JP7475003B2 - Stents - Google Patents

Description

The present invention relates to a stent used to treat a lumen in a living body, particularly a blood vessel.

Ischemic heart disease (myocardial infarction, angina, etc.) caused by stenosis or blockage of the coronary arteries is a serious disease that impedes the supply of blood (nutrients, oxygen, etc.) to the heart muscle, and is the second leading cause of death among Japanese people. In recent years, minimally invasive procedures using catheters (percutaneous transluminal coronary angioplasty) have become widespread as a treatment for this disease, rather than surgical procedures that involve opening the chest (coronary artery bypass surgery). Among these, coronary artery stent placement is considered to be the most effective treatment, as it has a lower incidence of recurrence of stenosis (restenosis) compared to conventional balloon angioplasty.

Many of the drug-eluting stents currently in use are coated with polyester polymers to carry intimal hyperplasia inhibitors. However, because the polyester inhibits endothelialization of the stent lumen by vascular endothelial cells, there is an inherent risk of causing thrombus formation due to platelet aggregation in the chronic phase, and there is also the problem that antiplatelet drugs, which have a high incidence of side effects, must be taken to prevent thrombosis.
Patent Document 1 discloses a biocompatible device (stent) that is used by being embedded or attached to a living body, the surface of which is covered with a biocompatible polymer layer that has both antithrombotic properties and vascular endothelial cell adhesive properties, and in which the polymer layer is made of a polymer matrix formed by crosslinking a polymer containing a cell adhesion peptide.
However, in the stent described in Patent Document 1, cross-linking is introduced into the coating layer, which raises concerns about the ability of the stent to follow deformation when inserted into a blood vessel. In addition, the stent is made of a non-bioabsorbable metal material such as stainless steel, and there is no suggestion regarding a bioabsorbable stent that disappears after functioning in the body for a certain period of time.

WO2011-096402

The present invention aims to provide a stent that is easy to insert into a blood vessel and has a coating layer on its surface that has both antithrombotic properties and vascular endothelial cell adhesive properties, and in particular, to provide a bioabsorbable stent that gradually disappears in the body after a certain period of time has passed.

In order to achieve the above object, the inventors conducted extensive research focusing on fibroin, which has excellent biocompatibility, as a biodegradable material for forming a coating layer for a stent, and arrived at the present invention.

The first configuration of the present invention is a stent comprising a core structure and one or more coating layers covering at least a portion of the surface of the core structure, at least one of the coating layers containing an intimal hyperplasia inhibitor and made of fibroin to which no cross-linking has been introduced, the stent being characterized by having deformation-following properties and having both vascular endothelial cell adhesive properties and anti-platelet adhesive properties.
In the present invention, the core structure refers to a tubular member (stent framework member) formed in a helical shape and having expandability. In the present invention, the thickness of the coating layer is preferably 1 μm or more and 10 μm or less.

The second aspect of the present invention is characterized in that, in the first aspect, the core structure is made of a metal material. As the metal material, a conventionally known metal material is used, and specific examples thereof include stainless steel, tantalum, nickel-titanium alloy (including nitinol), cobalt-chromium alloy, non-bioabsorbable magnesium alloy, and bioabsorbable magnesium alloy.
A third aspect of the present invention is the second aspect, characterized in that a cobalt-chromium alloy is used among the metallic materials.

The fourth aspect of the present invention is characterized in that the stent in the second aspect is characterized in that the metal material is a bioabsorbable magnesium alloy. Examples of bioabsorbable magnesium alloys used in the present invention include the AZ series (Mg-Al-Zn) (AZ31, AZ61, AZ91, etc.), AM series (Mg-Al-Mn), AE series (Mg-Al-RE), EZ series (Mg-RE-Zn), ZK series (Mg-Zn-Zr), WE series (Mg-RE-Zr), AX or AXJ series (Mg-Al-Ca), etc., and among them, magnesium alloys that do not contain aluminum (Al) and rare metals (RE), which are harmful to the human body, are included.

The sixth aspect of the present invention is characterized in that in the stent of the first aspect, the intimal hyperplasia inhibitor is sirolimus, everolimus, biolimus A9, zotarolimus and/or paclitaxel.

The stent of the first configuration of the present invention has a coating layer covering at least a portion of the surface of the core structure, preferably the entire surface of the core structure, which is formed from fibroin containing an intimal hyperplasia inhibitor, and therefore has vascular endothelial cell adhesiveness and antiplatelet adhesiveness (antithrombogenicity) while suppressing vascular intimal hyperplasia, and further, since the coating layer is formed from fibroin to which no cross-linking has been introduced, it has the ability to follow deformation, and the stent attached to a balloon has the property of being easily inserted into a blood vessel and retained at a predetermined location.
Furthermore, since the fibroin forming the coating layer in the present invention does not have cross-linking introduced therein, when the core structure of the stent is formed from a bioabsorbable magnesium alloy, after a predetermined period of time, the fibroin layer will biodegrade and disappear together with the magnesium alloy, thereby forming a bioabsorbable stent.

The stent of the third aspect of the present invention is made of a conventionally used cobalt-chromium alloy, but contains an intimal hyperplasia inhibitor and has a coating layer made of fibroin that is not cross-linked, so it has deformation-following properties and can be easily inserted into a blood vessel at a specified location. Moreover, it has vascular endothelial cell adhesive properties and antiplatelet adhesive properties, which reduces the side effects associated with the use of conventional stents.

In the fourth configuration of the present invention, when the core structure is formed from a bioabsorbable magnesium alloy, the fibroin coating layer has the effect of appropriately suppressing the elution of the magnesium alloy, and after a predetermined period of time, the stent disappears from the blood vessel, so there are no aftereffects associated with stent insertion, and the burden and side effects on the patient associated with stent insertion can be reduced.

The present invention will be more clearly understood from the following description of preferred embodiments with reference to the accompanying drawings. However, the embodiments and drawings are merely for illustration and explanation, and should not be used to define the scope of the present invention. The scope of the present invention is defined by the appended claims. In the accompanying drawings, the same reference numerals in multiple drawings indicate the same parts.
FIG. 1 is a schematic diagram showing components of a stent according to the present invention. FIG. 2 is a plan view showing an example of the framework structure of the stent of the present invention. FIG. 4 is a plan view showing another example of the framework structure of the stent of the present invention. FIG. 2 is a schematic diagram showing the physical changes caused by the contraction and expansion of the diameter of the stent of the present invention. 1 is an example of a microscope image of a stent of the present invention expanded to an inner diameter of 3 mm. 1 shows SEM images of the surface of a stent according to the present invention (Example 1) before and after radial expansion. 1 shows SEM images of the surface of a stent according to the present invention (Example 2) before and after radial expansion. 1 shows SEM images of the surface of Comparative Example 1 before and after diameter expansion. 1 is a SEM image of the surface of a stent according to the present invention (Example 3) after immersion in a plasma simulating solution (EMEM + 10% FBS) for 28 days. 1 shows SEM images of the surfaces of Comparative Examples 2(a) and 3(b) after immersion in a plasma simulating solution (EMEM + 10% FBS) for 28 days. 13 is a stained image of endothelial cells adhered to the surface of a stent according to the present invention (Example 3) after immersion in a plasma simulating solution (EMEM+10% FBS) for 4 days. 1 shows stained images of endothelial cells adhered to the surfaces of Comparative Examples 2(a) and 3(b) after immersion in a plasma simulating solution (EMEM + 10% FBS) for 4 days. 1 is a stained image of platelets adhered to the surface of a stent according to the present invention (Example 3) after immersion in a plasma simulating solution (EMEM + 10% FBS) for 4 days. 1 shows stained images of platelets adhered to the surfaces of Comparative Examples 2(a) and 3(b) after immersion in a plasma simulating solution (EMEM+10% FBS) for 4 days.

(Basic structure of a stent)
1, an example of the stent of the present invention is composed of a core structure 1 made of a metal material such as non-bioabsorbable SUS316L, CoCr alloy, NiTi alloy, and bioabsorbable magnesium alloy (bioabsorbable Mg alloy), and a drug-containing fibroin layer 2 formed on the entire surface or a part of the surface of the core structure 1. Note that a single drug-free fibroin layer may be formed between the core structure 1 and the drug-containing fibroin layer 2 or on the drug-containing fibroin layer 2.

(Core Structure)
The core structure of the stent of the present invention may be made of a conventionally known metallic material, such as stainless steel, tantalum, nickel-titanium alloys (including nitinol), cobalt-chromium alloys, non-bioabsorbable magnesium alloys, and bioabsorbable magnesium alloys.
The bioabsorbable magnesium alloy constituting the core structure of the stent of the present invention is preferably composed of a magnesium alloy containing 90 mass% or more of magnesium (Mg) as a main component, zinc (Zn), zirconium (Zr) and manganese (Mn) as accessory components, not containing at least one rare earth (RE) selected from scandium (Sc), yttrium (Y), dysprosium (Dy), samarium (Sm), cerium (Ce), gadolinium (Gd) and lanthanum (La) and not containing aluminum (Al), and containing 30 ppm or less of unavoidable impurities selected from the group consisting of iron (Fe), nickel (Ni), cobalt (Co) and copper (Cu).
In the present invention, a preferred bioabsorbable magnesium alloy contains, by mass%, 1.00 to 2.00% Zn, 0.05% or more but less than 0.80% Zr, 0.05 to 0.40% Mn, with the remainder being Mg and unavoidable impurities, and is preferably a magnesium alloy that does not contain aluminum (Al) or rare metals (RE).

(Fluoridation of magnesium alloy surface)
In order to improve the corrosion resistance of the magnesium alloy surface, it is considered to perform a chemical conversion treatment on the magnesium alloy surface. One of the most suitable chemical conversion treatments is fluoridation treatment. The conditions of the fluoridation treatment are not particularly limited as long as a magnesium fluoride layer can be formed, but for example, the magnesium alloy can be immersed in a treatment liquid such as an aqueous hydrofluoric acid solution. When immersing, it is preferable to shake the magnesium alloy at 50 to 200 ppm, preferably 80 to 150 ppm. Thereafter, the magnesium alloy on which the magnesium fluoride layer has been formed is taken out and thoroughly washed with a washing liquid (e.g., an aqueous acetone solution). For example, ultrasonic washing is performed, and when the magnesium alloy is dried after washing, it is preferable to use a method of drying the magnesium alloy at 50 to 60° C. under reduced pressure for 24 hours or more.
The magnesium fluoride layer is mainly composed of magnesium fluoride. For example, it may be mainly composed of _MgF2 , which is contained at 90% or more. Furthermore, it may contain oxides and hydroxides such as MgO and Mg(OH) ₂ as secondary components.

(Fibroin)
The fibroin used in the present invention is not particularly limited as long as it is a type of fibrous protein whose molecules are regularly arranged and composed of a crystalline portion mainly containing glycine, alanine, and serine and an amorphous portion containing tyrosine, etc. For example, it may be obtained as a commercial product, or may be extracted by a known method such as extraction from cocoons or silk glands. No crosslinking is introduced into the fibroin used in the present invention. An example of no crosslinking is when no covalent bond other than a peptide bond is formed between the functional groups of amino acids between fibroin molecules.

(Surface properties of the core structure)
As a pretreatment for smoothing the surface of the core structure and forming a uniform oxide film, the laser-machined stent framework is preferably mirror-polished.

(Structure of Core Structure of Stent)
The stent of the present invention may be of various scaffold configurations, including conventional ones, such as the scaffold configurations shown in Figures 2 and 3.

(Drug layer)
The stent of the present invention has a coating layer made of fibroin and a drug formed on the entire surface or a part of the surface of the core structure. The drug is preferably an intimal hyperplasia inhibitor, such as sirolimus, everolimus, biolimus A9, zotarolimus, paclitaxel, etc.

(Method of forming coating layer)
In order to form a coating layer containing fibroin (hereinafter, sometimes referred to as a fibroin layer), it is preferable to use a method of spray coating a fibroin solution using hexafluoroisopropanol (HFIP) as a solvent. It is preferable that the spray coating is performed by uniformly applying the fibroin solution to the entire surface of the stent framework. In addition, in order to form a fibroin layer with higher crystallinity, ethanol may be spray coated simultaneously with or after the spray coating of the fibroin solution. After the fibroin layer is formed, it is preferable to provide a drying process under reduced pressure for 24 hours or more.

(Stent performance)
As described above, a stent having a coating layer made of fibroin and a drug exhibits the desired drug release behavior in phosphate buffered saline (PBS) at 37°C, and exhibits excellent vascular endothelial cell adhesiveness and antiplatelet adhesiveness in a plasma-mimetic solution in a 5% CO2 atmosphere at ₃₇ °C.
In addition, when a stent is in use, it undergoes plastic-elastic deformation due to crimping (diameter reduction) onto a balloon catheter and stenting (diameter expansion) (Figure 4).

The present invention will be specifically explained below with reference to examples. Note that the present invention is not limited to the following examples.

As a stent sample, a core structure made of a CoCr alloy and a bioabsorbable Mg alloy was processed into a stent framework having the design shown in Figure 2. The same results were obtained when the design shown in Figure 3 was adopted.

(1) Preparation of Stent Framework Thin tubes of 150 μm thick (outer diameter 1.8 mm/inner diameter 1.5 mm) made of a CoCr alloy and a bioabsorbable Mg alloy were laser processed into the shape shown in FIG. 2 to obtain a stent framework.

(2) Electrolytic polishing The stent frameworks made of CoCr alloy and bioabsorbable Mg alloy were immersed in an electrolyte as the anode side, and connected to a metal plate as the cathode side via a DC power source, and then the stent framework of the anode was mirror-polished to a thickness of 70 μm (CoCr alloy) and 100 μm (bioabsorbable Mg alloy) by applying a voltage to obtain a core structure with a smooth surface. Note that, for the core structure made of bioabsorbable Mg alloy, surface treatment was performed using hydrofluoric acid after electrolytic polishing in order to improve the corrosion resistance of the bioabsorbable Mg alloy.

(3) Test Samples Using core structures made of CoCr alloy and bioabsorbable Mg alloy, stent samples shown in the following Examples and Comparative Examples were prepared, and then the stent samples were crimped (reduced in diameter) to an outer diameter of 1.1 mm (CoCr alloy) and 1.2 mm (bioabsorbable Mg alloy) on a balloon attached to the distal end of a balloon catheter, and then sterilized with ethylene oxide gas (EOG). A total of five samples were prepared under the same conditions.

(Evaluation of deformation conformity of fibroin layer)
In order for the stent to perform its function after placement in the blood vessel, the coating layer on the surface of the core structure must not peel off or detach. In other words, the drug-containing fibroin layer must follow the expansion (diameter expansion) of the core structure by the balloon catheter without peeling off or detaching. Therefore, a CoCr alloy stent sample crimped onto a balloon catheter was immersed in phosphate buffered saline (PBS) at 37°C for 2 minutes, and then uniformly expanded to an inner diameter of 3 mm (Figure 5), and shaken at 100 rpm for 14 days. On the 14th day, the stent sample was taken, and the changes in the surface of the stent sample were observed using a scanning electron microscope (SEM).

(Evaluation of sirolimus elution from fibroin layer)
In the same manner as in the above (evaluation of deformation tracking ability), the CoCr alloy stent sample expanded in PBS at 37° C. was shaken at 100 rpm for 14 days. The PBS was collected on the 1st, 3rd, 7th, and 14th days, and the UV absorption (278 nm) was measured using a UV-2450 ultraviolet-visible spectrophotometer (Shimadzu Corporation).

(Evaluation of corrosion prevention by fibroin layer)
The anticorrosive effect of the fibroin layer on the bioabsorbable Mg alloy stent sample was evaluated. In the same manner as described above (evaluation of deformation followability), the bioabsorbable Mg alloy stent sample expanded in a plasma simulant solution (EMEM + 10% FBS) at 37 ° C was shaken at 100 rpm for 28 days in a 5% _CO2 atmosphere. At this stage, the stent was subjected to crimping (diameter reduction) to the balloon catheter and plastic elastic deformation (physical change) due to diameter expansion (Figure 4). On the 28th day, the radial force of the extracted stent sample was measured and the surface was observed with an SEM. In addition, the sample was ultrasonically cleaned with chromic acid to completely remove corrosion products such as magnesium hydroxide, and the weight change of the core structure was evaluated (n = 5). For the radial force measurement, an RX550/650 (Machine Solutions) was used.

(Evaluation of endothelial cell adhesion of fibroin layer)
In the same manner as in the above (evaluation of deformation tracking ability), a bioabsorbable Mg alloy stent sample expanded in PBS at 37°C was placed in a cell culture medium containing 5 x ^105/500 μl of human umbilical vein endothelial cells (HUVEC) and cultured at 37°C under a 5% _CO2 atmosphere. After 4 days of culture, the stent sample was washed with PBS, and the cells on the surface of the stent sample were fixed using 2.5% glutaraldehyde + 4% paraformaldehyde. Next, after treatment with surfactant Triton X-100, the cell nuclei and cell actin were stained with DAPI and phalloidin, respectively. Then, the cell morphology on the surface of the stent sample was observed using a fluorescent microscope.

(Evaluation of anti-platelet adhesive properties of fibroin layer)
In the same manner as in the above (evaluation of deformation tracking), a bioabsorbable Mg alloy stent sample expanded in PBS at 37°C was placed in 500 μl of platelet-containing plasma and cultured under a 37°C, 5% _CO2 atmosphere. The platelet plasma was obtained by centrifuging rabbit blood at 1500 rpm for 15 minutes. After 1 hour of culture, the stent sample was washed with phosphate-buffered saline (PBS), and the cells on the surface of the stent sample were fixed using 2.5% glutaraldehyde + 4% paraformaldehyde. Next, after dehydration using an aqueous ethanol solution, platelet adhesion on the surface of the stent sample was observed using a scanning electron microscope (SEM).

[Example 1]
A 1 wt % fibroin solution containing 0.5 wt % sirolimus was spray-coated on the surface of a CoCr alloy core structure to prepare a stent sample having a sirolimus-containing fibroin layer weighing 200±20 μg and having a layer thickness of 2 μm (FIG. 1).
First, the core structure was polished, and then attached to the mandrel of the coating device. At a position 9 mm below the nozzle, the coating solution in which 0.5 wt% sirolimus and 1 wt% fibroin were dissolved in HFIP was sprayed from the nozzle at 0.02 mL/min while reciprocating at 120 rpm, and the surface of the core structure was coated from the edge to the center for about 120 seconds. Then, after drying for 3 minutes under reduced pressure, the remaining half was coated. Then, the whole surface coated sample was dried under reduced pressure for 24 hours.

[Example 2]
A 1 wt% fibroin solution containing 0.5 wt% sirolimus and ethanol were simultaneously spray-coated on the surface of a core structure made of a CoCr alloy to prepare a stent sample (FIG. 1) having a sirolimus-containing fibroin layer weighing 200±20 μg and having a layer thickness of 2 μm. First, the core structure was polished, and then attached to the mandrel of a coating device. At a position 9 mm below the nozzle, a coating solution in which 0.5 wt% sirolimus and 1 wt% fibroin were dissolved in HFIP and ethanol were simultaneously sprayed from the nozzle at 0.02 mL/min while performing a reciprocating motion with 120 rpm, and the surface of the core structure from the edge to the center was coated for about 120 seconds. Then, after drying under reduced pressure for 3 minutes, the remaining half was coated. Then, the entire surface coated sample was dried under reduced pressure for 24 hours.

[Comparative Example 1]
Using the same method as in Example 1, a THF solution of 1 wt % polylactic acid (PLLA) containing 0.5 wt % sirolimus was spray-coated onto the surface of a CoCr alloy core structure to prepare a stent sample having a sirolimus-containing PLLA layer weighing 200±20 μg and having a layer thickness of 2 μm.

(Results of evaluation of deformation conformity of fibroin layer)
The surfaces of the stent samples taken immediately after expansion to an inner diameter of 3 mm and on the 14th day after shaking were observed, and the results are shown in FIGS.
In the sirolimus-containing fibroin layer of the stent samples (Examples 1 and 2) based on the present invention, no cracks were observed during diameter expansion (Figs. 6 and 7), suggesting that the stent has excellent adhesion to the core structure and deformation conformability. On the other hand, in the stent sample (Comparative Example 1) having sirolimus-containing PLLA that does not correspond to the present invention, multiple cracks were observed during diameter expansion (Fig. 8), suggesting that PLLA with excellent crystallinity has difficulty in conforming to diameter expansion.

(Evaluation results of sirolimus elution from fibroin layer)
The amount of sirolimus dissolved in PBS was quantified on days 1, 3, 7, and 14 after shaking. The sirolimus dissolution rate was calculated based on the amount of sirolimus applied to the surface of the core structure before immersion in PBS, and the results are shown in Table 1.
The stent samples (Examples 1 and 2) having a sirolimus-containing fibroin layer based on the present invention showed sirolimus elution over time, suggesting that the crystal structure of fibroin has both excellent sirolimus-holding and sustained-release capabilities.On the other hand, the stent sample (Comparative Example 1) having a sirolimus-containing PLLA layer not corresponding to the present invention showed sirolimus elution on the first day, but did not change over time from the third day onwards, suggesting that the excellent crystallinity of PLLA suppressed sirolimus elution.

[Example 3]
Using the same method as in Example 1, a 1 wt % fibroin solution containing 0.5 wt % sirolimus was spray-coated onto the surface of a core structure made of a bioabsorbable Mg alloy to prepare a stent sample (Figure 1) having a sirolimus-containing fibroin layer of 200±20 μg in total.

[Comparative Example 2]
Using the same method as in Example 1, a THF solution of 1 wt % PLLA containing 0.5 wt % sirolimus was spray-coated onto the surface of a bioabsorbable Mg alloy core structure to prepare a stent sample having a total of 200±20 μg of a sirolimus-containing PLLA layer.

[Comparative Example 3]
Stent samples were prepared by polishing a core structure made of a bioabsorbable Mg alloy.

(Results of evaluation of corrosion prevention by fibroin layer)
On the 28th day after shaking, the weight of the core structure of the collected stent sample was measured and the surface of the core structure was observed. The weight remaining rate after immersion and shaking was calculated based on the weight of the core structure before immersion. The results are shown in Table 2, and the results of surface SEM observation are shown in Figures 9 and 10. The weight of the core structure before immersion was 5.9 mg in both cases.
Furthermore, the radial force remaining rate of the stent samples after immersion and shaking was calculated based on the radial force of the stent samples before immersion, and the results are shown in Table 3. The radial force of each of the stent samples before immersion was 64.0 N/mm.

The stent sample having a sirolimus-containing fibroin layer according to the present invention (Example 3) had a higher weight residual rate and radial force residual rate than the comparative samples (Comparative Examples 2 and 3), suggesting that corrosion was suppressed by the fibroin layer. In the stent sample having a sirolimus-containing PLLA layer not corresponding to the present invention (Comparative Example 2), it was suggested that multiple cracks caused by diameter expansion were the trigger for localized corrosion. In addition, it was suggested that severe corrosion occurred in the stent sample having no coating layer (Comparative Example 3).

(Results of evaluation of endothelial cell adhesion of fibroin layer)
The results of observing the cells adhered to the surface of the stent samples on the fourth day of culture are shown in FIGS.
The cells adhered to the surface of the stent sample according to the present invention (Example 3) had extended cytoskeleton, indicating excellent cytocompatibility of the fibroin layer, compared to the comparative samples (Comparative Examples 2 and 3). On the other hand, in the stent samples not corresponding to the present invention (Comparative Examples 2 and 3), the number of adhered cells was small and the extension of the cytoskeleton was slight.

(Evaluation results of anti-platelet adhesion of fibroin layer)
The results of observing platelets adhering to the surface of the stent samples on the fourth day of culture are shown in FIGS.
The density of platelets adhered to the surface of the stent sample according to the present invention (Example 3) was clearly smaller than that of the comparative samples (Comparative Examples 2 and 3), demonstrating the excellent anti-platelet adhesive property of the fibroin layer.

The present invention contributes greatly to the development of medical technology by providing a stent that has deformation-following properties and is both adhesive to vascular endothelial cells and anti-platelet adhesive properties, and therefore has extremely high industrial applicability.

As described above, a preferred embodiment has been described with reference to the drawings. However, various changes and modifications within the obvious scope will be interpreted as falling within the scope of the invention by those skilled in the art upon reading this specification.

Claims (2)

A method for producing a stent comprising a core structure formed of a cobalt-chromium alloy and a single or multiple coating layers covering at least a part of the surface of the core structure, at least one of the coating layers containing an intimal hyperplasia inhibitor and made of fibroin to which no cross-linking has been introduced, the stent having deformation conformability and both vascular endothelial cell adhesiveness and antiplatelet adhesiveness, comprising:
A method for producing a stent, comprising spray-coating a fibroin solution containing hexafluoroisopropanol as a solvent to form the coating layer,
At least one of the coating layers is formed by spray coating a fibroin solution containing the intimal hyperplasia inhibitor. The method for manufacturing a stent according to claim 1, wherein the intimal hyperplasia inhibitor is sirolimus, everolimus, biolimus A9, zotarolimus and/or paclitaxel.

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