Drug Coated Stents

• US 20100298928A1
• Filed: 10/17/2008
• Published: 11/25/2010
• Est. Priority Date: 10/19/2007
• Status: Abandoned Application

• Current Assignee: Micell Technologies Inc.
• Original Assignee: Micell Technologies Inc.
• Inventors: McClain, James B., Taylor, Douglas
• Application Number:
  US12/738,411
• Publication Number:
  US 20100298928A1
• Time in Patent Office: Days
• US Class Current: 623/1.42
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• 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 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• 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 2300/63 Crystals
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• 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 31/042 Polysaccharides
• 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: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

Provided herein is a coated coronary stent, comprising: a stent framework; heparin molecules attached to the stent framework; and a rapamycin-polymer coating wherein at least part of rapamycin is in crystalline form. In one embodiment, the rapamycin-polymer coating comprises one or more resorbable polymers.

Claims

1. A coated coronary stent, comprising:

a stent framework;

heparin molecules attached to the stent framework; and

a rapamycin-polymer coating wherein at least part of rapamycin is in crystalline form.

2. The coated coronary stent of claim 1, wherein the rapamycin-polymer coating comprises one or more resorbable polymers.

3. The coated coronary stent of claim 2, wherein said rapamycin-polymer coating has substantially uniform thickness and rapamycin in the coating is substantially uniformly dispersed within the rapamycin-polymer coating.

4. The coated coronary stent of claim 2 wherein the one or more resorbable polymers are selected from PLGA (poly(lactide-co-glycolide);

DLPLA—

poly(dl-lactide);

LPLA—

poly(1-lactide);

PGA—

polyglycolide;

PDO—

poly(dioxanone);

PGA-TMC—

poly(glycolide-co-trimethylene carbonate);

PGA-LPLA—

poly(1-lactide-co-glycolide);

PGA-DLPLA—

poly(dl-lactide-co-glycolide);

LPLA-DLPLA—

poly(1-lactide-co-dl-lactide);

PDO-PGA-TMC—

poly(glycolide-co-trimethylene carbonate-co-dioxanone) and combinations thereof.

5. The coronary stent of claim 2 wherein the polymer is 50/50 PLGA.

6. The coated coronary stent of claim 1, wherein at least part of said rapamycin forms a phase separate from one or more phases formed by said polymer.

7. The coated coronary stent of claim 1, wherein said rapamycin is at least 50% crystalline.

8. The coated coronary stent of claim 1, wherein said rapamycin is at least 75% crystalline.

9. The coated coronary stent of claim 1, wherein said rapamycin is at least 90% crystalline.

10. The coated coronary stent of claim 1, wherein said rapamycin is at least 95% crystalline.

11. The coated coronary stent of claim 1, wherein said rapamycin is at least 99% crystalline.

12. The coated coronary stent of claim 1, wherein said polymer is a mixture of two or more polymers.

13. The coated coronary stent of claim 12, wherein said mixture of polymers forms a continuous film around particles of rapamycin.

14. The coated coronary stent of claim 12, wherein said two or more polymers are intimately mixed.

15. The coated coronary stent of claim 14, wherein said mixture comprises no single polymer domain larger than about 20 nm.

16. The coated coronary stent of claim 12, wherein each polymer in said mixture comprises a discrete phase.

17. The coated coronary stent of claim 16, wherein discrete phases formed by said polymers in said mixture are larger than about 10 nm.

18. The coated coronary stent of claim 16, wherein discrete phases formed by said polymers in said mixture are larger than about 50 nm.

19. The coated coronary stent of claim 1, wherein rapamycin in said stent has a shelf stability of at least 3 months.

20. The coated coronary stent of claim 1, wherein rapamycin in said stent has a shelf stability of at least 6 months.

21. The coated coronary stent of claim 1, wherein rapamycin in said stent has a shelf stability of at least 12 months.

22. The coated coronary stent of claim 1 wherein said coating is substantially conformal.

23. The coated coronary stent of claim 1, wherein said stent provides an elution profile wherein about 10% to about 50% of rapamycin is eluted at week 1 after the composite 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 6.

24. The coated coronary stent of claim 1 wherein onset of heparin anti-coagulant activity is obtained at week 3 or later.

25. The coated coronary stent of claim 1 wherein heparin anti-coagulant activity remains at an effective level at least 90 days after onset of heparin activity.

26. The coated coronary stent of claim 1 wherein heparin anti-coagulant activity remains at an effective level at least 120 days after onset of heparin activity.

27. The coated coronary stent of claim 1 wherein heparin anti-coagulant activity remains at an effective level at least 200 days after onset of heparin activity.

28. The coated stent of claim 1, wherein the stent framework is a stainless steel framework.

29. The coated stent of claim 27, wherein heparin is attached to the stainless steel framework by reaction with an aminated silane.

30. The coated stent of claim 29 wherein the framework is coated with a silane monolayer.

31. A coated coronary stent, comprising:

a stent framework;

heparin molecules attached to the stent framework by an aminated silane; and

a rapamycin-polymer coating wherein at least part of rapamycin is in crystalline form and wherein the polymer is bioabsorbable.

34. The coated coronary stent of claim 31, wherein said macrolide immunosuppressive drug is at least 50% crystalline.

36. The method of claim 34 wherein the macrolide is deposited in dry powder form.

37. The method of claim 34 wherein the bioabsorbable polymer is deposited in dry powder form.

38. The method of claim 34 wherein the polymer is deposited by an e-SEDS process.

39. The method of claim 34 wherein the polymer is deposited by an e-RESS process.

40. The method of claim 34 further comprising sintering said coating under conditions that do not substantially modify the morphology of said macrolide.

41. The method of claim 34, 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-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 4O—

O-(6-Hydroxy)hexyl-rapamycin 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin 4O—

O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 4O—

O-(2-Acetoxy)ethyl-rapamycin 4O—

O-(2-Nicotinoyloxy)ethyl-rapamycin, 4O—

O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 4O—

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, 4O—

O-(2-Aminoethyl)-rapamycin, 4O—

O-(2-Acetaminoethyl)-rapamycin 4O—

O-(2-Nicotinamidoethyl)-rapamycin, 4O—

O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 4O—

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).

42. The method of claim 34 wherein one or more resorbable polymers are selected from PLGA (poly(lactide-co-glycolide);

DLPLA—

poly(dl-lactide);

LPLA—

poly(1-lactide);

PGA—

polyglycolide;

PDO—

poly(dioxanone);

PGA-TMC—

poly(glycolide-co-trimethylene carbonate);

PGA-LPLA—

poly(1-lactide-co-glycolide);

PGA-DLPLA—

poly(dl-lactide-co-glycolide);

LPLA-DLPLA—

poly(1-lactide-co-dl-lactide);

PDO-PGA-TMC—

poly(glycolide-co-trimethylene carbonate-co-dioxanone).

32. A coated coronary stent, comprising:

a stent framework having a heparin coating disposed thereon; and

a macrolide immunosuppressive (limus) drug-polymer coating wherein at least part of the drug is in crystalline form.

33. The coated stent of claim 32, 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-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 4O—

O-(6-Hydroxy)hexyl-rapamycin 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin 4O—

O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 4O—

O-(2-Acetoxy)ethyl-rapamycin 4O—

O-(2-Nicotinoyloxy)ethyl-rapamycin, 4O—

O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 4O—

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, 4O—

O-(2-Aminoethyl)-rapamycin, 4O—

O-(2-Acetaminoethyl)-rapamycin 4O—

O-(2-Nicotinamidoethyl)-rapamycin, 4O—

O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 4O—

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).

35. A method for preparing a coated coronary stent comprising the following steps:

forming a silane layer on a stainless or cobalt—

chromium stent framework;

covalently attaching heparin molecules to the silane layer;

forming a macrolide immunosuppressive (limus) drug-polymer coating on the stent framework wherein at least part of the drug is in crystalline form.

43. A coated coronary stent, comprising:

a stent framework;

heparin molecules attached to the stent framework;

a first layer of bioabsorbable polymer; and

a rapamycin-polymer coating wherein comprising rapamycin and a second bioabsorbable polymer wherein at least part of rapamycin is in crystalline form and wherein the first polymer is a slow absorbing polymer and the second polymer is a fast absorbing polymer.

44. The stent of claim 43 wherein the fast absorbing polymer is PLGA copolymer with a ratio of about 40:

60 to about 60;

40 and the slow absorbing polymer is a PLGA copolymer with a ration of about 70;

30 to about 90;

10.