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EP-3525722-B1 - DRUG ELUTING STENT FOR ENABLING RESTORATION OF FUNCTIONAL ENDOTHELIAL CELL LAYERS

EP3525722B1EP 3525722 B1EP3525722 B1EP 3525722B1EP-3525722-B1

Inventors

  • SUN, JIANHUA
  • BUREAU, CHRISTOPHE
  • CAI, Wenbin
  • LI, Tianzhu
  • KANG, Xiaoran

Dates

Publication Date
20260506
Application Date
20171030

Claims (18)

  1. A drug eluting stent (1), comprising: a stent framework (2); a drug-containing layer (3); a drug (4) embedded in the drug-containing layer (3); and a biocompatible base layer (5) disposed over the stent framework (2) and supporting the drug-containing layer (3), the drug-containing layer (3) has an uneven coating thickness, and a thickness of the drug-containing layer (3) on a luminal side of the stent (1) and a thickness of the drug-containing layer (3) on a lateral side of the stent (1) is less than a thickness of the drug-containing layer (3) on an abluminal side of the stent (1); characterized in that a ratio between the thickness of the drug-containing layer (3) on the luminal side and the thickness of the drug-containing layer (3) on the abluminal side is between 2:3 and 1:7; wherein one or more polymers forming the drug-containing layer (3) on a luminal side of the stent and the drug-containing layer (3) on a lateral side of the stent degrade faster than one or more polymers forming the drug-containing layers (3) on an abluminal side of the stent (1); optionally, the drug-containing layer (3) is configured to completely dissolve between 45 days and 60 days after implantation of the drug eluting stent (1); or the drug-containing layer (3) is configured to release the drug (4) within 30 days of implantation within a vessel.
  2. The drug eluting stent (1) of claim 1, characterized in that a ratio between the thickness of the drug-containing layer (3) on the lateral side (7) and the thickness of the drug-containing layer (3) on the abluminal side (8) is between 2:3 and 1:7; or the drug-containing layer (3) has a thickness between 5 and 12 µm, optionally the drug (4) is embedded only on the drug-containing layer (3) on an abluminal side (8) of the stent .
  3. The drug eluting stent (1) of any one of claims 1 to 2, characterized in that the stent framework (2) is fabricated from a biodegradable material or from a single piece of metal, wire, or tubing, preferably the metal comprises at least one of stainless steel, nitinol, tantalum, cobalt-chromium MP35N or MP20N alloys, platinum, and titanium.
  4. The drug eluting stent (1) of any one of claims 1 to 3, characterized in that the drug (4) comprises at least one of an antithrombogenic agent, an anticoagulant, an antiplatelet agent, an antineoplastic agent, an antiproliferative agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, a recombinant DNA product, a recombinant RNA product, a collagen, a collagen derivative, a protein analog, a saccharide, a saccharide derivative, an inhibitor of smooth muscle cell proliferation, a promoter of endothelial cell migration, proliferation, and/or survival, and combinations of the same, preferably the drug (4) comprises sirolimus and/or a derivative or analog.
  5. The drug eluting stent (1) of claim 1, characterized in that the drug-containing layer (3) is selected from the group consisting of poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs), poly(hydroxyalkanoate-co-ester amides), polyacrylates, polymethacrylates, polycaprolactones, poly(ethylene glycol)(PEG), poly(propylene glycol)(PPG), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG (PolyActive(R)), PEG-PPO-PEG(Pluronic(R)), and PPF-co-PEG, polycaprolactones, polyglycerol sebacate, polycarbonates, biopolyesters, polyethylene oxide, polybutylene terephalate, polydioxanones, hybrids, composites, collagen matrices with grouth modulators, proteoglycans, glycosaminoglycans, vacuum formed small intestinal submucosa, fibers, chitin, dexran and mixtures thereof.
  6. The drug eluting stent (1) of claim 5, characterized in that the drug-containing layer (3) is selected from tyrosine derived polycarbonates and poly(β-hydroxyalcanoate)s and derivatives thereof.
  7. The drug eluting stent (1) of claim 5, characterized in that the drug-containing layer (3) comprises a polylactide-co-glycolide 50/50 (PLGA).
  8. The drug eluting stent (1) of claim 1, characterized in that the biocompatible base layer (5) comprises at least one of poly n-butyl methacrylate, PTFE, PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), Parylene C, PVP, PEVA, SBS, PC, or TiO2; or the biocompatible base layer (5) comprises an electro-grafted polymeric layer having an interdigitated surface with the drug-containing layer (3), preferably the electro-grafted polymeric layer has a thickness between 10 nm and 1000 nm .
  9. The drug eluting stent (1) of claim 8, characterized in that the electro-grafted polymeric layer comprises a monomer selected from the group consisting of vinylics, epoxides, and cyclic monomers undergoing ring opening polymerization and aryl diazonium salts; preferably, the monomer is further selected from the group consisting of butyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate, epsilon caprolactone, and 4-aminophenyl diazonium tetrafluoro borate.
  10. The drug eluting stent (1) of claim 1, characterized in that the drug-containing layer (3) is formed from a plurality of polymers; preferably, one or more polymers forming the drug-containing layer (3) on a luminal side (6) of the stent and the drug-containing layer (3) on a lateral side (7) of the stent degrade faster than one or more polymers forming the drug-containing layers (3) on an abluminal side (8) of the stent, preferably, the drug-containing layer (3) has a thickness between 5 and 12 µm.
  11. A method of fabricating a drug eluting stent (1) of claim 1, the method comprising: providing a stent framework (2); and unevenly coating the stent framework (2) with at least one polymer mixed with at least one drug, wherein unevenly coating comprises coating the luminal (6) and/or lateral (7) sides of the stent with a thinner coating than the coating of the abluminal side (8), wherein the coating that is thinner is a drug-containing layer (3) and/or a biocompatible base layer (5) underneath the drug-containing layer (3); wherein the drug-containing layer (3) is configured to completely dissolve between 45 days and 60 days after implantation of the drug eluting stent (1); wherein a thickness of the drug-containing layer (3) on a luminal side of the stent (1) and a thickness of the drug-containing layer (3) on a lateral side of the stent (1) is less than a thickness of the drug-containing layer (3) on an abluminal side of the stent (1); wherein a ratio between the thickness of the drug-containing layer (3) on the luminal side and the thickness of the drug-containing layer (3) on the abluminal side is between 2:3 and 1:7; wherein one or more polymers forming the drug-containing layer (3) on a luminal side of the stent and the drug-containing layer (3) on a lateral side of the stent degrade faster than one or more polymers forming the drug-containing layers (3) on an abluminal side of the stent (1).
  12. The method of fabricating a drug eluting stent (1) according to claim 11, wherein a ratio between the thickness of the drug-containing layer (3) on the lateral side and the thickness of the drug-containing layer (3) on the abluminal side is between 2:3 and 1:7.
  13. The method of fabricating a drug eluting stent (1) according to claim 11, wherein the drug-containing layer (3) comprising a polylactide-co-glycolide 50/50 (PLGA).
  14. The stent according to any one of claims 1 to 10 or the method according to claim 11, characterized in that the stent framework (2) comprises an 8 crest design, a 10 crest design, or an 11 crest design.
  15. The stent according to any one of claims 1 to 10, characterized in that the stent framework (2) comprises a plurality of stent poles having a wave design.
  16. The stent according to any one of claims 1 to 10, characterized in that the stent framework (2) comprises a plurality of single linking poles alternating between two linking poles and three linking poles between stent poles in an axial direction, preferably, characterized in that the stent framework (2) comprises four linking poles on a first end in an axial direction and comprises four linking poles on a second end in the axial direction .
  17. The stent according to any one of claims 1 to 10, characterized in that a width of a crown is greater than a width of a pole.
  18. The stent according to any one of claims 1 to 10, characterized in that the stent comprises a cobalt-chromium alloy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims benefit of priority to U.S. Provisional Patent Application No. 62/438,432, filed December 22, 2016. TECHNICAL FIELD The present disclosure relates to drug eluting stents, methods of making and using the drug eluting stents, as well as methods for predicting long term stent efficacy and patient safety after implantation of a drug eluting stent. More specifically, and without limitation, the present disclosure relates to the design of a drug eluting stent comprising a stent framework (e.g., metal based or made with biodegradable materials) and a layer or layers covering all or part of the surface of said stent, capable of hosting a drug and releasing it in a sustained manner, in such a way that patient risks associated with the implantation of said drug eluting stent are minimized or eliminated. The stents disclosed herein are capable of enabling functional restoration of endothelial cell layers after implantation. BACKGROUND Over the years, the use of coatings for medical devices and drug delivery has become a necessity, notably for augmenting the capabilities of medical devices and implants. Drug eluting medical devices have emerged as a leading biomedical device for the treatment of cardiovascular disease. Heart disease and heart failure are two of the most prevalent health conditions in the U.S. and the world. In coronary artery disease, the blood vessels in the heart become narrow. When this happens, the oxygen supply is reduced to the heart muscle. A primary treatment of coronary artery disease was initially done by surgery, e.g., CABG (Coronary Artery Bypass Graft), which are normal and efficient procedures performed by cardiac surgeons. The mortality and morbidity, however, were rather high. In the 1960s, some physicians developed a less invasive treatment by using medical devices. These devices were inserted through a small incision at the femoral artery. For example, balloon angioplasty (which may be used to widen an artery that has become narrowed using a balloon catheter which is inflated to open the artery and is also termed PTCA (Percutaneous Transluminal Coronary Angioplasty)) is used in patients with coronary artery disease. Following balloon angioplasty, approximately 40 to 50% of coronaries arteries are generally affected by restenosis (the re-narrowing of a blood vessel after it has been opened, usually by balloon angioplasty), usually within 3 to 6 months due to either thrombosis (the development of a blood clot in the vessels which may clog a blood vessel and stop the flow of blood) or abnormal tissue growth. As a result, restenosis constitutes one of the major limitations to the effectiveness of PTCA. The introduction of the bare metal stent (BMS) in the late 1980s, when used to keep coronary arteries expanded, partially alleviated this problem, as well as that of the dissections of arteries upon balloon inflation in the PTCA procedure. The stent is a mesh tube mounted on a balloon catheter (e.g., a long thin flexible tube that can be inserted into the body). In this example, the stent is threaded to the heart. However, the BMS initially continued to be associated with a general restenosis rate of around 25% of patients affected 6 months after stent insertion. Usually, stent struts end up embedded by the arterial tissue in growth. This tissue is typically made of smooth muscle cells (SMCs), the proliferation of which may be provoked by the initial damaging of the artery upon stent apposition. As depicted in FIG. 1, the whole inner surface of the vessel 100 is covered by "active" of functional ECs 101, i.e. endothelial cells spontaneously producing nitrogen oxide (NO), a small molecule acting as a signal to stop the proliferation of SMCs 103 underneath. This natural release of NO by ECs 101 takes place generally when ECs 101 are in immediate contact to one another, e.g., paving the inner surface of the artery by a continuous and closely packed film. When a stent (or a balloon) is inflated inside vessel 150, stent struts in contact with the vessel walls will partly destroy the EC layer and injure the artery, e.g. at contact points 105a and 105b. The natural release of NO is thus - at least locally at contact points 105a and 105b - highly perturbed. This injury may trigger the proliferation of SMCs as a repair mechanism, e.g., SMCs 107a and 107b. The uncontrolled proliferation of SMCs may cause the re-closing of the vessel, or "restenosis." If, while SMCs 107a and 107b are proliferating, ECs 101 can also proliferate and eventually cover again the stent struts and SMCs 107a and 107b via a continuous film, then the NO release may be restored and the proliferation of SMC's may be stopped. Consequently, the risk of restenosis may be lessened (if not eliminated) and the situation may stabilize. One of the biggest challenges of the interventional cardiology industry since the 1990s has been to first understand and then secure