Polymer coatings containing drug powder of controlled morphology

• US 9,827,117 B2
• Filed: 04/25/2014
• Issued: 11/28/2017
• Est. Priority Date: 07/15/2005
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Micell Technologies Inc.
• Inventors: Taylor, Doug, McClain, Jim, Smoke, Clint, Cole, Mike, DeYoung, James
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US14/262,163
• Publication Number:
  US 20150025620A1
• Time in Patent Office: 1,313 Days
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2210/0076 multilayered, e.g. laminated structures
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• 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 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: Y10T 428/264 Up to 3 mils
• CPC Class Codes: Y10T 428/265 1 mil or less
• CPC Class Codes: Y10T 428/31507 : Of polycarbonate
• CPC Class Codes: Y10T 428/31544 : Addition polymer is perhalogenated
• CPC Class Codes: Y10T 428/31551 : Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
• CPC Class Codes: Y10T 428/31663 : As siloxane, silicone or silane
• CPC Class Codes: Y10T 428/31786 : Of polyester [e.g., alkyd, etc.]
• CPC Class Codes: Y10T 428/31935 : Ester, halide or nitrile of addition polymer
• CPC Class Codes: Y10T 428/31938 : Polymer of monoethylenically unsaturated hydrocarbon

Abstract

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.

Claims

1. A coated implantable medical device, comprising:

a substrate; and

a coating having thickness of about 1 to about 30 microns disposed on said substrate, wherein said coating comprises at least one polymer and at least one pharmaceutical agent uniformly dispersed within the polymer to create a continuous matrix, wherein said pharmaceutical agent comprises a crystalline macrolide immunosuppressive (limus) drug.

2. The medical device of claim 1, wherein said coating is substantially free of solvent residue.

3. The medical device of claim 1, wherein the coating is sintered at a temperature below the phase transition temperature of the polymer.

4. 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, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, dressings, bone substitutes, intraluminal devices, and vascular supports.

5. 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.

6. The medical device of claim 5, wherein said polymer film has a thickness of 0.5 to 10 microns.

7. The medical device of claim 1, wherein the substrate is a vascular stent.

8. The medical device of claim 1, wherein the substrate is a coronary stent.

9. The medical device of claim 1, wherein said coating covers substantially the entire surface of said substrate.

10. The medical device of claim 1, wherein said coating is substantially free of aggregated macrolide immunosuppressive (limus) drug particles.

11. 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) and 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).

12. The medical device of claim 1, wherein said polymer is poly(butyl methacrylate) (PBMA), polyethylene-co-vinyl acetate (PEVA) or a mixture thereof.

13. The medical device of claim 1, wherein said substrate is an orthopedic device.

14. The medical device of claim 1, wherein the coating is 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.

15. The medical device of claim 1, wherein said coating comprises at least two pharmaceutical agents.

16. The medical device of claim 1, wherein the pharmaceutical agent is in the form of particles having an average diameter from 2 nm to 500 nm.

17. The medical device of claim 1, wherein said 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, and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus).

18. The medical device of claim 1, wherein at least 50% of said pharmaceutical agent is in crystalline form.

19. The medical device of claim 1, wherein at least 75% of said pharmaceutical agent is in crystalline form.

20. The medical device of claim 1, wherein at least 90% of said pharmaceutical agent is in crystalline form.

21. The medical device of claim 1, wherein at least 95% of said pharmaceutical agent is in crystalline form.

22. The medical device of claim 1, wherein at least 99% of said pharmaceutical agent is in crystalline form.

23. The medical device of claim 1, wherein said polymer is a mixture of two or more polymers.

24. The medical device of claim 23, wherein said mixture of polymers forms a continuous film around particles of rapamycin.

25. The medical device of claim 23, wherein said two or more polymers are intimately mixed.

26. The medical device of claim 23, wherein said mixture comprises no single polymer domain larger than about 20 nm.

27. The medical device of claim 23, wherein each polymer in said mixture comprises a discrete phase.

28. The medical device of claim 27, wherein discrete phases formed by said polymers in said mixture are larger than about 10 nm.

29. The medical device of claim 27, wherein discrete phases formed by said polymers in said mixture are larger than about 50 nm.

30. The medical device of claim 1, wherein said macrolide immunosuppressive 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.