Polymer coatings containing drug powder of controlled morphology

• US 8,298,565 B2
• Filed: 07/14/2006
• Issued: 10/30/2012
• 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:
  US11/995,687
• Publication Number:
  US 20090123515A1
• Time in Patent Office: 2,300 Days
• Field of Search: None
• US Class Current: 424/423
• 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 the substrate, wherein an electrical potential is maintained between the substrate and the pharmaceutical and/or polymer particles, thereby forming the coating; and sintering the coating under conditions that do not substantially modify the morphology of the pharmaceutical agent.

Claims

1. A method for coating a substrate, said coating comprising at least one polymer;

and at least one pharmaceutical agent in a therapeutically desirable morphology;

said method comprising the following steps;

a) discharging the at least one pharmaceutical agent 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 pharmaceutical agent particles onto said substrate, wherein an electrical potential is maintained between the substrate and the polymer and pharmaceutical agent particles, thereby forming said coating; and

then

b) sintering said coating under conditions that do not substantially modify the morphology of said pharmaceutical agent, 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 pharmaceutical agent, wherein the therapeutically desirable morphology of said pharmaceutical agent is crystalline or semi-crystalline.

2. A substrate comprising a coating formed by the method of claim 1.

3. A biomedical implant comprising a coating formed by the method of claim 1.

4. The method of claim 1, further comprising depositing a top layer on said coating.

5. The method of claim 4, wherein said top coating is a polymer film.

6. The method of claim 1, wherein said first and said second orifices are provided as one single orifice.

7. The method of claim 1, wherein the substrate is electrostatically charged.

8. The method of claim 1, wherein said substrate is a biomedical implant.

9. The method of claim 8, wherein said biomedical implant is selected from the group consisting of stents, joints, screws, rods, pins, plates, staples, shunts, clamps, clips, sutures, suture anchors, electrodes, catheters, leads, grafts, dressings, pacemakers, pacemaker housings, cardioverters, cardioverter housings, defibrillators, defibrillator housings, prostheses, ear drainage tubes, ophthalmic implants, orthopedic devices, vertebral disks, bone substitutes, anastomotic devices, perivascular wraps, colostomy bag attachment devices, hemostatic barriers, vascular implants, vascular supports, tissue adhesives, tissue sealants, tissue scaffolds and intraluminal devices.

10. The method of claim 1, wherein at least 50% of said pharmaceutical agent in powder form is crystalline or semicrystalline.

11. The method of claim 1, wherein said pharmaceutical agent comprises at least one drug.

12. The method of claim 1, wherein said compressed gas, compressed liquid or supercritical fluid comprises carbon dioxide, isobutylene or a mixture thereof.

13. The method of claim 1, wherein the at least one polymer comprises two or more polymers, wherein the first polymer swells in aqueous media and the second polymer does not substantially swell in aqueous media.

14. The method of claim 13, wherein in aqueous media said pharmaceutical agent elutes from said first polymer, and substantially does not elute from second polymer.

15. The method of claim 13, wherein the first and/or second supercritical or near critical mixtures are discharged under RESS conditions.

16. The method of claim 1, wherein the substrate is a vascular stent.

17. The method of claim 1, wherein said at least one pharmaceutical agent is selected from:

Paclitaxel, Sirolimus, Everolimus, Zotarolimus, Dexamethasone, Tacrolimus, Biolimus, and derivatives.

18. The method of claim 1 wherein the pharmaceutical agent comprises a macrolide immunosuppressive drug comprising 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), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus).