JP2008119199A - Stent coated with medicine for suppressing production enhancement of calcineurin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stent coated with a medicine which efficiently suppresses the occurrence of restenosis easily after indwelling a stent and reduces serious adverse effects such as stent thrombosis, and to provide a stent coated with a medicament which minimizes the breaking or the separation of the medicament coating when the stent is introduced to or placed at a lesion. <P>SOLUTION: The stent is constituted of a base material, and at least a part of a surface of the base material is coated with the medicine which suppresses the production enhancement of calcineurin. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  _{The present invention relates to a stent placed for the purpose of expanding a stenotic portion of a blood vessel and maintaining the state. In particular, the present invention relates to a drug-coated stent coated with a drug that suppresses calcineurin production enhancement, which is a serine / threonine phosphatase.}

_{It is known that various diseases occur when a stenosis occurs in a blood vessel, which is a flow path for circulating blood in the body, and the circulation of blood is delayed. It is known that when a coronary artery that supplies blood to the heart, which is the source of blood circulation, is stenotic, it can cause serious diseases such as angina pectoris and myocardial infarction, resulting in an extremely high risk of death. Yes. One of the methods for treating such a stenotic portion of a blood vessel is angioplasty (PTA, PTCA) in which the stenotic portion is expanded using a balloon catheter, and is minimally invasive without requiring a thoracotomy such as a bypass operation. It is widely used because it is a therapy. However, in the case of angioplasty, restenosis occurs in a stenosis portion expanded at a frequency of about 40%, which has been pointed out as a major problem. As a treatment method for reducing the frequency of occurrence of restenosis (restenosis rate), stent placement is widely performed instead of angioplasty.}

_{A stent is a medical device that is placed for the purpose of expanding a stenotic site and maintaining the state when a living body lumen such as a blood vessel, a bile duct, or a urethra is stenotic. Generally, a stent is composed of a metal, a polymer, or a composite thereof, and is most commonly composed of a metal such as SUS316 steel, a Co—Cr alloy, or a Ni—Ti alloy.}

_{The expansion mechanism of the stent is roughly classified into a self-expandable type that expands due to shape memory property and superelasticity of the stent itself and a balloon expandable type that expands by a balloon catheter. A balloon expansion type is mainly used for treatment of a coronary artery stenosis.}

_{When treating a stenosis of a coronary artery with a balloon expandable stent, the stent is inserted and expanded while being held by a balloon catheter. The restenosis rate after stent placement is about 20% to 30%. Although it is significantly reduced compared to post-angioplasty with a balloon catheter alone, restenosis still occurs at a high frequency.}

_{Stent placement causes physical damage to the stenosis. Excessive neointimal thickening that occurs as a repair response to this injury is believed to cause restenosis after stenting. Thickening of the neointima is caused by proliferation of smooth muscle cells in the vascular media, migration of the proliferated smooth muscle cells to the intima, migration of T cells and macrophages to the intima, and the like.}

_{In recent years, as shown in Patent Document 1, for the purpose of reducing the restenosis rate after stent placement, a technique for coating a stent with a drug using various polymers has been disclosed. Drug-coated stents are called drug-coated stents, and many indications such as anticoagulants, antiplatelet drugs, antibacterial drugs, antitumor drugs, antimicrobial drugs, antiinflammatory drugs, and antimetabolite drugs are being studied. .}

_{Patent Document 2 discloses a stent coated with sirolimus (rapamycin), and Patent Document 3 discloses a stent coated with taxol (paclitaxel), which is an antitumor drug. Furthermore, Patent Document 4 and Patent Document 5 disclose a stent coated with tacrolimus (FK506).}

_{Tacrolimus (FK506) is a compound having CAS number 104987-11-3, and is disclosed in Patent Document 6, for example. Tacrolimus (FK506) forms a complex with intracellular FK506 binding protein (FKBP) and inhibits the production of cytokines such as IL-2 and INF-γ, which are differentiation / proliferation factors, from T cells. It is shown. Therefore, it is used as a preventive or therapeutic agent for rejection at the time of organ transplantation and autoimmune diseases. Non-patent document 1 confirms that tacrolimus (FK506) has antiproliferative activity against human vascular smooth muscle cells (non-patent document 1).}

_{As a method for retaining a drug on a stent, Patent Document 1 discloses that a drug is supported using a polymer, and that a biodegradable polymer is also used. Patent Document 7 also discloses the use of a biodegradable polymer, and a polymer such as polylactic acid is specifically exemplified.}

_{In Non-Patent Document 2, when a stent coated with sirolimus or paclitaxel using a polymer that does not degrade in vivo is placed in a patient who has hypersensitivity to these polymers, a serious condition such as stent thrombosis occurs in the chronic phase. It has been reported that side effects occur.}

_{Non-Patent Document 3 suggests that neointimal thickening becomes prominent from about 3 months after the placement of the drug-coated stent and continues at least until about 6 months.}

_{Calcineurin is a Ca2 + / calmodulin (CaM) -dependent serine / threonine phosphatase, a heterogeneous molecule comprising calcineurin A (CnA) having a molecular weight of 61 kDa having an active group and calcineurin B (CnB) having a molecular weight of 19 kDa as a regulatory subunit. It is a double protein.}

_{Calcineurin is a target molecule for the immunosuppressive drugs cyclosporine and tacrolimus, and it is known that the activity is inhibited by these drugs. This inhibition of activity results from the formation of a complex by binding cyclosporine and tacrolimus to a specific intracellular binding protein called immunophilin. This complex binds to calcineurin via CnB and inhibits its dephosphorylation activity, thereby suppressing cytokine production via NF-AT (Nucleor Factor of Activated T-cell), which is a transcription factor of T cells. It is known to exert an inhibitory action.}

_{In recent years, it has been suggested that calcineurin and its signaling mechanism may affect neointimal thickening after vascular injury by balloon, but its relevance to restenosis after stent placement has not been clarified.}
Japanese Patent Publication No. 5-502179 JP-A-6-009390 JP-T 9-503488 International Publication No. WO02 / 065947 European Patent Application Publication No. EP1255464 JP-A-61-148181 Japanese translation of PCT publication No. 2002-531183 Paul J. et al. Mohacsi MD, et al. The Journal of Heart and Lung Transplantation May 1997 Vol. 16, no. 5, 484-491 Jonathan R. Nebeker, et al. J Am Coll Cardiol. 2006 Volume 47 175-181 R Virmani, et al. Heart. 2003, 89, 133-138

_{The problem to be solved by the present invention is to easily provide a drug-coated stent that efficiently suppresses the occurrence of restenosis after stent placement and reduces serious side effects such as stent thrombosis. Another object of the present invention is to provide a drug-coated stent that minimizes the cracking and peeling of the drug coating when a stent is introduced into or placed in a lesion.}

  _{As a result of intensive studies by the present inventors in order to solve the above problems, the present invention having the following features has been completed.}

_{(1) One of the features of the present invention is a stent composed of a base material, and the stent is coated with a drug that suppresses calcineurin production enhancement on at least a part of the surface of the base material.}

_{(2) Another feature of the present invention is that a calcineurin expression rate in the intima of a blood vessel that comes into contact with the stent is 23% or less three months after the stent is placed in the blood vessel.}

_{(3) Another feature of the present invention is that the calcineurin expression rate in the media of the blood vessel in contact with the stent is 25% or less 3 months after the stent is placed in the blood vessel.}

_{(4) Another feature of the present invention is that the calcineurin expression suppression rate in the intima is 77% or more 3 months after the stent is placed in a blood vessel.}

_{(5) Another feature of the present invention is that the calcineurin expression suppression rate in the media is 68% or more 3 months after the stent is placed in a blood vessel.}

_{(6) Another feature of the present invention is that the drug is an immunosuppressant.}

_{(7) Another feature of the present invention is that the immunosuppressive agent is tacrolimus, cyclosporine, pimecrolimus, or an analog thereof.}

_{(8) Another feature of the present invention is that the immunosuppressive agent is tacrolimus.}

_{(9) Another feature of the present invention is that the weight of the tacrolimus coated per unit axial length of the stent is 6 μg / mm or more and 15 μg / mm or less.}

_{(10) Another feature of the present invention is that a polymer is coated together with the drug.}

_{(11) Another feature of the present invention is that the polymer is a biodegradable polymer.}

_{(12) Another feature of the present invention is that the biodegradable polymer contains 35% methanol by volume and has a pH of 3.0 or more and 4.0 or less in a buffer solution. Under the immersion conditions in which the functional polymer is immersed and maintained at 37 ° C.
(A) the weight of the biodegradable polymer is reduced to 50% of the weight before immersion at any point in the period of 6 to 12 weeks after immersion; and
(B) The weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 18 weeks after immersion.
It has the characteristic.}

_{(13) Another feature of the present invention is that the biodegradable polymer is further immersed under the immersion conditions.
(C) the weight of the biodegradable polymer is reduced to 50% of the weight before soaking at any point in the period of 8 to 10 weeks after soaking; and
(D) The weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 16 weeks after immersion.
It has the characteristic.}

_{(14) Another feature of the present invention is that the biodegradable polymer contains 35% methanol by volume and has a pH of 3.0 or more and 4.0 or less in a buffer solution. Under the immersion conditions in which the functional polymer is immersed and maintained at 37 ° C.
(E) The weight loss rate calculated from the weight of the biodegradable polymer does not exceed 2.0% per day until 3 weeks after immersion.
It has the characteristic.}

_{(15) Another feature of the present invention is that the biodegradable polymer is further immersed under the immersion conditions.
(F) The weight loss rate calculated from the weight of the biodegradable polymer does not exceed 2.0% per day during the period until the biodegradable polymer is completely degraded.
It has the characteristic.}

_{(16) Another feature of the present invention is that
(G) the biodegradable polymer weight per unit axial length of the stent is 23 μg / mm or more and 25 μg / mm or less; and
(H) After the biodegradable polymer is dissolved in chloroform within a concentration range of 0.5 wt% to 1 wt%, the intrinsic viscosity measured within a temperature range of 25 ° C. to 30 ° C. is 0.4 dL / g or more 0.7 dL / g or less.}

_{(17) Another feature of the present invention is that the drug / polymer weight ratio coated on the stent surface is 0.20 or more and 0.70 or less.}

_{(18) Another feature of the present invention is a polymer in which the biodegradable polymer is any of lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, and dioxanone. It is characterized by that.}

_{(19) Another feature of the present invention is that the biodegradable polymer comprises at least two kinds of lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, and dioxanone. It is a polymer.}

_{(20) Another feature of the present invention is that the polymer is polylactic acid.}

_{(21) Another feature of the present invention is that the polylactic acid measured by gel permeation chromatography has a standard polystyrene equivalent weight average molecular weight of 40,000 or more and 100,000 or less.}

_{(22) Another feature of the present invention is that the copolymer is a lactic acid-glycolic acid copolymer.}

_{(23) Another feature of the present invention is that the lactic acid-glycolic acid copolymer measured by gel permeation chromatography has a standard polystyrene equivalent weight average molecular weight of 80,000 or more and 100,000 or less, and the lactic acid-glycol The acid copolymer contains lactic acid in an amount of 80 mol% to 90 mol%, and glycolic acid in an amount of 10 mol% to 20 mol%.}

_{(24) Another feature of the present invention is that the drug coated on the stent and the polymer form a layered structure.}

_{(25) Another feature of the present invention is that the layered structure is a single layer structure.}

_{(26) Another feature of the present invention is a two-layer structure in which the layered structure is composed of an inner layer and an outer layer, and both the inner layer and the outer layer contain the drug and the polymer, and the drug in the inner layer The biodegradable polymer weight ratio is higher than the drug / biodegradable polymer weight ratio in the outer layer.}

_{The stent according to the present invention easily provides a drug-coated stent that efficiently suppresses the occurrence of restenosis after stent placement and reduces serious side effects such as stent thrombosis. Further, even when a drug is coated using a biodegradable polymer, it is possible to minimize the inflammatory reaction due to the degradation of the biodegradable polymer.}

  _{Hereinafter, a “stent” according to the present invention will be described based on embodiments. The “stent” of the embodiment is formed into a generally tubular body and is extensible radially outward of the tubular body.}

_{1. Base material
The “substrate” as an embodiment of the present invention forms a skeleton of a stent. For example, it can be produced by cutting a cylindrical material tube into a stent design by laser cutting or the like.}

  _{The “substrate” in the present invention is composed of a material that is substantially non-degradable in vivo. The “substantially non-degradable material in the living body” used in the present invention means that the material is not biodegradable, but does not require that it is not decomposed at all in the living body. That is, it is sufficient if the shape and function can be maintained for a long period of about 5 to 10 years, and these are referred to as “substantially non-degradable materials in vivo”.}

_{Examples of the “substantially non-degradable material in vivo” in the embodiment include stainless steel, Ni—Ti alloy, Cu—Al—Mn alloy, tantalum, Co—Cr alloy, iridium, iridium oxide, and niobium. Inorganic materials such as metal materials, ceramics, and hydroxyapatite are preferably used.}

_{The stent base material can be produced by a method that is usually produced by those skilled in the art. For example, as described above, the stent base material can be produced by cutting a cylindrical material tube into a stent design by laser cutting or the like. Electropolishing may be performed after laser cutting. In addition, the “substantially non-degradable material in the living body” in the embodiment is not limited to a metal material or an inorganic material, and polyolefin, polyolefin elastomer, polyamide, polyamide elastomer, polyurethane, polyurethane elastomer, polyester, polyester elastomer, polyimide Polymer materials such as polyamide imide and polyether ether ketone can also be used. The method for producing a stent base material using these polymer materials does not limit the effects of the present invention, and a processing method suitable for each material can be arbitrarily selected. In addition, since the stent base material of the present invention is composed of a substantially non-degradable material in vivo, the stent base material has sufficient stent strength when compared with a stent composed of a biodegradable material. It is maintained for a long period of time, and the effect of maintaining the expansion of the stenosis is extremely high.}

_{2. coating
In the stent of the present invention, it is sufficient that at least a part of the base material surface is coated with a drug that suppresses calcineurin production enhancement, but the outer surface, the inner surface, and the side surface of the base material are almost entirely coated. It is preferable. By having the coating layer on almost the entire surface of the base material, it becomes difficult for platelets to adhere to the surface of the stent after the stent placement. Such suppression of platelet adhesion can significantly reduce the risk of excessive thrombus formation and vascular occlusion in the acute phase after stent placement.}

_{3. Drug
The drug used in the present invention has the property of suppressing the increase in calcineurin production. The drug is preferably an immunosuppressant, and the immunosuppressant is preferably tacrolimus, cyclosporine, pimecrolimus, or an analog thereof, and particularly preferably tacrolimus. By using these drugs, calcineurin production enhancement can be efficiently suppressed, and restenosis after stent placement is efficiently suppressed.}

_{When tacrolimus is used as the drug, the weight of tacrolimus coated per axial unit length of the stent is preferably 6 μg / mm or more and 15 μg / mm or less. When the tacrolimus weight does not exceed 6 μg / mm, the absolute value of the tacrolimus weight is small and it becomes difficult to suppress restenosis. On the other hand, when tacrolimus weight exceeds 15 μg / mm, the biodegradable polymer weight used for coating tacrolimus on the stent is 23 μg / mm or more and 25 μg / mm or less per axial unit length of the stent. Therefore, the weight of tacrolimus with respect to the weight of the biodegradable polymer is increased, and as a result, dissolution of tacrolimus from the stent is accelerated, which is not preferable.}

_{4). Suppression of increased calcineurin production
The stent according to the present invention is coated with a drug that suppresses the increase in calcineurin production, but the calcineurin expression rate in the intima of the blood vessel that comes into contact with the stent three months after the stent is placed in the blood vessel Is preferably 23% or less. Moreover, it is preferable that the calcineurin expression rate in the media of the blood vessel contacting with the stent is 25% or less after 3 months from the placement of the stent in the blood vessel. By setting the calcineurin expression rate within the above range, restenosis after stent placement is efficiently suppressed.}

_{The method for evaluating the calcineurin expression rate is a method using pathologically common immunostaining, and the type of the evaluation method does not hinder the effects of the present invention. For example, three months after placing the stent in the blood vessel of the experimental animal, the stent is removed together with the blood vessel, and fixed by immersing in an arbitrary fixing solution. (Immersion fixation) Neutral buffered formalin solution may be used as a suitable fixing solution. In addition, the fixing method is not limited to the above-described immersion fixing, and fixing may be performed by perfusing a fixing solution into the blood vessel before extracting the stent together with the blood vessel. (Perfusion fixation) Although the kind of fixing solution used at the time of perfusion fixation is not particularly limited, a neutral buffered formalin solution is preferably used. Further, a combination of perfusion fixation and immersion fixation may be performed. According to a standard method, a block is prepared by embedding a fixed blood vessel with paraffin. Two continuous sliced sections are prepared from the block using a microtome. The stent may or may not be removed from the blood vessel when the sliced slice is prepared. The presence or absence of stent removal does not affect this evaluation method. The preferred section thickness is 1 μm to 30 μm.}

_{According to a standard method, hematoxylin-eosin staining (HE staining) is performed on one of the prepared sections. The remaining one is immunostained with calcineurin antibody. H. E. From the stained image of the stained section, the total number of cells present in the intima or media (hereinafter referred to as the total number of cells) is counted under a microscope. In addition, the number of calcineurin positive cells present in the intima or media of the blood vessel is counted under a microscope from the stained image of the section subjected to immunostaining for calcineurin. (Hereinafter referred to as the “cell number counting method”.) According to Equation 1, the expression rate in the intima or media is calculated.}

_{Here, the vascular intima generally corresponds to a portion closer to the blood vessel lumen than the inner elastic plate in an artery having a three-layer structure. Further, the media corresponds to a portion outside the inner elastic plate and inside the outer elastic plate in an artery generally having a three-layer structure.}

_{In this method of evaluating the expression rate, any animal species may be used as an experimental animal, but it is preferable to use a porcine coronary artery.
(Expression 1) Expression rate (%) = [(number of positive cells of calcineurin) / (total number of cells in inner membrane or media)] × 100}

_{As another method, the area of the vascular intima or media and the area of the stained portion are measured from the obtained immunostained image. You may calculate the expression rate in each according to Formula 2 from each area value. (Hereinafter referred to as “area measurement method”.) As the area measurement method, measurement using a computer is preferable, and commercially available image processing software can be used. However, as suitable software, developed by the National Institutes of Health. “NIH Image” can be used.
(Expression 2) Expression rate (%) = [(Area stained with calcineurin immunostaining) / (Total area of intima or media)] × 100}

_{In addition, the stent according to the present invention preferably has a calcineurin expression suppression rate of 77% or more in the intima three months after the stent is placed in a blood vessel. Furthermore, it is preferable that the calcineurin expression suppression rate in the media is 68% or more 3 months after the stent is placed in a blood vessel. By setting the calcineurin expression suppression rate within the above range, restenosis after stent placement is efficiently suppressed.}

_{The method for evaluating the calcineurin expression inhibition rate does not hinder the effects of the present invention. For example, the calcineurin expression rate in the intima or media is calculated by the cell count method or the area measurement method described above. Furthermore, a stent composed of only the base material is evaluated by the same method, and the calcineurin expression rate is calculated. The calcineurin expression suppression rate is determined according to Equation 3.
(Expression 3) Expression suppression rate (%) = [1 − {(Expression rate in stent according to the present invention) / (Expression rate in stent composed of only base material)}] × 100}

_{5-1. High molecular
The stent of the embodiment is preferably coated with a polymer together with the drug. Coating with the polymer not only slows the release of the drug, but also significantly reduces the risk of cracking and peeling of the coating layer associated with stent expansion. Furthermore, it becomes possible to coat a larger amount of the drug than when only the drug is coated. In the present application, “polymer” means a polymer compound.}

_{The polymer is preferably a biodegradable polymer. By using a biodegradable polymer, all of the polymer disappears due to biodegradation in the chronic period after stent placement, and only the base material remains in the body. By using SUS316L, a Co—Cr alloy, or a Ni—Ti alloy, for example, a proven material as a base material, it is possible to easily realize a safe and reliable stent even in the chronic phase.}

_{5-2. Degradation characteristics of biodegradable polymers
The biodegradable polymer of the embodiment contains 35% methanol by volume, and the biodegradable polymer is immersed in a buffer solution having a pH of 3.0 or more and 4.0 or less at 37 ° C. (A) the weight of the biodegradable polymer is reduced to 50% of the weight before soaking at any point in the period from 6 weeks to 12 weeks after soaking, b) Preferably, the biodegradable polymer has a characteristic that the weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 18 weeks after immersion.
As the buffer solution, an acidic phosphate buffer (pH3.4, NaCl: 6.1g / L} , NaH2 PO 4 · 2H 2 O: 7.1g / L, H 3 PO 4: 263μL / L) is used .

By using a biodegradable polymer having both the above characteristics (a) and (b), an inflammatory reaction due to the degradation of the biodegradable polymer after stent placement can be suppressed. In addition, an effective amount of the drug can be eluted over a long period of time.

From the viewpoint of lowering the inflammatory reaction due to the degradation of the biodegradable polymer, the weight of the biodegradable polymer at any point in the period of 8 to 10 weeks after the immersion (c) under the above immersion conditions. Is reduced to 50% of the weight before immersion, (d) the weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 16 weeks after immersion. It is preferable to use a biodegradable polymer having such characteristics.

On the other hand, when the above-mentioned property (a) is not satisfied, that is, when the weight does not decrease to 50% before immersion in any period from 6 weeks to 12 weeks after the immersion, the effective amount of the drug does not dissolve, It is not preferable. In addition, when the weight is less than 50% before immersion 6 weeks before immersion, the occurrence of an inflammatory reaction due to degradation of the biodegradable polymer is increased, which is not preferable.

Furthermore, when the characteristics of (a) are satisfied but the characteristics of (b) are not satisfied, that is, when the weight is reduced to 50% before immersion at any point in the period from 6 weeks to 12 weeks after immersion. Even if the weight does not decrease to 10% before immersion at any point in the period from 14 weeks to 18 weeks after immersion, elution of an effective amount of the drug does not occur, which is not preferable. Also, even if the weight decreases to 50% before immersion at any point in the period from 6 weeks to 12 weeks after immersion, the weight will be less than 10% before immersion by 14 weeks after immersion. In such a case, an inflammatory reaction due to degradation of the biodegradable polymer is increased, which is not preferable.

The biodegradable polymer of the embodiment contains 35% methanol by volume, and the biodegradable polymer is immersed in a buffer solution having a pH of 3.0 or more and 4.0 or less at 37 ° C. It is preferable that the following weight loss rate calculated from the weight measured every other week (e) does not exceed 2.0% per day until 3 weeks after immersion.

By using a biodegradable polymer exhibiting a weight loss rate not exceeding 2.0% per day until 3 weeks after immersion, an inflammatory reaction due to degradation of the biodegradable polymer after stent placement can be suppressed. In addition, an effective amount of the drug can be eluted over a long period of time. The use of a biodegradable polymer showing a weight reduction rate exceeding 2.0% per day until 21 days after immersion is not preferred because the induction of an inflammatory reaction due to the degradation of the biodegradable polymer is increased.

Furthermore, from the viewpoint of enabling an effective amount of drug to be eluted over a long period of time while maintaining the strength of the coating layer, the biodegradable polymer is (f) the biodegradable measured every other week under the above immersion conditions. It is preferable that the weight loss rate calculated from the weight of the degradable polymer does not exceed 2.0% per day during the period until the biodegradable polymer is completely degraded. In addition to this characteristic, it is preferable that the weight of the biodegradable polymer is reduced to 10% before immersion. This characteristic is expressed as “(f ′) the weight reduction rate does not always exceed 2.0% during the period up to the point when the weight of the biodegradable polymer is reduced to 10% of the weight before immersion”. can do.

By providing the above-described characteristics, it is possible to suppress a decrease in strength of the coating layer due to biodegradation of the biodegradable polymer to a minimum, and to significantly reduce the risk of cracking and peeling of the coating layer.

On the other hand, the weight loss rate does not exceed 2.0% per day until 21 days after immersion, but the weight loss rate exceeds 2.0% until the weight decreases to 10% before immersion. In the case of the biodegradable polymer having, the occurrence of an inflammatory reaction due to biodegradation of the biodegradable polymer is suppressed, but the coating layer is peeled off only slightly.

5-3. Intrinsic viscosity and coating amount of biodegradable polymer The weight of the biodegradable polymer per axial unit length of the stent in the embodiment is 23 μg / mm or more and 25 μg / mm or less, and After the biodegradable polymer is dissolved in chloroform within a concentration range of 0.5 wt% to 1 wt%, the intrinsic viscosity measured within a temperature range of 25 ° C. to 30 ° C. is 0.4 dL / g or more, and It is preferable that it is 7 dL / g or less. By constructing such a stent, it is possible to coat an effective amount of drug using a biodegradable polymer with as little weight as possible. Note that 1 dL = 100 cm ³ .

When the weight of the biodegradable polymer per unit axial length of the stent is less than 23 μg / mm, particularly less than 13 μg / mm, in order to coat an effective drug amount, Therefore, it is necessary to set the drug weight higher. In this case, the drug elutes from the stent very quickly, which is not preferable. Further, by setting the drug weight lower than the biodegradable polymer weight, it is possible to give sustained release to the elution of the drug, but it is not preferable because an effective drug amount cannot be coated.

On the other hand, when the weight of the biodegradable polymer per unit axial length of the stent exceeds 25 μg / mm, particularly when it exceeds 40 μg / mm, an inflammatory reaction due to biodegradation of the biodegradable polymer is strong. It is induced and exceeds the restenosis-suppressing effect of the drug, so that restenosis tends to occur, which is not preferable.

It is known that information on the molecular weight of a polymer can be obtained from the viscosity of a general polymer solution containing a biodegradable polymer. The viscosity of the polymer solution can be measured by using a viscosity type such as Ubbelohde type or Ostwald type. The viscosity of the polymer solution can be measured according to international standards such as ASTM D2857-95, ASTM D5225-98, ASTM D445-97, and ISO 1628-1. A measurement method is defined.

When the viscosity of the polymer solution thus measured is η and the viscosity of the solvent is η ₀ , the value obtained by subtracting 1 from the relative viscosity defined by η / η ₀ is called the specific viscosity η _sp , (η -[Eta] ₀ ) / [eta] ₀ . The specific viscosity corresponds to an increase in viscosity caused by dissolving the polymer in the solvent. The specific viscosity is a function of the concentration of the dissolved polymer, and the value obtained by extrapolating the specific viscosity to zero is called the intrinsic viscosity. Intrinsic viscosity is a value related to the particle size and molecular weight of a polymer dissolved in a solution, and it is considered that the larger the intrinsic viscosity, the larger the molecular weight.

In general, it is known that the biodegradation rate decreases as the molecular weight increases when the types and constituent ratios of the monomers constituting the biodegradable polymer are equal.

The biodegradable polymer used in the stent according to the present invention is dissolved in chloroform within a concentration range of 0.5 wt% to 1 wt%, and then has an intrinsic viscosity of 0 measured within a temperature range of 25 ° C. to 30 ° C. It is preferable that it is 4 dL / g or more and 0.7 dL / g or less. When the intrinsic viscosity is less than 0.4 dL / g, the molecular weight of the biodegradable polymer is relatively small, so that the degradation rate of the biodegradable polymer is slightly increased. As a result, the dissolution of the drug is relatively unfavorable. In addition, when the intrinsic viscosity exceeds 0.7 dL / g, the molecular weight of the biodegradable polymer is relatively large, and the flexibility of the biodegradable polymer is lowered. The decrease in flexibility is not preferable because it causes cracking and peeling of the coating layer accompanying expansion of the stent.

5-4. Biodegradable polymer (example of polymer)
Although there are a wide variety of biodegradable polymers (biodegradable polymers), the biodegradable polymer according to the present invention takes into account the biocompatibility of the biodegradable polymer itself and the safety of the degradation products. Then, a polymer composed of any one of lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, and dioxanone is preferable.

In view of preventing the coating layer from cracking and peeling when the stent is expanded, the polymer is more preferably polylactic acid.

Polylactic acid is composed of poly-D-lactic acid composed only of D-lactic acid, poly-L-lactic acid composed solely of L-lactic acid, and D-lactic acid and L-lactic acid. There are three types of poly-D and L-lactic acid, and any polylactic acid may be used to achieve the object of the present invention.

Since the molecular weight of the polymer is not monodispersed but distributed, there are multiple indicators such as number average molecular weight, weight average molecular weight, Z-average molecular weight, and viscosity average molecular weight as indicators for molecular weight, and there are multiple measurement methods. To do. For example, a number average molecular weight, a weight average molecular weight, and a Z-average molecular weight are obtained as standard polymer conversion values from a molecular weight distribution measured by gel permeation chromatography (GPC). The viscosity average molecular weight is determined from the viscosity measurement of the diluted solution. In addition, the weight average molecular weight is determined by the light scattering method and the sedimentation velocity method (ultracentrifugation method).

When the weight average molecular weight of the polylactic acid is measured by gel permeation chromatography (GPC), it is preferably 40,000 or more and 100,000 or less in terms of standard polystyrene. By using polylactic acid of 40,000 or more and 100,000 or less, the desired decomposition characteristics can be suitably achieved.

If less than 40,000, not only will the weight be less than 50% before soaking at any point in the 6 to 12 week period after soaking, but any of the 14 to 18 week periods after soaking Since the weight is less than 10% before immersion at the time, it is not preferable. Moreover, the weight reduction rate until 21 days after immersion exceeds 2.0% per day, which is not preferable because the occurrence of an inflammatory reaction due to the degradation of the biodegradable polymer is increased.

If it exceeds 100,000, not only does the weight decrease to 50% before soaking at any point in the period from 6 weeks to 12 weeks after soaking, but any of the periods from 14 weeks to 18 weeks after soaking Since the weight does not decrease to 10% before immersion at the time, it is not preferable. Moreover, although the weight reduction rate until 21 days after immersion does not exceed 2.0% per day, it is not preferable because the coating layer is easily cracked or peeled off due to the expansion of the stent.

5-5. Biodegradable polymer (example of copolymer)
In addition, the biodegradable polymer according to the present invention is lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, considering the biocompatibility of the biodegradable polymer itself and the safety of the degradation product. , Tetramethylene carbonate, and dioxanone are preferable.

Considering the viewpoint of preventing the coating layer from cracking and peeling when the stent is expanded, the copolymer is preferably a lactic acid-glycolic acid copolymer. When the lactic acid contained in the lactic acid-glycolic acid copolymer is only D-lactic acid, only L-lactic acid, and may contain both D-lactic acid and L-lactic acid. However, in order to achieve the object of the present invention, any lactic acid-containing copolymer may be used.

When the weight average molecular weight of the lactic acid-glycolic acid copolymer is measured by gel permeation chromatography (GPC), it is preferably 80,000 or more and 100,000 or less in terms of standard polystyrene, and the lactic acid- The glycolic acid copolymer preferably contains lactic acid in an amount of 80 mol% to 90 mol% and glycolic acid in an amount of 10 mol% to 20 mol%. By using such a lactic acid-glycolic acid copolymer, the intended weight change characteristic can be suitably achieved. In addition, the said composition shows mol% of the monomer contained in a copolymer. The mol% of the monomer contained in the copolymer can be measured using 1H NMR method.

The biodegradation behavior of the lactic acid-glycolic acid copolymer is determined by the weight average molecular weight and the molar ratio of lactic acid and glycolic acid. When the weight average molecular weight is constant, the decomposition rate becomes the fastest when lactic acid is contained at 50 mol% and glycolic acid is contained at 50 mol%, and the decomposition rate becomes slower as lactic acid increases or glycolic acid increases. In addition, when the molar ratio of lactic acid and glycolic acid is constant, the decomposition rate decreases as the weight average molecular weight increases.

When the weight average molecular weight of the lactic acid-glycolic acid copolymer is measured by gel permeation chromatography (GPC), the amount of lactic acid is more than 90 mol% even when the standard polystyrene conversion value is 80,000 or more and 100,000 or less. When glycolic acid is less than 10 mol%, not only does the weight decrease to 50% before soaking at any point in the period from 6 weeks to 12 weeks after soaking, but also the period from 14 weeks to 18 weeks after soaking At any point in time, the weight does not decrease to 10% before immersion, which is not preferable.

Furthermore, when lactic acid is less than 80 mol% and glycolic acid is more than 20 mol%, not only does the weight become less than 50% before immersion at any point in the period from 6 weeks to 12 weeks after immersion, It is not preferable because the weight becomes less than 10% before immersion at any point in the period from 14 weeks to 18 weeks. Moreover, the weight reduction rate until 21 days after immersion exceeds 2.0% per day, which is not preferable because the occurrence of an inflammatory reaction due to the degradation of the biodegradable polymer is increased.

Further, even when the lactic acid contained in the lactic acid-glycolic acid copolymer is 80 mol% or more and 90 mol% or less and the glycolic acid is 10 mol% or more and 20 mol% or less, the weight average molecular weight is measured by gel permeation chromatography. If the standard polystyrene equivalent value is less than 80,000, not only does the weight become less than 50% before soaking at any point in the period from 6 weeks to 12 weeks after soaking, but from 14 weeks after soaking. This is not preferred because the weight will be less than 10% before soaking at any point in the 18 week period. In addition, the rate of weight loss until 21 days after immersion exceeds 2.0% per day, which increases the induction of an inflammatory reaction due to the degradation of the biodegradable polymer.

Furthermore, if it exceeds 100,000, not only does the weight decrease to 50% before soaking at any point in the 6 to 12 week period after soaking, but also for the period of 14 to 18 weeks after soaking. Since the weight does not decrease to 10% before immersion at any time, it is not preferable. In addition, the risk of cracking and peeling of the coating layer accompanying the expansion of the stent increases, which is not preferable.

6-1. Coating layer (single layer structure)
The coating layer preferably has a layered structure. The layered structure can be a single layer structure or a multilayer structure as described below.

When the coating layer has a single layer structure, the drug / biodegradable polymer weight ratio defined as the weight of the drug contained in the coating layer divided by the weight of the biodegradable polymer contained in the coating layer. Is preferably 0.20 or more and 0.70 or less. When the value is less than 0.20, the thickness of the coating layer necessary for increasing the amount of drug retained on the stent is increased, and the flexibility of the stent is greatly reduced, which is not preferable. On the other hand, if it exceeds 0.70, the coating layer is liable to crack or peel during stent expansion, which is not preferable.

6-2. Coating layer (two-layer structure)
The coating layer may have a two-layer structure composed of an inner layer and an outer layer, and contains a drug in both the inner layer and the outer layer, and is a drug / biodegradable polymer defined in each of the inner layer and the outer layer. It is preferable that the inner layer has a higher weight ratio. The action of the outer layer having a low drug / biodegradable polymer weight ratio effectively reduces the occurrence of cracking and peeling of the coating layer during stent expansion. Since the weight ratio of the drug / biodegradable polymer in the outer layer is lower than that in the inner layer, drug elution is gradually released at the initial stage of stent placement. Since the inner layer drug elutes after the outer layer drug is completely eluted, the biodegradable polymer contained in the outer layer serves as a barrier layer, and the inner layer drug has a relatively high drug / biodegradable polymer weight ratio. With regard to the above, the sustained release of elution is realized. Moreover, since the weight ratio of the drug / biodegradable polymer in the inner layer is high, it is possible to increase the drug retention amount of the entire stent.

The weight ratio between the inner layer and the outer layer is arbitrarily determined according to the specifications of the target stent. For example, in the case of specifications focusing on increasing the amount of drug retained, it is preferable to set the weight of the inner layer higher than that of the outer layer, and specifications focusing on imparting sustained release of drug elution In this case, it is preferable to set the weight of the outer layer higher than that of the inner layer.

The drug / biodegradable polymer weight ratio defined as the sum of the drug weights contained in the inner layer and the outer layer divided by the sum of the biodegradable polymer weights contained in the inner layer and the outer layer is 0.20. As mentioned above, it is preferable that it is 0.70 or less. When the value is less than 0.20, the thickness of the coating layer necessary for increasing the amount of drug retained on the stent is increased, and the flexibility of the stent is greatly reduced, which is not preferable. On the other hand, if it exceeds 0.70, the coating layer is liable to crack or peel during stent expansion, which is not preferable.

Layers other than the inner layer and the outer layer may be provided for the purpose of further increasing the amount of drug retained, imparting sustained release of drug elution, and suppressing cracking and peeling of the coating layer during stent expansion. As an example, an intermediate layer may be provided between the inner layer and the stent surface in order to suppress cracking or peeling of the coating layer during stent expansion.

7). Method for forming a coating layer Method for forming each layer regardless of whether the coating layer has a single-layer structure or a two-layer structure in which the coating layer includes an inner layer and an outer layer Is not particularly limited.

Hereinafter, the case where the coating layer has a two-layer structure including an inner layer and an outer layer will be described in detail.

As a preferred example of the method for forming the coating layer, the drug constituting the inner layer and the biodegradable polymer are dissolved in an arbitrary solvent, adhered to the surface of the stent base material in a solution state, and the solvent is removed. Examples include a method in which a drug constituting the outer layer and a biodegradable polymer are dissolved in an arbitrary solvent and adhered to the outer surface of the inner layer in a solution state to remove the solvent.

Further, after separately preparing a film composed of a drug constituting the inner layer and a biodegradable polymer and attaching the film to a stent substrate, separately preparing a film composed of the drug constituting the outer layer and a biodegradable polymer You may affix on the outer surface of an inner layer.

Of course, the drug constituting the inner layer and the biodegradable polymer are dissolved in an arbitrary solvent, adhered to the surface of the stent base material in a solution state and removed, and then the drug constituting the outer layer and the biodegradable polymer are added. It may be formed by separately preparing a film made of molecules and affixing it to the outer surface of the inner layer, and after separately preparing a film made of the drug constituting the inner layer and a biodegradable polymer and affixing it to the stent substrate Alternatively, the agent and the biodegradable polymer constituting the outer layer may be dissolved in an arbitrary solvent, adhered to the outer surface of the inner layer in a solution state, and the solvent removed. The effect of the present invention is not limited by the method of forming the inner layer and the outer layer, and various methods can be suitably used.

When the biodegradable polymer and the drug constituting the inner layer and the outer layer are dissolved in an arbitrary solvent and adhered in a solution state, the method does not limit the effect of the present invention. That is, various methods such as a method of dipping the stent base material in each solution and a method of spraying each solution onto the stent base material by spraying can be used. The kind of solvent to be used is not particularly limited. A solvent having a desired solubility can be suitably used, and a mixed solvent using two or more solvents may be used in order to adjust volatility and the like. Further, the concentration of the drug or biodegradable polymer as a solute is not particularly limited, and can be set to any concentration in consideration of the surface properties of the inner layer and the outer layer. In order to adjust the surface properties, the drug constituting the inner layer and / or after the biodegradable polymer is dissolved in an arbitrary solvent and adhered in a solution state, or after the deposition, or the drug constituting the outer layer and An excessive solution may be removed during or / and after the biodegradable polymer is dissolved in an arbitrary solvent and attached in a solution state. Examples of the removing means include vibration, rotation, and decompression, and a plurality of these may be combined.

In each of the following Examples and Comparative Examples, tacrolimus is exemplified and described as a drug that suppresses calcineurin production enhancement. However, the aforementioned drugs other than tacrolimus, or immunosuppressive agents may be used.

(Example 1)
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: 85DG065, standard polystyrene equivalent weight average molecular weight 85,000, intrinsic viscosity 0.6 dL / g), coating layer: multilayer)

The stent base material is cut into a closed stent design by laser cutting a cylindrical tube of stainless steel (SUS316L) with an inner diameter of 1.50 mm and an outer diameter of 1.80 mm, in the same manner as those usually produced by those skilled in the art. It was prepared by polishing. The design was such that the stent length was 13 mm, the thickness was 120 μm, and the nominal diameter after expansion was 3.5 mm. The total surface area of the inner, outer and side surfaces of the stent substrate is 88.5 mm ² .

  Lactic acid-glycolic acid copolymer (product number: 85DG065, Absorbable Polymers International, lactic acid / glycolic acid = 85 mol% / 15 mol%, standard polystyrene equivalent weight average molecular weight 85,000) as biodegradable polymer, tacrolimus (as a drug) Astellas Pharma Inc.) was dissolved in chloroform (Wako Pure Chemical Industries, Ltd.) to prepare a solution having a drug concentration / biodegradable polymer concentration = 0.50 wt% / 0.50 wt%. A stainless steel wire having a diameter of 100 μm was fixed to one end of the stent, and the other end was fixed to a stainless steel rod having a diameter of 2 mm. The end of the stainless steel rod not connected to the stent was connected to a motor agitator to hold the stent vertically in the length direction. While rotating the stent at 100 rpm using a motor stirrer, the solution prepared using a spray gun having a nozzle diameter of 0.3 mm was sprayed onto the stent to adhere the solution to the stent. The distance from the spray gun nozzle to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spraying time was adjusted to form an inner layer (drug / biodegradable polymer weight ratio = 1.00) having a biodegradable polymer weight of 160 μg and a drug weight of 160 μg per stent.

  Lactic acid-glycolic acid copolymer (product number: 85DG065, Absorbable Polymers International, lactic acid / glycolic acid = 85 mol% / 15 mol%, standard polystyrene equivalent weight average molecular weight 85,000) as biodegradable polymer, tacrolimus (as a drug) Astellas Pharma Inc.) was dissolved in chloroform (Wako Pure Chemical Industries, Ltd.) to prepare a solution having a drug concentration / polymer concentration = 0.13 wt% / 0.50 wt%. A stainless steel wire having a diameter of 100 μm was fixed to one end of the stent on which the inner layer was formed, and the other end was fixed to a stainless steel rod having a diameter of 2 mm. The end of the stainless steel rod not connected to the stent was connected to a motor agitator to hold the stent vertically in the length direction. While rotating the stent at 100 rpm using a motor stirrer, the solution prepared using a spray gun having a nozzle diameter of 0.3 mm was sprayed onto the stent to adhere the solution to the stent. The distance from the spray gun nozzle to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spraying time was adjusted to form an outer layer (drug / biodegradable polymer weight ratio = 0.26) having a biodegradable polymer weight of 139 μg and a drug weight of 36 μg per stent.

  The total weight of the biodegradable polymer including the inner layer and outer layer per stent obtained was 299 μg, and the drug weight was 196 μg (drug / biodegradable polymer weight ratio = 0.66). A total of five stents were produced.

(Example 2)
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: 85DG065, standard polystyrene equivalent weight average molecular weight 85,000, intrinsic viscosity 0.6 dL / g), coating layer: single layer)
The stent substrate was produced in the same manner as in Example 1.

Lactic acid-glycolic acid copolymer (product number: 85DG065, Absorbable Polymers International, lactic acid / glycolic acid = 85 mol% / 15 mol%, standard polystyrene equivalent weight average molecular weight 85,000) as biodegradable polymer, tacrolimus (as a drug) Astellas Pharma Inc.) was dissolved in chloroform (Wako Pure Chemical Industries, Ltd.) to prepare a solution having a drug concentration / biodegradable polymer concentration = 0.13 wt% / 0.50 wt%. A stainless steel wire having a diameter of 100 μm was fixed to one end of the stent, and the other end was fixed to a stainless steel rod having a diameter of 2 mm. The end of the stainless steel rod not connected to the stent was connected to a motor agitator to hold the stent vertically in the length direction. While rotating the stent at 100 rpm using a motor stirrer, the solution prepared using a spray gun having a nozzle diameter of 0.3 mm was sprayed onto the stent to adhere the solution to the stent. The distance from the spray gun nozzle to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spray time was adjusted to form a coating layer (drug / biodegradable polymer weight ratio = 0.26) having a biodegradable polymer weight of 325 μg and a drug weight of 85 μg per stent. A total of five stents were produced.

(Example 3)
(Biodegradable polymer: poly-D, L-lactic acid (product number: 100D040, standard polystyrene equivalent weight average molecular weight 40,000, intrinsic viscosity 0.4 dL / g), coating layer: single layer)
The stent 1 was prepared in the same manner as in Example 2 except that poly-D, L-lactic acid (product number: 100D040, Absorbable Polymers International, standard polystyrene equivalent weight average molecular weight 40,000) was used as the biodegradable polymer. A coating layer (drug / biodegradable polymer weight ratio = 0.26) having a biodegradable polymer weight of 313 μg and a drug weight of 82 μg was formed. A total of five stents were produced.

Example 4
(Biodegradable polymer: poly-D, L-lactic acid (product number: 100D065, weight average molecular weight of standard polystyrene equivalent 86,000, intrinsic viscosity 0.7 dL / g), coating layer: single layer)
The stent 1 was prepared in the same manner as in Example 2 except that poly-D, L-lactic acid (product number: 100D065, Absorbable Polymers International, standard polystyrene equivalent weight average molecular weight 86,000) was used as the biodegradable polymer. A coating layer (drug / biodegradable polymer weight ratio = 0.26) having a biodegradable polymer weight of 322 μg and a drug weight of 84 μg was formed. A total of five stents were produced.

(Comparative Example 1)
Four stents composed only of a stent substrate were prepared.

(Weight change test (no drug))
As a weight change test, a stent using the biodegradable polymer used in each of the above examples was prepared as described below. However, unlike the above examples, no drug is used.

The same stent substrate as in Example 1 was used. Each of the three types of biodegradable polymers used in the production of Example 1 to Example 4 was dissolved in chloroform (Wako Pure Chemical Industries, Ltd.), and three types of solutions with biodegradable polymer = 0.50 wt% were obtained. Produced. A stainless steel wire having a diameter of 100 μm was fixed to one end of the stent, and the other end was fixed to a stainless steel rod having a diameter of 2 mm. The end of the stainless steel rod not connected to the stent was connected to a motor agitator to hold the stent vertically in the length direction.

While rotating the stent at 100 rpm using a motor agitator, three types of solutions prepared using a spray gun having a nozzle diameter of 0.3 mm were sprayed on different stents to attach the solutions to the stent. The distance from the spray gun nozzle to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spray time was adjusted, and a coating layer containing only the biodegradable polymer was formed on the stent.

The weight of the biodegradable polymer per stent is 305 μg for 85DG065, 400 μg for 100D040, and 420 μg for 100D065. Three stents were prepared for each biodegradable polymer.

To 100 mL of acidic phosphate buffer (pH 3.4, NaCl: 6.1 g / L, NaH ₂ PO ₄ .2H ₂ O: 7.1 g / L, H ₃ PO ₄ : 263 μL / L) containing 35 vol% methanol One stent was immersed and shaken in a 37 ° C. water bath. Under this immersion condition, each stent was pulled up from the buffer solution after a predetermined time and washed with distilled water. Thereafter, it was vacuum-dried at room temperature, and the weight of the biodegradable polymer was measured. The sample after the measurement was immersed in the original buffer and continued to be immersed in a 37 ° C. water bath. Compared with the weight before immersion, the residual ratio of the weight was calculated. Moreover, the weight reduction rate per day on any measurement day was also calculated. The results are shown in Table 1. In addition, the residual rate measurement of the weight was performed 1 day, 3 days, and 7 days after the start of shaking, and after 7 days, the measurement was performed every 7 days. The weight reduction rate per day was measured every 7 days from the start of shaking. (Measured at weekly intervals). The results are shown in Table 2.
Residual ratio of weight (%) = [(weight before immersion−weight after vacuum drying) / (weight before immersion)] × 100
Weight reduction rate per day (%) = (residual rate of weight 7 days ago−residual rate of weight on measurement day) / 7

As shown in Table 1, the biodegradable polymers (product numbers: 85DG065, 100D040, 100D065) used in Examples 1 to 4 according to the present invention are any one of 6 to 12 weeks after immersion. It was shown that the weight was reduced to 50% before soaking at the time point and that the weight was reduced to 10% before soaking at any point in the period from 14 to 18 weeks after soaking.

Referring to Tables 1 and 2, the biodegradable polymers (product numbers: 85DG065, 100D040, 100D065) used in Examples 1 to 4 according to the present invention were measured every other week. It was shown that the weight loss rate calculated from the weight did not exceed 2.0% per day until 21 days after immersion. Furthermore, the biodegradable polymer (Product No. 85DG065) used in Example 1 and Example 2 always has a weight loss rate of 2 per day during a period of at least 140 days after the start of soaking. It has a characteristic that the weight is reduced to 10% before immersion without exceeding 0.0%. Based on this result, in general, the biodegradable polymer (product number: 85DG065) is always used during the period until the biodegradable polymer is completely degraded (at a residual rate of 0%). The weight loss rate is estimated not to exceed 2.0% per day.

(Stent expansion test)
A stent expansion test was performed using each of the stents of Examples 1 to 4. (Since Comparative Example 1 is a stent made of only a base material, no test was conducted.) 2. A stent held in a balloon portion of a 3.5 × 15 mm balloon catheter in physiological saline kept at 37 ° C. Expanded to 5 mm. After expansion, the balloon catheter was removed from the stent. The expanded stent was taken out from physiological saline, washed with distilled water, and then vacuum-dried. Using a scanning electron microscope (S-3000N, Hitachi High-Technologies Corporation), the presence or absence of cracking or peeling of the coating layer was evaluated. The results are shown in Table 3.

In Example 1 and Example 2, no cracking or peeling of the coating layer was observed. In Examples 3 and 4, although the coating layer was only slightly cracked, it did not peel off.

(Evaluation of calcineurin expression rate and expression suppression rate)
A block embedded with paraffin was prepared using one stent-incorporated coronary artery sample (preliminarily immersed and fixed in a 10% neutral buffered formalin solution) obtained in an indwelling experiment in a minipig described later. Two thin slices having a thickness of 5 μm were obtained continuously from the block. Upon acquisition, the stent was removed from the section. For one of the prepared sections, H.P. E. Staining was performed, and immunostaining using calcineurin antibody was performed on the other sheet. Based on each stained image, the total number of cells existing in the intima or media and the number of calcineurin positive cells were counted under a microscope, and the expression rate was calculated from Equation 4. The results are shown in Table 4. Moreover, the expression suppression rate in Examples 1 to 4 was calculated from Equation 5 based on the expression rate in the stent of the base material only (Comparative Example 1). The results are shown in Table 5.
(Expression 4) Expression rate (%) = [(number of calcineurin positive cells) / (total number of cells in the intima or media)] × 100
(Expression 5) Expression suppression rate (%) = [1-{(expression rate in each example) / (expression rate in comparative example 1)}] × 100

As shown in Table 4, the calcineurin expression rate in Examples 1 to 4 is 23% or less in the intima and 25% or less in the media, whereas in Comparative Example 1, which is a base-only stent, in the intima As high as 98% and 78% in the middle film. Further, as shown in Table 5, the calcineurin expression inhibition rate in Examples 1 to 4 was 76% or more in the inner membrane and 68% or more in the media. The low calcineurin expression rate and the high calcineurin expression suppression rate in Examples 1 to 4 are considered to be due to suppression of calcineurin production enhancement by the effect of tacrolimus.

(Indwelling experiment in miniature pig)
Using each of the stents of Examples 1 to 4 and Comparative Example 1, a stent placement experiment was performed on a minipig (crown, female, age 8 to 12 months), and the vascular occlusion rate was evaluated. All stents were EOG sterilized in a state where the balloon was previously held in the balloon portion of a balloon catheter having a balloon size of 3.5 × 15 mm.

Under anesthesia, a 6Fr sheath introducer was inserted into the right femoral artery of the minipig, and the tip of the 6Fr guiding catheter inserted through the sheath was engaged with the left coronary artery entrance. After delivering the stent to the left anterior descending coronary artery and the left coronary artery via the guiding catheter, the stent was expanded and placed. After removing the guiding catheter and sheath, the right femoral artery was ligated and hemostasis was performed. The portion where the stent is placed is a portion having a blood vessel diameter of about 2.80 mm, and the stent expansion diameter is 3.50 mm, so that the stent diameter / blood vessel diameter ratio in the placement portion is about 1.25. When a site having a blood vessel diameter of 2.80 mm could not be selected, the expansion pressure of the balloon when the stent was expanded / indwelled was changed to adjust the stent diameter / blood vessel diameter ratio to about 1.25. In this experiment, the inner diameter of the stent was defined as the stent expansion diameter. If it is judged that it is difficult to expand or place the stent in the left anterior descending coronary artery or the left coronary artery due to problems with the vessel diameter or blood vessel running, the stent placement in that part is canceled and the right It was placed in the coronary artery. In both examples and comparative examples, an indwelling experiment was performed with n = 4. Ten minipigs were used, and two stents were placed per one.

Aspirin 330 mg / day and ticlopidine 250 mg / day were mixed and administered from the day before the indwelling experiment to the day of necropsy. Three months after placement, the minipig was euthanized and the heart was removed. The coronary artery in which the stent was placed was removed from the heart and immersed and fixed in a 10% neutral buffered formalin solution. Three of the fixed specimens were embedded using a polymethyl methacrylate resin. Subsequently, a thin slice of the center of each stent was prepared using a microtome. E. Staining (hematoxylin and eosin staining), and E. coli. V. G. Staining (Elastica one-Gieson staining) was performed and magnified observation was performed. In addition, the whole stent was sliced at the time of preparing the section, and the stent was not removed from the section. As evaluation items, the vascular lumen area (LA: Lumen Area) and the inner area of the intravascular elastic plate (IELA) were measured for each stent cross section. The vascular occlusion rate of each sample was calculated according to the following formula using the vascular lumen area (LA) and the intravascular elastic plate inner area (IELA). The average value of n = 3 occlusion rates was taken as the measured value. The results are shown in Table 6.
Vessel occlusion rate (%) = [1- (LA / IELA)] × 100

As shown in Table 6, in Examples 1 to 4, the vascular occlusion rate was less than 40%, and good patency was recognized. As a result of detailed examination of the stained sections, no findings suggesting inflammation judged to be caused by the degradation of the biodegradable polymer were found.

  Further, from Tables 4 and 6, since there is a correlation between the calcineurin expression rate and the vascular occlusion rate, and the calcineurin expression suppression rate and the vascular occlusion rate, it is important to enhance the production of calcineurin even in restenosis after stent placement. It was strongly suggested that he played a role.

Claims (26)

  _{A stent comprising a base material, wherein the stent is coated on at least a part of the base material with a drug that suppresses calcineurin production enhancement.   The stent according to claim 1, wherein a calcineurin expression rate in an intima of a blood vessel that comes into contact with the stent is 23% or less three months after the stent is placed in a blood vessel.   2. The stent according to claim 1, wherein a calcineurin expression rate in the media of the blood vessel in contact with the stent is 25% or less after 3 months from placement of the stent in a blood vessel.   2. The stent according to claim 1, wherein a calcineurin expression suppression rate in the intima is 77% or more 3 months after the stent is placed in a blood vessel.   The stent according to claim 1, wherein a calcineurin expression suppression rate in the media is 68% or more 3 months after the stent is placed in a blood vessel.   The stent according to any one of claims 1 to 5, wherein the drug is an immunosuppressant.   The stent according to claim 6, wherein the immunosuppressant is tacrolimus, cyclosporine, pimecrolimus, or an analog thereof.   The stent according to claim 7, wherein the immunosuppressive agent is tacrolimus.   The stent according to claim 8, wherein the weight of the tacrolimus coated per unit axial length of the stent is 6 µg / mm or more and 15 µg / mm or less.   The stent according to any one of claims 1 to 9, wherein a polymer is coated together with the drug.   The stent according to claim 10, wherein the polymer is a biodegradable polymer.   The biodegradable polymer is
  Under immersion conditions in which the biodegradable polymer is immersed in a buffer solution containing 35% methanol by volume and having a pH of 3.0 or more and 4.0 or less and maintained at 37 ° C.,
(A) the weight of the biodegradable polymer is reduced to 50% of the weight before immersion at any point in the period of 6 to 12 weeks after immersion; and
(B) The weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 18 weeks after immersion.
The stent according to claim 11, which has the following characteristics.   The biodegradable polymer is further immersed under the immersion conditions.
(C) the weight of the biodegradable polymer is reduced to 50% of the weight before soaking at any point in the period of 8 to 10 weeks after soaking; and
(D) The weight of the biodegradable polymer is reduced to 10% of the weight before immersion at any point in the period from 14 weeks to 16 weeks after immersion.
The stent according to claim 12, having the following characteristics.   The biodegradable polymer is
  Under immersion conditions in which the biodegradable polymer is immersed in a buffer solution containing 35% methanol by volume and having a pH of 3.0 or more and 4.0 or less and maintained at 37 ° C.,
(E) The weight loss rate calculated from the weight of the biodegradable polymer does not exceed 2.0% per day until 3 weeks after immersion.
The stent according to claim 11, which has the following characteristics.   The biodegradable polymer is further immersed under the immersion conditions.
(F) The weight loss rate calculated from the weight of the biodegradable polymer does not exceed 2.0% per day during the period until the biodegradable polymer is completely degraded.
The stent according to claim 14, which has the following characteristics.   The biodegradable polymer is:
(G) the biodegradable polymer weight per unit axial length of the stent is 23 μg / mm or more and 25 μg / mm or less; and
(H) After the biodegradable polymer is dissolved in chloroform within a concentration range of 0.5 wt% to 1 wt%, the intrinsic viscosity measured within a temperature range of 25 ° C. to 30 ° C. is 0.4 dL / g or more The stent according to claim 11, wherein the stent is 0.7 dL / g or less.   The stent according to claim 10, wherein a weight ratio of the drug / the polymer coated on the stent surface is 0.20 or more and 0.70 or less.   The biodegradable polymer is a polymer comprising any one of lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, and dioxanone. The stent according to any one of the above.   The biodegradable polymer is a copolymer composed of at least two of lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, and dioxanone. The stent according to any one of 11 to 17.   The stent according to claim 18, wherein the polymer is polylactic acid.   The stent according to claim 20, wherein the polylactic acid has a standard polystyrene equivalent weight average molecular weight of 40,000 or more and 100,000 or less as measured by gel permeation chromatography.   The stent according to claim 19, wherein the copolymer is a lactic acid-glycolic acid copolymer.   The polystyrene equivalent weight average molecular weight of the lactic acid-glycolic acid copolymer measured by gel permeation chromatography is 80,000 or more and 100,000 or less, and lactic acid is 80 mol% or more in the lactic acid-glycolic acid copolymer. The stent according to claim 22, wherein the stent is contained in an amount of 90 mol% or less and glycolic acid is contained in an amount of 10 mol% to 20 mol%.   The stent according to any one of claims 10 to 23, wherein the drug coated on the stent and the polymer form a layered structure.   The stent according to claim 24, wherein the layered structure is a single layer structure.   The layered structure is a two-layer structure composed of an inner layer and an outer layer, the drug and the polymer are included in both the inner layer and the outer layer, and the drug / biodegradable polymer weight ratio in the inner layer is 25. The stent of claim 24, wherein the stent is higher than the drug / biodegradable polymer weight ratio in the outer layer.}