Stent

Abstract

Provided is a stent capable of sustained release of a limus-based drug over a long period of time. A stent 1 comprises a cylindrical stent body 13 capable of expanding and contracting in the radial direction, and a drug coating layer 12 formed on at least a part of the surface of the stent body 13, wherein the drug coating layer 12 contains a limus-based drug, a biodegradable polymer, and one or more fat-soluble compounds selected from the group consisting of tocopherol and astaxanthin, the content mass ratio of the limus-based drug to the biodegradable polymer in the drug coating layer 12 (the content mass of the limus-based drug / the content mass of the biodegradable polymer) is 30 / 70 to 70 / 30, and the fat-soluble compound is contained in an amount of 0.001-30 mol% in the drug coating layer 12 with respect to 100 mol% of the limus-based drug.

Description

Stent

[0001] The present invention relates to a drug-eluting stent.

[0002] A stent is a medical device for treating various diseases caused by stenosis or occlusion of a biological lumen such as a blood vessel. More specifically, after a stent is delivered to a lesion site in a biological lumen by a stent delivery system, it is expanded (dilatated) to apply tensile force (expansion force) to the lesion site. By maintaining this tensile force over a predetermined period of time, the lesion site is kept pushed open, and the lumen of the biological lumen is secured.

[0003] However, it is known that after a certain period of time has elapsed, restenosis of the biological lumen may occur at and around the lesion site where the stent is placed. There are various causes of restenosis, one of which is the migration and proliferation of vascular smooth muscle cells in the vascular wall.

[0004] Therefore, in recent years, drug-eluting stents (DES: Drug Eluting Stent) have been developed, which prevent restenosis by coating the outer surface of the stent with a drug that has the effect of preventing restenosis by inhibiting the migration and proliferation of vascular smooth muscle cells, and eluting the drug at the stent placement site to prevent restenosis. For example, International Publication No. 2015 / 138862 describes an invention relating to a stent provided with a coating layer containing paclitaxel as a drug having the above-mentioned efficacy.

[0005] On the other hand, limus-based drugs are known as drugs that have higher safety compared to paclitaxel and are effective in preventing restenosis, and are also used in drug-eluting stents. However, conventional drug-eluting stents containing limus-based drugs have a problem that the limus-based drug is sustained-released in a short period of time. Since restenosis often occurs after a certain period of time following stent placement, drug-eluting stents are required to maintain the efficacy of preventing restenosis for a long period of time.

[0006] This invention has been made in view of the above circumstances, and aims to provide a stent that enables long-term sustained release of a limousine-based drug, which has high safety for living organisms.

[0007] The inventors of the present invention conducted diligent research to solve the above problems. As a result, they discovered that the above objectives can be achieved by a stent having a drug coating layer containing a limus-based drug, a biodegradable polymer, and a predetermined lipid-soluble compound in predetermined proportions, and thus completed the present invention.

[0008] The above objective can be achieved by the present invention having the following configuration, and the present invention encompasses the following aspects and forms.

[0009] One aspect of the present invention is a stent comprising: 1. A cylindrical stent body that can expand and contract radially; and a drug coating layer formed on at least a portion of the surface of the stent body, wherein the drug coating layer comprises a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, the mass ratio of the limus-based drug and the biodegradable polymer in the drug coating layer (mass content of the limus-based drug / mass content of the biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound in the drug coating layer is contained in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

[0010] 2. In the stent described in 1. above, it is preferable that the sustained release rate of the limus-based drug from the drug coating layer is 65% to 100% after 360 days from the start of release of the limus-based drug; 3. In the stent described in 1. or 2. above, it is preferable that the sustained release rate of the limus-based drug from the drug coating layer is 55% to 95% after 180 days from the start of release of the limus-based drug; 4. In the stent described in any of 1. to 3. above, it is preferable that the drug coating layer contains α-tocopherol; 5. In the stent described in any of 1. to 4. above, it is preferable that the monomer constituting the biodegradable polymer is one or more selected from the group consisting of lactic acid, glycolic acid, and caprolactone; 6. In the stent described in any of 1. to 5. above, it is preferable that the thickness of the drug coating layer is less than or equal to the thickness of the stent body skeleton; 7. In the stent described in any of the above, it is preferable that the limus-based drug is one or more selected from the group consisting of sirolimus, everolimus, temsirolimus, novolimus, biolimus, and zotalolimus; 8. In the stent described in any of the above 1 to 7, it is preferable that the mass ratio of the limus-based drug to the biodegradable polymer (mass of the limus-based drug / mass of the biodegradable polymer) is 45 / 55 to 60 / 40; 9. In the stent described in any of the above 1 to 8, it is preferable that the lipid-soluble compound is contained in the drug coating layer in an amount of 0.005 mol% to 25 mol% relative to 100 mol% of the limus-based drug.

[0011] Furthermore, one embodiment of the present invention is a stent delivery system comprising a stent described in any of items 1 to 9 above.

[0012] Figure 1A is a schematic diagram showing an example of the shape of a stent. Figure 1B is an enlarged cross-sectional view of a stent according to one embodiment, cut along the line A-A in Figure 1A. Figure 1C is an enlarged cross-sectional view of a stent according to one embodiment, cut along the line A-A in Figure 1A. Figure 1D is an enlarged cross-sectional view of a stent according to one embodiment, cut along the line A-A in Figure 1A. This is an overall configuration diagram showing a stent delivery system equipped with a stent according to an embodiment. This is a diagram showing the results of Test Example 1 and Test Example 2. This is a diagram showing the results of Test Examples 3 to 5. This is a diagram showing the results of Test Examples 6 to 12. This is a diagram showing the results of Test Examples 13 to 37.

[0013] A stent according to one aspect of the present invention is a stent having a cylindrical stent body that can expand and contract radially, and a drug coating layer formed on at least a part of the surface of the stent body. The drug coating layer contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, and the mass ratio of the limus-based drug to the biodegradable polymer in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound is contained in the drug coating layer in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

[0014] The inventors have found that a stent having such a configuration allows for the long-term sustained release of a drug while using a limus-based drug that is highly safe for living organisms. The mechanism by which the above effects are exerted by the configuration of the present invention is presumed to be as follows.

[0015] The risk of restenosis of blood vessels is said to persist for about a year after stent placement, but the sustained release period of limus-based drugs in conventional stents using limus-based drugs was short, ranging from a few days to about 90 days. In the stent according to the present invention, the drug coating layer formed on the surface of the stent body contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin in a predetermined ratio, thereby enabling long-term sustained release of the limus-based drug. First, it is thought that by having a predetermined mass ratio of limus-based drug to biodegradable polymer in the drug coating layer (mass of limus-based drug / mass of biodegradable polymer), it is possible to prevent the limus-based drug from being released from the drug coating layer in a short time. In addition, by including a predetermined lipid-soluble compound in the drug coating layer in a predetermined ratio, it is possible to prevent oxidative decomposition of the limus-based drug. Furthermore, it is presumed that the synergistic effect of the predetermined mass ratio of the limus-based drug and the biodegradable polymer, and the effect of the drug coating layer containing a predetermined lipid-soluble compound in a predetermined proportion, enables the long-term sustained release of the limus-based drug, although the detailed mechanism remains unclear. It should be noted that the above mechanism is a hypothesis and does not limit the technical scope of the present invention.

[0016] Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of any conflict, this specification (including definitions) shall prevail. This invention is not limited to the embodiments described below and can be modified in various ways within the scope of the claims. Also, in this specification, "X to Y" indicates a range including X and Y, meaning "X or greater and Y or less." "X and / or Y" means at least one of X and Y, encompassing X alone, Y alone, and combinations of X and Y. Furthermore, "%" of concentration refers to mass concentration "mass%" unless otherwise specified.

[0017] Unless otherwise specified, measurements of operation and physical properties shall be taken under room temperature (20-25°C) / relative humidity of 40-50% RH.

[0018] Embodiments of the present invention will be described below with reference to the attached drawings. The following description is not intended to limit the technical scope or the meaning of terms described in the claims. Furthermore, the dimensional ratios in the drawings are exaggerated for illustrative purposes and may differ from the actual ratios.

[0019] [Stent] Figure 1A is a schematic diagram showing an example of the shape of the stent 1 according to the present invention. Figures 1B to 1D are examples of enlarged cross-sectional views of the stent 1 cut along the line A-A in Figure 1A. The stent 1 of the present invention has a stent body 13 and a drug coating layer 12. The drug coating layer 12 is formed on a part of the surface of the stent body 13 that is in contact with the blood vessel wall.

[0020] Furthermore, in Figure 1B, the drug coating layer 12 is formed only on the side that contacts the blood vessel wall (the upper side in Figure 1B), but as shown in Figure 1C, the drug coating layer 12' may also be formed on the opposite side (the side that contacts body fluid (e.g., blood); the lower side in Figure 1C). Of these, since the drug coating layer 12 is formed between the stent body 13 and the blood vessel wall, it is preferable that the drug coating layer 12 is formed only on the side of the stent body 13 that contacts the blood vessel wall, as shown in Figure 1B. This effectively suppresses the proliferation of vascular endothelial cells and prevents restenosis of the blood vessel.

[0021] Furthermore, as shown in Figure 1D, a second drug coating layer 14 containing a drug different from the limus-based drug may be provided on the portion of the stent body 13 opposite to the portion in contact with the drug coating layer 12 (the portion facing body fluid (e.g., blood)).

[0022] [Stent Delivery System] One aspect of the present invention is a stent delivery system comprising a stent according to one aspect of the present invention. Figure 2 is an overall configuration diagram of a stent delivery system 10 comprising a stent according to an embodiment of the present invention.

[0023] As shown in Figure 2, the stent delivery system 10 includes an inner tube 20 through which a guide wire is inserted, a self-expanding stent 1 (hereinafter simply referred to as "stent 1") arranged around the tip of the inner tube 20, an outer tube 40 arranged on the outer surface side of the inner tube 20, traction wires 50a and 50b that can pull the outer tube 40 toward the proximal end, a tip member 60 arranged at the very tip, a traction wire insertion tube 70 through which the traction wires 50a and 50b are inserted, and an operating unit 80 that can wind up the traction wires 50a and 50b. The stent delivery system 10 further includes an insertion section 100 arranged in the lumen of the outer tube 40 through which the inner tube 20 is inserted. In this specification, the side inserted into the body cavity is referred to as the tip side (direction of arrow A in the figure), and the side where the operating unit 80 is provided is referred to as the proximal end (direction of arrow B in the figure).

[0024] The inner tube 20 is composed of a tubular body in which a guidewire lumen 20a is formed, extending from the tip to the base. A guidewire (not shown) is inserted through the guidewire lumen 20a to guide the stent delivery system 10 to the lesion in the biological lumen.

[0025] A tip member 60 is positioned at the very front of the stent delivery system 10. The tip member 60 is fixed to the tip portion of the inner tube 20 by a stopper 22. The stopper 22 is embedded within the tip member 60 and prevents the tip member 60 from detaching. The tip member 60 has a shape that gradually decreases in diameter towards the tip, making it easy to insert into a biological lumen. An opening 20b is formed at the tip of the tip member 60. The tip member 60 can be made from a separate component from the inner tube 20, or it may be made integrally from the same component as the inner tube 20.

[0026] The base end of the inner tube 20 is formed at an angle so as to slope toward the base end, and is provided to communicate with the guide wire outlet hole 43d of the outer tube 40, which will be described later. This facilitates the guidance of the guide wire.

[0027] The stent 1 shown in the stent delivery system 10 is a self-expanding stent. As shown by the dashed line in Figure 2, when inserted into a biological lumen, it is positioned in the housing section 41a (described later) in a state where it is compressed radially inward around the longitudinal axis of the outer tube 40. When the outer tube 40 moves towards the proximal end, the housing section 41a is exposed outward, and the stent 1 is released to the lesion in the biological lumen. This causes it to expand radially outward and return to its pre-compression shape.

[0028] The towing wires 50a and 50b are fixed to the first outer tube 41 and the second outer tube 42, respectively, of the outer tube 40, which will be described later, and pull the outer tube 40 toward the base end.

[0029] As shown in Figure 2, the traction wire insertion tube 70 is tubular in shape, with a traction wire lumen 70a that extends from the tip to the base. The traction wires 50a and 50b are inserted through the traction wire lumen 70a and guided to the operating section 80. The tip portion of the traction wire insertion tube 70 is positioned inside the lumen of the outer tube 40 and fixed to the base portion of the inner tube 20. The base portion of the traction wire insertion tube 70 is fixed to the operating section 80.

[0030] As shown in Figure 2, the outer tube 40 includes a first outer tube 41 positioned at the tip end and housing the stent 1, a second outer tube 42 positioned close to the base end of the first outer tube 41, and a third outer tube 43 positioned on the base end side of the second outer tube 42.

[0031] The first outer tube 41 has a housing portion 41a that can accommodate the stent 1 in a state compressed radially inward between itself and the inner tube 20. A tip-side movement restricting portion 23 that abuts against the tip side of the stent 1 to restrict its movement toward the tip side, and a base-side movement restricting portion 24 that abuts against the base-side of the stent 1 to restrict its movement toward the base side are fixed to the outer surface of the inner tube 20. The tip-side movement restricting portion 23 and the base-side movement restricting portion 24 are formed in an annular shape around the longitudinal axis of the outer tube 40. The housing portion 41a is formed by the portion surrounded by the base-side movement restricting portion 24, the tip-side movement restricting portion 23, and the first outer tube 41.

[0032] After the housing portion 41a is positioned at the lesion site, the first outer tube 41 is moved proximal to the inner tube 20. At this time, a frictional force acts on the stent 1, attempting to move it proximal to the lesion site as the first outer tube 41 moves. However, the stent 1's movement towards the proximal to the lesion site is restricted by contact with the proximal movement restricting portion 24. As a result, the stent 1 can be released from the lesion site without moving from the lesion site where it was positioned.

[0033] The first outer tube 41 is not fixed to the inner tube 20. Therefore, the first outer tube 41 is movable relative to the inner tube 20 in the longitudinal axis direction of the outer tube 40.

[0034] As shown in Figure 2, the second outer tube 42 is composed of two tubular bodies with different outer diameters: a tip section 42a and a main body section 42b. The second outer tube 42 can be moved toward the base end together with the first outer tube 41 by pulling wires 50a and 50b. Furthermore, the second outer tube 42 is not fixed to the first outer tube 41.

[0035] The tip-side cylindrical portion 42a is fixed so as to cover the tip portion of the main body portion 42b and has an outer diameter approximately equal to the outer diameter of the first outer tube 41. The main body portion 42b has an outer diameter smaller than the inner diameter of the tip-side tube 43a of the third outer tube 43, which will be described later, and is configured to be housed in the lumen of the tip-side tube 43a.

[0036] The lumen of the tip-side cylindrical portion 42a has an insertion portion 100 through which the inner tube 20 is inserted. The insertion portion 100 includes a fixing member 110 for fixing the towing wires 50a and 50b, a locking member 120 positioned on the tip side of the fixing member 110, and an intermediate member 130 positioned between the fixing member 110 and the locking member 120.

[0037] The fixing member 110 is positioned in a loosely fitted state with respect to the tip-side cylindrical portion 42a, and is configured to be rotatable around the longitudinal axis of the outer tube 40 and also movable in the longitudinal axis direction by the amount of the gap. When twisting occurs in the traction wires 50a and 50b at the base end (hand side), a force is generated that causes the fixing member 110 to rotate around the longitudinal axis of the outer tube 40 (in the twisting direction). At this time, an inertial force acts on the fixing member 110 in the direction opposite to the direction in which it is trying to rotate. This prevents the twisting of the traction wires 50a and 50b that occurs at the base end from being transmitted to the tip end.

[0038] The distal tube 43a is not fixed to the main body portion 42b, and can be accommodated inside the distal tube 43a by sliding the main body portion 42b toward the proximal end side. A second outer tube movement restricting portion 43c is provided on the proximal end side inside the distal tube 43a. The second outer tube 42 is movable toward the proximal end side until it abuts against the second outer tube movement restricting portion 43c, but further movement toward the proximal end side is restricted. Further, as shown in FIG. 2, the proximal tube 43b has a guide wire lead-out hole 43d that protrudes obliquely toward the radially outer side of the third outer tube 43 and opens therethrough. The guide wire lead-out hole 43d is provided to be able to communicate with the guide wire lumen 20a of the inner tube 20, and can lead a guide wire to the outside of the outer tube 40. Furthermore, a pulling wire insertion tube 70 is fixed to the inner lumen of the proximal tube 43b.

[0039] The operation unit 80 is fixed to the proximal end of the pulling wire insertion tube 70 through which pulling wires 50a and 50b are inserted, as shown in FIG. 2. The operation unit 80 moves the first outer tube 41 and the second outer tube 42 toward the proximal end side by winding up the pulling wires 50a and 50b.

[0040] The operation unit 80 includes an accommodation case 81 that accommodates each constituent member, a cylindrical portion 82 extending from the distal end side of the operation unit 80, a rotating roller 83 that performs an operation of winding up the pulling wires 50a and 50b, and a reverse rotation restricting member that restricts reverse rotation of the rotating roller 83.

[0041] [Method of Using Stent and Stent Delivery System] Hereinafter, a method for indwelling the stent 1 at a lesion site using the stent delivery system 10 of the present embodiment will be described.

[0042] First, a guide wire is inserted into the opening 20b of the distal end member 60 of the stent delivery system 10 shown in FIG. 2, and the guide wire (not shown) is led out from the guide wire lead-out hole 43d. Next, the stent delivery system 10 is advanced along the guide wire inserted into the living body, and the accommodation portion 41a for the stent 1 in the first outer tube 41 is placed at the target lesion site (stenotic portion).

[0043] Next, when the rotating roller 83 of the operation unit 80 is rotated in the direction of arrow B in FIG. 2, the pulling wires 50a and 50b are pulled toward the proximal end side. Accordingly, the first outer tube 41 to which the pulling wires 50a and 50b are fixed and the fixing member 110 are pulled and move toward the proximal end side relative to the inner tube 20. By moving toward the proximal end side, the fixing member 110 abuts against the distal end side end surface of the main body portion 42b of the second outer tube 42 and presses the main body portion 42b. When the fixing member 110 presses the main body portion 42b, the entire second outer tube 42 is pressed toward the proximal end side. At this time, since the outer diameter of the main body portion 42b is smaller than the inner diameter of the distal end side tube 43a in the third outer tube 43, the proximal end portion of the main body portion 42b is accommodated in the inner lumen of the distal end side tube 43a. Accordingly, the second outer tube 42 can move toward the proximal end side.

[0044] Along with the movement of the second outer tube 42 toward the proximal end side, the first outer tube 41 also moves toward the proximal end side. At this time, the proximal end side end surface of the stent 1 abuts against the distal end side end surface of the proximal end movement restricting portion 24 and is locked, so that the stent 1 is released from the distal end of the first outer tube 41 while maintaining its position without moving along with the movement of the first outer tube 41. Through this release, the stent 1 self-expands, dilates the stenosis, and is left indwelling at the stenosis.

[0045] The stent delivery system 10 according to one embodiment described above corresponds to a case where the stent according to the present invention is a self-expanding stent. However, the stent and the stent delivery system according to the present invention are not limited to self-expanding types, and may be balloon-expandable. For example, when the stent and the stent delivery system according to the present invention are used for coronary arteries of the heart, a balloon-expandable type is preferable. On the other hand, when the stent and the stent delivery system according to the present invention are used for lower limb blood vessels, a self-expanding type is preferable.

[0046] Hereinafter, a preferred example of materials, physical properties, and the like of each part (stent main body, drug coating layer, etc.) constituting the stent according to the present invention will be described.

[0047] <Stent> The stent according to the present invention comprises a cylindrical stent body that can expand and contract radially, and a drug coating layer formed on at least a part of the surface of the stent body, wherein the drug coating layer contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, the mass ratio of the limus-based drug and the biodegradable polymer in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound in the drug coating layer is contained in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

[0048] [Stent body] The stent body may be made of any material, and may be made of a non-biodegradable material or a biodegradable material.

[0049] <Non-biodegradable materials> Non-biodegradable materials that can be used for stents include carbon fibers and metal materials. From the viewpoint of further reducing inflammation, it is preferable that the non-biodegradable material be a metal material.

[0050] Here, the metal material used when the stent is composed of a metal material is not particularly limited, and metal materials commonly used in the field of stents can be used. Specifically, examples include stainless steels such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630, tantalum, titanium, nickel-titanium alloys, tantalum-titanium alloys, nickel-aluminum alloys, Inconel, gold, platinum, iridium, tungsten, and cobalt-chromium (Co-Cr) alloys. Among stainless steels, SUS316L is preferred because it has the best corrosion resistance. Among cobalt-based alloys, MP35N and L605 are preferred.

[0051] <Biodegradable Materials> There are no particular restrictions on the biodegradable materials that can be used for stents; generally, biodegradable resin materials commonly used in the medical field can be used.

[0052] The biodegradable resin material is not particularly limited, and known biodegradable resin materials such as those described in Japanese Patent Publication No. 2011-528275, Japanese Patent Publication No. 2008-514719, International Publication No. 2008 / 1952, Japanese Patent Publication No. 2004-509205, etc., can be used. Specifically, examples include (1) polymers selected from the group consisting of aliphatic polyesters, polyesters, polyacid anhydrides, polyoltoesters, polycarbonates, polyphosphazenes, polyphosphate esters, polyvinyl alcohols, polypeptides, polysaccharides, proteins, and cellulose; and (2) copolymers composed of two or more monomers constituting the above (1). Here, the aliphatic polyester is not particularly limited and includes, for example, polylactic acid (PLA) such as poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-DL-lactic acid (PDLLA), polyglycolic acid (PGA), polyhydroxybutyric acid, polyhydroxyvaleric acid, polyhydroxypentanoic acid, polyhydroxyhexanoic acid, polyhydroxyheptanoic acid, poly(ε-caprolactone) (PCL), polytrimethylene carbonate, poly-2,2-dimethyltrimethylene carbonate, polydioxanone, polybutyrolactone, polyvalerolactone, polymalic acid, polyethylene adipate, polyethylene succinate, polybutylene adipate, and polybutylene succinate. Furthermore, the polycarbonate is not particularly limited and includes, for example, tyrosine-derived polycarbonate.

[0053] Furthermore, the biodegradable resin material may be a copolymer formed by arbitrarily copolymerizing the monomers constituting the polymer. Here, the copolymer is not particularly limited. Specifically, PLLA-PDLLA, PLLA-PDLLA, PDLA-PDLLA, PDLLA-PCL, PLLA-r-PCL, PLLA-b-PCL, PLLA-r-PTMC (TMC = trimethylene carbonate), PLLA-r-PDTC (DCT = 2,2-dimethyltrimethylene carbonate), PLLA-b-PTMC, PLLA-b-PDTC, PLGA (poly(lactide-co-glycolide)), polyorthoester, poly(N-(2-hydroxypropyl)methacrylamide), PGA-TMC (poly(glycolide-co-trimethylene carbonate)), PGA-PLLA (poly(l-lactide-co-glycolide)), PGA-PDLLA (poly(dl-lactide-co-glycolide)), and PDO-PGA-TMC (poly(glycolide-co-trimethylene carbonate-co-dioxanone)), PAE (Polyanhydride) in which salicylic acid is chemically introduced into the polymer backbone. Examples include esters)-Salicylate (for example, polymers in which salicylic acid is bonded to both ends of polylactide anhydride or polyadipic acid).

[0054] The polymers and copolymers described above may be used individually, in combination of two or more types, or in combination of one or more polymers and one or more copolymers. Furthermore, the polymers and copolymers may be produced by synthesis or commercially available products. The synthesis method is not particularly limited, and known methods can be applied in the same manner or with appropriate modifications. For example, polylactic acid (PLA), polyglycolic acid (PGA), or lactic acid-glycolic acid copolymer (PLGA) can be obtained by selecting the desired structure from L-lactic acid, D-lactic acid, and glycolic acid as raw materials and performing dehydration polycondensation. Alternatively, they can be obtained by selecting the desired structure from lactide, a cyclic dimer of lactic acid, and glycolide, a cyclic dimer of glycolic acid, and performing ring-opening polymerization. Lactides include L-lactide, a cyclic dimer of L-lactic acid; D-lactide, a cyclic dimer of D-lactic acid; meso-lactide, a cyclic dimer of D-lactic acid and L-lactic acid; and DL-lactide, a racemic mixture of D-lactide and L-lactide. Any of these lactides can be used in this disclosure.

[0055] Of these, the biodegradable resin material is preferably a bulk erosion type polymer. More preferably, the biodegradable resin material is selected from the group consisting of a single monomer homopolymer or a copolymer of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate.

[0056] The materials constituting the stent may be used individually, or they may be used in combination as a mixture of two or more materials or as a copolymer of two or more monomers constituting any of the above-mentioned resins.

[0057] In this specification, "biodegradable" is not particularly limited, but refers to materials that satisfy at least one of the following standards: ISO 9408, ISO 9439, ISO 10707, ISO 14855-1, ISO 14855-2, ISO 14851, ISO 14852, ISO 17556, JIS K 6950:2000, JIS K 6951:2000, JIS K 6953-1:2011, JIS K 6953-2:2010, and JIS K 6955:2017. "Non-biodegradable" refers to materials that do not satisfy any of these standards.

[0058] Stents can be suitably formed from materials appropriately selected from the non-biodegradable materials and biodegradable resin materials exemplified above, depending on the application site (placement site in the body). For example, if a stent is formed from a metal material, the metal material has excellent strength, making it possible to leave the stent in the lesion for a desired period of time while maintaining the desired tensile strength. On the other hand, if a stent is formed from a resin material, the polymer material has excellent flexibility, exhibiting excellent effect in the delivery of the stent to the lesion. Furthermore, if the resin material is biodegradable, the stent will disappear by biodegradation after a predetermined period, thus reducing the potential impact on the biological lumen after treatment.

[0059] Furthermore, the stent may be a self-expanding stent or a balloon-expanding stent. When the stent is constructed as a self-expanding stent, it is preferable to use a superelastic alloy such as nickel-titanium alloy because it is necessary to restore it to its original shape. When the stent is balloon-expanding, it is preferable to use a cobalt-based alloy such as cobalt-chromium (Co-Cr) alloy or stainless steel because it is less likely to return to its original shape after expansion. In addition, when the stent is made of carbon fiber, it exhibits excellent effects in that it is high in strength, has excellent flexibility, and is highly safe in vivo.

[0060] [Drug Coating Layer] The drug coating layer in the stent according to the present invention is formed on at least a part of the surface of the stent body. The drug coating layer contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin. The mass ratio of the limus-based drug to the biodegradable polymer in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound is contained in the drug coating layer in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

[0061] <Limus-based drugs> The limus-based drugs included in the drug coating layer are not particularly limited, and various drugs can be used. Examples of limus-based drugs include sirolimus, everolimus, temsirolimus, tacrolimus, pimecrolimus, zotarolimus, biolimus, novolimus, ridaforolimus, and umirolimus. These may be used individually or in combination of two or more.

[0062] In particular, from the viewpoint of effectively preventing restenosis of blood vessels, it is preferable that the drug be one or more selected from the group consisting of sirolimus, everolimus, temsirolimus, novolimus, biolimus, and zotarolimus, which are limus-based drugs used as mTOR inhibitors; more preferably, it is one or more selected from the group consisting of sirolimus, everolimus, and zotarolimus; and even more preferably, it is sirolimus.

[0063] The content (mass%) of the limus-based drug in the drug coating layer of a stent according to one embodiment is preferably 30% by mass or more and 70% by mass or less, more preferably 35% by mass or more and 65% by mass or less, even more preferably 40% by mass or more and 65% by mass or less, even more preferably more than 40% by mass and 60% by mass or less, and particularly preferably 45% by mass or more and 60% by mass or less. By having the content (mass%) of the limus-based drug within the above range, a suitable amount of the limus-based drug for preventing restenosis of blood vessels can be released slowly over a long period of time. Here, if the drug coating layer contains multiple types of limus-based drugs, the content (mass%) of the limus-based drug is the sum of the total content of all limus-based drugs contained in the drug coating layer. The content (mass%) of the limus-based drug in the drug coating layer can be measured by liquid chromatography.

[0064] In one embodiment, the amount of limus-based drug applied per unit area in the drug coating layer of a stent is 5 μg / mm². ２ 100 μg / mm or more ２ The following is preferable: 10 μg / mm³ ２ 80 μg / mm or more ２ More preferably, the following is 20 μg / mm³ ２ 40μg / mm or more ２ The following is even more preferable: By having the limus-based drug content within the above range, a suitable amount of the limus-based drug for preventing vascular restenosis can be released slowly over a long period of time. Here, if the drug coating layer contains multiple types of limus-based drugs, the amount of limus-based drug loaded is the sum of the total amount of limus-based drugs contained in the drug coating layer. The amount loaded per unit area can be measured by dividing the amount obtained by liquid chromatography by the surface area of ​​the stent.

[0065] <Biodegradable Polymer> The biodegradable polymer included in the drug coating layer can be appropriately selected from the materials listed under <Biodegradable Material> in the [Stent] section. In particular, the monomer constituting the biodegradable polymer is preferably one or more selected from the group consisting of lactic acid, glycolic acid, and caprolactone, from the viewpoint of a favorable sustained release rate of the drug. Here, the biodegradable polymer may be a copolymer containing two or more of these monomers. Here, the copolymer may be a random copolymer, an alternate copolymer, a block copolymer, or a graft copolymer. As for lactic acid, examples include L-lactic acid, D-lactic acid, and DL-lactic acid, but L-lactic acid and / or DL-lactic acid are preferred.

[0066] For example, the biodegradable polymer is preferably one or more selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, glycolic acid-lactic acid copolymer, ε-caprolactone-lactic acid copolymer, and glycolic acid-ε-caprolactone copolymer; more preferably one or more selected from the group consisting of polylactic acid, ε-caprolactone-lactic acid copolymer, and glycolic acid-lactic acid copolymer; and even more preferably polylactic acid. Here, examples of polylactic acid include poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-DL-lactic acid (PDLLA), poly-L-lactic acid-poly-D-lactic acid copolymer (PLLA-PDLA), poly-L-lactic acid-poly-DL-lactic acid copolymer (PLLA-PDLLA), and poly-D-lactic acid-poly-DL-lactic acid copolymer (PDLA-PDLLA). In particular, it is preferable that one or more are selected from the group consisting of poly-L-lactic acid, poly-DL-lactic acid, and poly-L-lactic acid-poly-DL-lactic acid copolymer.

[0067] Furthermore, the polylactic acid according to one embodiment is preferably composed of L-lactide and / or DL-lactide, and more preferably composed of L-lactide and DL-lactide (i.e., a copolymer of L-lactide and DL-lactide). When composed of L-lactide and DL-lactide, the polymerization ratio (molar ratio (mol%)) of L-lactide to DL-lactide is preferably 10:90 to 90:10, more preferably 30:70 to 90:10, even more preferably 50:50 to 90:10, and particularly preferably 60:40 to 80:20. When the polymerization ratio (molar ratio (mol%)) of L-lactide and DL-lactide in the polylactic acid is within the above range, the sustained release rate of the limus-based drug becomes more favorable.

[0068] The viscosity (dL / g) of the biodegradable polymer according to one embodiment is not particularly limited, but is preferably 0.5 dL / g to 10 dL / g, more preferably 1 dL / g to 6 dL / g, even more preferably 1 dL / g to 5 dL / g, particularly preferably 1 dL / g to 4 dL / g, and most preferably 1.5 dL / g to 3 dL / g. Being within the above range results in a more favorable sustained release rate of the limus-based agent. The viscosity of the biodegradable polymer can be measured with a capillary viscometer.

[0069] The content (mass%) of biodegradable polymers in the drug coating layer of a stent according to one embodiment is preferably 30% by mass or more and 70% by mass or less, more preferably 35% by mass or more and 65% by mass or less, even more preferably 35% by mass or more and 60% by mass or less, even more preferably 40% by mass or more and 60% by mass or less, and particularly preferably 40% by mass or more and 55% by mass or less. By having the biodegradable polymer content (mass%) within the above range, a suitable amount of limus-based drug for preventing restenosis of blood vessels can be released slowly over a long period of time. Here, if the drug coating layer contains multiple types of biodegradable polymers, the biodegradable polymer content (mass%) is the total content of all biodegradable polymers contained in the drug coating layer. The biodegradable polymer content (mass%) in the drug coating layer can be measured by gel permeation chromatography.

[0070] <Lipidophilic Compounds> The lipidophilic compound contained in the drug coating layer is one or more selected from the group consisting of tocopherol and astaxanthin, but tocopherol is preferred from the viewpoint of enabling longer-term sustained release of the drug. The tocopherol contained in the drug coating layer is not particularly limited and includes α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, but among these, it is preferred that the drug coating layer contains α-tocopherol. By containing α-tocopherol in the drug coating layer, longer-term sustained release of the drug becomes possible.

[0071] In the drug coating layer, the lipid-soluble compound is contained in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug. However, from the viewpoint of enabling longer-term sustained release of the limus-based drug, it is preferable that the amount be 0.005 mol% to 25 mol%, preferably 0.008 mol% to 22.5 mol%, and more preferably 0.01 mol% to 20 mol%. The value (mol%) of the lipid-soluble compound relative to 100 mol% of the limus-based drug in the drug coating layer can be calculated from the content (mass%) of the limus-based drug and the lipid-soluble compound in the drug coating layer measured by liquid chromatography.

[0072] The content of lipid-soluble compounds in the drug coating layer is preferably 0.0005% to 10% by mass, more preferably 0.001% to 8% by mass, even more preferably 0.0015% to 7% by mass, and particularly preferably 0.002% to 6% by mass, based on the total mass of the drug coating layer. Having the content of lipid-soluble compounds in the drug coating layer within the above range enables longer-term sustained release of limus-based drugs. The content of lipid-soluble compounds (by mass) in the drug coating layer can be measured by liquid chromatography.

[0073] <Mass ratio of limus-based drug and biodegradable polymer> The mass ratio of limus-based drug and biodegradable polymer contained in the drug coating layer (mass of limus-based drug / mass of biodegradable polymer) is 30 / 70 to 70 / 30. From the viewpoint of enabling longer-term sustained release of the limus-based drug and further favoring a suitable rate of release, the mass ratio is preferably 40 / 60 to 60 / 40, more preferably 45 / 55 to 60 / 40, and even more preferably 45 / 55 to 55 / 45.

[0074] Furthermore, in the drug coating layer, if the lipid-soluble compound is contained in an amount of 0.001 mol% or more and less than 0.1 mol% relative to 100 mol% of the limus-based drug, the mass ratio of the limus-based drug and the biodegradable polymer contained in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is preferably 40 / 60 or more and 60 / 40 or less, more preferably greater than 40 / 60 and less than 60 / 40, and even more preferably 45 / 55 or more and 55 / 45 or less.

[0075] Furthermore, in the drug coating layer, if the lipid-soluble compound is contained in an amount of 0.1 mol% or more and less than 1.5 mol% relative to 100 mol% of the limus-based drug, the mass ratio of the limus-based drug and the biodegradable polymer contained in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is preferably 40 / 60 or more and 70 / 30 or less, more preferably greater than 40 / 60 and 70 / 30 or less, even more preferably greater than 45 / 55 and 70 / 30 or less, even more preferably greater than 45 / 55 and 70 / 30 or less, and particularly preferably 50 / 50 or more and 60 / 40 or less.

[0076] Furthermore, in the drug coating layer, if the lipid-soluble compound is contained in an amount of 1.5 mol% or more and less than 5 mol% relative to 100 mol% of the limus-based drug, the mass ratio of the limus-based drug and the biodegradable polymer contained in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is preferably 40 / 60 or more and 70 / 30 or less, more preferably greater than 40 / 60 and 70 / 30 or less, even more preferably 45 / 55 or more and 70 / 30 or less, even more preferably greater than 45 / 55 and 70 / 30 or less, and particularly preferably 50 / 50 or more and 60 / 40 or less.

[0077] Furthermore, in the drug coating layer, if the lipid-soluble compound is contained in an amount of 5 mol% or more and less than 15 mol% relative to 100 mol% of the limus-based drug, the mass ratio of the limus-based drug and the biodegradable polymer contained in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is preferably 40 / 60 or more and 60 / 40 or less, more preferably greater than 40 / 60 and less than 60 / 40, and even more preferably 45 / 55 or more and 55 / 45 or less.

[0078] Furthermore, in the drug coating layer, if the lipid-soluble compound is contained in an amount of 15 mol% to 30 mol% relative to 100 mol% of the limus-based drug, the mass ratio of the limus-based drug to the biodegradable polymer contained in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is preferably 30 / 70 to 60 / 40, more preferably 30 / 70 to less than 60 / 40, even more preferably 30 / 70 to less than 55 / 45, and even more preferably 40 / 60 to 50 / 50.

[0079] By ensuring that the value (mol%) of the lipid-soluble compound in the drug coating layer relative to 100 mol% of the limus-based drug, and the mass ratio of the limus-based drug and biodegradable polymer contained in the drug coating layer are within the above range, restenosis of blood vessels can be effectively suppressed. For example, by maintaining the sustained release of the limus-based drug during the period when vascular cell proliferation occurs due to stent placement, restenosis of blood vessels can be effectively suppressed.

[0080] <Changes in the sustained release rate of limus-based drugs over time> It is said that restenosis of blood vessels can occur for approximately 12 months after stent placement in a blood vessel. In particular, restenosis can occur after 6 months after stent placement due to cell proliferation caused by the long-term stimulation of the stent expanding the blood vessel. From these viewpoints, in a stent according to one embodiment of the present invention, the sustained release rate (mass%) of limus-based drugs from the drug coating layer is preferably 65% ​​to 100%, more preferably 70% to 100%, even more preferably 75% to 100%, even more preferably 80% to 100%, particularly preferably 85% to 100%, and most preferably 90% to 100% after 360 days from the start of release of limus-based drugs.

[0081] Furthermore, from the above viewpoint, in a stent according to one embodiment of the present invention, the sustained release rate of the limus-based drug from the drug coating layer is preferably 55% to 95%, more preferably 60% to 90%, even more preferably 65% ​​to 90%, and particularly preferably 70% to 90% after 180 days from the start of release of the limus-based drug.

[0082] Furthermore, from the above viewpoint, in a stent according to one embodiment of the present invention, the sustained release rate of the limus-based drug from the drug coating layer may be 55% to 95% after 180 days from the start of release of the limus-based drug, and may be 65% to 100% after 360 days, or 55% to 95% after 180 days, and may be 70% to 100% after 360 days, or 55% to 95% after 180 days, and may be 75% to 100% after 360 days, or 55% to 95% after 180 days, and may be 80% to 100% after 360 days. It is also fine if the percentage is 55% to 90% after 180 days and 70% to 100% after 360 days, or if the percentage is 55% to 90% after 180 days and 75% to 100% after 360 days, or if the percentage is 55% to 90% after 180 days and 80% to 100% after 360 days, or if the percentage is 60% to 90% after 180 days and 65% to 100% after 360 days, or if the percentage is 60% to 90% after 180 days and 70% to 100% after 360 days, or if the percentage is 60% to 90% after 180 days and 70% to 100% after 360 days. It is 0%, and may be 75% to 100% after 360 days, and 60% to 90% after 180 days, and may be 80% to 100% after 360 days, and 65% to 90% after 180 days, and may be 65% to 100% after 360 days, and 65% to 90% after 180 days, and may be 70% to 100% after 360 days, and 65% to 90% after 180 days, and may be 75% to 100% after 360 days, and 65% to 90% after 180 days, and 80% after 360 days It may be between 100% and 70% after 180 days, and between 70% and 90% after 360 days, and between 70% and 100% after 360 days, and between 70% and 90% after 180 days, and between 75% and 100% after 360 days, and between 70% and 90% after 180 days, and between 80% and 100% after 360 days, and between 70% and 90% after 180 days, and between 85% and 100% after 360 days, and between 70% and 90% after 180 days, and between 90% and 100% after 360 days.Among these, it is preferable that the percentage is 55% to 95% after 180 days and 65% to 100% after 360 days, and more preferably 60% to 90% after 180 days and 80% to 100% after 360 days.

[0083] If the sustained-release rate of limus-based drugs is within the above range during the above period, these restenosis can be suppressed more effectively.

[0084] As mentioned above, restenosis of the blood vessel can occur for approximately 12 months after stent placement, and restenosis due to cell proliferation caused by the long-term stimulation of the stent expanding the blood vessel can occur, especially after 6 months post-stent placement. It is also known that inflammation caused by stent placement occurs within 1 month after stent placement, and cell proliferation increases rapidly between 1 and 4 months post-placement. From these perspectives, in a stent according to one embodiment of the present invention, the sustained release rate of the limus-based drug from the drug coating layer is preferably 25% to 55% on day 30, 40% to 70% on day 90, 55% to 95% on day 180, and 65% to 100% on day 360, with a sustained release period of 210 days or more. More preferably, the sustained release rate is 30% to 50% on day 30, 45% to 65% on day 90, 60% to 90% on day 180, and 80% to 100% on day 360, with a sustained release period of 270 days or more. If the sustained release rate of the limus-based drug from the drug coating layer is within the above range during the above period, restenosis caused by these cell proliferations can be effectively suppressed. The sustained release rate of the limus-based drug can be measured according to the method described in the examples.

[0085] <Thickness of the drug coating layer> In a stent according to one embodiment of the present invention, it is preferable that the thickness of the drug coating layer is less than or equal to the thickness of the stent body skeleton. More specifically, the thickness of the drug coating layer is preferably 1 μm to 100 μm, and more preferably 10 μm to 60 μm. By having the thickness of the drug coating layer within the above range, the reachability (delivery) of the stent to the lesion is improved, and a sufficient amount of limus-based drug can be contained in the drug coating layer.

[0086] <Method for Manufacturing a Stent> The following describes a method for manufacturing a stent according to one embodiment of the present invention. The manufacturing method according to one embodiment of the present invention is a method for manufacturing a stent having a cylindrical stent body that can expand and contract radially, and a drug coating layer formed on at least a part of the surface of the stent body, wherein the drug coating layer contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, the mass content ratio of the limus-based drug and the biodegradable polymer in the drug coating layer (mass content of limus-based drug / mass content of biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound in the drug coating layer is contained in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

[0087] The following describes a method for manufacturing a stent according to one embodiment of the present invention, comprising the steps of preparing a coating solution for the drug coating layer (coating solution preparation step) and forming a drug coating layer on at least a part of the surface of the stent body (coating layer formation step).

[0088] (I) Coating solution preparation step: In the coating solution preparation step, a coating solution is prepared by dissolving a limus-based agent, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin in a predetermined solvent.

[0089] The solvent for the coating solution is not particularly limited as long as it can sufficiently dissolve or disperse the polymer material. Specifically, examples include ketones such as acetone and methyl ethyl ketone; esters such as ethyl acetate; halides such as chloroform; ethers such as tetrahydrofuran (THF); nitriles such as acetonitrile, propionnitrile, and benzonitrile; amides such as N,N-dimethylformamide (DMF); and sulfoxides such as dimethyl sulfoxide; however, the solvent is not limited to these. These may be used individually or in combination of two or more.

[0090] In particular, from the viewpoint of uniformly dissolving polymer materials, solvents such as ketones like acetone, halides like chloroform, ethers like tetrahydrofuran, and nitriles like acetonitrile are preferred. Furthermore, from the same viewpoint, the solvent preferably contains at least one selected from the group consisting of acetone, chloroform, tetrahydrofuran, and acetonitrile, and preferably contains chloroform.

[0091] The coating solution is prepared by mixing a limus-based agent, a biodegradable polymer, one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, and other components as needed, with a solvent. The order and method of adding the above components are not particularly limited. The above components can be added to a mixing container all at once or separately, in stages or continuously. Furthermore, the mixing method is not particularly limited, and known methods can be used.

[0092] The concentration of the limus-based agent in the coating solution is not particularly limited, as long as it satisfies the range of the mass ratio of the limus-based agent to the biodegradable polymer in the aforementioned drug coating layer, or a preferred range thereof. On the other hand, from the viewpoint of being able to sufficiently dissolve or disperse the limus-based agent in the solvent, the concentration of the limus-based agent in the coating solution is preferably 30 mg / mL to 200 mg / mL, and more preferably 50 mg / mL to 150 mg / mL.

[0093] The concentration of the biodegradable polymer in the coating solution is not particularly limited, as long as it satisfies the range of the mass ratio of the limus-based drug and the biodegradable polymer in the aforementioned drug coating layer, or a preferred range thereof. On the other hand, from the viewpoint of being able to sufficiently dissolve or disperse the biodegradable polymer in the solvent, the concentration of the biodegradable polymer in the coating solution is preferably 30 mg / mL to 200 mg / mL, and more preferably 50 mg / mL to 150 mg / mL.

[0094] The concentration of the lipid-soluble compound in the coating solution is not particularly limited, as long as it satisfies the range (mol%) of the lipid-soluble compound relative to 100 mol% of the limus-based drug in the aforementioned drug coating layer, or a preferred range thereof. On the other hand, from the viewpoint of being able to sufficiently dissolve or disperse the lipid-soluble compound in the solvent, the concentration of the lipid-soluble compound in the coating solution is preferably 0.001 mg / mL to 30 mg / mL, and more preferably 0.002 mg / mL to 25 mg / mL.

[0095] The temperature (liquid temperature) when mixing the above components is not particularly limited, but it is preferably 0 to 60°C, and more preferably 10 to 30°C.

[0096] (II) Coating layer formation process The coating layer formation process is a process of forming a drug coating layer on at least a part of the surface of the stent body by applying a coating solution to any part of the surface of the stent body.

[0097] The method for applying (coating) the coating solution to any part of the surface of the stent body is not particularly limited, and conventionally known methods such as coating / printing, immersion (dipping method, dip coating method), dispenser coating (nozzle coating method), spraying method, and spin coating method can be applied.

[0098] Of these, the preferred coating method is a contact coating method using a dispenser needle (dispenser coating method (nozzle coating method)) because it allows for easy formation of the coating solution even on the fine structure of the stent body and enables uniform application over a wide area. In this coating method, the dispenser nozzle is positioned close to the surface of the workpiece, and the coating solution is applied under set conditions (coating parameters). For example, the coating parameters include the discharge pressure of the coating solution, the discharge speed, and the discharge amount per unit time. As an example, the discharge amount of the coating solution per unit time is preferably 0.01 to 1.00 μl / sec, more preferably 0.10 to 0.75 μl / sec, and even more preferably 0.13 to 0.50 μl / sec.

[0099] Furthermore, while the coating solution is applied to the stent body, it is preferable to rotate the stent body circumferentially and / or move it axially.

[0100] Furthermore, by drying the applied coating solution, a coating is formed on at least a portion of the surface of the stent body. The coating solution may be dried at room temperature or by applying heat. When heat is applied, the heating temperature is preferably 40°C to 200°C, and more preferably 50°C to 150°C. The drying time is preferably 1 hour to 100 hours, more preferably 2 hours to 80 hours, and even more preferably 3 hours to 60 hours. For example, if the heating temperature is 50°C to 150°C, the heating time may be 3 hours to 60 hours.

[0101] The coating layer formation process described above may be performed multiple times. In other words, the drug coating layer may be one layer or multiple layers.

[0102] Here, the stent body may be a commercially available product or a manufactured product, as long as it has the configuration described in the [Stent Body] section. The method of manufacturing the stent is not particularly limited and can be appropriately selected from general manufacturing methods used depending on the structure and material of the stent. For example, a manufacturing method using etching techniques such as laser etching and chemical etching, and laser cutting techniques can be selected. Furthermore, the materials constituting the stent can be appropriately selected from the resin materials, metal materials, and ceramic materials described in the [Stent Body] section above.

[0103] While embodiments of the present invention have been described in detail, these are descriptive and illustrative, and not limiting, and it is clear that the scope of the present invention should be interpreted by the appended claims.

[0104] The effects of the present invention will be explained using the following examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, unless otherwise specified, the operations were carried out at room temperature (25°C). Unless otherwise specified, "%" and "parts" mean "mass%" and "parts by mass," respectively.

[0105] <Stent Preparation> Samples (stents) for Test Examples 1 to 37 were prepared according to the following procedure.

[0106] Table 1 shows the biodegradable polymers used in the test examples.

[0107]

[0108] (Preparation of coating solution) Sirolimus (SRL) and each biodegradable polymer were weighed out in the predetermined blend ratio (mass ratio (limus-based agent (D) / biodegradable polymer (P) ratio)) shown in Table 2, to a total mass of 230 mg. Next, the lipid-soluble compounds shown in Table 2 were weighed out in the same values ​​(mol%) as shown in Table 2 relative to 100 mol% sirolimus, and these were mixed with sirolimus and biodegradable polymers to obtain a mixture. Subsequently, chloroform was added to the mixture, and the volume was made up to 1 ml, dissolving the mixture to obtain the coating solution.

[0109]

[0110] (Application of coating solution) The coating solution was applied to the outer surface of the stent body. Specifically, a core rod with a diameter of φ5.0 to 9.0 mm was inserted into the lumen of the stent body, and while rotating at a rotation speed of 5 to 15 rpm, the aforementioned coating solution was applied to the stent by dispensing it at a rate of 0.13 to 0.50 μl / sec per unit time from a mechanical dispenser (dispensing time: 100 to 1500 seconds) connected to a 25G non-bevel needle.

[0111] Subsequently, the coated stents were dried under reduced pressure at 60°C for 55 hours to obtain samples (stents) for each test example. The amount of limus-based drug applied to the drug coating layer was 28.49 μg / mm³. ２ That was the case.

[0112] <Measurement of sustained release amount (sustained release rate) over time> For the samples (stents) of Test Examples 1 to 37 prepared above, the sustained release amount (sustained release rate) of the limus-based drug from the samples was measured over time according to the following procedure.

[0113] Each sample was placed in a test tube in a 37°C constant temperature bath. Subsequently, the test solution (0.05 M pH 6 citrate buffer with 5 v% ethanol) was added to the test tube, and this point was designated as day 0. The test solution was replaced (sampled) at predetermined time points (7 days), and this was carried out for one year. The test solution after elution (sustained release) was used as the sample solution. Separately, a 10 μg / mL SRL-containing acetonitrile (hereinafter referred to as "ACN") solution was prepared and used as the standard solution.

[0114] The sample solution and standard solution were tested by liquid chromatography under the HPLC conditions described below to determine the concentration of SRL (μg / mL) in the sample solution and the sustained release rate (%) relative to the drug load. Here, the sustained release rate was calculated by accumulating the amount (mass) of SRL released over time and dividing this accumulated amount by the amount (mass) initially contained in the coating layer (sustained release rate (% (mass%)) = (cumulative amount (mass) of SRL released over time) / (total amount (mass) of SRL initially contained in the coating layer) × 100). Furthermore, the detection limit during measurement was set to 0.02 μg / mL for the HPLC conditions.

[0115] (HPLC conditions) Detector: UV absorbance spectrophotometer (measurement wavelength: 277 nm) Guard column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 mm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography. Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: Constant temperature around 35°C Mobile phase: 0.05 M pH 4 citrate buffer / ACN mixture (2:3) Flow rate: Adjusted so that the retention time of the SRL was approximately 30 minutes.

[0116] The results of Test Example 1 and Test Example 2 are shown in Figure 3. The horizontal axis represents the number of days elapsed, and the vertical axis represents the sustained-release rate. In both Test Example 1, which used α-tocopherol as the lipid-soluble compound, and Test Example 2, which used astaxanthin, long-term sustained-release of sirolimus for more than 180 days was confirmed.

[0117] The results of Test Examples 3 to 5 are shown in Figure 4. Long-term sustained release of sirolimus was confirmed in all of Test Examples 3 to 5, but stable sustained release of sirolimus was confirmed in Test Example 3, which used LR704S as the biodegradable polymer, and in Test Example 4, which used LR706S.

[0118] The results of Test Examples 6 to 12 are shown in Figure 5. In Test Examples 6 to 11, which contained α-tocopherol, long-term sustained release of sirolimus was confirmed. On the other hand, in Test Example 12, which did not contain α-tocopherol, the sustained release of sirolimus stopped after approximately 45 days.

[0119] The results of Test Examples 13 to 37 are shown in Figure 6. As shown in the figure, long-term sustained release of sirolimus was confirmed in all of Test Examples 13 to 37. The results of Test Examples 13 to 37 were evaluated based on the following criteria. The results are shown in Table 3.

[0120] ○: The sustained-release rate is 30-50% on day 30, 45-65% on day 90, 60-90% on day 180, and 80-100% on day 360, with a sustained-release period of 270 days or more; △: The sustained-release rate is 25-55% on day 30, 40-70% on day 90, 55-95% on day 180, and 65-100% on day 360, with a sustained-release period of 210 days or more; ×: Conditions other than those of ○ and △.

[0121]

[0122] As shown in Table 3, test examples 13, 14, 18, 22, 26, 27, 31, 32, 33, and 37 received a △ rating. In these test examples, it was confirmed that sustained release continued for a long period, and that a favorable sustained release rate was achieved within the specified period. Test examples 15, 16, 17, 19, 20, 21, 23, 24, 25, 28, 29, 30, 34, 35, and 36 received a ○ rating. In these test examples as well, it was confirmed that sustained release continued for a long period, and that a favorable sustained release rate was achieved within the specified period. On the other hand, there were no test examples 13 to 37 that received an × rating.

[0123] This application is based on Japanese Patent Application No. 2025-053090, filed on 27 March 2025, the disclosures of which are referenced and incorporated in whole.

[0124] 1: Stent, 10: Stent delivery system, 12: Drug coating layer, 12': Drug coating layer, 13: Stent body, 14: Second drug coating layer, 20: Inner tube, 20a: Guide wire lumen, 20b: Opening, 22: Stopper, 23: Tip side movement restriction section, 24: Proximal end side movement restriction section, 40: Outer tube, 41: First outer tube, 41a: Housing section, 42: Second outer tube, 42a: Tip side cylindrical section, 42b: Main body section, 43: Third outer tube, 43a: Tip side tube, 43b: Proximal end tube, 43c: Second outer tube movement restriction section, 43d: Guide wire outlet hole, 50a: Traction wire, 50b: Traction wire 60: Tip member, 70: Pulling wire insertion tube, 70a: Pulling wire lumen, 80: Operating section, 81: Housing case, 82: Cylinder section, 83: Rotating roller, 100: Insertion section, 110: Fixing member, 120: Locking member, 130: Intermediate member.

Claims

1. A stent comprising a cylindrical stent body that can expand and contract radially, and a drug coating layer formed on at least a portion of the surface of the stent body, wherein the drug coating layer contains a limus-based drug, a biodegradable polymer, and one or more lipid-soluble compounds selected from the group consisting of tocopherol and astaxanthin, the mass ratio of the limus-based drug and the biodegradable polymer in the drug coating layer (mass content of the limus-based drug / mass content of the biodegradable polymer) is 30 / 70 to 70 / 30, and the lipid-soluble compound in the drug coating layer is contained in an amount of 0.001 mol% to 30 mol% relative to 100 mol% of the limus-based drug.

2. The stent according to claim 1, wherein the sustained release rate of the limus-based drug from the drug coating layer is 65% to 100% after 360 days from the start of release of the limus-based drug.

3. The stent according to claim 1, wherein the sustained release rate of the limus-based drug from the drug coating layer is 55% to 95% after 180 days from the start of release of the limus-based drug.

4. The stent according to claim 1, wherein the drug coating layer contains α-tocopherol.

5. The stent according to claim 1, wherein the monomer constituting the biodegradable polymer is one or more selected from the group consisting of lactic acid, glycolic acid, and caprolactone.

6. The stent according to claim 1, wherein the thickness of the drug coating layer is less than or equal to the thickness of the skeleton of the stent body.

7. The stent according to claim 1, wherein the limus-based drug is one or more selected from the group consisting of sirolimus, everolimus, temsirolimus, novolimus, biolimus, and zotarolimus.

8. The stent according to claim 1, wherein the mass ratio of the limus-based agent to the biodegradable polymer (mass of the limus-based agent / mass of the biodegradable polymer) is 45 / 55 to 60 / 40.

9. The stent according to claim 1, wherein the lipid-soluble compound is contained in the drug coating layer in an amount of 0.005 mol% to 25 mol% relative to 100 mol% of the limus-based drug.

10. A stent delivery system comprising a stent according to any one of claims 1 to 9.

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