Degradable Iron-Base Alloy Support

Abstract

A degradable iron-based alloy stem comprises an iron-based alloy substrate and a degradable polymer in contact with the surface of the substrate. The weight-average molecular weight of the degradable polymer is in the range of [1, 100]*10.sup.4, and the polydispersity index of the degradable polymer is in the range of (1.0. 50]. The degradable polymer is selected from a degradable polyamino acid that can generate an acidic amino acid after degradation; or a mixture of the degradable polyamino acid and a degradable polyester, or a copolymer of monomers of the two; or a mixture of the degradable polyamino acid and a degradable polymer that does not generate acidic products after degradation, or a copolymer of the monomers of the two; or a mixture of the degradable polyamino acid, the degradable polyester and the degradable polymer that does not generate acidic products after degradation, or a copolymer of monomers of the three, or a mixture of a copolymer of monomers of any two of the three with the remaining one.

Claims

1. A degradable iron-based alloy stem, comprising an iron-based alloy substrate and a degradable polymer in contact with the surface of the substrate, a weight-average molecular weight of the degradable polymer is in the range of [1,100]*10.sup.4, and a polydispersity index of the degradable polymer is in the range of (1.0, 50]. and the degradable polymer is selected from a degradable polyamino acid that can generate an acidic amino acid after degradation; or a mixture of the degradable polyamino acid and a degradable polyester, or a copolymer of monomers thereof; or a mixture of the degradable polyamino acid and a degradable polymer that does not generate acidic products after degradation, or a copolymer of the monomers thereof; or a copolymer of the degradable polyamic acid monomer and the degradable polyester monomer and a degradable polymer monomer that does not generate acidic products after degradation; or a mixture of the degradable polyamino acid and a degradable polyester and a degradable polymer that does not generate acidic products after degradation; or a copolymer of the degradable polyamic acid monomer and the degradable polyester monomer and a degradable polymer monomer that does not generate acidic products after degradation; or a mixture of the copolymer of monomers of any two of the degradable polyamino acid, the degradable polyester and the degradable polymers that does not generate acidic products after degradation and the remaining one.

2. The degradable iron-based alloy stent according to claim 1, wherein the weight-average molecular weight of the degradable polymer is in the range of [1, 10)*10.sup.4, or [10, 25)*10.sup.4, or [25, 40)*10.sup.4, or in the range of [40, 60)*10.sup.4, or [60, 100]*10.sup.4.

3. The degradable iron-based alloy stent according to claim 1, characterized in that the polydispersity index of the degradable polymer is in the range of [1.0, 2), or [2, 3), or [3, 5), or [5, 10), or [10, 20), or [20, 50].

4. The degradable iron-based alloy stent according to claim 1, characterized in that the mass ratio of the iron-based alloy substrate to the degradable polymer is in the range of [1, 200].

5. The degradable iron-based alloy stent according to claim 1, characterized in that the mass ratio of the iron-based alloy substrate to the degradable polymer is in the range of [5, 50].

6. The degradable iron-based alloy stent according to claim 1, characterized in that the degradable polymer is coated on the surface of the iron-based alloy substrate in form of a coating; or the iron-based alloy substrate is provided with an aperture or recess, and the degradable polymer is provided therein; or the iron-based alloy substrate has an internal cavity, in which the degradable polymer is filled.

7. The degradable iron-based alloy stent according to claim 6, characterized in that the degradable polymer is coated on the surface of the iron-based alloy substrate in form of a coating, the iron-based alloy substrate has a wall thickness in the range of [30, 50) μm, and the degradable polymer coating has a thickness in the range of [3, 5) μm, or [5, 10) μm, or [10, 15) μm, or [15, 20] μm; or the iron-based alloy substrate has a wall thickness in the range of [50, 100) μm, and the degradable polymer coating has a thickness in the range of [5, 10) μm, or [10, 15) μm, or [15, 20) μm, or [20, 25] μm; or the iron-based alloy substrate has a wall thickness in the range of [100, 200) μm, and the degradable polymer coating has a thickness in the range of [10, 15) μm, or [15, 20) μm, or [20, 25) μm, or [25, 35] μm; or the iron-based alloy substrate has a wall thickness in the range of [200, 300] μm. and the degradable polymer coating has a thickness in the range of [10, 15) μm, or [15, 20) μm, or [20, 25) μm, or [25, 35) μm, or [35, 45] μm.

8. The degradable iron-based alloy stent according to claim 1, characterized in that the degradable polyamine acid is selected from the group consisting of polyaspartic acid or polyglutamic acid, or a mixture of polyaspartic acid and polyglutamic acid, or a copolymer of a polyaspartic acid monomer and a polyglutamic acid monomer.

9. The degradable iron-based alloy stent according to claim 1, characterized in that the degradable polymer that does not generate acidic products after degradation is selected from the group consisting of starch, cellulose, polysaccharide, chitin, chitosan or derivatives thereof.

10. The degradable iron-based alloy stent according to claim 1, characterized in that when the degradable polymer is a mixture of a degradable polyamino acid and a degradable polyester, or a copolymer of a degradable polyamino acid monomer and a degradable polyester monomer, the proportion by which the degradable polyamino acid and the degradable polyester are mixed or the proportion of the comonomers thereof is [1:1, 10:1].

11. The degradable iron-based alloy stent according to claim 1, characterized in that when the degradable polymer is a mixture of a degradable polyamino acid and a degradable polymer that does not generate acidic products after degradation, or a copolymer of a degradable polyamino acid monomer and a degradable polymer monomer that does not generate acidic products after degradation, the proportion by which the degradable polyamino acid and the degradable polyester that does not generate acidic products after degradation are mixed or the proportion of the comonomers thereof is [1:1,10:1].

12. The degradable iron-based alloy stent according to claim 1, characterized in that a mixture of the degradable polyamino acid and a degradable polyester and a degradable polymer that does not generate acidic products after degradation, a copolymer of the degradable polyamic acid monomer and the degradable polyester monomer and a degradable polymer monomer that does not generate acidic products after degradation, or a mixture of the copolymer of monomers of any two of the degradable polyamino acid, the degradable polyester and the degradable polymers that does not generate acidic products after degradation and the remaining one. content of the degradable polyamino acid, the degradable polyester and the degradable polymer that does not generate acidic products after degradation or the comonomers thereof are respectively in the range of [10%, 80%], [10%, 80%] and [10%, 60%].

13. The degradable iron-based alloy stent according to claim 1, characterized in that the degradable polyesters are physical blends of at least two of polylactic acid, polyglycolic acid, polybutylene succinate, poly (β-hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer and polyhydroxybutyrate pentanoate copolymer, or a copolymer copolymerized from at least two of monomers that form polylactic acid, polyglycolic acid, polybutylene succinate, poly (β-hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer and polyhydroxybutyrate pentanoate copolymer.

14. The degradable iron-based alloy stent according to claim 1, characterized in that the degradable polymer is mixed with an active drug, and the mass ratio of the degradable polymer to the drug is in the range of [0.1, 20].

15. The degradable iron-based alloy stent according to claim 14, characterized in that the mass ratio of the degradable polymer to the drug is in the range of [0.5, 10].

16. The degradable iron-based alloy stent according to claim 1, characterized in that the iron-based alloy base material is selected from a pure iron or an iron-based alloy formed by doping the pure iron with C, N, O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, and Re.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 is a schematic cross-sectional view of an iron-based alloy stent and a coated support provided in example 5 of the present disclosure.

BEST EXAMPLE OF THE INVENTION

Best Implementation for the Invention

[0036] It is to be noted that, on the basis of an animal experiment for the degradable iron-based alloy stent provided by the present disclosure, it can be verified that the iron-based alloy stents are capable of rapidly corroding the iron-based alloy stent under the action of a degradable polymer, and it can be determined whether the iron-based stent is rapidly corroded or not primarily through early mechanical properties, and whether it is completely corroded in a certain period by the mass loss test.

[0037] Specifically, the iron-based alloy stent containing the degradable polymer is implanted into the animal and tested respectively at predetermined observation time points. For example, an OCT follow-up test for the stem being implanted in the body for 3 months. There is no significant difference between the area around the stem and the area of the just implanted stent. Or the animals are euthanised, the stent and the tissue at which it is located are removed from the body, and the stem and the blood vessel at which it is located are subjected to a radial support force test to determine whether the stem satisfies the early mechanical properties or not. The stent sample is removed after it has been implanted for 2 years to test the stent mass loss to determine whether the stent had been completely corroded or not.

[0038] The test for the radial support force may he performed using the radial support force tester RX550-100 produced by MSI company, including removal of the stent implanted in the animal with the vessel at a predetermined observation time point, and the test is then carried out to obtain the radial support force.

[0039] The complete corrosion is characterized by a mass loss test of an animal experiment. The test is performed by implanting an iron-based alloy stent of an iron-based alloy substrate (i.e., a bare stent that does not include a degradable polymer) of M.sub.0 into the abdominal aorta of a rabbit, and cutting out the iron-based alloy stent and the tissue at the implant location at a predetermined observation time point. Then the tissue and the stent are soaked in a solution of a certain concentration e.g., 1 mol/L sodium hydroxide solution) to decompose the tissue, and the stent is removed from the solution and placed in a solution of a certain concentration (such as a 3% of tartaric acid solution, and/or an organic solution) for ultrasonication, so that the corroded products on the surface of the stent all fall off or are dissolved in the solution. The remaining stent is removed from the solution, dried and weighed, and the mass is M.sub.t. The mass loss rate W is represented by a percentage that the difference of the weight loss of the corrosion-cleaned stent accounts for the weight of the iron-based alloy substrate, as shown in Equation 1-1:

W=[(M.sub.0−M.sub.1)/M.sub.0]×100%   (Equation 1-1)

[0040] W—mass loss rate

[0041] M.sub.1—the remaining mass of the corroded stent

[0042] M.sub.0—mass of the iron-based alloy substrate

[0043] When the stem mass loss rate W is greater than or equal to 90%, this indicates that the iron-based alloy stent is completely corroded. The weight-average molecular weight of the degradable polymer and its polydispersity index are detected by an octagonal laser light scattering instrument produced by Wyatt Technology Corporation (WTC).

[0044] The degradable iron-based alloy stent provided by the present disclosure will be further described below with reference to the accompanying drawings and examples. It is to be understood that the following examples are merely preferred examples of the invention and are not intended to limit the present invention; any modifications, equivalent replacements and modifications within the spirit and principles of the invention are included within the protection scope of the present disclosure.

Example 1

[0045] A pure iron stent comprises a pure iron substrate and a degradable polymer coating coated on the surface of the pure iron substrate, where the mass ratio of the pure iron substrate to the degradable polymer was 10:1. The degradable polymer was polyglutamic acid, the weight- average molecular weight was 15,000, the polydispersity index was 1.5, the wall thickness of the iron substrate was 80-90 μm. and the thickness of the degradable polymer coating was from 10 to 15 μm. The stem was implanted into the abdominal aorta of the rabbit. The stent and the tissue at which it was located were removed from the body after they had been implanted in the body for 3 months for the radial support force test. The test result was 70 kPa. Re-sampling after 2 years, carrying out the mass loss test, the stent mass loss rate was 95%, indicating that the stent had been completely corroded.

Example 2

[0046] A degradable polymer coating having a thickness of from 8 to 10 microns was uniformly coated on the surface of a nitrided pure iron bare stent (i.e., a nitrided pure iron substrate) having a wall thickness of from 50 to 70 microns, the mass percentage of the substrate and the degradable polymer was 25, the degradable polymer coating was a polyaspartic acid-lactic acid copolymer coating having a weight-average molecular weight of 100,000 and a polydispersity index of 3, and wherein the aspartic acid was copolymerized with lactic acid by a ratio of 1:1. After the coating was dried, the degradable iron-based alloy stent was prepared. The iron-based alloy stent was implanted into a porcine coronary artery. It was found from an OCT follow-up test for the stem implanted in the body for 3 months that there was no significant difference between the area around the stent and the area of the just-implanted stent. The mass loss test was carried out, and the stent mass loss rate was 92%, indicating that the stent had been completely corroded.

Example 3

[0047] A polyglutamic acid coating having a thickness of from of 3 to 5 microns was uniformly coated on the surface of an electrodeposited pure iron (550° C, annealed) bare stent (i.e., electrodeposited pure iron substrate) having a wall thickness of from 40 to 50 microns, and the polyglutamic acid coating was coated with a polycaprolactone (PCL) rapamycin mixed coating having a thickness of from 5-8 microns. The ratio of polycaprolactone to rapamycin was 2:1, the mass ratio of electrodeposited pure iron substrate to the degradable polymer was 35:1, in which the weight-average molecular weight of polycaprolactone was 30,000, the polydispersity index was 1.3, the weight-average molecular weight of the polyglutamic acid was 80,000, the polydispersity index was 1.6, and the mass ratio was 1:1. A degradable iron-based alloy stent was prepared after drying. The stent was implanted into the abdominal aorta of the rabbit and the stem was removed at a corresponding observation time point. The surface of the stent was observed with a microscope and a percentage of the radial support force to the mass loss of the stent was tested. Test results show that the 3-month radial support force was 60 kPa; the mass loss test was carried out after 1 year to find that the stent mass loss rate was 98%, indicating that the stent had been completely corroded.

Example 4

[0048] The surface of the outer wall of the carburized iron bare stent (i.e., the carburized iron base) after the heat treatment was coated with a mixed coating of polyaspartic acid and starch. The carburized iron base had a wall thickness of from 140 to 160 microns, the coating had a thickness of from 30 to 35 microns, and the mass ratio of the carburized iron substrate to the degradable polymer was 30:1. The coating was divided into two layers, the bottom layer was a polyaspartic acid having a molecular weight of 400,000, the top layer was a chitosan coating having a molecular weight of 30,0000. and the polydispersity index was 1.2. The mass ratio of the two degradable polymer coatings was 5:1. A degradable iron-based alloy stent was prepared after drying. The stent was implanted into the abdominal aorta of the rabbit and the stent was removed at a corresponding observation time point. The surface of the stent was observed with a microscope and a percentage of the radial support force to the mass loss of the stem was tested. The test results showed that the radial support force of 6 months was 50 kPa, and the mass loss rate of the stent was 93% after 5 years.

Example 5

[0049] An iron-manganese alloy bare stent (i.e., ferro-manganese alloy substrate) was polished, so that the surface of the stent was distributed with recesses, as shown in FIG. 1, the stent had a thickness 1 of from 100 to 120 microns, and the surface of the stent I was provided with a recess 2. A mixture coating 3 of two layers of degradable polymer was uniformly coated on the surface of the stent 1 and in the recess 2. The coating of the degradable polyester-based polymer was a polyglutamic acid-caprolactone copolymer having a weight-average molecular weight of 500,000 which was copolymerized by a mass ratio of 2:1. and the polymer polydispersity index was 10, the thickness of the coating of the mixture was from 20 to 25 microns. and the mass ratio of the iron-based alloy substrate to the degradable polymer was 40:1. A degradable iron-based alloy stent was prepared after drying. The stent was implanted into the porcine coronary artery, and the stent was removed at a corresponding observation time point. The mass loss rate and the radial support force were tested. The test results of 3 months showed that the radial support force was 60 kPa, it was found from the mass loss test after 4 years that the mass loss rate of the stent was 95%.

Example 6

[0050] A degradable polymer coating having a thickness of from 35 to 45 microns was coated relatively uniformly on the surface of a sulfurized iron bare stent (i.e., a sulfurized iron-based alloy substrate) having a wall thickness of from 250 to 270 microns, the coating was divided into two layers, including a bottom layer of chitosan having a molecular weight of 500,000, and a polydispersity index of 10, and a top layer of polyglutamic acid lactic acid-glycolic acid copolymer coating (a copolymerization ratio of 1:1) having a molecular weight of 300,000, and a polydispersity index of 5. The mass ratio of the carburized iron-based alloy substrate to the degradable polymer is 50:1, and the mass ratio of the two coatings is 1:2. A degradable iron-based alloy stent was prepared after drying. The stent was implanted into the porcine abdominal aorta, and the stent was removed at a corresponding observation time point to test the mass loss of the iron-based alloy stem. The test results showed that the radial support force of 6 months was 50 kPa, and the mass loss rate of the stem was 90% after 5 years.

Example 7

[0051] A mixed coating of polyaspartic acid and heparin having an average thickness of from 12 to 15 microns was coated on the surface of a carburized iron bare stem (i.e., a carburized iron substrate) having a wall thickness of from 50 to 70 microns, wherein the two were mixed by a ratio of 5:1, the aspartic acid molecular weight was 1 million, the polydispersity index was 20. and the mass ratio of the carburized iron-based alloy substrate to cocoa-degradable polymer was 30. The degradable iron-based alloy stem was implanted into the porcine coronary artery, and the iron-based alloy stent was removed at a corresponding observation time point for the mass loss test and radial support force test. The test results showed that the radial support force of 3 months was 60 kPa, and the mass loss rate of the stent was 98% after 4 years.

Comparative Example 1

[0052] A pure iron bare stent (pure iron substrate, i.e., the surface is not covered with any coating) having a wall thickness of from 60 to 70 microns was implanted into the abdominal aorta of the rabbit. After three months, the stent was removed, the radial support force was tested as 120 kPa, the stent was removed after being implanted for 3 years for a mass loss test, and at this time, the mass loss rate of the stent was 25%. indicating that the bare iron stent corrosion rate was slow.

Comparative Example 2

[0053] A polylactic acid coating having a thickness of from 25 to 35 microns was coated on a pure iron bare stent (i.e., pure iron substrate) having a wall thickness of from 60 to 70 microns, the mass ratio of the pure iron substrate to the polylactic acid was 10:1, the polylactic acid has a weight-average molecular weight of 15,000 and a polydispersity index of 1.8. An iron-based stent was prepared after drying, which was implanted in the abdominal aorta of a rabbit. The radial support force test result was 20 kPa after 3 months, the mass loss test for the stent showed that the mass loss rate of the stent was 100% after 6 months, indicating that the stent had been completely corroded fast, and the clinically required mechanical properties were not met at an expected time point.

[0054] It can be seen from the test results of Examples 1 to 7 and Comparative Examples 1 to 2 that the present invention provides a corrodible iron-based alloy stent having a weight-average molecular weight in the range of [20000, 1 million], and the degradable polymer with a polydispersity index in the range of (1.0, 50] not only achieves a complete corrosion of the iron-based alloy substrate within 10 years of implantation thereof, but also meets the clinical requirements of corrosion cycles of the degradable stent. In an OCT follow-up, there is no significant difference between the area around the stem and the area of the just implanted stent, or the radial support force is above 23.3 kPa (175 mm Hg) in the radial support force test, which has met clinical requirement for mechanical properties of the stent implanted in the body.