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WO2025201153A1 - Microsphères de poly (p-dioxanone) de masse moléculaire élevée, leur procédé de préparation et leur utilisation - Google Patents

Microsphères de poly (p-dioxanone) de masse moléculaire élevée, leur procédé de préparation et leur utilisation

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Publication number
WO2025201153A1
WO2025201153A1 PCT/CN2025/083613 CN2025083613W WO2025201153A1 WO 2025201153 A1 WO2025201153 A1 WO 2025201153A1 CN 2025083613 W CN2025083613 W CN 2025083613W WO 2025201153 A1 WO2025201153 A1 WO 2025201153A1
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Prior art keywords
ppdo
microspheres
molecular weight
pdo
high molecular
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English (en)
Chinese (zh)
Inventor
刘瑞霖
李睿智
张堃
赫童
王世炜
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Imeik Technology Development Co Ltd
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Imeik Technology Development Co Ltd
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Publication of WO2025201153A1 publication Critical patent/WO2025201153A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C08J3/14—Powdering or granulating by precipitation from solutions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones

Definitions

  • the present invention relates to the technical field of biomedical polymer materials, and in particular to high-molecular-weight polydioxanone microspheres, a preparation method thereof, and applications thereof.
  • Polydioxanone is a commonly used biodegradable polymer in medical applications. It belongs to the aliphatic polyester family and holds a significant position in the field of medical biodegradable materials. This type of material exhibits excellent biocompatibility and minimal tissue reaction upon implantation. This is due to the ester bonds within its polymer chain, which impart excellent biodegradability, and the ether bonds, which impart unique flexibility. In recent years, the field of medical aesthetics has rapidly developed, with numerous biomedical polymers being used in facial contouring applications. PPDO, due to its excellent properties, has been widely used in absorbable sutures and suture implants for medical aesthetics. While PPDO suture implants are relatively mature, PPDO microspheres are currently not commercially available in China.
  • PPDO microspheres are spherical particles dissolved in a solvent and then dispersed in an emulsifier. Due to the inherent properties of PPDO, PPDO microspheres also exhibit excellent biocompatibility and biodegradability. However, since PPDO is easily degraded when exposed to water, its molecular weight is easily reduced during its preparation process, which affects the performance of the final microspheres. This also limits the development and large-scale production of PPDO microspheres.
  • the main methods for preparing microspheres include phase separation, emulsion-solvent drying, freeze-drying, and spray drying.
  • Emulsion-solvent drying is convenient and most suitable for large-scale production.
  • the predominant methods used to prepare PPDO microspheres are emulsification and spray drying, both of which have been reported in previous studies.
  • these methods have limitations that affect the molecular weight and particle size of PPDO microspheres.
  • the molecular weight of PPDO is easily reduced by high temperatures during the spray drying process, while the rapid spraying process can result in excessively small particle sizes.
  • PPDO microspheres are composite microspheres of polydioxanone and another polymer, or copolymers of polydioxanone (PDO) with other materials, which can also affect the in vivo degradability of PPDO microspheres.
  • Patent document CN116589710A discloses a poly-4-dioxanone-based polymer microsphere, as well as its preparation method and application.
  • the polydioxanone used has a low molecular weight, which may cause the prepared microspheres to degrade quickly, affecting their subsequent use effects.
  • Patent document CN106492284A discloses a method for preparing a biodegradable filling material and its application. However, during the preparation process of this invention, drying treatment at 110-120°C is required, which exacerbates the degradation of PPDO and will affect the properties of the microspheres.
  • the present application provides a high molecular weight polydioxanone microspheres and a preparation method and application thereof, which adopts double-emulsion solvent evaporation technology (DESE method).
  • DSE method double-emulsion solvent evaporation technology
  • the amphiphilic polymer is utilized to jointly act with PVA to self-assemble at the two-phase interface formed by emulsification to form a double micelle protective layer, which effectively blocks the degradation of PPDO by water during the formation of the microspheres, and makes the high molecular weight PPDO microspheres have long-term stability, effectively solving the problem that the polydioxanone microspheres in the prior art generally have a low molecular weight and a complex preparation process.
  • high molecular weight polydioxanone microspheres are provided.
  • High molecular weight polydioxanone microspheres are obtained by adding an amphiphilic polymer to a high molecular weight PPDO raw material.
  • the amphiphilic polymer is an oligomeric PDO or a copolymer of PDO and a hydrophilic segment.
  • the hydrophilic segment comprises a polyethylene glycol or polypropylene glycol segment, for example, polyethylene glycol monomethyl ether (mPEG) or polypropylene glycol monomethyl ether (mPPG) and other hydrophilic polyether polymers.
  • mPEG polyethylene glycol monomethyl ether
  • mPPG polypropylene glycol monomethyl ether
  • the weight average molecular weight of the high molecular weight PPDO raw material is 20 ⁇ 10 4 -80 ⁇ 10 4 Da (e.g., 20 ⁇ 10 4 , 30 ⁇ 10 4 , 40 ⁇ 10 4 , 50 ⁇ 10 4 , 60 ⁇ 10 4 , 70 ⁇ 10 4 , 80 ⁇ 10 4 Da), preferably 20 ⁇ 10 4 -40 ⁇ 10 4 Da.
  • the weight average molecular weight of the hydrophilic segment is 500-2000 Da (e.g., 500, 600, 700, 800, 900, 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, 2000 Da).
  • step (2) adding the mixed solution obtained in step (1) to a polyvinyl alcohol (PVA) aqueous solution and emulsifying to obtain an emulsion;
  • PVA polyvinyl alcohol
  • step (3) removing the solvent A from the emulsion obtained in step (2), performing solid-liquid separation, and obtaining the high molecular weight PPDO microspheres.
  • the weight average molecular weight of the raw material in step (1) is 20 ⁇ 10 4 -80 ⁇ 10 4 Da (e.g., 20 ⁇ 10 4 , 30 ⁇ 10 4 , 40 ⁇ 10 4 , 50 ⁇ 10 4 , 60 ⁇ 10 4 , 70 ⁇ 10 4 , 80 ⁇ 10 4 Da), preferably 20 ⁇ 10 4 -40 ⁇ 10 4 Da.
  • amphiphilic polymer is oligomeric PDO or a copolymer of PDO and a hydrophilic segment.
  • the hydrophilic segment comprises a polyethylene glycol or polypropylene glycol segment, for example, polyethylene glycol monomethyl ether (mPEG) or polypropylene glycol monomethyl ether (mPPG) and other hydrophilic polyether polymers.
  • mPEG polyethylene glycol monomethyl ether
  • mPPG polypropylene glycol monomethyl ether
  • the weight average molecular weight of the oligomeric PDO is 500-2000 Da (e.g., 500, 600, 700, 800, 900, 1000, 1200, 1400, 1500, 1600, 1800, 2000 Da), preferably 500-1000 Da.
  • the weight average molecular weight of the hydrophilic segment is 500-2000 Da (e.g., 500, 600, 700, 800, 900, 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, 2000 Da).
  • the weight average molecular weight of the copolymer of PDO and hydrophilic segments is 800-5000 Da (such as 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000 Da, 3200, 3400, 3600, 3800, 4000 Da, 4200, 4400, 4600, 4800, 5000 Da), preferably 1000-4000 Da.
  • the amphiphilicity of lower molecular weight PDO oligomers allows for the formation of a micellar protective layer at the interface between the two phases.
  • PDO oligomers within this range due to their low molecular weight and amphiphilic nature, remain at the interface, protecting the high-molecular-weight PPDO microspheres without participating in their formation.
  • the molecular weight of oligomeric PDO is too high, its hydrophilicity is almost eliminated, and it remains in the oil phase, participating in microsphere formation and thus failing to form a micellar protective layer at the interface.
  • PDO can also be copolymerized with a hydrophilic segment, such as mPEG or mPPG, to form a PPDO-b-mPEG or PPDO-b-mPPG copolymer.
  • a hydrophilic segment such as mPEG or mPPG
  • the chain length (or molecular weight) of the PPDO in the copolymer is controlled to be equivalent to the chain length (or molecular weight) of the hydrophilic segment, thereby acting as a hydrophobic segment.
  • the resulting copolymer achieves a balance between hydrophilicity and hydrophobicity, making it easier to form a micellar protective layer at the interface between the two phases, thereby achieving a better protective effect.
  • the chain length (or molecular weight) of the hydrophobic segment PPDO is higher than that of the hydrophilic segment, which disrupts the hydrophilic-hydrophobic balance of the copolymer, making the copolymer more hydrophobic. Due to the increased hydrophobicity, it is difficult for the copolymer to stay at the water-oil interface, and it stays more in the oil phase, thus failing to form a protective layer at the water-oil interface.
  • the copolymer is PPDO-b-mPEG.
  • the oligomeric PDO and the copolymer of PDO and the hydrophilic segment can be prepared in-house or purchased.
  • the homemade method is to prepare them by conventional bulk polymerization in the laboratory.
  • the oligomeric PDO preparation process includes: polymerizing PDO monomers at 70-90° C. (such as 80° C.) for 8-16 hours (such as 12 hours) to obtain the oligomeric PDO.
  • the oligomeric PDO preparation process further includes the step of adding a catalyst (such as stannous octoate).
  • a catalyst such as stannous octoate
  • the oligomeric PDO preparation process further includes the step of adding an initiator (such as water).
  • the preparation process of the copolymer of PDO and hydrophilic segment includes: mixing PDO monomer with a hydrophilic segment (such as mPEG or mPPG), and polymerizing at 70-90° C. (such as 80° C.) for 8-16 hours (such as 12 hours) to obtain the copolymer.
  • a hydrophilic segment such as mPEG or mPPG
  • the process for preparing the copolymer of PDO and the hydrophilic segment further comprises the step of adding a catalyst (such as stannous octoate).
  • a catalyst such as stannous octoate
  • the mass ratio of the PDO monomer to the hydrophilic segment is 1:1-2.5 (e.g., 1:2.5, 1:2.2, 1:2.0, 1:1.8, 1:1.6, 1:1.4, 1:1.2, 1:1).
  • the amount of the amphiphilic polymer added in step (1) is 0.5-5 wt% (e.g., 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 4 wt%, 5 wt%) of the high molecular weight PPDO raw material, preferably 1-2 wt%.
  • the solvent A in step (1) is one or more of dichloromethane, chloroform or carbon tetrachloride, especially dichloromethane.
  • the concentration of the high molecular weight PPDO raw material in step (1) is 1-10 wt% (e.g., 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%).
  • step (1) includes: adding a high molecular weight PPDO raw material and an amphiphilic polymer to solvent A, heating and refluxing under the protection of an inert gas to obtain a mixed solution.
  • the inert gas is nitrogen or helium.
  • step (2) comprises: adding the mixed solution obtained in step (1) to the polyvinyl alcohol aqueous solution at a constant rate, stirring, and emulsifying the mixed solution in the polyvinyl alcohol aqueous solution to obtain an emulsion;
  • the rate is 5-50 ml/min (5 ml/min, 10 ml/min, 15 ml/min, 20 ml/min, 25 ml/min, 30 ml/min, 35 ml/min, 40 ml/min, 45 ml/min, 50 ml/min), preferably 30-50 ml/min.
  • the alcoholysis degree of the PVA in step (2) is 80-90% (such as 80%, 82%, 84%, 86%, 88%, 90%); preferably 86-88%.
  • the viscosity of the PVA in step (2) is 3.0-6.5 mPa ⁇ s (such as 3.0 mPa ⁇ s, 3.5 mPa ⁇ s, 4.0 mPa ⁇ s, 4.5 mPa ⁇ s, 5.0 mPa ⁇ s, 5.5 mPa ⁇ s, 6.0 mPa ⁇ s), preferably 4.5-5.5 mPa ⁇ s.
  • the mass volume concentration of the PVA aqueous solution in step (2) is 0.5%-10% (such as 0.5%, 1%, 2%, 3%, 5%, 7%, 9%, 10%, w/v unit is g/ml), preferably 1-3%.
  • the emulsification temperature in step (2) is 0-30°C (such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C), preferably 10-25°C.
  • the emulsification in step (2) is carried out by mechanically stirring the mixture; furthermore, the mechanical stirring speed is 100-500 rpm (such as 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm, 400 rpm, 450 rpm, 500 rpm), preferably 200-300 rpm.
  • the mechanical stirring speed is 100-500 rpm (such as 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm, 400 rpm, 450 rpm, 500 rpm), preferably 200-300 rpm.
  • polyvinyl alcohol will also self-assemble to form a micellar layer near the water phase end of the two-phase interface through water-in-oil emulsification, thereby forming a double micellar protective layer at the water-oil interface.
  • the preparation of microspheres by the double emulsification method effectively blocks the degradation of high-molecular-weight PPDO by water during the formation process, thereby improving the stability of the microspheres.
  • the volatilization temperature of the solvent A is 0-70°C (such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C), preferably 15-30°C.
  • the solid-liquid separation method may be a combination of one or more of precipitation, filtration and centrifugation.
  • the solid-liquid separation method includes: adding water to the solid-liquid mixture system. Since the microspheres are solid spheres with high density, the microspheres will precipitate after adding water, making it easy to further separate.
  • the solid-liquid separation is carried out by precipitation and filtration; specifically, the method comprises: adding 1-5 times the volume of purified water to the microsphere system from which solvent A has been removed, precipitating the microspheres, and separating by suction filtration to obtain microspheres. Furthermore, the volume of the purified water added is preferably 3-5 times.
  • the obtained microspheres may be washed after separation.
  • the method further comprises:
  • step (3) Sieving the microspheres obtained in step (3) (to obtain high molecular weight polydioxanone microspheres with a certain particle size).
  • the sieve used for screening is 50-2000 mesh (such as 50, 100, 200, 500, 100, 200 mesh), and the screening can obtain high molecular weight polydioxanone microspheres with a particle size of 5-100 ⁇ m; preferably, the obtained microspheres have a particle size of 10-50 ⁇ m.
  • the method further comprises:
  • step (3) or (4) vacuum drying the microspheres obtained in step (3) or (4) (preferably the microspheres obtained in step (4)) to obtain a high molecular weight polydioxanone microsphere product.
  • the third aspect of the present invention provides the use of the high molecular weight PPDO microspheres described in the first aspect or the high molecular weight PPDO microspheres prepared by the method described in the second aspect.
  • the application is the use of the high molecular weight PPDO microspheres in the preparation of tissue fillers (such as mixed gels), drug carriers and tissue scaffolds.
  • the tissue scaffold can be used as a scaffold material in bone tissue repair and liver tissue repair.
  • the holes and wrinkles on the high molecular weight PPDO microspheres can provide support for cell growth and promote tissue repair.
  • the present invention utilizes a double emulsion-solvent evaporation method to prepare high-molecular-weight polydioxanone microspheres.
  • the amphiphilic polymer particularly oligomeric PDO or PPDO-b-mPEG copolymer introduced during the preparation process synergizes with PVA to produce a double emulsion.
  • the hydrophobic end segments of the amphiphilic polymer contact the oil phase, while the hydrophilic end segments contact the water phase. These segments self-assemble near the oil phase at the interface between the two phases to form a micellar layer.
  • polyvinyl alcohol also self-assembles near the water phase through oil-in-water emulsification, forming a micellar layer.
  • the present method is highly operable, requires mild preparation conditions, and is suitable for mass production of high-molecular-weight polydioxanone microspheres. It has broad application prospects in tissue fillers, drug carriers, and tissue scaffolds.
  • Figure 1 shows a schematic structural diagram of a double micellar protective layer formed by PVA and an amphiphilic polymer (oligomeric PDO or PPDO-b-mPEG copolymer) at the two-phase interface of a high molecular weight PPDO dichloromethane solution droplet: the spherical structure inside the figure is a dichloromethane solution droplet of a high molecular weight PPDO, which is the oil phase; the outermost blank portion is a PVA aqueous solution, which is the water phase; at the two-phase interface, the black and white sticks near the oil phase end are the micellar protective layer formed by the amphiphilic polymer, where the white end is the hydrophobic end and the black end is the hydrophilic end; the gray sticks near the water phase end at the two-phase interface are the micellar protective layer formed by PVA.
  • an amphiphilic polymer oligomeric PDO or PPDO-b-mPEG copolymer
  • FIG2 is a scanning electron microscope image of microspheres obtained by the double emulsion-solvent evaporation method in Example 4.
  • PDO monomer 5 g was added to a polymerization tube, 1 mg of stannous octoate as a catalyst, and 0.1 g of water as an initiator.
  • the oligomeric PDO was obtained by polymerization at 80°C for 12 h.
  • the oligomeric PDO was dissolved in hexafluoroisopropanol and precipitated with ethanol. The precipitate was dried and set aside for use.
  • the weight-average molecular weight was 1080 Da as determined by GPC.
  • Example 1 High molecular weight polydioxanone microspheres A1
  • the mixed solution was added to the PVA solution at a rate of 20ml/min and fully emulsified at 23°C to form droplets of a high-molecular-weight PPDO-b-mPEG solution.
  • the PVA and amphiphilic polymer formed a double micellar protective layer at the interface between the two phases of the high-molecular-weight PPDO-b-mPEG solution droplets.
  • the specific structure is shown in Figure 1.
  • the amphiphilic polymer PPDO-b-mPEG500 forms a micellar protective layer near the oil phase at the water-oil interface, with the hydrophobic segment (such as PPDO in this example) closer to the oil phase (the white portion of the black and white sticks) and the hydrophilic segment (such as mPEG500 in this example) closer to the water phase (the black portion of the black and white sticks).
  • Polyvinyl alcohol forms a micellar protective layer near the water phase at the oil-water interface, forming a double micellar protective layer together with the amphiphilic polymer.
  • the solvent dichloromethane is completely evaporated at 30°C to obtain high molecular weight PPDO microspheres.
  • the dichloromethane solvent was then completely evaporated at 30°C. An appropriate amount of purified water was added to precipitate the high-molecular-weight PPDO microspheres. The supernatant was discarded, filtered, and the microspheres were washed. The microspheres were then sieved and dried to yield high-molecular-weight PPDO microspheres A8.
  • the preparation process was the same as that in Example 4, except that “60 mg of the PPDO-b-mPEG1000 copolymer prepared in Synthesis Example 2” was replaced with “60 mg of the PPDO-b-mPEG1000 copolymer prepared in Synthesis Example 5” to obtain high molecular weight polydioxanone microspheres B3.
  • the molecular weights of the microspheres prepared in Examples 1-8 are close to that of the high molecular weight PPDO raw material, and the molecular weight loss rates are all within 15%, indicating that the preparation process of the present invention, by utilizing an amphiphilic polymer for preparing microspheres, can maintain the high molecular weight of the microspheres and reduce the molecular weight loss rate.
  • Comparative Example 1 which uses the same high molecular weight PPDO raw material as in Example 4, is significantly lower than that in Example 4 due to the lack of the introduction of an amphiphilic polymer, indicating that the conventional emulsification-solvent evaporation method is difficult to prepare high molecular weight PPDO microspheres.
  • Comparative Example 2 mPEG is introduced during the emulsification process. Although the molecular weight of the microspheres is increased to a certain extent (20 ⁇ 10 4 ), it is still significantly lower than the molecular weight of the microspheres in Example 4 (30 ⁇ 10 4 ).
  • the high molecular weight PPDO microspheres obtained in Example 4 were observed using a scanning electron microscope, and the results are shown in Figure 2.
  • the prepared high molecular weight PPDO microspheres have a regular surface shape, a microsphere particle size ranging from 10 to 50 ⁇ m, an average particle size of 38 ⁇ m, and a uniform distribution, indicating that uniformly distributed high molecular weight PPDO microspheres can be obtained using the process of the present invention.
  • Example 4 One gram of each of the microspheres obtained in Example 4 and Comparative Examples 1-3 (after thorough drying) was subjected to accelerated degradation experiments at 70°C. Five parallel groups were collected from each sample and tested at five different time points (days) 1, 2, 3, 4, and 5. The samples after the accelerated degradation experiments were tested for mass and Mw, using constant weight determination and GPC for Mw. The results are shown in Table 2.
  • Comparative Examples 1 and 2 although the same PPDO raw material ratio is used, the conventional emulsification-solvent evaporation method is used to prepare polydioxanone microspheres.
  • the molecular weight of the microspheres obtained is much lower than that of Example 4.
  • the degradation quality and degradation rate of the microspheres are significantly higher than those of the microspheres in Example 4, indicating that the microspheres without the introduction of the amphiphilic polymer are easily affected by water and thus degrade quickly.
  • the microspheres in Comparative Example 3 also introduce the amphiphilic polymer under the premise of using the same PPDO raw material ratio, and the molecular weight of the microspheres is improved, and the degradation quality and degradation rate are slowed down to a certain extent.
  • the hydrophobic end PPDO accounts for too high a proportion of the amphiphilic polymer and the mPEG hydrophilic end accounts for too low a proportion, the hydrophobicity is enhanced and the hydrophilicity is weakened, resulting in the amphiphilic polymer being unable to stay at the interface between the two phases, so that the amphiphilic polymer stays more in the oil phase, making it difficult to form an effective protective layer, resulting in the molecular weight of the microspheres being lower than that of the microspheres.
  • Example 4 and the degradation quality and degradation rate are also significantly faster than Example 4.
  • the above results further demonstrate that the double micelle protective layer formed by the double emulsification method of PPDO-b-mPEG1000 and PVA introduced in Example 4 can effectively prolong the degradation time of high molecular weight polydioxanone microspheres. Because 3 days of accelerated degradation experiment is approximately equivalent to 100 days of conventional degradation at 37°C, 5 days is equivalent to 150 days of conventional degradation, and 7 days of accelerated degradation is equivalent to 200 days of conventional degradation, the double micelle protective layer formed by double emulsification can show a more obvious advantage in protecting the molecular weight of microspheres during actual clinical application, and the stability effect of the microspheres can be sustained longer.
  • microspheres Add 2.5g of microspheres to 10ml of sodium hyaluronate gel, mix thoroughly, and then aseptically fill it into a 1ml prefilled syringe to obtain a mixed gel containing high molecular weight polydioxanone microspheres.
  • the elastic modulus G' of the gel prepared using the microspheres of Comparative Example 1 in Application Example 3 is only 321 Pa, which is much lower than the gel formed using the microspheres of Example 4 in Application Examples 1-2 (546 Pa and 587 Pa). Therefore, the gel prepared from the PPDO microspheres of Comparative Example 1 may have a low elastic modulus and poor mechanical properties when used, which may lead to poor filling effect and fail to provide ideal support, which is not conducive to clinical application.
  • the gel prepared from the PPDO microspheres of Example 4 of the present invention has ideal viscosity and elastic modulus, good mechanical properties, can provide ideal support in clinical filling applications, can meet the clinical performance requirements for filling mixed gels, and is suitable for filling and plasticity for medical cosmetic purposes.

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Abstract

La présente invention concerne des microsphères de poly (p-dioxanone) (PPDO) de masse moléculaire élevée, leur procédé de préparation et leur utilisation. En utilisant une méthode de double émulsion-évaporation de solvant, une couche protectrice à double micelle est formée à l'aide d'un polymère amphiphile, tel que la p-dioxanone oligomère (PDO) ou un copolymère de PDO, et d'un fragment hydrophile (tel que mPEG ou mPPG), en vertu du caractère amphiphile du polymère amphiphile et de la co-action du polymère amphiphile et de l'alcool polyvinylique (PVA) au moyen d'un auto-assemblage à une interface de deux phases formée par émulsification. La couche protectrice bloque efficacement l'effet de dégradation de l'eau sur le PPDO pendant la formation des microsphères, et des microsphères de PPDO de masse moléculaire élevée ayant une performance stable sont finalement obtenues, et ainsi, les microsphères de PPDO de masse moléculaire élevée ont une stabilité à long terme. Le procédé de préparation présente une exploitabilité élevée et des exigences modérées, et est approprié pour une production en masse, et les microsphères de PPDO de masse moléculaire élevée obtenues présentent de larges perspectives d'application dans des produits de comblement tissulaire, des supports de médicaments, des échafaudages tissulaires, etc.
PCT/CN2025/083613 2024-03-27 2025-03-20 Microsphères de poly (p-dioxanone) de masse moléculaire élevée, leur procédé de préparation et leur utilisation Pending WO2025201153A1 (fr)

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KR20210041810A (ko) * 2019-10-08 2021-04-16 주식회사 메타바이오메드 폴리디옥사논계 필러용 미립구 및 이의 제조방법
CN116589710A (zh) * 2023-07-17 2023-08-15 成都普利铭医用材料科技有限责任公司 一种聚对二氧环己酮基聚合物微球及其制备方法和应用

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CN106727422A (zh) * 2017-03-09 2017-05-31 王秋玉 一种聚对二氧环己酮为核的核‑壳双层微球及其制备方法和应用
KR20210041810A (ko) * 2019-10-08 2021-04-16 주식회사 메타바이오메드 폴리디옥사논계 필러용 미립구 및 이의 제조방법
CN116589710A (zh) * 2023-07-17 2023-08-15 成都普利铭医用材料科技有限责任公司 一种聚对二氧环己酮基聚合物微球及其制备方法和应用

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