stents

Abstract

To provide a highly-safe bio-absorbable stent excellent in bio- followability, and having fewer complications.SOLUTION: A stent contains bio-absorbable polyester, in which stability defined by formula (1) is 80% or more: stability(%)=((L0×2-L1) / L0)×100...formula (1); L0: initial length, L1: length after repeating 10 times operation for generating tensile strain of 100% to the initial length, by applying tensile stress to the longest direction of the stent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a stent comprising a polyester that can develop biodegradability or bioabsorbability. [Background technology]

[0002] Stents are radially expandable implantable medical devices that are implanted inside various body cavities or vessels (e.g., the vascular system, esophagus, gastrointestinal tract, large and small intestines, bile duct, pancreatic duct, lungs, ureters, nasal cavities, trachea, etc.). When a body cavity or vessel narrows, a stent is placed in the narrowed area to maintain the lumen. Such stents include those that are placed in the body cavity or vessel for a long period of time, and those that are retrieved and removed from the body after maintaining the lumen patency for a predetermined period of time, as discussed, for example, in Non-Patent Document 1. In these cases, there is a need to treat using a polymeric material, particularly a bioabsorbable polymeric material, in contrast to a metal stent, so that the presence of the stent in the body cavity or vessel can be limited.

[0003] As polymeric materials for such bioabsorbable materials, attention has been focused on polylactic acid, polyglycolic acid, polycaprolactone, polydioxane, and bioabsorbable polyesters, which are copolymers of these.

[0004] For example, Patent Documents 1 and 2 disclose bioabsorbable stents made of polylactic acid or polycaprolactone, but many problems remain to be overcome in developing bioabsorbable stents. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6017617 [Patent Document 2] Patent No. 6505438 [Non-patent literature]

[0006] [Non-Patent Document 1] YueqiZhu, etal.,MaterialsToday2017, 20, 516-529 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a demand for bioabsorbable stents with high bio-following properties that enable them to function in an environment where multiple physical actions, such as bending, stretching, and compression, occur due to movements within a body cavity or a blood vessel. However, the bioabsorbable stents described in Patent Documents 1 and 2 and Non-Patent Document 1 are rigid and therefore have poor bio-following properties, and there are cases where they move or fall off from the placement site or even damage the surrounding tissue.

[0008] Therefore, an object of the present invention is to provide a stent that contains a bioabsorbable polyester and has excellent bio-followability. [Means for solving the problem]

[0009] The present invention for solving the above problems is as follows.

[0010] A stent comprising a bioabsorbable polyester and having a resilience of 80% or more as defined by formula (1).

[0011] Restorability (%) = ((L0 × 2 - L1) / L0) × 100 Equation (1) L0: initial length L1: The length after applying tensile stress in the longest direction of the stent to generate a tensile strain of 100% of the initial length 10 times [Effects of the Invention]

[0012] By using the stent of the present invention, a safer stent with fewer complications can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0013] The stent of the present invention comprises a bioabsorbable polyester and has a restoring property of 80% or more as defined by formula (1).

[0014] Restorability (%) = ((L0 × 2 - L1) / L0) × 100 Equation (1) L0: initial length L1: The length after applying tensile stress in the longest direction of the stent to generate a tensile strain of 100% of the initial length 10 times Specifically, the measurement is carried out by the tensile test described in Measurement Example 3 below.

[0015] The stent of the present invention preferably has a Young's modulus of 0.1 MPa or more and 15 MPa or less, as measured according to JIS K6251 (2017). The measurement method is as described in Measurement Example 3 below. Since stents are placed in various body cavities or blood vessels, if the Young's modulus of the stent is too high, external forces applied to the stent due to deformation such as bending or curvature may compress, abrade, puncture, or otherwise injure the tissue around the placement site. Therefore, the Young's modulus of the stent is preferably 15 MPa or less. On the other hand, if the Young's modulus of the stent is too low, the stent will not be able to maintain its shape when external forces are applied to the stent due to deformation such as bending or curvature. Therefore, the Young's modulus is preferably 0.1 MPa or more, more preferably 0.5 MPa or more, and even more preferably 1.0 MPa or more.

[0016] The stent of the present invention preferably has a tensile strength of 5 MPa or more as measured according to JIS K6251 (2017). The measurement method is as described in Measurement Example 3 below. Tensile strength is a factor directly linked to the breaking strength of the stent. Therefore, the tensile strength of the stent is preferably 5 MPa or more, and for stents used in areas where more severe deformation such as bending or curvature occurs, the tensile strength is preferably 20 MPa or more. The higher the tensile strength of the stent, the better, and there is no particular upper limit, but realistically the upper limit is thought to be around 500 MPa.

[0017] The stent of the present invention preferably has a breaking elongation of 200% or more as measured according to JIS K6251 (2017). This measurement method is as described in Measurement Example 3 below. Breaking elongation is a factor that indicates the breaking strength of a stent. Assuming that the stent will be used in an environment where multiple physical actions such as bending, stretching, and compression occur due to movement within a body cavity or a blood vessel, the breaking elongation of the stent is preferably 200% or more. For stents used in areas where more severe deformation occurs, the breaking elongation is more preferably 500% or more, and even more preferably 1000% or more. The greater the breaking elongation of the stent, the better, and there is no particular upper limit, but realistically the upper limit is thought to be around 2500%.

[0018] Furthermore, since the stent of the present invention is intended to be placed in various body cavities or blood vessels, it must have the restoring ability to return to its original shape even when deformed by multiple physical actions such as bending, stretching, and compression due to movement within the body cavity or blood vessel. Therefore, it is important that the stent of the present invention has a restoring ability defined by the following formula (1) of 80% or more. Note that restoring ability can be quantitatively evaluated from the following formula (1) as in Measurement Example 3 described below.

[0019] Restorability (%) = ((L0 × 2 - L1) / L0) × 100 Equation (1) L0: initial length L1: The length after applying tensile stress in the longest direction of the stent to generate a tensile strain of 100% of the initial length 10 times The closer the resilience of a stent is to 100%, the less likely it is that the function that the stent is to perform will be lost due to deformation. Because stents are subjected to multiple physical actions such as bending, stretching, and compression due to movement within a body cavity or a blood vessel, the resilience of the stent of the present invention is preferably 80% or more, more preferably 85% or more, and even more preferably 90% or more. The higher the resilience of a stent, the more preferable it is, with the upper limit being 100%.

[0020] The stent of the present invention contains a bioabsorbable polyester. The content of the bioabsorbable polyester in the stent of the present invention is not limited as long as it contains the bioabsorbable polyester, but it is preferable that the stent contains 50% by weight or more of the bioabsorbable polyester, and more preferably 80% by weight or more, based on 100% by weight of the entire stent. When it is required that the stent completely disappears when applied to a living body, it is particularly preferable that the stent is made solely of bioabsorbable polyester, i.e., that the stent contains 100% by weight of the bioabsorbable polyester based on 100% by weight of the stent. Furthermore, in order to obtain a stent with excellent bioabsorbability having a recovery of 80% or more, as required in the present invention, i.e., a stent with excellent biofollowing properties by maintaining high tensile strength and exhibiting a low Young's modulus, it is preferable that the stent contains the bioabsorbable polyester described below in the above-mentioned amount.

[0021] Here, bioabsorbability refers to the property of being naturally decomposed by hydrolysis or enzymatic reaction after placement inside or outside the body, and the decomposition products are metabolized or excreted and disappear. Examples of such bioabsorbable polyesters include polyesters selected from the group consisting of polyglycolic acid, polylactic acid (D, L, DL), polyε-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrate valerate, polyorthoester, polyhydroxyvaleric acid, polyhydroxyhexanoic acid, polyhydroxybutanoic acid, polybutylene succinate, polybutylene succinate, polytrimethylene terephthalate, polyhydroxyalkanoate, and copolymers thereof. Among these, it is more preferable that the stent of the present invention contains any one of polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, and a copolymer of polyglycolic acid and polyε-caprolactone.

[0022] In a more preferred embodiment of the bioabsorbable polyester in the stent of the present invention, the bioabsorbable polyester comprises a polyester copolymer having two types of ester bond-forming monomer residues as main structural units (hereinafter, such a bioabsorbable polyester polyester copolymer having two types of ester bond-forming monomer residues as main structural units will be simply referred to as the "polyester copolymer of the present invention"), and where the ester bond-forming monomers are designated as Monomer A and Monomer B, it is preferred that Monomer A and Monomer B are compounds selected from the group consisting of lactic acid, glycolic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxypentanoic acid, hydroxycaproic acid, hydroxyheptanoic acid, caprolactone, dioxepanone, ethylene oxalate, dioxanone, 1,4-dioxane-2,3-dione, trimethylene carbonate, β-propiolactone, δ-valerolactone, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, dilactide, glycolide, and tetramethylglycolide. This will be explained below.

[0023] The content of the polyester copolymer of the present invention is preferably 50% by weight or more, more preferably 70% by weight or more, even more preferably 95% by weight or more, and particularly preferably 100% by weight, based on 100% by weight of the bioabsorbable polyester in the stent. By adjusting the content to such an amount, the stent can have the restoring ability to return to its original shape even if it is deformed by multiple physical actions such as bending, stretching, and compression due to movement in a body cavity or a blood vessel.

[0024] The term "ester bond-forming monomer" refers to a monomer that, after polymerization, produces a polymer in which the monomer units are linked by ester bonds, i.e., a polyester.

[0025] As the ester bond-forming monomer, a hydroxycarboxylic acid is preferably used. Also preferably used are lactones, which are cyclic compounds formed by intramolecular dehydration condensation of the hydroxy group and the carboxyl group of a hydroxycarboxylic acid, and lactides, which are cyclic compounds formed by dehydration condensation of the hydroxy group and the carboxyl group of two molecules of hydroxycarboxylic acid.

[0026] It is particularly preferable to use an aliphatic hydroxycarboxylic acid as the hydroxycarboxylic acid, such as lactic acid, glycolic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxypentanoic acid, hydroxycaproic acid, and hydroxyheptanoic acid, with lactic acid, glycolic acid, hydroxypentanoic acid, and hydroxycaproic acid being particularly preferred.

[0027] Although L-lactic acid, D-lactic acid, and mixtures thereof can be used as lactic acid, it is preferable to use L-lactic acid in terms of the physical properties and biocompatibility of the resulting polymer. When a mixture is used as a monomer, the L-lactic acid content is preferably 85% or more, and more preferably 95% or more.

[0028] Examples of lactones that can be used include caprolactone, dioxepanone, ethylene oxalate, dioxanone, 1,4-dioxane-2,3-dione, trimethylene carbonate, β-propiolactone, δ-valerolactone, β-propiolactone, β-butyrolactone, γ-butyrolactone, and pivalolactone, with caprolactone and δ-valerolactone being particularly preferred.

[0029] As lactide, dilactide obtained by dehydration condensation of two molecules of lactic acid, glycolide obtained by dehydration condensation of two molecules of glycolic acid, and tetramethyl glycolide can be used.

[0030] As the ester bond-forming monomer, derivatives of the above-exemplified monomers can also be used.

[0031] Among these, in the present invention, it is more preferred that Monomer A and Monomer B are compounds selected from the group consisting of lactic acid, glycolic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxypentanoic acid, hydroxycaproic acid, hydroxyheptanoic acid, caprolactone, dioxepanone, ethylene oxalate, dioxanone, 1,4-dioxane-2,3-dione, trimethylene carbonate, β-propiolactone, δ-valerolactone, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, dilactide, glycolide, and tetramethylglycolide. It is particularly preferred that Monomer A is lactic acid or glycolic acid, and that Monomer B is caprolactone or δ-valerolactone.

[0032] In this specification, of the two types of ester-bonding monomers, the one with high crystallinity of the homopolymer composed only of the monomer residues is referred to as Monomer A, and the one with low crystallinity is referred to as Monomer B. The crystallinity of the homopolymer can be measured using a differential scanning calorimeter (DSC) as follows.

[0033] The homopolymer is collected on an aluminum pan and measured using a differential scanning calorimeter (EXTAR 6000, manufactured by Seiko Instruments Inc.) under the following condition A by the DSC method to calculate the heat of fusion. A higher heat of fusion per unit weight indicates higher crystallinity. For example, the heat of fusion per unit weight of polylactic acid, determined using the above method, is 93 J / g. (Condition A) Device name: EXSTAR 6000 (Seiko Instruments Inc.) Temperature conditions: 25℃→250℃(10℃ / min) Standard material: α-alumina In the present invention, when the bioabsorbable polyester is a polyester copolymer having two types of ester bond-forming monomer residues as main structural units, and the ester bond-forming monomers are monomer A and monomer B, it is preferable that the crystallinity of both the monomer A residue and the monomer B residue is less than 14%. If the crystallinity is less than 14%, an increase in Young's modulus is suppressed, and a polyester copolymer suitable for stents can be obtained. The crystallinity of the monomer A residue and the monomer B residue is preferably 10% or less, and more preferably 5% or less.

[0034] The crystallinity ratio of a monomer residue referred to here is the ratio of the heat of fusion per unit weight of the monomer residue in the polyester copolymer of the present invention to the product of the heat of fusion per unit weight of a homopolymer consisting only of a certain monomer residue and the weight fraction of that monomer residue in the polyester copolymer of the present invention. In other words, the crystallinity ratio of a monomer A residue is the ratio of the heat of fusion per unit weight of the monomer A residue in the polyester copolymer to the product of the heat of fusion per unit weight of a homopolymer consisting only of monomer A and the weight fraction of the monomer A residue in the polyester copolymer of the present invention. The crystallinity ratios of the monomer A residue and the monomer B residue indicate the proportion of the monomer A residue or the monomer B residue in the polyester copolymer of the present invention that form a crystalline structure, respectively.

[0035] In particular, when the monomer A residue is a lactic acid residue and the monomer B residue is a caprolactone residue, the crystallinity of the lactic acid residue and the caprolactone residue is preferably less than 14%, more preferably 10% or less. The crystallinity is specifically determined by the following method.

[0036] The polyester copolymer was dissolved in chloroform to a concentration of 5% by weight, and the solution was transferred to a Teflon (registered trademark) Petri dish and dried overnight at room temperature under normal pressure. This was then dried under reduced pressure to obtain a polyester copolymer film. The resulting polyester copolymer film was placed on an alumina PAN and measured using a differential scanning calorimeter under the following conditions by the DSC method. The heat of fusion was calculated from the measurement results under temperature conditions (D) and (E). The crystallization ratio was calculated using the following formula:

[0037] Crystallization rate of lactic acid residues = (heat of fusion per unit weight of lactic acid residues in polyester copolymer) / {(heat of fusion per unit weight of homopolymer consisting only of lactic acid residues) × (weight fraction of lactic acid residues in polyester copolymer)} × 100 (%) Crystallinity ratio of caprolactone residue=(Heat of fusion per unit weight of caprolactone residue in polyester copolymer) / {(Heat of fusion per unit weight of homopolymer consisting of only caprolactone residue)×(Weight fraction of caprolactone residue in polyester copolymer)}×100(%) Device name: EXSTAR 6000 (Seiko Instruments Inc.) Temperature conditions: (A) 25℃ → (B) 250℃ (10℃ / min) → (C) 250℃ (5min) → (D) -70℃ (10℃ / min) → (E) 250℃ (10℃ / min) → (F) 250℃ (5min) → (G) 25℃ (100℃ / min) Standard material: Alumina In this specification, the term "monomer residue" generally refers to a repeating unit of a chemical structure derived from a monomer in the chemical structure of a copolymer obtained by polymerizing two or more monomers including the monomer. For example, a copolymer of lactic acid (CH3CH(OH)COOH) and caprolactone (ε-caprolactone: formula below)

[0038] [ka]

[0039] When polymerized to form a copolymer of lactic acid and caprolactone,

[0040] [ka]

[0041] is a lactic acid monomer residue, and the unit represented by the following formula is a caprolactone monomer residue.

[0042] [ka]

[0043] However, as an exception, when a dimer such as lactide is used as a monomer, the term "monomer residue" refers to one of the two repeating structures derived from the dimer. For example, dilactide (L-(-)-lactide: formula below)

[0044] [ka]

[0045] When lactic acid is polymerized with caprolactone, the chemical structure of the copolymer is formed with two repeats of the structure shown in formula (R1) above as dilactide residues. In this case, one of the lactic acid units is considered to be a "monomer residue," and two "monomer residues," i.e., two lactic acid residues, are considered to have been formed derived from the dilactide.

[0046] When a bioabsorbable polyester is a polyester copolymer having two types of ester bond-forming monomer residues as its main structural units, the term "main structural units" refers to the fact that the sum of the two types of monomer residues is 50 mol% or more, when the sum of all monomer residues in the entire polymer, including other monomer residues, is taken as 100%, and each residue accounts for 20 mol% or more, when the sum of all monomer residues in the entire polymer is taken as 100%. For example, "main structural units" refers to the fact that the sum of the monomer A residues and monomer B residues is 50 mol% or more, when the sum of all monomer residues in the entire polymer is taken as 100%, and that the monomer A residues account for 20 mol% or more, and the monomer B residues account for 20 mol% or more. Here, the molar fractions of the monomer A residues, monomer B residues, and other residues can be determined by nuclear magnetic resonance (NMR) measurement from the area values ​​of the signals derived from each residue. For example, when the monomer A residue is a lactic acid residue and the monomer B residue is a caprolactone residue, the measurement can be carried out by the method described in Measurement Example 1 below.

[0047] The sum of the monomer A residues and the monomer B residues, as defined above, is 50 mol% or more, preferably 75 mol% or more, and more preferably 90 mol% or more, when the sum of all the monomer residues contained in the entire polymer, including other monomer residues, is taken as 100%. Furthermore, as defined above, the sum of the monomer A residues and the monomer B residues is each 20 mol% or more, preferably 30 mol% or more, and more preferably 40 mol% or more. A particularly preferred embodiment is a polymer in which the sum of the monomer A residues and the monomer B residues is 100% of the entire polymer, i.e., a polymer consisting only of monomer A and monomer B.

[0048] As long as the effects of the present invention are not impaired, other monomers that can be copolymerized with the two ester bond-forming monomers that constitute the main structural units can also be copolymerized. Such monomers can be other than the above-mentioned ester bond-forming monomers.

[0049] Copolymerization of a monomer that functions as a linker is also a preferred embodiment. Examples of the monomer that functions as a linker include hydroxycarboxylic acids other than the two ester bond-forming monomers that constitute the main structural units, dialcohols, dicarboxylic acids, amino acids, diamines, diisocyanates, and diepoxides.

[0050] In this specification, the term "polyester copolymer" also includes copolymers that contain monomers other than ester bond-forming monomers as constituent units, and thereby contain constituent units that are linked in part by bonds other than ester bonds.

[0051] The polyester copolymer of the present invention is preferably biodegradable or bioabsorbable. A person skilled in the art would be able to synthesize a copolymer that exhibits appropriate biodegradability or bioabsorbability depending on the application by appropriately combining the above-exemplified monomers and adjusting the ratio of the monomers within the range specified in the present invention.

[0052] In the polyester copolymer of the present invention, the molar ratio of monomer A residues to monomer B residues is preferably 20 to 80%, more preferably 30 to 70%, and even more preferably 40 to 60%, relative to the total number of moles of monomer A residues and monomer B residues (100%), since the polyester copolymer approaches the properties of a homopolymer when one of the monomers is present in excess.

[0053] The bioabsorbable polyester contained in the stent of the present invention is a polyester copolymer having two types of ester bond-forming monomer residues as main structural units, and when the ester bond-forming monomers are monomer A and monomer B, the polyester copolymer preferably has an R value represented by the following formula of 0.45 or more and 0.85 or less.

[0054] R = [AB] / (2[A][B]) × 100 [A]: Molar fraction (%) of monomer A residues in the polyester copolymer [B]: Molar fraction (%) of monomer B residues in the polyester copolymer [AB]: mole fraction (%) of structures (AB and BA) in which monomer A residue and monomer B residue are adjacent to each other in the polyester copolymer The R value is used as an index of the randomness of the arrangement of monomer residues in a copolymer whose main structural units are two types of ester bond-forming monomer residues, i.e., monomer A residue and monomer B residue. For example, a random copolymer in which the monomer arrangement is completely random has an R value of 1. In addition, the R value for a block copolymer is 0 to 0.44.

[0055] The R value can be determined by quantifying the ratio of combinations of two adjacent monomers (AA, BB, AB, BA) by nuclear magnetic resonance (NMR) measurement, and specifically, it is measured by the method described in Measurement Example 1 below.

[0056] To achieve high biotraceability, the R value is preferably 0.45 or more and 0.85 or less, and more preferably 0.50 or more and 0.85 or less.

[0057] In order to control the crystallinity conversion rate within a suitable range, the weight-average molecular weight of the polyester copolymer of the present invention is preferably 100,000 to 1,000,000, more preferably 120,000 to 750,000, and even more preferably 150,000 to 500,000. The weight-average molecular weight of the polyester copolymer can be measured, for example, by the method described in Measurement Example 2.

[0058] As an example, the polyester copolymer of the present invention can be prepared by a macromer synthesis step of blending and polymerizing two types of ester bond-forming monomers, namely, Monomer A and Monomer B, so that at the completion of polymerization, the sum of Monomer A residues and Monomer B residues accounts for 50 mol % or more of all residues, and Monomer A residues and Monomer B residues each accounts for 20 mol % or more of all residues; a multiplication step of linking the macromers obtained in the macromer synthesis step to each other or by adding the monomer A and the monomer B to the macromer solution obtained in the macromer synthesis step; The polyester copolymer can be produced by a method for producing the polyester copolymer having the formula:

[0059] [Macromer synthesis process] In the macromer synthesis step, monomer A and monomer B are polymerized by mixing them together so that, theoretically, at the completion of polymerization, the sum of monomer A residues and monomer B residues will be 50 mol % or more of all residues, and monomer A residues and monomer B residues will each be 20 mol % or more of all residues. This produces a polyester copolymer whose main structural units are monomer A residues and monomer B residues, but because this production method also includes a multi-component step described below, the polyester copolymer obtained by this step will be referred to as a "macromer" in this specification.

[0060] As the ester bond-forming monomer, the same ones as those described above can be used, and the preferred combinations etc. are also as described above.

[0061] The randomness of the distribution of monomer residues constituting a polyester copolymer, whose main structural units are two types of ester bond-forming monomer residues, varies depending on the reactivity of the monomers during polymerization. That is, if one of the two types of monomers is bound to the other with equal probability during polymerization, a copolymer with completely randomly distributed monomer residues is obtained. However, if there is a tendency for one monomer to be bound to the other, a gradient copolymer with a biased distribution of monomer residues is obtained. The resulting gradient copolymer has a continuously changing composition of monomer residues along its molecular chain from the initiation end to the termination end of polymerization.

[0062] Here, assuming that monomer A has a higher initial polymerization rate than monomer B, when monomer A and monomer B are copolymerized in the macromer synthesis step, monomer A is likely to bond after monomer A. Therefore, the synthesized macromer forms a gradient structure, which forms a compositional gradient in which the proportion of monomer A units gradually decreases from the polymerization initiation end to the polymerization termination end. That is, the macromer obtained in this step has a gradient structure in which monomer A residues and monomer B residues form a compositional gradient in the skeleton due to the difference in the initial polymerization rates of monomer A and monomer B. In other words, by using monomer A and monomer B with different initial polymerization rates in this step, it is possible to obtain a macromer with a gradient structure that forms a compositional gradient in the skeleton. Such a macromer may be referred to herein as a "gradient macromer."

[0063] In order to realize such a gradient structure in the macromer synthesis process, it is desirable to synthesize the macromer by a polymerization reaction that occurs in one direction from the initiation terminal. Preferred examples of such a synthesis reaction include ring-opening polymerization and living polymerization.

[0064] The macromer obtained in this step has an R value similar to that of the polyester copolymer, i.e., a macromer represented by the following formula, in order to facilitate the final production of a polyester copolymer satisfying the above-mentioned R value. R = [AB] / (2[A][B]) × 100 [A]: Molar fraction (%) of monomer A residues in the macromer [B]: Molar fraction (%) of monomer B residues in the macromer [AB]: Molar fraction (%) of structures in which monomer A residue and monomer B residue are adjacent (AB and BA) in the macromer It is preferable that the R value represented by the following formula is 0.45 or more and 0.85 or less.

[0065] The weight-average molecular weight of the macromer synthesized in the macromer synthesis step is preferably 10,000 or more, more preferably 20,000 or more, and in order to suppress crystallinity and maintain flexibility, it is preferably 150,000 or less, more preferably 100,000 or less.

[0066] [Mulching process] In the multi-polymerization step, the macromers obtained in the macromer synthesis step are linked together, or monomer A and monomer B are added to the macromer solution obtained in the macromer synthesis step to achieve multi-polymerization. In this step, macromers obtained in one macromer synthesis step may be linked together, or multiple macromers obtained in two or more macromer synthesis steps may be linked. Note that "multi-polymerization" means that, by either of these methods, a structure is formed in which multiple molecular chains having a gradient structure in which monomer A residues and monomer B residues have a compositional gradient in the backbone are repeated.

[0067] The number of multi-linked macromer units should be 2 or more, but since a larger number of linked units has the effect of improving tensile strength due to entanglement of molecular chains, it is preferably 3 or more, more preferably 4 or more, and even more preferably 6 or more. On the other hand, if the molecular weight of the polyester copolymer increases excessively as a result, there is a concern that the viscosity will increase and adversely affect moldability, so the number of macromer units is preferably 80 or less, more preferably 40 or less, and even more preferably 20 or less.

[0068] The number of linked macromer units can be adjusted by the catalyst used in the multi-polymerization process and the reaction time. When linking macromers to each other to form multi-polymers, the number of macromer units can be determined by dividing the weight-average molecular weight of the final polyester copolymer by the weight-average molecular weight of the macromer.

[0069] The polyester copolymer of the present invention may be a linear polymer in which macromer units are linearly linked, or a branched polymer in which macromer units are branched and linked.

[0070] A linear polyester copolymer can be synthesized, for example, by bonding one molecule of a gradient macromer to each end of a gradient macromer via the ends.

[0071] When the gradient macromer has a hydroxyl group and a carboxyl group at each end, the ends can be condensed with a condensing agent to obtain a multi-polyester copolymer. Examples of the condensing agent include 4,4-dimethylaminopyridinium p-toluenesulfonate, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-carbonyldiimidazole, 1,1'-carbonyldi(1,2,4-triazole), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholino. Trifluoromethanesulfonate (4,6-dimethoxy-1,3,5-triazin-2-yl)-(2-octoxy-2-oxoethyl)dimethylammonium, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, Lorotripyrrolidinophosphonium hexafluorophosphate, Bromotris(dimethylamino)phosphonium hexafluorophosphate, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(N-succinimidyl)-N,N, N',N'-Tetramethyluronium tetrafluoroborate, O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tetrafluoroborate, O-[2-oxo-1(2H)-pyridyl]-N,N,N',Examples of usable compounds include N'-tetramethyluronium tetrafluoroborate, {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate, 2-fluoro-1,3-dimethylimidazolinium hexafluorophosphate, and fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate.

[0072] Furthermore, if the polymerization reaction is living, i.e., if the polymerization reaction can be initiated continuously from the end of the polymer, multimerization can be achieved by repeatedly adding additional monomers A and B to the gradient macromer solution after the polymerization reaction has been completed.

[0073] Alternatively, gradient macromers may be multi-linked via a linker, provided that the mechanical properties of the polymer are not affected. In particular, the use of a linker having multiple carboxyl groups and / or multiple hydroxyl groups, such as 2,2-bis(hydroxymethyl)propionic acid, allows the synthesis of branched polyester copolymers at the linker.

[0074] The polyester copolymer obtained by the above-described production method is a copolymer having a structure in which two or more macromer units having a composition gradient in the backbone, each consisting of a residue of monomer A and a residue of monomer B, are linked together, and this is a preferred embodiment of the polyester copolymer of the present invention. In this specification, for convenience, such a structure may be referred to as a "multigradient" and a copolymer having a multigradient structure may be referred to as a "multigradient copolymer."

[0075] That is, the polyester copolymer of the present invention is preferably a multi-gradient copolymer, and the multi-gradient copolymer preferably has a structure in which two or more, and more preferably three or more, macromer units are linked together, each having a gradient structure in which monomer A residues and the monomer B residues form a composition gradient in the skeleton. Furthermore, the upper limit of the number of linked macromer units having a gradient structure in which monomer A residues and the monomer B residues form a composition gradient in the skeleton is preferably 80 or less, more preferably 40 or less, and even more preferably 20 or less.

[0076] As described above, a particularly preferred embodiment of the present invention is a polyester copolymer in which the residue of monomer A is a lactic acid residue and the residue of monomer B is a caprolactone residue. Such a polyester copolymer is preferably produced by the following production method.

[0077] First, in the macromer synthesis process, dilactide and ε-caprolactone are polymerized in the presence of a catalyst. The dilactide and ε-caprolactone monomers are preferably purified to remove impurities before use. Purification of dilactide is possible, for example, by recrystallization from toluene dried with sodium. ε-caprolactone is purified, for example, by vacuum distillation from CaH2 under an N2 atmosphere.

[0078] As a catalyst for the synthesis of a macromer having lactic acid residues and caprolactone residues, polyester polymerization catalysts such as conventional germanium-, titanium-, antimony-, and tin-based catalysts can be used. Specific examples of such polyester polymerization catalysts include tin octoate, antimony trifluoride, zinc powder, dibutyltin oxide, and tin oxalate. The method for adding the catalyst to the reaction system is not particularly limited, but it is preferably added in a dispersed state in the raw materials when they are charged, or in a dispersed state when the pressure reduction begins. The amount of catalyst used is 0.01 to 3 wt %, more preferably 0.05 to 1.5 wt %, calculated as metal atoms, based on the total amount of monomers used.

[0079] A macromer having lactic acid residues and caprolactone residues can be obtained by placing dilactide, caprolactone, and a catalyst in a reaction vessel equipped with a stirrer and reacting them at 120 to 250°C under a nitrogen stream. When water is used as a co-initiator, it is preferable to carry out a co-catalyst reaction at around 90°C prior to the polymerization reaction. The reaction time is 2 hours or more, preferably 4 hours or more, and even longer, such as 8 hours or more, is preferable to increase the degree of polymerization. However, since carrying out the reaction for too long can cause problems with polymer coloration, a time of 3 to 30 hours is preferred.

[0080] Next, in the multi-polymerization step, the terminals of the gradient macromers having lactic acid residues and caprolactone residues are linked together by a condensation reaction to form multi-polymers. The reaction temperature for the condensation reaction is preferably 10 to 100°C, more preferably 20 to 50°C. The reaction time is preferably one day or more, more preferably two days or more. However, if the reaction is carried out for too long, the polymer may become discolored, so two to four days is preferred.

[0081] The polyester copolymer of the present invention is a polyester copolymer having a structure in which two or more macromer units are linked together, and the rate of initial polymerization of the monomer A or the monomer B, whichever is faster, is V X , the slower initial polymerization rate is V Y In this case, the macromer unit satisfies the condition 1.1≦V X / V Y It is preferable that the polyester copolymer has as main structural units residues of monomer A and monomer B satisfying the condition 1.1≦V≦40. X / V Y By forming the polyester copolymer of the present invention into a structure in which two or more macromer units each consisting of a polyester copolymer having, as main structural units, monomer A residues and monomer B residues satisfying the condition (a) or (b) below 40, linked together, it is possible to obtain macromer units with a gradient structure, and as a result, the polyester copolymer of the present invention has a multi-gradient structure, which is preferable.

[0082] In this specification, the term "macromer" refers to the polyester copolymer obtained in the macromer synthesis process described above. It is referred to as a macromer because it is a polyester copolymer to be used in the multi-polymerization process described above after the macromer synthesis process. A macromer unit refers to a portion of the molecular chain of a polyester copolymer that consists of one macromonomer. For example, when two macromers are linked to form a polyester copolymer, the polyester copolymer has a structure in which two macromer units are linked.

[0083] Furthermore, the phrase "two types of monomer residues in a macromer unit are the main structural units" means that the sum of the number of the two types of monomer residues is 50 mol % or more, where the sum of all the number of monomer residues in the entire macromer unit, including other monomer residues, is 100%, and each residue accounts for 20 mol % or more, where the sum of all the number of monomer residues in the entire macromer unit is 100%. For example, the phrase "monomer A residues and monomer B residues are the main structural units" means that the sum of the number of monomer A residues and monomer B residues is 50 mol % or more, where the sum of all the number of monomer residues in the entire macromer unit is 100%, and that the monomer A residues account for 20 mol % or more and the monomer B residues account for 20 mol % or more. Here, the molar fractions of the monomer A residues, monomer B residues, and other residues can be determined by nuclear magnetic resonance (NMR) measurement from the area values ​​of the signals derived from each residue. For example, when the monomer A residues are lactic acid residues and the monomer B residues are caprolactone residues, measurement can be performed using the method described in Measurement Example 1 below.

[0084] Here, V is the initial polymerization rate of either monomer A or monomer B, whichever is faster. X , the slower of the initial polymerization rates, V Ycan be determined by the following method. Equimolar amounts of monomer A and monomer B are mixed, and a solvent and catalyst are added as necessary. The temperature and other conditions are adjusted so that the R value is the same as the R value of the polyester copolymer that has been synthesized or is to be synthesized, within an error range of 10%, as described below, and the polymerization reaction is initiated. Sampling is carried out periodically from the sample during polymerization, and the remaining amounts of monomer A and monomer B are measured. The remaining amounts are measured, for example, by chromatography or nuclear magnetic resonance (NMR) measurement. The amount of monomer used in the polymerization reaction can be determined by subtracting the remaining amount from the charged amount. When the amount of monomer used in the polymerization reaction is plotted against the sampling time, the initial slope of the curve is V X , V Y is.

[0085] When such monomer A and monomer B are reacted, there is a high probability that monomer A will bond to the polymer end during polymerization in the early stages of polymerization. On the other hand, in the later stages of polymerization when monomer A is consumed and its concentration in the reaction solution decreases, there is a high probability that monomer B will bond to the polymer end during polymerization. As a result, a gradient polymer is obtained in which the proportion of monomer A residues gradually decreases from one end. Such a gradient polymer has low crystallinity and suppresses the increase in Young's modulus. To facilitate the formation of such a gradient structure, V X / V Y is more preferably 1.3 or more, and even more preferably 1.5 or more. On the other hand, if the difference in the polymerization rate between the monomer A and the monomer B is too large, the resulting structure is similar to a block polymer in which only the monomer A is polymerized and then the monomer B is polymerized, which may result in high crystallinity and an increase in the Young's modulus. X / V Y is more preferably 30 or less, even more preferably 20 or less, and even more preferably 10 or less.

[0086] Preferred combinations of such monomer A and monomer B include dilactide and ε-caprolactone, glycolide and ε-caprolactone, glycolide and dilactide, dilactide and dioxepanone, ethylene oxalate and dilactide, dilactide and δ-valerolactone, and glycolide and δ-valerolactone.

[0087] As described above, the stent of the present invention preferably contains, as the bioabsorbable polyester, a polyester copolymer having two types of ester bond-forming monomer residues as main structural units, but it is also preferable that the bioabsorbable polyester further contains a homopolymer. In other words, a preferred embodiment of the stent of the present invention contains, as the bioabsorbable polyester, both a polyester copolymer having two types of ester bond-forming monomer residues as main structural units and a homopolymer.

[0088] When a bioabsorbable polyester is further contained in addition to the polyester copolymer having two types of ester bond-forming monomer residues as main structural units, a suitable homopolymer is not particularly limited, but is preferably a homopolymer selected from the group consisting of polylactic acid, polycaprolactone, polybutylene succinate, polyhydroxybutyrate, polydioxanone, and mixtures thereof.

[0089] In addition, in an embodiment in which the stent of the present invention contains both a polyester copolymer and a homopolymer as bioabsorbable polyesters, each having two types of ester bond-forming monomer residues as main constituent units, in order to maintain resilience, the content of the homopolymer in the stent is preferably 50% by weight or less, more preferably 30% by weight or less, based on 100% by weight of the bioabsorbable polyester.The lower limit is not particularly limited, but it is preferably 5% by weight or more.

[0090] The stent of the present invention can be produced by using such bioabsorbable polyester and molding it using a melt molding method, a solvent molding method, an electrospinning method, or a molding method using a 3D printer.

[0091] The melt molding method is a method in which a polymer is heated and melted, and then molded using a mold, extruder, press, etc., and a stent can be produced by molding it into a fiber, film, tube, etc. For example, the copolymer described in the present invention can be heated to 200°C in an extruder equipped with a φ1 mm die and extruded to form the polymer into a filament, and the filament can be woven or knitted to produce a stent.

[0092] Solvent casting is a method in which a polymer is dissolved in a solvent, poured into a mold or coagulation bath, and molded by separating the solvent and solute, and stents can be made by molding them into fibers, films, tubular shapes, etc. An example of solvent casting is to immerse a rod with a diameter of 0.5 to 20 mm in a 20% polymer solution in chloroform, then pull it out, wait for the solvent to evaporate, and then immerse it again, repeating this process 5 to 50 times, and finally pulling out the core rod to form a tubular stent.

[0093] Electrospinning is a technique that can produce a fiber structure consisting of nanofibers with a diameter of several nanometers by applying a high voltage to a polymer solution in a spinning nozzle, and the thickness of the fiber structure can be adjusted to a desired range by adjusting the spinning time. For example, a tubular fiber structure, that is, a stent, can be produced by accumulating polymer fibers while rotating a cylindrical collector and then removing the collector from the fiber structure.

[0094] Furthermore, by using such bioabsorbable polyester as ink material for 3D printers, it is possible to create custom-made stents.

[0095] Furthermore, the thickness of the stent of the present invention is preferably 0.2 mm or more and 2 mm or less, and more preferably 0.25 mm or more and 1.5 mm or less. By controlling the thickness in this manner, a safer stent with fewer complications can be provided. The thickness of the stent can be calculated by "(outer diameter of the stent - inner diameter of the stent) / 2".

[0096] The stent of the present invention can also be used as a drug-eluting stent by carrying or adsorbing a drug.

[0097] The stent of the present invention can be used for, but is not limited to, implanting it into a narrowed site in various body cavities or vessels (e.g., the vascular system, esophagus, gastrointestinal tract, large and small intestines, bile duct, pancreatic duct, lung duct, ureter, nasal cavity, trachea, etc.) to secure the lumen. Note that the stent of the present invention contains a bioabsorbable polyester, and therefore has high restoring properties while being biodegradable, and further can be used as a drug-eluting stent, and is therefore particularly suitable for use as a stent to be placed in the vascular system, trachea, nasal cavity, etc. [Example]

[0098] EXAMPLES The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these.

[0099] (Measurement Example 1: Measurement of the mole fraction and R value of each residue by nuclear magnetic resonance (NMR)) The purified polyester copolymer was dissolved in deuterated chloroform. 1 The ratios of lactic acid monomer residues and caprolactone monomer residues in the polyester copolymer were calculated by H-NMR. 1Using H homospin decoupling, the peak areas of the methine group of lactic acid (near 5.10 ppm), the α-methylene group of caprolactone (near 2.35 ppm), and the ε-methylene group (near 4.10 ppm) were separated by the signals derived from the adjacent monomer residues of lactic acid or caprolactone, and the peak areas were quantified. When δ-valerolactone was used instead of ε-caprolactone, the peak areas of the methine group of lactic acid (near 5.10 ppm), the α-methylene group of valerolactone (near 2.35 ppm), and the δ-methylene group of valerolactone (near 4.10 ppm) were similarly separated by the signals derived from the adjacent monomer residues of lactic acid or valerolactone, and the peak areas were quantified.

[0100] The R value was calculated from the ratio of each peak area using [AB] in Equation 1. Here, [AB] is the molar fraction of structures in which lactic acid residues are adjacent to caprolactone residues or valerolactone residues, specifically the ratio of the number of AB and BA residues to the total number of AA, AB, BA, and BB residues. The results are shown in Table 1. Device name: JNM-ECZ400R (manufactured by JEOL Ltd.) 1 H homospin decoupling irradiation position: 1.66 ppm Solvent: deuterated chloroform Measurement temperature: room temperature (Measurement Example 2: Measurement of weight average molecular weight by gel permeation chromatography (GPC)) Device name: Prominence (Shimadzu Corporation) Mobile phase: Chloroform (for HPLC) (Wako Pure Chemical Industries, Ltd.) Flow rate: 1mL / min Column: TSKgel GMHHR-M (φ7.8 mm x 300 mm; manufactured by Tosoh Corporation) Detector: UV (254 nm), RI Column and detector temperature: 35°C Standard material: polystyrene The purified polyester copolymer was dissolved in chloroform and passed through a 0.45 μm syringe filter (DISMIC-13HP; manufactured by ADVANTEC) to remove impurities, and then the weight-average molecular weight of the polyester copolymer was calculated by GPC. The results are shown in Table 1.

[0101] (Measurement example 3: Tensile test) The stents (0.25 mm thick) prepared in each Example and Comparative Example were cut into 50 mm x 5 mm pieces, and tensile tests were performed using a Tensilon universal testing machine RTM-100 (manufactured by Orientec Co., Ltd.) according to JIS K6251 (2017) under the following conditions to calculate the breaking elongation and tensile strength. Furthermore, in a graph plotting stress against strain, the slope of a linear equation that could be approximated from data from five points from the start of stress generation was calculated as Young's modulus.

[0102] When marking the test specimen, two marks were made on the specimen using an appropriate marker. The test specimen was kept in a relaxed state, and the marks were made accurately and clearly at right angles to the parallel part of the specimen and equidistant from the center of the specimen. Device name: EZ-1kNLX (Shimadzu Access) Gauge distance before test: 10 mm Distance between grips: 10 mm (gripped at the position of the marked line) Tensile speed: 500 mm / min Load cell: 1kN Number of tests: 5 Furthermore, to evaluate the resilience, a tensile strain of 100% of the pre-test grip distance was generated at a tensile speed of 500 mm / min (Operation 1). Immediately after Operation 1 (i.e., the shape retention time was set to 0 seconds), the tensile strain was relaxed at a speed of 500 mm / min, and the grip distance was returned to 10 mm (Operation 2). Immediately after Operation 2 (i.e., the shape retention time was set to 0 seconds), the above-mentioned Operations 1 and 2 were repeated. This was repeated a total of 10 times, and the resilience was calculated using the obtained L1 value according to the following formula. The results are shown in Table 1. Resiliency (%) = ((L0 x 2 - L1) / L0) x 100 L0: Initial length (gauge length before test) L1: The length after applying tensile stress in the longest direction of the stent to produce a tensile strain of 100% of the initial length, repeated 10 times (gauge line distance after test) Example 1 50.0 g of L-lactide (PURASORB L; manufactured by PURAC) and 39.6 g of ε-caprolactone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were placed in a separable flask as monomers, and 0.46 g of hydroxypivalic acid was used as an initiator. Under an argon atmosphere, 0.27 g of tin(II) octoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as a catalyst dissolved in 5.8 mL of ultra-dehydrated toluene (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). The mixture was reacted at 140°C for 9.5 hours to obtain a crude copolymer.

[0103] The resulting crude copolymer was dissolved in 200 mL of chloroform and added dropwise to 3000 mL of hexane under stirring to obtain a precipitate, which was then dried under reduced pressure at 50°C to obtain a macromer.

[0104] 50 g of the macromer, 2.9 g of the catalyst 4,4-dimethylaminopyridinium p-toluenesulfonate (synthetic product), and 1.2 g of 4,4-dimethylaminopyridine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were collected and dissolved in 200 mL of dichloromethane (dehydrated) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) under an argon atmosphere. 2.4 mL of the condensation agent diisopropylcarbodiimide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and condensation polymerization was carried out at room temperature overnight.

[0105] The reaction mixture was diluted with 220 mL of chloroform, and 470 mL of 0.5 M hydrochloric acid was added. The mixture was stirred for 30 minutes, and the aqueous layer was removed by decantation. This process of adding 470 mL of ion-exchanged water, stirring for 10 minutes, and removing the aqueous layer by decantation was repeated until the pH of the removed aqueous layer reached 7. The remaining organic layer was added dropwise to 2200 mL of stirred methanol to obtain a precipitate. This precipitate was dried under reduced pressure at 50°C to obtain the purified polyester copolymer of Example 1.

[0106] The purified polyester copolymer was then dried under reduced pressure and dissolved in chloroform to a concentration of 20 wt%. A 10 wt% aqueous solution of polyvinyl alcohol (Sigma-Aldrich) was prepared, and a 6 mm diameter metal rod was immersed in the solution to coat the surface with PVA. The tip of the PVA-coated metal rod was immersed in the purified polyester copolymer solution, removed, and left to dry in a fume hood for 10 minutes. This process of immersion in the copolymer solution and drying was then repeated at least 10 times, and finally left to dry overnight in a fume hood. After the polymer dried, the metal rod was immersed in a water bath set at 40°C for 5 minutes, then removed to obtain a tubular stent (inner diameter: 6 mm, thickness: 0.25 mm, length: 50 mm).

[0107] <Example 2> 60.0 g of L-lactide (PURASORB L; manufactured by PURAC) and 31.7 g of ε-caprolactone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were placed in a separable flask as monomers, and 0.46 g of hydroxypivalic acid was used as an initiator. Under an argon atmosphere, 0.27 g of tin(II) octoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 5.8 mL of toluene (ultra-dehydrated) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst. The mixture was reacted at 140°C for 9.5 hours to obtain a crude copolymer.

[0108] The resulting crude copolymer was dissolved in 200 mL of chloroform and added dropwise to 3000 mL of hexane under stirring to obtain a precipitate, which was then dried under reduced pressure at 50°C to obtain a macromer.

[0109] 50 g of the macromer, 2.1 g of the catalyst 4,4-dimethylaminopyridinium p-toluenesulfonate (synthetic product), and 0.87 g of 4,4-dimethylaminopyridine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were collected and dissolved in 200 mL of dichloromethane (dehydrated) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) under an argon atmosphere. 1.7 mL of the condensation agent diisopropylcarbodiimide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and condensation polymerization was carried out at room temperature overnight.

[0110] The reaction mixture was diluted with 220 mL of chloroform, and 470 mL of 0.5 M hydrochloric acid was added. The mixture was stirred for 30 minutes, and the aqueous layer was removed by decantation. This process of adding 470 mL of ion-exchanged water, stirring for 10 minutes, and removing the aqueous layer by decantation was repeated until the pH of the removed aqueous layer reached 7. The remaining organic layer was added dropwise to 2200 mL of stirred methanol to obtain a precipitate. This precipitate was dried under reduced pressure at 50°C to obtain the purified polyester copolymer of Example 2.

[0111] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0112] Example 3 The purified polyester copolymer of Example 3 was obtained by the same synthesis method as in Example 1, except that the amount of hydroxypivalic acid was changed to 0.45 g, the reaction temperature for obtaining the crude copolymer was changed to 150°C, the amount of 4,4-dimethylaminopyridinium p-toluenesulfonate was changed to 2.1 g, the amount of 4,4-dimethylaminopyridine was changed to 0.87 g, and the amount of diisopropylcarbodiimide was changed to 1.7 mL.

[0113] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0114] Example 4 50.0 g of L-lactide (PURASORB L; manufactured by PURAC) and 38.5 mL of ε-caprolactone (manufactured by Wako Pure Chemical Industries, Ltd.) were placed in a separable flask as monomers. Under an argon atmosphere, 0.81 g of tin(II) octoate (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 14.5 mL of toluene (ultra-dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) as a catalyst, and ion-exchanged water as a co-initiator were added so that the monomer / co-initiator ratio was 142.9. The co-catalyst reaction was carried out at 90°C for 1 hour, followed by copolymerization at 150°C for 6 hours to obtain a crude copolymer.

[0115] The resulting crude copolymer was dissolved in 100 mL of chloroform and added dropwise to 1,400 mL of stirred methanol to obtain a precipitate. This procedure was repeated three times, and the precipitate was dried under reduced pressure at 70°C to obtain a macromer.

[0116] 30 g of the macromer, 0.28 g of the catalyst 4,4-dimethylaminopyridinium p-toluenesulfonate (synthetic product), and 0.10 g of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were collected. These were dissolved in dichloromethane (dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) to a concentration of 30% under an argon atmosphere, and 0.47 g of the condensation agent Amylene (manufactured by Tokyo Chemical Industry Co., Ltd.) dissolved in 5 mL of dichloromethane was added, followed by condensation polymerization at room temperature for 2 days.

[0117] 30 mL of chloroform was added to the reaction mixture, and the mixture was added dropwise to 500 mL of stirred methanol to obtain a precipitate. This precipitate was dissolved in 50 mL of chloroform, and the mixture was added dropwise to 500 mL of stirred methanol to obtain a precipitate. This procedure was repeated twice, and the precipitate was dried under reduced pressure at 50°C to obtain the purified polyester copolymer of Example 4.

[0118] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0119] <Comparative Example 1> 50.0 g of L-lactide (PURASORB L; manufactured by PURAC) and 39.6 g of ε-caprolactone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were placed in a separable flask as monomers, and 0.036 g of octanol was used as an initiator. Under an argon atmosphere, 0.27 g of tin(II) octoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in 5.8 mL of toluene (ultra-dehydrated) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst. The mixture was reacted at 140°C for 24 hours to obtain a crude copolymer.

[0120] The obtained crude copolymer was dissolved in 200 mL of chloroform and added dropwise to 3000 mL of hexane under stirring to obtain a precipitate, which was dried under reduced pressure at 50°C to obtain the polyester copolymer of Comparative Example 1.

[0121] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0122] <Comparative Example 2> A purified polyester copolymer of Comparative Example 2 was obtained by synthesis in the same manner as in Example 1, except that the amount of 4,4-dimethylaminopyridinium p-toluenesulfonate was changed to 1.5 g and the amount of diisopropylcarbodiimide was changed to 1.2 mL.

[0123] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0124] <Comparative Example 3> 100.0 g of L-lactide (PURASORB L; manufactured by PURAC) as a monomer and 0.46 g of hydroxypivalic acid as an initiator were placed in a separable flask. Under an argon atmosphere, 0.27 g of tin(II) octoate (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) as a catalyst dissolved in 5.8 mL of ultra-dehydrated toluene (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) was added and the reaction was carried out at 140°C for 9.5 hours to obtain a crude copolymer.

[0125] The resulting crude copolymer was dissolved in 200 mL of chloroform and added dropwise to 3,000 mL of hexane under stirring to obtain a precipitate, which was then dried under reduced pressure at 50°C to obtain a PLA macromer.

[0126] Furthermore, 79.2 g of ε-caprolactone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a monomer and 0.46 g of hydroxypivalic acid as an initiator were placed in a separable flask. Under an argon atmosphere, 0.27 g of tin(II) octoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst dissolved in 5.8 mL of toluene (ultra-dehydrated) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and the reaction was carried out at 140°C for 9.5 hours to obtain a crude copolymer.

[0127] The resulting crude copolymer was dissolved in 200 mL of chloroform and added dropwise to 3,000 mL of hexane under stirring to obtain a precipitate, which was then dried under reduced pressure at 50°C to obtain a PCL macromer.

[0128] 27.9 g of PLA macromer, 22.1 g of PCL macromer, 2.9 g of the catalyst 4,4-dimethylaminopyridinium p-toluenesulfonate (synthetic product), and 1.2 g of 4,4-dimethylaminopyridine (Fujifilm Wako Pure Chemical Industries, Ltd.) were collected and dissolved in 200 mL of dehydrated dichloromethane (Fujifilm Wako Pure Chemical Industries, Ltd.) under an argon atmosphere. 2.4 mL of the condensation agent diisopropylcarbodiimide (Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and condensation polymerization was carried out at room temperature overnight.

[0129] The reaction mixture was diluted with 220 mL of chloroform, and 470 mL of 0.5 M hydrochloric acid was added. The mixture was stirred for 30 minutes, and the aqueous layer was removed by decantation. This process of adding 470 mL of ion-exchanged water, stirring for 10 minutes, and removing the aqueous layer by decantation was repeated until the pH of the removed aqueous layer reached 7. The remaining organic layer was added dropwise to 2200 mL of stirred methanol to obtain a precipitate. This precipitate was dried under reduced pressure at 50°C to obtain the purified polyester copolymer of Comparative Example 3.

[0130] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0131] <Comparative Example 4> Polylactic acid PDLLA (BMG Corporation) was purchased, and a tubular molded product, a stent, was obtained in the same manner as in Example 1.

[0132] <Comparative Example 5> Polycaprolactone (900288, Sigma-Aldrich) was purchased, and a tubular molded body, a stent, was obtained in the same manner as in Example 1.

[0133] <Comparative Example 6> 50.0 g of L-lactide (PURASORB L; manufactured by PURAC) was collected as a monomer in a separable flask. Under an argon atmosphere, 0.81 g of tin(II) octoate (manufactured by Wako Pure Chemical Industries, Ltd.) as a catalyst dissolved in 14.5 mL of toluene (ultra-dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) was added and polymerized at 150°C for 3 hours. 38.5 mL of ε-caprolactone (manufactured by Wako Pure Chemical Industries, Ltd.) was added and polymerized at 150°C for 6 hours to obtain a crude copolymer.

[0134] The resulting crude copolymer was dissolved in 100 mL of chloroform and added dropwise to 1,400 mL of stirred methanol to obtain a precipitate. This procedure was repeated three times, and the precipitate was dried under reduced pressure at 70°C to obtain a purified polyester copolymer of Comparative Example 6.

[0135] In addition, in the same manner as in Example 1, a stent, which is a tubular molded article, was obtained.

[0136] <Example 5> 900 mg of the polyester copolymer obtained in Example 3 and 100 mg of polylactic acid (Nature3D) were added to a 50 mL screw tube, dissolved in 20 mL of chloroform (Fujifilm Wako Pure Chemical Industries, Ltd.), and dried overnight at room temperature under normal pressure. This was then dried overnight under reduced pressure at 50°C to obtain the polymer composition of Example 5. In addition, a tubular stent (inner diameter: 6 mm, thickness: 0.25 mm, length: 50 mm) was obtained in the same manner as in Example 1.

[0137] Example 6 The same procedure as in Example 5 was carried out, except that the amount of polyester copolymer was changed to 700 mg and the amount of polylactic acid was changed to 300 mg, to obtain a polymer composition of Example 6. Also, a stent, which was a tubular molded product (inner diameter: 6 mm, thickness: 0.25 mm, length: 50 mm), was obtained in the same manner as in Example 1.

[0138] Table 1 shows the results of various measurements of the polymers and stents obtained in Examples 1 to 4 and Comparative Examples 1 to 6.

[0139] Similarly, Examples 5 and 6 are shown in Table 2.

[0140] [Table 1]

[0141] The ratio of monomer A residues in the table indicates the molar ratio of monomer A residues relative to the total number of moles of monomer A residues and monomer B residues, which is 100%.

[0142] [Table 2] [Industrial Applicability]

[0143] The stent of the present invention can be used for, but is not limited to, implantation into narrowed areas of various body cavities or vessels (e.g., the vascular system, esophagus, gastrointestinal tract, large and small intestines, bile duct, pancreatic duct, lung duct, ureter, nasal cavity, trachea, etc.) to secure the lumen.

Claims

1. comprising a bioabsorbable polyester; The bioabsorbable polyester is a multi-gradient copolymer having lactic acid residues and caprolactone residues as main structural units, in which two or more macromer units are linked together, and having a weight-average molecular weight of 195,936 to 368,512; A stent having a restoring property of 80% or more as defined by formula (1). Recovery rate (%) = ((L) ０ ×2-L １ ) / L ０ Formula (1) × 100 L ０ Initial length L １ : The length after repeating the operation of applying a tensile stress in the direction of the longest length of the stent to generate a tensile strain of 100% of the initial length 10 times

2. The stent according to claim 1 , comprising at least 50% by weight of the bioabsorbable polyester.

3. the bioabsorbable polyester is a multi-gradient copolymer that is a polyester copolymer having, as main structural units, two types of ester bond-forming monomer residues, that is, lactic acid residues and caprolactone residues; The stent according to claim 1 or 2, wherein the ester-bondable monomers are designated as monomer A and monomer B, where monomer A is lactic acid and monomer B is caprolactone.

4. The stent according to claim 3, wherein the multi-gradient copolymer has an R value represented by the following formula of 0.45 or more and 0.85 or less: R=[AB] / (2[A][B])×100 [A]: Molar fraction (%) of monomer A residues in the multi-gradient copolymer [B]: Molar fraction (%) of monomer B residues in the multi-gradient copolymer [AB]: Molar fraction (%) of structures in which a monomer A residue and a monomer B residue are adjacent to each other (AB and BA) in the multi-gradient copolymer.

5. The multi-gradient copolymer is a polyester copolymer having a structure in which two or more macromer units are linked together, 5. The stent according to claim 3, wherein the macromer unit has, as main constituent units, residues of monomer A and residues of monomer B that satisfy the relationship 1.1≦VX / VY≦40, where VX is the faster initial polymerization rate and VY is the slower initial polymerization rate in the monomer A or the monomer B.

6. The stent according to any one of claims 3 to 5, wherein the bioabsorbable polyester further comprises a homopolymer.

7. 7. The stent according to claim 6, wherein the homopolymer is any one selected from the group consisting of polylactic acid, polycaprolactone, polybutylene succinate, polyhydroxybutyrate, polydioxanone, and mixtures thereof.

8. The stent according to any one of claims 1 to 7, wherein the thickness of the stent is 0.2 mm or more and 2 mm or less.

9. The stent according to any one of claims 1 to 8, having a Young's modulus measured in accordance with JIS K6251 (2017) of 0.1 MPa to 15 MPa, and a tensile strength measured in accordance with JIS K6251 (2017) of 5 MPa or more.

10. The stent according to any one of claims 1 to 9, having a breaking elongation of 200% or more as measured in accordance with JIS K6251 (2017).

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