Stents having controlled elution

• US 9,775,729 B2
• Filed: 08/19/2016
• Issued: 10/03/2017
• Est. Priority Date: 04/17/2007
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Micell Technologies Inc.
• Inventors: McClain, James B., Taylor, Charles Douglas
• Primary Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US15/241,271
• Publication Number:
  US 20160374837A1
• Time in Patent Office: 410 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 2/86 Stents in a form characterised by the wire-like elements; Stents in the form 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: 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: A61L 2300/204 with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/022 Metals or alloys
• 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 31/08 Materials for coatings
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

Provided herein is a drug delivery system comprising: a. substrate; b. a plurality of components combined with the substrate to form the drug delivery system; wherein at least one components comprises a bioabsorbable polymer and at least one other component comprises one or more active agents; wherein at least part of the active agent is in crystalline form.

Claims

1. A drug delivery system comprising

a. a substrate;

and

b. a plurality of bioabsorbable polymer layers combined with said substrate; and

at least one active agent combined with said substrate;

wherein each of said plurality of bioabsorbable polymer layers comprises a separately sintered bioabsorbable polymer layer;

wherein said at least one active agent is present in crystalline form on at least one region of an outer surface of said drug delivery system.

2. The drug delivery system of claim 1, wherein 50% or less of the total amount of said at least one active agent is released after 24 hours in vitro elution.

3. The drug delivery system of claim 2, wherein in vitro elution is carried out in a 1:

1 spectroscopic grade ethanol/phosphate buffer saline at pH 7.4 and 37°

C.;

wherein the amount of active agent released is determined by measuring UV absorption.

4. The drug delivery system of claim 3, wherein UV absorption is detected at 278 nm by a diode array spectrometer.

5. The drug delivery system of claim 1, wherein between 25% and 45% of the total amount of said at least one active agent is released after 24 hours in vitro elution in a 1:

1 spectroscopic grade ethanol/phosphate buffer saline at pH 7.4 and 37°

C.;

wherein the amount of said at least one active agent released is determined by measuring UV absorption at 278 nm by a diode array spectrometer.

6. The drug delivery system of claim 1, wherein said at least one active agent is at least 50% crystalline.

7. The drug delivery system of claim 1, wherein said at least one active agent is at least 90% crystalline.

8. The drug delivery system of claim 1, wherein said bioabsorbable polymer comprises a PLGA copolymer.

9. The drug delivery system of claim 1, wherein said bioabsorbable polymer comprises a first PLGA copolymer with a ratio of about 40:

60 to about 60;

40 and a second PLGA copolymer with a ratio of about 60;

40 to about 90;

10.

10. The drug delivery system of claim 1, wherein said bioabsorbable polymer comprises a first PLGA copolymer having a molecular weight of about 10 kD and a second polymer is a PLGA copolymer having a molecular weight of about 19 kD.

11. The drug delivery system of claim 1, wherein said bioabsorbable polymer is selected from the group PLGA, 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 DLPL, 65/35 DLPLG, 50/50 DLPLG, TMC poly(trimethylcarbonate), p(CPP:

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

12. The drug delivery system of claim 1, wherein said substrate comprises a stent.

13. The drug delivery system of claim 12, wherein said stent is formed of stainless steel or cobalt alloy.

14. The drug delivery system of claim 12, wherein said stent has a thickness of from about 50% to about 90% of a total thickness of the drug delivery system.

15. The drug delivery system of claim 1, wherein said drug delivery system has a thickness of from about 20 μ

m to about 500 μ

m.

16. The drug delivery system of claim 1, wherein said stent has a thickness of from about 50 μ

m to about 80 μ

m.

17. The drug delivery system of claim 1, wherein said drug delivery system has an active agent content of from about 5 μ

g to about 500 μ

g.

18. The drug delivery system of claim 1, wherein said at least one active agent comprises a macrolide immunosuppressive (limus) drug.

19. The drug delivery system of claim 18, wherein said at least one active agent is rapamycin, a prodrug, a derivative, an analog, a hydrate, an ester, or a salt thereof.

20. The drug delivery system of claim 19, wherein said at least one active agent is of sirolimus, everolimus, zotarolimus or biolimus.

21. The drug delivery system of claim 18, wherein the macrolide immunosuppressive drug comprises one or more of rapamycin, biolimus (biolimus A9), 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), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotarolimus), and salts, derivatives, isomers, racemates, diastereoisomers, prodrugs, hydrate, ester, or analogs thereof.

22. A drug delivery system comprising

a. a substrate;

and

b. a coating on said substrate comprising a first layer comprising at least one polymer;

a second layer comprising at least one active agent; and

an outer layer comprising at least one polymer;

wherein each of said polymer layers comprises a separately sintered polymer layer;

wherein said outer layer comprising said at least one polymer is sufficiently thin so that the active agent is present in crystalline form on at least one region of an outer surface of the coating opposite the substrate and wherein between 25% and 50% of the total amount of active agent in the coating is released after 24 hours in vitro elution.

23. The drug delivery system of claim 22, wherein the polymer comprises is at least one of:

a fluoropolymer, PVDF-HFP comprising vinylidene fluoride and hexafluoropropylene monomers, PC (phosphorylcholine), Polysulfone, polystyrene-b-isobutylene-b-styrene, PVP (polyvinylpyrrolidone), alkyl methacrylate, vinyl acetate, hydroxyalkyl methacrylate, and alkyl acrylate.

24. The drug delivery system of claim 23, wherein the alkyl methacrylate comprises at least one of methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, hexyl methacrylate, octyl methacrylate, dodecyl methacrylate, and lauryl methacrylate;

and wherein the alkyl acrylate comprises at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, hexyl acrylate, octyl acrylate, dodecyl acrylates, and lauryl acrylate.

25. The drug delivery system of claim 22, wherein the polymer is not a polymer selected from:

PBMA (poly n-butyl methacrylate), Parylene C, and polyethylene-co-vinyl acetate.

26. The drug delivery system of claim 22, wherein the polymer comprises a durable polymer.

27. The drug delivery system of claim 22, wherein the polymer comprises a bioabsorbable polymer.

28. The drug delivery system of claim 27, wherein the bioabsorbable polymer is selected from the group PLGA, 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 DLPL, 65/35 DLPLG, 50/50 DLPLG, TMC poly(trimethylcarbonate), p(CPP:

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

29. The drug delivery system of claim 22, wherein said at least one active agent is at least 50% crystalline.

30. The drug delivery system of claim 22, wherein said at least one active agent is at least 90% crystalline.

31. The drug delivery system of claim 22, wherein said substrate is formed of at least one of stainless steel material and a cobalt chromium alloy.

32. The drug delivery system of claim 22, wherein said substrate has a thickness of from about 50% to about 90% of a total thickness of the system.

33. The drug delivery system of claim 22, wherein said drug delivery system has a thickness of from about 20 μ

m to about 500 μ

m.

34. The drug delivery system of claim 22, wherein said substrate has a thickness of from about 50 μ

m to about 80 μ

m.

35. The drug delivery system of claim 22, wherein the coating has a total thickness of from about 5 μ

m to about 50 μ

m.

36. The drug delivery system of claim 22, wherein said drug delivery system has an active agent content of from about 5 μ

g to about 500 μ

g.

37. The drug delivery system of claim 22, wherein the outer layer comprising at least one polymer has a thickness of less than about 5 μ

m.

38. The drug delivery system of claim 22, wherein said at least one active agent comprises a macrolide immunosuppressive (limus) drug.

39. The drug delivery system of claim 38, wherein said at least one active agent is rapamycin, a prodrug, a derivative, an analog, a hydrate, an ester, or a salt thereof.

40. The drug delivery system of claim 38, wherein the macrolide immunosuppressive drug comprises one or more of rapamycin, biolimus (biolimus A9), 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), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotarolimus), and salts, derivatives, isomers, racemates, diastereoisomers, prodrugs, hydrate, ester, or analogs thereof.