WO2023145886A1 - Nanofibres - Google Patents
Nanofibres Download PDFInfo
- Publication number
- WO2023145886A1 WO2023145886A1 PCT/JP2023/002672 JP2023002672W WO2023145886A1 WO 2023145886 A1 WO2023145886 A1 WO 2023145886A1 JP 2023002672 W JP2023002672 W JP 2023002672W WO 2023145886 A1 WO2023145886 A1 WO 2023145886A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- water
- based resin
- nanofibers
- polymer
- pva
- Prior art date
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- 239000002121 nanofiber Substances 0.000 title claims abstract description 91
- 229920005989 resin Polymers 0.000 claims abstract description 91
- 239000011347 resin Substances 0.000 claims abstract description 91
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 82
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 82
- 229920000642 polymer Polymers 0.000 claims abstract description 39
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 15
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims description 40
- 239000000835 fiber Substances 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 31
- 229920003168 pharmaceutical polymer Polymers 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 26
- 238000007127 saponification reaction Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- 238000001523 electrospinning Methods 0.000 claims description 17
- 239000011259 mixed solution Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 238000010828 elution Methods 0.000 abstract description 6
- 238000013268 sustained release Methods 0.000 abstract description 5
- 239000012730 sustained-release form Substances 0.000 abstract description 5
- 238000009987 spinning Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000007788 liquid Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 15
- 239000004745 nonwoven fabric Substances 0.000 description 14
- -1 ethylene, propylene, isobutylene Chemical group 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 230000005684 electric field Effects 0.000 description 11
- 239000000178 monomer Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102000016943 Muramidase Human genes 0.000 description 9
- 108010014251 Muramidase Proteins 0.000 description 9
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 9
- 239000004325 lysozyme Substances 0.000 description 9
- 229960000274 lysozyme Drugs 0.000 description 9
- 235000010335 lysozyme Nutrition 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000004140 cleaning Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 229920001567 vinyl ester resin Polymers 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 238000007664 blowing Methods 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 229920001290 polyvinyl ester Polymers 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000005484 gravity Effects 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000379 polymerizing effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000005639 Lauric acid Substances 0.000 description 2
- 229920001410 Microfiber Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 229920000459 Nitrile rubber Polymers 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- ZQMIGQNCOMNODD-UHFFFAOYSA-N diacetyl peroxide Chemical compound CC(=O)OOC(C)=O ZQMIGQNCOMNODD-UHFFFAOYSA-N 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 238000010041 electrostatic spinning Methods 0.000 description 2
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 229910052755 nonmetal Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- SQTUYFKNCCBFRR-UHFFFAOYSA-N (2,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(OC)=C1 SQTUYFKNCCBFRR-UHFFFAOYSA-N 0.000 description 1
- ORTVZLZNOYNASJ-UPHRSURJSA-N (z)-but-2-ene-1,4-diol Chemical compound OC\C=C/CO ORTVZLZNOYNASJ-UPHRSURJSA-N 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- BCITXCOYSHAADW-UHFFFAOYSA-N 1-[2-(4-oxoheptoxymethyl)prop-2-enoxy]heptan-4-one Chemical compound C(CCC(=O)CCC)OCC(COCCCC(=O)CCC)=C BCITXCOYSHAADW-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- CRSBERNSMYQZNG-UHFFFAOYSA-N 1-dodecene Chemical compound CCCCCCCCCCC=C CRSBERNSMYQZNG-UHFFFAOYSA-N 0.000 description 1
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- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical compound CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 1
- FKAKGSJLTBVQOP-UHFFFAOYSA-N 2-(acetyloxymethyl)prop-2-enyl acetate Chemical compound CC(=O)OCC(=C)COC(C)=O FKAKGSJLTBVQOP-UHFFFAOYSA-N 0.000 description 1
- ICENLAOCDMWIAT-UHFFFAOYSA-N 2-(dimethylamino)-n-methylprop-2-enamide Chemical compound CNC(=O)C(=C)N(C)C ICENLAOCDMWIAT-UHFFFAOYSA-N 0.000 description 1
- DIBCJRYCOGXPAM-UHFFFAOYSA-N 2-(propanoyloxymethyl)prop-2-enyl propanoate Chemical compound CCC(=O)OCC(=C)COC(=O)CC DIBCJRYCOGXPAM-UHFFFAOYSA-N 0.000 description 1
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- IGDCJKDZZUALAO-UHFFFAOYSA-N 2-prop-2-enoxypropane-1,3-diol Chemical compound OCC(CO)OCC=C IGDCJKDZZUALAO-UHFFFAOYSA-N 0.000 description 1
- SCHZETOYDJAZMO-UHFFFAOYSA-M 3-chloropropyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCCCl SCHZETOYDJAZMO-UHFFFAOYSA-M 0.000 description 1
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- IOMDIVZAGXCCAC-UHFFFAOYSA-M diethyl-bis(prop-2-enyl)azanium;chloride Chemical compound [Cl-].C=CC[N+](CC)(CC)CC=C IOMDIVZAGXCCAC-UHFFFAOYSA-M 0.000 description 1
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- YCUBDDIKWLELPD-UHFFFAOYSA-N ethenyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC=C YCUBDDIKWLELPD-UHFFFAOYSA-N 0.000 description 1
- WNMORWGTPVWAIB-UHFFFAOYSA-N ethenyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC=C WNMORWGTPVWAIB-UHFFFAOYSA-N 0.000 description 1
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- GLVVKKSPKXTQRB-UHFFFAOYSA-N ethenyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC=C GLVVKKSPKXTQRB-UHFFFAOYSA-N 0.000 description 1
- GFJVXXWOPWLRNU-UHFFFAOYSA-N ethenyl formate Chemical compound C=COC=O GFJVXXWOPWLRNU-UHFFFAOYSA-N 0.000 description 1
- AFSIMBWBBOJPJG-UHFFFAOYSA-N ethenyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC=C AFSIMBWBBOJPJG-UHFFFAOYSA-N 0.000 description 1
- BLZSRIYYOIZLJL-UHFFFAOYSA-N ethenyl pentanoate Chemical compound CCCCC(=O)OC=C BLZSRIYYOIZLJL-UHFFFAOYSA-N 0.000 description 1
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- JHEPBQHNVNUAFL-UHFFFAOYSA-N hex-1-en-1-ol Chemical compound CCCCC=CO JHEPBQHNVNUAFL-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011553 magnetic fluid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000005641 methacryl group Chemical group 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QRWZCJXEAOZAAW-UHFFFAOYSA-N n,n,2-trimethylprop-2-enamide Chemical compound CN(C)C(=O)C(C)=C QRWZCJXEAOZAAW-UHFFFAOYSA-N 0.000 description 1
- GBCKRQRXNXQQPW-UHFFFAOYSA-N n,n-dimethylprop-2-en-1-amine Chemical compound CN(C)CC=C GBCKRQRXNXQQPW-UHFFFAOYSA-N 0.000 description 1
- OMNKZBIFPJNNIO-UHFFFAOYSA-N n-(2-methyl-4-oxopentan-2-yl)prop-2-enamide Chemical compound CC(=O)CC(C)(C)NC(=O)C=C OMNKZBIFPJNNIO-UHFFFAOYSA-N 0.000 description 1
- BGDTWOQNFJNCKH-UHFFFAOYSA-N n-ethyl-n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCN(CC)CC=C BGDTWOQNFJNCKH-UHFFFAOYSA-N 0.000 description 1
- WGESLFUSXZBFQF-UHFFFAOYSA-N n-methyl-n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCN(C)CC=C WGESLFUSXZBFQF-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012811 non-conductive material Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- CCCMONHAUSKTEQ-UHFFFAOYSA-N octadec-1-ene Chemical compound CCCCCCCCCCCCCCCCC=C CCCMONHAUSKTEQ-UHFFFAOYSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000001254 oxidized starch Substances 0.000 description 1
- 235000013808 oxidized starch Nutrition 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000002685 polymerization catalyst Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- UIIIBRHUICCMAI-UHFFFAOYSA-N prop-2-ene-1-sulfonic acid Chemical compound OS(=O)(=O)CC=C UIIIBRHUICCMAI-UHFFFAOYSA-N 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 229940023143 protein vaccine Drugs 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002803 thermoplastic polyurethane Polymers 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- TZYULTYGSBAILI-UHFFFAOYSA-M trimethyl(prop-2-enyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC=C TZYULTYGSBAILI-UHFFFAOYSA-M 0.000 description 1
- OTRQTVHWMPQPOJ-UHFFFAOYSA-N trimethyl-(prop-2-enoylamino)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)NC(=O)C=C OTRQTVHWMPQPOJ-UHFFFAOYSA-N 0.000 description 1
- CCVMLEHYQVSFOM-UHFFFAOYSA-N trimethyl-[2-(prop-2-enoylamino)ethyl]azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCNC(=O)C=C CCVMLEHYQVSFOM-UHFFFAOYSA-N 0.000 description 1
- OEIXGLMQZVLOQX-UHFFFAOYSA-N trimethyl-[3-(prop-2-enoylamino)propyl]azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCCNC(=O)C=C OEIXGLMQZVLOQX-UHFFFAOYSA-N 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
- LTVDFSLWFKLJDQ-UHFFFAOYSA-N α-tocopherolquinone Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/04—Dry spinning methods
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/08—Melt spinning methods
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
- D01F6/02—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolymers obtained by reactions only involving carbon-to-carbon unsaturated bonds
- D01F6/14—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolymers obtained by reactions only involving carbon-to-carbon unsaturated bonds from polymers of unsaturated alcohols, e.g. polyvinyl alcohol, or of their acetals or ketals
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
- D01F6/44—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from mixtures of polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds as major constituent with other polymers or low-molecular-weight compounds
- D01F6/50—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from mixtures of polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds as major constituent with other polymers or low-molecular-weight compounds of polyalcohols, polyacetals or polyketals
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
- D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
- D04H1/4282—Addition polymers
- D04H1/4309—Polyvinyl alcohol
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
- D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
- D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
Definitions
- the present invention relates to nanofibers containing a polyvinyl alcohol-based resin (A) and a water-soluble pharmaceutical polymer (B), and a method for producing the same.
- Patent Document 1 describes drug-containing ultrafine fibers.
- Patent Document 2 discloses a method for improving the elution rate of a sparingly soluble drug by converting the sparingly soluble drug into nanofibers using a polyvinyl alcohol-based resin.
- Low-molecular-weight drugs have stable chemical structures, but high-molecular-weight drugs such as protein drugs have complex and heterogeneous structures. They also behave differently.
- high-molecular-weight drugs are less stable than low-molecular-weight drugs, and there is a concern that they may decompose in nanofiber formation processes such as electrospinning.
- due to the properties of water-soluble high-molecular drugs they are rapidly released from the matrix even if sustained release is desired, making it difficult to achieve sustained release using existing techniques. Therefore, there has been a demand for a method of forming nanofibers from water-soluble pharmaceutical macromolecules and controlling their release behavior.
- the object of the present invention is to provide nanofibers in which the elution of water-soluble pharmaceutical polymers is controlled to be released, and formulations made of the nanofibers.
- a method for producing nanofibers containing a polyvinyl alcohol-based resin and a water-soluble medicinal polymer comprising electrospinning or melt blowing using a mixed solution containing the polyvinyl alcohol-based resin and the water-soluble medicinal polymer.
- a method for producing nanofibers comprising a step of producing nanofibers by (8) The method for producing nanofibers according to (7) above, wherein the solvent of the mixture is water.
- a formulation comprising the nanofibers according to any one of (1) to (6) above.
- nanofiber preparation in which the water-soluble pharmaceutical polymer (B) is eluted in a controlled release can be obtained.
- the nanofiber of the present invention contains a polyvinyl alcohol resin (A) and a water-soluble medicinal polymer (B).
- a first form provides a nanofiber containing a water-soluble medicinal polymer (B) having a molecular weight of 1,000 or more and 50,000 or less.
- a nanofiber containing a water-soluble drug polymer (B), which is a protein drug is provided.
- PVA-based resin polyvinyl alcohol-based resin
- the PVA-based resin of the present invention is a resin obtained by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer. It is composed of vinyl ester structural units.
- the saponification degree of the PVA-based resin used in the present invention is preferably 75 to 99.9 mol%, more preferably 80 to 95 mol%, still more preferably 83 to 93 mol%, particularly preferably 85 to 90 mol %. If the degree of saponification of the PVA-based resin is too high or too low, it tends to be difficult to obtain the effects of the present invention. In the present invention, the degree of saponification of the PVA-based resin is a value determined by a method conforming to JIS K 6726, and is an average degree of saponification determined as an average value.
- the average degree of polymerization of the PVA-based resin used in the present invention is preferably 300 to 4000, more preferably 500 to 3500, still more preferably 1000 to 3000, particularly preferably 1300 to 2800, particularly preferably 1500 to 2600. If the average degree of polymerization of the PVA-based resin is too low, the strength of the nanofibers tends to be insufficient and the stability during use tends to decrease. Tend. In addition, in this invention, the average degree of polymerization calculated
- a method for producing the PVA-based resin used in the present invention will be described in detail.
- a PVA-based resin is obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer.
- vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, and vinyl benzoate. , vinyl versatate, etc., and vinyl acetate is practically preferred.
- a monomer having copolymerizability with the vinyl ester monomer can be copolymerized to the extent that the effect of the present invention is not impaired.
- copolymerizable monomers include olefins such as ethylene, propylene, isobutylene, ⁇ -octene, ⁇ -dodecene and ⁇ -octadecene; - hydroxy group-containing ⁇ -olefins such as hexen-1-ol and 3,4-dihydroxy-1-butene, and derivatives such as acylated products thereof; acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itacon acids, unsaturated acids such as undecylenic acid and salts thereof; nitriles such as monoesters or dialkyl esters, acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide and methacrylamide; ethylenes
- N-acrylamidotrimethylammonium chloride N-acrylamidoethyltrimethylammonium chloride, N-acrylamidopropyltrimethylammonium chloride, 2-acryloxyethyltrimethylammonium chloride, N-methyldimethylaminoacrylamide, allyltrimethylammonium chloride, methallyltrimethylammonium chloride, dimethylallylamine, dimethylmethacrylamine, dimethyldiallylammonium chloride, Examples thereof include compounds having a cationic group such as diethyldiallylammonium chloride, ethyldiallylamine, and methyldiallylamine.
- the content of such copolymerizable monomers is preferably 10 mol % or less, more preferably 5 mol % or less, based on the total amount of the polymer.
- PVA-based resins Two or more types can be used in combination.
- PVA-based resins having different saponification degrees, average polymerization degrees and block properties, and modified PVA-based resins copolymerized with copolymerizable monomers can be used in combination.
- the method of polymerizing the vinyl ester monomer and the copolymerizable monomer is not particularly limited, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. , solution polymerization is preferred.
- Solvents used in such polymerization include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol, and ketones such as acetone and methyl ethyl ketone. is preferably used.
- the polymerization reaction is carried out using known radical polymerization catalysts such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, and lauroyl peroxide, and various known low temperature active catalysts.
- the reaction temperature is selected from the range of about 35° C. to the boiling point.
- the obtained polyvinyl ester polymer is then saponified in a continuous or batch manner.
- Either alkali saponification or acid saponification can be employed for such saponification, but it is industrially preferable to dissolve the polymer in alcohol and perform the saponification in the presence of an alkali catalyst.
- alcohols include methanol, ethanol, butanol, and the like.
- concentration of polymer in alcohol is selected from the range of 20-60% by weight.
- about 0.3 to 10% by mass of water may be added, and further, various esters such as methyl acetate, benzene, hexane, and various solvents such as DMSO (dimethyl sulfoxide) are added.
- saponification catalysts include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate and potassium methylate, and alkali catalysts such as alcoholates.
- the amount of such catalyst used is preferably 1 to 100 millimol equivalents relative to the monomer.
- the saponification degree of the PVA-based resin can be adjusted by adjusting the saponification catalyst amount, saponification time, saponification solvent, and saponification temperature.
- the cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol, and butanol, and methanol is preferable from the viewpoint of cleaning efficiency and drying efficiency.
- the washing method may be a continuous type (rotating cylinder type, countercurrent contact type, centrifugal sprinkle washing, etc.), but usually a batch type is adopted.
- Examples of the stirring method (apparatus) for washing include a screw blade, a ribbon blender, and a kneader.
- the bath ratio mass of cleaning solution/mass of polyvinyl ester polymer particles is preferably 1-30, more preferably 2-20. If the bath ratio is too large, a large washing apparatus is required, which tends to lead to an increase in cost.
- the temperature during washing is preferably 10-80°C, particularly preferably 20-70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, and there is a tendency to require a reflux facility. If the temperature is too low, cleaning efficiency tends to decrease.
- the washing time is preferably 5 minutes to 12 hours, particularly preferably 30 minutes to 4 hours. If the cleaning time is too long, the production efficiency tends to decrease, and if the cleaning time is too short, the cleaning tends to be insufficient. Also, the number of times of washing is preferably 1 to 10 times, particularly preferably 1 to 5 times. Too many washes tend to reduce productivity and increase costs.
- the washed PVA-based resin particles are dried continuously or batchwise with hot air or the like to obtain the PVA-based resin used in the present invention in powder form.
- the drying temperature is preferably 50 to 150°C, more preferably 60 to 130°C, still more preferably 70 to 110°C. If the drying temperature is too high, the PVA-based resin tends to be thermally deteriorated, and if the drying temperature is too low, drying tends to take a long time.
- the drying time is preferably 1 to 48 hours, more preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally deteriorated.
- the content of the solvent contained in the PVA-based resin after drying is preferably 0 to 10% by mass, more preferably 0.01 to 5% by mass, and still more preferably 0.1 to 1% by mass. .
- the PVA-based resin usually contains an alkali metal salt of acetic acid derived from the alkali catalyst used for saponification.
- the content of the alkali metal salt is preferably 0.001-2% by mass, more preferably 0.005-1% by mass, and still more preferably 0.01-0. It is 1% by mass.
- Methods for adjusting the content of the alkali metal salt include, for example, adjusting the amount of alkali catalyst used in saponification and washing the PVA-based resin with an alcohol such as ethanol or methanol.
- As a method for quantifying the alkali metal salt used in the present invention there is a method of dissolving PVA-based resin powder in water, using methyl orange as an indicator, and performing neutralization titration with hydrochloric acid.
- the water solubility of the water-soluble medicinal polymer refers to a substance that is highly soluble in water. It means that the amount of water required for dissolution is usually less than 30 mL.
- the amount of water required to dissolve 1 g of water-soluble pharmaceutical polymer is preferably less than 10 mL, more preferably less than 1 mL.
- the molecular weight of the water-soluble medicinal polymer contained in the nanofibers of the first embodiment of the present invention is 1,000 or more and 50,000 or less, preferably 1,000 or more and 30,000 or less, and more preferably 1,000 or more and 20,000 or less. If the molecular weight is too low, entanglement with the molecular chains of the PVA-based resin is unlikely to occur, and the water-soluble pharmaceutical polymer tends not to be sustained release. On the other hand, if the molecular weight is too large, there is a tendency that the water-soluble medicinal polymer cannot be absorbed into the body, which is not preferable.
- the water-soluble pharmaceutical polymer contained in the nanofiber of the second embodiment of the present invention is registered in Article 2, Paragraph 1 of the Pharmaceuticals and Medical Devices Law and the Japanese Pharmacopoeia 18th Edition, and is a protein drug. use.
- a protein drug is a drug that is composed of amino acids and exhibits therapeutic or preventive effects on diseases through protein activity.
- protein pharmaceuticals include peptides, proteins, fusion proteins, antigens, growth factors, growth factors, cytokines, interferons, hormones, blood coagulation fibrinolytic factors, enzymes, conjugate proteins, protein vaccines, antibody-like proteins, cells, tissues etc.
- Protein pharmaceuticals also include biopharmaceuticals, which are pharmaceuticals containing proteins produced using biotechnology as active ingredients. Biopharmaceuticals include, for example, vaccines, antibody drugs, cellular drugs, and nucleic acid drugs.
- the nanofiber of the present invention can release the water-soluble pharmaceutical polymer in a controlled manner.
- the reason why sustained release is possible is not clear, but the base material has a gel-like property due to the entanglement of the molecular chains of the PVA-based resin or the formation of a network structure, and the PVA-based resin and the water-soluble pharmaceutical polymer interact with each other. It is thought that it is due to the action.
- the nanofibers of the present invention are ultrafine fibers containing a polyvinyl alcohol-based resin and a water-soluble medicinal polymer, and are formed into fibers by spinning a forming material containing at least a PVA-based resin and a water-soluble medicinal polymer.
- the nanofiber of the present invention preferably has a single fiber diameter (fiber diameter) of 1 nm to 10 ⁇ m, more preferably 1 to 2000 nm, particularly preferably 5 to 1000 nm, still more preferably 10 to 700 nm. If the fiber diameter is too large, the nanofibers will not be mixed uniformly when producing a formulation, and the nanofibers will tend to aggregate, which tends to reduce the production efficiency of the formulation. On the other hand, if the fiber diameter is too small, it becomes difficult to exhibit sufficient strength, and problems such as handling during use tend to occur, and production efficiency of the formulation tends to decrease.
- the fiber diameter of nanofibers is measured using an electron microscope.
- the average fiber length of the nanofibers is not particularly limited, but from the viewpoint of ease of handling, it is preferably 10 times or more, more preferably 100 times or more, and still more preferably 1000 times or more the diameter of the nanofibers (fiber diameter). .
- the nanofibers are entangled with each other and the strength of the formulation increases, which is preferable, so the upper limit is not particularly limited. Further, it is more preferable that the nanofibers are continuous fibers.
- the content ratio of the PVA-based resin and the water-soluble pharmaceutical polymer in the nanofiber varies depending on the physical properties of the water-soluble pharmaceutical polymer, but the PVA-based resin:water-soluble pharmaceutical polymer (mass ratio) is preferably 10:90 to 90. :10, more preferably 20:80 to 80:20, still more preferably 30:70 to 75:25, and particularly preferably 35:65 to 70:30.
- the method for producing nanofibers of the present invention has a step of producing nanofibers by an electrospinning method or a meltblowing method using a mixed solution containing a PVA-based resin and a water-soluble medicinal polymer.
- the nanofibers of the present invention are preferably formed in a sheet form, and it is preferable to form a nonwoven fabric from the nanofibers obtained by the above production method.
- a method for forming nanofibers and a nonwoven fabric hereinafter also referred to as "nanofiber nonwoven fabric" will be described.
- Nanofibers are obtained by applying a mixed liquid containing a PVA-based resin and a water-soluble medicinal polymer as a forming material to an electrospinning method (electrostatic spinning method) or a meltblowing method.
- the PVA-based resin is preferably dissolved in a solvent and used as a PVA-based resin solution.
- solvents for dissolving PVA-based resins include alcohols (methanol, ethanol, butanol, hexafluoro-2-propanol, etc.), esters (methyl acetate, ethyl acetate, etc.), and organic solvents such as DMSO (dimethyl sulfoxide). and water, and water is preferable from the viewpoint of reducing the environmental load.
- the solvent containing water may contain other solvents (organic solvents exemplified above such as methanol, ethanol, methyl acetate, ethyl acetate and DMSO).
- the concentration of the PVA-based resin in the PVA-based resin solution is preferably 1 to 40% by mass, more preferably 2 to 30% by mass, and even more preferably 5 to 20% by mass.
- the PVA-based resin solution can contain a water-soluble resin or a water-dispersible resin different from the water-soluble pharmaceutical polymer.
- water-soluble resins or water-dispersible resins that can be contained include starch derivatives such as starch, oxidized starch and cationic modified starch; natural proteins such as gelatin and casein; methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose (CMC ); Natural polymer polysaccharides such as sodium alginate and pectic acid; Water-soluble resins such as polyvinylpyrrolidone and poly(meth)acrylate; Styrene-butadiene rubber (SBR) latex, nitrile rubber (NBR) latex latexes; vinyl acetate resin emulsions, ethylene-vinyl acetate copolymer emulsions, (meth)acrylic ester resin emulsions, vinyl chloride resin emulsions, urethane resin e
- the PVA-based resin solution can contain an alkali metal salt or an alkaline earth metal salt.
- alkali metal salts include potassium salts and sodium salts of organic acids and inorganic acids.
- organic acids include acetic acid, propionic acid, butyric acid, lauric acid, stearic acid, oleic acid, and behenic acid.
- inorganic acids include sulfuric acid, sulfurous acid, carbonic acid, and phosphoric acid.
- alkaline earth metal salts include calcium salts and magnesium salts of organic acids and inorganic acids.
- organic acids include acetic acid, propionic acid, butyric acid, lauric acid, stearic acid, oleic acid, and behenin. acids, and examples of inorganic acids include sulfuric acid, sulfurous acid, carbonic acid, and phosphoric acid.
- components other than the above include, for example, plasticizers, lubricants, pigment dispersants, thickeners, anti-adhesives, fluidity improvers, surfactants, antifoaming agents, release agents, Well-known additives such as mold agents, penetrants, dyes, pigments, fluorescent brighteners, ultraviolet absorbers, antioxidants, preservatives, antifungal agents, paper strength enhancers, cross-linking agents, etc. can be added as appropriate. .
- the PVA-based resin solution preferably has a viscosity of 1 to 10,000 mPa ⁇ s at 25° C. in order to facilitate spinning of the nanofiber-forming material.
- the viscosity of the PVA-based resin solution at 25° C. is more preferably 10 to 5000 mPa ⁇ s, particularly preferably 100 to 3000 mPa ⁇ s.
- the viscosity of the PVA-based resin solution is measured with a Brookfield viscometer.
- a liquid mixture that is a nanofiber-forming material is obtained by adding a water-soluble medicinal polymer to the above PVA-based resin solution and mixing them uniformly.
- the water-soluble pharmaceutical polymer may be dissolved or dispersed in the PVA-based resin solution, but is preferably dissolved from the viewpoint of uniformity.
- the mixing ratio of the PVA-based resin solution and the water-soluble medicinal polymer may be appropriately adjusted according to the physical properties of the water-soluble medicinal polymer. Mixing in the range of 10:90 to 90:10 is preferred.
- the mass ratio of the PVA-based resin and the water-soluble medicinal polymer (PVA-based resin:water-soluble medicinal polymer) in the mixed solution is more preferably 20:80 to 80:20, more preferably 30:70 to 75:25. , particularly preferably 35:65 to 70:30.
- the viscosity of the mixed liquid at 25°C is preferably in the range of 1 to 10,000 mPa ⁇ s, more preferably 10 to 5,000 mPa ⁇ s, and particularly preferably 100 to 3,000 mPa ⁇ s.
- the mixed solution prepared as above is spun to obtain nanofibers.
- the nanofiber spinning method of the present invention includes "(i) an electrospinning method using a spinning nozzle”, “(ii) an electrospinning method not using a spinning nozzle”, and “(iii) a melt blowing method”. . These methods will be described in sequence below.
- Electrospinning method using a spinning nozzle In the electrospinning method using a spinning nozzle, a high voltage is applied to the spinning nozzle side when extruding the above-mentioned mixed solution, which is a forming material, from the spinning nozzle, and an electric field is applied to the mixed solution. is stretched to form nanofibers. Then, a nanofiber nonwoven fabric is obtained by depositing nanofibers on the counter electrode side. An electric field may be applied between the spinning nozzle and the counter electrode by applying a voltage to the counter electrode instead of the spinning nozzle.
- the concentration of the PVA-based resin in the mixed solution is preferably 1 to 40% by weight, more preferably 2 to 30% by weight, and still more preferably 5 to 20% by weight, but is not particularly limited, and is arbitrary. can be set to
- the direction in which the mixture is extruded is not particularly limited, it is preferable that the direction in which the mixture is extruded from the nozzle does not coincide with the direction in which gravity acts so that the mixture is less likely to drip. In particular, it is preferable to extrude the liquid mixture in a direction opposite to the direction of action of gravity or in a direction perpendicular to the direction of action of gravity.
- the diameter (inner diameter) of the spinning nozzle for extruding this mixed solution varies depending on the fiber diameter, but when forming nanofibers with a fiber diameter of 1 to 1000 nm, for example, it is preferably 0.1 to 5 mm, particularly It is preferably 0.5 to 2 mm. If the diameter is too large, there will be a tendency for a large amount of liquid to drip and electrospinning will be difficult.
- the spinning nozzle may be made of metal or non-metal. If the spinning nozzle is made of metal, the spinning nozzle can be used as one of the electrodes, and if the spinning nozzle is made of non-metal, an electric field can be applied to the mixed solution by installing an electrode inside the spinning nozzle. can work.
- the extruded mixed liquid is stretched into fibers by applying an electric field.
- This electric field is not particularly limited because it varies depending on the fiber diameter of the nanofiber, the distance between the spinning nozzle and the collecting body where the fibers are accumulated, the viscosity of the liquid mixture, and the like. It is preferably 2 to 10 kV/cm. If the applied electric field is large, the fiber diameter of nanofibers tends to decrease as the electric field value increases. If it is too much, it tends to be difficult to form a fibrous shape.
- Such an electric field provides a potential difference between the spinning nozzle (the nozzle itself in the case of a metallic nozzle, or the electrode inside the nozzle in the case of a non-metallic nozzle such as glass or resin) and the collector.
- the potential difference can be established by applying a voltage to the spinning nozzle and grounding the collector, or conversely, by applying a voltage to the collector and grounding the spinning nozzle.
- the applied voltage is not particularly limited as long as the electric field intensity as described above can be obtained, but is preferably 1 to 30 kV, more preferably 5 to 20 kV, and still more preferably 10 to 20 kV. If the voltage is too high, sparks will occur and spinning will tend to be difficult. Conversely, if the voltage is too low, the power to electrically pull the solution will be insufficient and spinning will tend to be difficult. .
- the voltage application device is not particularly limited, but a DC high voltage generator can be used, and a Van de Graaff generator can also be used.
- the polarity of the applied voltage may be either positive or negative. However, it is preferable to set the spinning nozzle side to a positive potential so that the spreading of the fibers can be suppressed and the fibers can be aggregated with a small pore size and a narrow pore size distribution. In particular, in order to easily suppress corona discharge during voltage application, it is preferable to ground the counter electrode on the collector side, apply a positive voltage to the spinning nozzle side, and set the spinning nozzle side to a positive potential.
- the collector for collecting and depositing the nanofibers is not particularly limited, and examples thereof include a drum, a nonwoven fabric, a flat plate, or a belt-shaped conductive material made of metal or carbon, or an organic polymer.
- Non-conductive materials such as.
- the collector does not need to be a conductive material as described above, and the counter electrode can be arranged behind the collector. In this case, the collector and the counter electrode may be in contact with each other or may be separated from each other.
- the electrospinning method is preferably performed in an atmosphere with a relative humidity of 30 to 80%, more preferably in an atmosphere of 35 to 70%. If the relative humidity is too low, the mixed solution at the exit of the spinning nozzle dries quickly and tends to solidify and block the nozzle. tends to become weaker.
- the spinning nozzle and collector are installed in a closed container, and humidified air is sent through a valve or the like so that the humidity in the closed container can be adjusted within the above range. is preferred.
- an exhaust device is connected to the closed container so as not to increase the pressure in the closed container and to discharge the solvent volatilized from the mixed liquid.
- Electrospinning method not using a spinning nozzle for example, a magnetic fluid is used as an electrode, and electrospinning is performed from the surface of the mixed solution that is the forming material (A L. Yarin, E. Zussman, "Polymer", 45 (2004), p.2977-2980).
- a rotating roll is immersed in a bath filled with the above mixed solution, the mixed solution is adhered to the surface of the roll, and a high voltage is applied to this surface to perform electrospinning (http://www.
- (iii) Melt blowing method In the melt blowing method, the mixed liquid is discharged from a spinning nozzle, and at the same time as the mixed liquid is discharged, heated air is blown from both sides of the spinning nozzle at high speed in the direction of discharging the mixed liquid, so that the mixed liquid is
- the thread can be thinned by blowing out in the form of a thread.
- the nozzle hole diameter generally used is about 0.2 mm, and the nozzles are arranged in a row at intervals of about 1 mm.
- the ejection amount per minute is about 0.5 g per nozzle, and a low ejection amount is adopted in order to obtain finer fibers.
- a nanofiber nonwoven fabric is formed by entangling and/or fusing the blown nanofibers.
- the thickness of the nanofiber nonwoven fabric obtained by the above method is preferably 0.1 to 500 ⁇ m, more preferably 0.3 to 300 ⁇ m, still more preferably 0.5 to 100 ⁇ m.
- the basis weight of the obtained nanofiber nonwoven fabric is appropriately set according to its application, preferably 0.1 to 40 g/m 2 , more preferably 0.5 to 20 g/m 2 , still more preferably 1 ⁇ 10 g/m 2 .
- PVA 1 to 4 having saponification degrees and polymerization degrees shown in Table 1 were used as PVA-based resins.
- Lysozyme (molecular weight 14300) was used as a model for water-soluble pharmaceutical macromolecules.
- a previously prepared 8% by mass PVA aqueous solution (PVA1; 2.0 g, distilled water; 23 g, viscosity at 25° C. of about 2000 mPa s) and 4.7 g of lysozyme were added to a flask equipped with a stirring blade and stirred at 200 rpm for 10 minutes. By mixing, the mixture of Example 1 was prepared.
- Mixtures of Examples 2 to 9 were prepared in the same manner as in Example 1, except that the type and amount of PVA used were changed to those shown in Table 2.
- a lysozyme-containing nanofiber nonwoven fabric was prepared by an electrospinning method using a spinning nozzle using the mixtures of Examples 1 to 8 in Table 2. Specifically, the diameter of the needle used was 22 G, the voltage between the electrodes was 10 kV, the distance from the tip of the needle to the collection plate was 12 cm, and the ejection speed of the mixed solution was 0.5 ml/hour. Nanofibers were formed and nonwoven fabrics were formed on the collection plate to prepare nanofiber nonwoven fabrics of Examples 1 to 8. Also, using the water-soluble pharmaceutical polymer solution of Example 9, a nanofiber nonwoven fabric of Comparative Example 1 was prepared in the same manner as in Examples 1 to 8.
- a glass vessel for a dissolution tester was charged with 900 ml of distilled water and immersed in a hot bath at 37°C. Subsequently, the nanofibers of Examples 1 to 8 and Comparative Example 1 were weighed in an amount containing 12 mg of lysozyme, added to distilled water, and stirred at a rotation speed of 50 rpm. After collecting the aqueous solution over time and sieving the collected solution with a 0.45 ⁇ m filter, the absorbance at 281 nm was measured with a UV-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation).
- UV-visible spectrophotometer UV-1800, manufactured by Shimadzu Corporation
- the dissolved lysozyme was quantified to determine the dissolved concentration.
- Table 3 shows the dissolution rate results.
- the amount of lysozyme contained in the nanofibers was calculated by measuring the amount of lysozyme contained in 1 mg of the nanofibers by HPLC.
- the present invention it is possible to release water-soluble pharmaceutical macromolecules such as protein drugs, and the nanofibers of the present invention can be applied to oral drugs, patches, and tapes.
- water-soluble pharmaceutical macromolecules such as protein drugs
- the nanofibers of the present invention can be applied to oral drugs, patches, and tapes.
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Abstract
La présente invention concerne des nanofibres qui régulent le comportement d'élution d'un polymère médical soluble dans l'eau et assurent la libération prolongée du polymère médical soluble dans l'eau, et un procédé de production des nanofibres. Les nanofibres selon la présente invention sont des nanofibres comprenant une résine d'alcool polyvinylique et le polymère médical soluble dans l'eau, le poids moléculaire du polymère médical soluble dans l'eau étant de 1000 à 50'000, ou sont des nanofibres comprenant une résine d'alcool polyvinylique et le polymère médical soluble dans l'eau, le polymère médical soluble dans l'eau étant un produit pharmaceutique protéique.
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