Coating system and method for drug elution management

• US 8,628,790 B2
• Filed: 10/08/2010
• Issued: 01/14/2014
• Est. Priority Date: 10/09/2009
• Status: Active Grant

• Current Assignee: Avantec Vascular Corporation
• Original Assignee: PLS Technologies, LLC
• Inventors: To, John Thao, Blaha, Charles M.
• Primary Examiner(s): FISHER, ABIGAIL L
• Application Number:
  US12/901,426
• Publication Number:
  US 20110086081A1
• Time in Patent Office: 1,194 Days
• Field of Search: 424/422, 424/423, 424/426, 623/1.42, 623/1.46
• 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 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• 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 2420/08 Coatings comprising two or more layers
• 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

The teachings are directed to a medical device having a drug-retaining coating that at least substantially delays the initial elution of a drug for a time effective at forming a functional endothelium over a surface of the medical device.

Claims

1. A therapeutic coating that promotes formation of a functional endothelium on a medical device, the coating comprising:

a biodegradable, drug-containing inner layer that is positioned over a surface of a medical device and serves as a source of a drug that functions as an anti-proliferative agent in a subject; and

,

a biodegradable, outer layer positioned over a surface of the inner layer and comprising a polymer adapted to render the coating non-eluting beginning at time of implantation in the subject and continuing thereafter for a time period of about 20 to about 40 days, the polymer being further adapted to block release of the drug from the coating into the subject during the aforesaid time period to form a functional endothelium over the surface of the medical device, the functional endothelium providing a source of thrombomodulin to the subject;

wherein the polymer is still further adapted to allow the drug to elute from the coating after the aforesaid time period;

wherein the polymer has ester-terminal groups, a molecular weight ranging from about 50 KDaltons to about 190 KDaltons, the structure comprising P—

CO2R, where P is the polymer backbone and R is an alkyl group having from 1 to 4 carbons;

whereby the coating promotes development of the functional endothelium as the source of the thrombomodulin when compared to a control development of such endothelium formation observed following implantation of a metal drug-eluting medical device; and

the coating inhibits development of a hyperproliferative tissue when compared to a control development of such hyperproliferative tissue observed following implantation of a metal medical device.

2. The coating of claim 1, wherein the medical device comprises a stent.

3. The coating of claim 1, wherein the drug-containing layer comprises a poly(lactic-co-glycolic acid), a monomer ratio of lactic acid to glycolic acid ranges from about 85:

15 to about 50;

50, and a molecular weight ranging from about 90 KDaltons to about 160 KDaltons.

4. The coating of claim 1, wherein the drug-retaining layer comprises a poly(lactic-co-glycolic acid) having ester terminal groups, a monomer ratio of lactic acid to glycolic acid ranging from about 85:

15 to about 50;

50, and a molecular weight ranging from about 90 KDaltons to about 160 KDaltons.

5. The coating of claim 1, wherein the thickness of the coating ranges from about 2 microns to about 9 microns.

6. The coating of claim 1, wherein the thickness ratio of the drug-retaining layer to the drug-containing layer ranges from about 4:

1 to about 7;

1.

7. The coating of claim 1 further comprising pockets of hydrophilic material in the drug-retaining layer, wherein the hydrophilic material comprises a component selected from the group consisting of dextran, heparin, ticlopidine, chlopidogrel, enoxaparin, dalteparin, hirudin, bivalirudin, argatroban, and danparoid.

8. The coating of claim 1, wherein the drug-reservoir layer further comprises an accelerant layer to accelerate the rate of elution, the accelerant layer having a poly(lactic-co-glycolic acid) with acid terminal groups, a monomer ratio of lactic acid to glycolic acid that ranges from about 85:

15 to about 50;

50, and a molecular weight that ranges from about 90 KDaltons to about 120 KDaltons.

9. A stent having a coating that promotes formation of a functional endothelium, the coating comprising:

a biodegradable drug-containing inner layer that is positioned over a surface of the stent and serves as a source of a drug that functions as an anti-proliferative agent in a subject, wherein the drug-containing layer comprises a poly(lactic-co-glycolic acid), a monomer ratio of lactic acid to glycolic acid ranges from about 85;

15 to about 50;

50, and a molecular weight ranging from about 110 KDaltons to about 160 KDaltons; and

,

a biodegradable, outer layer positioned over a surface of the inner layer and comprising a polymer adapted to render the coating non-eluting beginning

wherein, the drug retaining layer is void or substantially void of the drug at time of implantation in the subject and continuing thereafter for a time period of about 20 to about 40 days, the polymer being further adapted to, block release of the drug from the coating into the subject during the aforesaid time period to form a functional endothelium over the surface of the stent, the functional endothelium providing a source of thrombomodulin to the subject;

wherein the polymer is still further adapted to allow the drug to elute from the coating after the aforesaid time period;

wherein the drug-retaining layer comprises a poly(lactic-co-glycolic acid) polymer having ester terminal groups and the structure P—

CO2R, where P is the polymer backbone and R is an alkyl group having from 1 to 4 carbons, a monomer ratio of lactic acid to glycolic acid ranging from about 85;

15 to about 50;

50, a molecular weight ranging from about 50 KDaltons to about 190 KDaltons, and a structure that remains at least substantially undegraded during an initial release of the drug from the coating;

wherein the accelerant layer comprises a poly(lactic-co-glycolic acid) with acid terminal groups, a monomer ratio of lactic acid to glycolic acid that ranges from about 85;

15 to about 50;

50, a molecular weight that ranges from about 90 KDaltons to about 120 KDaltons, and functions to accelerate the rate of elution of drug from the coating;

wherein the thickness ratio of the drug-reservoir layer to the drug-containing layer ranges from about 4;

1 to about 10;

1;

whereby the coating promotes development of the functional endothelium as the source of the thrombomodulin when compared to a control development of such endothelium formation observed following implantation of a metal stent; and

the coating inhibits development of a restenosis when compared to a control development of such restenosis observed following implantation of a metal stent.

10. The stent of claim 9, wherein the thickness of the coating ranges from about 2 microns to about 9 microns.

11. The stent of claim 9, wherein the thickness ratio of the drug-retaining layer to the drug-containing layer ranges from about 4:

1 to about 7;

1.

12. The stent of claim 9, further comprising pockets of hydrophilic material in the drug-retaining layer, wherein the hydrophilic material comprises a component selected from the group consisting of dextran, heparin, ticlopidine, chlopidogrel, enoxaparin, dalteparin, hirudin, bivalirudin, argatroban, and danparoid.

13. The stent of claim 9, wherein the drug is selected from the group consisting of fluoroquinolone, paclitaxel, rapamycin, sirolimus, everolimus, biolimus, zotarolimus, tacrolimus, fibroblast growth factor (bFGF), rapamycin analogs, antisense dexamethasone, angiopeptin, batimistat, tranilast, transilast, halofuginon, acetylsalicylic acid, hirudin, steroids, ibuprofen, antimicrobials, antibiotics, actinomycin D, tissue plasma activators, estradiol, and transcription factor E2F1.

14. A medical device having a drug-retaining coating, comprising:

a drug-containing, inner layer applied over a surface of the medical device, the drug-containing layer having a drug that functions as an anti-proliferative agent; and

an outer layer applied over the inner layer and comprising a polymer adapted to render the drug-retaining coating non-eluting beginning at time of implantation in a subject and continuing thereafter for a time period of about 20 to about 40 days, the polymer being further adapted to block release of the drug from the coating into the subject during the aforesaid time period;

wherein the polymer is still further adapted to allow the drug to elute from the coating after the aforesaid time period;

whereby the coating promotes development of a functional endothelium as a source of thrombomodulin when compared to a control development of such endothelium formation observed following implantation of a metal medical device; and

,

the coating inhibits development of a hyperproliferative tissue when compared to a control development of such hyperproliferative tissue observed following implantation of a metal medical device.