Drug-eluting stents including biocompatible thermoplastic polymer lining and drug-containing coatings

Abstract

A drug-eluting stent (10) is provided, comprising: an expandable structural scaffold (20) configured to resist radial compression when placed in the lumen of a patient; and a lining (30) located only in the central part (21) of the structural scaffold, the central part being covered by the lining and the ends (22) and (23) not being covered by the lining, the lining comprising a biocompatible thermoplastic polymer; the proximal and distal ends being coated with a drug-containing coating (40) comprising a biodegradable polymer and a Limus drug, and the central part of the structural scaffold and the lining not being Limus drug. A method for preparing a drug-eluting stent is also provided.

Description

Technical Field

[0001] This application claims the benefit of European Patent Application No. 23382599.1, filed on Jun. 15, 2023.

[0002] This disclosure generally relates to medical devices. More specifically, this disclosure relates to drug-eluting stents.

Background Art

[0003] Stents can be deployed in various body lumens for various therapeutic purposes, including the treatment of obstructions within the lumen. A stent has a support structure, such as a metallic structure or a polymeric structure, to provide the strength necessary to maintain the patency of the blood vessel in which the stent is implanted.

[0004] One drawback of vascular stents is the potential for restenosis via the formation of scar tissue (neointima) within the lumen. The development of neointima can re-occlude the vascular lumen (restenosis). Substantial improvements have been made in reducing neointima after stent implantation through the use of biocompatible materials, anti-inflammatory drug-eluting stents, resorbable stents, etc. The approach lies in applying a biocompatible polymer (BP) coating to the stent to provide a biocompatible surface. Thus, BP-coated stents, such as polytetrafluoroethylene (PTFE)-coated stents, can avoid stent dysfunction, including thrombosis and abnormal pseudointimal hyperplasia.

[0005] A drug-eluting stent (DES) comprises a surface coating of a polymeric material loaded with a therapeutic agent, enabling local delivery of the therapeutic agent to the lumen wall adjacent to the stent. DES is particularly useful for the treatment of atherosclerotic stenosis in arteries and blood vessels and is effective in reducing neointimal proliferation within the stent and thus the occurrence of restenosis.

[0006] Although the use of BP-covered stents or DES can significantly reduce restenosis rates compared to bare stent placement, restenosis can occur at a higher rate near the outer edge of the stent, known as the "edge effect" (stent-edge stenosis). That is, after stent implantation, the artery near its edge continues to decrease in size, eventually leading to restenosis and re-occlusion of the artery.

[0007] Therefore, there remains interest in reducing the incidence of restenosis after stent placement, and more specifically, in reducing edge restenosis. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2010083530 [Patent Document 2] U.S. Patent Application Publication No. 2016296351 [Overview of the project]

[0009] The inventors have found that by covering the central portion of the longitudinal stent structural scaffold with a biocompatible thermoplastic polymer lining, that is, by leaving the ends of the structural scaffold unlined and coating the two ends of the structural scaffold with a drug polymer coating, not only is restenosis avoided, but stent end stenosis is also avoided.

[0010] By lining the central portion of the scaffold with a biocompatible thermoplastic polymer, it becomes possible to form a thin endothelial layer on the inner surface of the stent. Furthermore, any tissue growth that would obstruct the vascular lumen is avoided. This allows the stent to better conform to the surrounding body lumen, thereby reducing blood turbulence and decreasing the risk of thrombosis or thrombus formation. In addition, the formation of the endothelial layer can promote healing in the area of ​​the lumen where it is needed. Thus, in addition to ensuring vascular reperfusion, restenosis is avoided.

[0011] Simultaneously, coating the ends of the scaffold with a drug-containing coating allows for controlled drug release at the stent ends, thus minimizing or even avoiding edge effects (i.e., stent end stenosis).

[0012] Advantageously, since the central biocompatible thermoplastic polymer cover is not coated with a drug-containing polymer, the effect provided by the former remains unchanged. Thus, the edge effect is avoided while maintaining the effect of the biocompatible thermoplastic polymer.

[0013] Furthermore, it has been observed that the amount of drug in the polymer coating can be reduced compared to drug-eluting stents completely coated with a drug-containing polymer coating (either the anti-luminal surface, the luminal surface, or both), without causing adverse effects. Therefore, advantageously, secondary undesirable effects associated with the drug are reduced.

[0014] Therefore, a first aspect of this disclosure is a drug-eluting stent, An expandable structural scaffold configured to resist radial compression when placed in the lumen of a patient, the expandable structural scaffold includes a central portion located between a proximal end and a distal end, A lining is provided, which is located only in the central part, such that the central part is covered by the lining and the edges are not covered by the lining, and comprises a biocompatible thermoplastic polymer and optionally a fiberizing agent, and The proximal and distal ends are coated with a drug-containing coating, the coating comprising a biodegradable polymer and Limus drug. The central part and lining of the structural scaffold are free of Limus drug. Regarding drug-eluting stents.

[0015] A second aspect of this disclosure is a method for manufacturing a drug-eluting stent, (a) Providing an expandable structural scaffold configured to resist radial compression when placed in the lumen of a patient, wherein the structural scaffold includes a central portion located between a proximal end and a distal end, (b) A step of covering only the central portion of the structural scaffold with a biocompatible thermoplastic polymer lining, wherein the ends do not contain the lining, and optionally the structural scaffold has a length of 40 mm to 100 mm, and the drug-coated proximal and distal ends independently have a length of 2 mm to 3 mm. (c) The method comprises the steps of (c) preparing a coating solution comprising a biodegradable polymer, a Limus drug, a solvent, and optionally a second activator, and applying the coating solution to the proximal and distal ends of a structural scaffold. [Brief explanation of the drawing]

[0016] [Figure 1A] This figure shows a drug-eluting stent 10 according to one embodiment of the present invention, which includes a lining 30 containing an inner lining layer 31 that covers the luminal surface of the central part of the structural scaffold 20. [Figure 1C] Figure 1A is a cross-sectional view of the drug-eluting stent 10 along line A-A'. [Figure 1B]FIG. showing a drug-eluting stent 10 according to another embodiment of the present invention, including a lining 30 including an outer lining layer 32 covering the anti-luminal side surface of the central portion of the structural scaffold 20. [Figure 1D] FIG. is a cross-sectional view taken along line B-B' of the drug-eluting stent 10 of FIG. 1B. [Figure 1E] FIG. is a cross-sectional view taken along line B-B' of a drug-eluting stent including a lining 30 including an inner lining layer 31 covering the luminal side surface of the central portion of the structural scaffold 20 and an outer lining layer 32 covering the anti-luminal side surface of the central portion of the structural scaffold 20. [Figure 2] FIG. shows a shrink tube disposed on a Solaris® stent before shrinkage. [Figure 3] FIG. shows a shrink tube adapted to a Solaris® stent. [Figure 4] FIG. shows a comparison of the minimum vessel diameters measured by IVUS after implantation of a Solaris DE® vascular stent and a Solaris® stent. [Figure 5] FIG. shows a comparison of the average stent areas measured by IVUS after implantation of a Solaris DE® vascular stent and a Solaris® stent. [Figure 6] FIG. shows a comparison of the average stent diameters measured by IVUS after implantation of a Solaris DE® vascular stent and a Solaris® stent. [Figure 7] FIG. shows a comparison of the hyperplasia volumes measured by IVUS after implantation of a Solaris DE® vascular stent and a Solaris® stent. [Figure 8] FIG. shows a comparison of the lumen volumes measured by IVUS after implantation of a Solaris DE® vascular stent and a Solaris® stent. [Figure 9]This figure shows a comparison of neointimal hyperplasia volume measured by IVUS after implantation of Solaris DE® vascular stents and Solaris® stents. [Figure 10] This figure compares the percentage of occlusion due to neointimal hyperplasia measured by IVUS after implantation of Solaris DE® vascular stents and Solaris® stents. [Modes for carrying out the invention]

[0017] All terms used herein are to be understood in the ordinary sense known in the art unless otherwise specified. Other, more specific definitions of any particular terms used herein are set forth below and are intended to apply uniformly throughout the specification and claims unless a more explicit definition is provided.

[0018] As used herein, the term “lumen” refers to the open space or cavity inside a blood vessel.

[0019] The terms “drug,” “therapeutic agent,” and “activator” are used interchangeably herein. A therapeutic agent may be used alone or in combination with other therapeutic agents.

[0020] As used herein, the expression “therapeutic dose” with respect to a therapeutic agent means an amount of the therapeutic agent sufficient to prevent, or to some extent alleviate, the onset of one or more symptoms of the disease or abnormal condition being treated, when administered to a human or veterinary patient. The specific dose of a compound administered in accordance with the present invention will, of course, be determined by the specific circumstances surrounding the case, including the compound being administered, the route of administration, the specific condition being treated, the specific circumstances of the individual subject being treated, and similar considerations.

[0021] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more." Unless otherwise indicated, definite articles such as "the" as used herein also include plural nouns.

[0022] The term "and / or" means that either one of the related options is possible, or at least two options can be done simultaneously.

[0023] Stents typically consist of a metal or polymer structural scaffold containing a pattern or network of interconnecting structural elements or struts. The structural scaffold may include a polymer cover and / or coating.

[0024] As used herein, the term “structural scaffold” refers to a scaffold or stent frame, such as a laser-cut stent frame, a polymer stent frame, or a wire scaffold. For example, a stent may consist of wires shaped to form a scaffold. The structural scaffold of a stent can be formed in various ways to provide a suitable intraluminal support structure having an outer surface (anti-luminal surface) for contact with the vessel wall during implantation and an inner surface (luminal surface) facing the lumen of the vessel.

[0025] As used herein, the term “proximal end” of a stent is defined as the end of the stent closest to the operator when the stent is placed within the deployment device being used by the operator. The term “distal end” of a stent is defined as the end opposite the proximal end along the longitudinal direction of the stent. As used herein, the proximal and distal marked ends of a stent before deployment remain the same whether the stent is deployed or not. The “longitudinal direction” of a stent is the direction along the axis of a substantially tubular stent.

[0026] As used herein, the terms “coated” or “lining” refer to tubular structures of a biocompatible thermoplastic polymer that coat the central surface of a structural scaffold. Specifically, “internal lining” coats the luminal surface of the central part of the structural scaffold, while “external lining” coats the non-luminal surface of the central part of the structural scaffold.

[0027] As described above, a first aspect of the present disclosure relates to a drug-eluting stent comprising an expandable structural scaffold and a lining located only in the central part of the structural scaffold and comprising a biocompatible thermoplastic polymer, wherein the proximal and distal ends are coated with a drug-containing coating comprising a biodegradable polymer and a Limus drug, and the central part of the structural scaffold and the lining are not comprising a Limus drug.

[0028] In certain embodiments, the lining does not contain drugs.

[0029] In certain embodiments, the structural scaffold (also known as a stent frame) may be fabricated from a material selected from cobalt-chromium alloys (such as MP35N, L605), nitinol alloys (nickel-titanium alloys in which the two elements are present at approximately equal atomic percentages, such as nitinol 55 and nitinol 60), magnesium alloys, and biodegradable synthetic polymers, such as poly-L-lactic acid (PLLA), polyglycolic acid (PGA), poly(lactide-co-glycolic acid) (PLGA), polylactide-co-caprolactone (PLC), and poly-ε-caprolactone (PCL), as well as hyaluronic acid.

[0030] The structural scaffolds included in this disclosure may have various diameters and lengths depending on the specific stent application.

[0031] In one embodiment, the structural scaffold has a diameter of 5mm to 10mm, such as 5, 6, 7, 8, 9, and 10mm, and a length of 40mm to 100mm, such as 40, 60, 80, or 100mm, before deployment.

[0032] In one example, the drug-eluting stents of this disclosure may be used in aortic applications. Therefore, in another embodiment, optionally combined with one or more features of the various embodiments described above, the structural scaffold has a diameter of 16–45 mm and a length of 60–200 mm. Other product lines as aortic graft stents have expanded sizes.

[0033] As described above, the structural scaffold of a drug-eluting stent includes a luminal surface and an anti-luminal surface. The lining may be positioned to cover the luminal surface of the central part of the structural scaffold, the anti-luminal surface of the central part of the structural scaffold, or both.

[0034] Therefore, in another embodiment, optionally combined with one or more features of the various embodiments described above, the lining includes an inner lining layer covering the luminal surface of the central portion of the structural scaffold. This allows for the formation of an endothelial layer on the inner surface of the stent, which may be desirable for healing, biocompatibility, prevention of thrombosis, or reduction of blood turbulence within the stent.

[0035] In another embodiment, optionally combined with one or more features of the various embodiments described above, the lining includes an outer lining layer covering the anti-luminal surface of the central portion of the structural scaffold. This can, for example, allow for healing and integration of the stent into the body lumen by the growth of surrounding lumen tissue on the outer lining.

[0036] In another embodiment, optionally combined with one or more features of the various embodiments described above, the lining includes an inner lining layer covering the luminal-side surface of the central portion of the structural scaffold and an outer lining layer covering the non-luminal-side surface of the central portion of the structural scaffold.

[0037] In another embodiment, optionally combined with one or more features of the various embodiments described above, the lining includes an inner lining layer covering the intermediate portion of the luminal-side surface of the structural scaffold and an outer lining layer covering the intermediate portion of the non-luminal-side surface of the structural scaffold.

[0038] In another embodiment, the biocompatible thermoplastic polymer is selected from the group consisting of polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyurethane, and mixtures thereof, optionally combined with one or more features of the various embodiments described above. In a particular embodiment, the biocompatible thermoplastic polymer is PTFE, which, due to its high tissue compatibility, provided a good matrix for the neoinfiltration coating of the stent surface.

[0039] In certain embodiments, the biocompatible thermoplastic polymer is electrospun PTFE or stretched polytetrafluoroethylene (ePTFE), optionally combined with one or more features of the various embodiments described above.

[0040] In another embodiment, the lining further comprises a fibrous agent, optionally in combination with one or more features of the various embodiments described above. Examples of fibrous agents are disclosed, for example, in International Publication No. 2010083530. In certain embodiments, the fibrous agent is polyethylene oxide (PEO). In more specific embodiments, the lining comprises PTFE and PEO.

[0041] In another embodiment, the biocompatible thermoplastic polymer cover has a thickness of 10 to 200 μm, particularly 30 to 100 μm, optionally combined with one or more features of the various embodiments described above.

[0042] As described above, the drug-containing coating comprises a biodegradable polymer and the Limus drug.

[0043] In one embodiment, the biodegradable polymer is a poly-α-hydroxy acid, optionally combined with one or more features of the various embodiments described above, and optionally selected from the group consisting of poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), polylactic acid (PLA, poly-L,D-lactic acid of all chiral ratios), polyglycolic acid (PGA), poly(lactide-co-glycolic acid) (PLGA, of all chiralities and ratios of the lactic acid and glycolic acid groups forming them), and combinations thereof. In a particular embodiment, the biodegradable polymer is PLA, in particular PLA having a molecular weight (Mw) of 85,000 to 160,000 Da and a viscosity of 0.5 to 1.5 dl / g. In another embodiment, the biodegradable polymer is PLGA(50:50), particularly PLGA(50:50) having a Mw of 30,000 to 60,000 Da and a viscosity of 0.3 to 1.0 dl / g.

[0044] In certain embodiments, the biodegradable polymer is a mixture of PLA and PLGA. In more specific embodiments, the weight ratio of PLA to PLGA (PLA:PLGA) is 3:1 to 7:1, particularly 3:1 to 4:1.

[0045] In one embodiment, the drug-containing coating is placed on the luminal surface, the anti-luminal surface, or both of the proximal and distal ends, in combination with one or more features of the various embodiments described above.

[0046] In one embodiment, the Limus drug is selected from the group consisting of sirolimus (rapamycin), pimecrolimus, tacrolimus, everolimus, zotalolimus, novolimus, myolimus, temsirolimus, defololimus, biolimus, or a combination thereof, optionally combined with one or more features of the various embodiments described above.

[0047] In certain embodiments, the Limus drug is sirolimus, optionally combined with one or more features of the various embodiments described above.

[0048] Limus drugs should be incorporated into the device in a therapeutically effective dose; that is, the amount of Limus drug present in the coating should be effective in inhibiting restenosis, particularly stent-end stenosis, when the stent is deployed and the drug is delivered to the wall of the vessel being treated by the stent. As will be understood by those skilled in the art, the therapeutically effective level of drug varies depending on the specific drug being used, the implantation site, the condition being treated, the composition of the drug-containing coating, and other potential factors. Those skilled in the art will know what amount of Limus drug is therapeutically effective in any given situation.

[0049] In one embodiment, Limus drug is 1-10 μg / mm³, optionally combined with one or more features of the various embodiments described above. 2 The coated surface, especially 2-5 μg / mm² 2 It has a concentration on the coated surface.

[0050] In another embodiment, optionally combined with one or more features of the various embodiments described above, the weight ratio of the biodegradable polymer to the Limus drug is 1.7:1 to 3.5:1, particularly 1:7 to 2:1.

[0051] In another embodiment, the drug-containing coating has a thickness of 20 μm, optionally combined with one or more features of the various embodiments described above.

[0052] In another embodiment, the drug coating may optionally be combined with one or more features of the various embodiments described above, further comprising a second activator, which is optionally an anticoagulant.

[0053] In another embodiment, the anticoagulant is heparin or low molecular weight heparin (LMWH), optionally combined with one or more features of the various embodiments described above.

[0054] LMWH is a heparin salt having an average molecular weight of less than 8000 Da, with at least 60% of all chains having a molecular weight of less than 8000 Da. LMWH can be obtained by various fractionation or depolymerization methods of polymer heparin known in the art.

[0055] As described above, the drug-containing coating is applied only to the proximal and distal ends of the structural scaffold that are not covered with a biocompatible thermoplastic polymer lining. Therefore, after deployment, the drug is released from the scaffold struts coated with the drug-containing coating according to a drug release curve, and the biodegradable polymer contained in the drug-containing coating functions as a drug container. As described above, those skilled in the art will know how to obtain a drug-containing coating to provide the desired controlled release of a Limus drug, depending on the situation.

[0056] The lengths of the drug-coated proximal and distal ends should be sufficient to allow the drug-containing coating to deliver the amount of drug necessary to provide the desired effect of minimizing or even avoiding stent end stenosis. As an example, the lining can cover 92.5% to 95.0% of the structural scaffold, either along the luminal surface, the anti-luminal surface, or both longitudinally. Thus, the total length of the stent ends not covered by the lining is 5.0% to 7.5% of the structural scaffold.

[0057] In one embodiment, optionally combined with one or more features of the various embodiments described above, the drug-coated proximal and distal ends independently have a length of 0.5 to 30 mm, particularly 5 mm to 30 mm.

[0058] In certain embodiments, optionally combined with one or more features of the various embodiments described above, the drug-coated proximal end, drug-coated distal end, or both, have a length of 0.5 to 3 mm, for example, 2 mm, in an arteriovenous fistula (AVF), etc.

[0059] In another embodiment, optionally combined with one or more features of the various embodiments described above, the drug-coated proximal end, drug-coated distal end, or both, have a length of 10 mm to 30 mm, for example, 15 mm, in an aortic stent or the like.

[0060] Also disclosed herein is a method for producing a drug-eluting stent as defined herein, comprising: (a) providing an expandable structural scaffold as defined above; (b) coating only the central portion of the structural scaffold with a biocompatible thermoplastic polymer lining so that the proximal and distal ends are not lining; and (c) coating the proximal and distal ends with a coating solution comprising a biodegradable polymer, a Limus drug, a solvent, and optionally a second activator as defined above.

[0061] When discussing methods for manufacturing drug-eluting stents in this disclosure, it should be noted that each of the embodiments or features defined for drug-eluting stents may be considered applicable to methods of manufacture, where appropriate, whether or not they are explicitly discussed in the context of other embodiments. Therefore, when defining options such as biocompatible thermoplastic polymers, biodegradable polymers, Limus drugs, second activators, or structural features of drug-eluting stents (e.g., arrangement of covers or coatings on the luminal or anti-luminal surfaces of the central or end portion, drug concentration, length and diameter or structural scaffold, length of drug-coated end, etc.), such options also refer to methods for manufacturing drug-eluting stents, where applicable.

[0062] One example of a method for coating the central portion of a structural scaffold with a biocompatible thermoplastic polymer lining is electrospinning. Electrospinning is a method for producing ultrathin synthetic fibers on a charged surface. The use of electrospinning for stent coating allows for obtaining a durable, homogeneous coating while controlling the thickness, density, porosity, and other properties of the thus formed cover. When a stent is coated by electrospinning, the pores in the formed cover allow for the growth of endothelial cells, reducing negative flow properties, thrombosis formation on the luminal surface of the stent, or the likelihood of inflammatory responses in tissues in contact with the anti-luminal surface of the stent.

[0063] Therefore, in certain embodiments, the coating in step (b) is carried out by electrospinning, optionally in combination with one or more features of the various embodiments described above.

[0064] In one embodiment of the method of the present disclosure, in optionally combined with one or more features of the various embodiments described above, step (b) is carried out by electrospinning, wherein the biocompatible thermoplastic polymer is PTFE, i.e., electrospinned PTFE. Electrospinned PTFE consists of tubes, mats, or other shapes of PTFE formed from randomly deposited strings of PTFE. Electrospinning can be carried out by depositing the polymer onto the surface of a stent in the presence of an electrostatic field. Electrospinning of PTFE is described, for example, in International Publication No. 2010083530 and U.S. Patent Application Publication No. 2016296351.

[0065] A drug-containing coating on the proximal and / or distal end surfaces not covered by a biocompatible thermoplastic polymer lining can be applied by any suitable method. For example, the coating may be formed by preparing a coating solution containing a biodegradable polymer, a Limus drug, a solvent, and optionally additional activators, and applying the coating solution by dipping or spraying.

[0066] In certain embodiments of the method disclosed herein, the coating of the stent ends may be carried out by spray coating a solution comprising Limus drug, a polymer carrier, and optionally a stabilizer such as ethanol in a suitable solvent, optionally in combination with one or more features of the various embodiments described above. The spray coating may be carried out using a conventional spray coating machine. The solution may be prepared and applied as disclosed in detail in the following embodiments.

[0067] In one embodiment of the method of the present disclosure, the solvent is selected from water, organic solvents, and mixtures thereof, optionally in combination with one or more features of the various embodiments described above. In another embodiment, the organic solvent is a polar organic solvent. In yet another embodiment, the organic solvent is selected from the group consisting of ethanol, methanol, hexane, heptane, dichloromethane, chloroform, toluene, benzyl alcohol, and mixtures thereof. In a particular embodiment, the solvent is chloroform. In another embodiment, the solvent is ethanol. In yet another particular embodiment, the solvent is a mixture of chloroform and ethanol. In yet yet another particular embodiment, the solvent is a mixture of water and ethanol.

[0068] To avoid coating the lining covering the middle portion of the structural scaffold, especially when the coating is done by spray coating, the lining covering the structural scaffold may be protected in advance with a cover that will be removed once coating step (c) is complete, before performing the coating in step (c). An example of such a cover is heat shrink tubing.

[0069] For example, a cover protecting the lining before coating the proximal and distal ends may be made from a thermoplastic polymer selected from polyolefins such as polyethylene, including high-density polyethylene (HDPE) and low-density polyethylene (LDPE), fluorinated ethylene propylene, and Pebax® elastomer (a thermoplastic block copolymer composed of rigid polyamide blocks and flexible polyether blocks).

[0070] Referring to Figure 1A, one embodiment of a drug-eluting stent 10 according to one embodiment of the present invention is shown. Figure 1C shows a cross-sectional view of the drug-eluting stent 10 of Figure 1A along line A-A'. The stent 10 includes an expandable structural scaffold 20 including a central portion 21 positioned between a proximal end 22 and a distal end 23. The structural scaffold 20 includes a luminal-side surface 24 and an anti-luminal-side surface 25. The luminal-side surface 24 defines the inner surface of the structural scaffold, and the anti-luminal-side surface 25 defines the outer surface of the structural scaffold 20. A lining 30 containing a biocompatible thermoplastic polymer is arranged to cover only the central portion 21 so that the ends 22 and 23 do not have access to the lining 30. The lining 30 in these figures includes an inner lining layer 31 covering the luminal-side surface of the central portion of the structural scaffold 20. Therefore, the central portion 21 of the structural scaffold 20 covers the inner lining layer 31. The proximal end 22 and distal end 23 are coated with a drug-containing coating 40 containing a biodegradable polymer and Limus drug. The central portion 21 and lining 30 of the structural scaffold 20 do not contain Limus drug. The drug-containing coating 40 may be placed on the luminal surface, the anti-luminal surface, or both of the proximal and distal ends.

[0071] In another example, the lining 30 includes an outer lining layer 32 covering the anti-luminal surface of the central portion of the structural scaffold 20, as shown in Figure 1B. A cross-sectional view of the drug-eluting stent along line B-B' is shown in Figure 1D. As shown in Figures 1A and 1C, the proximal end 22 and distal end 23 in Figures 1B and 1D are not covered by the lining 30.

[0072] Figure 2E shows another example of a cross-sectional view of the central portion 21 of the structural scaffold 20. In this example, the lining includes an inner lining layer 31 covering the lumen-side surface of the central portion of the structural scaffold 20 and an outer lining layer 32 covering the non-lumen-side surface of the central portion of the structural scaffold 20.

[0073] Stents can be deployed in various body lumens for various purposes, for example, in central venous systems for various therapeutic purposes, including the treatment of occlusions within the lumen of the system. It will be understood that this disclosure may be applicable to stents designed for peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), arteriovenous fistula, etc.

[0074] The stents of this disclosure may be used to treat disorders in blood vessels, in particular to dilate narrowed vessels, more specifically to treat or prevent stenosis or restenosis in blood vessels, and even more specifically to prevent stent edge stenosis. In one embodiment, the stents of this disclosure may be used to treat arteriovenous fistulas, occlusive diseases, aneurysms, and vascular dissections.

[0075] Throughout the specification and claims, the word “contains” and its variations are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word “contains” includes the case of “consisting of.”

[0076] The following embodiments and drawings are provided for illustrative purposes only and are not intended to limit the invention. In relation to the drawings, the reference numerals placed in parentheses within the claims are merely for the purpose of enhancing clarity of the claims and should not be construed as limiting the claims. Furthermore, the invention encompasses all possible combinations of the specific embodiments and preferred embodiments described herein. [Examples]

[0077] Example 1 - Method for obtaining a Solaris drug-eluting (Solaris DE) stent Preparation of coating solution Solaris® is a flexible, self-expanding stent consisting of a thin, multi-directional, durable electrospun PTFE membrane that encapsulates a nitinol stent structure. The stent is laser-cut from a nickel-titanium alloy (nitinol) metal tube to form a metal scaffold, which is then coated with a polytetrafluoroethylene (PTFE) layer. At the ends of the stent's structural scaffold, there are radiopaque tantalum markers to demarcate the stent limits under fluoroscopy. The delivery system is a "pull back" type, an OTW (Over the Wire) consisting of a concentric tube that moves to allow the outer tube to be retracted during stent implantation.

[0078] Solaris® stents with diameters of 5, 6, 7, 8, 9, and 10 mm, lengths of 40–100 mm, and 2–3 mm of uncovered ends were used as starting materials for the preparation of Solaris DE stents.

[0079] To obtain a Solaris DE stent, a sirolimus coating was applied to the proximal and distal ends of a stent that was not coated with PTFE, as described below. The coating formulation contained sirolimus as the active ingredient, along with a biodegradable polymer matrix of PLA and PLGA.

[0080] Drug coating solutions containing PLA, PLGA, and rapamycin in chloroform were prepared according to the amounts shown in Table 1 below.

[0081] [Table 1]

[0082] Before coating, the stent was cleaned with isopropyl alcohol.

[0083] To prevent the drug-containing coating from covering the PTFE cover, a 20mm ± 5mm heat-shrinkable HDPE tube with a certain length was used as a protector. Notches were made on the sides of each tube to facilitate the insertion of the stent into the inside.

[0084] The heat-shrink tubing was placed at the end of the stent, resulting in the tubing overlapping with the PTFE coating and the cuts facing the center of the stent (Figure 2).

[0085] A stent assembly with heat-shrink tubing was placed in front of a hot air blower set to a temperature of 130°C ± 10°C, and the assembly was rotated while the heat flowing through it was at its minimum to promote conformation (Figure 3).

[0086] The conformation was fabricated to allow minimal movement of the heat-shrink tubing as needed, protecting the PTFE cover while keeping the structural scaffold ends free.

[0087] Drug coating of stent ends The ends of the stent were coated using spray coating (Coating Machine 1.0-Scitech Medical).

[0088] The process was carried out at a relative humidity of 60%–65% and a temperature of 25°C–30°C. The airbrush flow was calibrated to 0.5 ml in 35 seconds ± 2 seconds.

[0089] The stent was fixed to a mandrel to cover all ends. For each end or stent, the volume of coating solution shown in Table 2 was introduced into an airbrush container.

[0090] [Table 2]

[0091] This process was repeated for all ends of the stent by coating one end and then repositioning the stent so that the uncoated end was in front of the airbrush. In this way, the ends of the stent were coated with a whitish, uniform coating. Then, about 10 minutes after the coating process was complete, the heat shrink tubing was removed by tearing it at the cut end.

[0092] Stents with diameters of 5 mm, 6 mm, and 7 mm were packed into cryogenic tubes, and stents with diameters of 8 mm and 9 mm were packed into amber-colored glass tubes.

[0093] The obtained Solaris DE was stored in a Tyvek container, and then in a desiccator protected from light and moisture. A vacuum of at least 300 mmHg was also applied.

[0094] Example 2 and Comparative Example 1. Preclinical trials of Solaris DE vascular stent grafts. This study aimed to evaluate the mechanical and biological performance of the present invention's Solaris DE in vivo prosthesis in the peripheral arterial vascular system of a porcine model compared to Solaris® (a sirolimus-free PTFE-coated stent commercially available from Scitech Medical SA). Vascular responses were determined in vivo by intravascular imaging and associated histopathological evaluations.

[0095] The following specific objectives were considered: Safety evaluation of Solaris DE vascular stent grafts implanted in peripheral arteries in a pig model. A comparison of lumen diameter loss between two types of implanted stents: Solaris stents (drug-free) and Solaris DE stents (drug-based). Angiographic patency and a comparison of stenosis diameter percentage between Solaris DE and its sirolimus-free version (Solaris®), Comparison of the mean percentage of stenosis area between neointima formation and intravascular imaging (IVUS) tests and controls. The degree of thrombosis formation.

[0096] material [Table 3]

[0097] The animals included in the study had similar weight and age. The pigs were acclimated to the facility 7 days before the start of the study. Follow-up surveys were conducted at 30 and 90 days after implantation (n=6 / time). A total of 12 animals were used in the study.

[0098] sampling The stent characteristics of the test (example) and control (comparative example) are described in Tables 3 and 4, respectively. [Table 4]

[0099] [Table 5]

[0100] Pass / Fail Criteria This study evaluated Solaris DE end grafts against several endpoints and compared them to Solaris vascular stent graft products.

[0101] The primary endpoints are lumen area and stenosis percentage. Both parameters are inversely proportional.

[0102] Furthermore, the following parameters of the stent artery were also evaluated: Cell growth and cell type, Inflammation (severity and cell type), Formation of seroma / space between the graft and the outer membrane, Evaluation of the outer membrane (necrosis, fibrosis, inflammation, etc.).

[0103] Both Solaris DE end grafts and Solaris vascular stent grafts were identified as being comparable to competing products in terms of the primary endpoint.

[0104] As shown below, the results demonstrated that Solaris DE was more efficient than Solaris® in preventing treated vascular restenosis.

[0105] Test data The pigs included in the experiment had similar weights (40-43 kg) and ages. The pigs were acclimatized to the facility three days before the start of the experiment.

[0106] The animals were subjected to 12 hours of fasting and 6 hours of water deprivation, and anesthetized according to standard procedures before stent implantation.

[0107] To initiate implantation, an 8F or 9F sheath (depending on the diameter of the stent delivery system) was inserted into the femoral artery. Prior to the selective catheterization procedure for stent implantation, 100–200 IU / kg of heparin was administered intravenously.

[0108] First, angiography of the aorta and iliac arteries was performed using an appropriately sized multipurpose catheter placed in the distal aorta topography just below the renal artery. Next, under fluoroscopic guidance and with the help of a guidewire, one stent (as shown in Table 4) was placed in each of the left and right common iliac arteries, considering a maximum average diameter of 0.5 mm to 1 mm relative to the artery. The catheter was removed, and post-implantation images were obtained. Finally, the catheter and guidewire were removed, and hemostasis was achieved by suturing the access site. The animals remained in the supine position throughout the entire procedure. The implantation matrices used are shown in Table 5. [Table 6]

[0109] Each animal received a Solaris DE® vascular stent and a Solaris® stent in its respective iliac artery. Angiography was performed four times: before stent implantation, after stent implantation, 28 days later for all animals, and 60 days later (for a subgroup of four animals).

[0110] Angiography was performed immediately after stent implantation to assess the correct position of the stent. After angiographic imaging, animals evaluated 60 days later were also subjected to IVUS evaluation of the stent segments to determine the occurrence of neointimal formation. The acquired images were analyzed using appropriate measurement software to provide measurements of lumen area, stent area, neointimal hyperplasia area, and neointimal hyperplasia percentage.

[0111] Vascular access sites were observed and evaluated for signs of infection or inflammation once daily for at least 7 days.

[0112] After delivery of the test items and control devices, the delivery systems were evaluated for thrombosis. Thrombotic levels were graded using the FDA-approved thrombosis scale: 0 = no significant thrombosis, 1 = minimal thrombosis at a single site, 2 = minimal thrombosis at multiple sites, 3 = significant thrombosis in half of the inserted catheter segment, 4 = significant thrombosis >50%, 5 = 100% of the catheter circumference and length covered with thrombosis. Both items were evaluated as 0 = no significant thrombosis.

[0113] Qualitative vascular analysis was performed four times: before stent implantation, after stent implantation, at 28 days in all animals, and at 60 days (a subgroup of four animals). Technical success was defined as adequate stent implantation, i.e., stent placement in the artery, and a recoil of less than 30% after stent implantation was achieved in 100% of cases. No changes in stent integrity (i.e., stent deformation) or migration were observed at the implantation day or at the 28-day and 60-day follow-up. No fractures were observed either. Visual analysis could not identify any performance difference between the test device and the control device.

[0114] IVUS analysis was performed on three animals 60 days after implantation, and the results are shown in Tables 6 to 8 (see Figures 4 to 10). [Table 7] [Table 8] [Table 9]

[0115] The tested SOLARIS DE product met all expectations of efficiency in this preclinical trial without raising any safety concerns. The results showed that the test group demonstrated a sufficient safety profile in the preclinical mode, and that the stent of the present invention (Solaris DE stent) tended to have less hyperplasia than the control stent (Solaris non-drug-eluting stent).

[0116] Comparative Examples 2-4 Inspiron® DES (marketed by Scitech Medical SA) is a stent fabricated from a platform material consisting of CoCr and thin struts (75 μm), as well as an anti-luminal coating composed of a mixture of PLA and PLGA polymers and a low dose of sirolimus.

[0117] Thrombosis with sirolimus-polymer was compared to an uncoated control and polymer-coated stents without any drugs. Thrombosis was assessed clinically (sudden death of animals after necropsy indicated stent thromboembolism) and by angiographic or histological analysis. The presence of medial necrosis with aneurysm formation in polymer-coated stents using sirolimus, compared to an uncoated control and polymer-coated stents without drugs, was determined by histology or angiography (aneurysm defined as dilation of 150% of the reference vessel diameter). The occurrence of worsened neointimal formation in polymer-coated stents using sirolimus, compared to an uncoated control and polymer-coated stents without drugs, was assessed by histology (neointimal area by histomorphometry) or angiography (late lumen loss). The primary efficacy endpoint was reduced neointimal proliferation in polymer-coated stents using sirolimus compared to the control without drugs.

[0118] method Fourteen large white young pigs (22-30 kg) were pre-treated with 75 mg of clopidogrel and 100 mg of aspirin at least one day prior to the procedure, and maintained for 28 days and until the end of the experiment, respectively. Intramuscular antibiotics were administered as a prophylactic measure. The animals were anesthetized with bromazepam pre-treatment and thiopental (12 mg / kg), followed by endotracheal intubation and inhalation anesthesia with isoflurane. Intravenous heparin (10,000 IU) was administered prior to coronary artery manipulation.

[0119] The animals underwent implantation of three different types of coronary artery stents. Comparative Example 2: Bare Metal Stent (BMS) - Stent brand Cronus (registered trademark) - Cobalt-chromium stent Scitech. - No coating. Comparative Example 3: Stent coated with polymer only, Comparative Example 4: Stent coated with polymer and sirolimus - Inspiron® DES, i.e., 1.4 μg / mm³ 2Cronus® stents coated with sirolimus in a polymer carrier at a concentration of [concentration], polymer carrier: a biodegradable polymer blend of PLLA and PLGA.

[0120] Each animal received three stents implanted in the right coronary artery, left anterior descending artery, and circumflex artery. The animals were followed for one month. After one month, all animals were subjected to repeated coronary angiography and immediately sacrificed. Specimens were fixed by perfusion with 10% formalin and analyzed by light microscopy.

[0121] Basic angiography and control angiography were quantitatively analyzed to evaluate the presence of stent migration, negative intraluminal findings, or involvement of side branches.

[0122] Quantitative angiographic analysis was performed using the CASS II system (Pie Medical, Maastricht, Netherlands). The intrastent segment, as well as the stent 5 mm proximal and distal portions, were analyzed. The following parameters were measured in baseline and control angiographic images for each segment (intrastent, proximal edge, and distal edge): minimum lumen diameter (MLD), reference diameter (RD), and stenotic diameter (ELD). Based on these measurements, late angiographic loss, defined as the control DLM-DLM basis, was calculated. Aneurysm dilation was defined as a diameter increase to 150% of the reference diameter in the treated area.

[0123] Immediately after euthanasia, the heart was explanted and perfused through the aortic root with 10% formalin under pressure (approximately 80 mmHg) for 30 minutes. The incised arterial segments and adjacent tissues formed the epicardial surface and were dried in a progressive ethanol solution for inclusion in the plastic resin. The stent was cut into 5 mm segments. For each segment, sections of 1–10 microns thick were obtained and stained with hematoxylin-eosin, Wang Gieson dye, and Masson's trichrome for histological analysis.

[0124] All sections were measured with the help of software-based tissue morphometric analysis. Sections of larger stenoses were considered for final data aggregation ("worst-case view approach"). Cross-sectional area measured the internal elastic lamina (LEI) and vascular lumen. Neointimal area was calculated as 100 × (LAW - light area) / LAW. Neointimal thickness was measured perpendicular to light from each stent strut.

[0125] The severity of vascular damage caused by stent implantation was measured according to the following criteria. [Table 10]

[0126] The animals gained weight over a period of four weeks. Neointimal reduction as measured by angiography and intravascular ultrasound is shown in Table 9. The results indicate that the animals with restenosis were those in Comparative Example 2 (BMS) and Comparative Example 3 (coated with polymer only). [Table 11]

[0127] General data for test animals are shown in Table 10 below. [Table 12] JPEG2026521878000013.jpg209159

[0128] Mortality rates were low, and restenosis was infrequent. Outcomes from patients in the bare-metal stent (BMS) group were consistent with those expected for metal stents. The drug-free group demonstrated that coating with biodegradable polymers did not induce an inflammatory response. Coating with biodegradable polymers and sirolimus was most effective in reducing neointimal hyperplasia.

[0129] Therefore, the Solaris DE stent combines the advantages of the Solaris stent with the advantages of a drug-eluting stent (Inspiron®) that contains a smaller amount of drug applied only to the ends of the stent. Clinical significance was observed in imaging studies, where the volume of neointima-hyperplasia at 60 days of use was smaller and the lumen volume of the Solaris DE was larger compared to the control Solaris® (Table 8).

Claims

1. A drug-eluting stent (10), An expandable structural scaffold (20) configured to resist radial compression when placed in the lumen of a patient, the expandable structural scaffold (20) includes a central portion (21) located between a proximal end (22) and a distal end (23), The central portion is covered by the lining, and the ends are not covered by the lining, and the lining (30) is disposed only in the central portion, comprising a biocompatible thermoplastic polymer and optionally a fiberizing agent, The proximal end and the distal end are coated with a drug-containing coating (40), the coating comprising a biodegradable polymer and Limus drug, and The central portion and lining of the structural scaffold are free from the Limus drug. Drug-eluting stent (10).

2. The drug-eluting stent according to claim 1, wherein the lining does not contain a drug.

3. A drug-eluting stent according to claim 1 or 2, wherein the structural scaffold (20) includes a luminal surface (24) and an anti-luminal surface (25), and the lining (30) includes an inner lining layer (31) covering the luminal surface of the central portion of the structural scaffold and / or an outer lining layer (32) covering the anti-luminal surface of the central portion of the structural scaffold.

4. The drug-eluting stent according to any one of claims 1 to 3, wherein the biocompatible thermoplastic polymer is selected from the group consisting of polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyurethane, and mixtures thereof.

5. The drug-eluting stent according to claim 4, wherein the biocompatible thermoplastic polymer is electrospun PTFE or stretched polytetrafluoroethylene (ePTFE).

6. The drug-eluting stent according to any one of claims 1 to 5, wherein the biodegradable polymer is a poly-α-hydroxy acid, and optionally the poly-α-hydroxy acid is selected from the group consisting of poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), polylactic acid, polyglycolic acid (PGA), poly(lactide-co-glycolic acid) (PLGA), and mixtures thereof.

7. The drug-eluting stent according to any one of claims 1 to 6, wherein the drug-containing coating (40) is disposed on the luminal surface, the non-luminal surface, or both of the proximal end (22) and the distal end (23).

8. A drug-eluting stent according to any one of claims 1 to 7, wherein the Limus drug is selected from the group consisting of sirolimus (rapamycin), pimecrolimus, tacrolimus, everolimus, zotarolimus, novolimus, myolimus, temsirolimus, defololimus, biolimus, or a combination thereof.

9. The Limus drug is 1 to 10 μg / mm³ ２ Coated surfaces, especially 2-5 μg / mm² ２ A drug-eluting stent according to any one of claims 1 to 8, having a concentration on the coated surface.

10. The stent according to any one of claims 1 to 9, wherein the biodegradable polymer and the Limus drug are in a weight ratio of 1.7:1 to 3.5:1, and optionally the drug-containing coating has a thickness of 20 μm.

11. The drug-eluting stent according to any one of claims 1 to 10, wherein the drug-containing coating (40) further comprises a second activator, and optionally the second activator is an anticoagulant.

12. The drug-eluting stent according to claim 11, wherein the second activator is heparin or low molecular weight heparin (LMWH).

13. A drug-eluting stent according to any one of claims 1 to 12, wherein the structural scaffold (20) has a length of 40 to 100 mm, and the drug-coated proximal end (22) and distal end (23) independently have a length of 0.5 to 30 mm.

14. A method for manufacturing a drug-eluting stent (10), (a) Providing an expandable structural scaffold (20) configured to resist radial compression when placed in the lumen of a patient, wherein the structural scaffold includes a central portion (21) located between a proximal end (22) and a distal end (23), (b) A step of covering only the central portion of the structural scaffold with a biocompatible thermoplastic polymer lining (30) such that the ends do not include the lining, wherein the structural scaffold has a length of 40 to 100 mm, and the drug-coated proximal and distal ends independently have a length of 0.5 to 30 mm. (c) A method comprising the steps of preparing a coating solution comprising a biodegradable polymer, a Limus drug, a solvent, and optionally a second activator, and applying the coating solution to the proximal and distal ends of the structural scaffold.

15. The method according to claim 14, wherein step (b) is carried out by electrospinning and the biocompatible thermoplastic polymer is PTFE.

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