Drug-delivery endovascular stent and method for treating restenosis

• US 6,939,376 B2
• Filed: 04/24/2002
• Issued: 09/06/2005
• Est. Priority Date: 11/05/2001
• Status: Expired due to Term

• Current Assignee: Biosensors International Group, Ltd.
• Original Assignee: Sun Biomedical, Ltd.
• Inventors: Savage, Douglas R., Betts, Ronald E., Shulze, John E.
• Primary Examiner(s): Isabella, David J
• Application Number:
  US10/133,814
• Publication Number:
  US 20030125800A1
• Time in Patent Office: 1,231 Days
• Field of Search: 623/1.42, 623/1.43, 623/23.7, 623/1.11, 623/1.15, 623/1.39, 623/1.4, 514/1, 514/4, 424/422, 424/423, 427/2.24, 427/2.25, 427/2.3, 427/2.15, 427/2.28
• US Class Current: 623/1.42
• CPC Class Codes: A61F 2/90 characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2/915 with bands having a meander structure, adjacent bands being connected to each other
• CPC Class Codes: A61F 2002/072 Encapsulated stents, e.g. wire or whole stent embedded in lining
• CPC Class Codes: A61F 2002/91533 characterised by the phase between adjacent bands
• CPC Class Codes: A61F 2002/91575 connected peak to trough
• CPC Class Codes: A61F 2230/0054 V-shaped
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• 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 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C08L 29/04 : Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

An intravascular stent and method for inhibiting restenosis, following vascular injury, is disclosed. The stent has an expandable, linked-filament body and a drug-release coating formed on the stent-body filaments, for contacting the vessel injury site when the stent is placed in-situ in an expanded condition. The coating releases, for a period of at least 4 weeks, a restenosis-inhibiting amount of a monocyclic triene immunosuppressive compound having an alkyl group substituent at carbon position 40 in the compound. The stent, when used to treat a vascular injury, gives good protection against clinical restenosis, even when the extent of vascular injury involves vessel overstretching by more than 30% diameter. Also disclosed is a stent having a drug-release coating composed of (i) 10 and 60 weight percent poly-dl-lactide polymer substrate and (ii) 40-90 weight percent of an anti-restenosis compound, and a polymer undercoat having a thickness of between 1-5 microns.

Claims

1. An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising

a body formed of one or more filaments,

carried on the one or more filaments, a bioerodable drug-release coating having a thickness of between 3-20 microns, and composed of (i) 20-60 weight percent poly-dl-lactide polymer substrate and (ii) 40-80 weight percent of macrocyclic triene immunosuppressive compound, and

a polymer undercoat having a thickness of between 1-5 microns, disposed between the stent-body filaments and said coating,

said stent being expandable from a contracted condition in which the stent can be delivered to a vascular injury site via a catheter, and an expanded condition in which the stent coating can be placed in contact with the vessel at the injury site,

said coating being effective to release a restenosis-inhibiting amount of the compound over a period of at least 4 weeks after the stent is placed at the vascular injury site.

2. The stent of claim 1, wherein the stent body is a metal-filament structure, the undercoat is formed of a parylene polymer and has a thickness between 1 and 3 microns, and the coating has a thickness between 2 and 15 microns.

3. The stent of claim 2, wherein said compound is present in the coating in an amount between 50% and 75% by weight.

4. The stent of claim 1, wherein said macrocyclic triene immunosuppressive compound has the form

where (i) R is H or CH₂₋

—

X—

OH, and X is a linear or branched alkyl group containing 1 to 7 carbon atoms, when R′

is H (R′

is at the 28 position O) or (ii) at least one of R and R′

have the form

where m is an integer from 1 to 3 and R₁ and R₂ are each a hydrogen, or an alkyl radical having from one to three carbon atoms, or, alternatively, wherein R₁ and R₂ together with a nitrogen atom to which they are attached form a saturated heterocyclic ring having four carbon atoms.

5. The stent of claim 4, where R′

is H and X is —

CH₂₋

.

6. A method for inhibiting restenosis at an in vascular injury site, comprising

delivering to the vascular injury site, an endovascular stent comprising

(a) a body formed of one or more filaments,

(b) carried on the one or more filament(s), a bioerodable drug-release coating having a thickness of between 3-20 microns, and composed of (i) 20 to 60 weight percent poly-dl-lactide polymer substrate and (ii) 40-80 weight percent of macrocyclic triene immunosuppressive compound, and

(c) a polymer undercoat having a thickness of between 1-5 microns, disposed between the stent-body filaments and said coating, and

expanding the stent at the vascular injury site, to bring the stent coating in contact with the vessel at the injury site,

wherein said coating is effective to release a restenosis-inhibiting amount of the compound over a period of at least 4 weeks, thus to inhibit restenosis at the site.

7. The method of claim 6, wherein the stent body is a metal-filament structure, the undercoat is formed of a parylene polymer having a thickness between 1 and 3 microns, and the coating has a thickness between 2 and 15 microns.

8. The method of claim 7, wherein said compound is present in the coating in an amount between 50% and 75% by weight.

9. The method of claim 6, wherein said macrocyclic triene immunosuppressive compound has the form

where (i) R is H or CH₂₋

—

X—

OH, and X is a linear or branched alkyl group containing 1 to 7 carbon atoms, when R′

is H (R′

is at the 28 position O) or (ii) at least one of R and R′

have the form

where m is an integer from 1 to 3 and R₁ and R₂ are each a hydrogen, or an alkyl radical having from one to three carbon atoms, or, alternatively, wherein R₁ and R₂ together with a nitrogen atom to which they are attached form a saturated heterocyclic ring having four carbon atoms.

10. The method of claim 9, where R′

is H and X is —

CH₂.

11. The method of claim 9, for use where the vascular injury is produced during an angiographic procedure in which a vessel region is overstretched at least 30% in diameter.

12. An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising

a body having an open-lattice structure formed of linked filaments, and

carried on the one or more filaments, a drug-release coating having a thickness of between 3-30 microns, and composed of (i) 20 to 70 weight percent polymer substrate and (ii) 30-80 weight percent macrocyclic triene immunosuppressive compound having the form:

where R is CH₂₋

—

X—

OH, and X is a linear alkyl group containing 1 to 7 carbon atoms,

said stent being expandable from a contracted condition in which the stent can be delivered to a vascular injury site via catheter, and an expanded condition in which the stent coating can be placed in contact with the vessel at the injury site,

said coating being effective to release said a restenosis-inhibiting amount of the compound over a period of at least 4 weeks after the stent is placed at the vascular injury site.

13. The stent of claim 12, wherein X is —

CH₂—

.

14. The stent of claim 12, wherein the stent body is a metal-filament structure, and the polymer substrate in the coating is selected from the group consisting of polymethylmethacrylate, ethylene vinyl alcohol, and poly-dl-lactide polymer.

15. The stent of claim 14, wherein the polymer substrate in the coating is formed of a bioerodable poly-dl-lactide having a thickness between 3-20 microns and said monocyclic triene immunosuppressive is present in the coating at an initial concentration of between 35 and 80 weight percent of coating.

16. The stent of claim 15, which further includes a parylene polymer undercoat having a thickness of between 1-3 microns, disposed between the filaments of the stent body and said poly-dl-lactide coating substrate.

17. The stent of claim 16, wherein said coating includes the compound at an initial concentration of between 50 and 80 weight percent of coating.

18. The stent of claim 12, wherein said stent body and coating substrate are both formed of a bioerodable polymer.

19. The stent of claim 18, wherein said stent body is formed of a poly-l-or poly-dl-lactic acid, and the coating substrate is formed of poly-dl-lactide.

20. The stent of claim 12, wherein said coating is constructed to contact blood flowing through the stent when the stent is placed at the site in its expanded condition, and said coating contains said macrocyclic triene and said polymer in the specified proportions, which is further mixed with a bioactive agent selected from the group consisting of an antiplatelet, fibrinolytic, or thrombolytic agent in soluble crystalline form.

21. The stent of claim 20, wherein said antiplatelet, fibrinolytic, or thrombolytic agent is selected from the group consisting of heparin, aspirin, hirudin, ticlopadine(sp), eptifibatide, urokinase, streptokinase, tissue plasminogen activator (TPA), and abciximab, or a mixture thereof.

22. An endovascular stent for placement at a vascular injury site, for inhibiting restenosis at the site, comprising

a body having an open-lattice structure formed of linked filaments, and

carried on the stent-body filaments, a drug-release coating having a thickness 3-30 microns, said coating containing a mixture of polymer and a macrocyclic triene immunosuppressive compound effective for the control of restenosis, wherein said monocyclic triene immunosuppressive is present in a macrocyclic triene immunosuppressive-to-polymer ratio of greater than 50% by weight and wherein said coating is attached to said filament using a polymer underlayer of between 1-5 microns.