WO2021187354A1

WO2021187354A1 - Cylindrical molded body for medical instrument

Info

Publication number: WO2021187354A1
Application number: PCT/JP2021/010026
Authority: WO
Inventors: 張本乾一; 坂口博一
Original assignee: 東レ株式会社
Priority date: 2020-03-19
Filing date: 2021-03-12
Publication date: 2021-09-23
Also published as: JPWO2021187354A1

Abstract

A cylindrical molded body for a medical instrument, said molded body having a plurality of cylindrical bodies and a connecting layer connecting the cylindrical bodies. This cylindrical molded body for a medical instrument deforms flexibly in response to bending and curving due to a flexible layer connecting the plurality of cylindrical bodies, and has the effect of being able to suppress kinking.

Description

Cylindrical molded body for medical equipment

The present invention relates to a tubular molded body for medical devices.

When a defect or disorder occurs in a tissue of the human body, an implant treatment is performed in which a molded body made of a material harmless to the human body is transplanted for the purpose of replacing or supporting the original tissue for the treatment. ing. A tubular molded body with a hollow inside is a shape often used in implant treatment, and it surrounds and protects tissues, fills the hollow part with a drug and releases it slowly, and is tubular like blood vessels and nerves. It is used in various medical applications such as as a substitute for body tissues. A nerve regeneration induction tube is known as a tubular molded body that induces and treats nerve regeneration. By using the nerve regeneration induction tube, the invasion of connective tissue, which interferes with nerve regeneration, into the injured site is suppressed.

FIG. 1 is a diagram illustrating an example of using a conventional nerve regeneration induction tube. In the nerve regeneration induction tube 10 shown in FIG. 1, a nerve cell 200 and a Schwann cell 210 are arranged on one end side. The scaffolding material 11 is filled inside the nerve regeneration induction tube 10. In the nerve regeneration induction tube 10, Schwann cells 211 proliferate inside. Axons 201 extend inside the proliferated Schwann cells 211. During this time, the nerve regeneration-inducing tube 10 suppresses the entry of connective tissue, thereby suppressing the inhibition of the pathway in which the axon 201 tries to extend. In this way, nerve regeneration using the nerve regeneration induction tube 10 proceeds.

By the way, in order to protect the nerves that regenerate in the tube, the shape of the nerve regeneration induction tube that improves the strength of the tube has been studied. For example, Patent Document 1 reports a tubular body having a single-layer structure of braids in which threads formed from a plurality of organic polymer fibers are braided so that the braiding angle is 50 ° to 87.5 °. There is.

Japanese Unexamined Patent Publication No. 2014-155622

If the strength of the tube is high, it can exert strong resistance to the pressure of crushing the short axis of the tube and can protect the inside. However, if the tube is too strong, it will be inadequately flexible against bending and refraction deformation and may damage the tissue around the implant site. On the other hand, when the Young's modulus of the tube is simply adjusted to add flexibility, a kink occurs when the tube is curved, which causes a problem that the tube is occluded and the internal tissue is damaged.

The present invention has been made in view of the above problems, and when an external force is generated due to bending or refraction, the tube can be flexibly deformed with respect to bending or refraction while maintaining the pressure resistance of the tube, and kink generation can be suppressed. An object of the present invention is to provide a tubular molded body for medical instruments.

In order to solve the above problems, the present invention is as follows.

A tubular molded body for medical instruments having a plurality of tubular bodies and a connecting layer connecting the tubular bodies.

Medical device including the above-mentioned molded body.

A nerve regeneration induction tube containing the above-mentioned molded body.

According to the tubular molded body for medical instruments of the present invention, the flexible layer connecting a plurality of tubular bodies can be flexibly deformed with respect to bending and refraction, and can suppress the occurrence of kink. .. The tubular molded body for medical devices of the present invention is suitably applicable to a nerve regeneration induction tube. The nerve regeneration induction tube of the present invention is particularly useful for regeneration of, for example, muscle tissue, vascular tissue, nerve tissue, spinal cord tissue, skin tissue and the like.

FIG. 1 is a diagram illustrating a usage example of a conventional nerve regeneration induction tube. The schematic diagram of the mode in which a tubular body and a connecting layer are in contact with each other, and the connecting layer is arranged outside the tubular body. The schematic diagram of the mode in which a tubular body and a connecting layer are in contact with each other, and the connecting layer is arranged inside the tubular body. The schematic diagram of the mode in which a tubular body and a connecting layer are in contact with each other, and the connecting layer is arranged outside the tubular body. The schematic diagram of the mode in which a tubular body and a connecting layer are in contact with each other, and the connecting layer is arranged inside the tubular body. FIG. 6 is a schematic view of an embodiment in which a tubular body and a connecting layer are in contact with each other, and the connecting layer is arranged inside the tubular body A and outside the tubular body B. Photographs of a cylindrical molded body for a medical device of Examples and Comparative Examples bent at a 60 ° angle in Measurement Example 6. A photograph showing the kink resistance of the tubular molded body for medical equipment of Example 2.

Hereinafter, a mode for carrying out the present invention will be described in detail together with drawings. The present invention is not limited to the following embodiments. In addition, each of the figures referred to in the following description merely schematically shows the shape, size, and positional relationship to the extent that the content of the present invention can be understood. That is, the present invention is not limited to the shape, size, and positional relationship exemplified in each figure. Further, in the description of the drawings, the same parts are designated by the same reference numerals.

The tubular molded body for medical devices of the present invention has a plurality of tubular bodies and a connecting layer for connecting the tubular bodies. That is, the molded body of the present invention has at least two tubular bodies. The portion where two adjacent cylindrical bodies are connected by a connecting layer is called a connecting portion. The tubular molded body for medical devices of the present invention has at least one connecting portion. The number of tubular bodies is not limited to two, and the number of connecting portions is not limited to one. That is, the molded body of the present invention is not particularly limited in the number of tubular bodies and the number of connecting portions, and may have, for example, three tubular bodies and two connecting portions.

The tubular molded body for medical instruments of the present invention exhibits pressure resistance by having a hard cylindrical body, and exhibits flexibility and kink resistance against bending and refraction by having a soft connecting layer. can. If the distance between the adjacent cylinders is too large, sufficient pressure resistance cannot be exhibited. Therefore, the distance between the adjacent cylinders is preferably 1 mm or less. The lower limit of the distance between adjacent cylindrical bodies is not particularly limited, but there is no space, that is, the distance is 0 mm.

The distance between adjacent cylindrical bodies is the distance from one end of one cylinder to the other close to the end in a state where no external force is applied to the molded body and the connecting layer does not expand or contract with respect to the initial state. It is the distance to the end of the tubular body, and can be measured with a caliper or the like. Further, in the case of a molded body having a structure in which one tubular body is inserted into the other tubular body, that is, as will be described later, the inner diameter A of one tubular body A at the connecting portion is the other tubular body. In the case where the tubular body B is larger than the outer diameter B of B and the tubular body B is inserted inside the tubular body A, there is no spacing between adjacent tubular bodies, so that the spacing between adjacent tubular bodies is not provided. Is 0 mm. Here, the initial state is a state in which no external force is applied in the long axis direction of the molded body after the molded body is produced.

Further, even if the length of the tubular body is too short, the pressure resistance cannot be exhibited. Therefore, the length of the tubular body in the direction along the long axis direction of the molded body is preferably 1.0 mm or more. On the other hand, if the length of the tubular body is long, the flexibility of the tubular body cannot be sufficiently exhibited. Therefore, the length of the tubular body in the direction along the long axis direction of the molded body is preferably 10 mm or less.

And in the tubular molded body for medical devices of the present invention, a plurality of tubular bodies are connected by a connecting layer. As shown in FIG. 2, the mode in which the connecting layer is arranged on the outside of the tubular body and the mode in which the connecting layer is arranged on the inside of the tubular body as shown in FIG. 3 are both preferable.

In the tubular molded body for medical instruments of the present invention, as shown in FIGS. 4 to 6, the inner diameter of one tubular body A is larger than the outer diameter of one tubular body B at the connecting portion, and the cylinder is formed. The connecting portion may be configured so that the tubular body B can be inserted inside the body A. Here, the inner diameter of the tubular body is the diameter of the inner circle in the vertical cross section of the minor axis of the tubular body. The outer diameter of the tubular body is the diameter of the outer circle of the vertical cross section of the short axis of the tubular body. In this case, as shown in FIG. 4, the tubular body and the connecting layer are in contact with each other, and the connecting layer is arranged outside the tubular body. As shown in FIG. 5, the tubular body and the connecting layer are connected. Among the tubular bodies in which the layers are in contact and the connecting layer is arranged inside the tubular body, as shown in FIG. 6, the tubular body and the connecting layer are in contact with each other and the connecting layers are adjacent to each other. , Any of the embodiments arranged inside one tubular body (cylindrical body A) and outside the other tubular body (cylindrical body B) is preferable.

In this aspect, the tubular body B can be inserted inside the tubular body A when pushed in from both ends of the molded body. At the connecting portion, the tubular body B may or may not be inserted inside the tubular body A.

Further, in the tubular molded body for medical instruments of the present invention, the shape of the entire molded body becomes tubular by connecting a plurality of tubular bodies by a connecting layer.

When the tubular molded body for a medical device of the present invention is used as a medical device such as a nerve regeneration induction tube, it is placed inside or outside the living body, so that an external force is applied to the molded body due to deformation such as compression, refraction or curvature. It is expected to join. Therefore, in order to protect the inside of the tubular body forming the tubular molded body from pressure, the Young's modulus of the tubular body is preferably 6.3 MPa or more. Assuming that there is hard tissue such as bone around the indwelling place, the Young's modulus of the tubular body is more preferably 10 MPa or more. On the other hand, when used to induce regeneration of tissues that are softer than hard tissues such as bones and teeth (for example, fascia, tendons, ligaments, nerves, muscles, etc.), pain may occur if they are too hard. The Young's modulus is preferably 100 GPa or less, more preferably 10 GPa or less, and even more preferably 1 GPa or less.

Further, it is preferable that the Young's modulus of the connecting layer connecting the tubular bodies is less than 6.3 MPa. By doing so, the tubular molded body can exhibit flexibility against deformation such as refraction and curvature and can be deformed following the deformation, and the occurrence of kink of the tubular molded body can be suppressed. .. This is preferable because it can protect the tissue in the tubular body from pressure. On the other hand, if the Young's modulus of the connecting layer is too low, the connecting strength becomes insufficient, and the tubular body is dissociated during refraction or bending of the tubular molded body, and crushing or kinking occurs at the connecting portion. The Young's modulus of the connecting layer is not limited, but is preferably 1 MPa or more.

The tubular molded body for medical devices of the present invention can be suitably used for medical devices, particularly nerve regeneration induction tubes. Therefore, in the following, details will be described by taking a nerve regeneration induction tube using the molded product of the present invention as an example.

(Embodiment)
The nerve regeneration induction tube according to the embodiment of the present invention is composed of a plurality of tubular bodies and a connecting layer connecting the plurality of tubular bodies.

The connecting layer preferably covers the entire connecting portion, and more preferably covers the entire tubular molded body for medical devices so that the fibrous tissue or cells do not invade through the gaps between the connecting portions.

By having a structure in which a plurality of cylindrical bodies are connected by a connecting layer, the tubular bodies on both sides of the connecting portion become movable, and flexibility and suppression of kink generation become possible. The number of connecting portions included in the tubular molded body for medical devices is preferably one or more, and more preferably four or more in order to sufficiently suppress the generation of kink. From the viewpoint of reducing the durability of the tube, the number of connecting portions is preferably 100 or less.

In a tubular molded body for medical equipment, the inner diameter A of one of the adjacent tubular bodies A is larger than the outer diameter B of the other tubular body B, and the cylinder is inside the tubular body A. In the embodiment in which the connecting portion is configured so that the body B can be inserted, the tubular body B is inserted into the tubular body A when a pressure for compressing in the long axis direction of the molded body is generated. It is preferable because it can buffer the pressure. Let X be the length of the portion where the tubular body B is inserted into the tubular body A. Let Y be the length of the tubular body A that is not inserted into the tubular body B. Of the tubular body B, the length not inserted into the tubular body A is Z. It is preferable that X is larger than 0 in order to prevent the tubular body B and the tubular body A from being inserted into the tubular body A due to the deviation between the centers of the tubular body B and the tubular body A in the tubular body. Further, since the portion where the tubular body B moves in the tubular body A is the buffer region, the sum of the smaller values of Y and Z at each connecting portion is the length of the cylindrical molded body for medical instruments. It is preferably 5% or more, and preferably 50% or less.

The lengths of the plurality of tubular bodies constituting the tubular molded body for medical instruments may be uniform, or tubular bodies having different lengths may be used. The length of the tubular body is preferably 10 mm or less from the viewpoint of exhibiting flexibility when the tubular molded body for medical equipment is curved and suppressing the occurrence of kink. From the viewpoint of strengthening the connecting strength by the connecting layer, the length of the tubular body is preferably 1.0 mm or more.

The inner diameter of the tubular molded body for medical instruments of the present invention is preferably selected according to the site to be used. For example, in the case of a nerve regeneration induction tube, it is preferably 20 mm to 0.5 mm. Further, the inner diameters of both ends of the tubular molded body for medical equipment are not limited to the same. Since there is a difference in the inner diameters at both ends, it is easy to connect nerves having different thicknesses on the central side and the peripheral side, and it is possible to prevent the thin peripheral nerves from falling off. The difference between the inner diameter of one end and the inner diameter of the other end of the molded product of the present invention, that is, the difference between the inner diameters of both ends is preferably 0 mm or more and 20 mm or less.

The higher the strength of the tubular molded body for medical instruments, the more the protrusion accident can be suppressed. Therefore, the Young's modulus of the tubular body is preferably 6.3 MPa or more. On the other hand, since the flexibility of the tubular molded product for medical devices is exhibited by the connecting layer, the Young's modulus of the connecting layer is preferably less than 6.3 MPa. The Young's modulus of the tubular body can be measured by cutting out the corresponding portion from the tubular molded body and performing a tensile test described later. The Young's modulus of the connecting layer can be measured by performing a tensile test on the tubular molded body as described in Measurement Example 8 described later. As another method, the Young's modulus of the linking layer can also be measured by dissolving the polymer used for the linking layer in a solvent as described in Measurement Example 3 described later to produce a film, and pulling the film for a tensile test.

In the tubular molded body for medical instruments of the present invention, when an external force is applied due to bending or refraction, the soft connecting layer expands or contracts, which enables flexibility and suppression of kink generation. It is desirable to spontaneously restore to length. Therefore, it is preferable to use a material having resilience for the connecting layer. Restorability can be quantitatively evaluated by determining the work load preservation rate as in Measurement Example 5 described later. The work load preservation rate is the work load at the time of the first operation when the operation of applying a tensile stress in the longitudinal direction of the tubular molded body to generate a tensile strain of 100% with respect to the initial length is repeated 10 times. It is the ratio of the amount of work at the time of the 10th operation, and can be specifically calculated by the method described in Measurement Example 5 described later. The closer the work load preservation rate of the material used for the connecting layer is to 100%, the easier it is for the compact to recover after pressure buffering. Since the molded body used proximal to the muscle is frequently deformed, the work load preservation rate of the tubular molded body for medical instruments of the present invention is preferably 55% or more, and large deformation frequently occurs due to bending or bending of joints or the like. The workload storage rate of the tubular body used for the site is more preferably 60% or more.

Tensile strength is a factor that is directly linked to the breaking strength of the tubular molded product. Assuming that it is used for a part that receives an external force due to deformation such as expansion or contraction of muscle, the tensile strength of the tubular molded body is preferably 5 MPa or more. The tubular molded body used for a portion where more severe deformation such as refraction or curvature occurs preferably has a tensile strength of 20 MPa or more.

Break elongation is a factor that indicates the breaking strength of a tubular molded product. Assuming that it is used in a portion that receives an external force due to muscle expansion, contraction, vibration, or the like, the breaking elongation of the tubular molded body is preferably 200% or more. The tubular molded body used for a portion where more severe deformation such as refraction or curvature occurs preferably has a breaking elongation of 500% or more. It is more preferable that the elongation at break is 1000% or more in a tubular molded body used for a portion such as a joint where a particularly large deformation occurs due to refraction or curvature. The elongation at break is a value measured according to JIS K6251 (2010) (indicated as "elongation during cutting" in JIS), and specifically, it shall be measured by a tensile test described later.

Further, since the tubular molded body for medical devices of the present invention is used by being placed inside and outside the living body, it is assumed that it receives repeated force due to the movement of muscles and joints and repeatedly deforms and restores. Therefore, the present molded product is required to have durability against repeated deformation. Durability can be quantitatively evaluated by measuring the permanent strain generated when measuring the work preservation rate. Since the tubular body used proximal to the muscle is frequently deformed, the tubular molded body has a permanent strain of 20% or less, and is used for a part such as a joint where large deformation frequently occurs due to bending or bending. The permanent strain of is preferably 15% or less.

The tubular molded body for medical instruments of the present invention is preferable because it can exhibit bioabsorbability by containing bioabsorbable polyester. As long as the degree of bioabsorbability required for each application is exhibited, the blending ratio is not limited, but in general, it is preferable to contain bioabsorbable polyester in an amount of 50% by weight or more of the tubular molded product, 80%. It is more preferable to include% by weight or more. When it is required to completely disappear when applied to a living body, it is preferably composed of only bioabsorbable polyester.

Since the tubular molded body for medical instruments of the present invention contains a bioabsorbable polyester, it is preferable that the tubular molded body constituting the tubular molded body contains a bioabsorbable polyester.

Here, bioabsorbability is a property that, after being placed inside or outside the living body, is naturally decomposed by a hydrolysis reaction or an enzymatic reaction, and disappears when the decomposed product is metabolized or excreted. Examples of such bioabsorbable polyesters include polyglycolic acid, polylactic acid (D, L, DL form), polyε-caprolactone, polyhydroxybutyrate, polyhydroxybutyrate valeric acid, polyorthoester, and polyhydroxyvaleryric acid. , Polyhydroxyhexanoic acid, polyhydroxybutanoic acid, butylene polysuccinate, polybutylene succinate, trimethylene polyterephthalate, polyhydroxyalkanoate, and polyesters selected from the group consisting of copolymers thereof. Among them, it is more preferable that the tubular body contains any one of polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, and a copolymer of polyglycolic acid and polyε-caprolactone.

In a preferred embodiment, the connecting layer comprises, as the bioabsorbable polyester, a polyester copolymer having a monomer residue selected from a hydroxycarboxylic acid residue and a lactone residue as a main constituent unit, and in a more preferred embodiment, the hydroxycarboxylic acid residue. It contains a polyester copolymer having two types of monomer residues, a group and a lactone residue, as main constituent units. Lactone is a cyclic compound in which a hydroxy group and a carboxyl group of a hydroxycarboxylic acid are intramolecularly dehydrated and condensed.

Here, using a certain monomer residue as the "main constituent unit" means that the monomer residue is 50 mol% or more of the total number of residues of the polymer including other monomer residues. .. Further, the two types of monomer residues are used as the "main constituent unit", which means that the sum of the numbers of the two types of monomer residues is 50 mol% of the total number of residues of the polymer including the other monomer residues. This means that each of the two types of residues is 20 mol% or more of the total number of residues in the polymer.

For example, the main constituent unit is a hydroxycarboxylic acid residue and a lactone residue, which means that the sum of the number of hydroxycarboxylic acid residues and the number of lactone residues is 50 mol% or more of the total number of residues in the polymer. It means that the hydroxycarboxylic acid residue is 20 mol% or more of the total number of residues of the polymer, and the lactone residue is 20 mol% or more of the total number of residues of the polymer. The mole fraction of each monomer residue can be determined from the area value of the signal derived from each residue by nuclear magnetic resonance (NMR) measurement. For example, when the hydroxycarboxylic acid residue is a lactic acid residue and the lactone residue is a caprolactone residue, it can be measured by the method described in Measurement Example 2 described later.

Aliphatic hydroxycarboxylic acid is particularly preferable as the monomer for forming the hydroxycarboxylic acid residue. Examples of the aliphatic hydroxycarboxylic acid include lactic acid, glycolic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxypentanoic acid, hydroxycaproic acid, hydroxyheptanic acid and the like, and lactic acid, glycolic acid and hydroxycaproic acid are particularly preferable. As lactic acid, L-lactic acid, D-lactic acid, and a mixture thereof can be used. From the viewpoint of physical properties and biocompatibility of the obtained polymer, it is preferable to use lactic acid, and it is more preferable to use L-lactic acid. When a mixture is used as the monomer, the L-form content is preferably 85 mol% or more, and more preferably 95 mol% or more.

As a monomer for forming a hydroxycarboxylic acid residue, lactide, which is a cyclic compound in which the hydroxy groups and carboxyl groups of two molecules of hydroxycarboxylic acid are dehydrated and condensed, may be used. As the lactide, dilactide in which two lactic acid molecules are dehydrated and condensed, glycolide in which two glycolic acid molecules are dehydrated and condensed, and tetramethylglycolide can be used.

Examples of the monomer for forming the lactone residue include ε-caprolactone, dioxepanone, ethyleneoxalate, dioxanone, 1,4-dioxane-2,3-dione, β-propiolactone, δ-valerolactone, and β-. Examples thereof include propiolactone, β-butyrolactone, γ-butyrolactone and pivalolactone.

Further, the derivative of the monomer exemplified above can also be used.

In the present specification, the "monomer residue" contained in the polyester copolymer is, in principle, a repetition of the chemical structure derived from the monomer in the chemical structure of the polyester copolymer obtained from the polymerization stock solution containing the monomer. Say the unit. For example, lactic acid (CH ₃ CH (OH) COOH) and ε-caprolactone (formula below).

When and are polymerized to form a copolymer of lactic acid and caprolactone, the unit represented by the following formula

Is a lactic acid monomer residue, and the unit represented by the following formula is a ε-caprolactone monomer residue.

As an exception, when a dimer such as lactide is used as the monomer, the "monomer residue" means one of the two-fold repeating structures derived from the dimer. For example, dilactide (L- (-)-lactide: formula below)

When ε-caprolactone and ε-caprolactone are polymerized, the chemical structure of the copolymer forms a structure in which the structure represented by the above formula (R1) is repeated twice as a dilactide residue. In this case, one of them is formed. It is assumed that the lactic acid unit is regarded as a "monomer residue" and that two "monomer residues", that is, two lactic acid residues are formed from dilactide.

The weight average molecular weight of the bioabsorbable polyester used in the present invention is preferably 100,000 or more in order to obtain the effect of improving the tensile strength due to the entanglement of the polymer chains. The upper limit is not particularly limited, but is preferably 1.6 million or less, more preferably 800,000 or less, still more preferably 400,000 or less, considering the problem of the production method due to the increase in viscosity and the decrease in moldability. The weight average molecular weight can be determined by a gel permeation chromatography (GPC) method, and specifically, it is determined by the method described in Measurement Example 1 described later.

Hereinafter, a polyester copolymer containing a hydroxycarboxylic acid residue and a lactone residue as main constituent units, which are particularly preferable bioabsorbable polyesters in the present invention, will be described.

In the polyester copolymer, the sum of the hydroxycarboxylic acid residue and the lactone residue is, from the above definition, 50 mol% or more, preferably 75 mol% or more, of the total polymer including other monomer residues. , 90 mol% or more is more preferable. Further, the hydroxycarboxylic acid residue and the lactone residue are 20 mol% or more, preferably 30 mol% or more, and more preferably 40 mol% or more, respectively, from the above definition. A polymer in which the sum of the hydroxycarboxylic acid residue and the lactone residue is 100% of the whole polymer, that is, the polymer consisting only of the hydroxycarboxylic acid residue and the lactone residue is mentioned as a particularly preferable embodiment.

The molar ratio of hydroxycarboxylic acid residue to lactone residue is preferably 7/3 to 3/7, more preferably 6/4 to 4 because the presence of one in excess approaches homopolymer-like properties. / 6.

Further, another monomer that can be copolymerized with the hydroxycarboxylic acid and the lactone can be further copolymerized. It is a preferred embodiment to copolymerize a monomer that functions as a linker. Examples of the monomer that functions as a linker include a hydroxycarboxylic acid other than the hydroxycarboxylic acid constituting the main constituent unit, a dialcohol, a dicarboxylic acid, an amino acid, a diamine, a diisocyanate, and a diepoxide. In the present specification, by including a monomer unit other than hydroxycarboxylic acid and lactone in the constituent unit, the "polyester copolymer" includes a copolymer containing a constituent unit partially linked by a bond other than an ester bond. It shall be written.

The polyester copolymer is obtained by copolymerizing a monomer forming a hydroxycarboxylic acid residue (referred to as "monomer A") and a monomer forming a lactone residue (referred to as "monomer B") in an equimolar amount. when the initial rate of polymerization was used as _V a, _{V B,} respectively, it is preferable that satisfy _{_{1.1 ≦ V a / V B ≦}} 40.

Here, V _A and V _B are obtained by the following method. Monomer A and Monomer B are equimolarally mixed, a solvent and a catalyst are added as necessary, and the R value is the same as that of the polyester copolymer finally synthesized or to be synthesized within a range of 10% error. Conditions such as temperature are adjusted so that the R value is obtained, and the polymerization reaction is started. Sampling is periodically performed from the sample being polymerized, and the remaining amount of monomer A and monomer B is measured. The remaining amount is measured, for example, by chromatography or nuclear magnetic resonance (NMR) measurement. By subtracting the remaining amount from the charged amount, the amount of the monomer used in the polymerization reaction can be obtained. When the amount of monomer subjected to the polymerization reaction is plotted against the sampling time, the initial gradients of the curve are V _A and V _B.

When such a monomer A and the monomer B are reacted, there is a high probability that the monomer A will be bonded to the polymer terminal during the polymerization at the initial stage of the polymerization. On the other hand, in the late stage of polymerization in which the monomer A is consumed and the concentration of the monomer A in the reaction solution decreases, the probability that the monomer B binds to the polymer terminal during the polymerization increases. As a result, a gradient polymer is obtained in which the proportion of the monomer A residue is high at one end and the proportion of the monomer A residue gradually decreases toward the other end. Such a gradient polymer has low crystallinity and suppresses an increase in Young's modulus. In order to facilitate the formation of such a gradient structure, _VA / V _B is more preferably 1.3 or more, and even more preferably 1.5 or more. On the other hand, if the difference in polymerization rate between monomer A and monomer B is too large, the structure is similar to that of a block polymer in which monomer B is polymerized after only monomer A is polymerized, and the crystallinity may be increased, leading to an increase in Young's modulus. Therefore, _VA / V _B is more preferably 30 or less, further preferably 20 or less, and even more preferably 10 or less.

Preferred combinations of such monomer A and monomer B include dilactide and ε-caprolactone, glycolide and ε-caprolactone, dilactide and dioxepanone, dilactide and δ-valerolactone, and glycolide and δ-valerolactone.

Further, the polyester copolymer contained in the connecting layer preferably satisfies the following conditions (A) and (B). The mole fraction in the polyester copolymer is a percentage of the total 100% of the monomer residues that make up the polyester copolymer.

Condition (A) R value is 0.45 or more and 0.99 or less.

R value = [AB] / (2 [A] [B]) x 100
[A]: Mole fraction (%) of hydroxycarboxylic acid residues in the polyester copolymer
[B]: Mole fraction (%) of lactone residue in polyester copolymer
[AB]: Mole fraction (%) of the structure (AB, and BA) in which the hydroxycarboxylic acid residue and the lactone residue are adjacent to each other in the polyester copolymer.
Condition (B) The crystallization rate of at least one of the hydroxycarboxylic acid residue and the lactone residue is less than 14%.

The R value is used as an index showing the randomness of the sequence of the monomer residues in the copolymer having two kinds of monomer residues, that is, the hydroxycarboxylic acid residue and the lactone residue as the main constituent units. For example, a random copolymer with a completely random monomer sequence has an R value of 1. Further, in the block copolymer, the R value is 0 to 0.44.

The R value can be determined by quantifying the ratio of the combination of two adjacent monomers (AA, BB, AB, BA) by nuclear magnetic resonance (NMR) measurement. Specifically, it is assumed that the measurement is performed by the method described in Measurement Example 2 described later. When the R value is less than 0.45, the crystallinity is high, the molded product of the copolymer becomes hard, and the Young's modulus increases. On the other hand, when the R value exceeds 0.99, the copolymer molded product becomes too soft and becomes sticky, and the handleability is lowered. From the same viewpoint, the R value of the polyester copolymer used in the present invention is preferably 0.50 or more, and preferably 0.80 or less.

It is also known that the crystallinity of the polymer has a great influence on the mechanical strength of the molded product. In general, low crystallinity polymers exhibit low Young's modulus, so low crystallinity is desirable for flexibility. The crystallization rate of the polymer is determined from the heat of fusion by differential scanning calorimetry (DSC) measurement.

In the polyester copolymer, the crystallization rate of at least one of the hydroxycarboxylic acid residue and the lactone residue is preferably less than 14%. When the crystallization rate is less than 14%, an increase in Young's modulus is suppressed, and a polyester copolymer suitable for a tubular body can be obtained. The crystallization rate of the hydroxycarboxylic acid residue and / or the lactone residue is more preferably 10% or less, and further preferably 5% or less.

The crystallization rate of the monomer residue referred to here is the per unit weight of the monomer residue in the polyester copolymer when the heat of fusion per unit weight of the homopolymer consisting of only a certain monomer residue is 100%. It is a relative value of heat of fusion. Specifically, the crystallization rate of a hydroxycarboxylic acid residue is the product of the heat of fusion per unit weight of the homopolymer consisting only of the hydroxycarboxylic acid and the weight fraction of the hydroxycarboxylic acid residue in the polyester copolymer. As the denominator, the ratio calculated as the numerator of the heat of fusion per unit weight of the polyester copolymer of the residue, which is obtained from the melting peak derived from the hydroxycarboxylic acid residue detected when the heat of fusion of the polyester copolymer is measured. Is. The crystallization rate of the hydroxycarboxylic acid residue and the lactone residue in the polyester copolymer indicates the ratio of forming the crystal structure in each of the hydroxycarboxylic acid residue and the lactone residue forming the copolymer. Specifically, the crystallization rate shall be determined by the method described in Measurement Example 4 described later.

Furthermore, since the present invention is used by indwelling in the body, it is preferably a bioabsorbable polyester copolymer having a high track record of clinical safety. That is, it is preferable that the link layer contains a dilactide / ε-caprolactone copolymer, and the dilactide / ε-caprolactone copolymer satisfies the following conditions (C) and (D). The mole fraction in the dilactide / ε-caprolactone copolymer is the percentage of the dilactide / ε-caprolactone copolymer to 100% of the total dilactide and ε-caprolactone residues.

Condition (C) R value is 0.45 or more and 0.99 or less.

R value = [AB] / (2 [A] [B]) x 100
[A]: Mole fraction (%) of dilactide residues in the dilactide / ε-caprolactone copolymer
[B]: Mole fraction (%) of ε-caprolactone residue in dilactide / ε-caprolactone copolymer
[AB]: Mole fraction (%) of the structure (AB and BA) in which the dilactide residue and the ε-caprolactone residue are adjacent to each other in the dilactide / ε-caprolactone copolymer.
Condition (D) At least one of the dilactide residue and the ε-caprolactone residue has a crystallization rate of less than 14%.

In the polyester copolymer as described above, for example, monomer A forming a hydroxycarboxylic acid residue and monomer B forming a lactone residue are completely left with the sum of the hydroxycarboxylic acid residue and the lactone residue at the completion of polymerization. Macromer synthesis step in which 50 mol% or more of the groups and 20 mol% or more of each of the hydroxycarboxylic acid residues and the lactone residues are mixed and polymerized;
A mulching step of linking the macromers obtained in the macromer synthesis step or adding hydroxycarboxylic acid and lactone to the macromer solution obtained in the macromer synthesis step to mulch;
It can be produced by a synthetic method having.

In the macromer synthesis step, the sum of the hydroxycarboxylic acid residue and the lactone residue is 50 mol, which is theoretically the sum of the hydroxycarboxylic acid residue and the lactone residue when the polymerization of the monomer A forming the hydroxycarboxylic acid residue and the monomer B forming the lactone residue is completed. % Or more, and the hydroxycarboxylic acid residue and the lactone residue are 20 mol% or more of the total residues, respectively, and the polymerization is carried out. As a result, a polyester copolymer containing a hydroxycarboxylic acid residue and a lactone residue as main constituent units can be obtained. The polyester copolymer produced is referred to as "macromer".

The randomness of the distribution of hydroxycarboxylic acid residues and lactone residues changes depending on the difference in the reactivity of the monomers during polymerization. That is, at the time of polymerization, if the same monomer and the other monomer are bonded to each other with the same probability after one of the two types of monomers, a random copolymer in which the monomer residues are completely randomly distributed can be obtained. However, if one of the monomers tends to be followed by one of the monomers, a gradient copolymer having a biased distribution of monomer residues can be obtained. In the obtained gradient copolymer, the composition of the monomer residues is continuously changed from the polymerization initiation end to the polymerization termination end along the molecular chain.

Here, since hydroxycarboxylic acid is generally a monomer having a higher initial polymerization rate than lactone, when hydroxycarboxylic acid and lactone are copolymerized in the macromer synthesis step, hydroxycarboxylic acid is likely to be bonded after hydroxycarboxylic acid. .. Therefore, in the synthesized macromer, a gradient structure is formed in which the proportion of the hydroxycarboxylic acid unit gradually decreases from the polymerization initiation end to the polymerization termination end. That is, the macromer obtained in this step becomes a macromer having a gradient structure in which the hydroxycarboxylic acid residue and the lactone residue form a composition gradient in the skeleton due to the difference in the initial polymerization rate between the hydroxycarboxylic acid and the lactone. Such a macromer may be referred to as a "gradient macromer" in the present specification.

In the macromer synthesis step, in order to realize such a gradient structure, it is desirable to synthesize macromer by a polymerization reaction that occurs in one direction from the start end. As such a synthetic reaction, it is preferable to use ring-opening polymerization or living polymerization.

The macromer obtained in this step has the same R value as the above condition (A) in order to facilitate the production of a polyester copolymer finally satisfying the R value shown in the above condition (A), that is, the following formula R. Value = [AB] / (2 [A] [B]) x 100
[A]: Mole fraction (%) of hydroxycarboxylic acid residues in macromer
[B]: Mole fraction (%) of lactone residue in macromer
[AB]: Mole fraction (%) of the structure (AB, and BA) in which the hydroxycarboxylic acid residue and the lactone residue are adjacent to each other in the macromer.
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.

Similarly, the macromer obtained in this step facilitates the production of a polyester copolymer having the crystallization rate of the hydroxycarboxylic acid residue or the lactone residue shown in the above condition (B). ), That is, the crystallization rate of at least one of the hydroxycarboxylic acid residue and the lactone residue is preferably less than 14%, and more preferably 10% or less. It is preferably 5% or less, more preferably 1% or less, and most preferably 1% or less.

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. Further, in order to suppress crystallinity and maintain flexibility, it is preferably 150,000 or less, and more preferably 100,000 or less.

In the mulching step, the macromers obtained in the macromer synthesis step are linked to each other, or hydroxycarboxylic acid and lactone are additionally added to the macromer solution obtained in the macromer synthesis step to mulch. In this step, the macromers obtained in one macromer synthesis step may be linked to each other, or a plurality of macromers obtained in two or more macromer synthesis steps may be linked. In addition, "multiplying" means forming a structure in which a plurality of molecular chains having a gradient structure in which a hydroxycarboxylic acid residue and a lactone residue have a composition gradient in the skeleton are repeated by any of these methods. Means.

The number of macromer units to be mulched may be 2 or more, but if the number of connections is large, the effect of improving the tensile strength due to the entanglement of the molecular chains is obtained, so that the number is preferably 3 or more, and 4 or more. Is more preferable, and 6 or more is further preferable. On the other hand, if the molecular weight of the polyester copolymer is excessively increased as a result, there is a concern that the increase in viscosity may adversely affect the moldability. Therefore, the number of macromer units is preferably 80 or less, more preferably 40 or less. , 20 or less is more preferable.

The number of connected macromers can be adjusted according to the catalyst used in the mulching process and the reaction time. When the macromers are connected to each other for mulching, the number of macromer units can be obtained by dividing the weight average molecular weight of the finally obtained polyester copolymer by the weight average molecular weight of the macromer.

The polyester copolymer may be a linear polymer in which macromer units are linearly linked, or may be a branched chain polymer in which the macromer units are branched and linked.

A linear polyester copolymer can be synthesized, for example, by binding one molecule of the same gradient macromer to both ends of the gradient macromer via the ends.

When the gradient macromer has a hydroxyl group and a carboxyl group at each end, a mulched polyester copolymer can be obtained by condensing the ends with a condensing agent. Condensing agents include 4,4-dimethylaminopyridinium p-toluenesulfonate, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. , N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N'-carbonyldiimidazole, 1,1'-carbonyldi (1,2,4-triazole), 4- (4,6- Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium = chloride n hydrate, trifluoromethanesulfonic acid (4,6-dimethoxy-1,3,5-triazine-2-yl) )-(2-Octoxi-2-oxoethyl) dimethylammonium, 1H-benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 1H-benzotriazole-1-yloxytripyrrolidinophosphonium Hexafluorophosphate, (7-azabenzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, bromotris (dimethylamino) phosphonium hexafluorophosphate Salt, 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one, O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyl Uronium hexafluorophosphate, O- (7-azabenzotriazole-1-yl) -NN, 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-benzotriazine-3-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate, S- (1-oxide- 2-Pyridyl) -N, N, N', N'-Tetramethylthiuronium tetrafluoroborate, O- [2-oxo-1 (2H) -Pyridyl] -N, N, N', N' -Tetramethyluronium tetrafluoroborate, {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium Xafluorophosphate, 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate, 1- (chloro-1-pyrrolidinyl methylene) pyrrolidinium hexafluorophosphate, 2-fluoro-1 , 3-Dimethylimidazolinium hexafluorophosphate, fluoro-N, N, N', N'-tetramethylform amidineium hexafluorophosphate and the like can be used.

Further, when the polymerization reaction has a living property, that is, when the polymerization reaction can be started continuously from the end of the polymer, hydroxycarboxylic acid and lactone are additionally added to the gradient macromer solution after the polymerization reaction is completed. By repeating the operation, it can be multi-layered.

Alternatively, the gradient macromers may be mulched via a linker as long as they do not affect the mechanical properties of the polymer. In particular, linkers having multiple carboxyl groups and / or multiple hydroxy groups, such as 2,2-bis (hydroxymethyl) propionic acid, can be used to synthesize branched polyester copolymers in which the linker is a branch point. Can be done.

The polyester copolymer obtained by the above-mentioned production method is a copolymer having a structure in which two or more macromer units having a composition gradient in the skeleton of hydroxycarboxylic acid residues and lactone residues are linked. In the present specification, such a structure may be referred to as "multi-gradient" for convenience, and a copolymer having a multi-gradient structure may be referred to as "multi-gradient copolymer". The multigradient copolymer preferably has a structure in which two or more macromer units having a gradient structure in which the hydroxycarboxylic acid residue and the lactone residue form a composition gradient in the skeleton are linked, and three or more are linked. It is preferable to have.

As described above, a polyester copolymer in which the hydroxycarboxylic acid residue is a lactic acid residue and the lactone residue is a caprolactone residue or a valerolactone residue is a particularly preferable embodiment for application to a connecting layer. Such a polyester copolymer is preferably produced by the following production method.

First, in the macromer synthesis step, dilactide and ε-caprolactone (or valerolactone; the same applies hereinafter) are polymerized in the presence of a catalyst. Dilactide, ε-caprolactone monomer, is preferably purified to remove impurities prior to use. Purification of dilactide is possible, for example, by recrystallization from toluene dried with sodium. ε-Caprolactone is purified by vacuum distillation, for example, from CaH ₂ to N _{2 atmosphere.}

The reactivity of dilactide with ε-caprolactone is significantly different as described in the literature (DW Grjpmaetal. Polymer Bulletin 25, 335, 341), with dilactide monomers having a higher initial polymerization rate than ε-caprolactone. _{V A} of the dilactide, when indicated by the reaction rate (%) was 3.6% / h, the _{V B} of ε- caprolactone, a 0.88% / _h, V A / _{V B} is 4.1 Become. Therefore, the macromer obtained by copolymerizing dilactide and ε-caprolactone is a gradient macromer.

As a catalyst for the macromer synthesis step having a lactic acid residue and a caprolactone residue, a polyester polymerization catalyst such as a normal germanium-based, titanium-based, antimony-based, or tin-based catalyst can be used. Specific examples of such a polyester polymerization catalyst include tin octylate, antimony trifluoride, zinc powder, dibutyltin oxide, tin oxalate and the like. The method of adding the catalyst to the reaction system is not particularly limited, but it is preferably a method of adding the catalyst in a state of being dispersed in the raw material at the time of charging the raw material or in a state of being dispersed in the raw material at the start of depressurization. The amount of the catalyst used is 0.01 to 3% by weight, more preferably 0.05 to 1.5% by weight, in terms of metal atoms, based on the total amount of the monomers used.

Macromer having a lactic acid residue and a caprolactone residue can be obtained by putting dilactide, caprolactone and a catalyst in a reaction vessel equipped with a stirrer and reacting them at 150 to 250 ° C. under a nitrogen stream. When water is used as the co-initiator, it is preferable to carry out a co-catalytic reaction at around 90 ° C. prior to the polymerization reaction. The reaction time is preferably 2 hours or more, preferably 4 hours or more, and more preferably a longer time, for example, 8 hours or more in order to increase the degree of polymerization. However, if the reaction is carried out for an excessively long time, a problem of polymer coloring occurs, so the reaction time is preferably 3 to 12 hours.

Next, in the mulching step, the ends of the gradient macromer having a lactic acid residue and a caprolactone residue are connected to each other by a condensation reaction to mulch. The reaction temperature of the condensation reaction is preferably 10 to 100 ° C, more preferably 20 to 50 ° C. The reaction time is preferably 1 day or longer, more preferably 2 days or longer. However, if the reaction is carried out for an excessively long time, a problem of polymer coloring occurs, so the reaction time is preferably 2 to 4 days.

<Cylindrical body>
The tubular body constituting the tubular molded body for medical instruments of the present invention preferably contains the above-mentioned biodegradable polymer fiber. Examples of the structure of the tubular body include knitting, weaving, orientation, and non-woven fabric. Among these, a non-woven fabric structure is preferable. In the non-woven fabric structure, the fibers are three-dimensionally and irregularly entangled with each other, so that the number of voids increases, and the effect of improving the permeability by increasing the fiber diameter is more remarkable.

As a method for producing a tubular body, a polymer as described above can be used, and the tubular body can be molded into a tubular shape by using a melt molding method or a solvent molding method. The melt molding method is a method in which a polymer is heated and melted, and molded using a mold, an extrusion molding machine, a press machine, electrospinning, melt blow, or the like. For example, the polymer can be formed into a cylindrical shape by heating the polymer to 200 ° C. in an extrusion molding machine in which a core inlet metal having a diameter of 0.5 to 4 mm is set and extruding the polymer. The solvent molding method is a method in which a polymer is dissolved in a solvent, injected into a mold or a coagulation bath, and molded by separating the solvent and the solute, or an electrospinning method or a spray method. As an example of the solvent molding method, a rod of φ0.5 to 4 mm is immersed in a polymer solution dissolved in chloroform at 20%, pulled up, waited for the solvent to volatilize, and then immersed again about 5 to 10 times. As a result, it can be molded into a tubular shape. It is also possible to form a cylinder by depositing fibers in a cylinder using an electrospinning method on a rod having a diameter of 0.5 to 4 mm.

By cutting the tubular molded body thus obtained with a razor or the like, a tubular body having a desired length can be obtained.

The thickness of the tubular body is preferably 100 μm or more, more preferably 200 μm or more, from the viewpoint of improving the strength. Here, the thickness of the tubular body can be measured by magnifying and observing the cross section of the tubular body using a microscope. The thickness of the tubular body can be adjusted to a desired range by, for example, the spinning time by the electrospinning method.

<Manufacturing method of tubular molded product>
For example, it is possible to connect two tubular bodies by applying a material constituting a connecting layer to a plurality of tubular bodies manufactured as described above to manufacture the tubular molded body for medical instruments of the present invention. can. Examples of the method for applying the connecting layer include an electrospinning method.

As an example of the manufacturing method, (1) the bioabsorbable polymer constituting the tubular body is formed into fibers by the electrospinning method and accumulated in the collector, (2) the tubular body is collected together with the collector, and any Make a notch in the direction of rotation of the collector with a razor or the like, and set the fiber aggregate with the notch obtained in step (3) step (2) again in the electrospinning device to form the connecting layer. Examples thereof include a method in which a polymer is formed into fibers by an electrospinning method and accumulated on a tubular body.

The obtained molded body can be used as a nerve regeneration induction tube that protects nerve regeneration by attaching it to both ends of the torn nerve.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention should not be construed as being limited to those Examples, and can be conceived and implemented by those skilled in the art who are familiar with the concept of the present invention. It should be understood that any technical idea and its specific aspects, which would be considered to be, are included in the present invention.

[Measurement Example 1: Measurement of Weight Average Molecular Weight by Gel Permeation Chromatography (GPC)]
Device 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 (φ7.8mmX300mm; manufactured by Tosoh Corporation)
Detector: UV (254 nm), RI
Column, detector temperature: 35 ° C
Standard substance: Polystyrene The purified polymer is dissolved in chloroform, passed through a 0.45 μm syringe filter (DISMIC-13HP; manufactured by ADVANTEC) to remove impurities, etc., and then measured by GPC to measure the weight average molecular weight of the polymer. Was calculated.

[Measurement Example 2: Measurement of mole fraction and R value of each residue by nuclear magnetic resonance (NMR)]
The purified polymer was dissolved in deuterated chloroform and ^{measured by 1} H-NMR to calculate the ratio of the lactic acid monomer residue and the caprolactone monomer residue in the polymer. ^{Further, 1} by H homo spin decoupling method, (near 5.10Ppm) methylene group of lactic acid, (around 2.35 ppm) alpha-methylene group of caprolactone, the ε methylene group (around 4.10 ppm), monomeric adjacent residues Whether it was derived from lactic acid or caprolactone was separated by a signal, and the peak area of each was quantified. [A], [B], and [AB] were calculated from the respective peak area ratios, and the R value was calculated.
Device name: JNM-EX270 (manufactured by JEOL Ltd.)
¹ H homospin decoupling irradiation position: 1.66 ppm
Solvent: Deuterated chloroform Measurement temperature: Room temperature R value = [AB] / (2 [A] [B]) × 100
[A]: Mole fraction (%) of lactic acid monomer residue in the polymer
[B]: Mole fraction (%) of caprolactone monomer residue in the polymer
[AB]: Mole fraction (%) of the structure (AB, and BA) in which the lactic acid monomer residue and the caprolactone monomer residue are adjacent to each other in the polymer.

[Measurement example 3: Tensile test]
The polymer was dried under reduced pressure and dissolved in chloroform to a concentration of 5% by weight. The solution was transferred onto a Teflon petri dish and dried at normal pressure and room temperature for a whole day and night. This was dried under reduced pressure to obtain a film.

A dried film (thickness of about 0.1 mm) was cut into a size of 50 mm × 5 mm, and a tensile test was measured with a desktop tensile tester (EZ-LX manufactured by SHIMAZU) according to JIS K6251 (2010) under the following conditions. Degrees and tensile strengths were calculated. Further, in the graph plotting the stress with respect to the displacement, the slope of the linear equation that can be approximated from the data of 5 points from the start of stress generation was calculated as Young's modulus.
Equipment name: Desktop tensile tester (SHIMAZU EZ-LX)
Initial length: 10 mm
Tensile rate: 500 mm / min
Load cell: 1kN
Number of tests: 5 times.

[Measurement Example 4: Measurement of crystallization rate of lactic acid residue by differential scanning calorimetry (DSC)]
The purified polymer was dried under reduced pressure, dissolved in chloroform so as to have a concentration of 5% by weight, the solution was transferred onto a Teflon petri dish, and the polymer was dried at normal pressure at room temperature for 24 days. This was dried under reduced pressure to obtain a film.

The obtained film was sampled on an alumina PAN, measured under the following conditions by the DSC method with a differential scanning calorimeter, and the heat of fusion was calculated from the measurement results in the range of temperature conditions (D) to (E). The crystallization rate was calculated from the following formula.

Crystallization rate = (heat of fusion of lactic acid residues per unit weight of 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
Device name: EXSTAR 6000 (manufactured by Seiko Instruments Inc.)
Temperature conditions: (A) 25 ° C → (B) 250 ° C (10 ° C / min) → (C) 250 ° C (5 min) → (D) -70 ° C (10 ° C / min) → (E) 250 ° C (10) ° C / min) → (F) 250 ° C (5 min) → (G) 25 ° C (100 ° C / min)
Standard substance: Alumina.

[Measurement Example 5: Measurement of Work Conservation Rate and Permanent Strain]
The purified polymer was dried under reduced pressure, dissolved in chloroform so as to have a concentration of 5% by weight, the solution was transferred onto a Teflon petri dish, and the polymer was dried at normal pressure at room temperature for 24 days. This was dried under reduced pressure to obtain a film.

The film (thickness: about 0.1 mm) was cut into strips (50 mm × 5 mm) and set in a desktop tensile tester (EZ-LX manufactured by SHIMAZU). Under the following conditions, the film is stretched to a tensile length (L) of 10 mm, that is, a tensile strain of 100% with respect _{to an initial length (L 0} ) of 10 mm, and then restored to the _{initial length (L 0).} Repeated times, changes in tensile stress and displacement were recorded.
Equipment name: Desktop tensile tester (SHIMAZU EZ-LX)
Holding time: 1s
Tensile rate: 500 mm / min
Restoration speed: 500 mm / min
Load cell: 1kN
When the stress for displacement (X ₁ , X ₂ , ...) Is (N ₁ , N ₂ , ...), the work (W) that causes 100% tensile strain is the area under the displacement-stress curve. Is equivalent to, and is calculated by the following formula.
W = ΣN _n (X _n −X _n-1 ) where X ₀ = 0.
When the first W is W ₁ and the 10th W is W ₁₀ , the work load preservation rate (%) = W ₁₀ / W ₁ × 100.

As described above, after repeating the stretching and restoring operations 10 times to measure the work preservation rate, when the film is stretched again at the same tensile speed and the changes in tensile stress and displacement are recorded, the amount of displacement at which stress begins to occur is determined. and L _1. The permanent distortion can be calculated by the following formula.
Permanent strain (%) = L ₁ / L ₀ × 100.

[Measurement Example 6: Kink generation suppression test of tubular molded product]
A wire with a total length of 6 cm was prepared. Starting from the center of the wire, 180 ° (the one that remains straight), one that was bent at a 120 ° angle, one that was bent at a 90 ° angle, and one that was bent at a 60 ° angle were prepared.

The created tubular molded body for medical equipment was cut to a length of 40 mm, and the wires created above were passed through the inside and bent into the shape of each wire. After that, when the inner upper parts of both ends of the molded body were pressed against the wire, it was visually observed whether or not kink was generated in the molded body at the corners of each of the prepared wires. The case where kink was observed was recorded as "yes", and the case where no kink was observed was recorded as "no".

[Measurement Example 7: Pressure Resistance Test of Cylindrical Mold]
The total length of the tubular molded product for medical equipment was adjusted to 20 mm, and a compression test was conducted with a tabletop tensile tester (EZ-LX manufactured by SHIMAZU) under the following conditions, and the height became 50% of the initial height. The pressure at the time point was recorded.
Equipment name: Desktop tensile tester (SHIMAZU EZ-LX)
Compression distance: 6mm
Holding time: 1s
Compression rate: 10 mm / min
Load cell: 1 kN.

[Measurement Example 8: Tension Test of Cylindrical Body and Cylindrical Mold]
To measure the Young's modulus of a tubular body, the tubular body before cutting is cut to a length of 20 mm, and a tensile test is carried out with a desktop tensile tester (EZ-LX manufactured by SHIMAZU) under the following conditions, and the Young's modulus is measured. , Elongation rate and breaking strength were determined. The Young's modulus of the tubular molded body was measured in the same manner by cutting the tubular molded body to a length of 20 mm. Since only the connecting layer expands and contracts in the tensile test of the tubular molded body, the Young's modulus, elongation and breaking strength obtained in the tensile test of the tubular molded body are the Young's modulus and elongation of the connecting layer. And treated as breaking strength.
Equipment name: Desktop tensile tester (SHIMAZU EZ-LX)
Initial length (L ₀ ): 10 mm
Tensile speed: 500 mm / min.
Load cell: 1 kN.

<Example 1>
(Making a tubular body)
Poly-L-lactic acid (PLLA) (manufactured by BMG Co., Ltd., Mw = 220,000, Mw / Mn = 1.51) was dissolved in chloroform so as to have a concentration of 20% by weight. The PLLA solution was collected in a 5 mL syringe (Terumo), and an 18 G needle (MECC) dedicated to the MECC spinning device NANON-3 was attached to the syringe. A syringe containing the PLLA solution and a φ4 mm metal mandrel were set in a spinning device NANON-3, and the PLLA solution was spun onto the mandrel by an electrospinning method to obtain a tubular body made of PLLA. The spinning conditions were spinning distance: 15 cm, spinning voltage: 25 kV, spinning speed: 3 mL / hour, rotation speed: 50 to 100 rpm, spinning amplitude: 15 cm, spinning time: 60 minutes. After spinning, the obtained tubular body (before cutting) was vacuum-dried overnight at room temperature together with the mandrel without removing it. The thickness of the PLLA layer forming the tubular body was 487 μm as a result of measurement with a microscope (KH-1300, Hirox Co., Ltd.). After that, without removing the tubular body (before cutting) from the mandrel, using a microtome blade (Feather Safety Razor Co., Ltd., S35TYPE, standard product), the circumferential direction (total circumference) of the tubular body (before cutting) ) Was cut every 5 mm to prepare a tubular body (after cutting).

(Synthesis of polymer for link layer)
The polymer for the link layer was synthesized as follows. 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 collected in a separable flask as monomers. The inside of the flask is placed under an argon atmosphere, and 0.81 g of tin octylate (II) (manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in 14.5 mL of toluene (ultra-dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) as a catalyst. As a co-initiator, ion-exchanged water was added in an amount such that the monomer / co-initiator ratio was 142.9. A co-catalyst reaction was carried out at 90 ° C. for 1 hour, and then a copolymerization reaction was carried out at 150 ° C. for 6 hours to obtain a crude copolymer.

The obtained crude copolymer was dissolved in 100 mL of chloroform and added dropwise to 1400 mL of methanol in a stirred state to obtain a precipitate. After repeating this operation three times, the precipitate was dried under reduced pressure at 70 ° C. to obtain macromer.

7.5 g of the macromer, 0.28 g of the catalyst, 4,4-dimethylaminopyridinium p-toluenesulfonic acid (synthetic product), and 0.10 g of 4,4-dimethylaminopyridine (Wako Pure Chemical Industries, Ltd.) Made) was collected. These were placed in an argon atmosphere, and dichloromethane (dehydrated) (manufactured by Wako Pure Chemical Industries, Ltd.) was added and dissolved so that the concentration became 30%. To this, 0.47 g of amylene (manufactured by Tokyo Chemical Industry Co., Ltd.) dissolved in 5 mL of dichloromethane was added as a condensing agent, and condensation polymerization was carried out at room temperature for 2 days.

30 mL of chloroform was added to the obtained reaction mixture, and the mixture was added dropwise to 500 mL of hexane to which acetic acid was added so as to be 15 mM in a stirred state to obtain a precipitate. This precipitate was dissolved in 50 mL of chloroform and added dropwise to 500 mL of methanol in a stirred state to obtain a precipitate. After repeating this operation twice, a purified polyester copolymer was obtained as a precipitate.

As a result of measuring the obtained purified polyester copolymer by the method described in Measurement Examples 1 to 5, the weight average molecular weight was 240,000, and the copolymerization ratio was lactic acid: caprolactone = 53.0: 47.0 (weight ratio). , R value is 0.60, crystallization rate is 0%, Young's modulus is 2.98 MPa, tensile strength is 33.7 MPa, elongation at break is 1032%, work preservation rate is 57.5%, permanent strain is 20%. Met.

(Manufacturing a tubular molded body for medical equipment (a molded body in which a plurality of tubular bodies are connected by a connecting layer))
The mandrel having the tubular body (after cutting) cut in the above-mentioned "preparation of the tubular body" was set again in the spinning device NANON-3. The polymer for the link layer synthesized as described above was dissolved in chloroform so as to have a concentration of 30% by weight. The polymer solution for the link layer was collected in a 5 mL syringe (Terumo), and an 18 G needle (MECC) dedicated to the MECC spinning device NANON-3 was attached to the syringe. A syringe containing a polymer solution for a connecting layer is set in a spinning device NANON-3, and the polymer solution for a connecting layer is spun onto a mandrel having the tubular body (after cutting) by an electrospinning method. A connecting layer was created on the outside of the tubular body (after cutting). The spinning conditions were spinning distance: 15 cm, spinning voltage: 30 kV, spinning speed: 3 mL / hour, rotation speed: 50 to 100 rpm, spinning amplitude: 15 cm, spinning time: 60 minutes. After spinning, the tubular molded body was vacuum-dried overnight at room temperature together with the mandrel without removing it. Then, by removing the mandrel, a tubular molded body for medical devices in which a plurality of tubular bodies were connected by a connecting layer was obtained. The thickness of the connecting layer is calculated to be 309 μm by measuring the thickness of the tubular molded body including the connecting layer with a microscope (KH-1300, Hirox) and subtracting the thickness of the PLLA layer forming the tubular body. rice field.

In the tubular molded body for medical instruments of Example 1, a plurality of cylindrical bodies having a length of 5 mm are arranged at intervals of 0.2 mm, and the plurality of tubular bodies are connected by a connecting layer, and the connecting layer is connected. Was arranged in contact with the outside of the tubular body.

Further, in order to measure the Young's modulus of the tubular body, a tubular body cut to 20 mm was prepared by the same method as in the above-mentioned "Production of tubular body" except that the cutting interval was set to 20 mm. As described in Measurement Example 8, the prepared 20 mm cylindrical body was set in a testing machine so as to have an initial length of 10 mm, and a tensile test was carried out. As a result, the Young's modulus of the tubular body was 34.8 MPa.

Table 1 shows the results of carrying out the kink generation suppression test described in Measurement Example 6 and the pressure resistance test described in Measurement Example 7 on the obtained tubular molded product for medical devices. Further, FIG. 5 shows a photograph of the cylindrical molded body bent at a 60 ° angle in Measurement Example 6. As shown in FIG. 5, the cylindrical molded body of Example 1 does not generate kink even when bent at a 60 ° angle. In the photograph, the thin thing inserted in the tubular molded body is the wire.

Further, as described above, the Young's modulus of the tubular body was 6.3 MPa or more, and the Young's modulus of the connecting layer was less than 6.3 MPa.

<Comparative example 1>
After preparing a tubular body (before cutting) in the same manner as in Example 1, a tubular molded body for medical instruments was prepared in the same manner as in Example 1 except that the tubular body (before cutting) was not cut with a microtome blade.

Table 1 shows the results of carrying out the kink generation suppression test described in Measurement Example 6 and the pressure resistance test described in Measurement Example 7 on the obtained tubular molded product. Since the kink is generated at a 120 ° angle, it can be seen that there is no effect of suppressing the occurrence of kink.

Comparing Example 1 and Comparative Example 1, the 50% compression pressure was almost the same, so that the pressure resistance was almost the same between Example 1 and Comparative Example 1. Nevertheless, in Example 1, kink generation did not occur up to a 60 ° angle, indicating that in Example 1, kink generation could be suppressed.

<Example 2>
(Making a tubular body)
As a polymer solution for producing a tubular body, instead of a PLLA solution, a glycolic acid / L-lactic acid copolymer (PGLA) (manufactured by BMG Co., Ltd., Mw = 260,000, Mw / Mn = 1.64, A tubular body (before cutting) was prepared in the same manner as in Example 1 except that a solution prepared by dissolving GA: LA = 10.1: 89.9) in chloroform so as to have a concentration of 10% by weight was used. bottom.

The thickness of the PGLA layer forming the tubular body was 336 μm as a result of measurement with a high-speed, high-precision dimensional measuring instrument (LS-9030 manufactured by KEYENCE CORPORATION). After that, without removing the tubular body (before cutting) from the mandrel, using a microtome blade (manufactured by Feather Safety Razor Co., Ltd., S35TYPE, standard product), the circumferential direction of the tubular body (before cutting) (all). Cuts were made in the circumference) every 2.5 mm to prepare a tubular body (after cutting).

(Manufacturing a tubular molded body for medical equipment (a molded body in which a plurality of tubular bodies are connected by a connecting layer))
The mandrel having the tubular body (after cutting) cut in the above-mentioned "preparation of the tubular body" was set again in the spinning device NANON-3. Using the polymer for the connecting layer described in Example 1, a tubular molded body for a medical device in which a plurality of tubular bodies were connected by a connecting layer was obtained in the same manner as in Example 1.

The thickness of the tubular molded body including the connecting layer is measured with a high-speed, high-precision dimensional measuring device (LS-9030 manufactured by KEYENCE CORPORATION), and the thickness of the PGLA layer forming the tubular body is subtracted to obtain the connecting layer. The thickness was calculated to be 362 μm.

Moreover, when the Young's modulus of the tubular body was measured in the same manner as in Example 1, it was 74.4 MPa.

In the tubular molded body for medical instruments of Example 2, a plurality of cylindrical bodies having a length of 2.5 mm are arranged at intervals of 0.2 mm, and the plurality of tubular bodies are connected by a connecting layer. The connecting layer was arranged so as to be in contact with the outside of the tubular body.

Table 1 shows the results of carrying out the kink generation suppression test described in Measurement Example 6 and the pressure resistance test described in Measurement Example 7 on the obtained tubular molded product for medical devices. As shown in the photograph of FIG. 6, the cylindrical molded body of Example 2 does not generate kink even in a one-rolled state, which is more severe than the conditions of Measurement Example 6.

Further, as a result of carrying out the tensile test described in Measurement Example 8, Young's modulus was 1.5 MPa, elongation rate was 1900%, and breaking strength was 4.4 MPa.

<Example 3>
(Making a tubular body)
As a polymer solution for producing a tubular body, instead of a PLLA solution, a glycolic acid / L-lactic acid copolymer (PGLA) (manufactured by BMG Co., Ltd., Mw = 250,000, Mw / Mn = 1.63, A tubular body (before cutting) was prepared in the same manner as in Example 1 except that a solution prepared by dissolving GA: LA = 20.5: 79.5) in chloroform so as to have a concentration of 10% by weight was used. bottom.

The thickness of the PGLA layer was 328 μm as a result of measurement with a high-speed, high-precision dimensional measuring device (LS-9030 manufactured by KEYENCE CORPORATION). After that, without removing the tubular body (before cutting) from the mandrel, using a microtome blade (manufactured by Feather Safety Razor Co., Ltd., S35TYPE, standard product), the circumferential direction of the tubular body (before cutting) (all). Cuts were made in the circumference) every 2.5 mm to prepare a tubular body (after cutting).

By measuring the thickness of the cylindrical molded body including the connecting layer with a high-speed, high-precision dimensional measuring device (LS-9030 manufactured by KEYENCE CORPORATION) and subtracting the thickness of the PGLA layer, the thickness of the connecting layer is calculated to be 384 μm. rice field.

Moreover, when the Young's modulus of the tubular body was measured in the same manner as in Example 1, it was 79.2 MPa.

In the tubular molded body for medical instruments of Example 3, a plurality of cylindrical bodies having a length of 2.5 mm are arranged at intervals of 0.2 mm, and the plurality of tubular bodies are connected by a connecting layer. The connecting layer was arranged so as to be in contact with the outside of the tubular body.

Table 1 shows the results of carrying out the kink generation suppression test described in Measurement Example 6 and the pressure resistance test described in Measurement Example 7 on the obtained tubular molded product for medical devices.

Further, as a result of carrying out the tensile test described in Measurement Example 8, Young's modulus was 0.7 MPa, elongation rate was 1200%, and breaking strength was 4.3 MPa.

The tubular molded body for medical instruments of the present invention can be flexibly deformed with respect to bending and refraction by a flexible layer connecting a plurality of tubular bodies, and can suppress the generation of kink. Therefore, a nerve regeneration induction tube It can be suitably used for such purposes.

10 Nerve regeneration induction tube 11 Scaffolding material 200 Nerve cell 201 Axle 210 Schwann cell 211 Schwann cell A Adjacent one tubular body B Adjacent other tubular body C connecting layer

Claims

A tubular molded body for medical instruments having a plurality of tubular bodies and a connecting layer connecting the tubular bodies.
The molded body according to claim 1, wherein the distance between adjacent tubular bodies is 1 mm or less.
The molded product according to claim 1 or 2, wherein the length of the tubular body in the direction along the long axis direction of the molded product is 1.0 mm to 10 mm.
The molded product according to any one of claims 1 to 3, wherein the tubular body and the connecting layer are in contact with each other, and the connecting layer is arranged outside the tubular body.
The molded product according to any one of claims 1 to 3, wherein the tubular body and the connecting layer are in contact with each other, and the connecting layer is arranged inside the tubular body.
The tubular body and the connecting layer are in contact with each other, and the connecting layer is arranged inside one of the adjacent tubular bodies (cylindrical body A) and the other tubular body (cylindrical body). The molded body according to any one of claims 1 to 3, which is arranged outside the body B).
The molded product according to any one of claims 1 to 6, wherein the tubular body has a Young's modulus of 6.3 MPa or more and the connecting layer has a Young's modulus of less than 6.3 MPa.
The connecting layer contains a polyester copolymer having a hydroxycarboxylic acid residue and a lactone residue as main constituent units.
The molded article according to any one of claims 1 to 7, wherein the polyester copolymer satisfies the following conditions (A) and (B).
Condition (A) R value is 0.45 or more and 0.99 or less;
R value = [AB] / (2 [A] [B]) x 100
[A]: Mole fraction (%) of hydroxycarboxylic acid residues in the polyester copolymer
[B]: Mole fraction (%) of lactone residue in polyester copolymer
[AB]: Mole fraction (%) of the structure (AB, and BA) in which the hydroxycarboxylic acid residue and the lactone residue are adjacent to each other in the polyester copolymer.
Condition (B) The crystallization rate of at least one of the hydroxycarboxylic acid residue and the lactone residue is less than 14%.
The link layer contains a dilactide / ε-caprolactone copolymer
The molded product according to any one of claims 1 to 8, wherein the dilactide / ε-caprolactone copolymer satisfies the following conditions (C) and (D).
Condition (C) R value is 0.45 or more and 0.99 or less;
R value = [AB] / (2 [A] [B]) x 100
[A]: Mole fraction (%) of dilactide residues in the dilactide / ε-caprolactone copolymer
[B]: Mole fraction (%) of ε-caprolactone residue in dilactide / ε-caprolactone copolymer
[AB]: Mole fraction (%) of the structure (AB and BA) in which the dilactide residue and the ε-caprolactone residue are adjacent to each other in the dilactide / ε-caprolactone copolymer.
Condition (D) At least one of the dilactide residue and the ε-caprolactone residue has a crystallization rate of less than 14%.
The molded product according to any one of claims 1 to 9, wherein the tubular body contains a bioabsorbable polyester.
A medical device containing the molded product according to any one of claims 1 to 10.
A nerve regeneration induction tube containing the molded product according to any one of claims 1 to 10.