JPWO2015147183A1 - Zinc alloy tubular material and method for producing the same, stent using the same, and method for producing the same - Google Patents

Abstract

As a metal material constituting a medical instrument such as a stent, it is easy to be absorbed by a living body after being implanted into a living body, but its absorption rate is not too fast, and has mechanical properties such as a predetermined high strength, Provided are a bioabsorbable zinc alloy tube material excellent in workability in cold working or the like and a stent using the same. SOLUTION: Al is selected from the group consisting of 0.1-5% by mass, Mn 0.1-5% by mass, Mg 0.1-5% by mass, and rare earth 0.1-5% by mass. A zinc alloy containing at least one element, Fe less than 0.05% by mass, O less than 0.1% by mass, and the balance consisting of zinc and 0.1% by mass or less of inevitable impurities Tubing material and manufacturing method thereof, and stent for vasodilation using the same and manufacturing method thereof. [Selection figure] None

Description

  The present invention relates to a zinc alloy tube material exhibiting bioabsorbability and a method for producing the same, and a stent for blood vessel expansion using the same and a method for producing the same.

  A stent may be placed in a blood vessel such as a coronary artery that has been narrowed due to angina or the like for the purpose of expanding the blood vessel from the inside of the lumen. In this case, since the indwelled stent is a foreign substance to the living body, a neointimal proliferation abnormality may occur on the surface of the stent, and a thrombus may be formed. In severe cases, restenosis occurs. Therefore, it is important that vascular endothelial cells cover the stent surface and become endothelialized as early as possible. In addition, as a scaffold material for cells, the stent has a function of expanding blood vessels for a predetermined period, generally 3 to 6 months. After the endothelialization, the stent is generally 6 to 12 months or 1 to 2 years later. It is required to elute and be completely absorbed by the living body.

Currently, nickel-titanium alloys (Nitinol), stainless steel (typically SUS316L), and the like are used as metal materials for stents used for coronary artery dilation. However, these metallic materials are poorly bioabsorbable and may cause restenosis after being placed in a blood vessel. Therefore, in order to suppress this, a cell growth inhibitor, an immunosuppressant, an anti-inflammatory active agent, or the like may be used. In particular, among cell growth inhibitors, sirolimus, paclitaxel, zotarolimus, and the like, which are anticancer agents, are often used. Techniques such as applying these drugs to the stent surface have been adopted, but they have not yet completely prevented restenosis. In addition, when a stent is applied to a child, there is a problem that the attached stent cannot follow the growth of the body. Therefore, there is a demand for a metal material for a stent that is excellent in bioabsorbability and melts after a predetermined period and is absorbed by the body.
However, what has been studied as a bioabsorbable metal material until now has a problem that it is decomposed too quickly after being inserted into a blood vessel.

Therefore, as a metal material constituting a medical device such as a stent, it is easy to be endothelialized and bioabsorbed after implantation into the body, and is not too high as a stainless steel (SUS) type and is not as high as a polymer type. There is a need for a bioabsorbable zinc alloy material, for example, a zinc alloy material for stents, which is not low, has a predetermined strength and is excellent in workability.
In addition, it is a major premise that a medical device used by being implanted in a living body such as a stent is not toxic to the living body. For metal materials, in addition to the fact that the individual alloy components of the metal material are elements that are not toxic to the living body (not containing a large amount of tin, etc.), the decomposed product is also toxic to the living body. It is also important that there is no damage to the living tissue such as blood vessels due to the metal pieces not falling off during decomposition. On the other hand, from this point of view, ordinary zinc alloys that are currently generally used for structural materials and the like are not necessarily satisfactory as metal materials for medical devices.

  Here, “bioabsorbability” refers to the property of being taken into a living body when implanted in the living body. In addition to having so-called “biocompatibility” that does not harm biological functions even when implanted in a living body, it has so-called “biocompatibility” that is compatible with a living body when implanted in a living body. It is a premise and can be said to be a high-dimensional characteristic.

  Patent Document 1 includes a Zn-0.1-1 mass% Ti alloy, a Zn-0.1-2 mass% Au-0.1-1 mass% Ti alloy, a Zn-4.5 mass% or more Ca alloy ( Example 1) is disclosed, and the use of the alloy as a biodegradable coronary stent is disclosed.

US Pat. No. 6,287,332

  Regarding the Ca alloy of Zn-4.5 mass% or more described in Patent Document 1, the strength is improved as the Ca addition amount is increased, but the decomposition rate in vivo is increased. In particular, when the Fe concentration exceeds 0.05% by mass, the decomposition rate is remarkably increased. The zinc alloy described in Patent Document 1 is not yet satisfactory in terms of dissolution and absorption speed because dissolution in vivo is too fast.

  In view of the problems in the prior art as described above, the present invention, as a metal material constituting a medical instrument such as a stent, is easy to be absorbed into the living body after implantation into the living body, but its absorption speed is not too fast, It is another object of the present invention to provide a bioabsorbable zinc alloy tube material having a mechanical property such as a predetermined high strength and excellent workability in cold working or the like and a stent using the bioabsorbable zinc alloy tube material.

  The inventors of the present invention have a bioabsorbable zinc alloy that is easy to be absorbed after being implanted in a living body, but whose absorption rate is not too high, has mechanical properties such as a predetermined high strength, and is excellent in workability. We have intensively studied to develop pipe materials. As a result, by setting a specific zinc alloy composition, preferably by appropriately controlling the average crystal grain size as a metal structure, and more preferably the ratio of the tube thickness / outer diameter as the shape of the tube, A bioabsorbable zinc alloy tube material that is easy to be absorbed after implantation in a living body but has an excessively high absorption rate and has mechanical properties such as a predetermined high strength and excellent workability. I found it. The present invention has been completed based on this finding.

That is, according to the present invention, the following means are provided:
(1) At least selected from the group consisting of 0.1 to 5% by mass of Al, 0.1 to 5% by mass of Mn, 0.1 to 5% by mass of Mg, and 0.1 to 5% by mass of rare earth One or more elements are contained, Fe is less than 0.05% by mass, O is less than 0.1% by mass, and the balance is composed of zinc and 0.1% by mass or less of inevitable impurities. Zinc alloy tubing.
(2) One side or both sides of the surface of the pipe material is the composition according to claim 1, wherein at least one content of the Al, Mn, Mg and rare earth is inclined in the thickness direction of the pipe material. The zinc alloy tube material according to item (1).
(3) The zinc alloy pipe according to (1), further containing 0.1 to 5 mass% of Ca. (4) One or both sides of the pipe material surface is the composition according to (1), wherein the Al, The zinc alloy pipe according to the item (3), wherein the content of at least one of Mn, Mg, rare earth, and Ca is inclined in the thickness direction of the pipe.
(5) The zinc alloy tube material according to any one of (1) to (4), wherein the base material has an average crystal grain size of 1 to 20 μm.
(6) The zinc alloy pipe according to any one of (1) to (5), wherein a ratio of the thickness of the pipe to the pipe outer diameter is 0.02 to 0.5.
(7) The zinc alloy tube material according to any one of (1) to (6), wherein the tensile strength is higher than 300 MPa, the 0.2% proof stress is higher than 150 MPa, and the tensile breaking elongation is higher than 10%.
(8) Na ⁺ 142 mM, K ⁺ 5 mM, Mg ²⁺ 1.5 mM, Ca ²⁺ 2.5 mM, Cl ⁻ 148.8 mM, HCO ₃ ⁻ 4.2 mM, HPO ₄ ²⁻ 1 mM, SO ₄ ^2- when immersed in 37 ° C. pseudo body fluid containing (SBF) at 0.5 mM, any one of thickness reduction after 6 months is 100μm or less (1) to (7) Zinc alloy pipe material described in 1.
(9) A zinc alloy material giving the composition described in (1) or (3) is melt-cast to obtain a billet [Step A-1], and the billet is drilled [Step B-1 After that, a zinc alloy tube material is obtained by hot extrusion [Step C-1], and the steps are performed in this order (1), (3), (5), (6), (7) Or the manufacturing method of the zinc alloy pipe material as described in (8) term.
(10) The method for producing a zinc alloy tubular material according to (9), wherein cold working [step D-1] is performed after the hot extrusion processing [step C-1].
(11) The method for producing a zinc alloy tube material according to (9) or (10), wherein the hot extrusion [Step C-1] is performed while rapid cooling is performed on the die exit side.
(12) A zinc alloy material is melt cast to obtain a billet [Step A-2], and after drilling the billet [Step B-2], hot extrusion is performed to obtain a zinc pipe material. [Step C-2], a single layer containing at least one selected from the group consisting of Al, Mn, Mg, rare earths and Ca by at least one of sputtering, thermal spraying and electrodeposition on the surface of the obtained tube material Alternatively, a multilayer film is formed [Step E-2], and the single layer or multilayer film is subjected to at least one or more heating selected from the group consisting of radiation, laser irradiation, and energization [Step F-2], The method according to any one of (1) to (8), wherein the steps are performed in this order.
(13) The method for producing a zinc alloy tubular material according to (12), wherein cold working [step D-2] is performed after the hot extrusion processing [step C-2].
(14) The method for producing a zinc alloy tube material according to (12) or (13), wherein the hot extrusion process [Step C-2] is performed while rapid cooling is performed on the die exit side.
(15) A vascular dilatation stent comprising the zinc alloy tube material according to any one of (1) to (8).
(16) The zinc alloy tube material obtained by the manufacturing method according to any one of (9) to (14) is laser-processed into a stent shape [Step G], and the surface is polished [Step H Then, a surface treatment is performed [Step I], and a method for manufacturing a vascular dilatation stent in which the steps are performed in this order.

The zinc alloy tube of the present invention is easily absorbed by the body after implantation in the living body, but its absorption rate is not too fast, and has mechanical properties such as a predetermined high strength, and is excellent in workability. It is suitable as a metal material for a medical device represented by a bioabsorbable stent.
The above and other features and advantages of the present invention will become more apparent from the following description, with reference where appropriate to the accompanying drawings.

[Alloy composition]
First, the composition of the zinc alloy constituting the zinc alloy tube of the present invention will be described.

(Essential additive element)
The content and action of at least one element selected from the group consisting of the essential additive elements Al, Mn, Mg and rare earths to the zinc alloy constituting the zinc alloy pipe of the present invention will be described.
By containing a predetermined amount of at least one element selected from the group consisting of Al, Mn, Mg and rare earth, it is possible to achieve high strength and high elongation, and to appropriately suppress the degradation rate in vivo. .

(Al)
In the present invention, the Al content is 0.1 to 5 mass%. If the Al content is too high, the decomposition rate is rapidly increased. When the Al content is too high, there is a trade-off relationship between increasing the strength and reducing the bioabsorbability, so that the desired bioabsorbability at an appropriate rate, which is the object of the present invention, cannot be obtained. On the other hand, if the Al content is too low, the strength of the obtained zinc alloy material is drastically reduced, and it is not possible to increase the strength for expressing the retention force during vascular dilation in stent applications. From the viewpoint of workability, the Al content is preferably 0.1 to 1% by mass.

(Mn)
In the present invention, the Mn content is set to 0.1 to 5% by mass. When the content of Mn is too high, the decomposition rate is rapidly increased. On the other hand, if the content of Mn is too low, the strength of the obtained zinc alloy material is drastically reduced, and it is not possible to increase the strength for expressing the retention force during vascular dilation in stent applications. From the viewpoint of workability, the Mn content is preferably 0.1 to 1% by mass.

(Mg)
In the present invention, the Mg content is 0.1 to 5% by mass. If the Mg content is too high, the workability is significantly reduced. On the other hand, when the content of Mg is too low, it does not contribute to increasing the strength of the obtained zinc alloy material. From the viewpoint of workability, the Mg content is preferably 0.1 to 1% by mass.

(rare earth)
In the present invention, the rare earth content is 0.1 to 5% by mass. As the rare earth, yttrium (Y) is preferable. The rare earth (RE, preferably Y) contributes to increasing the strength while avoiding a decrease in elongation. If the rare earth content is too high, cell proliferation is abnormal, suggesting the presence of a cytotoxin, and the rate of degradation in vivo rapidly increases. On the other hand, if the rare earth content is too low, the effect of increasing the strength is not exhibited. From the viewpoint of workability, the rare earth content is preferably 0.1 to 1% by mass.

(Optional addition element)
In addition to at least one element selected from the group consisting of the essential additive elements Al, Mn, Mg and rare earths, the zinc alloy constituting the zinc alloy tube of the present invention contains Ca at a predetermined content. Also good. The content of the optional additive element Ca and the action thereof will be described below.
By containing a predetermined amount of Ca, the strength and elongation can be increased, and the decomposition rate in the living body can be appropriately slowed down.

(Ca)
In this invention, when adding, content of Ca shall be 0.1-5 mass%. When the content of Ca is too high, the decomposition rate is rapidly increased. On the other hand, if the content of Ca is too low, the strength cannot be increased in order to develop the holding power during vasodilation. From the viewpoint of workability, the Ca content is preferably 0.1 to 1% by mass.

(Regulated elements)
Next, the allowable contents of the elements Fe and O whose contents are regulated in the zinc alloy constituting the zinc alloy tube of the present invention and the reasons for the regulation will be described.

(Fe)
In the present invention, the Fe content is restricted to less than 0.05% by mass. When the content of Fe is too high, the decomposition rate of the obtained zinc alloy in vivo is rapidly increased.

(O)
In the present invention, the O content is restricted to less than 0.1% by mass. Oxygen combines with Mg, Al, Ca and the like to form inclusions. When this inclusion is taken into the matrix during casting, if a repeated stress is applied, it becomes the starting point of fracture and becomes a zinc alloy inferior in fatigue characteristics. The formation of the oxygen-containing inclusions and the deterioration of fatigue characteristics caused thereby can be prevented by regulating the O content to less than 0.1% by mass.

(Inevitable impurities)
In the present invention, examples of inevitable impurities in the zinc alloy include Cu, Li, Ni, Si, and Pd. In the zinc alloy constituting the zinc alloy pipe of the present invention, the inclusion of these inevitable impurities in a total amount of 0.1% by mass or less is allowed.

The zinc alloy tube material of the present invention has the zinc alloy composition defined above, but may be a uniform composition throughout the tube material (first aspect, production method 1 or 2 below), or the surface of the tube material may have the above composition. The inside of the pipe material may have a gradient composition in which at least one concentration (content) selected from the group consisting of Al, Mn, Mg, rare earth and Ca is different from that of the pipe material surface (second aspect, below) Production method 2).
In the case of this second aspect, the concentration of at least one or more selected from the group consisting of Al, Mn, Mg, rare earth and Ca is highest on the surface of the tube material, and decreases in the thickness direction from the surface of the tube material toward the inside. Yes. Such a change in concentration is called a gradient composition.

[Average crystal grain size of base material of zinc alloy tube]
In the present invention, the average crystal grain size of the base material is preferably 1 to 20 μm. By refining the crystal grains, it is possible to reduce pitting corrosion and intergranular corrosion of a zinc alloy that is easily corroded. If the average crystal grain size of the base material is too large, the corrosion rate increases rapidly and the bioabsorption rate is too fast. On the other hand, if the average crystal grain size of the base material is too small, breakage or the like may occur at the time of applying a large strain before heat treatment for crystal grain refinement, for example, during cold working, and corrosion. The rate is saturated and the effect of relaxing the bioabsorption rate is reduced.

[Zinc alloy tube shape]
In the present invention, it is preferable that the ratio of the thickness of the zinc alloy pipe material / the outer diameter of the pipe is 0.02 to 0.5.
Zinc alloys are known as metal materials with particularly poor cold workability because they have a close-packed hexagonal lattice structure (hcp structure). For this reason, a zinc alloy pipe is manufactured by a hot extrusion method at 300 to 400 ° C., more preferably 320 to 360 ° C. At that time, if the ratio of the wall thickness / outside diameter of the pipe material is too small, defects such as cracks may occur due to the limit of the metal during extrusion. On the other hand, when the ratio of the wall thickness / outer diameter of the tube is too large, an excessive force is required particularly when expanding as a stent.

The thickness of the tube material is not particularly limited, but is preferably about 100 to 700 μm when used as a stent.
The outer diameter of the tube is not particularly limited, but is preferably about 0.3 to 13 mm when used as a stent.

[Method of manufacturing zinc alloy tube]
In the method for producing a zinc alloy pipe according to the present invention, the material that gives the obtained zinc alloy composition has a uniform composition throughout the pipe (the following production method 1), or a uniform composition or a gradient composition (the following production method 2). Thus, it is roughly divided into two manufacturing methods.

(Production method 1)
As for the zinc alloy pipe material of this invention obtained by this manufacturing method, the whole pipe | tube has a uniform composition.

  First, a zinc alloy material giving the predetermined composition is blended, and melted at a melting point or higher (for example, 420 ° C. or higher, depending on the alloy composition) at 600 ° C. or lower in a vacuum melting furnace or an atmospheric furnace. A billet is obtained by a casting method or the like [Step A-1]. The billet is drilled (preferably in the center) with a drill or the like [Step B-1]. A tube material is obtained by subjecting this perforated billet to forward extrusion using a mandrel at a temperature of 300 to 400 ° C., preferably 320 to 360 ° C. [Step C-1]. Further, if necessary, this pipe material is subjected to cold working [step D-1], for example, cold drawing using a reducer or the like. If a predetermined tube size and tube shape are obtained by hot extrusion, this cold working (drawing) can be omitted. By appropriately adjusting the area reduction rate (cross-sectional area reduction rate) in this hot extrusion process and any cold process, the wall thickness ratio of the processed tube material (ratio of the wall thickness / outer tube diameter) is 0. 0.02 to 0.5.

For the production method 1, preferable conditions and the like will be described.
Preferably, the melting and casting [Step A-1] is performed in an inert gas atmosphere, for example, in an argon atmosphere.
After the drilling [Step B-1], the perforated billet is set to 1 to 3 at 300 to 400 ° C., preferably 320 to 360 ° C. in an inert gas atmosphere, for example, an argon atmosphere in an atmosphere heating furnace. It is preferable to hold for a time. Thereafter, the hot extrusion process [Step C-1] is preferably performed at this temperature.
At the time of the hot extrusion process [Step C-1], using a quenching device capable of directly spraying a refrigerant such as liquid nitrogen on the exit side of the extrusion die, the extrusion process is performed while performing rapid cooling on the exit side of the die. preferable. By rapid cooling immediately after this hot extrusion, the structure control for refining the crystal grains of the base material can be performed.
When performing the cold work, the area reduction rate of the cold work [Step D-1] is preferably 10 to 50%.

(Manufacturing method 2)
The zinc alloy tubular material of the present invention obtained by this production method may have a uniform composition throughout the tubular material as in Production Method 1, or one side or both sides of the surface of the tubular material has a high content of, for example, aluminum other than zinc. (For example, Al-rich), a gradient composition having a high zinc content inside the pipe (Zn-rich) and a gradient in concentration in the thickness direction of the pipe may be used. However, even in the case of the latter gradient composition, the alloy composition on one side or both sides of the tube material surface is as defined above, and is the same as the uniform composition in Production Method 1.

  First, a zinc alloy material is melted at a melting point or more (depending on the alloy composition, for example, 420 ° C. or more) and 600 ° C. or less in a vacuum melting furnace or an atmospheric furnace, and a billet is obtained by die casting, continuous casting method, etc. [Process A-2]. Next, drilling is performed inside the billet (preferably at the center) with a drill or the like [Step B-2]. The billet is subjected to forward extrusion using a mandrel at a temperature of 300 to 400 ° C., preferably 320 to 360 ° C. to obtain a pipe [Step C-2]. Further, if necessary, the pipe material is subjected to cold working [Step D-2], for example, cold drawing using a reducer or the like. If a predetermined tube size and tube shape are obtained by hot extrusion, this cold working (drawing) can be omitted.

  Thereafter, the surface of the obtained zinc alloy tube material is a single layer or a multilayer containing at least one selected from the group consisting of Al, Mn, Mg, rare earth and Ca by at least one of sputtering, thermal spraying and electrodeposition A film is formed [Step E-2]. At least one selected from the group consisting of radiation, laser irradiation, and energization is applied to the single layer or multilayer film at a temperature of 250 ° C. or higher and 10 ° C. lower than the solidus of the alloy, particularly preferably a temperature around 400 ° C. Heat for 1 hour or longer [Step F-2]. By this heating [Step F-2], at least one or more selected from the group consisting of Al, Mn, Mg, rare earth and Ca from the single layer or multilayer film provided on the surface of the zinc alloy tube is formed into the wall thickness of the tube. Spread in the direction. By appropriately adjusting the heating temperature and the heating time applied to this heating [Step F-2], the zinc alloy tube material having a uniform composition or the zinc alloy having a gradient composition having a concentration gradient in the thickness direction of the tube material Manufacture any of the tubing. Here, in the zinc alloy tube material obtained by this production method 2, the entire tube material, or at least one side or both sides of the tube material surface has the zinc alloy composition as defined above.

Regarding the production method 2, preferable conditions and the like will be described.
The zinc alloy material to be subjected to the melting and casting [Step A-2] is at least one selected from the group consisting of Al, Mn, Mg, rare earth and Ca, and later in [Step E-2]. Contains a predetermined amount of each element other than the constituent elements of the single layer or multilayer film provided on the zinc alloy tube, restricts Fe and O as regulatory elements to less than the prescribed amount, and the remainder from Zn and inevitable impurities The composition is as follows. For example, when an Al film is formed in [Step E-2], the zinc alloy material subjected to the melting and casting [Step A-2] includes Mn other than Al, Mg, and necessary elements of rare earths. If necessary, Ca is contained in a predetermined amount, Fe and O are regulated to less than the prescribed amount, and the balance is made of Zn and inevitable impurities.

Preferably, the melting and casting [Step A-2] is performed in an inert gas atmosphere, for example, in an argon atmosphere.
After the drilling [Step B-2], the perforated billet is heated in an atmosphere heating furnace in an inert gas atmosphere, for example, in an argon atmosphere, at 300 to 400 ° C., preferably 320 to 360 ° C. It is preferable to hold for a time. Thereafter, the hot extrusion process [Step C-2] is preferably performed at this temperature.
At the time of the hot extrusion process [Step C-2], an extrusion process may be performed while rapid cooling is performed on the die outlet side using a quenching apparatus capable of directly spraying a refrigerant such as liquid nitrogen on the outlet side of the extrusion die. preferable. By rapid cooling immediately after this hot extrusion, the structure control for refining the crystal grains of the base material can be performed.
When performing the cold work, the area reduction rate of the cold work [Step D-2] is preferably 10 to 50%.

When providing at least one monolayer or multilayer film of Al, Mn, Mg, rare earth and Ca on the zinc alloy tube in [Step E-2], for example, an ionic liquid is used in a dry chamber. The target additive element can be electrodeposited by using. For example, if an Al single layer or multilayer film is provided on the zinc alloy tube in [Step E-2], Al can be electrodeposited using an AlCl ₃ —NaCl—KCl-based ionic liquid. it can. The thickness of the single layer or multilayer film formed on the surface of the zinc alloy tube at this time is preferably about 0.1 to 300 μm. Depending on the specific gravity relationship between the Zn constituting the tube and the metal species (for example, Mg) constituting the single layer or multilayer film formed on the surface thereof, the single layer or multilayer film may be thick plated. .
In the heating [Step F-2], the heating temperature is preferably 250 ° C. or higher and 10 ° C. or lower than the solidus of the alloy, and the heating time is preferably 1 to 20 hours. If the heating temperature is increased and / or the heating time is increased, the constituent elements of the single layer or multilayer film can be completely diffused from the single layer or multilayer film in the thickness direction of the tube. On the other hand, if the heating temperature is lowered and / or the heating time is shortened, the constituent elements of the single layer or the multilayer film are diffused from the single layer or the multilayer film in the thickness direction of the tube material before the desired inclination. Diffusion can be stopped in the composition state.

[Stent manufacturing method]
The stent of the present invention is manufactured through the following steps with respect to the zinc alloy pipe of the present invention.
The zinc alloy tube material of the present invention is cut by laser processing using a pulse laser or the like and processed into a predetermined mesh-like stent shape (mesh tube) [Step G]. Thereafter, burrs generated during laser processing are removed by chemical polishing [Step H]. As the polishing, for example, dissolution / polishing using an acid (dilute sulfuric acid or the like) can be performed. Thereafter, the surface of the material is subjected to a surface treatment such as apatite [Step I]. The stent thus obtained is sterilized before use to obtain a vasodilator stent.
In the said laser processing [process G], what is necessary is just to be able to process in the shape of an expandable stent by performing laser processing to the magnesium alloy pipe material of this invention, for example, what is necessary is just to make it a general mesh shape. The shape of the stent is not limited to the mesh shape.

  In this surface treatment, for example, a layer made of a biocompatible substance such as apatite (such as hydroxyapatite (Hap)), polyvinyl alcohol (PVA), polylactic acid (PLLA), or calcium carbonate is provided on the outer surface of the tube. By imparting biocompatibility by this surface treatment, the resulting stent can be further biocompatible.

[Characteristics of zinc alloy tube]
The zinc alloy tube material of the present invention can satisfy the characteristics required for a bioabsorbable stent, for example. The zinc alloy tube material of the present invention preferably has the following characteristics.
(1) Mechanical properties-The tensile strength (TS) is preferably higher than 300 MPa. More preferably, it is higher than 300 MPa and not higher than 415 MPa.
-It is preferable that 0.2% yield strength (YS) is higher than 150 MPa. More preferably, it is higher than 150 MPa and not higher than 317 MPa.
-It is preferable that tensile elongation at break (El) is larger than 10%. More preferably, it is more than 10% and 13% or less.
(2) Fatigue property It is preferable that it is 100 million times (one year) or more by the conversion value of the acceleration test result equivalent to pulsation.
(3) Bioabsorption characteristics When a solution simulating human body fluid, for example, simulated body fluid (SBF, composition is as shown in the examples) is held at 37 ° C., the thickness loss after 6 months immersion is 100 μm or less. It is preferable that It is more preferable that the thinning amount be 50 μm or less. More specifically, when a magnesium alloy tube material having an outer diameter of 8 mm and an inner diameter of 7.2 mm is used, the bioabsorbability is preferably such that the thickness loss after immersion for 2 months is 100 μm or less. The amount of thinning refers to the amount by which the wall thickness of the pipe is dissolved and reduced from the inner and outer surfaces of the pipe after the predetermined pipe is immersed in a predetermined liquid. Or it is preferable that the decomposition | disassembly period until it lose | disappears after immersion in simulated body fluid (SBF, 37 degreeC) is as long as 6 months or more. There is no particular upper limit on the time (decomposition time) until the zinc alloy tube material is completely dissolved in the SBF, which is a measure of bioabsorbability, but it is preferably 1 year (12 months).
Unless otherwise specified, detailed measurement conditions for each characteristic are as described in the examples.

  As described above, the zinc alloy pipe of the present invention has been described with respect to the bioabsorbable stent as its application. However, the use of the zinc alloy tube material of the present invention is not limited to the stent, and it can be applied to medical devices other than stents by appropriately adjusting predetermined bioabsorption characteristics (decomposition rate in vivo). it can. Examples of medical device applications other than stents include bioabsorbable implants such as bone fixation devices such as plates, pins, and screws, and bone and soft tissue fixation devices.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.

(Examples 1-3, 6)
[Manufacture of zinc alloy tubing]
As zinc alloy material, special zinc ingot, Al ingot, Mn ingot, high purity magnesium ingot 1 type A, high purity metal Ca, metal Y, Al, Mn, Mg, Ca, Y are contained. Fe and O were regulated so that the balance was composed of Zn and unavoidable impurities as shown in Table 1 and dissolved at 420 to 600 ° C. by induction heating in an argon atmosphere furnace. A billet of φ50 mm × 100 mmL was die-cast in an argon atmosphere. Billet components were measured using an ICP emission spectrometer and oxygen analysis. Using a drill, a 9 mm hole was mechanically drilled in the center of the billet. After holding this perforated billet at 350 ° C. for 1 hour in an argon atmosphere furnace, hot extrusion was performed at this temperature to obtain a zinc alloy tube (average thickness: 0.5 mm) having an outer diameter of φ10 mm and an inner diameter of φ9 mm. It was. The container containing the billet during hot extrusion was heated from the outside to stabilize the billet temperature (± 10 ° C.). Moreover, the crystal grains were refined by quenching using a quenching apparatus capable of directly spraying liquid nitrogen on the exit side of the extrusion die, and the average crystal grain size of the base material was controlled.
This zinc alloy pipe material can be cold drawn (reduction ratio 36%) to an outer diameter of φ8 mm and an inner diameter of φ7.2 mm using a reducer to obtain a zinc alloy pipe material having no surface cracks. It was.

(Examples 4 to 5)
[Manufacture of zinc alloy tubing]
As a zinc alloy material, special zinc ingot, metal Ca, metal Y are used, Ca, Y are contained, Fe and O are regulated, and the balance is composed of Zn and inevitable impurities. It melt | dissolved at 420-600 degreeC by the induction heating in the argon atmosphere furnace. A billet of φ50 mm × 100 mmL was die-cast in an argon atmosphere. Billet components were measured using an ICP emission spectrometer and oxygen analysis. Using a drill, a 9 mm hole was mechanically drilled in the center of the billet. After holding this perforated billet at 350 ° C. for 1 hour in an argon atmosphere furnace, hot extrusion was performed at this temperature to obtain a zinc alloy tube (average thickness: 0.5 mm) having an outer diameter of φ10 mm and an inner diameter of φ9 mm. It was. The container containing the billet during hot extrusion was heated from the outside to stabilize the billet temperature (± 10 ° C.). In addition, the crystal grains were controlled by quenching using a quenching apparatus capable of spraying liquid nitrogen directly on the exit side of the extrusion die.
This zinc alloy pipe material can be cold drawn (reduction ratio 36%) to an outer diameter of φ8 mm and an inner diameter of φ7.2 mm using a reducer to obtain a zinc alloy pipe material having no surface cracks. It was.

Next, Al was electrodeposited on the zinc alloy pipe using an ionic liquid (AlCl ₃ —NaCl—KC system) in a dry chamber. At this time, the thickness of the aluminum layer formed on the surface of the zinc alloy tube was 19 μm.

  Thereafter, the zinc alloy tube material having an Al coating layer formed on the surface was heated and held at 400 ° C. for 1 hour in an argon atmosphere. By this heating, Al on the surface of the pipe material was diffused in the thickness direction of the pipe material to achieve a gradient composition of the zinc alloy composition. The resulting composition on the tube surface was measured by fluorescent X-rays.

(Examples 1-6)
[Manufacture of stents]
Next, each of the obtained zinc alloy pipes was subjected to mesh-like stent processing with a peak output of 500 W using a CW laser (SM500W). Thereafter, the burr on the inner surface of the tube generated during laser processing was dissolved and polished with acid. Thereafter, the surface of the stent material was subjected to a surface treatment for coating apatite. The stent thus obtained was sterilized before use to prepare a vasodilator stent.

(Comparative Examples 1-5)
About each comparative example, the zinc alloy pipe material and the stent were produced like the said Example except having set it as the zinc alloy composition of Table 1, and the manufacturing method.

  In addition, about each obtained said zinc alloy pipe material, various physical properties and characteristics were tested, measured, and evaluated as follows. The results are shown in Table 1. The distinction between production methods 1 and 2 in Table 1 is the meaning of “production method 1” and “production method 2” as described above. In the case of production method 1, the zinc alloy composition is a value measured with an ICP emission analyzer, and in the case of production method 2, it is a value measured on the surface of the tube with fluorescent X-rays.

(Average crystal grain size (GS))
The average crystal grain size of the tube base material was determined by a crossing method in a cross section perpendicular to the extrusion direction of the zinc alloy tube before being subjected to the stent processing (laser processing).

(Thickness ratio as tube shape)
The average thickness of the zinc alloy tube before being subjected to the stent processing was measured, and the ratio of the wall thickness / tube outer diameter was calculated as the ratio to the outer diameter.

(Mechanical properties)
A tensile test was performed on the zinc alloy tube material before being subjected to the stent processing in accordance with JIS Z2201 and Z2241, and tensile strength (TS), 0.2% proof stress (YS), and tensile elongation at break (El) were obtained.

(Bioresorbability)
The zinc alloy tube material before being subjected to stent processing was immersed in a predetermined amount of simulated body fluid (SBF) controlled at 37 ± 1 ° C. And the time-dependent change of Zn ^<2+ > density ^| concentration eluted from a zinc alloy pipe material in a pseudo body fluid was measured with the ICP emission spectrometer, and the decomposition rate was computed as a corrosion rate from the weight change of the immersed zinc alloy pipe material. The ionic species and each ion concentration contained in the simulated body fluid are as follows. Na ⁺ : 142 mM, K ⁺ : 5 mM, Mg ²⁺ : 1.5 mM, Ca ²⁺ : 2.5 mM, Cl ⁻ : 148.8 mM, HCO ³⁻ : 4.2 mM, HPO ₄ ²⁻ : 1 mM, SO ₄ ^2−. : 0.5 mM (mM means millimole / liter).
Based on this decomposition rate, the time required for the stent to be processed and manufactured from the zinc alloy tube material to completely dissolve in the thickness direction is calculated, and the time required for complete dissolution is 6 months or more (that is, The bioabsorbability (decomposition rate) was judged on the basis of the case where the dissolution was not too fast.
For each test result, the case where the time required for complete dissolution (decomposition period) is 6 months or more is judged to be excellent in bioabsorbability and indicated as “A” in the table, and dissolution is too fast at less than 6 months. The case was judged to be inferior in bioabsorbability and indicated as “D” in the table.

(Cold workability)
It was evaluated by whether or not fine cracks were generated when cold drawing with a reducer with a surface reduction rate of 36% was performed. A tube with a length of 1 m observed with a microscope (magnification × 100), and the one without cracks (defects) was judged to be excellent in cold workability and indicated as “A” in the table, and a crack was detected Was determined to be inferior in cold workability and indicated as “D” in the table.

(Comprehensive judgment)
The results of comprehensive evaluation of the mechanical characteristics obtained as described above, the bioabsorbability evaluated during the decomposition period in SBF, and the cold workability were shown as comprehensive judgments. Good ones were indicated as “A” and bad ones were indicated as “D”.

  As is apparent from the results shown in Table 1, the zinc alloy pipes of each Example obtained by the production method defined by the present invention with the alloy composition defined by the present invention have high strength, high elongation, and good It showed cold workability and proper bioabsorbability not too fast. The zinc alloy pipes of each of these examples also satisfied a preferable average crystal grain size and pipe shape (ratio of wall thickness / tube outer diameter). Therefore, the zinc alloy tubular material of the present invention is suitably used for a material for a minimally invasive medical device represented by a stent.

  On the other hand, in the sample of each comparative example, one of the characteristics was inferior.

In all of Comparative Examples 1 to 5, the alloy composition was outside the specified range of the present invention. In Comparative Examples 1 to 5, the absorption rate to the living body (SBF) was too fast and was unfit for the stent. Further, Comparative Examples 1 to 4 were inferior in cold workability. Moreover, all of Comparative Examples 1 to 5 were inferior in strength (TS and YS) or elongation (El).
In addition, although the upper limit of bioabsorbability is not prescribed | regulated in particular, neither the said Example and the comparative example exceeded one year.

  While this invention has been described in conjunction with its embodiments, we do not intend to limit our invention in any detail of the description unless otherwise specified and are contrary to the spirit and scope of the invention as set forth in the appended claims. I think it should be interpreted widely.

  This application claims the priority based on Japanese Patent Application No. 2014-070223 for which it applied for a patent in Japan on March 28, 2014, and this is referred to here for the contents of this description. Capture as part.

Claims (16)

  At least one or more selected from the group consisting of 0.1 to 5 mass% Al, 0.1 to 5 mass% Mn, 0.1 to 5 mass% Mg, and 0.1 to 5 mass% rare earth A zinc alloy characterized in that Fe is less than 0.05% by mass, O is less than 0.1% by mass and the balance is composed of zinc and 0.1% by mass or less of inevitable impurities. Tube material.   The composition according to claim 1, wherein one or both sides of the surface of the tube material is the composition according to claim 1, wherein the content of at least one of the Al, Mn, Mg and rare earth is inclined in the thickness direction of the tube material. Zinc alloy pipe material described in 1.   Furthermore, the zinc alloy pipe | tube of Claim 1 containing 0.1-5 mass% of Ca.   The composition according to claim 1, wherein one side or both sides of the surface of the tube material is a composition in which the content of at least one of Al, Mn, Mg, rare earth and Ca is inclined in the thickness direction of the tube material. Item 4. The zinc alloy tube material according to Item 3.   The zinc alloy pipe according to any one of claims 1 to 4, wherein the base material has an average crystal grain size of 1 to 20 µm.   The zinc alloy pipe according to any one of claims 1 to 5, wherein a ratio of the thickness of the pipe / the outer diameter of the pipe is 0.02 to 0.5.   The zinc alloy pipe according to any one of claims 1 to 6, wherein the tensile strength is higher than 300 MPa, the 0.2% proof stress is higher than 150 MPa, and the tensile breaking elongation is higher than 10%. Na ⁺ 142 mM, K ⁺ 5 mM, Mg ²⁺ 1.5 mM, Ca ²⁺ 2.5 mM, Cl ⁻ 148.8 mM, HCO ₃ ⁻ 4.2 mM, HPO ₄ ²⁻ 1 mM, SO ₄ ²⁻ The zinc alloy according to any one of claims 1 to 7, wherein a thickness loss after 6 months is 100 µm or less when immersed in a simulated body fluid (SBF) containing 37 mM at 37 ° C. Tube material.   A zinc alloy material giving the composition according to claim 1 or 3 is melt-cast to obtain a billet [Step A-1], and after drilling the billet [Step B-1], hot extrusion is performed. The method for producing a zinc alloy tube material according to claim 1, 3, 5, 6, 7 or 8, wherein the zinc alloy tube material is processed to obtain a zinc alloy tube material [step C-1], and the respective steps are performed in this order.   The manufacturing method of the zinc alloy pipe material of Claim 9 which performs cold work [process D-1] after the said hot extrusion process [process C-1].   The method for producing a zinc alloy tube material according to claim 9 or 10, wherein the hot extrusion process [Step C-1] is performed while rapid cooling is performed on the die exit side.   A zinc alloy material is melted and cast to obtain a billet [Step A-2], and after drilling the billet [Step B-2], hot extrusion is performed to obtain a zinc pipe [Step C]. -2] Single layer or multilayer film containing at least one selected from the group consisting of Al, Mn, Mg, rare earth and Ca by at least one of sputtering, thermal spraying and electrodeposition on the surface of the obtained tube [Step E-2], and subjecting the single layer or multilayer film to at least one or more heating selected from the group consisting of radiation, laser irradiation, and energization [Step F-2]. It performs in order, The manufacturing method of the zinc alloy pipe | tube material of any one of Claims 1-8 characterized by the above-mentioned.   The manufacturing method of the zinc alloy pipe material of Claim 12 which performs a cold work [process D-2] after the said hot extrusion process [process C-2].   The method for producing a zinc alloy tube material according to claim 12 or 13, wherein the hot extrusion [Step C-2] is performed while rapid cooling is performed on the die exit side.   A stent for vasodilation comprising the zinc alloy tube material according to any one of claims 1 to 8.   The zinc alloy tube material obtained by the manufacturing method according to claim 9 is laser-processed into a stent shape [Step G], the surface is polished [Step H], and then the surface A method for producing a stent for vasodilation, in which treatment is performed [step I] and each step is performed in this order.