Fiber structure and method for producing the same

Abstract

The purpose of the present invention is to provide a fiber structure having high permeability and long residence time in a body. The present invention relates to a fiber structure comprising fibers of biodegradable polymer, wherein there are at least two peaks in the molecular weight distribution of the biodegradable polymer, as obtained through GPC measurement.

Description

Technical Field

[0001] The present invention relates to a fibrous structure and a method for producing the same.

Background Art

[0002] Nonwoven fabrics and porous bodies having a three-dimensionally entangled structure of fibers have voids inside and have been used for filters and adsorbents for a long time in order to exhibit the wettability and permeability of substances. In recent years, research has also been actively conducted on using nonwoven fabrics as a base material (scaffold base material) for cell scaffold materials. After cells are seeded inside a nonwoven fabric made of a biodegradable material, the nonwoven fabric as a scaffold material is decomposed and replaced by self-tissue during the tissue regeneration process. Therefore, nonwoven fabrics made of biodegradable materials are expected to be used as scaffold materials for transplantation.

[0003] Regarding the production of nanofiber nonwoven fabrics applicable as a scaffold material suitable for cell adhesion and cell proliferation for angiogenesis and nerve regeneration, a method for producing polymer fibers by an electrospinning method in which a voltage is applied to a polymer solution and a jet of the polymer solution is ejected to form polymer fibers, a method for producing a blended polymer fiber is proposed, in which the spinning start points of a plurality of types of polymer solutions are made the same or close to each other, and each of the plurality of types of polymer solutions is ejected to form a single fiber containing a plurality of types of polymer components (see, for example, Patent Document 1).

[0004] On the other hand, as a material excellent in cell wettability, a porous tissue regeneration base material which is a laminate of at least two layers made of a bioabsorbable material, has at least one layer of ultrafine fiber nonwoven fabric layer, and has at least one porous layer with an average pore diameter of 0.1 to 800 μm on the surface of the ultrafine fiber nonwoven fabric layer has been proposed (see, for example, Patent Document 2).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0006] For a scaffold substrate implanted in the body, high permeability and a long in-vivo retention time are required. The permeability of non-woven fabric depends on the fiber diameter, and in order to increase the permeability, it is effective to increase the fiber diameter. In order to spin fibers with a thick fiber diameter by the electrospinning method, it is effective to increase the concentration of the resin solution. On the other hand, when the concentration of the resin solution increases, the viscosity increases and the surface tension becomes stronger than the repulsive force of the charges. Therefore, in the method described in Patent Document 1, it is difficult to spin fibers with a thick fiber diameter, and there is a problem of insufficient permeability.

[0007] Also, in order to spin fibers with the fiber diameter described in Patent Document 2 by the method described in Patent Document 2, it is necessary to use a polymer with a relatively small molecular weight. Since the degradation rate of the obtained porous tissue regeneration substrate is high, there is a problem of a short in-vivo retention time.

[0008] In view of the above technical problems, an object of the present invention is to provide a fiber structure having high permeability and a long in-vivo retention time.

Means for Solving the Problems

[0009] The present invention is a fiber structure containing biodegradable polymer fibers, and in the molecular weight distribution obtained by GPC measurement of the biodegradable polymer, it is a fiber structure having two or more peaks.

Effects of the Invention

[0010] According to the present invention, a fiber structure having high permeability and a long in-vivo retention time can be obtained.

Modes for Carrying Out the Invention

[0011] The fibrous structure of the present invention contains biodegradable polymer fibers.

[0012] <Biodegradable polymer> Examples of the biodegradable polymer include polyglycolic acid, polylactic acid (D, L, DL forms), polycaprolactone, polyhydroxybutyric acid, polyhydroxybutyrate valerate, polyorthoester, polyhydroxyvaleric acid, polyhydroxyhexanoic acid, polyhydroxybutanoic acid, polybutylene succinate, polybutylene succinate, trimethylene terephthalate, polyhydroxyalkanoate, and copolymers thereof. Two or more of these may be used. Among the biodegradable polymers, biodegradable polyesters that are easily decomposed into monomers are preferred. Among the biodegradable polyesters, polylactic acid, polycaprolactone, polyglycolic acid, and copolymers thereof, which have abundant clinical results on the safety of decomposition products and are easy to ensure safety, are more preferred. A dilactide / ε-caprolactone copolymer (a copolymer of polylactic acid and polycaprolactone), which has a simple synthesis method, is even more preferred.

[0013] In the present invention, the maximum stress of the biodegradable polymer is preferably 1 MPa or more and 1000 MPa or less, which is about the same as that of living tissue, and more preferably 5 MPa or more and 30 MPa or less from the viewpoint of preventing yarn breakage during spinning. Also, the Young's modulus of the biodegradable polymer is preferably 0.1 Mpa or more and 1000 MPa or less, which is about the same as that of living tissue, and more preferably 1.0 MPa or more and 6.3 MPa or less from the viewpoint of easily spinning thicker fibers.

[0014] Here, the maximum stress and Young's modulus of the biodegradable polymer can be measured by the method specified in JIS K6251 (2010). Specifically, the biodegradable polymer is dried under reduced pressure, and a solution prepared by dissolving it in chloroform to a concentration of 5 wt% is transferred onto a petri dish made of "Teflon" (registered trademark) and dried at normal pressure and room temperature for one day and one night. The polymer film with a thickness of 0.1 mm obtained by drying it under reduced pressure is cut into strips (30 mm × 5 mm), and a tensile test is conducted using a small bench-top testing machine EZ-LX (manufactured by Shimadzu Corporation) under the conditions of an initial length of 10 mm, a tensile speed of 500 mm / min, and a load cell of 50 N to measure the maximum stress and Young's modulus. Each measurement is taken three times, and the number average value is calculated to determine the maximum stress and Young's modulus of the biodegradable polymer.

[0015] <Polylactic acid> Polylactic acid is L - lactic acid, D - a polymer or copolymer of lactic acid such as lactic acid. From the viewpoints of physical properties and biocompatibility, L - the homopolymer of lactic acid is preferred.

[0016] <Method for producing polylactic acid> Polylactic acid can be synthesized, for example, by ring-opening polymerization of dilactide. In the present invention, dilactide means a dimer of lactic acid. An example of a method for synthesizing polylactic acid using L - dilactide is described below.

[0017] First, L - dilactide and a co-initiator are placed in a separable flask. Examples of the co-initiator include lauryl alcohol and the like.

[0018] Next, a catalyst is added under a nitrogen atmosphere, and the mixture is stirred while heating to uniformly dissolve or melt the raw materials. Examples of the catalyst include tin(II) octylate. From the viewpoint of uniformly dissolving or melting the raw materials, the dissolution or melting temperature is preferably 95°C or higher, while from the viewpoint of suppressing excessive reactions, it is preferably 110°C or lower. The stirring speed is preferably 80 rpm or higher and 200 rpm or lower. The dissolution or melting time is preferably 10 minutes or longer and 60 minutes or shorter.

[0019] After dissolution or melting, the mixture is further stirred while heating to react the raw materials. From the viewpoint of suppressing precipitation of the raw materials, the reaction temperature is preferably 120°C or higher, while from the viewpoint of suppressing volatilization of the raw materials, it is preferably 140°C or lower. The stirring speed is preferably 80 rpm or higher and 200 rpm or lower. The reaction time is preferably 12 hours or longer and 48 hours or shorter. Then, while maintaining the temperature, the inside of the flask is put under reduced pressure to remove unreacted L -dilatide. Finally, the reaction mixture is dissolved in chloroform or the like and dropped into methanol being stirred to precipitate polylactic acid. The stirring speed of the methanol is preferably 200 rpm or higher and 300 rpm or lower. It is preferable to dry in order to remove the solvent in the obtained polylactic acid. The drying time is preferably 12 hours or longer.

[0020] <Polycaprolactone> Polycaprolactone is a copolymer of ε-caprolactone.

[0021] <Method for producing polycaprolactone> Polycaprolactone can be synthesized, for example, by ring-opening polymerization of ε-caprolactone. An example of a method for synthesizing polycaprolactone using ε-caprolactone is described below.

[0022] First, ε-caprolactone and a co-initiator are placed in a separable flask. Examples of the co-initiator include 1,4-butanediol.

[0023] Next, a catalyst is added under a nitrogen atmosphere, and the mixture is stirred while heating to react the raw materials. Examples of the catalyst include tin(II) octylate. From the viewpoint of enhancing reactivity, the reaction temperature is preferably 110°C or higher, while from the viewpoint of suppressing volatilization of the raw materials, it is preferably 250°C or lower. The stirring speed is preferably 80 rpm or higher and 200 rpm or lower. The reaction time is preferably 6 hours or longer and 48 hours or shorter.

[0024] Thereafter, the reaction mixture is dissolved in chloroform or the like and dropped into methanol being stirred to precipitate polycaprolactone. The stirring speed of the methanol is preferably 200 rpm or higher and 300 rpm or lower. In order to remove the solvent in the obtained polycaprolactone, it is preferably dried. The drying time is preferably 12 hours or longer.

[0025] <Polyglycolic acid> Polyglycolic acid is a copolymer of glycolic acid.

[0026] <Method for producing polyglycolic acid> Polyglycolic acid can be synthesized, for example, by ring-opening polymerization of glycolide, which is a cyclic diester of glycolic acid. An example of the synthesis method of polyglycolic acid is described below.

[0027] First, glycolide is placed in a round-bottom flask. Next, a catalyst is added under a nitrogen atmosphere, and the mixture is stirred while heating to react the raw materials. Examples of the catalyst include tin(II) 2-ethylhexanoate. From the viewpoint of enhancing reactivity, the reaction temperature is preferably 190°C or higher. The stirring speed is preferably 80 rpm or higher and 200 rpm or lower. The reaction time is preferably 2 hours or longer and 12 hours or shorter. Further heating is performed and stirring is continued. From the viewpoint of enhancing reactivity, the reaction temperature is preferably 220°C or higher, and from the viewpoint of preventing volatilization of the raw materials, it is preferably 300°C or lower. The stirring speed is preferably 80 rpm or higher and 200 rpm or lower. The reaction time is preferably 15 minutes or longer and 1 hour or shorter.

[0028] Thereafter, the reaction mixture is dissolved in chloroform or the like and dropped into methanol being stirred to precipitate polyglycolic acid. The stirring speed of the methanol is preferably 200 rpm or more and 300 rpm or less. In order to remove the solvent in the obtained polyglycolic acid, it is preferably dried. The drying time is preferably 12 hours or more.

[0029] <Dilactide / glycolic acid copolymer> The dilactide / glycolic acid copolymer can be synthesized by ring-opening polymerization of lactide and glycolide. An example of the synthesis method of the dilactide / glycolic acid copolymer is described below.

[0030] First, dry nitrogen was passed through a vertical reaction tube to remove oxygen from the reaction tube. The flow rate of the dry nitrogen is preferably 150 mL / min or more. Dilactide and glycolic acid were placed in the reaction tube, heated and reacted. The reaction temperature is preferably 180°C or more from the viewpoint of increasing the reaction rate. The reaction time is preferably 4 hours or more and 24 hours or less.

[0031] Thereafter, the reaction mixture is dissolved in chloroform or the like and dropped into methanol being stirred to precipitate the dilactide / glycolic acid copolymer. The stirring speed of the methanol is preferably 200 rpm or more and 300 rpm or less. In order to remove the solvent in the obtained dilactide / glycolic acid copolymer, it is preferably dried. The drying time is preferably 12 hours or more.

[0032] <Dilactide / ε-caprolactone copolymer> The dilactide / ε-caprolactone copolymer in the present invention preferably satisfies the following (1) and (2). By satisfying the following (1) and (2), an increase in viscosity when dissolved at a high concentration in a solvent can be suppressed, and in the method for producing a biodegradable polymer fiber described later, it is possible to easily spin a fiber having a thicker fiber diameter. Such a dilactide / ε-caprolactone copolymer can be obtained, for example, by the method for producing a dilactide / ε-caprolactone copolymer having a multi-step process described later.

[0033] (1) The R value represented by the following formula is 0.45 or more and 0.99 or less. R = [AB] / 2[A][B] × 100 [A]: The molar fraction (%) of the dilactide residue in the dilactide / ε-caprolactone copolymer [B]: The molar fraction (%) of the ε-caprolactone residue in the dilactide / ε-caprolactone copolymer [AB]: The molar fraction (%) of the structure (A-B and B-A) in which the dilactide residue and the ε-caprolactone residue are adjacent to each other in the dilactide / ε-caprolactone copolymer (2) The crystallinity of at least one of the dilactide residue or the ε-caprolactone residue is less than 14%.

[0034] The R value is used as an index indicating the randomness of the monomer residue sequence in the dilactide / ε-caprolactone copolymer. For example, in a completely random copolymer with a random monomer sequence, the R value is 1. When the R value is 0.45 or more, the crystallinity is low and the flexibility is excellent. The R value is preferably 0.50 or more. On the other hand, when the R value is 0.99 or less, the adhesiveness can be suppressed. The R value is preferably 0.80 or less.

[0035] The R value can be determined by quantifying the ratio of the combination (A-A, B-B, A-B, B-A) of two adjacent monomers by nuclear magnetic resonance (NMR) measurement. Specifically, the dilactide / ε-caprolactone copolymer is dissolved in deuterated chloroform, 1 The ratio of the dilactide residue and the ε-caprolactone residue in the dilactide / ε-caprolactone copolymer is calculated by 1H-NMR analysis. Also, 1By the H homospin decoupling method, for the methine group (around 5.10 ppm) of dilactide, the α-methylene group (around 2.35 ppm) of ε-caprolactone, and the ε-methylene group (around 4.10 ppm), the signals of adjacent monomer residues derived from lactide or ε-caprolactone are separated, and the peak areas of each are quantified. [AB] in Equation 1 is calculated from the area ratio of each, and the R value is calculated. Here, [AB] is the molar fraction of the structure in which dilactide residues and ε-caprolactone residues are adjacent, specifically, the ratio of the number of A-B and B-A to the total number of A-A, A-B, B-A, and B-B.

[0036] The crystallinity of a polymer is known to have a great influence on its mechanical strength. Generally, a polymer with low crystallinity exhibits a low Young's modulus, so a low crystallinity is desirable to obtain flexibility. In the present invention, it is preferable that the crystallization rate of at least one of the dilactide residues and the ε-caprolactone residues is less than 14%. If the crystallization rate is less than 14%, the Young's modulus can be suppressed, and a polyester copolymer suitable for medical materials and elastomer applications can be obtained. In the present invention, it is preferable that the crystallization rate of the dilactide residues is less than 14%. The crystallization rate of the dilactide residues is more preferably 10% or less.

[0037] The crystallization rate of a monomer residue referred to herein is the ratio of the heat of fusion per unit weight of a homopolymer composed of only a certain monomer residue to the heat of fusion per unit weight of the monomer residue in the dilactide / ε-caprolactone copolymer, with respect to the product of the heat of fusion per unit weight of the monomer residue in the dilactide / ε-caprolactone copolymer and the weight fraction of the monomer residue in the dilactide / ε-caprolactone copolymer. That is, the crystallization rate of the dilactide residue is the ratio of the heat of fusion per unit weight of a homopolymer composed of only dilactide to the heat of fusion per unit weight of the dilactide residue in the dilactide / ε-caprolactone copolymer, with respect to the product of the heat of fusion per unit weight of the dilactide residue in the dilactide / ε-caprolactone copolymer and the weight fraction of the dilactide residue in the dilactide / ε-caprolactone copolymer. The crystallization rates of the dilactide residue and the ε-caprolactone residue respectively indicate the proportion of the dilactide residue or the ε-caprolactone residue in the dilactide / ε-caprolactone copolymer that forms a crystal structure. Here, the crystallization rate can be measured by the DSC method using a differential scanning calorimeter.

[0038] The dilactide / ε-caprolactone copolymer may be linear or branched.

[0039] Note that by the production method having a multi-step process described later, the maximum stress and Young's modulus of the dilactide / ε-caprolactone copolymer can be easily adjusted to the aforementioned preferred ranges.

[0040] <Production Method of Dilactide / ε-Caprolactone Copolymer> As an example, the dilactide / ε-caprolactone copolymer is prepared by a macromer synthesis step in which dilactide and ε-caprolactone are blended and polymerized such that at the completion of polymerization, the sum of the dilactide residue and the ε-caprolactone residue is 50 mol% or more of all residues, and the dilactide residue and the ε-caprolactone residue are each 20 mol% or more of all residues; A multi-step process in which the macromers obtained in the macromer synthesis step are linked together, or in which dilactide and ε-caprolactone are additionally added to the macromer solution obtained in the macromer synthesis step to effect multi-step polymerization; It can be produced by a production method having the above steps.

[0041] [Macromer synthesis step] In the macromer synthesis step, dilactide and ε-caprolactone are blended and polymerized such that, theoretically at the completion of polymerization, the sum of the dilactide residues and the ε-caprolactone residues is 50 mol% or more of all the residues, and each of the dilactide residues and the ε-caprolactone residues is 20 mol% or more of all the residues. Thereby, a dilactide / ε-caprolactone copolymer having dilactide residues and ε-caprolactone residues as main constituent units is obtained. However, in this production method, since a multi-functionalization step described later is further performed, in this specification, the dilactide / ε-caprolactone copolymer obtained by this step is expressed as a "macromer".

[0042] The randomness of the distribution of the monomer residues constituting the dilactide / ε-caprolactone copolymer varies depending on the difference in the reactivity of the monomers during polymerization. That is, during polymerization, if, after one of the monomers (either dilactide or caprolactone), the same monomer and the other monomer bind with the same probability, a random copolymer in which the monomer residues are completely randomly distributed is obtained. However, if there is a tendency for one of the monomers to bind more easily after one of the monomers, a gradient copolymer with a biased distribution of monomer residues is obtained. In the obtained gradient copolymer, the composition of the monomer residues changes continuously along the molecular chain from the polymerization start end to the polymerization end.

[0043] Here, the reactivity of dilactide and ε-caprolactone differs greatly as described in the literature (D.W. Grijpma et al., Polymer Bulletin 25, 335, 341), and the initial polymerization rate of dilactide is higher than that of ε-caprolactone. The initial polymerization rate VA of dilactide is 3.6% / h in terms of the reaction rate (%), and the initial polymerization rate VB of ε-caprolactone is 0.88% / h. When dilactide and ε-caprolactone are copolymerized in the macromer synthesis step, dilactide is more likely to bind after dilactide. Therefore, in the synthesized macromer, a gradient structure is formed in which the proportion of dilactide units gradually decreases from the polymerization start end to the polymerization end. That is, the macromer obtained in this step becomes a macromer having a gradient structure in which dilactide residues and ε-caprolactone residues form a compositional gradient in the backbone due to the difference in the initial polymerization rates of dilactide and ε-caprolactone. Such a macromer may be referred to as a "gradient macromer" in this specification.

[0044] In the macromer synthesis step, in order to realize such a gradient structure, it is desirable to synthesize a macromer by a polymerization reaction occurring in one direction from the start end. As such a synthesis reaction, ring-opening polymerization and living polymerization are preferably used as examples.

[0045] An example of the method for synthesizing a lactide / caprolactone macromer will be described more specifically. First, dilactide, ε-caprolactone, and a catalyst are placed in a reaction vessel equipped with a stirrer and stirred while heating under a nitrogen stream. In order to remove the moisture inside the reaction vessel, it is preferable to reduce the pressure of the reaction vessel and heat and stir it.

[0046] As the stirrer, a stirrer equipped with a propeller-type stirring blade is preferable, and the rotation speed of the stirring blade is preferably 50 rpm or more and 200 rpm or less.

[0047] The heating temperature of the polymerization reaction is preferably 100°C or higher and 250°C or lower. From the viewpoint of increasing the degree of polymerization, the reaction time of the polymerization reaction is preferably 3 hours or longer, more preferably 5 hours or longer, and even more preferably 7 hours or longer. On the other hand, from the viewpoint of further improving productivity, the reaction time of the polymerization reaction is preferably 24 hours or shorter.

[0048] It is preferable to preliminarily purify and use dilactide and ε-caprolactone in order to remove impurities.

[0049] Examples of the catalyst include tin octylate, antimony trifluoride, zinc powder, dibutyltin oxide, tin oxalate, etc. Examples of the method for adding the catalyst to the reaction system include a method of adding it in a dispersed state in the raw material at the time of charging the raw materials, and a method of adding it in a dispersed state in the medium at the start of decompression or immediately before the start of heating in the above-described method. From the viewpoint of shortening the reaction time and further improving productivity, the amount of the catalyst used is preferably 0.01 part by weight or more and more preferably 0.04 part by weight or more in terms of the metal atom conversion value with respect to a total of 100 parts by weight of dilactide and ε-caprolactone. On the other hand, from the viewpoint of further reducing the metal residual amount in the dilactide / ε-caprolactone copolymer, the amount of the catalyst used is preferably 0.5 part by weight or less in terms of the metal atom conversion value with respect to the total amount of dilactide and ε-caprolactone.

[0050] 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.

[0051] In order to easily produce a dilactide / ε-caprolactone copolymer that finally satisfies the R value shown in the above (1) in this step, the macro-monomer obtained in this step has the same R value as the dilactide / ε-caprolactone copolymer described in the above (1), that is, the following formula R value = [AB] / (2[A][B]) × 100 [A]: Mole fraction (%) of dilactide residues in the macro-monomer [B]: Mole fraction (%) of ε-caprolactone residues in the macro-monomer [AB]: Molar fraction (%) of the structure (A-B and B-A) in the macro-monomer where the dilactide residue and the ε-caprolactone residue are adjacent to each other The R value represented by is preferably 0.45 or more and 0.99 or less, and more preferably 0.50 or more and 0.80 or less.

[0052] Similarly, the macro-monomer obtained in this step is finally easy to produce a dilactide / ε-caprolactone copolymer having the crystallization rate of the dilactide residue or the ε-caprolactone residue shown in (2) above. Therefore, it preferably has the crystallization rate of the monomer residue described in (2) above, that is, the crystallization rate of at least one of the dilactide residue or the ε-caprolactone residue is less than 14%, more preferably 10% or less, still more preferably 5% or less, and most preferably 1% or less.

[0053] The weight average molecular weight of the macro-monomer synthesized in the macro-monomer synthesis step is preferably 10,000 or more, more preferably 20,000 or more. Further, in order to further reduce the crystallinity and improve the flexibility, it is preferably 150,000 or less, and more preferably 100,000 or less.

[0054] 〔Multiplication step〕 In the multiplication step, the macro-monomers obtained in the macro-monomer synthesis step are linked to each other, or the macro-monomer solution obtained in the macro-monomer synthesis step is multiplied by additionally adding dilactide and caprolactone. In this step, the macro-monomers obtained in one macro-monomer synthesis step may be linked to each other, or a plurality of macro-monomers obtained in two or more macro-monomer synthesis steps may be linked to each other. Note that "multiplication" means forming a structure in which a molecular chain having a gradient structure in which the dilactide residue and the caprolactone residue have a composition gradient in the skeleton is repeated a plurality of times by any of these methods.

[0055] From the perspective of promoting the condensation reaction efficiently, the reaction temperature of the condensation reaction in the multiplication step is preferably 20 °C or higher. On the other hand, from the perspective of suppressing the volatilization of the solvent, the reaction temperature of the condensation reaction is preferably 50 °C or lower. Also, from the perspective of making the number of macromer units to be multiplied fall within the aforementioned preferred range, the reaction time of the condensation reaction is preferably 15 hours or longer. On the other hand, from the perspective of narrowing the molecular weight distribution, the reaction time of the condensation reaction is preferably 24 hours or shorter.

[0056] When producing a linear dilactide / ε-caprolactone copolymer, for example, it can be synthesized by bonding one molecule of the same gradient macromer to each of the two ends of the gradient macromer through the ends.

[0057] When the gradient macromer has a hydroxyl group and a carboxyl group at each end, a multiplied dilactide / ε-caprolactone copolymer can be obtained by condensing the ends with a condensing agent. Examples of the condensing agent include 4,4-dimethylaminopyridinium p-toluenesulfonate, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-carbonyldiimidazole, etc. Two or more of these may be used.

[0058] Also, when the polymerization reaction has living properties, that is, when the polymerization reaction can be continuously initiated from the end of the polymer, the multiplication can be achieved by repeating the operation of adding dilactide and ε-caprolactone to the gradient macromer solution after the polymerization reaction has ended.

[0059] Alternatively, the gradient macromers may be multiplied via a linker within a range that does not affect the mechanical properties of the polymer. In particular, when using a linker having a plurality of carboxyl groups and / or a plurality of hydroxy groups, such as 2,2-bis(hydroxymethyl)propionic acid, a branched-chain polyester copolymer with the linker as a branching point can be synthesized.

[0060] The dilactide / ε-caprolactone copolymer obtained by the production method as described above is a copolymer having a structure in which two or more macromer units having a composition gradient of dilactide residues and caprolactone residues in the backbone are linked, and this is a preferred embodiment of the dilactide / ε-caprolactone copolymer of the present invention. In this specification, such a structure may be conveniently described as "multi-gradient", and a copolymer having a multi-gradient structure may be described as a "multi-gradient copolymer". As the multi-gradient copolymer, it preferably has a structure in which two or more macromer units having a gradient structure in which dilactide residues and ε-caprolactone residues form a composition gradient in the backbone are linked, and more preferably has a structure in which three or more are linked.

[0061] <Biodegradable polymer fiber> The biodegradable polymer fiber of the present invention is a fiber formed from a biodegradable polymer and has two or more peaks in the molecular weight distribution obtained by GPC measurement of the biodegradable polymer. In the present invention, having two or more peaks means containing biodegradable polymers having different molecular weights, a biodegradable polymer having a relatively large molecular weight (high molecular weight biodegradable polymer) having a peak on the high molecular weight side, and a biodegradable polymer having a relatively small molecular weight (low molecular weight biodegradable polymer) having a peak on the low molecular weight side.

[0062] The larger the molecular weight of the biodegradable polymer, the longer the in-vivo retention time of the fibrous structure can be. Also, the smaller the molecular weight of the biodegradable polymer, the relatively lower viscosity and higher concentration biodegradable polymer solution can be obtained. Therefore, fibers with a thicker fiber diameter can be spun by the electrospinning method, and the permeability of the fibrous structure can be improved. That is, by containing biodegradable polymers with different molecular weights, the in-vivo retention time of the fibrous structure can be prolonged by the biodegradable polymer with a relatively larger molecular weight (high molecular weight biodegradable polymer), and the permeability of the fibrous structure can be improved by the biodegradable polymer with a relatively smaller molecular weight (low molecular weight biodegradable polymer). In the molecular weight distribution, as the biodegradable polymer having two or more peaks, the same kind of biodegradable polymers with different molecular weights may be used, or different kinds of biodegradable polymers with different molecular weights may be used.

[0063] The ratio of the high molecular weight biodegradable polymer to the low molecular weight biodegradable polymer is preferably 1:2 to 2:1. The ratio of the high molecular weight biodegradable polymer to the low molecular weight biodegradable polymer is the ratio of the polymer weights, respectively, and can be measured before mixing respectively, or calculated by the area ratio of the differential molecular weight distribution curve on the high molecular side and the differential molecular weight distribution curve on the low molecular side obtained by the GPC measurement described later.

[0064] The biodegradable polymer preferably has at least one peak in the region with a molecular weight of 100,000 or less and at least one peak in the region with a molecular weight greater than 100,000. By having a peak in the region with a molecular weight of 100,000 or less, fibers with a thicker fiber diameter can be spun, and the permeability of the fiber structure can be further improved. The low molecular weight biodegradable polymer preferably has a peak in the region with a molecular weight of 100 or more and 70,000 or less, and more preferably has a peak in the region with a molecular weight of 1,000 or more and 70,000 or less. On the other hand, by having a peak in the region with a molecular weight greater than 100,000, the in-vivo residence time of the fiber structure can be made longer. The high molecular weight biodegradable polymer more preferably has a peak in the region with a molecular weight of 200,000 or more. The peak in the molecular weight distribution of the biodegradable polymer refers to the maximum value of the differential molecular weight distribution curve obtained from GPC measurement.

[0065] Here, the GPC measurement can be performed under the following conditions. Equipment name: Prominence (manufactured by Shimadzu Corporation) Mobile phase: chloroform (for HPLC) (manufactured by Wako Pure Chemical Industries, Ltd.) Flow rate: 1 mL / min Column: TSKgel GMHHR-M (φ7.8 mm × 300 mm; manufactured by Tosoh Corporation) Guard column: TSKgel guardcolumn HHR-H (φ6.0 mm × 40 mm; manufactured by Tosoh Corporation) Detector: UV (254 nm), RI Column and detector temperature: 35 °C Standard substance: polystyrene.

[0066] The fiber diameter of the biodegradable polymer fiber in the present invention is preferably 3 μm or more. By setting the fiber diameter to 3 μm or more, the permeability of the fiber structure can be further improved. The fiber diameter is more preferably 5 μm or more. Here, the fiber diameter of the biodegradable polymer fiber refers to the average value of the diameters of 20 fibers. The surface of the fiber structure is magnified 500 times using a microscope, and for 20 biodegradable polymer fibers randomly selected from the observation image, the average value of the fiber diameters measured by measuring the distance between two points can be calculated to obtain the value. The fiber diameter of the biodegradable polymer fiber can be adjusted to a desired range, for example, by the molecular weight of the biodegradable polymer used in the manufacturing method of the biodegradable polymer fiber described later, the concentration of the biodegradable polymer solution, the spinning speed, and the like.

[0067] <Manufacturing Method of Biodegradable Polymer Fiber> The biodegradable polymer fiber can be produced, for example, from the biodegradable polymer having the aforementioned molecular weight distribution by the electrospinning method. More specifically, a solution obtained by dissolving the biodegradable polymer having the aforementioned molecular weight distribution in a solvent may be injected for solvent spinning, or the biodegradable polymer having the aforementioned molecular weight distribution may be melted and injected for melt spinning. In the present invention, since the fiber diameter can be increased, a more remarkable effect can be achieved in solvent spinning in which the fiber diameter is likely to decrease due to the volatilization of the solvent. Therefore, it is preferable to form fibers from a solution of the biodegradable polymer having the aforementioned molecular weight distribution by the electrospinning method.

[0068] As described above, the fiber diameter of the biodegradable polymer fiber depends on the biodegradable polymer concentration, and at a high concentration, the fiber diameter can be made thicker. In the present invention, the biodegradable polymer concentration is preferably 0.25 g / mL or more. On the other hand, from the viewpoint of suppressing excessive viscosity increase, the biodegradable polymer concentration is preferably 1.0 g / mL or less.

[0069] As described above, the fiber diameter of the biodegradable polymer fiber depends on the spinning speed, and the faster the spinning speed, i.e., the larger the amount of biodegradable polymer solution injected, the thicker the fiber diameter can be. In the present invention, the injection speed is preferably 0.5 mL / hour or more, and more preferably 0.8 mL / hour or more from the viewpoint of suppressing thread breakage. On the other hand, the injection rate is preferably 5 mL / hour or less from the viewpoint of appropriately suppressing the amount of biodegradable polymer solution injected at one time and suppressing charge repulsion.

[0070] <Fiber structure> The fiber structure of the present invention includes the biodegradable polymer fiber described above. Examples of the structure of the fiber structure include knitted, woven, oriented, and nonwoven structures. Among these, a nonwoven structure is preferred. In a nonwoven structure, the fibers are three-dimensionally and irregularly entangled with each other, resulting in a large number of voids, and the effect of improving permeability due to the increased fiber diameter is more pronounced.

[0071] The fiber structure of the present invention preferably has a small resistance to serum protein permeation, which is an index of permeability. Here, the resistance to permeation of the fiber structure can be determined by the following method. First, 100 μL of fetal bovine serum is added to the inside of the fiber structure and 1 mL of phosphate buffered saline (PBS) is added to the outside, and the structure is allowed to stand for 3 hours. After that, the concentration of serum protein in the PBS is measured, and the total amount (Q) (ng) of serum protein that has permeated to the outside is calculated. The surface area (S) (mm 2 ) and the standing time (T) (s), the protein flux per unit time (J) (ng / mm 2 s) is calculated. J = Q / (S × T) The slope of the approximate line was calculated from a scatter plot with the calculated protein permeation flux (J) on the vertical axis and the thickness (d) (mm) of the fiber structure on the horizontal axis, and the permeation resistance (ng / mm) was calculated from the absolute value. 3 The permeation resistance can be reduced, for example, by increasing the fiber diameter of the biodegradable polymer fibers forming the fiber structure.

[0072] From the viewpoint of improving strength, the thickness of the fibrous structure of the present invention is preferably 100 μm or more, more preferably 200 μm or more. Here, the thickness of the fibrous structure can be measured by magnifying and observing the cross-section of the fibrous structure using a microscope. The thickness of the fibrous structure can be adjusted to a desired range, for example, by the spinning time in the electrospinning method.

[0073] <Manufacturing method of fibrous structure> The fibrous structure of the present invention can be manufactured, for example, by accumulating the ejected yarns on a collector in the manufacturing method of the biodegradable polymer fibers described above.

[0074] The shape of the collector can be selected according to the shape of the target fibrous structure. For example, when manufacturing a sheet-like fibrous structure, the biodegradable polymer fibers are accumulated while rotating a roller-type collector, and the sheet-like fibrous structure can be manufactured by cutting from one end to the other end of the accumulated biodegradable polymer fibers in a straight line. From the viewpoint of obtaining a flat sheet-like fibrous structure, the diameter of the roller is preferably 100 mm or more. Further, when manufacturing a tubular fibrous structure, the biodegradable polymer fibers are accumulated while rotating a columnar collector, and then the collector is pulled out from the fibrous structure to manufacture a tubular fibrous structure.

[0075] From the viewpoint of making the thickness of the fibrous structure uniform, the rotation speed of the collector is preferably 30 rpm or more. On the other hand, from the viewpoint of easily increasing the fiber diameter, the rotation speed of the collector is preferably 1000 rpm or less.

[0076] From the viewpoint of sufficiently volatilizing the solvent, the distance between the solution ejection port and the collector is preferably 13 cm or more. On the other hand, from the viewpoint of suppressing the elongation of the fibers due to electrostatic force, the distance between the solution ejection port and the collector is preferably 30 cm or less.

Examples

[0077] Hereinafter, the present invention will be described specifically using examples. However, the present invention should not be construed as being limited to these examples, and all technical ideas and their specific embodiments that those skilled in the art who are in contact with the concept of the present invention can conceive and implement should be understood to be included in the present invention. Note that Examples 3 to 7 shall be read as Reference Examples 1 to 5.

[0078] [Measurement Example 1: Measurement of Gel Permeation Chromatography (GPC)] Chloroform was added to the dilactide / ε-caprolactone copolymer obtained in Synthesis Examples 1 to 3, the biodegradable polymer solutions prepared in each Example and Comparative Example, and polymer solutions were prepared to be 1 mg / mL. Then, after passing through a 0.45 μm syringe filter (DISMIC-13HP; manufactured by ADVANTEC) to remove impurities and the like, a differential molecular weight distribution curve in terms of polystyrene was obtained by GPC measurement under the following conditions. From the obtained distribution curve, the weight average molecular weight was calculated, and the molecular weight corresponding to the maximum value was determined. Equipment name: Prominence (manufactured by Shimadzu Corporation) Mobile phase: Chloroform (for HPLC) (manufactured by Wako Pure Chemical Industries, Ltd.) Flow rate: 1 mL / min Column: TSKgel GMHHR-M (φ7.8 mm × 300 mm; manufactured by Tosoh Corporation) Guard column: TSKgel guardcolumn HHR-H (φ6.0 mm × 40 mm; manufactured by Tosoh Corporation) Detector: UV (254 nm), RI Column and detector temperature: 35 °C Standard substance: Polystyrene.

[0079] [Measurement Example 2: Measurement of Crystallization Rate of Dilactide Residue by Differential Scanning Calorimetry (DSC)] The dilactide / ε-caprolactone copolymer obtained in Synthesis Examples 1 to 3 was sampled into an aluminum PAN, and the heat of fusion was calculated by the DSC method under the following conditions using a differential scanning calorimeter (EXTAR 6000; manufactured by Seiko Instruments Inc.). The crystallization rate was calculated from the obtained heat of fusion value by the following formula. Crystallinity = (Heat of fusion per unit weight of the dilactide residue in the dilactide / ε-caprolactone copolymer) / {(Heat of fusion per unit weight of the homopolymer consisting only of dilactide residues) × (Weight fraction of dilactide residues in the dilactide / ε-caprolactone copolymer)} × 100 Equipment name: EXSTAR 6000 (manufactured by Seiko Instruments Inc.) Temperature conditions: 25°C → 250°C (10°C / min) → 250°C (5 min) → -70°C (10°C / min) → 250°C (10°C / min) → 250°C (5 min) → 25°C (100°C / min) Standard substance: Aluminum

[0080] [Measurement Example 3: Measurement of the molar fraction of each residue and R value by nuclear magnetic resonance (NMR)] The dilactide / ε-caprolactone copolymers obtained in Synthesis Examples 1 to 3 were dissolved in deuterated chloroform, and under the following conditions 1 The ratios of the dilactide residues and caprolactone residues in the dilactide / ε-caprolactone copolymer were calculated by 1H-NMR, respectively. Also 1 By the 1H homospin decoupling method, for the methine group of lactide (around 5.10 ppm), the α-methylene group of caprolactone (around 2.35 ppm), and the ε-methylene group of caprolactone (around 4.10 ppm), the signals of adjacent monomer residues derived from lactide or caprolactone were separated, and the peak areas of each were quantified. [AB] in Formula 1 was calculated from the area ratio of each, and the R value was calculated. Here, [AB] is the molar fraction of the structure in which dilactide residues and caprolactone residues are adjacent, specifically, the ratio of the number of A-B and B-A to the total number of A-A, A-B, B-A, and B-B Equipment name: JNM-EX270 (manufactured by JEOL Ltd.) 1 1H homospin decoupling irradiation position: 1.66 ppm Solvent: Deuterated chloroform Measurement temperature: Room temperature

[0081] [Measurement Example 4: Measurement of fiber diameter] The tubes under the condition of a spinning time of 10 minutes obtained in each of the examples and comparative examples were set on the sample stage of a microscope (KH-1300, manufactured by HiRox), magnified 500 times, the surface of the tubes was observed, and images were taken using the attached image analysis software "2D measuree". When the entire screen was out of focus depending on the depth of the sample during imaging, depth composition was performed using the function of this software. Twenty fibers were randomly selected from the taken images, and the fiber diameter was measured by measuring the distance between two points using the function of this software. The average value was taken as the fiber diameter of the fiber structure.

[0082] [Measurement Example 5: Measurement of Permeation Resistance] The tubes under the respective conditions of spinning times of 10 minutes, 30 minutes, and 60 minutes obtained in each of the examples and comparative examples were cut perpendicular to the major axis and set on the sample stage of a microscope (KH-1300; manufactured by HiRox). The cross-section of the tubes was observed magnified 250 times, and images were taken using the attached image analysis software "2D measuree". When the entire screen was out of focus depending on the depth of the sample during imaging, depth composition was performed using the function of this software. Five locations were randomly selected from the taken images, and the respective thicknesses were measured by measuring the distance between two points. The average value was taken as the thickness of the tubes at each spinning time.

[0083] The tubes under the respective conditions of spinning times of 10 minutes, 30 minutes, and 60 minutes obtained in each of the examples and comparative examples were cut into lengths of 1 cm and vertically fixed to each well of a 24-well plate (product name "Non-Treat"; manufactured by Falcon). Then, 100 μl of fetal bovine serum (manufactured by Gibco) was added inside the tubes, and 1 ml of PBS (manufactured by Fujifilm) was added outside, and they were left standing for 3 hours. Then, using a BSA measurement kit (manufactured by invitrogen), the concentration of serum protein in the PBS was measured, and the total amount Q (ng) of serum protein that had permeated outside was calculated. Let the surface area of the tubes (outer diameter × π × 1 cm) be S (mm 2 ), the standing time be T (s), and the protein permeation flux J (ng / mm 2 ·s) per unit time was calculated by the following formula. J = Q / (S×T) For each tube, the slope of the approximate straight line was calculated from a scatter plot with the protein permeation flux J on the vertical axis and the tube thickness d (mm) on the horizontal axis, and the permeation resistance (ng / mm 3 ·s) was determined from the absolute value thereof.

[0084] [Measurement Example 6: Measurement of the number of days required for decomposition] As an index of the in vivo residence time of the fibrous structure, the change in molecular weight over time was measured using a film made of a polymer composition having the same composition as the biodegradable polymer fibers of Examples 1 to 2 and Comparative Examples 2 to 4. The biodegradable polymer solutions prepared in Examples 1 to 2 and Comparative Examples 2 to 4 were transferred onto a petri dish made of "Teflon" (registered trademark) and dried at normal pressure and room temperature for 24 hours. The polymer film with a thickness of 0.1 mm obtained by drying this under reduced pressure was cut into strips (30 mm × 5 mm). Each of the cut films was placed in each well of a 6-well plate (trade name "Non-Treat"; manufactured by Falcon), 3 mL of PBS (manufactured by Fujifilm Corporation) was added, and it was immersed. This was placed in a thermostat at 37°C and shaken under the condition of 100 rpm. The PBS was changed twice a week, and 1 mg of the immersed film was cut out once a week, and the weight average molecular weight was measured by the method described in Measurement Example 1. The number of days when the weight average molecular weight became 500 or less, which is the measurement limit, was recorded. It can be said that the longer the number of days required for decomposition, the longer the in vivo residence time.

[0085] [Synthesis Example 1: Synthesis of a dilactide / ε-caprolactone copolymer] 25 g of L-Dilactide (manufactured by Corbion) and 18.3 mL of ε-caprolactone (manufactured by Wako Pure Chemical Industries, Ltd.) were taken as monomers into a separable flask. These were placed under a nitrogen atmosphere. As a catalyst, a solution of 0.05 parts by weight (in terms of tin) of tin(II) octylate (manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 3.5 mL of toluene (ultra-dehydrated, manufactured by Wako Pure Chemical Industries, Ltd.) with respect to a total of 100 parts by weight of dilactide and ε-caprolactone, and 227.4 mg of hydroxypivalic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) as a co-initiator were added. While heating to 140 °C, stirring was carried out at a stirring speed of 100 rpm for 12 hours to cause a copolymerization reaction, obtaining a macromer solution.

[0086] To the obtained macromer solution, 1.67 g of 4,4-dimethylaminopyridinium p-toluenesulfonate (synthetic product) and 617.9 mg of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added as catalysts. These were dissolved in 255 mL of dichloromethane (dehydrated, manufactured by Wako Pure Chemical Industries, Ltd.) under a nitrogen atmosphere, and 5.76 g of dicyclohexylcarbodiimide (manufactured by Sigma-Aldrich) was added as a condensing agent. Stirring was carried out at 25 °C and a stirring speed of 100 rpm for 18 hours for condensation polymerization.

[0087] To the reaction mixture, 3.0 mL of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and chloroform in an amount such that the concentration of the dilactide / ε-caprolactone copolymer was 15% by weight were added, and stirring was carried out at 25 °C and a stirring speed of 200 rpm for 2 hours. Then, the reaction mixture was dropped into 2.0 L of methanol under stirring at 300 rpm to obtain a precipitate. The obtained precipitate was dried for 18 hours to obtain a dilactide / ε-caprolactone copolymer. As a result of measuring the obtained dilactide / ε-caprolactone copolymer by the methods of Measurement Example 1, Measurement Example 2, and Measurement Example 3, the weight average molecular weight and the molecular weight corresponding to the maximum value were 240,000, the crystallization rate of the dilactide residue was 0.0%, and the R value was 0.60.

[0088] [Synthesis Example 2: Synthesis of Dilactide / ε-Caprolactone Copolymer] A macro-monomer solution was obtained in the same manner as in Synthesis Example 1. To the obtained macro-monomer solution, 3.0 mL of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and chloroform in an amount such that the concentration of the dilactide / ε-caprolactone macro-monomer was 15% by weight were added, and the mixture was stirred at 25 °C and a stirring speed of 200 rpm for 2 hours. Thereafter, the reaction mixture was dropped into 2.0 L of methanol under stirring at 300 rpm to obtain a precipitate. The obtained precipitate was dried for 18 hours to obtain a dilactide / ε-caprolactone copolymer. The weight average molecular weight of the obtained dilactide / ε-caprolactone copolymer and the molecular weight corresponding to the maximum value were 60,000, the crystallization rate of the dilactide residue was 0.0%, and the R value was 0.58.

[0089] [Synthesis Example 3: Synthesis of dilactide / ε-caprolactone copolymer] 50.0 g of L -dilactide (manufactured by PURAC) and 38.5 mL of ε-caprolactone (manufactured by Wako Pure Chemical Industries, Ltd.) were collected as monomers in a separable flask. These were placed under an argon atmosphere, and a solution prepared by dissolving 0.1 part by weight of tin(II) octylate (manufactured by Wako Pure Chemical Industries, Ltd.) in 14.5 mL of toluene (ultra-dehydrated, manufactured by Wako Pure Chemical Industries, Ltd.) with respect to a total of 100 parts by weight of dilactide and ε-caprolactone as a catalyst, and ion-exchanged water in an amount such that the monomer / cocatalyst ratio was 142.9 as a cocatalyst were added. After performing a cocatalyst reaction by stirring at a stirring speed of 100 rpm for 1 hour while heating to 90 °C, a copolymerization reaction was carried out by stirring at a stirring speed of 100 rpm for 6 hours while heating to 150 °C to obtain a crude copolymer. The obtained crude copolymer was dissolved in 100 mL of chloroform and dropped into 1400 mL of methanol under stirring to obtain a precipitate. This operation was repeated 3 times, and the precipitate was dried under reduced pressure at 70 °C to obtain a macro-monomer.

[0090] 7.5 g of the obtained macromer, 0.28 g of p-toluenesulfonic acid 4,4-dimethylaminopyridinium (synthetic product) as a catalyst, and 0.10 g of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were collected in the same container. These were dissolved in dichloromethane (dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) so that the macromonomer concentration was 30% by weight under an argon atmosphere, and stirred at a stirring speed of 100 rpm for 2 hours under an environment of 1.3 kPa. A solution prepared by dissolving 0.47 g of amylene (manufactured by Tokyo Chemical Industry Co., Ltd.) in 5 mL of dichloromethane was added as a condensing agent, and the mixture was stirred at a stirring speed of 100 rpm at 25°C for 48 hours for condensation polymerization.

[0091] 30 mL of chloroform was added to the reaction mixture, and the mixture was stirred at 25°C and a stirring speed of 200 rpm for 2 hours. Then, the reaction mixture was dropped into 2.0 L of methanol stirred at 300 rpm to obtain a precipitate. This precipitate was dissolved in 50 mL of chloroform and dropped into 500 mL of methanol stirred at 300 rpm to obtain a precipitate again. This operation was repeated twice to obtain a dilactide / ε-caprolactone copolymer as a precipitate. The weight average molecular weight and the molecular weight corresponding to the maximum value of the obtained dilactide / ε-caprolactone copolymer were 100,000, the crystallization rate of the dilactide residue was 0.0%, and the R value was 0.78.

[0092] [Example 1] 1 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 1 as a high molecular weight biodegradable polymer and 2 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 2 as a low molecular weight biodegradable polymer were each collected and mixed while dissolving in 10 mL of chloroform to obtain a biodegradable polymer solution. The weight average molecular weight of the obtained biodegradable polymer solution was measured by the method described in Measurement Example 1.

[0093] The obtained biodegradable polymer solution was collected in a 5-mL syringe (Terumo), and an 18G needle (MECC) dedicated to the spinning device NANON-3 of MECC was attached. The syringe containing the biodegradable polymer solution and a φ4-mm mandrel collector were set in NANON-3, and electrospinning was performed. The spinning conditions were as follows: spinning distance: 17 cm, spinning voltage: 25 kV, spinning speed: 1 mL / hour, rotation speed: 50 rpm, spinning amplitude: 15 cm, spinning time: 10 minutes, 30 minutes, and 60 minutes. After spinning, the fiber structure was removed from the mandrel collector to obtain a tube with a nonwoven fabric-like structure. For the tube obtained under the condition of a spinning time of 10 minutes, the fiber diameter was measured by the method described in Measurement Example 4. Also, for the tubes obtained under the conditions of spinning times of 10 minutes, 30 minutes, and 60 minutes, the permeation resistance was calculated by the method described in Measurement Example 5.

[0094] The biodegradable polymers used and the evaluation results are shown in Table 1.

[0095] [Example 2] A tube was prepared and evaluated in the same manner as in Example 1, except that 1 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 2 was used as the low-molecular-weight biodegradable monomer. The results are shown in Table 1.

[0096] [Comparative Example 1] A tube was prepared and evaluated in the same manner as in Example 1, except that 2 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 1 was used as the high-molecular-weight biodegradable polymer and no low-molecular-weight biodegradable monomer was used. The results are shown in Table 1.

[0097] [Comparative Example 2] A tube was prepared and evaluated in the same manner as in Example 1, except that no low-molecular-weight biodegradable monomer was used. The results are shown in Table 1.

[0098] [Comparative Example 3] A tube was prepared and evaluated in the same manner as in Example 1, except that 2 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 3 as a low molecular weight biodegradable polymer was used without using a high molecular weight biodegradable monomer. The results are shown in Table 1.

[0099] [Comparative Example 4] A tube was prepared and evaluated in the same manner as in Example 1, except that 3 g of the dilactide / ε-caprolactone copolymer obtained in Synthesis Example 3 as a low molecular weight biodegradable polymer was used without using a high molecular weight biodegradable monomer. The results are shown in Table 1.

[0100] [Example 3] 2 g of polylactic acid (trade name "PURASORB PL24", manufactured by Coribion, weight average molecular weight and molecular weight corresponding to the maximum value: 240,000) as a high molecular weight biodegradable polymer and 2.5 g of polylactic acid (trade name "PURASORB PL0.2", manufactured by PURAC, weight average molecular weight and molecular weight corresponding to the maximum value: 2,000) as a low molecular weight biodegradable polymer were each collected and mixed while dissolving in 10 mL of chloroform to obtain a biodegradable polymer solution. The weight average molecular weight of the obtained biodegradable polymer solution was measured by the method described in Measurement Example 1.

[0101] The obtained biodegradable polymer solution was collected in a 5 mL syringe (Terumo), and a 22G needle (MECC) dedicated to the spinning device NANON-3 of MECC was attached. The syringe containing the biodegradable polymer solution and a φ4 mm mandrel collector were set on NANON-3, and electrospinning was performed. The spinning conditions were: spinning distance: 15 cm, spinning voltage: 22 kV, spinning speed: 3 mL / hour, rotation speed: 50 rpm, spinning amplitude: 15 cm, spinning time: 10 minutes, 30 minutes, 60 minutes. After spinning, the fiber structure was removed from the mandrel collector to obtain a tube with a non-woven fabric-like structure. The fiber diameter of the tube obtained under the condition of a spinning time of 10 minutes was measured by the method described in Measurement Example 4. Also, for the tubes obtained under the conditions of spinning times of 10 minutes, 30 minutes, and 60 minutes, the permeation resistance was calculated by the method described in Measurement Example 5.

[0102] The biodegradable polymers used and the evaluation results are shown in Table 2.

[0103] [Example 4] As the high molecular weight biodegradable polymer, 2.0 g of polylactic acid (trade name "PLLA", manufactured by BMG, weight average molecular weight and molecular weight corresponding to the maximum value are 320,000), and as the low molecular weight biodegradable polymer, polylactic acid (trade name "PLA10", manufactured by Wako Pure Chemical Industries, Ltd.) was hydrolyzed, and a tube was prepared and evaluated in the same manner as in Example 3 except that 2.5 g of polylactic acid corresponding to a weight average molecular weight and a maximum value of 6,000 in GPC measurement was used. The results are shown in Table 2.

[0104] [Comparative Example 5] A tube was prepared and evaluated in the same manner as in Example 3 except that no low molecular weight biodegradable polymer was used. The results are shown in Table 2.

[0105] [Comparative Example 6] As the high molecular weight biodegradable polymer, 4.5 g of polylactic acid (trade name "PURASORB PL24", manufactured by Coribion, weight average molecular weight and molecular weight corresponding to the maximum value are 240,000) was used, and a tube was prepared and evaluated in the same manner as in Example 3 except that no low molecular weight biodegradable monomer was used. The results are shown in Table 2.

[0106] [Comparative Example 7] As the high molecular weight biodegradable polymer, 4.5 g of polylactic acid (trade name "PURASORB PL12", manufactured by Coribion, weight average molecular weight and molecular weight corresponding to the maximum value are 120,000) was used, and a tube was prepared and evaluated in the same manner as in Example 3 except that no low molecular weight biodegradable monomer was used. The results are shown in Table 2.

[0107] [Comparative Example 8] As the high molecular weight biodegradable polymer, 2.0 g of polylactic acid (trade name "PLLA", manufactured by BMG, weight average molecular weight and molecular weight corresponding to the maximum value are 320,000), and a tube was prepared and evaluated in the same manner as in Example 4 except that no low molecular weight biodegradable polymer was used. The results are shown in Table 2.

[0108] [Example 5] As the high molecular weight biodegradable polymer, 2.0 g of polylactic acid (trade name "PURASORB PL24", manufactured by Coribion, weight average molecular weight and molecular weight corresponding to the maximum value are 240,000), and as the low molecular weight biodegradable polymer, polylactic acid (trade name "PLA10", manufactured by Wako Pure Chemical Industries, Ltd.) was hydrolyzed, and a tube was prepared and evaluated in the same manner as in Example 3 except that 1.0 g of polylactic acid corresponding to a weight average molecular weight and a maximum value of 200 in GPC measurement was used. The results are shown in Table 2.

[0109] [Example 6] As the high molecular weight biodegradable polymer, poly(dilactide / glycolic acid copolymer) (trade name "PGLA(10:90)", manufactured by BMG, C GA :C LA =10:90, weight average molecular weight and molecular weight corresponding to the maximum value are 260,000) 2.0 g, and as the low molecular weight biodegradable polymer, poly(dilactide / glycolic acid copolymer) (trade name "PLGA5020", manufactured by Wako Pure Chemical Industries, Ltd., currently manufactured by Fujifilm Wako Pure Chemical Corporation) was hydrolyzed, and 1.0 g of poly(dilactide / glycolic acid copolymer) corresponding to a weight average molecular weight and a maximum value of 10,000 in GPC measurement was collected and mixed while dissolving in 10 mL of chloroform to obtain a biodegradable polymer solution. For the obtained biodegradable polymer solution, the weight average molecular weight was measured by the method described in Measurement Example 1. A tube was prepared and evaluated in the same manner as in Example 3, and the results are shown in Table 3.

[0110] [Example 7] As the low molecular weight biodegradable polymer, poly(dilactide / glycolic acid copolymer) (trade name "PLGA5020", manufactured by Wako Pure Chemical Industries, Ltd., currently manufactured by Fujifilm Wako Pure Chemical Corporation) was hydrolyzed, and a tube was prepared and evaluated in the same manner as in Example 3 except that 4.0 g of poly(dilactide / glycolic acid copolymer) corresponding to a weight average molecular weight and a maximum value of 10,000 in GPC measurement was used. The results are shown in Table 3.

[0111] [Comparative Example 9] A tube was produced and evaluated in the same manner as in Example 6 except that a low molecular weight biodegradable polymer was not used. The results are shown in Table 3.

[0112] [Comparative Example 10] As the high molecular weight biodegradable polymer, 3.0 g of poly(dilactide / glycolic acid copolymer) (trade name "PGLA(10:90)", manufactured by BMG, CGA:CLA = 10:90, weight average molecular weight and molecular weight corresponding to the maximum value are 260,000). A tube was produced and evaluated in the same manner as in Example 6 except that a low molecular weight biodegradable polymer was not used. The results are shown in Table 3.

[0113] [Table 1]

[0114] [Table 2]

[0115] [Table 3]

Claims

1. A fiber structure containing biodegradable polymer fibers, wherein the cross-sectional structure of the biodegradable polymer fibers is single-layered, and in the weight-average molecular weight obtained by GPC measurement of the biodegradable polymer, it has two or more peaks, the biodegradable polymer is a biodegradable polyester, the biodegradable polymer is polylactic acid, polycaprolactone, polyglycolic acid or a copolymer thereof, the biodegradable polymer is a dilactide / ε-caprolactone copolymer satisfying the following (1) and (2), and the dilactide / ε-caprolactone copolymer is a copolymer having a structure in which two or more macromer units having a compositional gradient of dilactide residues and caprolactone residues in the backbone are linked. (1) The following formula R = [AB] / (2[A][B])×100 [A]: The molar fraction (%) of dilactide residues in the dilactide / ε-caprolactone copolymer [B]: The molar fraction (%) of ε-caprolactone residues in the dilactide / ε-caprolactone copolymer [AB]: The molar fraction (%) of the structure (A-B and B-A) in which dilactide residues and ε-caprolactone residues are adjacent to each other in the dilactide / ε-caprolactone copolymer The R value represented by is 0.45 or more and 0.99 or less. (2) The crystallinity of at least one of dilactide residues or ε-caprolactone residues is less than 14%.

2. The fiber structure according to claim 1, which has one or more peaks in the region of a molecular weight of 100,000 or less and in the region of a molecular weight greater than 100,000 in the molecular weight distribution obtained by GPC measurement of the biodegradable polymer.

3. The fiber structure according to claim 1 or 2, wherein the fiber diameter of the biodegradable polymer fiber is 3 μm or more and has a non-woven fabric-like structure.

4. The fiber structure according to any one of claims 1 to 3, which has peaks in the region of a molecular weight of 100 or more and 70,000 or less and in the region of a molecular weight of 200,000 or more.

5. A method for producing a fiber structure according to any one of claims 1 to 4, comprising a step of forming fibers from a solution of the biodegradable polymer by an electrospinning method.

Images