WO2018047848A1 - Composé constitué d'un oligomère biodégradable, d'un segment hydrophile et d'un peptide d'adhérence cellulaire, et application de ce composé - Google Patents

Composé constitué d'un oligomère biodégradable, d'un segment hydrophile et d'un peptide d'adhérence cellulaire, et application de ce composé Download PDF

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WO2018047848A1
WO2018047848A1 PCT/JP2017/032050 JP2017032050W WO2018047848A1 WO 2018047848 A1 WO2018047848 A1 WO 2018047848A1 JP 2017032050 W JP2017032050 W JP 2017032050W WO 2018047848 A1 WO2018047848 A1 WO 2018047848A1
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seq
biodegradable
ikvav
peptide
molded article
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PCT/JP2017/032050
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English (en)
Japanese (ja)
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山岡　哲二
于懿 徐
敦史 岩井
琢也 中越
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国立研究開発法人国立循環器病研究センター
東洋紡株式会社
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Publication of WO2018047848A1 publication Critical patent/WO2018047848A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology

Definitions

  • a technique relating to a compound comprising a biodegradable oligomer, a hydrophilic segment, and a cell adhesive peptide and its use are disclosed.
  • peripheral nerve damage due to accidents cannot be repaired.
  • peripheral nerves have to be excised with general surgery.
  • direct anastomosis and autologous nerve transplantation have been the main conventional treatments.
  • the results were never satisfactory.
  • Patent Document 1 the outer surface of a tubular body knitted with ultrafine fibers made of a plurality of biodegradable polymers is coated by applying a collagen solution multiple times, and the inside of the tubular body is filled with collagen.
  • Patent Document 2 discloses a nerve regeneration-inducing tube that uses collagen that has been treated so that the sodium chloride-containing concentration is 2.0% by weight or less in a dry state in a nerve regeneration-inducing tube that uses collagen as a scaffold for nerve regeneration. It is disclosed.
  • Patent Document 3 collagen is coated on the outer surface of a tubular body knitted with a fiber bundle obtained by bundling a plurality of ultrafine fibers made of a biodegradable absorbable polymer, and the tubular body is mainly a biodegradable absorbable first polymer. And a nerve regeneration-inducing tube composed of a second polymer having higher biodegradability than the first polymer.
  • Patent Document 4 discloses a nerve guide tube formed by molding a resin composition containing a molecule in which a cell adhesive peptide and oligolactic acid are bonded by a peptide bond.
  • JP 2009-136575 A WO / 2010/087015 JP 2009-153947 A JP 2009-66227 A
  • One problem is to provide a nerve regeneration induction tube with improved characteristics of the conventional nerve regeneration induction tube and a material therefor.
  • the present inventors have examined the nerve regeneration induction tube disclosed in Patent Document 4 and found that there is room for improvement as follows. That is, the nerve regeneration inducing tube disclosed in Patent Document 4 proposes to promote nerve regeneration in the tube by using a cell adhesive peptide as a raw material for the nerve regeneration inducing tube.
  • the nerve regeneration inducing tube disclosed in Patent Document 4 proposes to promote nerve regeneration in the tube by using a cell adhesive peptide as a raw material for the nerve regeneration inducing tube.
  • most of the cell-adhesive peptides are not exposed on the surface of the nerve regeneration-inducing tube and are buried in the resin or fiber constituting the tube.
  • Item 1 The following compounds (A) to (C) are bonded, and (B) and (C) have adjacent structures: (A) an oligomer composed of at least one selected from the group consisting of a lactic acid monomer, a glycolic acid monomer, and a caprolactone monomer (B) a hydrophilic segment represented by the following general formula (1) or general formula (2) (Where n is an integer from 1 to 10) (Wherein m is an integer of 1 to 20 and R 1 is a hydrophilic group) (C) IKVAV (SEQ ID NO: 1), RGD, RGDS (SEQ ID NO: 2), WQPPRARI (SEQ ID NO: 3), EILDVPST (SEQ ID NO: 4), REDV (SEQ ID NO: 5), LDV, GTPGPQGGIAGQRGVV (SEQ ID NO: 6), GFOGER A cell adhesion peptide selected from the group consisting of (SEQ ID NO: 7), YIGSR (SEQ ID NO: 8),
  • Item 2. The compound according to Item 1, wherein the degree of polymerization of the oligomer (A) is 2 to 100.
  • Item 3. Item 3. The compound according to any one of Items 1 and 2, wherein the cell adhesion peptide is IKVAV (SEQ ID NO: 1).
  • Item 4. Item 4. A composition comprising the compound according to any one of Items 1 to 3 and a biodegradable polymer.
  • Item 5. The composition according to Item 4, wherein the biodegradable polymer is one or more biodegradable polymers selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, and copolymers thereof.
  • Item 6. Item 6.
  • a biodegradable molded article comprising the composition according to Item 4 or 5.
  • Item 7. The biodegradable molded article according to Item 6, which is in the form of a fiber, a sheet, or a tube.
  • Item 8. The biodegradable molded article according to item 6 or 7, wherein the cell adhesive peptide is exposed on the surface of the molded article.
  • Item 9. A nerve regeneration induction tube comprising the biodegradable molded article according to any one of Items 6 to 8.
  • Item 11. Item 8.
  • a method for producing a biodegradable molded article having a cell-adhesive peptide exposed on the surface comprising at least a step of immersing the biodegradable molded article according to Item 6 or 7 in water.
  • Item 12. The method according to Item 11, wherein the water temperature is in the range of ⁇ 5 ° C. to + 10 ° C. based on the glass transition temperature (Tg) of the biodegradable molded article.
  • Tg glass transition temperature
  • Item 14 A molded body in which (C) is exposed on the surface of the molded body, comprising a step of immersing a molded body composed of a composition containing the compound including the following (A) and (C) and a biodegradable polymer in water: Manufacturing method: (A) Oligomer composed of at least one selected from the group consisting of lactic acid monomer, glycolic acid monomer, and caprolactone monomer (C) IKVAV (SEQ ID NO: 1), RGD, RGDS (SEQ ID NO: 2), WQPPPARI (SEQ ID NO: 3), EILDVPST (SEQ ID NO: 4), REDV (SEQ ID NO: 5), LDV, GTPGPQGGIAGQRGVV (SEQ ID NO: 6), GFOGER (SEQ ID NO: 7), YIGSR (SEQ ID NO: 8), RQVFQVAYIIIKA (SEQ ID NO: 9), RKRLQVQLSIRT (sequence) No.
  • Item 15 The method according to Item 14, wherein the water temperature is in the range of ⁇ 5 ° C. to + 10 ° C. based on the glass transition temperature (Tg) of the biodegradable molded article.
  • the cell adhesive peptide can be efficiently exposed on the surface of various resin moldings.
  • a nerve regeneration inducing tube formed of a resin having a cell adhesion peptide exposed on the surface is provided.
  • Such a nerve regeneration-inducing tube effectively promotes nerve regeneration in a preferred embodiment because the function of the cell adhesion peptide is efficiently exhibited.
  • means for efficiently modifying the surfaces of nerve regeneration-inducing tubes and other resin moldings with cell adhesion peptides is provided.
  • the reaction which acetylates lactic acid is shown.
  • the reaction which binds diethyl ether and a cell adhesion peptide is shown.
  • the reaction for binding lactic acid and diethyl ether-cell adhesion peptide is shown.
  • the schematic diagram which produces a nonwoven fabric by the electrospinning method is shown. In an Example, the result of having detected the cell adhesion peptide exposed on the surface about three types of nonwoven fabrics with the confocal microscope is shown.
  • “PLA” refers to a nonwoven fabric made only of polylactic acid.
  • PLA-IKVAV refers to a non-woven fabric prepared by mixing a cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid.
  • PHA-diEG-IKVAV refers to a nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol into polylactic acid.
  • IKVAV cell adhesion peptide
  • 1 is a non-heat treated non-woven fabric (control) made of poly L lactic acid not containing a cell adhesion peptide.
  • 2 is a non-heat treated nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid.
  • 3 is a non-heat treated nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol into polylactic acid.
  • 4 is a nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol into polylactic acid and heat-treating at 60 ° C.
  • 5 is a nonwoven fabric prepared by mixing a cell adhesive peptide (IKVAV) combined with diethylene glycol into polylactic acid and heat-treating it at 70 ° C.
  • 6 is a nonwoven fabric prepared by mixing a cell adhesive peptide (IKVAV) combined with diethylene glycol into polylactic acid and heat-treating it at 80 ° C. It is an image figure of the molded object which the cell adhesive peptide exposed on the surface.
  • a is a cell adhesion peptide
  • b is a hydrophilic segment
  • c is an oligomer
  • d is a biodegradable polymer.
  • 1 is a sample obtained by treating a poly-L lactic acid non-woven fabric containing no cell adhesion peptide at room temperature.
  • 2 is a sample obtained by heat-treating a poly-L-lactic acid non-woven fabric containing no cell adhesion peptide at 60 ° C.
  • 3 is a sample obtained by heat-treating a poly-L lactic acid non-woven fabric containing no cell adhesion peptide at 70 ° C.
  • 4 is a sample obtained by heat-treating a poly-L lactic acid non-woven fabric containing no cell adhesive peptide at 80 ° C.
  • 5 is a sample obtained by treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid at room temperature.
  • 6 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 60 ° C.
  • 7 is a sample obtained by heat-treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 70 ° C.
  • 8 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 80 ° C.
  • 9 is a sample obtained by treating a nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol with polylactic acid at room temperature.
  • 10 is a sample prepared by mixing a cell adhesive peptide (IKVAV) combined with diethylene glycol into polylactic acid and heat-treating another nonwoven fabric at 60 ° C.
  • 11 is a sample obtained by heat-treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol with polylactic acid at 70 ° C.
  • FIG. 12 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) combined with diethylene glycol into polylactic acid at 80 ° C.
  • IKVAV cell adhesive peptide
  • the schematic diagram of the experimental method which measures the adhesiveness of the nerve cell with respect to a nonwoven fabric is shown.
  • attached on three types of nonwoven fabrics is shown.
  • 1 is a sample obtained by treating a poly-L lactic acid non-woven fabric containing no cell adhesion peptide at room temperature.
  • 2 is a sample obtained by heat-treating a poly-L-lactic acid non-woven fabric containing no cell adhesion peptide at 60 ° C.
  • 3 is a sample obtained by heat-treating a poly-L lactic acid non-woven fabric containing no cell adhesion peptide at 70 ° C.
  • 4 is a sample obtained by heat-treating a poly-L lactic acid non-woven fabric containing no cell adhesive peptide at 80 ° C.
  • 5 is a sample obtained by treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid at room temperature.
  • 6 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 60 ° C.
  • FIG. 7 is a sample obtained by heat-treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 70 ° C.
  • 8 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) not bound to diethylene glycol with polylactic acid at 80 ° C.
  • 9 is a sample obtained by treating a nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol with polylactic acid at room temperature.
  • 10 is a sample obtained by heat-treating a nonwoven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol into polylactic acid at 60 ° C.
  • 11 is a sample obtained by heat-treating a non-woven fabric prepared by mixing cell adhesion peptide (IKVAV) combined with diethylene glycol with polylactic acid at 70 ° C.
  • 12 is a sample obtained by heat-treating a non-woven fabric prepared by mixing a cell adhesive peptide (IKVAV) combined with diethylene glycol into polylactic acid at 80 ° C.
  • the oligomer (A) is preferably composed of at least one selected from the group consisting of a lactic acid monomer, a glycolic acid monomer, and a caprolactone monomer.
  • the lactic acid monomer may be either D-form or L-form, and both of them (racemate) can also be used.
  • the oligomer (A) may be composed of only one selected from the group consisting of lactic acid monomer, glycolic acid monomer, and caprolactone monomer, and any combination of lactic acid monomer, glycolic acid monomer, and / or caprolactone monomer It may be comprised.
  • the oligomer (A) is constituted by a lactic acid monomer alone (oligolactic acid), a glycolic acid monomer alone (oligoglycolic acid), or a combination of a lactic acid monomer and a glycolic acid monomer (oligolactic acid-glycolic acid copolymer). It is preferred that
  • the degree of polymerization of the oligomer (A) is not particularly limited.
  • the degree of polymerization of the oligomer (A) can be 2 or more and 100 or less.
  • the lower limit of the degree of polymerization of the oligomer (A) is preferably 3, 5, or 10, and the upper limit is preferably 75, 50, or 25. These lower limits and upper limits can be arbitrarily combined to form a range.
  • the degree of polymerization of the oligomer (A) can be 3 or more and 75 or less, 5 or more and 50 or less, or 10 or more and 25 or less.
  • the oligomer (A) may be linear or branched, and in one embodiment, the oligomer (A) is preferably linear.
  • the oligomer (A) can be obtained from the monomer by any method. For example, it can be obtained by dehydrating and condensing a monomer according to the method of Examples described later.
  • hydrophilic segment (B) is a hydrophilic segment represented by the following general formula (1) or general formula (2)
  • n is an integer from 1 to 10.
  • n in the general formula (1) may be 2 or more, 3 or more, or 4 or more, and may be 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, or 5 or less.
  • M in the general formula (2) may be 2 or more, 3 or more, or 4 or more, and may be 20 or less, 15 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, or 5 or less.
  • n is 1-8, preferably 2-5.
  • m is 1-20, preferably 2-5.
  • the hydrophilic segment represented by the general formula (1) is a divalent group obtained by removing hydrogen atoms from hydroxyl groups at both ends of oligoethylene glycol.
  • any of the linking groups at both ends may be a hydrogen atom, an alkyl group, or an acetyl group, but is not limited thereto. is not.
  • the alkyl group include a linear or branched lower alkyl group (having 1 to 6 carbon atoms), and specifically include methyl, ethyl, propyl, butyl, pentyl, hexyl, and 1-methylethyl. , Tert-butyl, and 2-methylbutyl group.
  • the hydrophilic segment represented by the general formula (2) is a divalent vinyl oligomer having a hydrophilic group in the side chain.
  • Examples of the side chain structure of the hydrophilic segment having such a structure include a carboxyl group, a sulfate group, an amino group, and a zwitterionic group (betaine).
  • Cell adhesion peptide is IKVAV (SEQ ID NO: 1), RGD, RGDS (SEQ ID NO: 2), WQPPPARI (SEQ ID NO: 3), EILDVPST (SEQ ID NO: 4), REDV (SEQ ID NO: 5), LDV, GTPGPQGGIAGQRGVV ( SEQ ID NO: 6), GFOGER (SEQ ID NO: 7), YIGSR (SEQ ID NO: 8), RQVFQVAYIIIKA (SEQ ID NO: 9), RKRLQVQLSIRT (SEQ ID NO: 10), and at least one selected from the group consisting of WRTQIDSPLNGK (SEQ ID NO: 11) It is preferable that A cell adhesion peptide may be used individually by 1 type, and may combine 2 or more types. Moreover, the same kind of cell-adhesive peptide can be repeatedly present in one molecule. In one embodiment, the preferred cell adhesion peptide is IKVAV.
  • the oligomer (A), the hydrophilic segment (B), and the cell adhesive peptide (C) can be combined in any order, but the cell adhesive peptide is bonded to the resin surface in a resin formed of a biodegradable polymer.
  • the cell adhesion peptide (C) is preferably adjacent to the hydrophilic segment (B).
  • preferred compound structures are (A)-(B)-(C), (A)-(C)-(B), and (A)-(B)-(C)-(B). More preferably, (A)-(B)-(C).
  • the oligomer (A), the hydrophilic segment (B), and the cell adhesive peptide (C) can be bound by any method.
  • the terminal hydroxyl group of the hydrophilic segment (B) and the terminal amino group of the cell adhesive peptide are subjected to dehydration condensation to bond (B) and (C).
  • this is reacted with terminally acetylated oligomer (A) to obtain a compound having a structure (A)-(B)-(C).
  • the bonds (A) to (C) can be performed via a linker.
  • it is preferable that (A) to (C) are directly bonded without using a linker. Accordingly, in the structure of the above preferable compound, “-” is preferably a single bond.
  • a compound in which (A) to (C) are linked as described above (hereinafter also referred to as “AC compound”) is mixed with a biodegradable polymer to form a composition, which is used to form resins of various shapes.
  • the compound can be used as a surface modifier for a resin (preferably a resin formed from a biodegradable polymer) for modifying the resin surface with a cell adhesive peptide.
  • the surface modifier containing the AC compound may be modified by applying the surface modifier to the surface of the biodegradable polymer molding formed without the AC compound. it can.
  • biodegradable polymers include polylactic acid, polyglycolic acid, polycaprolactone, lactic acid-glycolic acid copolymer, lactic acid-caprolactone copolymer, glycolic acid-caprolactone copolymer, polydioxanone, glycolic acid-trimethylenecarboxylic acid.
  • examples include acid, polybutylene succinate, polyethylene succinate, polybutylene succinate adipate, polypropylene carbonate, and polyparadioxanone.
  • preferred biodegradable polymers are polylactic acid, polyglycolic acid, polycaprolactone, and copolymers thereof (eg, lactic acid-glycolic acid copolymer, lactic acid-caprolactone copolymer, and glycolic acid- It is at least one selected from the group consisting of caprolactone copolymers), more preferably at least one selected from the group consisting of polylactic acid, polyglycolic acid, and polycaprolactone.
  • a biodegradable polymer may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the weight average molecular weight of the biodegradable polymer is preferably 10,000 or more, more preferably 40,000 or more, and particularly preferably 80,000 or more.
  • the weight average molecular weight is a polymethyl methacrylate (PMMA) equivalent weight average molecular weight measured by gel permeation chromatography (GPC) using hexafluoroisopropanol as a solvent.
  • PMMA polymethyl methacrylate
  • the polylactic acid may be poly L-lactic acid, poly D-lactic acid or poly DL-lactic acid, but is preferably poly L-lactic acid.
  • the biodegradable polymer may further include a biodegradable polymer derived from a living body.
  • a biodegradable polymer for example, one or more selected from the group consisting of collagen, gelatin, fibronectin, laminin, chitin, and chitosan can be employed, and collagen is preferred.
  • the mixing ratio of the AC compound and the biodegradable polymer in the composition containing the AC compound and the biodegradable polymer is not particularly limited and can be appropriately adjusted according to the purpose.
  • the AC compound is 40 parts by mass or less, preferably 30 parts by mass or less, 20 parts by mass or less, 10 parts by mass or less, or 5 parts by mass or less with respect to 100 parts by mass of the biodegradable polymer. 0.01 parts by mass or more, preferably 0.1 parts by mass or more, or 1 part by mass or more.
  • the composition containing the AC compound and the biodegradable polymer may further contain optional components.
  • Such components include plasticizers and stabilizers.
  • the composition may be one in which the AC compound and the biodegradable polymer are dissolved in an appropriate solvent.
  • the type of such a solvent is not particularly limited.
  • (A) is mainly composed of a lactic acid oligomer, methylene chloride, chloroform, benzene, acetone and the like can be mentioned, and (A) is mainly a glycolic acid oligomer.
  • DMSO dimethyl sulfoxide
  • HFIP hexafluoroisopropanol
  • NMP N-methylpyrrolidone
  • biodegradable molded articles can be produced using a composition containing an AC compound and a biodegradable polymer as raw materials.
  • the shape of the biodegradable molded product can be appropriately selected depending on the purpose and is not particularly limited, and examples thereof include a fiber shape, a sheet shape, and a tube shape.
  • the method for obtaining these molded products is not particularly limited, and a known method can be appropriately employed depending on the shape of the molded product. Examples of such a method include a melt spinning method, a wet spinning method, a dry spinning method, a gel spinning method, a melt extrusion molding method, a cast molding method, an injection molding method, a spin coating method, and an electrospinning method. .
  • the diameter of the fiber is preferably 1 to 50 ⁇ m, more preferably 3 to 40 ⁇ m, and still more preferably 6 to 30 ⁇ m, from the viewpoint of handleability and strength. is there.
  • the cell-degradable peptide is preferably exposed on the surface of the biodegradable molded article.
  • the cell adhesive peptide (C) is adjacent to the hydrophilic segment (B)
  • cell adhesion with the hydrophilic segment (B) can be obtained by immersing the molded article in water.
  • Peptide (A) can be exposed on the surface in contact with water molecules.
  • FIG. 7 shows an image of the state where the cell adhesive segment is exposed on the surface of the molded body.
  • a solvent other than water a solvent that does not dissolve a biodegradable polymer (for example, polylactic acid) and has high affinity with a cell adhesive peptide is preferable.
  • a mixed solvent of water and alcohol, a mixed solvent of water and acetone, or acetonitrile can be considered.
  • the temperature of water in which the molded body is immersed for the above purpose is not particularly limited, but for example, it is preferably in the range of ⁇ 5 ° C. to + 10 ° C. based on the glass transition temperature (Tg) of the biodegradable molded body.
  • the glass transition temperature of the biodegradable molded product can be measured by any method.
  • the glass transition temperature can be measured by a method based on JIS K7121. Specifically, using a differential scanning calorimeter, 10 mg of a resin sample was heated at a rate of 20 ° C./min over a temperature range of ⁇ 140 ° C. to 250 ° C., and the extrapolated glass transition start temperature obtained from the DSC curve was calculated. It can be the glass transition temperature.
  • the range of ⁇ 5 ° C. to 10 ° C. based on the glass transition temperature of the biodegradable molded product may be 50 to 65 ° C.
  • the temperature of water in which the molded body is immersed is preferably ⁇ 10 ° C. or lower based on the temperature of the melting point of the biodegradable molded body. In one embodiment, it can be from 5 to 35 ° C.
  • the immersion time is not particularly limited, and may be, for example, 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, 50 minutes or more, 60 minutes or more, 1.5 hours or more, or 2 hours or more.
  • the upper limit of immersion time can be 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, or 3 hours or less, for example.
  • the compound to which the cell adhesive peptide is linked is A
  • it is preferably a —C compound
  • it may be a compound containing no (B) hydrophilic segment. That is, even if it is a compound in which only the oligopeptide (A) and the cell adhesion peptide (C) are bound as disclosed in Patent Document 4, the resin molded body containing the compound is immersed in water, preferably constant. By subjecting to the above temperature, the cell adhesion peptide can be exposed on the surface of the molded article.
  • the molded body can be used, for example, as a nerve regeneration induction tube.
  • the tube-shaped molded body can be used as it is as a nerve regeneration-inducing tube, and the molded body of other shapes (for example, fiber or sheet) is further formed into a tube shape to form a nerve regeneration tube. be able to.
  • the fibrous molded body can be formed into a tube by, for example, knitting a bundle of about 5 to 100 fibers into a tubular shape.
  • a non-woven fabric or a woven fabric or a knitted fabric can be formed from fibers, and formed into a tubular shape by making it into a tube and stitching or adhering or fusing it.
  • the inner and outer diameters of the nerve regeneration induction tube can be set according to the thickness of the nerve to be joined.
  • the size of the tubular body can be designed, for example, within a range of an inner diameter of 0.1 to 20 mm, an outer diameter of 0.11 to 25 mm, a film thickness of 0.05 to 5 mm, and a length of 10 to 150 mm. If the film thickness is too thick, it may be an obstacle to the regeneration of living tissue. If the film thickness is too thin, the nerve regeneration-inducing tube is decomposed too early, and the shape may not be maintained until the nerve has been regenerated.
  • the nerve regeneration-inducing tube preferably contains collagen (or is filled with collagen) in the tube.
  • collagen collagen conventionally used as a scaffold for nerve regeneration can be used.
  • type I collagen, type III collagen, type IV collagen and the like can be mentioned, and these may be used alone or in combination.
  • the collagen preferably comprises one or more components selected from the group consisting of laminin, heparan sulfate proteoglycan, entactin and growth factor.
  • Growth factors include EGF (epidermal growth factor), ⁇ FGF (fibroblast growth factor), NGF (nerve growth factor), PDGF (platelet derived growth factor), IGF-1 (insulin-like growth factor), and TGF- ⁇ . (Transforming growth factor).
  • EGF epidermal growth factor
  • ⁇ FGF fibroblast growth factor
  • NGF nerve growth factor
  • PDGF platelet derived growth factor
  • IGF-1 insulin-like growth factor
  • TGF- ⁇ Transforming growth factor
  • the nerve regeneration induction tube has its outer surface coated with collagen.
  • the coating of the external surface can be performed, for example, by applying the collagen solution once or plural times by a known method.
  • the collagen may be the same or different from the collagen used to fill the nerve regeneration induction tube.
  • the nerve regeneration-inducing tube coated and / or filled with collagen is preferably subjected to freezing, freeze-drying, and / or crosslinking treatment. Freezing can be performed preferably at ⁇ 10 to ⁇ 196 ° C. for 3 to 48 hours. By freezing, fine ice is formed between collagen molecules, and the collagen solution undergoes phase separation and becomes sponge. The frozen collagen solution can then be lyophilized under vacuum, preferably at about ⁇ 40 to ⁇ 80 ° C., preferably for about 12 to 48 hours. By freeze-drying, fine ice between collagen molecules is vaporized and the collagen sponge is refined.
  • Crosslinking can be performed by, for example, a technique selected from the group consisting of ⁇ -ray crosslinking, ultraviolet crosslinking, electron beam crosslinking, thermal dehydration crosslinking, glutaraldehyde crosslinking, epoxy crosslinking, and water-soluble carbodiimide crosslinking.
  • the nerve regeneration induction tube is preferably sterilized.
  • the sterilization method is not particularly limited, and for example, ⁇ -ray sterilization and / or ultraviolet sterilization can be employed. Further, the nerve regeneration induction tube may be further molded and / or surface-treated depending on the purpose. *
  • IKVAV A peptide (IKVAV) was synthesized by the following procedure. (1) Resin (1 g) was put in a column, and further methylene chloride was added and stirred for 10 minutes to swell. (2) Methylene chloride was removed, Fmoc-Val-OH (809.45 mg) was added, and methylene chloride (8 ml) was added again and stirred uniformly. (3) DIPEA (830.83 ml) was further added and stirred for 2 minutes for washing. (4) The washing was repeated twice. (5) 10 ml of DCM / methanol / DIPEA mixed solvent was put in the column and stirred for 10 minutes. (6) DMF was further added and the resin was washed by stirring for 10 minutes.
  • Oligolactic acid was polycondensed by the reaction shown in FIG. (1) 20 g of 90% D-lactic acid (Musashino Chemical) was placed in an eggplant flask, and water was removed while stirring at 150 ° C. under atmospheric pressure for 2 hours. (2) The reaction was carried out at 150 ° C. under reduced pressure at 100 mmHg for 2 hours, 30 mmHg for 1 hour, and 20 mmHg for 2 hours. (3) After completion of the reaction, the mixture was dried under reduced pressure, dissolved in methylene chloride, and reprecipitated with cooled diethyl ether. (4) The supernatant was discarded and the precipitate was dried under reduced pressure.
  • D-lactic acid Malashino Chemical
  • Synthesis of oligolactic acid-diethylene glycol-IKVAV 5-1 Synthesis of diethylene glycol- IKVAV Diethylene glycol and oligopeptide (IKVAV) were bound by the reaction shown in FIG.
  • the oligopeptide (IKVAV) -attached resin synthesized and dried in 2 above was placed in a column, and further methylene chloride was added and stirred for 10 minutes to swell. The methylene chloride was removed and the resin was washed 3 times with DMF.
  • the resin was transferred to a glass bottle, the solvent DMF (1 ml), 1.5 times equivalent Fmoc-diEG-COOH (23.7 mg) and 1.5 times equivalent HBTU (22.57 mg) with respect to the resin with IKVAV. ), 1.5 times the same amount of HOBT (9.1 mg) and 3 times the same amount of DIPEA (20.7 ⁇ l) were added, the lid was closed and the Biotage Initiator was set and reacted at 60 ° C. for 15 minutes. . After completion of the reaction, the product was put in a column, further DMF was added, and the mixture was stirred for 1 minute and washed. This washing was repeated 5 times.
  • a nonwoven fabric was produced using the electrospinning method shown schematically in FIG. 1 ml of hexafluoroisopropyl alcohol (HFIP), 138.5 mg of poly L lactic acid (PLA, Musashino Chemicals, number average molecular weight 60000), and oligolactic acid-IKVAV obtained in the above 4 or oligolactic acid-diethylene glycol-obtained in the above 5 IKVAV 1.5 mg was added to prepare a polymer solution (14 w / v%).
  • HFIP hexafluoroisopropyl alcohol
  • the polymer solution was taken in a plastic syringe 1 and extruded (4 kV, 1 mL / h) while applying voltage by a high voltage supply system 2 and spun onto a target 3.
  • the spinning distance was 10 cm.
  • the target 3 was spun for 10 minutes using a stainless steel plate.
  • the obtained nonwoven fabric was cut into a size of 5 mm ⁇ 5 mm, placed in an Eppendorf tube containing ion-exchanged water, and exposed to a temperature of 60 ° C., 70 ° C., or 80 ° C. for 1 hour in water. Then, it returned to room temperature and 200 microliters fluorescein isothiocyanate (FITC) solution (concentration: 1 mg / ml) was put, and it was made to react for 4 hours, stirring. After the reaction, washing for replacing ion-exchanged water was repeated three times. Next, DMF was added, ultrasonic cleaning was performed for 5 minutes, and cleaning for replacing ion-exchanged water was repeated three times. Then, the nonwoven fabric was observed with the confocal microscope, and the fluorescence image was imaged and compared.
  • FITC fluorescein isothiocyanate
  • the surface exposure rate of IKVAV after heat treatment was: 60 ° C.> unheat treated> 70 ° C.> 80 ° C.
  • the amount of peptide exposed on the surface was quantified by measuring the fluorescence intensity with a fluorescence spectrophotometer after dissolving the nonwoven fabric in a 1: 1 mixed solvent of 100 ⁇ l of HFIP and PBS.
  • the amount of fluorescence was [nonwoven fabric made of PLA with oligolactic acid-diethylene glycol-IKVAV]> [nonwoven fabric made of PLA with oligolactic acid-IKVAV]> [nonwoven fabric made of PLA] It was consistent with the results observed with a confocal microscope.
  • the non-woven fabric made of PLA with oligolactic acid-diethylene glycol-IKVAV heat-treated at 60 ° C. has the highest fluorescence, and the amount of fluorescence decreases as the heat treatment temperature is raised to 70 or 80 ° C. The results were consistent with those observed with a confocal microscope.
  • the nonwoven fabric obtained by the electrospinning method was cut into a size of 15 mm ⁇ 15 mm and placed in a 24-well plate. The weight of each nonwoven fabric was measured. Ion exchange water was placed in each well and exposed to a temperature of 60 ° C., 70 ° C., or 80 ° C. in water for 1 hour. After returning to room temperature, 100 ⁇ l of fluorescein isothiocyanate (FITC) solution (concentration: 1 mg / ml) was added and reacted for 4 hours. After the reaction, washing for replacing ion-exchanged water was repeated three times.
  • FITC fluorescein isothiocyanate
  • the non-woven fabric made of PLA to which oligolactic acid-IKVAV was not added did not change the fluorescence amount by heat treatment.
  • Non-woven fabric made of PLA with oligolactic acid-IKVAV and non-woven fabric made of PLA with oligolactic acid-diethylene glycol-IKVAV react with the most FITC when heat treated at 60 ° C. It was found that the IKVAV peptide was exposed on the outermost surface of the nonwoven fabric. The decrease in the amount of fluorescence by increasing the heat treatment temperature to 70 ° C. and 80 ° C. is considered to be because the oligolactic acid-IKVAV peptide was eluted from the surface layer.
  • the nonwoven fabric obtained by electrospinning was cut into a size of 15 mm x 15 mm, placed in a 24-well plate as shown in Fig. 9, and the nonwoven fabric was fixed with a metal ring. Ion exchange water was placed in each well and exposed to a temperature of 60 ° C., 70 ° C., or 80 ° C. in water for 1 hour. Thereafter, the nonwoven fabric was dried and UV sterilized twice for 30 minutes.
  • PC-12 cells neurovascular cells
  • a sterilized nonwoven fabric adjusted with 1 mL medium so that the number of cells was 1 ⁇ 10 4 , and cultured at 37 ° C., 5% CO 2 for 3 hours. . Thereafter, the cultured medium was removed, and 1 mL fresh medium and 100 ⁇ L Cell Counting Kit-8 (Dojindo Laboratories) were added, followed by further culturing for 2 hours. The culture solution was collected in a 96-well plate, and the adhesion amount of nerve cells on the nonwoven fabric was quantified with a plate reader.
  • the number of nerve cells adhered was [nonwoven fabric made of PLA with oligolactic acid-diethylene glycol-IKVAV]> [nonwoven fabric made of PLA with oligolactic acid-IKVAV]> [prepared with PLA
  • the result was consistent with the results observed with a confocal microscope.
  • the number of nerve cell adhesion of the nonwoven fabric made of PLA with heat-treated oligolactic acid-diethylene glycol-IKVAV at 60 ° C. is the highest, and the cell adhesion number decreases by raising the temperature of heat treatment to 70 or 80 ° C.
  • the peptide density exposed on the surface and the results observed with a confocal microscope were consistent.

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Abstract

L'invention fournit un tube de guidage pour régénération nerveuse dont les caractéristiques sont améliorées, et un matériau de celui-ci. Selon l'invention, un composé est tel que les composants (A) à (C) sont liés, et possède une structure dans laquelle (B) et (C) sont adjacents. (A) est un oligomère configuré par au moins un monomère choisi dans un groupe constitué d'un monomère d'acide lactique, d'un monomère d'acide glycolique, et d'un monomère de caprolactone. (B) est un segment hydrophile représenté par la formule générale (1) ou par la formule générale (2). (C) est un peptide d'adhérence cellulaire choisi dans un groupe constitué de ＩＫＶＡＶ（SEQ ID no : 1）, ＲＧＤ、ＲＧＤＳ（SEQ ID no : 2）, ＷＱＰＰＲＡＲＩ（SEQ ID no : 3）, ＥＩＬＤＶＰＳＴ（SEQ ID no : 4）, ＲＥＤＶ（SEQ ID no : 5）, ＬＤＶ, ＧＴＰＧＰＱＧＧＩＡＧＱＲＧＶＶ（SEQ ID no : 6）, ＧＦＯＧＥＲ（SEQ ID no : 7）, ＹＩＧＳＲ（SEQ ID no : 8）, ＲＱＶＦＱＶＡＹＩＩＩＫＡ（SEQ ID no : 9）, ＲＫＲＬＱＶＱＬＳＩＲＴ（SEQ ID no : 10） et ＷＲＴＱＩＤＳＰＬＮＧＫ（SEQ ID no : 11）.
PCT/JP2017/032050 2016-09-09 2017-09-06 Composé constitué d'un oligomère biodégradable, d'un segment hydrophile et d'un peptide d'adhérence cellulaire, et application de ce composé WO2018047848A1 (fr)

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JP3771510B2 (ja) 2001-04-13 2006-04-26 泰彦 田畑 組織の体内再生用材料
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JP2009066227A (ja) * 2007-09-13 2009-04-02 National Cardiovascular Center 神経誘導管
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