WO2023214551A1 - 相分離構造を有する高分子材料 - Google Patents
相分離構造を有する高分子材料 Download PDFInfo
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- WO2023214551A1 WO2023214551A1 PCT/JP2023/016922 JP2023016922W WO2023214551A1 WO 2023214551 A1 WO2023214551 A1 WO 2023214551A1 JP 2023016922 W JP2023016922 W JP 2023016922W WO 2023214551 A1 WO2023214551 A1 WO 2023214551A1
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- Prior art keywords
- polymer
- polymeric
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- 239000002861 polymer material Substances 0.000 title claims abstract description 48
- 238000005191 phase separation Methods 0.000 title abstract description 20
- 229920000642 polymer Polymers 0.000 claims abstract description 147
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims description 67
- 239000000654 additive Substances 0.000 claims description 64
- 230000000996 additive effect Effects 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 54
- 150000003077 polyols Chemical group 0.000 claims description 41
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 35
- 229920001223 polyethylene glycol Polymers 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 125000003827 glycol group Chemical group 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 6
- 150000001543 aryl boronic acids Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 235000000346 sugar Nutrition 0.000 claims description 4
- 229920001222 biopolymer Polymers 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000007791 liquid phase Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- 239000012071 phase Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 125000002947 alkylene group Chemical group 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 11
- 125000000524 functional group Chemical group 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 5
- 125000004450 alkenylene group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 235000012209 glucono delta-lactone Nutrition 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 4
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 3
- 229920002385 Sodium hyaluronate Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000010724 Wisteria floribunda Nutrition 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 229960003681 gluconolactone Drugs 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229940010747 sodium hyaluronate Drugs 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005620 boronic acid group Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- ZHOGHWVKKXUAPI-UHFFFAOYSA-N fluorooxy(phenyl)borinic acid Chemical compound FOB(O)C1=CC=CC=C1 ZHOGHWVKKXUAPI-UHFFFAOYSA-N 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- -1 methylene, ethylene, propylene, butylene Chemical group 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000006174 pH buffer Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 150000000180 1,2-diols Chemical class 0.000 description 1
- 150000000185 1,3-diols Chemical class 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- CZDWJVSOQOMYGC-UHFFFAOYSA-N 4-borono-2-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C(F)=C1 CZDWJVSOQOMYGC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L101/00—Compositions of unspecified macromolecular compounds
- C08L101/02—Compositions of unspecified macromolecular compounds characterised by the presence of specified groups, e.g. terminal or pendant functional groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
- C08L51/08—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
- C08F283/06—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polyethers, polyoxymethylenes or polyacetals
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/42—Introducing metal atoms or metal-containing groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2201/00—Properties
- C08L2201/54—Aqueous solutions or dispersions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
- C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/04—Polymer mixtures characterised by other features containing interpenetrating networks
Definitions
- the present invention relates to an associative polymer material having a phase-separated structure.
- Typical slime consists of polymers forming meeting points through reversible interactions (ionic bonds, hydrophobic functional groups, dynamic covalent bonds, etc.) with each other or with other compounds. It is a substance that forms a transient three-dimensional network structure in a solvent such as. Because the meeting point has a finite lifespan, it is a liquid material that has both viscosity and elasticity, unlike polymer gels with similar compositions.
- a polymer gel is a solid material that exhibits a constant stress in an equilibrium state when a constant strain is applied and the time evolution of stress is observed, such as in stress relaxation measurements. Conversely, polymeric materials that do not have these characteristics are called non-gelling polymeric materials.
- slime-like polymeric materials are being studied for use as rheology control agents for foods and cosmetics, and as injectable internal tamponades and drug carriers (for example, Non-Patent Documents 1 and 2).
- conventional slime-like polymer materials exhibit fluid hardening (shear thickening), which causes an increase in viscosity in response to shearing, which hinders injection with syringes.
- an object of the present invention is to provide a novel artificial slime-like polymer material whose flow characteristics can be controlled without changing the chemical composition of the main chain skeleton, solvent, etc. that constitute the polymer material.
- the present inventors have discovered that, in addition to the polymer unit that forms the basic skeleton of the polymer material, by adding a polymer that is inactive to react with the polymer unit, - We have discovered that it is possible to provide a slime-like polymer material that induces liquid phase separation, and that its fluidity can be controlled, leading to the completion of the present invention.
- a non-gelling polymer material containing a solvent A three-dimensional structure in which a first region in which the polymer units are densely present and a second region in which the polymer units are sparsely exist in a phase-separated state by connecting a plurality of polymer units;
- the polymer unit includes a first polymer unit having a total of two or more boronic acid-containing groups at the end, and a second polymer unit having a total of two or more polyol groups at the end;
- the polymeric material further includes a polymeric additive having neither a boronic acid-containing group nor a polyol group at a terminal;
- the total concentration (c 1 ) of the first and second polymer units in the polymer material is 1 to 200 g/L, and 0.02 to 5 times the overlap concentration (c 1 * ) of the polymer units.
- the concentration (c 2 ) of the polymeric additive in the polymeric material is expressed by the following relational expression with respect to the overlap concentration (c 2 * ) of the polymeric additive: satisfy, The polymer material; ⁇ 2> The polymeric material according to ⁇ 1> above, wherein the solvent is water and the polymer unit is a hydrophilic polymer; ⁇ 3> The polymer material according to ⁇ 1> above, wherein the polymer unit has a polyethylene glycol skeleton or a polyvinyl skeleton; ⁇ 4> The polymeric material according to ⁇ 1> above, wherein the polymer units are each independently bi-branched, tri-branched, tetra-branched, or eight-branched polyethylene glycol; ⁇ 5> The polymer material according to ⁇ 1> above, wherein the polymer unit has a molecular weight (Mw) of 5x10 3 to 1x10 5 ; ⁇ 6> The polymeric material according to ⁇ 1> above, wherein the boronic acid
- the invention provides: ⁇ 12> A kit for forming the polymer material according to any one of ⁇ 1> to ⁇ 11> above, At least a composition A containing a first polymer unit having a total of two or more boronic acid-containing groups at the terminal, and a composition B containing a second polymer unit having a total of two or more polyol groups at the side chain or terminal.
- a container separately storing a solution A containing a first polymer unit having a total of two or more boronic acid-containing groups at the end and a solution B containing a second polymer unit having a total of two or more polyol groups at the end.
- At least one of the solutions A and B further includes a polymeric additive having neither a boronic acid-containing group nor a polyol group at the end, or solution C containing the polymeric additive is stored separately. further comprising a container containing;
- the total concentration (c 1 ) of the first and second polymer units in the mixed solution of the solutions A and B (and the solution C, if present) is 1 to 200 g/L, and the The overlap concentration (c 1 * ) of polymer units is in the range of 0.02 to 5;
- the concentration of the polymeric additive (c 2 ) in the mixed solution of the solutions A and B (and the solution C, if present) is relative to the overlap concentration (c 2 * ) of the polymeric additive.
- the kit satisfies the following; ⁇ 13>
- the present invention provides a manufacturing method including the step of adding the polymeric additive so as to satisfy the following.
- FIG. 1 is a phase diagram of phase separation behavior when the slime concentration and the added polymer concentration are variables. Both concentrations are normalized by the overlap concentration C*.
- Examples 1 to 3 Results of mixing linear PEG with slime ( ⁇ : Formation of phase-separated structure, ⁇ : Single phase without phase separation).
- Example 4 Results of mixing linear polyvinyl alcohol with slime ( ⁇ : Formation of phase-separated structure, 10: Single phase without phase separation).
- Example 5 Results of mixing linear hyaluronic acid with slime ( ⁇ : Formation of phase-separated structure, 10: Single phase without phase separation).
- FIG. 2 is an image observed by a confocal microscope of a sample subjected to fluorescence modification (left: single phase, right: phase separation, Example 2).
- FIG. 3 is a graph showing the strain rate dependence of viscosity ( ⁇ : conventional slime material, ⁇ : part of Example 3).
- the polymer material of the present invention is a slime-like associative polymer that does not gel (that is, in a non-gelled state), and has a plurality of polymer units connected to each other. It has a three-dimensional structure in which two phases with different polymer concentrations exist in a phase-separated state: a dense phase (first region) in which the units are densely present, and a dilute phase (second region) in which the polymer units are sparsely present. It is an associative polymer material.
- a polymer additive different from the polymer unit at a predetermined concentration liquid-liquid phase separation can be induced and the fluidity of the polymer material can be controlled. It has the following characteristics.
- the polymer material of the present invention is further characterized by satisfying the following requirements.
- the polymer unit constituting the polymeric material includes a first polymer unit having a total of two or more boronic acid-containing groups at the end, and a second polymer unit having a total of two or more polyol groups at the end.
- the polymeric material further comprises a polymeric additive having neither a boronic acid-containing group nor a polyol group at the end;
- the total concentration (c 1 ) of the first and second polymer units is 1 to 200 g/L and is in the range of 0.02 to 5 times the overlap concentration (c 1 * ) of the polymer units. ;
- the concentration of the polymeric additive (c 2 ) is expressed by the following relational expression with respect to the overlap concentration (c 2 * ) of the polymeric additive: to satisfy.
- the polymer material of the present invention is characterized by forming a three-dimensional network structure/porous structure through this phase separation, and the network size is on the ⁇ m order.
- the first region is referred to as a "dense phase" in the relative sense that the concentration (density) of polymer units present in that region is greater than the density in the second region.
- the first region has a concentration (density) about three times or more than the second region.
- the polymer units constituting the polymer material of the present invention can form a non-gelling polymer material by being connected to each other, and more specifically, the polymer units constituting the polymer material of the present invention can form a non-gelling polymer material.
- it is a polymer that can form a network structure, particularly a three-dimensional network structure, by linking the polymer units through chemical bonds caused by equilibrium reactions.
- Such polymer units are preferably hydrophilic polymers.
- a polymer having an affinity for water known in the art can be used, but preferably a biocompatible polymer having a polyalkylene glycol skeleton or a polyvinyl skeleton.
- the polymer having a polyalkylene glycol skeleton is preferably a polymer species having a plurality of branches of a polyethylene glycol skeleton, and bi-branched, tri-branched, quadri-branched or 8-branched polyethylene glycol is particularly preferred.
- a polymeric material consisting of a 4-branched polyethylene glycol skeleton is generally known as a Tetra-PEG polymeric material, and is composed of 4-branched polymers each having two or more types of functional groups that can react with each other at their ends. It is known that a network structure network is constructed by AB type cross-end coupling reaction (Matsunaga et al., Macromolecules, Vol. 42, No. 4, pp. 1344-1351, 2009).
- Tetra-PEG polymer materials can be easily produced on the spot by simply mixing two polymer solutions, and the polymer material production time can be reduced by adjusting the pH and ionic strength during polymer material preparation. It is also possible to control Furthermore, since this polymeric material has PEG as its main component, it also has excellent biocompatibility.
- hydrophilic polymer having a polyvinyl skeleton examples include polyalkyl methacrylates such as polymethyl methacrylate, polyacrylates, polyvinyl alcohol, polyN-alkylacrylamide, polyacrylamide, and the like.
- the hydrophilic polymer has a weight average molecular weight (Mw) in the range 5x10 3 to 1x10 5 , preferably in the range 1x10 4 to 5x10 4 .
- the hydrophilic polymer used in the present invention includes a first polymer unit having a total of two or more boronic acid-containing groups in its side chain or terminal, and a second polymer unit having a total of two or more polyol groups in its side chain or terminal. It is a combination of Here, the total number of boronic acid-containing groups and polyol groups is preferably 5 or more. It is further preferred that these functional groups exist at the ends.
- each branch end has a boronic acid-containing group
- the polymer unit has a two-branched, three-branched, four-branched, or eight-branched structure, it is preferable to have a polyol group at the end of each branch.
- the polymer unit has such a boronic acid-containing group and a polyol group
- the boronic acid moiety and the OH group of the polyol chemically react, as illustrated in the equilibrium reaction formula below, and the polymer units mutually interact.
- a polymeric material of the present invention having a structure in which the molecules are connected and associated can be obtained.
- the specific structures of the boronic acid-containing group and polyol group shown in the reaction formula are merely examples and are not limited to these, and as described later, other types of boronic acid-containing group and polyol group may be used. You can do something.
- the boronic acid-containing group present in the first polymer unit is not particularly limited as long as it has a structure having a boronic acid, but for example, an arylboronic acid, preferably an arylboronic acid which may be substituted with a halogen atom. can be.
- an arylboronic acid preferably an arylboronic acid which may be substituted with a halogen atom.
- phenylboronic acid is preferred.
- the boronic acid-containing groups may be the same or different, but are preferably the same. By having the same functional groups, the reactivity with the polyol group becomes uniform, making it easier to obtain a polymeric material having a uniform structure.
- the polyol group present in the second polymer unit is not particularly limited as long as it is a functional group having two or more hydroxyl groups (OH groups) such as 1,2-diol and 1,3-diol, but It can be a sugar alcohol having the structure, preferably one having an open ring structure of a sugar derivative.
- Such sugars can be monosaccharides, disaccharides, or polysaccharides, and typically monosaccharides such as glucose or fructose. Further, it may be an aromatic polyol group, an aliphatic polyol group, or a polyol group in which one or more carbon atoms in the molecule are substituted with a hetero atom.
- the polyol groups may be the same or different, but it is preferable that the polyol groups are the same.
- the reactivity with the boronic acid-containing group becomes uniform, making it easier to obtain a polymeric material having a uniform structure.
- the first polymer unit include, for example, a compound represented by the following formula (I) having four polyethylene glycol skeleton branches and a boronic acid-containing group at each end. can be mentioned.
- X is a boronic acid-containing group, and in a preferred embodiment, X can be a phenylboronic acid-containing group or a fluorophenylboronic acid-containing group having the following structure (in the partial structure , the wavy lines are the connections to R 11 to R 14 ).
- n 11 to n 14 may be the same or different. The closer the values of n 11 to n 14 are, the more uniform the three-dimensional structure can be, and the higher the strength. Therefore, in order to obtain a high-strength polymeric material, it is preferable that they be the same. If the value of n 11 to n 14 is too high, the strength of the polymeric material will be weakened, and if the value of n 11 to n 14 is too low, it will be difficult to form a polymeric material due to steric hindrance of the compound. Therefore, n 11 to n 14 have integer values of 25 to 250, preferably 35 to 180, more preferably 50 to 115, and particularly preferably 50 to 60.
- R 11 to R 14 which are the same or different, are linker moieties that connect the functional group and the core portion.
- R 11 to R 14 may be the same or different, but are preferably the same in order to produce a high-strength polymeric material having a uniform three-dimensional structure.
- R 11 to R 14 are a direct bond, a C 1 -C 7 alkylene group, a C 2 -C 7 alkenylene group, -NH-R 15 -, -CO-R 15 -, -R 16 -O-R 17 -, -R 16 -NH-R 17 -, -R 16 -CO 2 -R 17 -, -R 16 -CO 2 -NH-R 17 -, -R 16 -CO-R 17 -, or -R 16 -CO -NH-R 17 - is shown.
- R 15 represents a C 1 -C 7 alkylene group.
- R 16 represents a C 1 -C 3 alkylene group.
- R 17 represents a C 1 -C 5 alkylene group.
- C 1 -C 7 alkylene group means an alkylene group having 1 or more and 7 or less carbon atoms, which may have a branch, and is a straight chain C 1 -C 7 alkylene group or 1 or 2 carbon atoms. It means a C 2 -C 7 alkylene group having three or more branches (the number of carbon atoms including branches is 2 or more and 7 or less). Examples of C 1 -C 7 alkylene groups are methylene, ethylene, propylene, butylene.
- C 1 -C 7 alkylene groups are -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH(CH 3 )-, -(CH 2 ) 3 -, -( CH(CH 3 )) 2 -, -(CH 2 ) 2 -CH(CH 3 )-, -(CH 2 ) 3 -CH(CH 3 )-, -(CH 2 ) 2 -CH(C 2 H 5 )-, -(CH 2 ) 6 -, -(CH 2 ) 2 -C(C 2 H 5 ) 2 -, and -(CH 2 ) 3 C(CH 3 ) 2 CH 2 -.
- a "C 2 -C 7 alkenylene group” is a branched or branched alkenylene group having 2 to 7 carbon atoms and having one or more double bonds in the chain. Examples include divalent groups having a double bond formed by removing 2 to 5 hydrogen atoms from adjacent carbon atoms from an alkylene group.
- non-limiting specific examples preferable as the second polymer unit include, for example, a compound represented by the following formula (II) having four polyethylene glycol skeleton branches and a polyol group at each end. can be mentioned.
- Y is a polyol group, and in a preferred embodiment, Y can be a group having the following structure (in the partial structure, the wavy line portion is a link to R 21 to R 24 ).
- n 21 to n 24 may be the same or different. The closer the values of n 21 to n 24 are, the more uniform the three-dimensional structure of the polymer material can be, resulting in higher strength, so it is preferable, and it is preferable that they are the same. If the value of n 21 to n 24 is too high, the strength of the polymeric material will be weakened, and if the value of n 21 to n 24 is too low, it will be difficult to form a polymeric material due to steric hindrance of the compound. Therefore, n 21 to n 24 have an integer value of 5 to 300, preferably 20 to 250, more preferably 30 to 180, even more preferably 45 to 115, and even more preferably 45 to 55.
- R 21 to R 24 are linker moieties that connect the functional group and the core portion.
- R 21 to R 24 may be the same or different, but are preferably the same in order to produce a high-strength polymeric material having a uniform three-dimensional structure.
- R 21 to R 24 are each the same or different and include a direct bond, a C 1 -C 7 alkylene group, a C 2 -C 7 alkenylene group, -NH-R 25 -, -CO-R 25 - , -R 26 -O-R 27 -, -R 26 -NH-R 27 -, -R 26 -CO 2 -R 27 -, -R 26 -CO 2 -NH-R 27 -, -R 26 -CO -R 27 - or -R 26 -CO-NH-R 27 -.
- R 25 represents a C 1 -C 7 alkylene group.
- R 26 represents a C 1 -C 3 alkylene group.
- R 27 represents a C 1 -C 5 alkylene group.
- the alkylene group and alkenylene group may have one or more arbitrary substituents.
- substituents include an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group.
- the polymeric material can include, but is not limited to, a group, an aryl group, or the like. When an alkyl group has two or more substituents, they may be the same or different. The same applies to the alkyl moieties of other substituents containing alkyl moieties (eg, alkyloxy groups, aralkyl groups, etc.).
- substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. There isn't. Further substituents may be present in these substituents.
- the total concentration (c 1 ) of the first and second polymer units is 1 to 200 g/L, preferably 5 to 100 g/L. At the same time, the total concentration c 1 is in the range 0.02 to 3 times the overlap concentration (c 1 * ) of the polymer units, preferably in the range 0.1 to 2.
- overlap concentration refers to the concentration at which polymers in the solvent begin to spatially contact each other
- overlap concentration c * is expressed by the following formula: expressed. (where M w is the weight average molecular weight of the polymer; ⁇ is the specific gravity of the solvent; N A is Avogadro's constant; R g is the radius of gyration of the polymer).
- a method of calculating the overlap density c * for example, refer to Polymer Physics (written by M. Rubinstein and R. Colby). Specifically, for example, it can be determined by measuring the viscosity of a dilute solution using the Flory-Fox equation.
- the polymeric material of the present invention has an additional polymer component different from the first and second polymer units, that is, either a boronic acid-containing group or a polyol group at the terminal. It further includes no polymeric additives. As mentioned above, by adding such a polymeric additive at a predetermined concentration, liquid-liquid phase separation is induced and a slime-like polymeric material is obtained.
- the polymeric additive may preferably be a hydrophilic polymer or a biopolymer, such as polyethylene glycol, polyethylene oxide, polyvinyl alcohol, sodium hyaluronate, sodium polyacrylate, sodium polyvinylsulfonate, etc. It is.
- the polymeric additive is a polymer having a polyethylene glycol backbone or a polyvinyl backbone.
- the polymeric additive can be a polymer having the same type of main chain skeleton as the first and second polymer units.
- the present invention is not limited to this, and those having different main chain skeletons can also be used.
- using polyvinyl alcohol or sodium hyaluronate as a polymeric additive can also be used to create a slime-like polymer with a phase-separated structure. molecules can be obtained.
- the concentration (c 2 ) of the polymeric additive in the polymeric material is determined by the following relational expression with respect to the overlap concentration (c 2 * ) of the polymeric additive: satisfy.
- the polymeric additive typically has a weight average molecular weight (Mw) in the range 1x10 3 to 1x10 8 , preferably in the range 1x10 4 to 1x10 7 .
- the polymeric material of the present invention is characterized by having a structure in which liquid-liquid phase separation is induced by containing the above-mentioned polymeric additive at a predetermined concentration, and having excellent flow softening properties. That is, the polymeric material of the present invention exhibits a behavior in which the viscosity decreases as the strain rate increases in a low strain rate region. This phenomenon in which viscosity decreases with respect to strain rate is generally called "shear thinning.” Shear thinning means that the dependence of viscosity on strain rate is negative. For example, shear thinning occurs from a region where the strain rate is as low as 1 s -1 , making it possible to easily inject the polymer material with a syringe or syringe.
- the polymer material of the present invention contains a solvent and has a polymer content of 200 g/L or less, preferably 150 g/L or less, more preferably 100 g/L or less.
- the lower limit of the polymer content is not particularly limited, but from the viewpoint of obtaining desired physical properties such as viscosity, the lower limit is preferably 5 g/L or more.
- the polymer material of the present invention is characterized by having a porous structure on the order of ⁇ m due to a phase separation structure.
- the mesh size formed by the first region can be from 1 to 500 ⁇ m, preferably from 10 to 100 ⁇ m.
- the mesh size means the length of the long side of a mesh unit (i.e., a hole) whose outer periphery is formed by the first region, which is a dense phase. Alternatively, if the mesh unit is approximately circular, the length may be the diameter of the mesh unit. Inside such network units there is a second region of dilute phase and/or a solvent.
- the first region, the concentrated phase has a polymer concentration of 1 to 20% by weight, based on the entire gel including solvent, and the second region, the dilute phase, has a polymer concentration of 0 to 3% by weight. It has a high molecular concentration.
- the first region has a polymer concentration of 1 to 10% by weight and the second region has a polymer concentration of 0.01 to 2% by weight.
- any solvent can be used as long as it dissolves the aggregate formed by the polymer units, but typically water or an organic solvent can be used.
- an organic solvent can be used.
- alcohols such as ethanol and polar solvents such as DMSO can be used.
- the solvent is water.
- the polymeric material of the present invention can typically be produced by mixing a raw material containing a first polymer unit, a raw material containing a second polymer unit, and a polymeric additive.
- a solution containing polymer units as a raw material
- concentration, addition rate, mixing rate, and mixing ratio of each solution are not particularly limited, and can be adjusted as appropriate by those skilled in the art.
- water, alcohols such as ethanol, DMSO, etc. can be used as the solvent for such a solution.
- a suitable pH buffer such as a phosphate buffer can be used.
- the polymeric material of the present invention can be prepared using the kit described below.
- Kit and manufacturing method The present invention, in another aspect, relates to a kit and manufacturing method for forming the above-mentioned polymeric material.
- Such a kit separately comprises a solution A containing a first polymer unit having a total of two or more boronic acid-containing groups at the end, and a solution B containing a second polymer unit having a total of two or more polyol groups at the end. 1) at least one of the solutions A and B further contains a polymeric additive having neither a boronic acid-containing group nor a polyol group at its terminal; or 2) ) The method further includes a separate container containing a solution C containing a polymeric additive having neither a boronic acid-containing group nor a polyol group at its terminal end.
- the polymer units and polymeric additives in solutions A and B are set in the following concentration ranges.
- the total concentration (c 1 ) of the first and second polymer units in the mixed solution of solutions A and B (and the solution C, if present) is 1 to 200 g/L
- the overlap concentration (c 1 * ) of polymer units is in the range of 0.02 to 5.
- concentration (c 2 ) of the polymeric additive in the mixed solution of Solutions A and B (and the solution C, if present) is equal to the overlap concentration (c 2 * ) of the polymeric additive.
- the above-described polymeric material of the present invention can be obtained in-situ by mixing solutions A and B (and the solution C, if present). Details of the first and second polymer units, the types of polymeric additives, etc. are as described above.
- the solvent in polymer solutions A, B, and C is water, but in some cases, a mixed solvent containing alcohols such as ethanol or other organic solvents may be used.
- these polymer solutions are aqueous solutions containing water as the sole solvent.
- the volume of each polymer solution can be adjusted as appropriate depending on the area and complexity of the structure of the affected area to which it is applied, but typically it is in the range of 0.1 to 20 ml, preferably in the range of 0.1 to 20 ml. The volume is 1 to 10 ml.
- the pH of each polymer solution is typically in the range of 4 to 8, preferably in the range of 5 to 7.
- a pH buffer agent known in the art can be used.
- the pH can be adjusted within the above range by using a citric acid-phosphate buffer (CPB) and changing the mixing ratio of citric acid and disodium hydrogen phosphate.
- CPB citric acid-phosphate buffer
- a two-component mixing syringe as disclosed in International Publication No. WO 2007/083522 can be used.
- the temperature of the two liquids at the time of mixing is not particularly limited, and may be any temperature at which each polymer unit is dissolved and each liquid has fluidity.
- the temperatures of the two liquids may be different, but it is preferable that the two liquids are at the same temperature because the two liquids can be mixed easily.
- a device such as a sprayer containing a polymer solution can be used as a container in the kit of the present invention.
- a device such as a sprayer containing a polymer solution
- the nebulizer any one known in the art can be used as appropriate, and preferably a medical nebulizer.
- the present invention also relates to a method of manufacturing the above-mentioned polymeric material.
- the production method involves mixing a first polymer unit having a total of two or more boronic acid-containing groups at the end, a second polymer unit having a total of two or more polyol groups at the end, and a solvent to prepare a polymer solution. and adding a polymeric additive having neither a boronic acid-containing group nor a polyol group at the end, the total concentration of the first and second polymer units in the polymeric material being c. 1 , the overlapping concentration of the polymer unit is c 1 * , the concentration of the polymeric additive is c 2 * , the following relational expression:
- the method includes the step of adding the polymeric additive so as to satisfy the following.
- the polymer unit constituting the polymeric material is Tetra-PEG-GDL, which has a polyol group (opened ring structure of gluconolactone) at the end of four-branched tetrapolyethylene glycol, and a fluorophenylboronic acid group at the end.
- Tetra-PEG-FPBA having the following structure was synthesized.
- Tetra-PEG-NH 2 molecular weight Mw used: 5k, 10k, and 20k, respectively; Yuka Sangyo Co., Ltd.
- 4-carboxy-3-fluorophenylboronic acid FPBA
- FPBA Fluji Film Wako Pure Chemical Industries, Ltd.
- DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
- DMT-MM Glucono- ⁇ -lactone
- GDL Tokyo Kasei Kogyo Co., Ltd.
- Tetra-PEG-GDL Tetra-PEG-NH 2 having an amino group at the end was dissolved in methanol at a concentration of 50 mg/mL, and the molar ratio was 10 times that of the terminal amino group of Tetra-PEG-NH 2 .
- of gluconolactone and 20 times as much triethylamine were added, and the mixture was stirred at 35°C for 3 days.
- Transfer the reaction solution to a dialysis membrane MWCO: 6-8,000 for 20k, MWCO: 3,500 for 10k, 5k
- dialyze with methanol for 2 days and water for 2 days pass through a 0.45 um syringe filter. , freeze-dried and recovered as a powder. Completion of the synthesis was confirmed by 1 H-NMR.
- Tetra-PEG-FPBA Tetra-PEG-FPBA Tetra-PEG-NH 2 was dissolved in methanol at a concentration of 50 mg/mL, and the molar ratio of FPBA to the terminal amino group of Tetra-PEG-NH 2 was 5 times that of FPBA and 10 times that of Tetra-PEG-NH 2 . DMT-MM was added and stirred at room temperature overnight. Transfer the reaction solution to a dialysis membrane (MWCO: 6-8,000 for 20k, MWCO: 3,500 for 10k, 5k), and soak in hydrochloric acid aqueous solution (10 mM) for half a day and sodium hydroxide aqueous solution (10 mM) for half a day.
- MWCO dialysis membrane
- linear polyvinyl alcohol 100k
- Seikagaku Corporation linear sodium hyaluronate (2500k)
- Figure 1 shows a plot of the results of confirming the formation of a phase-separated structure for various polymer materials synthesized in .
- a sample that has undergone fluorescence modification such as fluorescein is observed using a confocal laser microscope (LSM800, manufactured by Zeiss) at an excitation wavelength of 498 nm and an observation wavelength of 598 nm.
- LSM800 confocal laser microscope
- Tetra-PEG-NH2 (molecular weight Mw used: 5k, 10k, and 20k, respectively; Yuka Sangyo Co., Ltd.) was dissolved in methanol at a concentration of 50mg/ml, and the It was reacted with fluorescein isothiocyanate (FITC) (manufactured by Sigma Aldrich) and stirred at 25°C for 1 day. Thereafter, 10 times the amount of gluconolactone and 20 equivalents of triethylamine were added to the NH2 terminal, and the mixture was stirred at 35°C for 3 days.
- FITC fluorescein isothiocyanate
- reaction solution Transfer the reaction solution to a dialysis membrane (MWCO: 6-8,000 for 20k, MWCO: 3,500 for 10k, 5k), dialyze with methanol and deionized water for 1 day each, and filter with a 0.45 ⁇ m syringe filter. Ta. Thereafter, the reaction solution was freeze-dried and the reaction product was recovered as a solid.
- a fluorescently modified sample was obtained by mixing Tetra-PEG-FPBA synthesized in 1 and a polymeric additive. It has been confirmed that there is almost no change in physical properties due to fluorescence modification.
- the horizontal axis is the total concentration of first and second polymer units (c 1 )/overlapping concentration of polymer units (c 1 * ); the vertical axis is the concentration of added polymeric additive (c 1 *); c 2 )/overlap concentration of polymeric additive (c 2 * ).
- Results of mixing linear PEG with slime ⁇ : Formation of phase-separated structure, ⁇ : Single phase without phase separation) (Example 1-3); Results of mixing linear polyvinyl alcohol with slime ( ⁇ : Formation of phase-separated structure Formation, 10: single phase without phase separation) (Example 4); result of mixing linear hyaluronic acid with slime ( ⁇ : formation of phase separated structure, 10: single phase without phase separation) (Example 5) be.
- Viscosity Measurement The steady-state viscosity change of the polymer material of Example 3 was also measured under strain rates of 0.001-100 s -1 . The results are shown in FIG. As shown in Figure 3, in the polymer material ( ⁇ ) containing no polymer additive, the viscosity decreased with respect to the strain rate ( ⁇ ) after taking a constant value up to about 1 s -1 . On the other hand, the polymer material of Example 3 ( ⁇ , ⁇ , ⁇ ) exhibited a so-called "shear thinning" behavior in which the viscosity already decreased from the low strain rate region around 10 -2 s -1 , and was excellent. It was found that it has flow softening properties.
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Abstract
Description
<1>溶媒を含有する非ゲル化高分子材料であって、
複数のポリマーユニットが連結することで、前記ポリマーユニットが密に存在する第1領域と、前記ポリマーユニットが疎に存在する第2領域が相分離状態で存在する3次元構造を有し;
前記ポリマーユニットが、末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットと、末端に合計2以上のポリオール基を有する第2のポリマーユニットとを含み;
前記高分子材料が、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含み;
前記高分子材料中における第1及び第2のポリマーユニットの合計濃度(c1)が、1~200g/Lであり、かつ前記ポリマーユニットの重なり合い濃度(c1 *)の0.02~5倍の範囲であり;
前記高分子材料中における前記ポリマー性添加剤の濃度(c2)が、前記ポリマー性添加剤の重なり合い濃度(c2 *)に対して以下の関係式:
該高分子材料;
<2>前記溶媒が水であり、前記ポリマーユニットが親水性ポリマーである、上記<1>に記載の高分子材料;
<3>前記ポリマーユニットが、ポリエチレングリコール骨格又はポリビニル骨格を有する、上記<1>に記載の高分子材料;
<4>前記ポリマーユニットが、それぞれ独立に、2分岐、3分岐、4分岐、又は8分岐のポリエチレングリコールである、上記<1>に記載の高分子材料;
<5>前記ポリマーユニットが、5x103~1x105の分子量(Mw)を有する、上記<1>に記載の高分子材料;
<6>前記ボロン酸含有基が、ハロゲン原子で置換されていてもよいアリールボロン酸である、上記<1>に記載の高分子材料;
<7>前記ポリオール基が、糖誘導体の開環構造を有する、上記<1>に記載の高分子材料;
<8>前記ポリマー性添加剤が、親水性ポリマー又は生体高分子である、上記<1>に記載の高分子材料;
<9>前記ポリマー性添加剤が、ポリエチレングリコール骨格又はポリビニル骨格を有する、上記<1>に記載の高分子材料;
<10>前記ポリマー性添加剤が、前記ポリマーユニットと同種の主鎖骨格を有するポリマーである、上記<1>に記載の高分子材料;
<11>前記ポリマー性添加剤が、1x103~1x108の分子量(Mw)を有する、上記<1>に記載の高分子材料
を提供するものである。
<12> 上記<1>~<11>のいずれか1に記載の高分子材料を形成するためのキットであって、
末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットを含む組成物Aと、側鎖又は末端に合計2以上のポリオール基を有する第2のポリマーユニットを含む組成物Bを少なくとも含み、
末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットを含む溶液Aと、末端に合計2以上のポリオール基を有する第2のポリマーユニットとを含む溶液Bをそれぞれ別個に格納した容器を含み;
前記溶液A及びBの少なくともいずれか一方に、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含み、或いは、前記ポリマー性添加剤を含む溶液Cを別個に格納した容器をさらに含み;
前記溶液A及びB(及び、存在する場合、前記溶液C)を混合した溶液における、前記第1及び第2のポリマーユニットの合計濃度(c1)が、1~200g/Lであり、かつ前記ポリマーユニットの重なり合い濃度(c1 *)の0.02~5の範囲であり;
前記溶液A及びB(及び、存在する場合、前記溶液C)を混合した溶液における、前記ポリマー性添加剤の濃度(c2)が、前記ポリマー性添加剤の重なり合い濃度(c2 *)に対して以下の関係式:
<13>上記<1>~<11>のいずれか1に記載の高分子材料の製造方法であって、末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットと、末端に合計2以上のポリオール基を有する第2のポリマーユニットと、溶媒を混合し、ポリマー溶液を調製する工程と、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤を添加する工程であって、前記高分子材料中における第1及び第2のポリマーユニットの合計濃度をc1とし、前記ポリマーユニットの重なり合い濃度をc1 *とし、前記ポリマー性添加剤の濃度をとし、前記ポリマー性添加剤の重なり合い濃度をc2 *とした場合に、
以下の関係式:
を含む製造方法
を提供するものである。
本発明の高分子材料は、ゲル化しない(すなわち、非ゲル化状態)、かつスライム状の会合性高分子であって、複数のポリマーユニットが連結することで、前記ポリマーユニットが密に存在する濃厚相(第1領域)と、前記ポリマーユニットが疎に存在する希薄相(第2領域)というポリマー濃度が異なる2つの相が相分離状態で存在する3次元構造を有する会合性高分子材料である。そして、本発明では、上記ポリマーユニットとは異なるポリマー性添加剤を所定の濃度で添加することにより、液-液相分離が誘起され、高分子材料の流動性を制御し得ることを見出した点に特徴を有する。
1)高分子材料を構成するポリマーユニットが、末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットと、末端に合計2以上のポリオール基を有する第2のポリマーユニットとを含むこと
2)高分子材料が、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含むこと;
3)第1及び第2のポリマーユニットの合計濃度(c1)が、1~200g/Lであり、かつポリマーユニットの重なり合い濃度(c1 *)の0.02~5倍の範囲であること;
4)ポリマー性添加剤の濃度(c2)が、ポリマー性添加剤の重なり合い濃度(c2 *)に対して以下の関係式:
本発明の高分子材料を構成するポリマーユニットは、互いに連結することによって非ゲル性の高分子材料を形成し得るものであって、より詳細には、最終的な高分子材料において、当該ポリマーユニットが平衡反応による化学結合を介して連結することにより網目構造、特に、3次元網目構造の会合体を形成し得るポリマーである。かかるポリマーユニットは、好ましくは親水性ポリマーである。親水性ポリマーは、当該技術分野において公知の水に対して親和性を有するポリマーを用いることができるが、好ましくは、ポリアルキレングリコール骨格又はポリビニル骨格を有する生体適合性ポリマーである。
本発明の高分子材料は、上記第1及び第2のポリマーユニットとは異なる更なるポリマー成分、すなわち、末端にボロン酸含有基及び前記ポリオール基のいずれをも有しないポリマー性添加剤をさらに含む。上述のように、かかるポリマー性添加剤を所定の濃度で添加することにより、液-液相分離が誘起されスライム状の高分子材料が得られる。
かかる流動軟化性は、従来のスライム状高分子材料では実現されていなかった特定である。
本発明は、別の観点において、上記高分子材料を形成するためのキット及び製造方法に関する。
1)前記溶液A及びBの少なくともいずれか一方に、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含み、或いは
2)末端にボロン酸含有基及び前記ポリオール基のいずれをも有しないポリマー性添加剤を含む溶液Cを別個に格納した容器をさらに含む。
を含むものである。
高分子材料を構成するポリマーユニットとして、4分岐テトラポリエチレングリコールの末端にポリオール基(グルコノラクトンの開環構造)を有するTetra-PEG-GDL、及び末端にフルオロフェニルボロン酸基を有するTetra-PEG-FPBAを合成した。
アミノ基を末端に有するTetra-PEG-NH2をメタノールに50 mg/mLの濃度で溶解し、Tetra-PEG-NH2の末端アミノ基に対してモル比で10倍のグルコノラクトン、20倍のトリエチルアミンを添加し、35℃で3日間撹拌した。反応液を透析膜に移し(20kの場合はMWCO: 6-8,000、10k, 5kの場合はMWCO: 3,500)、メタノールで2日間、水で2日間透析し、0.45 umのシリンジフィルターを通した後、凍結乾燥して粉体で回収した。1H-NMRで合成の完了を確認した。
Tetra-PEG-NH2をメタノールに50 mg/mLの濃度で溶解し、Tetra-PEG-NH2の末端アミノ基に対してモル比で5倍のFPBA、10倍のDMT-MMを添加し、室温で一晩撹拌した。反応液を透析膜に移し(20kの場合はMWCO: 6-8,000、10k, 5kの場合はMWCO: 3,500)、塩酸水溶液(10 mM)で半日間・水酸化ナトリウム水溶液(10 mM)で半日、リン酸緩衝液(pH 7.4、10 mM)で半日、食塩水(100 mM)で1日、最後に純水で1日透析し、0.45 umのシリンジフィルターを通した後、凍結乾燥して粉体で回収した。1H-NMRで合成の完了を確認した。
得られたポリマーユニットを含む溶液A及びB、さらに、ポリマー性添加剤を含む溶液Cを以下の条件で調製し、これらポリマー溶液を混合して、以下の表に示す組成の高分子材料を合成した。
[ポリマー溶液A]
濃度:0.2-4wt% Tetra-PEG-GDL(ポリオール末端)
pH:7.4
[ポリマー溶液B]
濃度:0.2-4wt% Tetra-PEG-FPBA(ボロン酸末端)
pH:7.4
[ポリマー溶液C]
濃度:0.0025-10wt% 各種ポリマー性添加剤
pH:7.4
上記1.で合成した各種高分子材料について、相分離構造の形成の有無を確認した結果をプロットしたものを図1に示す。ここで、相分離構造の形成の確認は、フルオロセインなどの蛍光修飾を施した試料について共焦点レーザー顕微鏡(LSM800 、Zeiss社製)にて励起波長498nm、観察波長598nmで観察し、5μm以上の構造体(すなわち、取得される画像上に異なる色で示される構造)が確認されたものを相分離構造と認定した(図2)。
Tetra-PEG-NH2 (分子量Mwは、それぞれ5k、10k、20kのものを用いた;油化産業株式会社)をメタノールに 50mg/ml の濃度で溶解し、NH2 末端に対して0.001倍の Fluorescein isothiocyanate (FITC) (Sigma Aldrich社製) と反応させ、25°Cで1日間攪拌した。その後、NH2 末端に対して 10 倍のグルコノラクトン、20等量のトリエチルアミンを加え、35℃ で 3 日間攪拌した。反応液を透析膜 (20kの場合はMWCO: 6-8,000、10k, 5kの場合はMWCO: 3,500)に移し、メタノールと脱イオン水で 1 日間ずつ透析し、0.45 μm のシリンジフィルターでフィルタリングを行った。その後、反応液に凍結乾燥をかけ反応物を固体として回収した。
得られた蛍光修飾されたTetra-PEG-GDLと上記1.で合成したTetra-PEG-FPBAおよびポリマー性添加剤を混合することで、蛍光修飾試料を取得した。蛍光修飾による物性の変化はほぼないことを確認している。
また、上記実施例3の高分子材料について、0.001‐100s‐1のひずみ速度下における定常粘度変化を測定した。その結果を図3に示す。図3に示すように、ポリマー添加剤を含まない高分子材料 (○) では、粘度がひずみ速度(γ)に対して、1s‐1 程度まで一定値を取った後、減衰した。一方で、実施例3の高分子材料(●・△・□) は、10-2s‐1付近の低いひずみ速度領域から、既に粘度が減衰する、いわゆる「シアシニング」の挙動を示し、優れた流動軟化性を有することが分かった。
Claims (13)
- 溶媒を含有する非ゲル化高分子材料であって、
複数のポリマーユニットが連結することで、前記ポリマーユニットが密に存在する第1領域と、前記ポリマーユニットが疎に存在する第2領域が相分離状態で存在する3次元構造を有し;
前記ポリマーユニットが、末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットと末端に合計2以上のポリオール基を有する第2のポリマーユニットとを含み;
前記高分子材料が、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含み;
前記高分子材料中における第1及び第2のポリマーユニットの合計濃度(c1)が、1~200g/Lであり、かつ前記ポリマーユニットの重なり合い濃度(c1 *)の0.02~5倍の範囲であり;
前記高分子材料中における前記ポリマー性添加剤の濃度(c2)が、前記ポリマー性添加剤の重なり合い濃度(c2 *)に対して以下の関係式:
該高分子材料。 - 前記溶媒が水であり、前記ポリマーユニットが親水性ポリマーである、請求項1に記載の高分子材料。
- 前記ポリマーユニットが、ポリエチレングリコール骨格又はポリビニル骨格を有する、請求項1に記載の高分子材料。
- 前記ポリマーユニットが、それぞれ独立に、2分岐、3分岐、4分岐、又は8分岐のポリエチレングリコールである、請求項1に記載の高分子材料。
- 前記ポリマーユニットが、5x103~1x105の分子量(Mw)を有する、請求項1に記載の高分子材料。
- 前記ボロン酸含有基が、ハロゲン原子で置換されていてもよいアリールボロン酸である、請求項1に記載の高分子材料。
- 前記ポリオール基が、糖誘導体の開環構造を有する、請求項1に記載の高分子材料。
- 前記ポリマー性添加剤が、親水性ポリマー又は生体高分子である、請求項1に記載の高分子材料。
- 前記ポリマー性添加剤が、ポリエチレングリコール骨格又はポリビニル骨格を有する、請求項1に記載の高分子材料。
- 前記ポリマー性添加剤が、前記ポリマーユニットと同種の主鎖骨格を有するポリマーである、請求項1に記載の高分子材料。
- 前記ポリマー性添加剤が、1x103~1x108の分子量(Mw)を有する、請求項1に記載の高分子材料。
- 請求項1~11のいずれか1に記載の高分子材料を形成するためのキットであって、
末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットを含む溶液Aと、末端に合計2以上のポリオール基を有する第2のポリマーユニットとを含む溶液Bをそれぞれ別個に格納した容器を少なくとも含み;
前記溶液A及びBの少なくともいずれか一方に、末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤をさらに含み、或いは、前記ポリマー性添加剤を含む溶液Cを別個に格納した容器をさらに含み;
前記溶液A及びB(及び、存在する場合、前記溶液C)を混合した溶液における、前記第1及び第2のポリマーユニットの合計濃度(c1)が、1~200g/Lであり、かつ前記ポリマーユニットの重なり合い濃度(c1 *)の0.02~5倍の範囲であり;
前記溶液A及びB(及び、存在する場合、前記溶液C)を混合した溶液における、前記ポリマー性添加剤の濃度(c2)が、前記ポリマー性添加剤の重なり合い濃度(c2 *)に対して以下の関係式:
該キット。 - 請求項1~11のいずれか1に記載の高分子材料の製造方法であって、
末端に合計2以上のボロン酸含有基を有する第1のポリマーユニットと、末端に合計2以上のポリオール基を有する第2のポリマーユニットと、溶媒を混合し、ポリマー溶液を調製する工程と、
末端にボロン酸含有基及びポリオール基のいずれをも有しないポリマー性添加剤を添加する工程であって、
前記高分子材料中における第1及び第2のポリマーユニットの合計濃度をc1とし、前記ポリマーユニットの重なり合い濃度をc1 *とし、前記ポリマー性添加剤の濃度をとし、前記ポリマー性添加剤の重なり合い濃度をc2 *とした場合に、
以下の関係式:
を含む製造方法。
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