JP2013215332A - Bioabsorbable medical instrument and decomposition speed adjusting method for the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical instrument which has a dynamic strength required for supporting a lumen wall in a living body for a predetermined period (at least one month), is excellent in corrosion resistance, and is made from a base material of magnesium or magnesium alloy.SOLUTION: A bioabsorbable medical instrument is made from a base material 7 containing magnesium or magnesium alloy. In the instrument, an oxide film 8 is coated on the surface of the base material 7 by ozone oxidation treatment, and the oxide film 8 adjusts the decomposition speed of the base material 7.

Description

The present invention relates to a bioabsorbable medical device and a method for adjusting the degradation rate thereof, and in particular, a bioabsorbable medical device capable of reliably holding the mechanical strength of the medical device for a time sufficient to ensure revascularization. And a method for adjusting the decomposition rate thereof.

Examples of the medical device of the present invention include various devices such as a stent, a cannula, a catheter, an artificial blood vessel, a stent graft, and a drug-loaded cancer treatment device. Hereinafter, a stent will be described as an example.

In-vivo stents are used to expand the stenosis or occlusion site and secure the lumen to treat various diseases caused by stenosis or occlusion of blood vessels or other in-vivo lumens. In general, it is a tubular medical device.
Since the stent is inserted into the body from outside the body, the diameter is small at that time. The stent is expanded at the target stenosis or occlusion site to increase the diameter, and the lumen is held as it is.

As the stent, a metal wire such as stainless steel or Co—Cr, or a cylindrical shape obtained by processing a metal tube is generally used. On the other hand, a catheter or the like is attached in a thin state, inserted into a living body, expanded by a certain method at a target site, and tightly fixed to the inner wall of the lumen to maintain the lumen shape.

At present, non-absorbable metal-based stents have become the standard of medical care and have achieved many successes. However, permanently implanted stents have had the problem that permanent interaction with the surrounding tissue poses endothelial cell dysfunction and later risk of thrombosis.

Recently, as a stent that solves the above problems, the stent is present in the body for a period until it completes functions such as maintaining the open circuit of the blood vessel and / or delivering the drug, and after the stent has played a role, it is completely in vivo. Bioabsorbable stents that are absorbed in the body have been proposed.

Such stents include stents based on bioabsorbable polymers such as polylactic acid and polyglycolic acid (Patent Document 1) and stents based on bioabsorbable metals such as magnesium and magnesium alloys (patents). Document 2, Patent document 3, Patent document 4).

Stents using bioabsorbable polymers as the base material may not have the mechanical properties necessary to perform functions such as maintaining the open circuit of the blood vessels and / or delivering the drug, so that sufficient mechanical properties can be obtained. Stents based on bioabsorbable metals such as magnesium and magnesium alloys are desired.

However, bioabsorbable metals such as magnesium and magnesium alloys tend to degrade rapidly in vivo, so it is not possible to maintain the mechanical strength of the stent for a time sufficient to ensure revascularization. It is extremely difficult.

Patent No. 455845 Special table 2001-511049 JP 2006-167078 A JP 2004-160236 A

Accordingly, an object of the present invention is to adjust the rate of in vivo degradation of a stent for indwelling made of a bioabsorbable metal such as magnesium or a magnesium alloy to ensure revascularization (for example, at least one). (More than a month) To provide a bioabsorbable medical device that retains the mechanical strength necessary to support the lumen wall.
Another object of the present invention is to provide a method for adjusting the decomposition rate of the bioabsorbable medical device.

As a result of thorough examination of bioabsorbable medical devices made of bioabsorbable metals such as magnesium or magnesium alloys, the present inventors have focused on treating the surface of medical devices with oxygen gas containing ozone, As a result of the examination, it was surprisingly found that the oxide film having a specific thickness formed on the stent surface by ozone oxidation treatment is effective in adjusting the degradation rate of the bioabsorbable medical device. It has been reached.

That is, the present invention
(1) A bioabsorbable medical device based on magnesium or a magnesium alloy, wherein the surface of the base material is coated with an oxide film by ozone oxidation treatment, and the oxide film adjusts the decomposition rate of the base material The bioabsorbable medical device is characterized by being configured as described above.
(2) The bioabsorbable medical device according to (1), wherein the medical device is a stent.
(3) The surface of the oxide film contains a polymer and a therapeutic agent that does not inhibit the proliferation of endothelial cells, and the weight composition ratio of the polymer and the therapeutic agent is 8 to 3 for the polymer versus 2 to 7 for the therapeutic agent. Coated with a first polymer in the range, the first polymer being formed by the polymer alone or comprising a polymer and a therapeutic agent, wherein the weight fraction of the therapeutic agent to 80% by weight of the polymer is less than 20% by weight The bioabsorbable medical device according to (1) or (2), which is coated with a second polymer.
(4) The bioabsorbable medical device according to the above (3), wherein the polymer is poly (lactic acid-glycolic acid) and the therapeutic agent is argatroban, sirolimus, taxol, decoy and / or tamibarotene.
(5) A bioabsorbable medical device based on magnesium or a magnesium alloy is brought into contact with dry oxygen gas having a temperature of less than 20 to 150 ° C. and an ozone content of less than 2 to 10% by volume for 1 hour or more. An oxide film is formed on the surface of the bioabsorbable medical device.
(5) The method according to (4) above, wherein the dry oxygen gas has an ozone content of 3 to 10% by volume and a temperature of 30 to 100 ° C.

The bioabsorbable medical device of the present invention can adjust the decomposition rate of the substrate in vivo by providing an oxide film for adjusting the decomposition rate on the surface of the substrate. Further, by adopting the ozone oxidation method, an extremely thin oxide film can be formed, and the composition of the oxide film, in other words, the thickness can be easily controlled by changing the oxidation conditions. The present invention can solve the risk of endothelial cell dysfunction and later thrombosis due to permanent interaction of a medical device placed in the living body, which is currently a problem, with the living body. Furthermore, since the required degradation rate of the stent may differ depending on the state of the stenosis, a corresponding stent can be provided.

Top view of stent Cross section of stent Cross section of drug coated stent Enlarged view after the stent of Example 1 was immersed in physiological saline at 37 ° C. for 48 hours Enlarged view after the stent of Example 2 was immersed in physiological saline at 37 ° C. for 48 hours Enlarged view after the stent of Comparative Example 1 is immersed in physiological saline at 37 ° C. for 6 hours An image of the stent of Example 1 and five stents of Comparative Example 1 each placed in the rabbit iliac artery, and the stent taken 28 days after placement A graph comparing the lumen area at the time of stent collection in Comparative Example 1 and Comparative Example 1

As the stent base material, magnesium having excellent bioabsorbability or a magnesium alloy having a magnesium ratio of 90% or more is used. Further, the surface of the stent base material is covered with an oxide film formed by an ozone oxidation method.

Although a stent base material made of magnesium or a magnesium alloy is usually subjected to ozone oxidation treatment at a temperature of 100 to 200 ° C., the crystal structure of the magnesium alloy may change when the base material is exposed to such heating conditions. If the crystal structure changes, the decomposition conditions of the magnesium alloy in vivo may change. For the bioabsorbable medical device, it is preferable to use a magnesium alloy having a dense crystal structure that does not change the crystal structure by heating and having excellent strength as a base material. Examples of such a magnesium alloy having a dense crystal structure and excellent strength include, for example, a long-period stack structure described in JP-A-2008-69418 or the like, a crystal having a close-packed atomic area layer defect, and a hcp-structure magnesium phase. There is a magnesium alloy with a texture.

In addition, since all alloying elements of the magnesium alloy are finally decomposed in vivo, biocompatibility is very important from the viewpoint of biological safety. For example, calcium, zinc and manganese, which are alloying elements of magnesium alloys, are essential elements of the human body, and after entering the body, they are metabolized and discharged out of the body, so there are problems as alloying elements used in magnesium alloys However, the amount of elements released per day due to corrosion is on the order of mg and does not exceed the allowable daily intake, but the effects of toxicity are relatively serious. Therefore, when the alloying element used for the magnesium alloy is used, it is necessary to strictly control the content. Yttrium and rare earth elements are very important elements for improving the mechanical properties and corrosivity of magnesium alloys, but their toxicity and metabolic pathways are not clear.

Therefore, a magnesium alloy with few alloying elements of the magnesium alloy is preferable from the viewpoint of biological safety. As such a magnesium alloy with a small amount of alloying elements, there is a magnesium alloy having 97% by weight or more of magnesium and 0.1 to 3.0% by weight of niobium. Since niobium stabilizes the crystal structure of the magnesium alloy, the crystal structure of the magnesium alloy does not change even in the ozone oxidation treatment at 100 to 200 ° C. and is preferably used as a base material for a bioabsorbable medical device.

The magnesium alloy described above is manufactured by various metal material manufacturing processes such as normal casting, die casting, cast plastic working, strong casting, chip solidification, rapid solidification, and rapid solidification powder metallurgy. In the process, it is known that the rapid solidification powder metallurgy method is particularly important in order to achieve high strength, high ductility, and high corrosion resistance.

In the present invention, the ozone oxidation treatment of the stent substrate made of magnesium or magnesium alloy is performed at a temperature of 20 to less than 150 ° C. using dry oxygen gas having an ozone content of less than 2 to 10% by volume, preferably 3 to 10% by volume. The oxide film is formed on the surface of the stent base material, preferably at 30 to 100 ° C., for a treatment time of 1 hour or longer, preferably 1 to 2 hours.

If the ozone content in the dry gas is less than 2% by volume, the oxidizing power is insufficient, and if it exceeds 10% by volume, the problem of excessive oxidation occurs. Further, if the treatment temperature is less than 30 ° C., ozone does not react sufficiently, and if it exceeds 100 ° C., there is a possibility that a thermal effect on the metal crystal of the base material may occur. If the treatment time is less than 1 hour, ozone does not react sufficiently and a stable oxide film is not formed. Usually, the ozone content and the treatment time in the dry gas are adjusted under the condition of a constant temperature in order to avoid the heat effect on the base material. The degradation rate of the stent can be adjusted by the thickness of the oxide film formed by the ozone oxidation treatment. The thickness of the oxide film may be a thickness that maintains the mechanical strength necessary to support the lumen wall for a period that ensures revascularization. For example, when the period for ensuring revascularization is 1 to 2 months, the thickness of the oxide film is desirably 20 to 150 mm.

The ozone-containing dry oxygen gas used for adjusting the decomposition rate of the bioabsorbable medical device of the present invention preferably has a higher ozone concentration in terms of reaction kinetics. For ozone gas, the ozone concentration obtained with a discharge-type ozonizer generally used is 5
A volume% of ozone gas may be diluted with dry oxygen gas, or may be used after being absorbed by an adsorbent such as silica gel. As a raw material gas supplied to the ozonizer, a high purity oxygen gas cylinder is generally used, and it can be said that a raw material gas having a high oxygen concentration is preferable in terms of reaction kinetics, but has an oxygen capacity of at least 99.99. (5N)
It is good that it is more than volume%, preferably 99.999 (6N) volume% or more. If such a high purity oxygen gas cylinder is used, no additional drying treatment is necessary. As for the heating method for adjusting the decomposition rate of the medical device, it is preferable to use a heating chamber or the like in which the entire surface of the medical device is uniformly heated to a predetermined temperature. Further, when only the inner surface of the medical instrument is processed, partial heating from the outside of the processed product can be handled, and the heating chamber can be omitted.

Next, an embodiment of the stent of the present invention will be described with reference to the drawings. As shown in FIG. 1, the base material of the stent is formed in a substantially tubular body, and is expandable in the radial direction from the inside of the tubular body, and a plurality of cells (6) are connected vertically, and these are connected to the base material ( A plurality of annular units (4) are arranged by surrounding the central axis (C1) of 1), and the plurality of the annular units (4) are connected to each other by at least one connecting portion (5). Is forming. FIG. 2 is a sectional view of the stent, and an oxide film (8) is provided on the surface (7) of the stent base material by ozone oxidation treatment. The oxide film made it possible to reduce the corrosion rate of magnesium or a magnesium alloy.

In the case of a drug stent, as shown in FIG. 3, the surface of the oxide film (8) further includes a polymer and a therapeutic drug (10) that does not inhibit the proliferation of endothelial cells. The first drug layer (9) is coated with a first polymer layer (9) having a weight composition ratio of the drug (10) in the range of the polymer 8 to 3 to the therapeutic drug 2 to 7 (10 in total). ) Is formed by the polymer alone or is coated with a second polymer layer (11) comprising the polymer and the therapeutic agent, wherein the weight proportion of the therapeutic agent to the polymer is greater than 80% is less than 20%. In the first polymer layer (9), when the ratio of the drug is less than 2, the drug release rate from the coat layer is too small, and when it exceeds 7, the coat layer becomes brittle and it is difficult to adhere to the stent substrate. In the second polymer layer, a layer in which the polymer is 80% or more and the weight ratio of the drug is less than 20% is formed, so that the drug can be continuously released at an appropriate release rate. A stent capable of exerting a drug effect without being inhibited can be obtained. In particular, the second polymer layer does not contain or contain a small amount of drug. In particular, when the second polymer layer does not contain a drug, the polymer structure constituting the second polymer layer has a high density. Since it is maintained, the release of the drug contained in the first polymer layer is suppressed, and the effect of continuously releasing is great. In addition, there is an advantage that the corrosion resistance of the stent can be improved by coating a bioabsorbable polymer on the oxide film formed on the surface of the stent substrate. Furthermore, by changing the thickness of the polymer layer, it is possible to easily adjust the degradation time of the stent together with the thickness of the oxide film.

In the present invention, the polymer is preferably bioabsorbable. Bioabsorbable polymers include polylactic acid (DL form), poly (lactic acid-glycolic acid) and polyglycolic acid, polyε-caprolactone, polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), polyalkyl carbonate, Polyorthoesters, polyethylene terephthalate (PET), polymalonic acid (PML), polyanhydrides, polyphosphatidine, polyamino acids, cellulose, collagen, albumin, casein, polysaccharides (PSAC) and copolymers thereof, hyaluronic acid and its derivatives, etc. There is. Poly (lactic acid-glycolic acid), polyglycolic acid, poly (lactic acid-ε-caprolactone), and polyε-caprolactone are preferable.

Therapeutic agents include anti-proliferative drugs such as sirolimus, biolimus and everolimus, anti-inflammatory drugs such as steroidal anti-inflammatory drugs, anti-neoplastic drugs such as taxol and docetaxel and / or anti-mitotic drugs, heparin sodium, hirudin Anti-platelet drugs such as argatroban, ximelagatran, melagatran, dabigatran, dabigatran etechelate, anticoagulant drugs, antifibrin drugs, and cytostatic or antiproliferative drugs such as antithrombin drugs, angiopeptin, captopril, antibiotics, Antiallergic drugs such as permirolast potassium, antioxidants, atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, simvastatin and other HMG-CoA reductase inhibitors, plasmid DNA, genes, decoy, siR There are nucleic acid drugs such as NA, oligonucleotide, antisense oligonucleotide, ribozyme and aptamer, and blood vessel restenosis inhibitor such as tamibarotene.

Next, the manufacturing process of the stent of the present invention will be described. First, a tool path in laser processing is created using CAM based on the shape data of a stent designed in advance. The tool path is set in consideration of the fact that the stent shape can be maintained after laser cutting and that no chips remain. Next, laser processing is performed on the metal thin-film meat tube. In doing so, select the machining conditions with the goal of high-speed and high-quality machining by suppressing the generation of burrs.

After the mesh shape is formed by laser cutting, the surface is finished glossy using electropolishing and the edge portion is finished in a smooth shape. In the processing process of a magnesium or magnesium alloy stent, a post-processing process after laser cutting is important. In the stent after laser cutting, the oxide on the metal cut surface is first dissolved with an acid solution, and then electropolishing is performed. In electropolishing, the stent, stainless steel, and other metal plates are immersed in the electrolyte, and the two are connected via a DC power source. Abrasion effect is obtained by applying a voltage with the stent side as the anode and the metal plate side as the cathode, and dissolving the stent on the anode side. In order to obtain an appropriate polishing effect, it is necessary to examine the composition of the electrolyte and electrical conditions in detail.
Next, the stent is subjected to ozone oxidation treatment using a dry oxygen gas having an ozone content of less than 2 to 10% by volume and a temperature of 20 to less than 150 ° C. and a treatment time of 1 hour or more. After the stent is placed in the glass tube, ozone oxidation of the stent surface can be performed by bringing the ozone-containing oxygen gas generated by the ozonizer into air contact with the stent. An advantage of this method is that a thin oxide film can be easily formed on the stent surface by a gas phase reaction.

Hereinafter, the present invention will be described with reference to Examples and Comparative Examples.
A magnesium alloy stent (φ1.8 mm × 0.2 mm × 18 mmL) is placed in a glass cylindrical tube, and ozone (4% vol) generated by a silent discharge type ozonizer using pure oxygen (99.999%) as a raw material is {100 ° C. 1 hour} The ozone oxidation treatment was carried out by aeration contact. Next, the magnesium alloy stent was immersed in physiological saline at 37 ° C. for 48 hours, but the shape of the stent was maintained (FIG. 4). In addition, a part of the stent began to dissolve after 72 hours, and the shape of the stent could not be retained after 96 hours.

The same magnesium alloy stent as in Example 1 was put in a glass cylindrical tube, and ozone (4% vol) generated by a silent discharge type ozonizer using pure oxygen (99.999%) as a raw material {25 ° C., 6.5 hours} Ozone oxidation treatment was performed by aeration contact. Next, the magnesium alloy stent was immersed in physiological saline at 37 ° C., but a part of the stent began to dissolve after 24 hours, and the shape of the stent could not be maintained after 48 hours (FIG. 5).
(Comparative Example 1)

As a result of immersing the surface-untreated magnesium alloy stent (φ1.8 mm × 0.2 mm × 18 mmL) in physiological saline at 37 ° C. in the same manner as in Example 1, a part of the stent began to dissolve after 6 hours (FIG. 6). After 18 hours, the stent was completely dissolved.

From the above Examples 1 and 2 and Comparative Example 1, the corrosion resistance of the magnesium stent is improved by the ozone oxidation treatment. Moreover, the degradation rate of the magnesium stent can be adjusted by the ozone oxidation treatment conditions.

Nine magnesium alloy stents similar to those in Example 1 were prepared, and ozone oxidation treatment was performed by changing the treatment temperature in the range of 15 to 175 ° C. under the conditions of an ozone concentration of 4 vol% and a treatment time of 1 hour. Next, the results of examining the corrosion resistance by immersing nine stents subjected to ozone oxidation treatment in physiological saline at 37 ° C. for 48 hours are shown in (Table 1). In Table 1, “◯” indicates that “the shape of the stent is retained after 48 hours of immersion”, and “Δ” indicates that “the shape of the stent is retained after immersion for 24 hours, but is not retained after 48 hours. “No” and “x” respectively represent “the shape of the stent cannot be maintained after immersion for 24 hours”.

Prepare five ozonized magnesium alloy stents of Example 1 and non-surface treated magnesium alloy stents of Comparative Example 1, and place them in 5 rabbit iliac arteries one by one, 28 days after placement. A stent was collected. It was confirmed that five rabbits with stents were alive and all the stents were patented by angiography at the time of follow-up.
Measurement of the vascular lumen area of each stent using the images at the proximal, middle, and distal portions of the stent revealed that the ozonated magnesium stent had a significantly larger vascular lumen area at a remote stage. Was shown (FIGS. 7 and 8).

The magnesium stent treated with the ozone oxidation of the present invention can be adjusted in vivo degradation rate by providing an oxide film for regulating degradation rate on the surface of the substrate, and placed in the living body which is currently a problem. The risk of endothelial cell dysfunction and subsequent thrombosis due to the permanent interaction of the stent with the living body can be solved.

Claims (6)

A bioabsorbable medical device based on magnesium or a magnesium alloy, wherein the surface of the base material is coated with an oxide film by ozone oxidation treatment, and the oxide film is configured to adjust the decomposition rate of the base material. A bioabsorbable medical device characterized by that.    2. The bioabsorbable medical device according to claim 1, wherein the bioabsorbable medical device is a stent.    The surface of the oxide film contains a polymer and a therapeutic agent that does not inhibit the proliferation of endothelial cells, and the weight composition ratio of the polymer and the therapeutic agent is in the range of 8 to 3 polymers vs. 2 to 7 therapeutic agents. Coated with a first polymer, the first polymer being formed by the polymer alone or comprising a polymer and a therapeutic agent, wherein the weight percentage of the therapeutic agent to 80% by weight of the polymer is less than 20% by weight. The bioabsorbable medical device according to claim 1 or 2, coated with two polymers. The bioabsorbable medical device according to claim 3, wherein the polymer is poly (lactic acid-glycolic acid) and the therapeutic agent is argatroban, sirolimus, taxol, decoy and / or tamibarotene. A bioabsorbable medical device based on magnesium or a magnesium alloy is brought into contact with a dry oxygen gas having a temperature of less than 20 to 150 ° C. and an ozone content of less than 2 to 10% by volume for 1 hour or more to form a surface of the substrate. A method for adjusting a decomposition rate of a bioabsorbable medical device, comprising forming an oxide film. The method for adjusting the decomposition rate of a bioabsorbable medical device according to claim 5, wherein the ozone content of the dry oxygen gas is 3 to 10% by volume and the temperature is 30 to 100 ° C.