WO2023035384A1 - Microsphère d'embolisation d'hydrogel et son procédé de préparation - Google Patents

Microsphère d'embolisation d'hydrogel et son procédé de préparation Download PDF

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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
preparation
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PCT/CN2021/128171
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Chinese (zh)
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郭平
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苏州浩微生物医疗科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/12—Esters of monohydric alcohols or phenols
    • C08F220/16—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms
    • C08F220/18—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms with acrylic or methacrylic acids
    • C08F220/1802—C2-(meth)acrylate, e.g. ethyl (meth)acrylate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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

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

L'invention concerne un procédé de préparation d'une microsphère d'embolisation d'hydrogel. La microsphère est formée au moyen d'une polymérisation par réticulation d'un monomère acrylate et d'un monomère dérivé d'acide carboxylique d'alcool vinylique par l'intermédiaire d'un agent de réticulation. Le procédé comprend les étapes suivantes consistant à : ajouter un dispersant à de l'eau désionisée pour former une solution de phase aqueuse ; mélanger un monomère acrylate, un monomère dérivé d'acide carboxylique d'alcool vinylique, un agent de réticulation et un initiateur pour former un premier mélange ; mélanger le premier mélange avec la solution de phase aqueuse, et générer un intermédiaire de microsphère au moyen d'une réaction de polymérisation ; et mélanger l'intermédiaire de microsphère avec une solution d'hydroxyde de sodium, et faire réagir celui-ci pour générer une microsphère d'hydrogel. La présente invention concerne une microsphère d'hydrogel ayant une bonne élasticité et un bon ajustement vasculaire et une déformation élastique relativement élevée et une performance de récupération relativement élevée. La microsphère d'hydrogel selon l'invention peut adsorber efficacement un grand nombre de médicaments en une courte période de temps lorsqu'elle est utilisée pour charger un médicament hydrophile.
PCT/CN2021/128171 2021-09-10 2021-11-02 Microsphère d'embolisation d'hydrogel et son procédé de préparation WO2023035384A1 (fr)

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CN116850333A (zh) * 2023-07-19 2023-10-10 湖南爱杰特生物科技有限公司 一种复合纳米纤维敷料及其制备方法
CN116850333B (zh) * 2023-07-19 2024-01-26 湖南爱杰特生物科技有限公司 一种复合纳米纤维敷料及其制备方法
CN117323294A (zh) * 2023-09-25 2024-01-02 至微(深圳)医学科技有限公司 一种载药栓塞微球及其制备方法和应用
CN117323294B (zh) * 2023-09-25 2024-05-31 至微(深圳)医学科技有限公司 一种载药栓塞微球及其制备方法和应用

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