JP2007312987A - Stent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To easily provide a stent for which an effective medicament amount for enabling a restenosis to be suppressed is coated by using as little weight as possible of a biodegradable polymer. <P>SOLUTION: This stent uses a material which is practically non-degradable in the living body as the stent base material, and has a coating layer the major components of which are the medicament and the biodegradable polymer at least at a part of the surface of the stent base material. The biodegradable polymer keeps (a) the biodegradable polymer weight per unit length in the axial direction of the stent ranging from 13 μg/mm to 25 μg/mm, and (b) the intrinsic viscosity which is measured at 30°C by dissolving the biodegradable polymer with chloroform ranging from 0.6 dL/g to 0.7 dL/g. <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.

  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 have many indications such as anticoagulants, antiplatelet drugs, antibacterial drugs, antitumor drugs, antimicrobial drugs, anti-inflammatory drugs, antimetabolite drugs, and immunosuppressive drugs. It is being considered. Examples for immunosuppressive agents include: coating a stent with cyclosporine, tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil, and their analogs (evalolimus, ABT-578, CCI-779, AP23573, etc.) Attempts have been made to reduce restenosis.

  For example, Patent Document 2 discloses a stent coated with sirolimus (rapamycin) known as an immunosuppressive agent, and Patent Document 3 discloses a stent coated with taxol (paclitaxel), which is an antitumor agent. Furthermore, for example, 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, such as a stent thrombosis in the chronic phase It has been reported that side effects occur.
Japanese Patent Publication No. 5-502179 JP-A-6-009390 JP-T 9-503488 WO02 / 065947 EP1254644 JP-A-61-148181 Japanese translation of PCT publication No. 2002-531183 Paul J. 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 47: 175-181

  Many of the biodegradable polymers used in stents have higher biocompatibility than the polymers described above in the background art section, and generally, it is difficult to cause serious side effects such as stent thrombosis. It is considered. However, when a specific biodegradable polymer is used for medical applications, there is a report that an inflammatory reaction due to a decomposition product occurs. Against this background, when coating a biodegradable polymer with a drug on a stent, it is necessary to use a biodegradable polymer that has an effective amount of drug that can suppress restenosis as little as possible. Is not disclosed.

  In view of these circumstances, an object of the present invention is to easily provide a stent coated with a biodegradable polymer having a weight as small as possible with an effective amount of drug capable of suppressing restenosis.

As a result of intensive studies by the present inventors in order to solve the above-mentioned problems, the present invention having the following features has been completed.
(1) One of the characteristics of the present invention is a stent using a substantially non-degradable material in vivo as a stent base material, and the stent has a drug on at least a part of the surface of the stent base material. The biodegradable polymer has a coating layer mainly composed of a biodegradable polymer, and the biodegradable polymer includes the following: (a) the biodegradable polymer per unit axial length of the stent The weight is 13 μg / mm or more and 25 μg / mm or less, and (b) the intrinsic viscosity measured at 30 ° C. by dissolving the biodegradable polymer in chloroform is 0.6 dL / g or more and 0.7 dL / g It is characterized by having the following characteristics.
(2) Another feature of the present invention is that the drug is an immunosuppressant.
(3) Another feature of the present invention is that the immunosuppressive agent is tacrolimus (FK506), cyclosporine, sirolimus, azathioprine, mycophenolate mofetil, or an analog thereof.
(4) Another feature of the present invention is that the immunosuppressive agent is tacrolimus (FK506).
(5) Another feature of the present invention is that the tacrolimus further has (a ′) a weight of the tacrolimus per axial unit length of the stent of 6 μg / mm to 16 μg / mm.
(6) Another feature of the present invention is that the weight ratio of tacrolimus / biodegradable polymer in the coating layer is 0.20 or more and 0.70 or less.
(7) Another feature of the present invention is that the biodegradable polymer is polylactic acid.
(8) Another feature of the present invention is that the polylactic acid contains 50 mol% of D-lactic acid and 50 mol% of L-lactic acid.
(9) Another feature of the present invention is that the biodegradable polymer is a lactic acid-glycolic acid copolymer.
(10) Another feature of the present invention is that the lactic acid-glycolic acid copolymer contains 85 mol% of lactic acid and 15 mol% of glycolic acid.
(11) Another feature of the present invention is that the coating layer has a single layer structure.
(12) Another feature of the present invention is a two-layer structure in which the coating layer is composed of an inner layer and an outer layer, and both the inner layer and the outer layer contain the drug and the biodegradable polymer, The drug / biodegradable polymer weight ratio of the inner layer is higher than the drug / biodegradable polymer weight ratio of the outer layer.

  Other features of the present invention and their advantages will become apparent from the description of the embodiments below.

  With the stent according to the present invention, a stent coated with a biodegradable polymer having an effective drug amount as low as possible can be easily provided, and restenosis can be efficiently reduced.

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. Stent base material A “stent base material” as an embodiment of the present invention can be produced, for example, by cutting a tubular material tube into a stent design by laser cutting or the like.

  The “stent substrate” in the present invention is composed of a material that is substantially non-degradable in vivo. The “substantially non-degradable material in vivo” used in the present invention means that the material is not biodegradable, but does not require that it is not degraded 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. The stent of the coating layer embodiment may have a coating layer mainly composed of a drug and a biodegradable polymer on at least a part of the surface of the stent substrate. It is preferable to have the coating layer on almost the entire inner surface and side surface. As described above, when the coating layer is provided on almost the entire surface of the stent base material, platelets hardly 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.

In the concept of “consisting mainly of a drug and a biodegradable polymer”, the weight ratio of the total of the drug and the biodegradable polymer among all the components contained in the coating layer is 50% or more. In addition to the case, it includes a case where an amount that exhibits each function of the drug effect and biodegradability is included regardless of the weight ratio.
3-1. The weight of the biodegradable polymer per unit axial length of the stent in the biodegradable polymer embodiment is 13 μg / mm or more and 25 μg / mm or less, and the biodegradable polymer is dissolved in chloroform. The intrinsic viscosity measured at 30 ° C. is preferably 0.6 dL / g or more and 0.7 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.

  When the biodegradable polymer weight per axial unit length of the stent is less than 13 μg / mm, the drug weight is increased with respect to the biodegradable polymer weight in order to coat an effective drug amount. Must be set to 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, Ostwald type, etc. A measurement method is defined.

  When the viscosity of the polymer solution measured in this way is η and the viscosity of the solvent is η0, a value obtained by subtracting 1 from the relative viscosity defined by η / η0 is called a specific viscosity ηsp, and (η−η0) / Η0. 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.

  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 preferably dissolved in chloroform and the intrinsic viscosity measured at 30 ° C. is 0.6 dL / g or more and 0.7 dL / g or less. When the intrinsic viscosity does not exceed 0.6 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.
4). Drug The drug is preferably an immunosuppressant. Further, the immunosuppressive agent is preferably tacrolimus (FK506), cyclosporine, sirolimus, azathioprine, mycophenolate mofetil, or an analog thereof, and more preferably tacrolimus (FK506). By using a drug having an effect of suppressing the proliferation of vascular smooth muscle cells in this way, restenosis after stent placement can be suppressed.

  When tacrolimus is used as the drug, the weight of the tacrolimus per unit axial length of the stent is preferably 6 μg / mm or more and 16 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 the tacrolimus weight exceeds 16 μg / mm, the biodegradable polymer weight used for coating the stent with the tacrolimus is not less than 13 μg / mm and 25 μg / mm per axial unit length of the stent. Therefore, the weight of the tacrolimus is larger than the weight of the biodegradable polymer, and as a result, the dissolution of the tacrolimus from the stent is accelerated, which is not preferable.

  That is, the tacrolimus / biodegradable polymer weight ratio in the coating layer of the stent is preferably 0.20 or more and 0.70 or less. When it exceeds 0.70, the weight of the tacrolimus coated on the stent becomes larger than the weight of the biodegradable polymer, and as a result, the dissolution of the tacrolimus from the stent is accelerated. On the other hand, when it is less than 0.20, the absolute value of the tacrolimus weight coated on the stent is small, and it becomes difficult to suppress restenosis.

  There are various types of the biodegradable polymer. As an example, among monomer components selected from lactic acid, glycolic acid, γ-butyrolactone, δ-valerolactone, ε-caprolactone, tetramethylene carbonate, dioxanone, etc. Molecule and the like. The biodegradable polymer according to the present invention is a polylactic acid composed only of lactic acid, or lactic acid and glycolic acid, considering the biocompatibility of the biodegradable polymer itself and the safety of the degradation product produced by biodegradation. It is preferable that it is either the lactic acid-glycolic acid copolymer comprised from these.

  Lactic acid is known to have two types of optical isomers, which are referred to as D-lactic acid and L-lactic acid, respectively. Accordingly, polylactic acid includes poly-D-lactic acid composed only of D-lactic acid, poly-L-lactic acid composed solely of L-lactic acid, poly-D composed of D-lactic acid and L-lactic acid, There are three types of L-lactic acid. Poly-D-lactic acid and poly-L-lactic acid are crystalline polymers, and poly-D, L-lactic acid is an amorphous polymer.

  When the biodegradable polymer according to the present invention is polylactic acid, the polylactic acid is preferably poly-D, L-lactic acid, and preferably contains 50 mol% of D-lactic acid and 50 mol% of L-lactic acid. When the polylactic acid is poly-D-lactic acid or poly-L-lactic acid, it is a polymer that exhibits high crystallinity with any type of polylactic acid, which causes cracking and peeling of the coating layer as the stent expands. Easy and not preferred.

  When the polylactic acid contains a large amount of D-lactic acid, only the poly-D-lactic acid component remains with the decomposition of the polylactic acid. Since the poly-D-lactic acid component has high crystallinity, it tends to cause cracking or peeling of the coating layer, which is not preferable. Furthermore, when the polylactic acid contains a large amount of L-lactic acid, only the poly-L-lactic acid component remains with the decomposition of the polylactic acid. Since the poly-L-lactic acid component has high crystallinity, it tends to cause cracking and peeling of the coating layer, which is not preferable.

  When the biodegradable polymer according to the present invention is a lactic acid-glycolic acid copolymer, it is preferable that 85 mol% of lactic acid and 15 mol% of glycolic acid are contained. When the lactic acid-glycolic acid copolymer contains less than 85 mol% lactic acid and more than 15 mol% of glycolic acid, an inflammatory reaction is strongly induced due to biodegradation of the biodegradable polymer. In addition, when the lactic acid-glycolic acid copolymer contains more than 85 mol% of lactic acid and less than 15 mol% of glycolic acid, the lactic acid-glycolic acid copolymer becomes less flexible, and the coating is associated with the expansion of the stent. It is not preferable because the layer is easily cracked or peeled off.

The lactic acid component contained in the lactic acid-glycolic acid copolymer may be D-lactic acid alone, L-lactic acid alone, or both D-lactic acid and L-lactic acid. As in the case of polylactic acid, it is preferable that D-lactic acid and L-lactic acid are contained in equal mol%.
5. Coating layer The coating layer may have a single-layer structure or a two-layer structure composed of an inner layer and an outer layer.

  When the coating layer has a two-layer structure, both the inner layer and the outer layer contain a drug, and the drug / biodegradable polymer weight ratio defined in each of the inner layer and the outer layer is higher in the inner layer. It is preferable. 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 in the inner layer is preferably 0.50 or more and 1.60 or less. If it is less than 0.50, it is difficult to efficiently increase the amount of drug retained, which is not preferable. On the other hand, when the ratio is larger than 1.60, it is not preferable because there is a high possibility that the inner layer and the outer layer are cracked or peeled due to the expansion of the stent.

  The drug / polymer weight ratio in the outer layer is preferably 0.10 or more and 0.40 or less. If it is less than 0.10, the amount of drug retained in the outer layer is low, and it is difficult to realize a drug elution amount effective in preventing restenosis. On the other hand, when the ratio is larger than 0.40, it is not preferable because not only the possibility that the outer layer is cracked or peeled off due to the expansion of the stent is increased, but also sufficient elution and sustained release of the drug cannot be obtained. In a more preferred embodiment, a living body having a drug / polymer weight ratio in the inner layer of 0.50 to 1.60 and a drug / polymer weight ratio in the outer layer of 0.10 to 0.40. An indwelling stent is mentioned.

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.
6). Forming method of coating layer Whether the coating layer has a single layer structure or the coating layer has a two-layer structure composed of an inner layer and an outer layer, the method for forming each 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. 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), intrinsic viscosity 0.68 dL / g))
For the stent base material, a stainless steel (SUS316L) cylindrical tube having an inner diameter of 1.50 mm and an outer diameter of 1.80 mm is cut into a stent design by laser cutting and subjected to electropolishing in the same manner as those usually produced by those skilled in the art. It was produced by. 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 mm2.

  A lactic acid-glycolic acid copolymer (product number: 85DG065, lot number: API-102203-1, Absorbable Polymers International, lactic acid / glycolic acid = 85 mol% / 15 mol%) was used as the biodegradable polymer. The intrinsic viscosity measured at 30 ° C. after dissolving the biodegradable polymer in chloroform is 0.68 dL / g.

  The biodegradable polymer and tacrolimus (Astellas Pharma Inc.) are dissolved in chloroform (Wako Pure Chemical Industries, Ltd.), and a solution having a drug concentration / biodegradable polymer concentration = 0.50 wt% / 0.50 wt% is 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 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.

  A lactic acid-glycolic acid copolymer (product number: 85DG065, lot number: API-102203-1, Absorbable Polymers International, lactic acid / glycolic acid = 85 mol% / 15 mol%) was used as the biodegradable polymer. Half of the lactic acid component contained is D-lactic acid and the other half is L-lactic acid. The intrinsic viscosity measured at 30 ° C. after dissolving the biodegradable polymer in chloroform is 0.68 dL / g.

  The biodegradable polymer and tacrolimus (Astellas Pharma Inc.) were 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 (biodegradable polymer weight per axial unit length of the stent = 23.0 μg / mm), drug Is 196 μg (drug / biodegradable polymer weight ratio = 0.66, drug weight per axial unit length of the stent = 15.1 μg / mm). A total of three stents were produced.

(Example 2)
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: B6006-1P), intrinsic viscosity 0.62 dL / g))
The stent substrate was produced in the same manner as in Example 1.

  A lactic acid-glycolic acid copolymer (product number: B6006-1P, lot number: A05-003, Direct Corporation, lactic acid / glycolic acid = 85 mol% / 15 mol%) was used as the biodegradable polymer. Half of the lactic acid component contained is D-lactic acid and the other half is L-lactic acid. The intrinsic viscosity measured at 30 ° C. after dissolving the biodegradable polymer in chloroform is 0.62 dL / g.

  The biodegradable polymer and tacrolimus (Astellas Pharma Inc.) are dissolved in chloroform (Wako Pure Chemical Industries, Ltd.), and a solution having a drug concentration / biodegradable polymer concentration = 0.13 wt% / 0.50 wt% is 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 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 so that the biodegradable polymer weight per stent was 325 μg (biodegradable polymer weight per axial unit length of the stent = 25.0 μg / mm) and the drug weight was 85 μg. A coating layer (drug / biodegradable polymer weight ratio = 0.26, drug weight per axial unit length of the stent = 6.54 μg / mm) was formed. A total of three stents were produced.

(Example 3)
(Biodegradable polymer: poly-D, L-lactic acid (product number: 100D040), intrinsic viscosity 0.65 dL / g))
Poly-D, L-lactic acid (product number: 100D065, lot number: D02038, Absorbable Polymers International) was used as the biodegradable polymer. Of the lactic acid components contained, half is D-lactic acid and the other half is L-lactic acid. The intrinsic viscosity measured at 30 ° C. after dissolving the biodegradable polymer in chloroform is 0.65 dL / g.

  The biodegradable polymer was prepared in the same manner as in Example 2 except that the biodegradable polymer was used, and the weight of the biodegradable polymer per stent was 322 μg (the biodegradable polymer weight per unit axial length of the stent). = 24.8 μg / mm), drug coating weight 84 μg (drug / biodegradable polymer weight ratio = 0.26, drug weight per axial unit length of stent = 6.46 μg / mm) Formed. A total of three stents were produced.

Example 4
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: 85DG065), intrinsic viscosity 0.68 dL / g))
An inner layer (drug / biodegradable polymer weight ratio = 1.00) having a biodegradable polymer weight of 90 μg and a drug weight of 90 μg per stent is formed, and biodegradability per stent is further formed. It was produced in the same manner as in Example 1 except that an outer layer (drug / biodegradable polymer weight ratio = 0.27) having a polymer weight of 79 μg and a drug weight of 21 μg was formed. The total weight of the biodegradable polymer including the inner layer and outer layer per stent obtained was 169 μg (biodegradable polymer weight per axial unit length of the stent = 13.0 μg / mm), drug Is 111 μg (drug / biodegradable polymer weight ratio = 0.66, drug weight per axial unit length of stent = 8.54 μg / mm).

(Comparative Example 1)
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: B6006-1P)
Weight of biodegradable polymer per stent is 634 μg (biodegradable polymer weight per axial unit length of stent = 48.8 μg / mm), drug weight is 166 μg (drug / biodegradable high This was prepared in the same manner as in Example 2 except that the molecular weight ratio was 0.26 and the drug weight per unit axial length of the stent was 12.8 μg / mm.

(Comparative Example 2)
(Biodegradable polymer: lactic acid-glycolic acid copolymer (product number: 85DG065))
An inner layer (drug / biodegradable polymer weight ratio = 1.00) having a biodegradable polymer weight of 334 μg and a drug weight of 334 μg per stent is formed, and biodegradability per stent is further formed. It was produced in the same manner as in Example 1 except that an outer layer (drug / biodegradable polymer weight ratio = 0.26) having a polymer weight of 294 μg and a drug weight of 76 μg was formed. The total biodegradable polymer weight of the obtained inner layer and outer layer per stent obtained is 628 μg (biodegradable polymer weight per axial unit length of stent = 48.3 μg / mm), drug Is 410 μg (drug / biodegradable polymer weight ratio = 0.65, drug weight per axial unit length of the stent = 31.5 μg / mm).

(Indwelling experiment in miniature pig)
Using each of the stents of Example 1 to Example 4 and Comparative Example 1 to Comparative Example 2, a stent placement experiment on a minipig (crown, female, age 8 to 12 months) was performed and 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.

  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. After embedding the resin, a section at the center of each stent was prepared. E. Staining (hematoxylin and eosin staining), and E. coli. V. G. Staining (Elastica one-Gieson staining) was performed and magnified observation was performed. 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).

Vessel occlusion rate (%) = [1- (LA / IELA)] × 100
In both Examples and Comparative Examples, an indwelling experiment was performed with n = 3, and an average value of n = 3 was taken as a measured value.

  Table 1 is a table | surface which shows the vascular occlusion rate (%) in each Example and a comparative example.

表１に示すように本発明に係る実施例１から４では、血管閉塞率が４０％を下回っており、良好な開存性が認められた。染色切片を詳細に検討した結果、生分解性高分子の分解に起因すると判断される炎症を示唆する所見は認められなかった。

As shown in Table 1, in Examples 1 to 4 according to the present invention, 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.

On the other hand, in Comparative Examples 1 and 2, the vascular occlusion rate was as high as 60% or more, and it was determined that restenosis occurred. In the stained section, infiltration of inflammatory cells was remarkably observed in the thickened neointima, and it was estimated that the influence of the biodegradable polymer degradation (inflammatory action) was expressed more than the effect of the drug. .

Claims (12)

A stent based on a substantially non-degradable material in vivo, as a stent substrate,
The stent is
It has a coating layer mainly composed of a drug and a biodegradable polymer on at least a part of the surface of the stent base material,
The biodegradable polymer includes the following:
(A) the biodegradable polymer weight per unit axial length of the stent is not less than 13 μg / mm and not more than 25 μg / mm, and
(B) The intrinsic viscosity measured at 30 ° C. by dissolving the biodegradable polymer in chloroform is 0.6 dL / g or more and 0.7 dL / g or less.
A stent characterized by having the following characteristics.   The stent according to claim 1, wherein the drug is an immunosuppressant.   The stent according to claim 2, wherein the immunosuppressive agent is tacrolimus (FK506), cyclosporine, sirolimus, azathioprine, mycophenolate mofetil, or an analog thereof.   The stent according to claim 3, wherein the immunosuppressive agent is tacrolimus (FK506). The tacrolimus is further
(A ′) the tacrolimus weight per axial unit length of the stent is 6 μg / mm or more and 16 μg / mm or less;
The stent according to claim 4.   The stent according to claim 5, wherein the weight ratio of tacrolimus / biodegradable polymer in the coating layer is 0.20 or more and 0.70 or less.   The stent according to any one of claims 1 to 6, wherein the biodegradable polymer is polylactic acid.   The stent according to claim 7, wherein the polylactic acid contains 50 mol% of D-lactic acid and 50 mol% of L-lactic acid.   The stent according to any one of claims 1 to 6, wherein the biodegradable polymer is a lactic acid-glycolic acid copolymer.   The stent according to claim 9, wherein the lactic acid-glycolic acid copolymer contains 85 mol% of lactic acid and 15 mol% of glycolic acid.   The stent according to any one of claims 1 to 10, wherein the coating layer has a single-layer structure. The coating layer has a two-layer structure composed of an inner layer and an outer layer, the drug and the biodegradable polymer are included in both the inner layer and the outer layer, and the drug / biodegradable polymer weight ratio of the inner layer The stent according to any one of claims 1 to 10, wherein the ratio is higher than the drug / biodegradable polymer weight ratio of the outer layer.