WO2018113345A1 - 低温可注射丙烯酸树脂骨水泥及其制备方法 - Google Patents

低温可注射丙烯酸树脂骨水泥及其制备方法 Download PDF

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WO2018113345A1
WO2018113345A1 PCT/CN2017/100780 CN2017100780W WO2018113345A1 WO 2018113345 A1 WO2018113345 A1 WO 2018113345A1 CN 2017100780 W CN2017100780 W CN 2017100780W WO 2018113345 A1 WO2018113345 A1 WO 2018113345A1
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component
bone cement
acrylic resin
liquid phase
low temperature
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PCT/CN2017/100780
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English (en)
French (fr)
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卓清山
张鹏云
汪宇
吕世文
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宁波华科润生物科技有限公司
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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
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L25/00—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 aromatic carbocyclic ring; Compositions of derivatives of such polymers
    • C08L25/02—Homopolymers or copolymers of hydrocarbons
    • C08L25/04—Homopolymers or copolymers of styrene
    • C08L25/08—Copolymers of styrene
    • C08L25/14—Copolymers of styrene with unsaturated esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/04—Homopolymers or copolymers of esters
    • C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
    • C08L33/08—Homopolymers or copolymers of acrylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/04—Homopolymers or copolymers of esters
    • C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
    • C08L33/10—Homopolymers or copolymers of methacrylic acid esters
    • C08L33/12—Homopolymers or copolymers of methyl methacrylate
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Definitions

  • the invention relates to the field of medical biomaterials, in particular to a low temperature injectable acrylic resin bone cement and a preparation method thereof.
  • Osteoporosis is one of the most common bone diseases in the middle-aged and elderly population.
  • the number of osteoporosis patients in China is close to 100 million, and at least 210 million people have lower bone mass than normal, which is the country with the largest number and potential number of osteoporosis patients.
  • a set of data published by the International Osteoporosis Foundation shows that an osteoporotic fracture occurs every three seconds in the world, and one-third of women and one-fifth of men suffer a fracture after 50 years, 20%. Patients with hip fractures will die within 6 months of the fracture, and half of the patients will not be able to take care of themselves. Injection of bone cement into damaged bone or vertebrae is currently a simple and effective method for treating osteoporosis.
  • Polymethyl Methacrylate can be used not only as a bone substitute material for filling bone defects, such as filling material for kyphoplasty (KP), but also for enhanced internal implantation.
  • the holding power of the object such as the injection of screws or around the prosthesis, stabilizes the internal fixation.
  • PMMA has the advantages of being used for bone substitutes, which has good biocompatibility and high mechanical strength. As a holding force enhancer, it can not only greatly increase the axial pull-out resistance, but also increase the shear resistance and torsion. Force, this is not available in other materials, so PMMA is currently the most commonly used bone cement.
  • German Patent No. 3,245,956 A1 discloses a bone cement based on a liquid monomer and a powdered polymeric acrylate and/or methacrylate, a catalyst and an accelerator, which is added to a bone cement solution which does not participate in the polymerization reaction.
  • the surface active liquid can effectively reduce the heat released during the polymerization of the bone cement, but the final product introduces a surface active liquid, which limits the clinical application;
  • 104784753A discloses a composite bone cement having a thermal necrosis effect, the bone cement powder A phase change microcapsule material (PCM) is added to reduce the maximum temperature during curing, which is significantly lower than the clinical application requirements. Although the thermal necrosis can be reduced, the final product changes, and the clinical application needs further verification. .
  • PCM phase change microcapsule material
  • the component B of the particle size range of 500-2000 ⁇ m is added to the solid phase of the low-temperature injectable acrylic resin bone cement of the present invention, and the total specific surface area of the solid phase is lowered, when the total solid phase is constant.
  • the total reaction amount of the solid-liquid interface is reduced, so that the exothermic temperature of the bone cement of the invention is significantly reduced during the curing process, which can effectively improve the thermal burn and thermal necrosis of the tissue during clinical use.
  • Another object of the present invention is to provide a low temperature injectable acrylic resin bone cement having a final product consistent with current clinical products.
  • the low temperature injectable acrylic resin bone cement of the present invention comprises a solid phase comprising a component A and a component B, and a component B comprising the component A and the The liquid phase is prepared by mixing, so that the bone cement of the invention does not introduce new products after curing, and the clinical safety is ensured, and can be directly used in clinical practice.
  • a low temperature injectable acrylic resin bone cement comprising a solid phase and a liquid phase, the solid phase ratio of the solid phase and the liquid phase being 0.25-0.5 mL/g, in mass percentage,
  • the solid phase comprises 25-80 wt% of component A and 20-75 wt% of component B, wherein the component A comprises 59.5-99.5 wt% of a powdered acrylate polymer and 0.5-2 wt% of An oxide initiator comprising, in percentage by volume, 95-99.9 vol% of an acrylate monomer and 0.1-5 vol% of an accelerator, the component B being the component A and the
  • the liquid phase is prepared by mixing a solid-liquid ratio of 0.25-0.8 mL/g.
  • the component A further comprises 10-40% by weight of a developer selected from barium sulfate, zirconium oxide or Barium sulfate, the developer having an average particle diameter of 1 to 50 ⁇ m; the liquid phase further comprising 20 to 150 ppm of a polymerization inhibitor selected from the group consisting of hydroquinone or hydroquinone monomethyl ether.
  • a developer selected from barium sulfate, zirconium oxide or Barium sulfate, the developer having an average particle diameter of 1 to 50 ⁇ m
  • the liquid phase further comprising 20 to 150 ppm of a polymerization inhibitor selected from the group consisting of hydroquinone or hydroquinone monomethyl ether.
  • the powdered acrylate-based polymer is one or more selected from the group consisting of polymethyl methacrylate, styrene-methyl methacrylate copolymer or methyl acrylate-methyl methacrylate copolymer.
  • the powdery acrylate-based polymer has a particle diameter ranging from 20 to 200 ⁇ m.
  • the peroxide initiator comprises benzoyl peroxide, benzoyl peroxide or methyl ethyl ketone, and the acrylate monomer comprises methyl methacrylate, methyl acrylate or methyl peroxide.
  • the accelerator includes NN-dimethyl-p-toluidine.
  • the component B particles have a particle size ranging from 500 to 2000 ⁇ m.
  • a method for preparing a powdery acrylate polymer by suspension polymerization first preparing an acrylate polymer suspension, then washing and drying the suspension, and sieving to obtain a powdery acrylate polymer;
  • step f The liquid phase obtained in step c is added to the solid phase prepared in step e, the solid-liquid ratio of the solid phase and the liquid phase is 0.25-0.5 mL/g, and the low-temperature injectable acrylic resin bone is obtained after stirring. cement.
  • the developer is added in step b, and 20-150 ppm of a polymerization inhibitor is added in step c, the developer being selected from barium sulfate, zirconium oxide or barium sulfate, the particle size range of the developer
  • the polymerization inhibitor is selected from the group consisting of hydroquinone or hydroquinone monomethyl ether.
  • the peroxide initiator comprises benzoyl peroxide, benzoyl peroxide or terephthalate peroxide A ketone, the acrylate monomer comprising methyl methacrylate, methyl acrylate or butyl methacrylate, and the promoter comprises N-N-dimethyl p-toluidine.
  • the powdery acrylate-based polymer has a particle diameter ranging from 20 to 200 ⁇ m, and the component B particles have a particle diameter ranging from 500 to 2000 ⁇ m.
  • the powdered acrylate-based polymer is one or more selected from the group consisting of polymethyl methacrylate, styrene-methyl methacrylate copolymer or methyl acrylate-methyl methacrylate copolymer. .
  • the low temperature injectable acrylic resin bone cement of the present invention the solid phase comprising component A and component B, the component B particles having a particle size ranging from 500 to 2000 ⁇ m, and after component B is added to the solid phase
  • the total specific surface area of the solid phase is reduced.
  • the total reaction amount of the solid-liquid interface is reduced during the solidification of the bone cement. Therefore, during the curing process, the exothermic temperature is greatly reduced, which can be effectively improved.
  • the problem of thermal burn and thermal necrosis on the tissue during clinical use in addition, when the total solid phase is constant, the liquid phase ratio is also lower than the current clinical product, so the residual monomer amount after curing is reduced, and the monomer can be reduced. Residues pose a risk of complications and improve the biocompatibility of bone cement.
  • the low temperature injectable acrylic resin bone cement of the present invention comprises a solid phase comprising a component A and a component B, the component B being mixed by the component A and the liquid phase It is prepared. Therefore, the bone cement of the invention does not introduce new products after curing, and ensures the safety of clinical use, and can be directly used in clinical practice.
  • the low temperature injectable acrylic resin bone cement of the present invention wherein the particle size of the component B ranges from 500 to 2000 ⁇ m, that is, the maximum particle diameter of the solid phase does not exceed 2000 ⁇ m, and still has good fluidity after mixing and stirring. And injectability, and the coagulation time and mechanical properties are similar to the current clinical products, which is convenient for clinical operation and use.
  • Example 1 is an exothermic temperature curve of a bone cement prepared by Formulation 2 in Example 1 of the present invention
  • FIG. 2 is a comparison diagram of the maximum exothermic temperature of the bone cement and the Spineplex bone cement prepared by the five formulations in the first embodiment of the present invention
  • Example 3 is a comparison diagram of solidification time of bone cement and Spineplex bone cement prepared by five formulations in Example 1 of the present invention
  • Example 5 is a comparison diagram of monomer residual amounts of bone cement and Simplex P bone cement prepared by five formulations in Example 1 of the present invention
  • Fig. 6 is a SEM image of the bone cement after solidification in Example 2 of the present invention.
  • the powdery acrylate polymer is prepared by suspension polymerization, and includes the following steps:
  • polyvinyl alcohol 5g was added to 500mL of purified water at a speed of 100-200r/min. After the polyvinyl alcohol was completely dissolved, 1-3g of peroxide initiator and 100-300mL of acrylate polymer were added. Monomer, heat to 50 ° C, heat 30-60min, continue to heat to 70 ° C, heat 1-3h, then warm to 90 ° C, heat 30-60min, the resulting suspension is ultrasonically cleaned and dried, sieved to obtain a grain A powdery acrylate polymer having a diameter in the range of 20 to 200 ⁇ m.
  • the preparation method of low temperature injectable acrylic resin bone cement comprises the following steps:
  • step b 50% by weight of polymethyl methacrylate prepared in step a, 25 wt% of styrene-methyl methacrylate copolymer prepared in step a, 0.8 wt% of benzoyl peroxide Butyl ester and 24.2% by weight of barium sulfate having a particle size ranging from 30 to 50 ⁇ m are uniformly mixed to obtain component A;
  • the liquid phase prepared in the step c is added to the component A obtained in the step b, and uniformly mixed, wherein the solid-liquid ratio of the component A and the liquid phase is 0.38 mL/g, and the pulverized sieve is obtained after solidification.
  • step f The liquid phase obtained in step c is added to the solid phase prepared in step e, the solid-liquid ratio of the solid phase and the liquid phase is 0.25-0.5 mL/g, and the low-temperature injectable acrylic resin bone is obtained after stirring. cement.
  • Steps e and f use the following five recipes:
  • Component B 75wt%
  • Component B 50wt%
  • Component B 20wt%
  • Example 2 Prepare component A, component B and liquid phase according to the preparation method of Example 1, and then prepare solid phase and liquid phase according to the above five formulations, and mix and stir for 1-3 min at 23 ⁇ 1 °C, refer to "YY0459-2003 surgery".
  • the implant acrylic resin bone cement was tested for exothermic temperature, solidification time and compressive strength, and the current clinical product Spineplex bone cement was selected as a control group for comparison. After the cement is solidified, the residual amount of bone cement is detected by gas chromatography and compared with the clinical product Simplex P bone cement.
  • Example 1 is an exothermic temperature curve of a bone cement prepared by Formulation 2 in Example 1 of the present invention, and is also a typical exothermic temperature profile of the bone cement of the present invention, and the experimental results show that the low temperature injectable acrylic resin bone cement of the present invention is placed at the highest level.
  • the hot temperature was 53.4 ° C and the solidification time was 12 min 15 s.
  • FIG. 2 is a comparison diagram of the highest exothermic temperature of the bone cement and the Spineplex bone cement prepared by the five formulations in the first embodiment of the present invention, and the experimental results show that the highest exothermic temperature of the low temperature injectable acrylic resin bone cement of the present invention is below 60 ° C.
  • the highest exothermic temperature of the control group is about 80 ° C.
  • the experimental results show that the low temperature injectable acrylic resin bone cement of the invention has a significantly lower exothermic temperature during the curing process, and can effectively improve the heat burning of the tissue during clinical use. Burning and heat necrosis problems improve the safety of bone cement during clinical use.
  • FIG. 3 is a comparison chart of the solidification time of the bone cement and the Spineplex bone cement prepared by the five formulations in the first embodiment of the present invention, and the experimental results show that the solidification time of the low temperature injectable acrylic resin bone cement of the present invention is 11-15 minutes, and the control group The solidification time is 14 ⁇ 0.5min.
  • the experimental results show that the solidification time of the low-temperature injectable acrylic resin bone cement of the invention is basically the same as that of the Spineplex bone cement, which can meet the clinician's operation.
  • Example 4 is a comparison diagram of compressive strength of bone cement and Spineplex bone cement prepared by five formulations in Example 1 of the present invention, and experimental results show that the compressive strength distribution of the low temperature injectable acrylic resin bone cement of the present invention is 69 after curing. -80MPa, the pressure resistance of the control group is 73 ⁇ 2MPa.
  • the experimental results show that the compressive strength of the low temperature injectable acrylic resin bone cement of the present invention is not significantly different from that of Spineplex bone cement, and can provide sufficient mechanical support to ensure products. Biomechanical stability after implantation.
  • FIG. 5 is a comparison chart of monomer residual amounts of bone cement and Simplex P bone cement prepared by the five formulations in the first embodiment of the present invention, and the experimental results show that the monomer residual amount of the low temperature injectable acrylic resin bone cement of the present invention is 3%. Left and right, the monomer residue of Simplex P bone cement is 4.3 ⁇ 0.05wt%. The experimental results show that the monomer residue of the low temperature injectable acrylic resin bone cement of the invention is lower than that of Simplex P bone cement, which can reduce the residual monomer. Causes the risk of complications and improves the biocompatibility of bone cement.
  • step c The liquid phase prepared in step c is added to the component A prepared in the step b, and uniformly mixed, wherein the solid-liquid ratio of the component A and the liquid phase is 0.5 mL/g, and the pulverization and sieving is obtained after solidification.
  • Component B particles having a particle size ranging from 1500 to 2000 ⁇ m;
  • the liquid phase obtained in the step c is added to the solid phase prepared in the step e, and the solid-liquid ratio of the solid phase and the liquid phase is 0.5 mL/g, and the low-temperature injectable acrylic resin bone cement is obtained after stirring.
  • the bone cement was prepared according to the preparation method of Example 2 and the performance test was carried out. The results showed that the bone cement had good fluidity after stirring for 1 min, the highest exothermic temperature was 55.2 ° C, the solidification time was 13 min 25 s, and the average compressive strength was 73.5 MPa. The residual amount of the body was 2.95%. After the bone cement was solidified, the surface morphology of the bone cement was observed by SEM.
  • Fig. 6 is a SEM image of the bone cement in the second embodiment of the present invention. It can be seen that a part of the white particles exist on the surface and the distribution is uniform, indicating that the bone cement of the present invention has uniform composition and relatively stable performance.
  • the preparation method of low temperature injectable acrylic resin bone cement comprises the following steps:
  • component A 45 wt% of polymethyl methacrylate prepared in step a, 44 wt% of methyl acrylate-methyl methacrylate copolymer prepared in step a, and 1 wt% of benzoyl peroxide Butyl ester and 10% by weight of zirconia having a particle size ranging from 10 to 30 ⁇ m are uniformly mixed to obtain component A;
  • the liquid phase prepared in the step c is added to the component A obtained in the step b, and uniformly mixed, wherein the solid-liquid ratio of the component A and the liquid phase is 0.6 mL/g, and the pulverization and sieving after curing is obtained.
  • the liquid phase obtained in the step c is added to the solid phase prepared in the step e, and the solid-liquid ratio of the solid phase and the liquid phase is 0.4 mL/g, and the low-temperature injectable acrylic resin bone cement is obtained after stirring.
  • the bone cement was prepared according to the preparation method of Example 3 and the performance test was carried out. The results showed that the bone cement had good fluidity after stirring for 1.5 min, the highest exothermic temperature was 53.8 ° C, the solidification time was 12 min 50 s, and the average compressive strength was 79 MPa. The residual amount was 3.2%.
  • the preparation method of low temperature injectable acrylic resin bone cement comprises the following steps:
  • the liquid phase prepared in the step c is added to the component A obtained in the step b, and uniformly mixed, wherein the solid-liquid ratio of the component A and the liquid phase is 0.25 mL/g, and the pulverization and sieving after curing is obtained.
  • Component B particles having a particle size ranging from 500 to 1000 ⁇ m;
  • the liquid phase obtained in the step c is added to the solid phase prepared in the step e, and the solid-liquid ratio of the solid phase and the liquid phase is 0.48 mL/g, and the low-temperature injectable acrylic resin bone cement is obtained after stirring.
  • the bone cement was prepared according to the preparation method of Example 4 and tested for performance. The results showed that the bone cement had good fluidity after stirring for 1 min, the highest exothermic temperature was 56.4 ° C, the solidification time was 14 min 25 s, and the average compressive strength was 72 MPa. The residual amount was 3.0%.
  • the preparation method of low temperature injectable acrylic resin bone cement comprises the following steps:
  • step c The liquid phase prepared in step c is added to the component A obtained in the step b, and uniformly mixed, wherein the solid-liquid ratio of the component A and the liquid phase is 0.8 mL/g, and the pulverization and sieving is obtained after solidification.
  • the liquid phase obtained in the step c is added to the solid phase prepared in the step e, and the solid-liquid ratio of the solid phase and the liquid phase is 0.43 mL/g, and the low-temperature injectable acrylic resin bone cement is obtained after stirring.
  • the bone cement was prepared according to the preparation method of Example 5 and tested for performance. The results showed that the bone cement had good fluidity after stirring for 2 minutes, the highest exothermic temperature was 52.4 ° C, the solidification time was 13 min 45 s, and the average compressive strength was 75 MPa. The residual amount was 3.1%.
  • the invention adds the component B prepared from the main component of the bone cement with different particle size ranges in the solid phase of the bone cement, and adjusts the ratio of the solid phase by adjusting the particle size of each component in the solid phase.
  • the surface area regulates the reaction amount and reaction rate at the solid-liquid interface, thereby achieving the purpose of lowering the exothermic temperature of the reaction, and effectively improving the thermal burn and thermal necrosis of the tissue during clinical use.
  • the component B of the present invention is prepared by mixing the main component of the bone cement and the liquid phase, so that the bone cement of the present invention does not introduce new products after curing, and the clinical condition is ensured. With safety, the product can be used directly in the clinic.

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Abstract

一种低温可注射丙烯酸树脂骨水泥及其制备方法，低温可注射丙烯酸树脂骨水泥包括固相和液相，固相和液相的固液比为0.25-0.5ml/g，以质量百分比计，固相包括25-80wt％的组分A和20-75wt％的组分B，组分A包括59.5-99.5wt％的粉末状丙烯酸酯类聚合物和0.5-2wt％的过氧化物引发剂，以容量百分比计，液相包括95-99.9vol％的丙烯酸酯类单体和0.1-5vol％的促进剂；组分B是由组分A和液相以固液比0.25-0.8ml/g混合制备而成的颗粒。低温可注射丙烯酸树脂骨水泥在固化过程中放热温度低，固化后未引入新的产物、单体残留量少、生物相容性良好。

Description

低温可注射丙烯酸树脂骨水泥及其制备方法
相关申请
本申请要求2016年12月22日申请的，申请号为201611195118.X，名称为“低温可注射丙烯酸树脂骨水泥及其制备方法”的中国专利申请的优先权，在此将其全文引入作为参考。
技术领域
本发明涉及医用生物材料领域，具体涉及低温可注射丙烯酸树脂骨水泥及其制备方法。
背景技术
骨质疏松症是中老年人群最常见的骨骼疾病之一。我国骨质疏松患者人数已接近1亿，并且有至少2.1亿人骨量低于正常值，是骨质疏松患者数量和潜在数量最多的国家。国际骨质疏松基金会发表的一组数据显示，全球每3秒钟就会发生一起骨质疏松性骨折，1/3的女性和1/5的男性会在50岁后遭遇一次骨折，20％的髋部骨折患者会在骨折后的6个月内死亡，一半的病人生活不能自理。而向受损伤的骨骼或椎骨中注射骨水泥，是目前治疗骨质疏松较简便而又有效的方法。
聚甲基丙烯酸甲酯(Polymethyl Methacrylate，PMMA)不仅可以作为骨替代材料用于填充骨质缺损，如作为椎体后凸成形术(Kyphoplasty，KP)的填充材料；也可以用于增强内植入物的把持力，如注入螺钉或者假体周围达到稳定内固定物的作用。PMMA优点在于用于骨替代物，其生物相容性好，力学强度高；而作为把持力增强物，它不仅可以大幅度增加轴向的抗拔出力，也可以增加抗剪切力和扭转力，这是其他材料所不具备的，故PMMA是目前临床最常用的骨水泥。
然而在临床实际应用中，PMMA最突出的缺点就是聚合过程中大量放热，其最高温度超过人体组织可以耐受范围，从而造成其周围组织的坏死。非生理性的热效应会带来很多的不足，并最终导致治疗的失败：(1)关节置换手术时，造成周围骨组织坏死，使的PMMA无法与骨结构形成一个稳定的绞锁结构，PMMA和故结构之间存在微动，产生大量PMMA颗粒，长期累积会形成无菌性松动；(2)KP手术时，造成椎体内松质骨坏死，PMMA周围出现一个环形坏死带，此区域的力学强度差，不仅易造成骨折复位后的再次坍塌，且同一椎体再骨折的发生率也会相应增高；(3)KP灾难性的并发症就是PMMA进入椎管损伤神经，而损伤的致病因素除了力学挤压外，热灼伤起重要作用；(4)在骨折手术使用骨水泥加固时，会造成皮质骨外表面的骨膜坏死，无法形成外骨痂，最终造成骨折延迟愈 合或者不愈合。故目前临床上迫切需要解决PMMA固化过程放热温度高造成的热坏死问题。
近年来，部分学者对降低骨水泥聚合温度的进行了一些研究。例如，德国专利3245956A1公开了一种基于液体单体和粉状聚合丙烯酸酯和/或甲基丙烯酸酯，催化剂和促进剂的骨水泥，该骨水泥液剂中添加了一种不参与聚合反应的表面活性液体，可以有效降低骨水泥聚合时释放的热量，但最终产物引入了表面活性液体，限制了临床应用；中国专利104784753A公开了一种具有降低热坏死效应的复合骨水泥，该骨水泥粉剂中添加了一种相变微胶囊材料(PCM)，可以降低固化时的最高温度，使其明显低于临床应用要求，虽然能够减少热坏死，但最终产物发生了变化，临床应用还有待进一步验证。
发明内容
鉴于现有技术的上述缺陷，本发明的目的在于提供一种放热温度明显降低、单体残留量低的低温可注射丙烯酸树脂骨水泥。为实现这一目的，本发明的低温可注射丙烯酸树脂骨水泥的固相中添加了粒径范围为500-2000μm的组分B，降低了固相的总比表面积，在固相总量一定时，骨水泥固化过程中，固-液界面的总反应量减少，因此本发明骨水泥在固化过程中，放热温度明显降低，可以有效改善临床使用过程中对组织产生的热灼伤、热坏死问题；另外，在固相总量一定时，因所需总反应量减少，液相比例也比目前临床产品低，故固化后的单体残留量降低，可降低因单体残留引起并发症的风险，提高了骨水泥的生物相容性。
本发明的另一个目的在于提供一种最终产物与目前临床产品一致的低温可注射丙烯酸树脂骨水泥。为实现这一目的，本发明的低温可注射丙烯酸树脂骨水泥包括固相和液相，所述固相包括组分A和组分B，所述组分B是由所述组分A和所述液相混合制备而成，因此本发明骨水泥固化后没有引入新的产物，保证临床使用安全性，可直接用于临床。
本发明解决其技术问题所采用的技术方案是：
一种低温可注射丙烯酸树脂骨水泥，所述低温可注射丙烯酸树脂骨水泥包括固相和液相，所述固相和液相的固液比为0.25-0.5mL/g，以质量百分比计，所述固相包括25-80wt％的组分A和20-75wt％的组分B，其中所述组分A包括59.5-99.5wt％的粉末状丙烯酸酯类聚合物和0.5-2wt％的过氧化物引发剂，以容量百分比计，所述液相包括95-99.9vol％的丙烯酸酯类单体和0.1-5vol％的促进剂，所述组分B是由所述组分A和所述液相以固液比0.25-0.8mL/g混合制备而成的颗粒。
优选的，所述组分A还包括10-40wt％的显影剂，所述显影剂选自硫酸钡、氧化锆或 硫酸锶，所述显影剂的平均粒径是1-50μm；所述液相还包括20-150ppm的阻聚剂，所述阻聚剂选自氢醌或氢醌单甲醚。
优选的，所述粉末状丙烯酸酯类聚合物选自聚甲基丙烯酸甲酯、苯乙烯-甲基丙烯酸甲酯共聚物或丙烯酸甲酯-甲基丙烯酸甲酯共聚物中的一种或多种，所述粉末状丙烯酸酯类聚合物的粒径范围为20-200μm。
优选的，所述过氧化物引发剂包括过氧化苯甲酰、过氧化苯甲酰叔丁酯或过氧化甲乙酮，所述丙烯酸酯类单体包括甲基丙烯酸甲酯、丙烯酸甲酯或甲基丙烯酸丁酯，所述促进剂包括N-N-二甲基对甲苯胺。
优选的，所述组分B颗粒的粒径范围为500-2000μm。
本发明解决其技术问题所采用的另一个技术方案是：
上述低温可注射丙烯酸树脂骨水泥的制备方法，包括下列步骤：
(1)组分A的制备
a.采用悬浮聚合法制备粉末状丙烯酸酯类聚合物：先制备丙烯酸酯类聚合物悬浊液，再将悬浊液清洗并干燥，筛分后得到粉末状丙烯酸酯类聚合物；
b.以质量百分比计，将59.5-99.5wt％步骤a制得的粉末状丙烯酸酯类聚合物和0.5-2wt％的过氧化物引发剂混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将95-99.9vol％的丙烯酸酯类单体和0.1-5vol％的促进剂混合均匀后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.25-0.8mL/g，固化后粉碎筛分得到组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将25-80wt％步骤b制得的组分A和20-75wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.25-0.5mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
优选的，在步骤b中加入10-40wt％显影剂，在步骤c中加入20-150ppm阻聚剂，所述显影剂选自硫酸钡、氧化锆或硫酸锶，所述显影剂的粒径范围为1-50μm，所述阻聚剂选自氢醌或氢醌单甲醚。
优选的，所述过氧化物引发剂包括过氧化苯甲酰、过氧化苯甲酰叔丁酯或过氧化甲乙 酮，所述丙烯酸酯类单体包括甲基丙烯酸甲酯、丙烯酸甲酯或甲基丙烯酸丁酯，所述促进剂包括N-N-二甲基对甲苯胺。
优选的，所述粉末状丙烯酸酯类聚合物的粒径范围为20-200μm，所述组分B颗粒的粒径范围为500-2000μm。
优选的，所述粉末状丙烯酸酯类聚合物选自聚甲基丙烯酸甲酯、苯乙烯-甲基丙烯酸甲酯共聚物或丙烯酸甲酯-甲基丙烯酸甲酯共聚物中的一种或多种。
同现有技术相比，本发明的优点与进步如下：
1.本发明的低温可注射丙烯酸树脂骨水泥，所述固相包括组分A和组分B，所述组分B颗粒的粒径范围为500-2000μm，固相中加入组分B后，降低了固相的总比表面积，在固相总量一定时，骨水泥固化过程中，固-液界面的总反应量减少，因此骨水泥在固化过程中，放热温度大幅降低，可以有效改善临床使用过程中对组织产生的热灼伤、热坏死问题；另外，在固相总量一定时，液相比例也比目前临床产品低，故固化后的单体残留量降低，可降低因单体残留引起并发症的风险，提高骨水泥的生物相容性。
2.本发明的低温可注射丙烯酸树脂骨水泥包括固相和液相，所述固相包括组分A和组分B，所述组分B是由所述组分A和所述液相混合制备而成，因此本发明骨水泥固化后没有引入新的产物，保证临床使用安全性，可直接用于临床。
3.本发明的低温可注射丙烯酸树脂骨水泥，所述组分B颗粒的粒径范围为500-2000μm，即固相的最大粒径不超过2000μm，在混合搅拌后，仍具有良好的流动性和可注射性，并且凝固时间、力学性能与目前临床产品相近，方便临床操作和使用。
附图说明
图1为本发明实施例1中配方2制备的骨水泥的放热温度曲线；
图2为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的最高放热温度对比图；
图3为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的凝固时间对比图；
图4为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的抗压强度对比图；
图5为本发明实施例1中五种配方制备的骨水泥和Simplex P骨水泥的单体残留量对比图；
图6为本发明实施例2中骨水泥固化后的SEM图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下参照附图并举实施例对本发明进行详细说明。
本发明中，所述粉末状丙烯酸酯类聚合物采用悬浮聚合法制备，包括以下几个步骤：
在转速为100-200r/min的条件下，将5g聚乙烯醇加入到500mL纯化水中，待聚乙烯醇完全溶解后，加入1-3g过氧化物引发剂和100-300mL丙烯酸酯类聚合物的单体，升温至50℃，保温30-60min，继续升温至70℃，保温1-3h，再升温至90℃，保温30-60min，将所得悬浊液超声清洗并干燥，过筛后得到粒径范围为20-200μm的粉末状丙烯酸酯类聚合物。
实施例1
低温可注射丙烯酸树脂骨水泥的制备方法，包括以下几个步骤：
(1)组分A的制备
a.采用悬浮聚合法分别制备粒径范围为60-120μm的聚甲基丙烯酸甲酯和粒径范围为80-150μm的苯乙烯-甲基丙烯酸甲酯共聚物；
b.以质量百分比计，将50wt％步骤a制得的聚甲基丙烯酸甲酯、25wt％步骤a制得的苯乙烯-甲基丙烯酸甲酯共聚物、0.8wt％的过氧化苯甲酰叔丁酯和24.2wt％的粒径范围为30-50μm的硫酸钡混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将99vol％的丙烯酸甲酯和1vol％的N-N-二甲基对甲苯胺混合均匀，再加入20ppm氢醌后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.38mL/g，固化后粉碎筛分得到粒径范围为800-1300μm组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将25-80wt％步骤b制得的组分A和20-75wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.25-0.5mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
步骤e和f选用以下五种配方：
配方1
固相：组分A  25wt％
      组分B  75wt％
固液比：0.25mL/g
配方2
固相：组分A  35wt％
      组分B  65wt％
固液比：0.3mL/g
配方3
固相：组分A  50wt％
      组分B  50wt％
固液比：0.38mL/g
配方4
固相：组分A  65wt％
      组分B  35wt％
固液比：0.43mL/g
配方5
固相：组分A  80wt％
      组分B  20wt％
固液比：0.5mL/g
按实施例1制备方法制备组分A、组分B和液相，然后按上述5种配方制备固相和液相，在23±1℃条件下混合搅拌1-3min，参照《YY0459-2003外科植入物丙烯酸类树脂骨水泥》进行放热温度、凝固时间及抗压强度测试，并选择目前临床产品Spineplex骨水泥作为对照组进行对比。待骨水泥固化后，采用气相色谱法来检测骨水泥的单体残留量，并与临床产品Simplex P骨水泥进行比较。
图1为本发明实施例1中配方2制备的骨水泥的放热温度曲线，也是本发明骨水泥典型的放热温度曲线图，实验结果显示，本发明的低温可注射丙烯酸树脂骨水泥最高放热温度为53.4℃，凝固时间为12min15s。
图2为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的最高放热温度对比图，实验结果显示，本发明的低温可注射丙烯酸树脂骨水泥最高放热温度在60℃以下，而对照组的最高放热温度为80℃左右，实验结果表明，本发明的低温可注射丙烯酸树脂骨水泥在固化过程中放热温度显著降低，可有效改善临床使用过程对组织产生的热灼烧、热坏死问题，提高骨水泥在临床使用过程中的安全性。
图3为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的凝固时间对比图，实验结果显示，本发明的低温可注射丙烯酸树脂骨水泥凝固时间分布在11-15min，对照组的凝固时间为14±0.5min，实验结果表明，本发明的低温可注射丙烯酸树脂骨水泥的凝固时间与Spineplex骨水泥基本一致，可满足临床医生操作。
图4为本发明实施例1中五种配方制备的骨水泥和Spineplex骨水泥的抗压强度对比图，实验结果显示，本发明的低温可注射丙烯酸树脂骨水泥固化后的抗压强度分布在69-80MPa，对照组的抗压强的为73±2MPa，实验结果表明，本发明的低温可注射丙烯酸树脂骨水泥的抗压强度与Spineplex骨水泥无明显差异，可提供足够的力学支撑，保证产品植入后的生物力学稳定性。
图5为本发明实施1中五种配方制备的骨水泥和Simplex P骨水泥的单体残留量对比图，实验结果显示，本发明的低温可注射丙烯酸树脂骨水泥的单体残留量为3％左右，Simplex P骨水泥的单体残留量为4.3±0.05wt％，实验结果表明，本发明的低温可注射丙烯酸树脂骨水泥的单体残留量低于Simplex P骨水泥，可降低因单体残留引起并发症的风险，提高骨水泥的生物相容性。
实施例2
低温可注射丙烯酸树脂骨水泥的制备方法，包括以下几个步骤：
(1)组分A的制备
a.采用悬浮聚合法分别制备粒径范围为20-100μm的聚甲基丙烯酸甲酯和粒径范围为100-200μm的苯乙烯-甲基丙烯酸甲酯共聚物；
b.以质量百分比计，将30wt％步骤a制得的聚甲基丙烯酸甲酯、29.5wt％步骤a制得的苯乙烯-甲基丙烯酸甲酯共聚物、2wt％的过氧化苯甲酰叔丁酯和38.5wt％的粒径范围为1-20μm的硫酸钡混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将95vol％的甲基丙烯酸丁酯和5vol％的N-N-二甲基对甲苯胺混合均匀，再加入80ppm氢醌单甲醚后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.5mL/g，固化后粉碎筛分得到粒径范围为1500-2000μm的组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将45wt％步骤b制得的组分A和55wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.5mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
按实施例2制备方法制备骨水泥并进行性能测试，测得结果显示，搅拌1min后骨水泥流动性良好，最高放热温度为55.2℃，凝固时间为13min25s，平均抗压强度为73.5MPa，单体残留量为2.95％。待骨水泥固化后，通过SEM观察骨水泥的表面形貌。
图6为本发明实施2中骨水泥固化后的SEM图，可看出表面存在部分白色颗粒并且分布均匀，表明本发明骨水泥成分均一、性能比较稳定。
实施例3
低温可注射丙烯酸树脂骨水泥的制备方法，包括以下几个步骤：
组分A的制备
a.采用悬浮聚合法分别制备粒径范围为20-80μm的聚甲基丙烯酸甲酯和粒径范围为80-150μm的丙烯酸甲酯-甲基丙烯酸甲酯共聚物；
b.以质量百分比计，将45wt％步骤a制得的聚甲基丙烯酸甲酯、44wt％步骤a制得的丙烯酸甲酯-甲基丙烯酸甲酯共聚物、1wt％的过氧化苯甲酰叔丁酯和10wt％的粒径范围为10-30μm的氧化锆混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将98vol％的丙烯酸甲酯和2vol％的N-N-二甲基对甲苯胺混合均匀，再加入60ppm氢醌后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.6mL/g，固化后粉碎筛分得到粒径范围为1000-1500μm组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将42wt％步骤b制得的组分A和58wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.4mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
按实施例3制备方法制备骨水泥并进行性能测试，测得结果显示，搅拌1.5min后骨水泥流动性良好，最高放热温度为53.8℃，凝固时间为12min50s，平均抗压强度为79MPa，单体残留量为3.2％。
实施例4
低温可注射丙烯酸树脂骨水泥的制备方法，包括以下几个步骤：
(1)组分A的制备
a.采用悬浮聚合法制备粒径范围为20-100μm的聚甲基丙烯酸甲酯；
b.以质量百分比计，将99.5wt％步骤a制得的聚甲基丙烯酸甲酯和0.5wt％的过氧化苯甲酰混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将99.9vol％的甲基丙烯酸甲酯和0.1vol％的N-N-二甲基对甲苯胺混合均匀，再加入50ppm氢醌混合均匀后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.25mL/g，固化后粉碎筛分得到粒径范围为500-1000μm的组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将63wt％步骤b制得的组分A和37wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.48mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
按实施例4制备方法制备骨水泥并进行性能测试，测得结果显示，搅拌1min后骨水泥流动性良好，最高放热温度为56.4℃，凝固时间为14min25s，平均抗压强度为72MPa，单体残留量为3.0％。
实施例5
低温可注射丙烯酸树脂骨水泥的制备方法，包括以下几个步骤：
(1)组分A的制备
a.采用悬浮聚合法分别制备粒径范围为60-110μm的聚甲基丙烯酸甲酯、粒径范围为80-150μm的苯乙烯-甲基丙烯酸甲酯共聚物和粒径范围为120-200μm的丙烯酸甲酯-甲基丙烯酸甲酯共聚物；
b.以质量百分比计，将25wt％步骤a制得的聚甲基丙烯酸甲酯、20wt％步骤a制得的苯乙烯-甲基丙烯酸甲酯共聚物、13.5wt％步骤a制得的丙烯酸甲酯-甲基丙烯酸甲酯共聚物、1.5wt％的过氧化甲乙酮和40wt％的粒径范围为5-30μm的硫酸锶混合均匀后得到组分A；
(2)液相的制备
c.以容量百分比计，将96vol％的丙烯酸甲酯和4vol％的N-N-二甲基对甲苯胺混合均 匀，再加入150ppm氢醌单甲醚后得到液相；
(3)组分B的制备
d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.8mL/g，固化后粉碎筛分得到粒径范围为900-1600μm组分B颗粒；
(4)低温可注射丙烯酸树脂骨水泥的制备
e.以质量百分比计，将50wt％步骤b制得的组分A和50wt％步骤d制得的组分B混合均匀后得到固相；
f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.43mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
按实施例5制备方法制备骨水泥并进行性能测试，测得结果显示，搅拌2min后骨水泥流动性良好，最高放热温度为52.4℃，凝固时间为13min45s，平均抗压强度为75MPa，单体残留量为3.1％。
本发明在骨水泥的固相中添加了粒径范围不同的由骨水泥的主要组分制备而成的组分B，通过调节固相中各组分的粒径大小，即调节固相的比表面积，进而调控固-液界面的反应量及反应速度，从而达到降低反应放热温度的目的，有效地改善了临床使用过程中对组织产生的热灼伤、热坏死问题。本领域的技术人员同样也可以利用这一原理，通过调节制备骨水泥的各组分的粒径来调节固相的比表面积，进而调控固-液界面的反应量及反应速度，或者通过调节各组分的聚合度来调控固-液界面的反应速度，来达到降低反应放热温度的目的。此外，在固相总量一定时，本发明因所需总反应量减少，液相比例也比目前临床产品低，因此固化后的单体残留量降低，可降低因单体残留引起并发症的风险，提高了骨水泥的生物相容性。更重要的是，本发明的所述组分B是由所述骨水泥的主要组分和所述液相混合制备而成，因此本发明的骨水泥固化后没有引入新的产物，保证了临床使用安全性，产品可直接用于临床。
最后应当说明的是，以上所述仅为本发明的较佳的实施例而已，并不用于限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种低温可注射丙烯酸树脂骨水泥，其特征在于：所述低温可注射丙烯酸树脂骨水泥包括固相和液相，所述固相和液相的固液比为0.25-0.5mL/g，以质量百分比计，所述固相包括25-80wt％的组分A和20-75wt％的组分B，其中所述组分A包括59.5-99.5wt％的粉末状丙烯酸酯类聚合物和0.5-2wt％的过氧化物引发剂，以容量百分比计，所述液相包括95-99.9vol％的丙烯酸酯类单体和0.1-5vol％的促进剂，所述组分B是由所述组分A和所述液相以固液比0.25-0.8mL/g混合制备而成的颗粒。
  2. 根据权利要求1所述的低温可注射丙烯酸树脂骨水泥，其特征在于：所述组分A还包括显影剂，所述显影剂选自硫酸钡、氧化锆或硫酸锶，所述显影剂的粒径范围为1-50μm；所述液相还包括阻聚剂，所述阻聚剂选自氢醌或氢醌单甲醚。
  3. 根据权利要求1所述的低温可注射丙烯酸树脂骨水泥，其特征在于：所述粉末状丙烯酸酯类聚合物选自聚甲基丙烯酸甲酯、苯乙烯-甲基丙烯酸甲酯共聚物或丙烯酸甲酯-甲基丙烯酸甲酯共聚物中的一种或多种，所述粉末状丙烯酸酯类聚合物的粒径范围为20-200μm。
  4. 根据权利要求1所述的低温可注射丙烯酸树脂骨水泥，其特征在于：所述过氧化物引发剂包括过氧化苯甲酰、过氧化苯甲酰叔丁酯或过氧化甲乙酮，所述丙烯酸酯类单体包括甲基丙烯酸甲酯、丙烯酸甲酯或甲基丙烯酸丁酯，所述促进剂包括N-N-二甲基对甲苯胺。
  5. 根据权利要求1所述的低温可注射丙烯酸树脂骨水泥，其特征在于：所述组分B颗粒的粒径范围为500-2000μm。
  6. 一种根据权利要求1-5中任一项所述的低温可注射丙烯酸树脂骨水泥的制备方法，包括下列步骤：
    (1)组分A的制备
    a.采用悬浮聚合法制备粉末状丙烯酸酯类聚合物：先制备丙烯酸酯类聚合物悬浊液，再将悬浊液清洗并干燥，筛分后得到粉末状丙烯酸酯类聚合物；
    b.以质量百分比计，将59.5-99.5wt％步骤a制得的粉末状丙烯酸酯类聚合物和0.5-2wt％的过氧化物引发剂混合均匀后得到组分A；
    (2)液相的制备
    c.以容量百分比计，将95-99.9vol％的丙烯酸酯类单体和0.1-5vol％的促进剂混合均匀后得到液相；
    (3)组分B的制备
    d.在步骤b制得的组分A中加入步骤c制得的液相，并混合均匀，其中所述组分A和液相的固液比为0.25-0.8mL/g，固化后粉碎筛分得到组分B颗粒；
    (4)低温可注射丙烯酸树脂骨水泥的制备
    e.以质量百分比计，将25-80wt％步骤b制得的组分A和20-75wt％步骤d制得的组分B混合均匀后得到固相；
    f.在步骤e制得的固相中加入步骤c制得的液相，所述固相和液相的固液比为0.25-0.5mL/g，搅拌后得到所述低温可注射丙烯酸树脂骨水泥。
  7. 根据权利要求6所述的低温可注射丙烯酸树脂骨水泥的制备方法，其特征在于：在步骤b中加入显影剂，在步骤c中加入阻聚剂，所述显影剂选自硫酸钡、氧化锆或硫酸锶，所述显影剂的粒径范围为1-50μm，所述阻聚剂选自氢醌或氢醌单甲醚。
  8. 根据权利要求6所述的低温可注射丙烯酸树脂骨水泥的制备方法，其特征在于：所述过氧化物引发剂包括过氧化苯甲酰、过氧化苯甲酰叔丁酯或过氧化甲乙酮，所述丙烯酸酯类单体包括甲基丙烯酸甲酯、丙烯酸甲酯或甲基丙烯酸丁酯，所述促进剂包括N-N-二甲基对甲苯胺。
  9. 根据权利要求6所述的低温可注射丙烯酸树脂骨水泥的制备方法，其特征在于：所述粉末状丙烯酸酯类聚合物的粒径范围为20-200μm，所述组分B颗粒的粒径范围为500-2000μm。
  10. 根据权利要求6所述的低温可注射丙烯酸树脂骨水泥的制备方法，其特征在于：所述粉末状丙烯酸酯类聚合物选自聚甲基丙烯酸甲酯、苯乙烯-甲基丙烯酸甲酯共聚物或丙烯酸甲酯-甲基丙烯酸甲酯共聚物中的一种或多种。
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* Cited by examiner, † Cited by third party
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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106620841B (zh) * 2016-12-22 2019-09-03 宁波华科润生物科技有限公司 低温可注射丙烯酸树脂骨水泥及其制备方法
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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3245956A1 (de) * 1982-12-11 1984-06-14 Beiersdorf Ag, 2000 Hamburg Chirurgisches material
WO1986002370A1 (en) * 1984-10-16 1986-04-24 Ferring Laboratories, Inc. Improved cold-curing bone cement
DE3826886A1 (de) * 1988-06-01 1989-12-07 Tecres Spa Zementiermischung mit zwei phasen, insbesondere geeignet fuer orthopaedische verwendung
CN101370465A (zh) * 2006-01-23 2009-02-18 奥赛恩治疗公司 含有以非均匀的空间分布颗粒的骨粘固剂复合材料和用于实施的装置
WO2009108893A2 (en) * 2008-02-28 2009-09-03 Dfine, Inc. Bone treatment systems and methods
CN102333553A (zh) * 2009-02-25 2012-01-25 国立大学法人京都大学 骨水泥组合物和骨水泥组合物试剂盒以及骨水泥固化体的形成方法
CN104204078A (zh) * 2012-03-30 2014-12-10 璐彩特国际英国有限公司 可硬化的两部分丙烯酸类组合物
CN104231507A (zh) * 2013-06-10 2014-12-24 贺利氏古萨有限公司 由pmma粉末作为假牙制造的单一的计量助剂制成的模制件
US9072808B2 (en) * 2006-07-17 2015-07-07 Syracuse University Multi-solution bone cements and methods of making the same
CN104784753A (zh) * 2015-04-01 2015-07-22 北京大学第三医院 一种具有降低热坏死效应的复合骨水泥
CN104906637A (zh) * 2015-05-15 2015-09-16 武汉大学 一种可注射-多孔-载药的聚甲基丙烯酸甲酯基复合支架骨移植材料及其制备方法
CN105031738A (zh) * 2015-09-09 2015-11-11 山东明德生物医学工程有限公司 一种低放热骨水泥及制备方法和应用
WO2016128933A1 (en) * 2015-02-12 2016-08-18 Tecres S.P.A. Ternary mixture for a bone cement and method for its realisation
CN106620841A (zh) * 2016-12-22 2017-05-10 宁波华科润生物科技有限公司 低温可注射丙烯酸树脂骨水泥及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104147639B (zh) * 2014-08-06 2016-01-06 山东明德生物医学工程有限公司 含锶可注射骨水泥及制备方法

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3245956A1 (de) * 1982-12-11 1984-06-14 Beiersdorf Ag, 2000 Hamburg Chirurgisches material
WO1986002370A1 (en) * 1984-10-16 1986-04-24 Ferring Laboratories, Inc. Improved cold-curing bone cement
DE3826886A1 (de) * 1988-06-01 1989-12-07 Tecres Spa Zementiermischung mit zwei phasen, insbesondere geeignet fuer orthopaedische verwendung
CN101370465A (zh) * 2006-01-23 2009-02-18 奥赛恩治疗公司 含有以非均匀的空间分布颗粒的骨粘固剂复合材料和用于实施的装置
US9072808B2 (en) * 2006-07-17 2015-07-07 Syracuse University Multi-solution bone cements and methods of making the same
WO2009108893A2 (en) * 2008-02-28 2009-09-03 Dfine, Inc. Bone treatment systems and methods
CN102333553A (zh) * 2009-02-25 2012-01-25 国立大学法人京都大学 骨水泥组合物和骨水泥组合物试剂盒以及骨水泥固化体的形成方法
CN104204078A (zh) * 2012-03-30 2014-12-10 璐彩特国际英国有限公司 可硬化的两部分丙烯酸类组合物
CN104231507A (zh) * 2013-06-10 2014-12-24 贺利氏古萨有限公司 由pmma粉末作为假牙制造的单一的计量助剂制成的模制件
WO2016128933A1 (en) * 2015-02-12 2016-08-18 Tecres S.P.A. Ternary mixture for a bone cement and method for its realisation
CN104784753A (zh) * 2015-04-01 2015-07-22 北京大学第三医院 一种具有降低热坏死效应的复合骨水泥
CN104906637A (zh) * 2015-05-15 2015-09-16 武汉大学 一种可注射-多孔-载药的聚甲基丙烯酸甲酯基复合支架骨移植材料及其制备方法
CN105031738A (zh) * 2015-09-09 2015-11-11 山东明德生物医学工程有限公司 一种低放热骨水泥及制备方法和应用
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CN113855855B (zh) * 2021-11-05 2022-07-08 浙江科惠医疗器械股份有限公司 一种聚甲基丙烯酸甲酯骨水泥及其制备方法
CN114225108A (zh) * 2021-12-17 2022-03-25 上海纳米技术及应用国家工程研究中心有限公司 一种高黏度防渗漏pmma骨水泥的制备方法及其产品和应用
CN114404658A (zh) * 2022-02-18 2022-04-29 中国科学技术大学先进技术研究院 骨水泥及其制备方法、骨科植入材料
CN114632186A (zh) * 2022-03-25 2022-06-17 深圳清华大学研究院 含有表面改性氧化锆骨水泥增强力学性能的制备方法
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