CN114099765B - Photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and preparation method thereof - Google Patents
Photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and preparation method thereof Download PDFInfo
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- 239000004372 Polyvinyl alcohol Substances 0.000 title claims abstract description 104
- 229920002451 polyvinyl alcohol Polymers 0.000 title claims abstract description 104
- 239000004005 microsphere Substances 0.000 title claims abstract description 69
- 229940079593 drug Drugs 0.000 title claims abstract description 46
- 239000003814 drug Substances 0.000 title claims abstract description 46
- 208000005189 Embolism Diseases 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 238000004132 cross linking Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 15
- -1 2-acrylamide-2-methylpropanesulfonic acid sodium salt Chemical class 0.000 claims abstract description 12
- 238000005406 washing Methods 0.000 claims abstract description 12
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims abstract description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007171 acid catalysis Methods 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 7
- 230000000977 initiatory effect Effects 0.000 claims abstract description 6
- 239000011259 mixed solution Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000010102 embolization Effects 0.000 claims description 6
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical group CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000012716 precipitator Substances 0.000 claims description 4
- 230000003073 embolic effect Effects 0.000 claims description 3
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 3
- 239000000178 monomer Substances 0.000 claims description 3
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical compound CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- IGAAQDGISNXKQL-UHFFFAOYSA-L P(=O)(OC(C1=C(C(=C(C=C1C)C)C1=CC=CC=C1)C)=O)([O-])[O-].[Li+].[Li+] Chemical compound P(=O)(OC(C1=C(C(=C(C=C1C)C)C1=CC=CC=C1)C)=O)([O-])[O-].[Li+].[Li+] IGAAQDGISNXKQL-UHFFFAOYSA-L 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229920000536 2-Acrylamido-2-methylpropane sulfonic acid Polymers 0.000 claims 1
- XHZPRMZZQOIPDS-UHFFFAOYSA-N 2-Methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(C)(C)NC(=O)C=C XHZPRMZZQOIPDS-UHFFFAOYSA-N 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000012567 medical material Substances 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003431 cross linking reagent Substances 0.000 description 6
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- FWFUWXVFYKCSQA-UHFFFAOYSA-M sodium;2-methyl-2-(prop-2-enoylamino)propane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CC(C)(C)NC(=O)C=C FWFUWXVFYKCSQA-UHFFFAOYSA-M 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 231100000086 high toxicity Toxicity 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 230000001678 irradiating effect Effects 0.000 description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 3
- 239000008213 purified water Substances 0.000 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 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- DZSVIVLGBJKQAP-UHFFFAOYSA-N 1-(2-methyl-5-propan-2-ylcyclohex-2-en-1-yl)propan-1-one Chemical compound CCC(=O)C1CC(C(C)C)CC=C1C DZSVIVLGBJKQAP-UHFFFAOYSA-N 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- LSWCMUBJZBXTDM-UHFFFAOYSA-M P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] Chemical compound P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] LSWCMUBJZBXTDM-UHFFFAOYSA-M 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 230000010108 arterial embolization Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- DIHKMUNUGQVFES-UHFFFAOYSA-N n,n,n',n'-tetraethylethane-1,2-diamine Chemical compound CCN(CC)CCN(CC)CC DIHKMUNUGQVFES-UHFFFAOYSA-N 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012719 thermal polymerization Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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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- 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
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
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- 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
- C08F261/00—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00
- C08F261/02—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols
- C08F261/04—Macromolecular compounds obtained by polymerising monomers on to polymers of oxygen-containing monomers as defined in group C08F16/00 on to polymers of unsaturated alcohols on to polymers of vinyl alcohol
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/622—Microcapsules
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Abstract
The invention provides a photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and a preparation method thereof, belonging to the technical field of medical materials. The method comprises the following steps: s1, reacting polyvinyl alcohol by an acid catalysis method or an alkali catalysis method to obtain a photocrosslinkable polyvinyl alcohol intermediate; s2, dissolving the photo-crosslinkable polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropanesulfonic acid sodium salt and a water-soluble photoinitiator in water under the condition of keeping out of the sun, adding the solution into a mixed solution of butyl acetate and cellulose acetate butyrate, stirring to form a suspension, initiating a crosslinking reaction under the irradiation of a light source, and washing after the reaction is finished to obtain the photo-initiated crosslinked polyvinyl alcohol drug-loaded embolism microsphere. The invention can reduce the polymerization reaction time and energy consumption, only needs 5 minutes to 2 hours to completely react, can react at room temperature, uses the environment-friendly photoinitiator, and is more suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and a preparation method thereof.
Background
Embolic microspheres have become an important clinical treatment for tumor diseases, especially liver tumors. The microspheres can be selectively and controllably injected into blood supply vessels of tumor bodies through the catheter to realize occlusion and block blood supply of the tumor. Meanwhile, the microspheres can also carry chemotherapeutic drugs, so that arterial perfusion chemotherapy and local arterial embolization are organically combined together, tumor blood vessels are embolized and tumor blood supply is blocked at different levels, the chemotherapeutic drugs can be slowly released through the microspheres, a local chemotherapeutic effect with a longer time and a higher drug concentration is achieved, the concentration of the chemotherapeutic drugs in systemic circulation can be remarkably reduced, and the toxicity of systemic chemotherapy is relieved.
At present, polyvinyl alcohol microspheres are common embolic microspheres in the market and are generally prepared by thermal-initiated polymerization or crosslinking with crosslinking agents such as glutaraldehyde and the like. The thermal-initiated polymerization reaction has long time and high energy consumption, and the cross-linking agents such as glutaraldehyde have high toxicity, which affects the biocompatibility of the microsphere.
CN 111417459B introduces a preparation method of polyvinyl alcohol drug-loaded microspheres, which adopts a mixed solution of liquid paraffin and sorbitan fatty acid ester as an oil phase, adopts a mixed solution of polyvinyl alcohol water solution and hydroxyapatite particles as a water phase, and adopts concentrated hydrochloric acid as a catalyst and glutaraldehyde as a cross-linking agent for reaction. The method still requires reaction at 50-60 ℃ for at least 3 hours and uses the more toxic glutaraldehyde as the crosslinking agent.
CN 110327300B introduces a preparation method of drug-loaded polyvinyl alcohol microspheres, and the obtained polyvinyl alcohol microspheres have good shape, high dispersibility and uniform particle size distribution. However, this method uses potassium persulfate and tetraethylethylenediamine, which are highly toxic, as thermal initiators and requires reaction at 55 ℃ for 3 hours.
CN 110201215A discloses a preparation process of gradient cross-linked polyvinyl alcohol embolism microsphere, which can rapidly rebound and recover to spherical form after compression. However, the method uses potassium persulfate and tetramethylethylenediamine which have high toxicity as initiating systems and glutaraldehyde as a polymer crosslinking agent, and needs to react for at least 6 hours at 60 ℃.
Disclosure of Invention
The invention aims to provide a photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and a preparation method thereof, which can reduce the polymerization reaction time and energy consumption, only needs 5 minutes to 2 hours to completely react, can react at room temperature, uses an environment-friendly photoinitiator, and is more suitable for large-scale production.
The technical scheme of the invention is realized as follows:
the invention provides a preparation method of photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microspheres, which comprises the following steps:
s1, preparation of a photo-crosslinkable polyvinyl alcohol intermediate: reacting polyvinyl alcohol with the weight-average molecular weight of 30000-80000 with acrylamide or acrylic monomers by an acid catalysis method or a base catalysis method to obtain a photo-crosslinkable polyvinyl alcohol intermediate containing double bonds;
s2, preparing polyvinyl alcohol embolism microsphere by photo-initiated crosslinking: dissolving a photo-crosslinkable polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropanesulfonic acid sodium salt and a water-soluble photoinitiator in water under a dark condition, adding the solution into a mixed solution of butyl acetate and cellulose acetate butyrate, stirring to form a suspension, then initiating a crosslinking reaction under the irradiation of a light source, and washing after the reaction is finished to obtain the photo-initiated crosslinked polyvinyl alcohol drug-loaded embolization microsphere.
As a further improvement of the invention, the acid catalysis method in the step S1 comprises the following specific steps: adding polyvinyl alcohol into water, completely dissolving at 80-100 ℃, then adding N- (2, 2-dimethoxyethyl) -2-acrylamide and acid, reacting for 4-8 hours at 10-30 ℃, adjusting the pH of a reaction system to 7-8 after the reaction is finished, and then concentrating the solution until the viscosity is more than or equal to 1800cps to obtain a photocrosslinkable polyvinyl alcohol intermediate.
As a further improvement of the invention, the mass ratio of the polyvinyl alcohol to the N- (2, 2-dimethoxyethyl) -2-acrylamide to the acid is 1: (0.01-0.5): (0.5-5).
As a further improvement of the invention, the acid is concentrated hydrochloric acid with the mass fraction of 36-38%.
As a further improvement of the invention, the alkali catalysis method in the step S1 comprises the following specific steps: adding polyvinyl alcohol into dimethyl sulfoxide, completely dissolving at 40-90 ℃, adding glycidyl methacrylate and an alkaline catalyst, stirring at 20-80 ℃ for reacting for 2-24 hours, adding a precipitator into a reaction system after the reaction is finished, separating out modified polyvinyl alcohol obtained by the reaction, and dissolving the modified polyvinyl alcohol in water again to ensure that the mass fraction of the polyvinyl alcohol is 10% -30%, thus obtaining a photocrosslinkable polyvinyl alcohol intermediate.
As a further improvement of the invention, the mass ratio of the polyvinyl alcohol to the glycidyl methacrylate to the basic catalyst is 1: (0.01-0.5): (0.01-1).
As a further improvement of the invention, the basic catalyst is tetramethylethylenediamine or 4-dimethylaminopyridine.
As a further improvement of the invention, the precipitant is ethanol or acetone.
As a further improvement of the present invention, in step S2, the water-soluble photoinitiator is at least one selected from the group consisting of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate, and eosin Y.
As a further improvement of the invention, a photo-crosslinking accelerator is also added in step S2.
As a further improvement of the invention, the photocrosslinking accelerator is N-vinylpyrrolidone.
As a further improvement of the invention, the mass ratio of the photocrosslinkable polyvinyl alcohol intermediate, the 2-acrylamide-2-methyl propanesulfonic acid sodium salt, the water-soluble photoinitiator, the photocrosslinking accelerator, the butyl acetate and the cellulose acetate butyrate in the step S2 is 1: (0.001-0.5): (0.001-0.05): (0-0.01): (1-10): (0.001-0.05).
As a further improvement of the present invention, the reaction temperature in step S2 is room temperature; the reaction time is 5-120 minutes.
As a further improvement of the present invention, the washing in step S2 is washing with ethyl acetate and acetone in this order.
As a further improvement of the invention, the wavelength of the light source in the step S2 is 250-650nm, and the light intensity is 10-1000mW/cm 2 。
The invention further protects the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere prepared by the preparation method.
As a further improvement of the invention, the particle size of the microspheres is in the range of 1 to 2000 microns.
The invention has the following beneficial effects:
the invention provides a preparation method of polyvinyl alcohol embolism microsphere by photo-initiation crosslinking, which is characterized in that a photoinitiator generates free radicals under the radiation energy of ultraviolet light or visible light to enable a polymer monomer to rapidly generate crosslinking reaction. Compared with the traditional thermal polymerization, the polyvinyl alcohol embolism microsphere is prepared by utilizing the photo-initiated crosslinking technology, so that the polymerization reaction temperature is reduced, the polymerization reaction time is shortened, the energy is saved, meanwhile, the use of a thermal initiator and a crosslinking agent with high toxicity is avoided, the reaction can be completed only within 5 minutes to 2 hours, the reaction can be carried out at room temperature, and the environment-friendly photoinitiator is used, so that the equipment is simple, and the preparation method is more suitable for large-scale production. Because the reaction rate is high, the microsphere prepared by photo-initiated crosslinking has good balling property, the particle size range of the microsphere is 1-2000 microns, the internal structure of the microsphere is more uniform, and the drug loading effect is better.
Drawings
FIG. 1 is a microscope picture of photo-initiated cross-linked PVA drug-loaded embolized microspheres prepared in example 1;
FIG. 2 is a microscope photograph of photo-initiated cross-linked PVA drug-loaded embolization microspheres prepared in example 3;
fig. 3 is a microscope picture of the thermally-initiated cross-linked polyvinyl alcohol drug-loaded embolization microsphere prepared in comparative example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
S1, synthesizing photo-crosslinkable polyvinyl alcohol intermediate by acid catalysis method
100g of purified water and 12g of polyvinyl alcohol having a weight average molecular weight of 67000 were put into a reaction flask, and heated to 95 ℃ to completely dissolve the polyvinyl alcohol. 1.5g of N- (2, 2-dimethoxyethyl) -2-acrylamide and 20mL of concentrated hydrochloric acid were added and reacted at 30 ℃ for 4 hours, and after completion of the reaction, the pH of the reaction system was adjusted to 7 with 2mol/L of sodium hydroxide solution. Finally, the solution was concentrated to a viscosity of 1800cps to give about 40g of microsphere intermediate.
S2, preparing polyvinyl alcohol embolism microsphere by photo-initiated crosslinking
9g of the microsphere intermediate, 0.6g of 2-acrylamido-2-methylpropanesulfonic acid sodium salt, and 0.09g of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl group were added to a reaction flask under exclusion of light]-1-acetone, and 5mL of water is added to dissolve completely. Then 60mL of butyl acetate and 0.4g of cellulose acetate butyrate are added, stirred to form a suspension, and at room temperature, an LED lamp with the wavelength of 365nm is used for irradiating the reaction flask to initiate a crosslinking reaction, wherein the light intensity is 20mW/cm 2 And reacting for 2 hours. After the reaction is finished, washing the product by using ethyl acetate and acetone to obtain the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere. Fig. 1 is a microscope picture of the photo-induced cross-linking polyvinyl alcohol drug-loaded embolism microsphere prepared in example 1, and it can be known from the figure that the polyvinyl alcohol drug-loaded embolism microsphere prepared by photo-induced cross-linking has round and smooth surface and good dispersibility.
Example 2
S1, synthesizing photo-crosslinkable polyvinyl alcohol intermediate by acid catalysis method
1000g of purified water and 300g of polyvinyl alcohol having a weight-average molecular weight of 35000 were put into a reaction flask, and heated to 85 ℃ to completely dissolve the polyvinyl alcohol. 100g of N- (2, 2-dimethoxyethyl) -2-acrylamide and 150mL of concentrated hydrochloric acid were added and reacted at 20 ℃ for 5 hours, and after completion of the reaction, the pH of the reaction system was adjusted to 7.5 with 1mol/L sodium hydroxide solution. Finally, the solution was concentrated to a viscosity of 2000cps to give 900g of microsphere intermediate.
S2, preparing polyvinyl alcohol embolism microsphere by photo-initiated crosslinking
100g of microsphere intermediate, 20g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt and 2g of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl are added into a reaction bottle under the condition of keeping out of the sun]-1-propanone, 0.3g N-vinylpyrrolidone, and then 20mL of water was dissolved completely. Adding the solution into a mixed solution of 1000mL of butyl acetate and 2g of cellulose acetate butyrate, stirring to form a suspension, irradiating a reaction bottle by using a mercury lamp with the wavelength of 320nm at room temperature to initiate a crosslinking reaction, wherein the light intensity is 200mW/cm 2 And the reaction is carried out for 20 minutes. After the reaction is finished, washing the product by using ethyl acetate and acetone to obtain the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere.
Example 3
S1, synthesizing photocrosslinkable polyvinyl alcohol intermediate by using alkali catalysis method
600mL of dimethyl sulfoxide and 100g of polyvinyl alcohol having a weight average molecular weight of 78000 were added to a reaction flask, and heated to 80 ℃ to completely dissolve the polyvinyl alcohol. 5g of glycidyl methacrylate and 10mL of tetramethylethylenediamine were added, and the reaction was stirred at 60 ℃ for 5 hours. After the reaction is finished, adding a precipitator ethanol into the reaction system to separate out the modified polyvinyl alcohol. Filtering to obtain modified polyvinyl alcohol, and redissolving to form a 23% polyvinyl alcohol aqueous solution serving as a photocrosslinkable polyvinyl alcohol intermediate.
S2, preparing the polyvinyl alcohol embolism microsphere by photo-initiated crosslinking
20g of the polyvinyl alcohol intermediate described above, 0.34g of 2-acrylamido-2-methylpropanesulfonic acid sodium salt and 0.052g of phenyl (2, 4, 6-trimethylbenzoyl) phosphoric acid lithium salt were completely dissolved in 5mL of deionized water under exclusion of light. Then 100mL of butyl acetate and 0.9g of cellulose acetate butyrate are added, stirred to form a suspension, and at room temperature, an LED lamp with the wavelength of 405nm is used for irradiating the reaction flask to initiate a crosslinking reaction, wherein the light intensity is 300mW/cm 2 And reacting for 1h. After the reaction is finished, washing the mixture by using ethyl acetate and acetone to obtain the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere. Fig. 2 is a microscope picture of the photo-induced cross-linking polyvinyl alcohol drug-loaded embolism microsphere prepared in example 3, and it can be known from the figure that the polyvinyl alcohol drug-loaded embolism microsphere prepared by photo-induced cross-linking has round and smooth surface and good dispersibility.
Example 4
S1, synthesizing photo-crosslinkable polyvinyl alcohol intermediate by alkali catalysis method
60g of polyvinyl alcohol having a weight-average molecular weight of 50000 are added to 1000mL of dimethyl sulfoxide and dissolved completely at 60 ℃. 18g of glycidyl methacrylate and 1g of 4-dimethylaminopyridine were added thereto, and the mixture was reacted at 25 ℃ for 24 hours. After the reaction is finished, adding a precipitator acetone into the reaction system to separate out the modified polyvinyl alcohol. Filtering to obtain modified polyvinyl alcohol, and redissolving to form a polyvinyl alcohol aqueous solution with the mass fraction of 15 percent, wherein the polyvinyl alcohol aqueous solution is used as a photocrosslinkable polyvinyl alcohol intermediate.
S2, preparing the polyvinyl alcohol embolism microsphere by photo-initiated crosslinking
10g of the polyvinyl alcohol intermediate described above, 0.9g of 2-acrylamido-2-methylpropanesulfonic acid sodium salt, 0.3g of eosin Y and 0.09g of N-vinylpyrrolidone were completely dissolved in 10mL of deionized water with exclusion of light. 100mL of butyl acetate and 0.02g of cellulose acetate butyrate were added, and the mixture was stirred to form a suspension, after whichIrradiating the reaction flask with xenon lamp with wavelength of 400-600nm at room temperature to initiate crosslinking reaction with light intensity of 800mW/cm 2 And the reaction was carried out for 30 minutes. After the reaction is finished, washing the mixture by using ethyl acetate and acetone to obtain the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere.
Comparative example 1 preparation of polyvinyl alcohol drug-loaded embolization microsphere by thermal initiation and crosslinking
S1, synthesizing a polyvinyl alcohol intermediate
60g of polyvinyl alcohol having a weight-average molecular weight of 50000 are added to 400mL of purified water and dissolved completely at 90 ℃. Then, 1.596g of N- (2, 2-dimethoxyethyl) -2-acrylamide and 20mL of concentrated hydrochloric acid were added and reacted at 30 ℃ for 6 hours. After the reaction was completed, the pH of the reaction system was adjusted to 7.5 with a sodium hydroxide solution. Finally, the solution is concentrated to a viscosity of 1800cps to obtain the microsphere intermediate.
S2, preparing polyvinyl alcohol drug-loaded embolism microsphere through thermal-induced crosslinking
10g of the microsphere intermediate, 0.85g of 2-acrylamido-2-methylpropanesulfonic acid sodium salt and 0.139g of potassium persulfate or ammonium persulfate initiator were completely dissolved in 15mL of deionized water. Then, 100mL of butyl acetate and 0.034g of cellulose acetate butyrate were added, and finally, 0.16mL of tetramethylethylenediamine was added under an inert gas atmosphere, and the reaction was carried out at 55 ℃ for 6 hours. After the reaction is finished, washing the mixture by using ethyl acetate and acetone to obtain the polyvinyl alcohol drug-loaded embolism microsphere. Fig. 3 is a microscope picture of the thermally-initiated cross-linked polyvinyl alcohol drug-loaded embolization microsphere prepared in comparative example 1. As can be seen from the figure, the polyvinyl alcohol drug-loaded embolism microsphere prepared by thermal initiation crosslinking has good sphere, but the edge of the microsphere is less clear.
Test example 1 drug Loading Performance test
The photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere prepared in the example 1-4 and the thermal-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere prepared in the comparative example 1 are taken, the surface clear water of the microspheres is sucked dry by filter paper, 1g of microspheres are weighed into a penicillin bottle, 4mL of doxorubicin hydrochloride aqueous solution with the concentration of 20mg/mL is added, the penicillin bottle is sealed and placed on a flat plate oscillator to oscillate at the speed of 180rpm, and 10 mu L of sample is respectively sucked at a preset time point and diluted to 2mL. The concentration of the doxorubicin hydrochloride solution is tested at 480nm by using an ultraviolet spectrophotometer, and the drug adsorption capacity and the drug loading rate of the embolism microsphere are calculated, wherein the data of the drug loading rate is shown in table 1.
TABLE 1 measurement data of drug loading rate of PVA embolism microsphere prepared by photo-induced crosslinking
The table shows that the drug loading rate of the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere prepared by the method can reach more than 90% in 30min, the highest drug loading rate of 120min can reach 99.38%, and the photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere is slightly superior to the polyvinyl alcohol drug-loaded embolism microsphere prepared by thermal-initiated cross-linking, and has good drug loading performance.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (14)
1. A preparation method of photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microspheres is characterized by comprising the following steps:
s1, preparation of a photo-crosslinkable polyvinyl alcohol intermediate: reacting polyvinyl alcohol with the weight-average molecular weight of 30000-80000 with acrylamide or acrylic monomers by an acid catalysis method or a base catalysis method to obtain a photo-crosslinkable polyvinyl alcohol intermediate containing double bonds;
s2, preparing polyvinyl alcohol embolism microsphere by photo-initiated crosslinking: dissolving a photo-crosslinkable polyvinyl alcohol intermediate, 2-acrylamide-2-methylpropanesulfonic acid sodium salt and a water-soluble photoinitiator in water under the condition of keeping out of the sun, adding the solution into a mixed solution of butyl acetate and cellulose acetate butyrate, stirring to form a suspension, initiating a crosslinking reaction under the irradiation of a light source, and washing after the reaction is finished to obtain photo-initiated crosslinked polyvinyl alcohol drug-loaded embolism microsphere;
wherein:
the acid catalysis method in the step S1 comprises the following specific steps: adding polyvinyl alcohol into water, completely dissolving at 80-100 ℃, adding N- (2, 2-dimethoxyethyl) -2-acrylamide and acid, reacting for 4-8 hours at 10-30 ℃, adjusting the pH of a reaction system to 7-8 after the reaction is finished, and concentrating the solution until the viscosity is more than or equal to 1800cps to obtain a photocrosslinkable polyvinyl alcohol intermediate;
the alkali catalysis method in the step S1 comprises the following specific steps: adding polyvinyl alcohol into dimethyl sulfoxide, completely dissolving at 40-90 ℃, adding glycidyl methacrylate and an alkaline catalyst, stirring at 20-80 ℃ for reacting for 2-24 hours, adding a precipitator into a reaction system after the reaction is finished, separating out modified polyvinyl alcohol obtained by the reaction, and dissolving the modified polyvinyl alcohol in water again to ensure that the mass fraction of the polyvinyl alcohol is 10% -30%, thus obtaining a photocrosslinkable polyvinyl alcohol intermediate; the alkaline catalyst is tetramethylethylenediamine or 4-dimethylaminopyridine.
2. The method according to claim 1, wherein the mass ratio of the polyvinyl alcohol, N- (2, 2-dimethoxyethyl) -2-acrylamide and acid is 1: (0.01-0.5): (0.5-5).
3. The method according to claim 1, wherein the acid is concentrated hydrochloric acid.
4. The production method according to claim 1, wherein the mass ratio of the polyvinyl alcohol, the glycidyl methacrylate and the basic catalyst is 1: (0.01-0.5): (0.01-1).
5. The method according to claim 1, wherein the precipitant is ethanol or acetone.
6. The method of claim 1, wherein the water-soluble photoinitiator in step S2 is at least one selected from the group consisting of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate, and eosin Y.
7. The method according to claim 1, wherein a photo-crosslinking accelerator is further added in step S2.
8. The method according to claim 7, wherein the photo-crosslinking accelerator is N-vinylpyrrolidone.
9. The method according to claim 7, wherein the mass ratio of the photo-crosslinkable polyvinyl alcohol intermediate in step S2, the sodium salt of 2-acrylamido-2-methylpropanesulfonic acid, the water-soluble photoinitiator, the photo-crosslinking accelerator, butyl acetate, and cellulose acetate butyrate is 1: (0.001-0.5): (0.001-0.05): (0-0.01): (1-10): (0.001-0.05).
10. The production method according to claim 1, wherein the reaction temperature in step S2 is room temperature; the reaction time is 5-120 minutes.
11. The method according to claim 1, wherein the washing in step S2 is washing with ethyl acetate and acetone in this order.
12. The method according to claim 1, wherein the light source in step S2 has a wavelength of 250 to 650nm and a light intensity of 10 to 1000mW/cm 2 。
13. A photo-initiated cross-linked polyvinyl alcohol drug-loaded embolization microsphere prepared according to the preparation method of any one of claims 1 to 12.
14. The photo-initiated cross-linked polyvinyl alcohol drug-loaded embolic microsphere of claim 13, wherein the particle size of the microsphere ranges from 1 to 2000 microns.
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