claim 1 , wherein said coating has substantially uniform thickness and covers substantially the entire surface of said substrate.
18. The medical device of claim 1 , wherein said coating comprises at least two pharmaceutical agents.
19. The medical device of claim 1 , wherein the macrolide immunosuppressive (limus) drug is in the form of particles having an average diameter from 2 nm (0.002 microns) to 3000 nm (3 microns).
20. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug is at least 50% crystalline.
21. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug is at least 75% crystalline.
22. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug is at least 90% crystalline.
23. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug is at least 95% crystalline.
24. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug is at least 99% crystalline.
25. The medical device of claim 1 , wherein said polymer is a mixture of two or more polymers.
26. The medical device of claim 25 , wherein said mixture of polymers forms a continuous film around particles of rapamycin.
27. The medical device of claim 25 , wherein said two or more polymers are intimately mixed.
28. The medical device of claim 25 , wherein said mixture comprises no single polymer domain larger than about 20 nm.
29. The medical device of claim 25 , wherein each polymer in said mixture comprises a discrete phase.
30. The medical device of claim 29 , wherein discrete phases formed by said polymers in said mixture are larger than about 10 nm.
31. The medical device of claim 29 , wherein discrete phases formed by said polymers in said mixture are larger than about 50 nm.
32. The medical device of claim 1 , wherein said macrolide immunosuppressive (limus) drug comprises rapamycin, wherein said substrate is a stent, and wherein said medical device provides an elution profile wherein about 10% to about 50% of rapamycin is eluted at week 1 after the medical device is implanted in a subject under physiological conditions, about 25% to about 75% of rapamycin is eluted at week 2 and about 50% to about 100% of rapamycin is eluted at week 4.
33. The medical device of claim 1 , wherein the coating process comprises sintering the coating in a supercritical fluid following depositing particles of the macrolide immunosuppressive (limus) drug in dry powder form on the substrate, and following depositing particles of the polymer in dry powder form on the substrate.
34. The medical device of claim 1 , wherein the first and second orifices are provided as a single orifice.
35. The medical device of claim 1 , wherein the discharging of the macrolide immunosuppressive (limus) drug and the polymer is sequential or simultaneous.