WO2023035384A1 - 水凝胶栓塞微球及其制备方法 - Google Patents
水凝胶栓塞微球及其制备方法 Download PDFInfo
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- WO2023035384A1 WO2023035384A1 PCT/CN2021/128171 CN2021128171W WO2023035384A1 WO 2023035384 A1 WO2023035384 A1 WO 2023035384A1 CN 2021128171 W CN2021128171 W CN 2021128171W WO 2023035384 A1 WO2023035384 A1 WO 2023035384A1
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- hydrogel
- microsphere
- microspheres
- sodium hydroxide
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- 239000004005 microsphere Substances 0.000 title claims abstract description 138
- 239000000017 hydrogel Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims description 12
- 230000010102 embolization Effects 0.000 title abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 66
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- 229940079593 drug Drugs 0.000 claims abstract description 19
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
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- 238000000034 method Methods 0.000 claims abstract description 14
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims abstract description 13
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- 238000002156 mixing Methods 0.000 claims abstract description 10
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- 238000006116 polymerization reaction Methods 0.000 claims abstract description 6
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- 230000003073 embolic effect Effects 0.000 claims description 22
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 13
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 13
- HCLJOFJIQIJXHS-UHFFFAOYSA-N 2-[2-[2-(2-prop-2-enoyloxyethoxy)ethoxy]ethoxy]ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOCCOCCOC(=O)C=C HCLJOFJIQIJXHS-UHFFFAOYSA-N 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 claims description 9
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- ZQMHJBXHRFJKOT-UHFFFAOYSA-N methyl 2-[(1-methoxy-2-methyl-1-oxopropan-2-yl)diazenyl]-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC ZQMHJBXHRFJKOT-UHFFFAOYSA-N 0.000 claims description 8
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
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- 238000007873 sieving Methods 0.000 claims description 7
- ZMFWTUBNIJBJDB-UHFFFAOYSA-N 6-hydroxy-2-methylquinoline-4-carboxylic acid Chemical compound C1=C(O)C=CC2=NC(C)=CC(C(O)=O)=C21 ZMFWTUBNIJBJDB-UHFFFAOYSA-N 0.000 claims description 6
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 6
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims description 6
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 claims description 6
- HFCUBKYHMMPGBY-UHFFFAOYSA-N 2-methoxyethyl prop-2-enoate Chemical compound COCCOC(=O)C=C HFCUBKYHMMPGBY-UHFFFAOYSA-N 0.000 claims description 4
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 claims description 4
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 4
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 4
- 125000004386 diacrylate group Chemical group 0.000 claims description 4
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 claims description 4
- GFJVXXWOPWLRNU-UHFFFAOYSA-N ethenyl formate Chemical compound C=COC=O GFJVXXWOPWLRNU-UHFFFAOYSA-N 0.000 claims description 4
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 4
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims description 4
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 4
- AYGYHGXUJBFUJU-UHFFFAOYSA-N n-[2-(prop-2-enoylamino)ethyl]prop-2-enamide Chemical compound C=CC(=O)NCCNC(=O)C=C AYGYHGXUJBFUJU-UHFFFAOYSA-N 0.000 claims description 4
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 4
- 229920005651 polypropylene glycol dimethacrylate Polymers 0.000 claims description 4
- NHARPDSAXCBDDR-UHFFFAOYSA-N propyl 2-methylprop-2-enoate Chemical compound CCCOC(=O)C(C)=C NHARPDSAXCBDDR-UHFFFAOYSA-N 0.000 claims description 4
- SAPGBCWOQLHKKZ-UHFFFAOYSA-N 6-(2-methylprop-2-enoyloxy)hexyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCCCCOC(=O)C(C)=C SAPGBCWOQLHKKZ-UHFFFAOYSA-N 0.000 claims description 3
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims description 3
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims description 2
- 229960000779 irinotecan hydrochloride Drugs 0.000 claims description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 claims description 2
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- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims 1
- 238000011068 loading method Methods 0.000 abstract description 12
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- 238000012360 testing method Methods 0.000 description 13
- 208000005189 Embolism Diseases 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
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- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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Definitions
- the invention relates to the technical field of medical materials, in particular to hydrogel embolic microspheres and a preparation method thereof.
- TACE transcatheter arterial embolization
- Embolic agents are the core material for TACE treatment.
- Existing embolic agents include polyvinyl alcohol particles, gelatin sponge particles, polyvinyl alcohol microspheres, sodium alginate microspheres, and triplyl gelatin microspheres, among which polyvinyl alcohol particles and gelatin Sponge particles are irregular products, which are easy to block the catheter during clinical use and affect the operation process; polyvinyl alcohol microspheres and sodium alginate microspheres are regular in shape, which solves the problem of blocked catheters; swelling, which limits its clinical application; when polyvinyl alcohol microspheres embolize blood vessels, the fit between the microspheres and blood vessels is not good, and there are still large gaps between the microspheres.
- the production process of polyvinyl alcohol microspheres Complex long production cycle, more "three wastes" produced.
- the purpose of the present invention is to provide hydrogel embolic microspheres and a preparation method thereof, which can solve one or more of the above-mentioned problems in the prior art.
- the present invention provides a method for preparing hydrogel embolic microspheres, which comprises acrylic ester monomers and vinyl alcohol carboxylic acid derivative monomers cross-linked and polymerized by a cross-linking agent to form microspheres.
- the first mixture is mixed with the aqueous phase solution to form a microsphere intermediate through polymerization reaction.
- it also includes mixing the microsphere intermediate with sodium hydroxide solution to react to form hydrogel microspheres.
- the acrylate structural units and vinyl alcohol carboxylic acid derivative structural units in the microspheres can be hydrolyzed to generate sodium acrylate and vinyl alcohol structural units, thus preparing the
- the hydrogel microspheres with good elasticity and vascular adhesion also enable the hydrogel microspheres to efficiently adsorb a large amount of drugs in a short time when they are loaded with hydrophilic drugs.
- the reaction temperature of the first mixture and the aqueous phase solution is 35-75° C., and the reaction time is 1-10 h.
- reaction temperature of the microsphere intermediate and the sodium hydroxide solution is 25-80° C.
- reaction time is 1-24 h.
- the dispersant includes but is not limited to one or more of polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone;
- the acrylate monomer includes but is not limited to methyl acrylate, One or more of ethyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, ethylene glycol methyl ether acrylate, propyl methacrylate, tert-butyl methacrylate;
- the Vinyl carboxylic acid derivative monomers include but not limited to one or more of vinyl formate, vinyl acetate, vinyl benzoate, allyl formate, vinyl butyrate;
- the crosslinking agent includes but not Limited to N,N'-methylenebisacrylamide, N,N'-ethylenebisacrylamide, ethylene glycol dimethacrylate, tetraethylene glycol diacrylate, 1,6-hexanediol dimethyl Acrylate, polyethylene glycol diacrylate, polypropylene glycol
- the sodium hydroxide solution comprises an aqueous sodium hydroxide solution, a methanolic sodium hydroxide solution, or an ethanolic sodium hydroxide solution.
- the mass percentage of the dispersant is 0.1 wt.%-10 wt.%.
- the mass percentages of acrylate monomers, vinyl alcohol carboxylic acid derivative monomers, crosslinking agents, and initiators are 10wt.%-90wt.%, 10wt.%-90wt.%, respectively. %, 0.1wt.%-5wt.%, 0.1wt.%-5wt.%.
- the mass percentage of sodium hydroxide is 0.1 wt.%-5 wt.%, and the mass percentage of the microsphere intermediate is 1 wt.%-30 wt.%.
- hydrogel embolic microspheres provided by the present invention and the preparation method of the hydrogel embolic microspheres comprise the following steps:
- acrylate monomers vinyl alcohol carboxylic acid derivatives and cross-linking agents are reacted and connected together to form macromolecular chains, and many macromolecular chains are intertwined and cross-linked to form microspheres.
- the hydrogel embolic microspheres are capable of compression set of greater than 50%.
- the size of the hydrogel microspheres is between 30-1200 ⁇ m.
- the hydrogel microsphere has the characteristics of regular shape and uniform size, and the particle size distribution of the microsphere is narrower, and the particle size range is between 30-1200 ⁇ m and the particle size is adjustable. In most applications it will be desirable to have microspheres with a narrow particle size distribution in order to provide predictable embolization.
- the method used to prepare the microspheres can be manipulated to achieve a particular desired size range of microspheres. Methods such as sieving can be used to control the size range of the microspheres.
- the hydrophilic drugs include doxorubicin hydrochloride or irinotecan hydrochloride.
- the present invention provides a hydrogel microsphere with good elasticity and vascular adhesion, and has relatively large elastic deformation and recovery performance;
- the present invention provides a hydrogel microsphere with a narrower particle size distribution
- hydrogel microspheres provided by the present invention When used to load hydrophilic drugs, they can efficiently adsorb a large amount of drugs in a short period of time.
- the microspheres have higher drug loading and better slow-controlled release capabilities, solving It solves the problem of low drug loading of similar products in the prior art, and has a good application prospect in the field of liver cancer interventional therapy.
- Fig. 1 is the optical microscope photograph of microsphere after filling in the embodiment of the present invention 1;
- Fig. 2 is a schematic diagram of microspheres before and after compression deformation in Example 2 of the present invention (Fig. a is a schematic diagram before compression deformation test, and Fig. b is a schematic diagram after compression deformation (50%) test);
- Fig. 3 is the optical microscope photograph (figure A is the optical microscope photograph before microsphere compressive deformation test before microsphere compressive deformation in the embodiment 2 of the present invention and after compressive deformation, and Fig. B is after microsphere compressive deformation (50%) test optical microscope photographs).
- polyvinyl alcohol is added to deionized water to form a water phase solution, and methyl acrylate, vinyl formate, N,N'-methylenebisacrylamide, and azobisisobutylcyanide are mixed to form a mixed solution.
- the mass percentage of vinyl alcohol is 1wt.%
- the mass percentages of methyl acrylate, vinyl formate, N,N'-methylenebisacrylamide, and azobisisobutylcyanide are 30wt.% and 68wt.%, respectively. %, 1wt.%, 1wt.%.
- polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and butyl acrylate, vinyl benzoate, ethylene glycol dimethacrylate, and dimethyl azobisisobutyrate are mixed to form a mixed solution, Wherein the mass percentage of polyvinylpyrrolidone is 5wt.%, and the mass percentages of butyl acrylate, vinyl benzoate, ethylene glycol dimethacrylate, and dimethyl azobisisobutyrate are respectively 50wt.%. , 42wt.%, 3wt.%, 5wt.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 65°C for 3 hours to form a microsphere intermediate;
- (1) first polyvinyl alcohol is added into deionized water to form an aqueous phase solution, methyl methacrylate, allyl formate, tetraethylene glycol diacrylate, benzoyl tert-butyl peroxide are mixed to form a mixed solution, Wherein the mass percent composition of polyvinyl alcohol is 0.1wt.%, the mass percent composition of methyl methacrylate, allyl formate, tetraethylene glycol diacrylate, benzoyl tert-butyl peroxide is 80wt respectively .%, 10wt.%, 5wt.%, 5wt.%. Then drop the mixed solution into the aqueous phase solution under stirring conditions, and react at 75°C for 1 hour to generate a microsphere intermediate;
- (1) First add polyethylene glycol to deionized water to form a water phase solution, mix ethyl methacrylate, vinyl butyrate, 1,6-hexanediol dimethacrylate, and azobisisobutylcyanide Form a mixed solution, wherein the mass percentage of polyethylene glycol is 0.1wt.%, ethyl methacrylate, vinyl butyrate, 1,6-hexanediol dimethacrylate, azobisisobutyrocyanide The mass percentages are respectively 90wt.%, 5wt.%, 2wt.%, 3wt.%. Then drop the mixed solution into the aqueous phase solution under stirring condition, and react at 60°C for 3 hours to form a microsphere intermediate;
- polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and ethylene glycol methyl ether acrylate, vinyl benzoate, polyethylene glycol diacrylate, and dimethyl azobisisobutyrate are mixed to form Mixed solution, wherein the mass percent of polyvinylpyrrolidone is 10wt.%, the mass percent of ethylene glycol methyl ether acrylate, vinyl benzoate, polyethylene glycol diacrylate, dimethyl azobisisobutyrate The component contents are 10wt.%, 89.8wt.%, 0.1wt.%, 0.1wt.%. Then drop the mixed solution into the aqueous phase solution under stirring conditions, and react at 35°C for 10 hours to form a microsphere intermediate;
- polyvinyl alcohol is added to deionized water to form an aqueous phase solution, and propyl methacrylate, vinyl acetate, polypropylene glycol dimethacrylate, and dimethyl azobisisobutyrate are mixed to form a mixed solution, wherein the mass percentage content of polyvinyl alcohol is 1wt.%, the mass percentage content of propyl methacrylate, vinyl acetate, polypropylene glycol dimethacrylate, dimethyl azobisisobutyrate is 30wt. %, 68wt.%, 1wt.%, 1wt.%.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 45°C for 6 hours to form a microsphere intermediate;
- polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and tert-butyl methacrylate, allyl formate, tetraethylene glycol diacrylate, and benzoyl tert-butyl peroxide are mixed to form a mixed solution , wherein the mass percentage of polyvinylpyrrolidone is 5wt.%, and the mass percentages of tert-butyl methacrylate, allyl formate, tetraethylene glycol diacrylate, and benzoyl tert-butyl peroxide are respectively 50wt.%, 42wt.%, 3wt.%, 5wt.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 65°C for 3 hours to form a microsphere intermediate;
- the elastic deformation of the microspheres is tested by a strain gauge, and the specific method is as follows:
- the filled hydrogel microspheres on the test platform, and when the probe of the deformation meter moves down the contacted microspheres, it moves down a distance of 50% of the diameter of the microspheres, and then withdraws the probe after keeping it for a certain period of time. Take out the microspheres and observe whether they are broken. If the microspheres return to a spherical shape without breaking, it means that the microspheres can withstand 50% compression deformation test.
- Example 2 the hydrogel microspheres in Example 2 were taken to perform a 50% compression set test, and the schematic diagram of the test is shown in FIG. 2 .
- the 30-50 ⁇ m embolic microspheres prepared in Example 1 were added to the 25 mg/mL doxorubicin hydrochloride solution, and samples were taken at the load times of 0 min, 5 min, 15 min, 30 min, and 60 min respectively, and HPLC (ultraviolet detection wavelength was 254 nm , chromatographic column is Waters C18) measure the content of doxorubicin in the sample of above-mentioned different loading time.
- the drug loading efficiency of the degradable embolization microspheres was calculated by the difference method.
- microsphere drug-loading efficiency (1-the content of doxorubicin in the sample/doxorubicin feeding amount) * 100%
- the drug loading efficiency has reached about 90%. It shows that the embolic microspheres prepared by the present invention have rapid drug-loading property for doxorubicin.
- the present invention provides a hydrogel microsphere with good elasticity and vascular adhesion, and has greater elastic deformation and recovery performance; the present invention provides a hydrogel microsphere with a narrower particle size distribution.
- Glue microspheres when the hydrogel microspheres provided by the present invention are used to load hydrophilic drugs, they can efficiently absorb a large amount of drugs in a short time, and the microspheres have higher drug loading and better slow-controlled release capabilities , which solves the problem of low drug loading of similar products in the prior art, and has good application prospects in the field of liver cancer interventional therapy.
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Abstract
一种水凝胶栓塞微球的制备方法,其由丙烯酸酯类单体、乙烯醇羧酸衍生物类单体通过交联剂发生交联聚合形成微球。包括以下步骤:将分散剂加入去离子水中形成水相溶液;将丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂和引发剂混合,形成第一混合物;将所述第一混合物与水相溶液混合,通过聚合反应生成微球中间体;将所述微球中间体与氢氧化钠溶液混合,反应生成水凝胶微球。其提供了一种具有良好弹性和血管贴合性的水凝胶微球,具有较大的弹性形变和恢复性能;提供的水凝胶微球用于负载亲水性药物时,可在短时间内高效大量吸附药物。
Description
本发明涉及医用材料技术领域,特别涉及水凝胶栓塞微球及其制备方法。
据统计,2020年中国有超过41万人新患肝癌,有超过39万人死于肝癌。由于肝癌患者在确诊时大多已处于中晚期或合并肝硬化,只有约20%-30%的患者具有手术切除的机会。对于不能接受手术治疗的肝癌患者,经导管动脉栓塞术(TACE)是一类非常重要的治疗方法,主要是经动脉将栓塞剂注入到病变靶器官的血管内,使血管发生闭塞,中断血液供应,最终达到治疗目的。TACE具有创伤小、疗效快、副作用小等优势,该方法已经在临床癌症治疗尤其是晚期肝癌的治疗中发挥着越来越重要的作用。
栓塞剂是TACE治疗的核心材料,现有栓塞剂包括聚乙烯醇颗粒、明胶海绵颗粒、聚乙烯醇微球、海藻酸钠微球、三丙烯基明胶微球等,其中聚乙烯醇颗粒和明胶海绵颗粒为不规则产品,在临床使用时容易堵塞导管,影响手术进程;聚乙烯醇微球和海藻酸钠微球形状规则,解决堵塞导管的问题;但海藻酸钠微球栓塞时会出现体积膨胀,限制了其临床应用推广;聚乙烯醇微球栓塞血管时,微球与血管的贴合性不佳,微球之间仍然存在较大的空隙,另外,聚乙烯醇微球的生产工艺复杂,生产周期长,产生的“三废”较多。
发明内容
本发明的目的是提供水凝胶栓塞微球及其制备方法,解决上述现有技术问题中的一个或者多个。
第一方面,本发明提供的水凝胶栓塞微球的制备方法,其由丙烯酸酯类单体和乙烯醇羧酸衍生物类单体通过交联剂交联聚合,形成微球。
在某些实施方案中,包括以下步骤:
将分散剂加入去离子水中形成水相溶液;
将丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂和引发剂混合,形成第一混合物;
将所述第一混合物与水相溶液混合,通过聚合反应生成微球中间体。
在某些实施方案中,还包括将所述微球中间体与氢氧化钠溶液混合,反应生成水凝胶微球。
其中:通过将微球中间体与氢氧化钠溶液反应,能够将微球中的丙烯酸酯类结构单元和乙烯醇羧酸衍生物类结构单元水解,生成丙烯酸钠和乙烯醇结构单元,这样制备出具有良好弹性和血管贴合性的水凝胶微球,同时使得该水凝胶微球在负载亲水性药物时,能够在短时间内高效大量吸附药物。
在某些实施方案中,第一混合物与水相溶液反应温度为35-75℃,反应时间为1-10h。
在某些实施方案中,微球中间体与氢氧化钠溶液反应温度为25-80℃,反应时间为1-24h。
其中:上述两种反应,通过将反应温度设置在合理的范围内,避免了低温反应时间长;高温反应时间短,反应过于剧烈的情况发生。
在某些实施方案中,所述分散剂包括但不限于聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮中的一种或多种;所述丙烯酸酯类单体包括但不限于丙烯酸甲酯、丙烯酸乙酯、丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、乙二醇甲醚丙烯酸酯、甲基丙烯酸丙酯、甲基丙烯酸叔丁酯中的一种或多种;所述乙烯醇羧酸衍生物类单体包括但不限于甲酸乙烯酯、乙酸乙烯酯、苯甲酸乙烯酯、甲酸烯丙酯、丁酸乙烯酯的一种或多种;所述交联剂包括但不限于N,N'-甲叉双丙烯酰胺、N,N'-乙撑二丙烯酰胺、乙二醇二甲基丙烯酸酯、四乙二醇二丙烯酸酯、1,6-己二醇二甲基丙烯酸酯、聚乙二醇二丙烯酸酯、聚丙二醇二甲基丙烯酸酯;所述引发剂包括但不限于偶氮二异丁氰、过氧化苯甲酰、偶氮二异丁酸二甲酯、过氧化苯甲酰叔丁酯中的一种或多种。
在某些实施方案中,所述氢氧化钠溶液包括氢氧化钠水溶液、氢氧化钠甲醇溶液或氢氧化钠乙醇溶液。
在某些实施方案中,分散剂的质量百分含量为0.1wt.%-10wt.%。
在某些实施方案中,丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂、引发剂的质量百分含量分别为10wt.%-90wt.%、10wt.%-90wt.%、 0.1wt.%-5wt.%、0.1wt.%-5wt.%。
在某些实施方案中,氢氧化钠的质量百分含量为0.1wt.%-5wt.%,所述微球中间体的质量百分含量为1wt.%-30wt.%。
第二方面,本发明提供的水凝胶栓塞微球,水凝胶栓塞微球的制备方法,包括以下步骤:
将分散剂加入去离子水中形成水相溶液;
将丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂和引发剂混合,形成第一混合物;
将所述第一混合物与水相溶液混合,通过聚合反应生成微球中间体;
将所述微球中间体与氢氧化钠溶液混合,反应生成水凝胶微球;以及
清洗、分筛、灌装步骤。
其中:丙烯酸酯类单体、乙烯醇羧酸衍生物和交联剂反应后,连接到一起,形成大分子链,又有许多的大分子链相互缠绕、交联形成微球。
在某些实施方案中,水凝胶栓塞微球能够压缩形变达到50%以上。
在某些实施方案中,水凝胶微球的粒径在30-1200μm之间。
其中:该水凝胶微球具有形状规整和尺寸均一的特点,同时微球的粒径分布更窄,粒径范围在30-1200μm之间且粒径可调。在大多数应用中,其将需要具有粒径分布较窄的微球以便提供可预测的栓塞。可控制用于制备微球的方法以实现特定所需的大小范围的微球。如筛分的方法可用于控制微球的大小范围。
第三方面,本发明提供的水凝胶栓塞微球在亲水溶性药物中的应用,所述亲水性药物包括盐酸阿霉素或盐酸伊利替康。
与现有技术相比,本发明产生的有益效果是:
1、本发明提供了一种具有良好弹性和血管贴合性的水凝胶微球,具有较大的弹性形变和恢复性能;
2、本发明提供了一种粒径分布更窄的水凝胶微球;
3、本发明提供的水凝胶微球用于负载亲水性药物时,可在短时间内高效大量吸附药物,该微球具有更高的载药量以及更好的缓控释放能力,解决了现有技术中同类产品载药量低的问题,在肝癌介入治疗领域具有很好的应用前景。
图1是本发明实施例1中灌装后微球的光学显微镜照片;
图2是本发明实施例2中微球压缩形变前和压缩形变后的示意图(图a是压缩形变测试前的示意图,图b是压缩形变(50%)测试后的示意图);
图3是本发明实施例2中微球压缩形变前和压缩形变后的光学显微镜照片(图A是微球压缩形变测试前的光学显微镜照片,图B是微球压缩形变(50%)测试后的光学显微镜照片)。
下面通过实施方式对本发明进行进一步详细的说明。
实施例1
(1)首先将聚乙二醇加入去离子水中形成水相溶液,将丙烯酸乙酯、乙酸乙烯酯、N,N'-乙撑二丙烯酰胺、过氧化苯甲酰混合形成混合溶液,其中聚乙二醇的质量百分含量为10wt.%,丙烯酸乙酯、乙酸乙烯酯、N,N'-乙撑二丙烯酰胺、过氧化苯甲酰的质量百分含量分别为89.8wt.%、10wt.%、0.1wt.%、0.1wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,35℃下反应10h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为0.1wt.%,微球中间体的质量百分含量为1wt.%,25℃下反应24h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径30-60um栓塞微球产品。
其中:如图1所示,可以看出水凝胶微球粒径大小均一,分散性好。
实施例2
(1)首先将聚乙烯醇加入去离子水中形成水相溶液,将丙烯酸甲酯、甲酸乙烯酯、N,N'-甲叉双丙烯酰胺、偶氮二异丁氰混合形成混合溶液,其中聚乙烯醇的质量百分含量为1wt.%,丙烯酸甲酯、甲酸乙烯酯、N,N'-甲叉双丙烯酰胺、偶氮二异丁氰的质量百分含量分别为30wt.%、68wt.%、1wt.%、1wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,45℃下反6h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为1wt.%,微球中间体的质量百分含量为10wt.%,50℃下反应6h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径70-100um栓塞微球产品。
实施例3
(1)首先将聚乙烯吡咯烷酮加入去离子水中形成水相溶液,将丙烯酸丁酯、苯甲酸乙烯酯、乙二醇二甲基丙烯酸酯、偶氮二异丁酸二甲酯混合形成混合溶液,其中聚乙烯吡咯烷酮的质量百分含量5wt.%,丙烯酸丁酯、苯甲酸乙烯酯、乙二醇二甲基丙烯酸酯、偶氮二异丁酸二甲酯的质量百分含量分别为50wt.%、42wt.%、3wt.%、5wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,65℃下反应3h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为5wt.%,微球中间体的质量百分含量为20wt.%,80℃下反应1h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径100-150um栓塞微球产品。
实施例4
(1)首先将聚乙烯醇加入去离子水中形成水相溶液,将甲基丙烯酸甲酯、甲酸烯丙酯、四乙二醇二丙烯酸酯、过氧化苯甲酰叔丁酯混合形成混合溶液,其中聚乙烯醇的质量百分含量为0.1wt.%,甲基丙烯酸甲酯、甲酸烯丙酯、四乙二醇二丙烯酸酯、过氧化苯甲酰叔丁酯的质量百分含量分别为80wt.%、10wt.%、5wt.%、5wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,75℃下反应1h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为5wt.%,微球中间体的质量百分含量为20wt.%,70℃下反应3h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径200-250um栓塞微球产品。
实施例5
(1)首先将聚乙二醇加入去离子水中形成水相溶液,将甲基丙烯酸乙酯、丁酸乙烯酯、1,6-己二醇二甲基丙烯酸酯、偶氮二异丁氰混合形成混合溶液,其中聚乙二醇的质量百分含量为0.1wt.%,甲基丙烯酸乙酯、丁酸乙烯酯、1,6-己二醇二甲基丙烯酸酯、偶氮二异丁氰的质量百分含量分别为90wt.%、5wt.%、2wt.%、3wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,60℃下反应3h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为5wt.%,微球中间体的质量百分含量为20wt.%,65℃下反应3h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径200-250um栓塞微球产品。
实施例6
(1)首先将聚乙烯吡咯烷酮加入去离子水中形成水相溶液,将乙二醇甲醚丙烯酸酯、苯甲酸乙烯酯、聚乙二醇二丙烯酸酯、偶氮二异丁酸二甲酯混合形成混合溶液,其中聚乙烯吡咯烷酮的质量百分含量为10wt.%,乙二醇甲醚丙烯酸酯、苯甲酸乙烯酯、聚乙二醇二丙烯酸酯、偶氮二异丁酸二甲酯的质量百分含量分别为10wt.%、89.8wt.%、0.1wt.%、0.1wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,35℃下反应10h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为0.1wt.%,微球中间体的质量百分含量为1wt.%,25℃下反应20h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径30-60um栓塞微球产品。
实施例7
(1)首先将聚乙烯醇加入去离子水中形成水相溶液,将甲基丙烯酸丙酯、乙酸乙烯酯、聚丙二醇二甲基丙烯酸酯、偶氮二异丁酸二甲酯混合形成混合溶液,其中聚乙烯醇的质量百分含量为1wt.%,甲基丙烯酸丙酯、乙酸乙烯酯、聚丙二醇二甲基丙烯酸酯、偶氮二异丁酸二甲酯的质量百分 含量分别为30wt.%、68wt.%、1wt.%、1wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,45℃下反应6h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为1wt.%,微球中间体的质量百分含量为10wt.%,50℃下反应6h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径70-100um栓塞微球产品。
实施例8
(1)首先将聚乙烯吡咯烷酮加入去离子水中形成水相溶液,将甲基丙烯酸叔丁酯、甲酸烯丙酯、四乙二醇二丙烯酸酯、过氧化苯甲酰叔丁酯混合形成混合溶液,其中聚乙烯吡咯烷酮的质量百分含量为5wt.%,甲基丙烯酸叔丁酯、甲酸烯丙酯、四乙二醇二丙烯酸酯、过氧化苯甲酰叔丁酯的质量百分含量分别为50wt.%、42wt.%、3wt.%、5wt.%。再在搅拌条件下将混合溶液滴入水相溶液中,65℃下反应3h,生成微球中间体;
(2)将微球中间体加入到氢氧化钠甲醇溶液中,其中氢氧化钠的质量百分含量为5wt.%,微球中间体的质量百分含量为20wt.%,60℃下反应4h,生成水凝胶微球;
(3)对水凝胶微球进行清洗、分筛、灌装得到粒径100-150um栓塞微球产品。
性能测试
1、弹性形变的测试
通过形变仪测试微球的弹性形变,具体方法如下:
将灌装后的水凝胶微球平铺于测试平台上,形变仪探头下移接触的微球时,再向下移动微球直径的50%的距离,保持一定时间后,再撤回探头,取出微球观察是否有破碎。若微球恢复球形、无破碎,则说明微球能够承受50%压缩形变测试。
按照上述方法,取实施例2中的水凝胶微球,进行50%压缩形变测试,测试的示意图见图2。
测试的结果如图3所示,可以看出,测试后观察微球均恢复球形,且无破碎,说明上述水凝胶微球具有良好的弹性。
2、载药量的测试
将实施例1制得的30-50μm栓塞微球加入到25mg/mL的盐酸阿霉素溶液中,分别在0min、5min、15min、30min、60min的负载时间取样,使用HPLC(紫外检测波长为254nm,色谱柱为Waters C18)测定上述不同负载时间的样品中阿霉素的含量。
通过差量法计算可降解栓塞微球的载药效率。
其中:微球载药效率=(1-样品中阿霉素的含量/阿霉素投料量)×100%
当负载时间为5min时,载药效率已达90%左右。说明本发明制备的栓塞微球对阿霉素具有快速载药性。
综上所述:本发明提供了一种具有良好弹性和血管贴合性的水凝胶微球,具有较大的弹性形变和恢复性能;本发明提供了一种粒径分布更窄的水凝胶微球;本发明提供的水凝胶微球用于负载亲水性药物时,可在短时间内高效大量吸附药物,该微球具有更高的载药量以及更好的缓控释放能力,解决了现有技术中同类产品载药量低的问题,在肝癌介入治疗领域具有很好的应用前景。
以上表述仅为本发明的优选方式,应当指出,对本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些也应视为发明的保护范围之内。
Claims (10)
- 水凝胶栓塞微球的制备方法,其特征在于,其由丙烯酸酯类单体和乙烯醇羧酸衍生物类单体通过交联剂发生交联聚合,形成微球。
- 根据权利要求1所述的水凝胶栓塞微球的制备方法,其特征在于,包括以下步骤:将分散剂加入去离子水中形成水相溶液;将丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂和引发剂混合,形成第一混合物;将所述第一混合物与水相溶液混合,通过聚合反应生成微球中间体。
- 根据权利要求2所述的水凝胶栓塞微球的制备方法,其特征在于,还包括将所述微球中间体与氢氧化钠溶液混合,反应生成水凝胶微球。
- 根据权利要求2所述的水凝胶栓塞微球的制备方法,其特征在于,所述分散剂包括但不限于聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮中的一种或多种;所述丙烯酸酯类单体包括但不限于丙烯酸甲酯、丙烯酸乙酯、丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、乙二醇甲醚丙烯酸酯、甲基丙烯酸丙酯、甲基丙烯酸叔丁酯中的一种或多种;所述乙烯醇羧酸衍生物类单体包括但不限于甲酸乙烯酯、乙酸乙烯酯、苯甲酸乙烯酯、甲酸烯丙酯、丁酸乙烯酯的一种或多种;所述交联剂包括但不限于N,N'-甲叉双丙烯酰胺、N,N'-乙撑二丙烯酰胺、乙二醇二甲基丙烯酸酯、四乙二醇二丙烯酸酯、1,6-己二醇二甲基丙烯酸酯、聚乙二醇二丙烯酸酯、聚丙二醇二甲基丙烯酸酯;所述引发剂包括但不限于偶氮二异丁氰、过氧化苯甲酰、偶氮二异丁酸二甲酯、过氧化苯甲酰叔丁酯中的一种或多种。
- 根据权利要求3所述的水凝胶栓塞微球的制备方法,其特征在于,所述氢氧化钠溶液包括氢氧化钠水溶液、氢氧化钠甲醇溶液或氢氧化钠乙醇溶液。
- 根据权利要求5所述的水凝胶栓塞微球的制备方法,其特征在于, 分散剂的质量百分含量为0.1wt.%-10wt.%。
- 根据权利要求5所述的水凝胶栓塞微球的制备方法,其特征在于,丙烯酸酯类单体、乙烯醇羧酸衍生物类单体、交联剂、引发剂的质量百分含量分别为10wt.%-90wt.%、10wt.%-90wt.%、0.1wt.%-5wt.%、0.1wt.%-5wt.%。
- 根据权利要求5所述的水凝胶栓塞微球的制备方法,其特征在于,氢氧化钠的质量百分含量为0.1wt.%-5wt.%,所述微球中间体的质量百分含量为1wt.%-30wt.%。
- 由权利要求1至8中任一权利要求所述的制备方法制得的水凝胶栓塞微球,其特征在于,所述水凝胶栓塞微球的制备方法还包括清洗、分筛、灌装步骤。
- 权利要求9所述的水凝胶栓塞微球在亲水溶性药物中的应用,其特征在于,所述亲水性药物包括盐酸阿霉素或盐酸伊利替康。
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