WO2020015276A1 - 可注射的聚氨酯及其制备方法 - Google Patents

可注射的聚氨酯及其制备方法 Download PDF

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WO2020015276A1
WO2020015276A1 PCT/CN2018/118990 CN2018118990W WO2020015276A1 WO 2020015276 A1 WO2020015276 A1 WO 2020015276A1 CN 2018118990 W CN2018118990 W CN 2018118990W WO 2020015276 A1 WO2020015276 A1 WO 2020015276A1
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catalyst
polyurethane
soft segment
oil
injectable
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PCT/CN2018/118990
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English (en)
French (fr)
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左奕
王尖
李玉宝
李吉东
邹琴
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四川大学
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/36—Hydroxylated esters of higher fatty acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/67—Unsaturated compounds having active hydrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/32—Phosphorus-containing compounds

Definitions

  • the invention relates to an injectable polyurethane and a preparation method thereof, and belongs to the field of medical biomaterials.
  • a urethane copolymer namely, polyurethane (Polyurethane, PU) is a general term for a class of polymers containing a repeating urethane bond (-NH-COO-) on the main chain. Because of its superior physical and chemical properties, flexible control performance and good biocompatibility, it is widely used in many medical devices and artificial organ devices, such as artificial blood vessels, artificial hearts, artificial skin, artificial catheters, artificial cartilage, Nerve catheters and more. However, the existing polyurethane-based biomaterials are mainly applied because polyurethane materials have excellent mechanical properties and good stability after curing, and the injectability of polyurethane has not been studied in depth.
  • Du Jingjing et al. Reported castor oil-based polyurethane / nano-hydroxyapatite (HA) composite bone repair scaffold materials DuJJ, ZuoY., ZouQ., SunB., Zhou MB, Li LM, Man Y. LiYYBPreparation and evaluation in terms of polyurethane and scaffolds based on glycerol-esterified castor oil and hydroxylapatite [J] .MaterialsResearchInnovations, 2014,18 (3): 160-168.
  • the results show that the three-dimensional scaffold has a good Mechanical and biocompatibility.
  • the scaffold material prepared by this synthetic technology is highly cross-linked and does not have injectability.
  • the standard requires expansion rate ⁇ 0.1%).
  • the macromolecular polyol polymers used as the soft segment of polyurethane such as polyethylene glycol, polytetrahydrofuran diol, polypropylene glycol, and polyether triol, are all downstream products of the petroleum industry, and with the depletion of petroleum resources, and Environmental requirements are increasing, and the development of new, environmentally friendly materials is particularly important.
  • the purpose of the present invention is to provide an injectable polyurethane and a preparation method thereof, so as to solve the problems of high curing expansion rate and unfriendly environment of the existing medical polyurethane materials.
  • the invention provides the use of an ester formed by a C 2-6 polyol and a C 8-18 fatty acid as a soft segment to prepare an injectable polyurethane, wherein the ester contains two or more hydroxyl groups.
  • the curing expansion rate of the injectable polyurethane is ⁇ 0.5%.
  • the curing expansion rate of the injectable polyurethane is ⁇ 0.1%.
  • the curing expansion rate of the injectable polyurethane is ⁇ 0.03%.
  • the hydroxyl value of the ester is 10-500 mgKOH / g.
  • the ester has a hydroxyl value of 50-300 mgKOH / g.
  • the ester has a hydroxyl value of 100-250 mgKOH / g.
  • the C 2-6 polyol is glycerol.
  • ester is derived from a vegetable oil.
  • the vegetable oil is selected from one or two or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil, and coconut oil.
  • the vegetable oil is castor oil.
  • the following method is used for modification: taking the vegetable oil and performing an alcoholysis reaction with a C 2-6 polyol to obtain an ester containing more than two hydroxyl groups.
  • the C 2-6 polyol is trimethylolpropane or glycerol.
  • the C 2-6 polyol is glycerol.
  • the mass ratio of the C 2-6 polyol to the vegetable oil is 1: (0.2-0.8).
  • the mass ratio of the C 2-6 polyol to the vegetable oil is 1: (0.3 to 0.5).
  • an alcoholysis reaction is performed at 180-250 degreeC.
  • the alcoholysis reaction time is 1 to 8 hours.
  • the alcoholysis reaction is performed under a protective atmosphere.
  • the catalyst is one or two or more of calcium oxide, lead oxide, and calcium naphthenate.
  • the catalyst is calcium oxide or calcium naphthenate.
  • the amount of the catalyst is 0.01 to 10% of the total mass of the vegetable oil and the C 2-6 polyol.
  • the amount of the catalyst is 0.01 to 5% of the total mass of the vegetable oil and the C 2-6 polyol.
  • the invention provides an injectable polyurethane, which is prepared from raw materials containing the following components:
  • Prepolymer prepared from a soft segment, an aliphatic diisocyanate, a catalyst, and a chain extender, wherein the soft segment is an ester formed by a C 2-6 polyol and a C 8-18 fatty acid, and the ester contains Two or more hydroxyl groups; and,
  • Curing agent the main component is the catalyst
  • the molar ratio of isocyanate groups in the aliphatic diisocyanate: hydroxyl groups in the soft segment is (1.0 to 5.0): 1;
  • the mass of the catalyst is 0.01 to 0.5% of the total mass of the soft segment and the aliphatic diisocyanate;
  • the mass of the chain extender is 1-12% of the soft segment
  • the mass of the curing agent is 0.1 to 3% of the prepolymer.
  • the hydroxyl value of the soft segment is 10-500 mgKOH / g.
  • the soft segment has a hydroxyl value of 50-300 mgKOH / g.
  • the hydroxyl value of the soft segment is 100-250 mgKOH / g.
  • the C 2-6 polyol is glycerol.
  • the soft segment is derived from a vegetable oil.
  • the vegetable oil is selected from one or two or more of tung oil, linseed oil, soybean oil, cottonseed oil, castor oil, dehydrated castor oil, and coconut oil.
  • the vegetable oil is castor oil.
  • the aliphatic diisocyanate is selected from one or two or more of isophorone diisocyanate, lysine diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, and hexamethylene diisocyanate.
  • the aliphatic diisocyanate is isophorone diisocyanate.
  • the molar ratio of the isocyanate group to the hydroxyl group in the soft segment in the aliphatic diisocyanate is (1.2 to 3.0): 1.
  • the molar ratio of isocyanate group to hydroxyl group in the soft segment in the aliphatic diisocyanate is (1.5 to 2.0): 1.
  • the catalyst is a tin-containing catalyst.
  • the catalyst is selected from one or two or more of dibutyltin dilaurate, stannous octoate, and stannous chloride.
  • the catalyst is dibutyltin dilaurate or stannous octoate.
  • the mass of the catalyst is 0.02 to 0.05% of the total mass of the soft segment and the aliphatic diisocyanate.
  • the chain extender is selected from a polyol, a diamine, or a mixture thereof.
  • the chain extender is selected from one of 1,4-butanediol, 1,6-hexanediol, glycerol, ethylenediamine, 2,2-dimethylolpropionic acid, and polyethylene glycol. Or two or more.
  • the chain extender is selected from one or two or more of 2,2-dimethylolpropionic acid, 1,4-butanediol, ethylenediamine, and polyethylene glycol.
  • the molecular weight of the polyethylene glycol is 200-2000.
  • the molecular weight of the polyethylene glycol is 400-1000.
  • the mass of the chain extender is 2 to 6% of the soft segment.
  • the viscosity of the prepolymer is 1000 to 20000 mPa ⁇ s.
  • the viscosity of the prepolymer is 2000 to 15000 mPa ⁇ s.
  • the viscosity of the prepolymer is 2000 to 10000 mPa ⁇ s.
  • the viscosity of the prepolymer is 8400 mPa ⁇ s.
  • the prepolymer is prepared by the following method: under a protective atmosphere, taking the soft segment and the aliphatic diisocyanate blending reaction, adding a catalyst to continue the reaction, and then adding a chain extender reaction to obtain a prepolymer body.
  • reaction was carried out while maintaining the temperature at 40 to 90 ° C.
  • the reaction is carried out while maintaining the temperature at 50 to 80 ° C.
  • the time of the blending reaction is 1-12 hours.
  • the time of the blending reaction is 4-6 hours.
  • reaction is performed for 0.5 to 4 hours.
  • the reaction is performed for 0.5 to 10 hours.
  • the reaction is performed for 20 minutes to 5 hours after the chain extender is added.
  • the mass of the curing agent is 0.1 to 1% of the prepolymer.
  • the catalyst is a tin-containing catalyst.
  • the catalyst is selected from one or two or more of dibutyltin dilaurate, stannous octoate, and stannous chloride.
  • the catalyst is dibutyltin dilaurate or stannous octoate.
  • the curing agent further contains a tertiary amine.
  • the addition of tertiary amine to the curing agent can improve the curing efficiency of the material, shorten the curing time, and improve the crosslinking efficiency.
  • the tertiary amine is selected from N, N-dimethylcyclohexylamine, bis (2-dimethylaminoethyl) ether, N, N, N ', N'-tetramethylalkylenediamine , Triethanolamine, dimethylethanolamine, one or two or more.
  • the tertiary amine is triethanolamine.
  • the mass ratio of the tertiary amine: catalyst is (0.5: 1) to (4: 1).
  • the mass ratio of tertiary amine: catalyst is (0.8: 1) to (3: 1).
  • the injectable polyurethane also contains a functional component.
  • the functional component is selected from one or two or more of apatite, bioglass, antibacterial agent, and X-ray blocking agent.
  • it contains 5-40% of apatite and / or bioglass.
  • it contains 5-30% of apatite and / or bioglass in the total mass of the polyurethane.
  • the antibacterial agent contains 1 to 10% of the total mass of the polyurethane.
  • it contains an antibacterial agent in an amount of 3 to 8% of the total mass of the polyurethane.
  • it contains an X-ray blocker in an amount of 3 to 20% of the total mass of the polyurethane.
  • it contains 5 to 15% of zirconia or bismuth oxide in the total mass of the polyurethane.
  • the invention provides a method for preparing the injectable polyurethane: taking a prepolymer, adding or not adding functional ingredients, and mixing it with a curing agent, and the obtained injectable polyurethane can be cured at room temperature.
  • the polyhydric alcohol in the present invention is an alcohol containing two or more hydroxyl groups in a molecule.
  • the ester formed by the C 2-6 polyhydric alcohol and C 8-18 fatty acid in the present invention can form ⁇ 1 ester bond in the molecule, as long as the number of hydroxyl groups in the molecule is ⁇ 2, it can be polymerized with the aliphatic diisocyanate.
  • the ester formed with C 8-18 fatty acid can be monoglyceride, diglyceride or triglyceride.
  • the apatite described in the present invention may be nano-apatite, micro-apatite, apatite doped with other ions or groups, such as fluoroapatite, carbonate apatite, magnesium-doped apatite, zinc Doped with apatite and other ingredients. Preference is given to nano-hydroxyapatite or micro-hydroxyapatite particles. More preferred are spherical nano-hydroxyapatite particles.
  • the size of the active functional component may be 10 to 1,000 nm. It is preferably 10 to 100 nm.
  • the active functional component may be spherical or rod-shaped crystals, preferably spherical crystals.
  • the preparation method of nano-hydroxyapatite can refer to "The release properties of silver ions from Ag-nHA / TiO 2 / PA66 antimicrobial composite scaffolds, Xia Wu, Jidong Li, LiWang, Di Huang, Yi Zuo and Yubao Li, BIOMEDICAL MATERIALS, 5 (2010) 044105 (7pp) "and other known methods have been reported in the literature.
  • the antibacterial agent according to the present invention may be an inorganic and / or organic antibacterial agent.
  • the inorganic antibacterial agent contains at least one of nano silver, silver salt, zinc oxide, zinc salt or copper salt. Zinc oxide and a zinc salt component are preferable. More preferred is nano zinc oxide. The size is 30 to 50 nm.
  • the organic antibacterial agent contains at least one of imidazoles, thiazoles, isothiazolone derivatives, quaternary ammonium salts or phenols. Depending on the application, the inorganic antibacterial component and the organic antibacterial component can also be used in proportion.
  • the X-ray blocking agent according to the present invention is composed of a medical heavy metal salt and / or an oxide of a medical heavy metal salt, and may be at least one of metal barium, zirconium, and bismuth oxides or a corresponding metal salt.
  • the prepolymer is cooled to room temperature
  • 20 to 40% of nano-hydroxyapatite and / or 5% of nano-zinc oxide and / or 10 are added to the target prepolymer in a total mass.
  • % Bismuth oxide continue stirring at room temperature for 0.5h to 3h, and then add a curing agent. It is preferable to stir at room temperature for 1 to 2 hours, and then add a curing agent.
  • the invention provides the use of an ester formed by a C 2-6 polyol and a C 8-18 fatty acid as a soft segment to prepare an injectable polyurethane, which can reduce the curing expansion ratio of the prepared polyurethane material to less than 0.03%, making it more suitable for Filling in narrow spaces such as root canal filling, and moreover, vegetable oil can be directly used as a raw material.
  • the present invention has the advantage of being environmentally friendly.
  • the present invention also provides an injectable polyurethane, which has good biocompatibility, hard / soft tissue adhesion properties, antibacterial properties, X-ray blocking properties, physicochemical properties, and functions that meet a variety of clinical use needs. And can adjust the curing rate to meet the requirements of different medical fields, the application prospect is broad.
  • FIG. 1 is a graph of reactant conversion rate within 48 hours of curing of the medical polyurethane material in Example 1;
  • Example 2 is a fluorescence staining diagram of cell proliferation on the surface of the material after curing the medical polyurethane material in Example 1, co-cultured with mouse fibroblasts for 1, 4, and 7 days;
  • FIG. 3 is a scanning electron microscope image of the adhesion of bacteria to the surface of the material after co-cultured with Enterococcus faecalis after curing the medical polyurethane material in Example 2.
  • FIG. 3 is a scanning electron microscope image of the adhesion of bacteria to the surface of the material after co-cultured with Enterococcus faecalis after curing the medical polyurethane material in Example 2.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products, which are obtained by purchasing commercially available products.
  • the invention provides the use of an ester formed by a C 2-6 polyol and a C 8-18 fatty acid as a soft segment to prepare an injectable polyurethane, wherein the ester contains two or more hydroxyl groups.
  • the macromolecular polyol polymer (such as polyethylene glycol, polytetrahydrofuran diol, polypropylene glycol, polyether triol, etc.) is used as the main body of the soft segment.
  • Molecular polyols can significantly reduce the cure expansion rate of polyurethane materials and make them more suitable for filling narrow spaces.
  • the present invention can directly use vegetable oil as a raw material, which not only has a wide range of sources and low cost, but is also environment-friendly.
  • the polyurethane material prepared is also more biosafe and suitable for biomedical applications.
  • an ester formed from a fatty acid with a carbon number of less than 8 and a C 2 to 6 polyol is used as the soft segment, it is difficult to ensure the formation of a sufficient degree of crosslinking, which will adversely affect the curing performance and other physical properties of the material.
  • an ester formed from a fatty acid with more than 18 carbon atoms and a C 2 to 6 polyol is used, its hydroxyl value is low and its reactivity is weak. It cannot guarantee sufficient polymerization of the material, and it is also difficult to ensure the physical properties of the material.
  • the present invention provides an injectable polyurethane, which is prepared from raw materials containing the following components:
  • Prepolymer prepared from a soft segment, an aliphatic diisocyanate, a catalyst, and a chain extender, wherein the soft segment is an ester formed by a C 2-6 polyol and a C 8-18 fatty acid, and the ester contains Two or more hydroxyl groups; and,
  • Curing agent the main component is the catalyst
  • the molar ratio of isocyanate groups in the aliphatic diisocyanate: hydroxyl groups in the soft segment is (1.0 to 5.0): 1;
  • the mass of the catalyst is 0.01 to 0.5% of the total mass of the soft segment and the aliphatic diisocyanate;
  • the mass of the chain extender is 1-12% of the soft segment
  • the mass of the curing agent is 0.1 to 3% of the prepolymer.
  • the polyurethane material provided by the present invention has good physical and chemical properties and biocompatibility, and has the advantage of controllable curing rate.
  • the amount of curing agent can be adjusted to 0.1 to 3% to achieve tens of minutes to 48 hours. Curing time range.
  • the curing agent addition amount is adjusted to 0.1 to 1%, and the curing time can be controlled to about 11 hours.
  • the compounding content of the curing agent can be appropriately increased, preferably 2 to 3%.
  • the polyurethane of the present invention can also be compounded with a variety of active ingredients, X-ray blocking ingredients and / or antibacterial ingredients to form a multifunctional biomaterial to satisfy the filling of different clinical tissues in various biomedical fields. It is suitable for but not limited to the clinical application of bone defect repair, root canal filling, dental adhesive, bone adhesive and soft tissue adhesive, and has a good application prospect in the field of biomedicine.
  • Nano-hydroxyapatite with a total mass of 20% was compounded in the urethane prepolymer and stirred for 1.5 h. Then, a catalyst of 0.1 g of dibutyltin dilaurate and 0.1 g of the functional urethane prepolymer was added. Triethanolamine is mixed to obtain the target injectable medical biological material, and the material is cured after about 10-12 hours.
  • Figure 1 shows the change of the infrared spectrum of the material over time during the curing process of the material ( Figure 1A), and the conversion of isophorone diisocyanate (Figure 1B). It can be seen from FIG. 1A that with the extension of the curing time of the material, the characteristic peak (2270 cm -1 ) of isocyanate corresponding to isophorone diisocyanate gradually decays. Using the half-peak width of its -NCO characteristic peak as the reference, the time-varying trend corresponding to the peak area of the spectrum was calculated as the reaction conversion rate. After 11 hours of curing, the conversion rate of the reactants exceeded 90%, which indicates that the material can be relatively High monomer conversion.
  • Figure 2 shows the growth of mouse fibroblasts L929 on the surface of the above materials using Live / Dead fluorescence staining.
  • Green cells represent live cells and red cells represent dead cells.
  • Figures 2A, 2B, and 2C represent growth conditions of 1, 4, and 7 days, respectively. It can be seen from the figure that after 4 days of culture, most of the cells showed strong cell viability (stained green), and the cells on the material surface showed typical spindle-shaped cells. After 7 days of culture, living cells proliferated in large numbers, and the cells overlapped to form thick Multi-layered cells indicate that the material has good cell compatibility and does not cause significant cytotoxicity.
  • the mold (6mm inner diameter, 12mm height teflon mold) was placed on a polyethylene film, and a glass plate was placed at the bottom, filled with an excessive amount of sealant. Another glass plate was pressed against the sealant with a polyethylene film. Then use a C-clamp to fix the model and the glass. After 5 minutes, place the device in a 37 ⁇ 1 ° C 95-100% humidity incubator. For materials with curing times longer than 2 hours, 3 times the curing time is required. After preparing the sample, use 600 mesh sandpaper to smooth both ends of the sample. After removing the sample from the mold, measure the distance between the two ends to the nearest 10 ⁇ m. Measure again at 37 ⁇ 1 °C distilled water for 30 days. The measured value is accurate to 10 ⁇ m. Calculate the percentage change in length. The result should be less than 0.1%.
  • the polyurethane material of the present invention has excellent physical properties and is conducive to the injection characteristics of the material, especially having only a slight swelling property, which is beneficial to the sealing performance of the material for tissue filling.
  • Figure 3 shows the adhesion of bacteria on the surface of the material after co-culturing Enterococcus faecalis with the above materials for 24 hours.
  • Figures 3A, 3B, 3C, and 3D show functional carbamic acid without adding nano zinc oxide, adding nano zinc oxide with a total mass of 1%, adding nano zinc oxide with a total mass of 3%, and adding nano zinc oxide with a total mass of 5%.
  • the adhesion of bacteria on the surface of the ester polymer material can be seen.
  • the material of the agent has good antibacterial ability and antibacterial adhesion ability, which is beneficial to reduce the infection or inflammatory reaction that may be caused during the filling and repairing process.
  • Preparation of modified coconut oil In a protective atmosphere, put glycerol and coconut oil in a three-necked flask at a molar ratio of 1: 0.5 of hydroxyl groups, add 3wt% calcium naphthenate as a catalyst, and stir the reaction at 200 ° C 1 to 8 hours, until the reactant can be completely dissolved in methanol, and then a suitable amount of phosphoric acid is added dropwise to terminate the reaction.
  • Segmented urethane prepolymer compounded with 20% nano-hydroxyapatite rod-shaped particles and 5% zinc oxide powder in the urethane prepolymer, and stirred for 1.5h, and then added 0.15g of subcaprylic acid Tin and 0.15g of triethanolamine can be used to obtain target injectable medical biological materials with biological and antibacterial activity.

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Abstract

本发明涉及可注射的聚氨酯及其制备方法，属于医用生物材料领域。本发明所要解决的是现有医用聚氨酯材料固化膨胀率高、环境不友好等问题，其技术方案是提供了C2～6多元醇与C8～18脂肪酸形成的酯作为软段制备可注射聚氨酯的用途，其中，所述的酯含有两个以上羟基。本发明制备得到的可注射聚氨酯材料固化膨胀率低、环境友好而且生物安全性高，应用前景广阔。

Description

可注射的聚氨酯及其制备方法 技术领域
本发明涉及可注射的聚氨酯及其制备方法，属于医用生物材料领域。
背景技术
氨基甲酸酯共聚物，即聚氨酯(Polyurethane,PU)，是主链上含有重复氨基甲酸酯键(-NH-COO-)的一类高分子的总称。因其优越的物理化学性能、可灵活调控性能及良好的生物相容性，被广泛用于诸多医疗器械和人工器官装置等领域，如人造血管、人工心脏、人工皮肤、人工导管、人工软骨、神经导管等。然而，现有的聚氨酯基生物材料，主要应用的是聚氨酯材料固化以后具有优良的力学性能以及良好稳定性，对聚氨酯的可注射性能尚未进行深入研究。
比如，杜晶晶等人报道了蓖麻油基聚氨酯/纳米羟基磷灰石(HA)复合骨修复支架材料(Du J.J.,Zuo Y.,Zou Q.,Sun B.,Zhou M.B.,Li L.M.,Man Y.,Li Y.B.Preparation and in vitro evaluation of polyurethane composite scaffolds based on glycerol-esterified castor oil and hydroxyapatite[J].Materials Research Innovations,2014,18(3):160-168.)，结果表明该三维支架具有良好的力学性及生物相容性。但该合成技术制备的支架材料高度交联，不具备可注射性。
本申请人前期申请号为201210554248.3的授权专利《可注射型快速固化医用聚氨酯组合物及制备方法》，及李宽宽等人报道的可注射聚氨酯与纳米羟基磷灰石复合物(Li K,Zuo Y,Zou Q,et al.Synthesis and Characterization of Injectable Nano-Hydroxyapatite/Polyurethane Composite Cement Effective Formulations for Management of Osteoporosis[J].Journal of Nanoscience and Nanotechnology,2016,16(12):12407-12417.)，虽然其技术涉及具有可注射性能的骨水泥材料，但上述材料的固化膨胀率较高(达到了1.5％)，固化后可能对充填的部位造成较大的应力刺激，从而对组织修复产生不良影响，较难满足可注射材料在口腔根管应用标准(YY 0717牙科根管封闭材料)的要求(该标准要求膨胀率≤0.1％)。而且，作为聚氨酯软段使用的大分子多元醇聚合物，如聚乙二醇、聚四氢呋喃醚二醇、聚丙二醇、聚醚三醇等均属于石油工业下游产品，随着石油资源日渐枯竭，以及环保要求日渐提高，开发新型的、环境友好的材料尤为重要。
因此，需进一步优化材料配方及工艺，为临床应用提供更多具优势特性的可注射材料。
发明内容
本发明的目的在于提供可注射的聚氨酯及其制备方法，以解决现有医用聚氨酯材料固化膨胀率高、环境不友好等问题。
本发明提供了C 2～6多元醇与C 8～18脂肪酸形成的酯作为软段制备可注射聚氨酯的用途，其中，所述的酯含有两个以上羟基。
进一步地，所述可注射聚氨酯的固化膨胀率≤0.5％。
优选地，所述可注射聚氨酯的固化膨胀率≤0.1％。
进一步优选地，所述可注射聚氨酯的固化膨胀率≤0.03％。
进一步地，所述酯的羟基值为10～500mg KOH/g。
优选地，所述酯的羟基值为50～300mg KOH/g。
进一步优选地，所述酯的羟基值为100～250mg KOH/g。
进一步地，所述C 2-6多元醇为甘油。
进一步地，所述的酯来源于植物油。
优选地，所述植物油选自桐油、亚麻仁油、豆油、棉籽油、蓖麻油、脱水蓖麻油、椰子油中一种或两种以上。
进一步优选地，所述植物油为蓖麻油。
进一步地，当植物油所含羟基数量小于2时，采用如下方法进行改性：取植物油，与C 2-6多元醇发生醇解反应，即得含有两个以上羟基的酯。
进一步地，所述C 2-6多元醇为三羟甲基丙烷或甘油。
优选地，所述C 2-6多元醇为甘油。
进一步地，所述C 2-6多元醇与植物油的质量比为1:(0.2～0.8)。
优选地，所述C 2-6多元醇与植物油的质量比为1:(0.3～0.5)。
进一步地，于180～250℃进行醇解反应。
进一步地，醇解反应时间1～8h。
进一步地，醇解反应在保护气氛下进行。
进一步地，所述催化剂为氧化钙、氧化铅、环烷酸钙中一种或两种以上。
优选地，所述催化剂为氧化钙或环烷酸钙。
进一步地，所述催化剂的用量为植物油与C 2-6多元醇总质量的0.01～10％。
优选地，所述催化剂的用量为植物油与C 2-6多元醇总质量的0.01～5％。
本发明提供了可注射的聚氨酯，包含如下组分的原料制备而成：
预聚体：软段、脂肪族二异氰酸酯、催化剂和扩链剂制备而成，其中，所述的软段为C 2～6多元醇与C 8～18脂肪酸形成的酯，所述的酯含有两个以上羟基；和，
固化剂：主要成分为催化剂；
其中，所述脂肪族二异氰酸酯中异氰酸酯基：所述软段中羟基的摩尔比为(1.0～5.0):1；
所述催化剂质量为软段和脂肪族二异氰酸酯总质量的0.01～0.5％；
所述扩链剂质量为软段的1～12％；
所述固化剂的质量为预聚体的0.1～3％。
进一步地，所述软段的羟基值为10～500mg KOH/g。
优选地，所述软段的羟基值为50～300mg KOH/g。
进一步优选地，所述软段的羟基值为100～250mg KOH/g。
进一步地，所述C 2-6多元醇为甘油。
进一步地，所述软段来源于植物油。
优选地，所述植物油选自桐油、亚麻仁油、豆油、棉籽油、蓖麻油、脱水蓖麻油、椰子油中一种或两种以上。
进一步优选地，所述植物油为蓖麻油。
进一步地，所述脂肪族二异氰酸酯选自异佛尔酮二异氰酸酯、赖氨酸二异氰酸酯、4,4'-二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯中一种或两种以上。
优选地，所述脂肪族二异氰酸酯为异佛尔酮二异氰酸酯。
进一步地，脂肪族二异氰酸酯中异氰酸酯基：软段中羟基的摩尔比为(1.2～3.0):1。
优选地，脂肪族二异氰酸酯中异氰酸酯基：软段中羟基的摩尔比为(1.5～2.0):1。
进一步地，所述催化剂为含锡催化剂。
优选地，所述催化剂选自二丁基锡二月桂酸酯、辛酸亚锡、氯化亚锡中一种或两种以上。
进一步优选地，所述催化剂为二丁基锡二月桂酸酯或辛酸亚锡。
进一步地，所述催化剂质量为软段和脂肪族二异氰酸酯总质量的0.02～0.05％。
进一步地，所述扩链剂选自多元醇、二元胺或其混合物。
优选地，所述扩链剂选自1,4-丁二醇、1,6-己二醇、甘油、乙二胺、2,2-二羟甲基丙 酸、聚乙二醇中一种或两种以上。
进一步优选地，所述扩链剂选自2,2-二羟甲基丙酸、1，4-丁二醇、乙二胺、聚乙二醇中一种或两种以上。
优选地，所述聚乙二醇的分子量为200～2000。
进一步优选地，所述聚乙二醇的分子量为400～1000。
进一步地，所述扩链剂质量为软段的2～6％。
进一步地，所述预聚体的黏度为1000～20000mPa·s。
优选地，所述预聚体的黏度为2000～15000mPa·s。
进一步优选地，所述预聚体的黏度为2000～10000mPa·s。
更优选地，所述预聚体的黏度为8400mPa·s。
进一步地，所述预聚体由下述方法制备得到：在保护气氛下，取所述软段与脂肪族二异氰酸酯共混反应，加入催化剂继续反应，再加入扩链剂反应，即得预聚体。
进一步地，保持温度于40～90℃反应。
优选地，保持温度于50～80℃反应。
进一步地，所述共混反应的时间为1～12h。
优选地，所述共混反应的时间为4～6h。
进一步地，加入催化剂后反应0.5～4h。
进一步地，加入扩链剂后反应0.5～10h。
优选地，加入扩链剂后反应20min～5h。
进一步地，所述固化剂的质量为预聚体的0.1～1％。
进一步地，所述催化剂为含锡催化剂。
优选地，所述催化剂选自二丁基锡二月桂酸酯、辛酸亚锡、氯化亚锡中一种或两种以上。
进一步优选地，所述催化剂为二丁基锡二月桂酸酯或辛酸亚锡。
进一步地，所述固化剂还含有叔胺。
其中，固化剂中加入叔胺可以提升材料的固化效率，缩短固化时间，提升交联效率。
进一步地，所述叔胺选自N,N-二甲基环己胺、双(2-二甲氨基乙基)醚、N,N,N',N'-四甲基亚烷基二胺、三乙醇胺、二甲基乙醇胺中一种或两种以上。
进一步优选地，所述叔胺为三乙醇胺。
进一步地，叔胺：催化剂的质量比为(0.5:1)～(4:1)。
优选地，叔胺：催化剂的质量比为(0.8:1)～(3:1)。
进一步地，所述的可注射的聚氨酯还含有功能性成分。
优选地，所述功能性成分选自磷灰石、生物玻璃、抗菌剂、X射线阻射剂中一种或两种以上。
优选地，含有占所述聚氨酯总质量5～40％的磷灰石和/或生物玻璃。
进一步优选地，含有占所述聚氨酯总质量5～30％的磷灰石和/或生物玻璃。
优选地，含有占所述聚氨酯总质量1～10％的抗菌剂。
进一步优选地，含有占所述聚氨酯总质量3～8％的抗菌剂。
优选地，含有占所述聚氨酯总质量3～20％的X射线阻射剂。
进一步优选地，含有占所述聚氨酯总质量5～15％的氧化锆或氧化铋。
最优选地，含有占所述聚氨酯总质量5～15％的氧化铋。
本发明提供了所述可注射的聚氨酯的制备方法：取预聚体，加入或不加入功能性成分，与固化剂混合，即可，所得可注射的聚氨酯可于室温固化。
本发明所述多元醇即分子中含有两个或两个以上羟基的醇类。
本发明所述C 2～6多元醇与C 8～18脂肪酸形成的酯，其分子中可以形成≥1个酯键，只要保证分子中羟基数量≥2，即可与脂肪族二异氰酸酯聚合。以C 3多元醇甘油为例，它与C 8～18脂肪酸形成的酯可以为甘油单酯，甘油二酯或者甘油三酯。
本发明所述磷灰石可以为纳米磷灰石、微米磷灰石、掺杂其他离子或基团的磷灰石，如氟磷灰石、碳酸磷灰石、镁掺杂磷灰石、锌掺杂磷灰石等成分。优选为纳米羟基磷灰石或微米羟基磷灰石粒子。更优选为纳米羟基磷灰石球形粒子。其活性功能成分尺寸可以为10～1,000nm。优选为10～100nm。其活性功能成分可以为球状或棒状晶体，优选为球状晶体。其中，纳米羟基磷灰石的制备方法可以参照“The release properties of silver ions from Ag-nHA/TiO 2/PA66 antimicrobial composite scaffolds,Xia Wu,Jidong Li,LiWang,Di Huang,Yi Zuo and Yubao Li,BIOMEDICAL MATERIALS,5(2010)044105(7pp)”等在内的目前已有文献报道的已知方法。
本发明所述抗菌剂可以为无机和/或有机抗菌剂。所述无机抗菌剂，含纳米银、银盐、氧化锌、锌盐或铜盐成分中的至少一种。优选为氧化锌及锌盐成分。更加优选为纳米氧化锌。尺寸为30～50nm。所述有机抗菌剂，含咪唑类、噻唑类、异噻唑酮衍生物、季铵盐类或酚类制剂中的至少一种。也可依据用途将无机抗菌成分与有机抗菌成分按比例搭配使用。
本发明所述X射线阻射剂，由医用重金属盐和/或医用重金属盐的氧化物构成，可为金属钡、锆、铋的氧化物或对应的金属盐中的至少一种。
在本发明的优选实施方案中，预聚体冷却至室温后，在目标预聚物中添加总质量20～40％的纳米羟基磷灰石和(或)5％纳米氧化锌和(或)10％氧化铋，继续常温搅拌0.5h～3h，再加入固化剂。优选常温搅拌1h～2h，再加入固化剂。
在以上制备方法中，可根据不同的用途采取不同的固化方式：1)对于医用聚氨酯，可将制备过程所用反应物做干燥处理，固化后可形成低孔隙结构的医用聚合物材料；2)对于需要实现材料固化后具有更高强度特性的材料，可添加所述预聚体质量5～40％的生物活性无机成分；3)对于需要实现优良抗菌性能的聚氨酯医用材料，可在预聚体中复合所述的抗菌剂成分；4)对于需要实现具有X射线阻射特性的医用聚氨酯材料，可在预聚体中复合所述X射线阻射成分；5)对于需要实现预聚体更加快速固化的特性，可适当提高固化剂的复合含量，优选为2～3％；6)对于需要实现其他特性的医用聚氨酯材料，可添加其他活性成分；8)以上所述的不同固化方式，可以单一或复合使用。
本发明提供了C 2～6多元醇与C 8～18脂肪酸形成的酯作为软段制备可注射聚氨酯的用途，能够将制备得到的聚氨酯材料固化膨胀率降低至0.03％以下，使之更加适合于根管充填等狭窄空间充填，而且，可直接采用植物油作为原料，相较于以石油工业下游产品作为原料制备聚氨酯的方法，本发明具有环境友好的优点。
另外，本发明还提供了可注射的聚氨酯，其具有良好的生物相容性、硬/软组织粘接性能、抗菌性能、X射线阻射特性、物理化学性能以及满足多种临床使用需求的功能，并可以通过调节固化速率满足不同医用领域的要求，应用前景广阔。
附图说明
图1为实施例1中医用聚氨酯材料固化48小时内反应物转化率图；
图2为实施例1中医用聚氨酯材料固化后，与小鼠成纤维细胞共培养1、4、7天，细胞在材料表面增殖的荧光染色图；
图3为实施例2中医用聚氨酯材料固化后，与粪肠球菌共培养24，细菌在材料表面的粘附的扫描电子显微镜图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
本发明提供了C 2～6多元醇与C 8～18脂肪酸形成的酯作为软段制备可注射聚氨酯的用途，其中，所述的酯含有两个以上羟基。
区别于现有的可注射聚氨酯以大分子多元醇聚合物(如聚乙二醇、聚四氢呋喃醚二醇、聚丙二醇、聚醚三醇等)作为软段主体，本发明使用的软段为小分子多元醇，能够显著降低聚氨酯材料的固化膨胀率，使之更加适合于狭窄空间充填。
此外，本发明能够直接采用植物油作为原料，不仅来源广泛、成本低廉，而且环境友好，制备得到的聚氨酯材料生物安全性也更高，适合于生物医疗用途。
其中，若采用碳原子数量＜8的脂肪酸与C 2～6多元醇形成的酯作为软段，难以保证形成足够交联度的聚氨酯，会对材料的固化性能及其他物理性能产生不利影响。如果采用碳原子数量>18的脂肪酸与C 2～6多元醇形成的酯，其羟基值较低，反应活性较弱，不能保证材料充分的聚合，材料的物理性能同样难以保证。
进一步地，本发明提供了可注射聚氨酯，包含如下组分的原料制备而成：
预聚体：软段、脂肪族二异氰酸酯、催化剂和扩链剂制备而成，其中，所述的软段为C 2～6多元醇与C 8～18脂肪酸形成的酯，所述的酯含有两个以上羟基；和，
固化剂：主要成分为催化剂；
其中，所述脂肪族二异氰酸酯中异氰酸酯基：所述软段中羟基的摩尔比为(1.0～5.0):1；
所述催化剂质量为软段和脂肪族二异氰酸酯总质量的0.01～0.5％；
所述扩链剂质量为软段的1～12％；
所述固化剂的质量为预聚体的0.1～3％。
本发明提供的上述聚氨酯材料物理化学性能以及生物相容性良好，而且具有固化速率可控的优势，比如，可以通过调整固化剂的添加量至0.1～3％，实现数十分钟至48小时的固化时间范围。在本发明的优选实施方式中，调整固化剂添加量为0.1～1％，能够将固化时间控制在11h左右。对于需要实现更加快速固化的情况，可适当提高固化剂的复合含量，优选为2～3％。
在此基础上，本发明聚氨酯还可复合多种活性成分、X射线阻射成分和/或抗菌成分而形成具多功能性的生物材料，以满足多种生物医学领域的不同临床组织充填，可适用但不仅限于骨缺损修复、根管充填、牙科粘接剂、骨粘接剂及软组织粘接剂方面的临床应用，在生物医学领域具有很好的应用前景。
实施例1 本发明可注射医用生物材料的制备
改性蓖麻油的制备：在保护气氛下，将甘油与蓖麻油按羟基摩尔比为1:0.4的配比投入三口烧瓶中，加入0.02wt％氧化钙作为催化剂，在200℃下充分搅拌反应1h后滴加适量的磷酸终止反应。
在充满氮气的三口烧瓶中，加入15g异佛尔酮二异氰酸酯和15g改性蓖麻油,在60～80℃下反应4h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h,再加入所述软段质量2％的2,2-二羟甲基丙酸,并保持反应1h，冷却至室温后得到嵌段氨基甲酸酯预聚体，黏度值约为8400mPa·s。在氨基甲酸酯预聚体中复合总质量20％的纳米羟基磷灰石，并搅拌1.5h，随后在功能氨基甲酸酯预聚体中加入催化剂0.1g二丁基锡二月桂酸酯与0.1g三乙醇胺，混合后得到目标可注射性的医用生物材料，大约10～12个小时后材料固化。
图1展示了上述材料固化过程中材料红外图谱随时间的变化(图1A)，以及异佛尔酮二异氰酸酯的转化率(图1B)。从图1A中可见，随着材料的固化时间的延长，异佛尔酮二异氰酸酯对应的异氰酸根的特征峰(2270cm -1)逐渐衰减。以其-NCO特征峰半峰宽为基准计算谱峰面积对应的时间变化趋势作为反应转化率，可以分析得出固化11h后，反应物的转化率超过90％，说明材料在常温下可实现较高的单体转化率。
图2展示了采用Live/Dead荧光染色法检测小鼠成纤维细胞L929在上述材料表面生长情况，绿色细胞代表活细胞，红色细胞代表死细胞。图2A、2B、2C分别代表生长1、4、7天的情况。从图中可见，培养4天后，大部分细胞呈现较强的细胞活力(被染成绿色)，材料表面可见呈典型纺锤状的细胞；培养7天后活细胞大量增殖，细胞重叠生长形成厚厚的多层细胞，说明材料具有良好的细胞相容性，不会造成明显细胞毒性。
参照ISO 6876-2001对实施例1制备的医用氨基甲酸酯聚合物材料的可注射性及固化参数进行测试：
(1)固化时间测试
将模具放在玻板上，用混合后的聚氨酯材料水平充满。从调拌结束计数120±10s后，将此装置放在37℃孵箱中。小心将吉尔摩针探头垂直加压在固化的封闭剂上持续5s。30s后再次加压试验测量固化时间，直到尖端不能在产生压痕。清洁探头后多次重复该步骤。初步确定固化时间后，以10s为间隔，直到封闭剂上无压痕。固化时间应以调拌时间计时，到不能产生压痕为止，此时记录从调拌到固化的时间。
(2)流动性测试
取玻璃板两块，面积不得小于40mm×40mm，厚度约5mm，其中一块质量约20g，调拌时开始计时。使用注射器取0.05±0.005ml或0.5ml聚氨酯材料滴加在玻板中央。于 调拌开始后180±5s时压上另一块玻板，并加上重物加压，施加重物约120g。于调拌10min后，去除重物并测量待测封闭剂分布的最大与最小直径，如果二者相差1mm以内，记录均值数据。如果相差超过1mm，重复实验。流动性应不小于17mm。
(3)膜厚度测试
将两块玻璃重叠标记箭头，测量两块玻璃板叠加起来的厚度为A，精确到1μm。在一块玻板中央放置聚氨酯材料0.1ml，然后将另一块玻板按照标记箭头沿同一方向压上去，放入孵箱。180±10s后，将150N重物小心加载在玻板上，保证封闭剂完全充满两块玻板之间。加力10min后，使用千分尺测量两块玻板及封闭剂的厚度B。通过比较玻板间是否存在聚氨酯材料时厚度差异，计算出膜厚度。膜厚度应不大于50mm。
(4)体积膨胀率测试(即固化膨胀率)
将模具(内径6mm，高12mm teflon模具)放置在聚乙烯薄膜上，底部放置一块玻璃板，填充过量的封闭剂。将另一块玻璃板隔着聚乙烯膜压在封闭剂上。然后使用C型夹将模型和玻板固定。5min后将该装置放入37±1℃ 95-100％湿度孵箱内。对于固化时间超过2小时的材料，需要3倍于固化时间。制备出样本后，使用600目砂纸打磨平样本两端。将样本从模具取出后，测量两端距离，精确到10μm。在37±1℃蒸馏水30天后再次测量，测量值精确到10μm。计算长度变化的百分率。结果应小于0.1％。
测试结果见下表：
表1 可注射性及固化参数测试结果
固化时间(min) 流动性(mm) 膜厚度(μm) 体积膨胀率(％)
712±17 38.21±1.96 37.71±2.54 0.030±0.008
以上测试结果表明，本发明聚氨酯材料各项物理性能优良，有利于材料的注射特性，尤其是仅具有轻微的膨胀性，有利于材料对组织充填的封闭性能。
实施例2 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入15g异佛尔酮二异氰酸酯和15g改性蓖麻油,在60～80℃下反应4h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h,再加入所述软段质量2％的2,2-二羟甲基丙酸,并保持反应1h，冷却至室温后得到嵌段氨基甲酸酯预聚体。在氨基甲酸酯预聚体中复合总质量20％的纳米羟基磷灰石，以及纳米氧化锌粉末(设置4个实验组，分别不添加纳米氧化锌、添加总质量1％的纳米氧化锌、添加总质量3％的纳米氧化锌、添加总质量5％的纳米氧化锌)，并搅拌1.5h，随后在功能氨基甲酸酯预聚体中加入催化剂0.1g二丁基锡二月桂酸酯与0.1g三乙醇胺，混合后得到目标可注射性的医用生物材料，大约10～12个小时后材料固化。
图3展示了将粪肠球菌(Enterococcus faecalis)与上述材料共培养24h后，细菌在材料表面的粘附情况。图3A、3B、3C、3D分别表示不添加纳米氧化锌、添加总质量1％的纳米氧化锌、添加总质量3％的纳米氧化锌、添加总质量5％的纳米氧化锌的功能氨基甲酸酯聚合物材料表面细菌粘附情况，可以看出，不含抗菌剂纳米氧化锌的材料表面粘附大量细菌，而随着纳米氧化锌含量的增加，材料表面细菌含量也逐渐减少，说明添加抗菌剂的材料具有良好的抗菌能力与抗细菌粘附能力，有利于减少充填修复过程中可能造成的感染或炎性反应。
实施例3 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入15g异佛尔酮二异氰酸酯和15g改性蓖麻油,在60～80℃下反应4h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h,再加入所述软段质量2％的2,2-二羟甲基丙酸,并保持反应1h，冷却至室温后得到嵌段氨基甲酸酯预聚体。在氨基甲酸酯预聚体中复合总质量20％的纳米镁磷灰石、5％的纳米氧化锌粉末和10％的氧化铋粉末，并搅拌1.5h，随后在功能氨基甲酸酯预聚体中中加入催化剂0.1g二丁基锡二月桂酸酯与0.1g三乙醇胺，混合后得到具生物活性、抗菌活性和X阻射性的目标可注射性医用生物材料，大约10～12个小时后材料固化。
实施例4 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入15.0g蓖麻油和20.0g的赖氨酸二异氰酸酯。在80℃下反应6h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h，再加入所述软段质量3％的1，4-丁二醇，反应2h后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量10％的纳米羟基磷灰石和5％纳米氧化锆粉末，并搅拌1.5h，随后在功能氨基甲酸酯预聚体中加入催化剂0.3g二丁基锡二月桂酸酯与0.2g N,N-二甲基环己胺，可得具生物活性和抗菌活性的目标可注射性医用生物材料。
实施例5 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入25.0g蓖麻油和15.0g的异佛尔酮二异氰酸酯。在60℃下反应4h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h，加入所述软段2％的2,2-二羟甲基丙酸，反应1h后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量40％的纳米氟磷灰石，并搅拌1.5h，随后在功能聚氨酯预聚体中加入0.05g二丁基锡二月桂酸酯与0.05g三乙醇胺，可得具生物活性的目标可注射性医用生物材料。
实施例6 本发明可注射医用生物材料的制备
改性亚麻仁油的制备：在保护气氛下，将甘油与亚麻仁油按羟基摩尔比为1:0.3的 配比投入三口烧瓶中，加入1.2wt％环烷酸钙作为催化剂，在200℃下充分搅拌反应1～8h，直至反应物能够完全溶解于甲醇中，后滴加适量的磷酸终止反应。
在充满氮气的三口烧瓶中，加入15.0g改性亚麻仁油和15.0g的异佛尔酮二异氰酸酯。在80℃下反应5h后，加入软硬段总质量0.03％的二丁基锡二月桂酸酯，继续反应0.5h，加入所述软段质量3％的乙二胺，反应2h后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量20％的微米羟基磷灰石，8％氧化锆粉末，并搅拌1.5h，随后在功能氨基甲酸酯预聚体中加入0.2g辛酸亚锡与0.1g三乙醇胺，可得具生物活性和X阻射性的目标可注射性医用生物材料。
实施例7 本发明可注射医用生物材料的制备
改性豆油的制备：在保护气氛下，将甘油与豆油按羟基摩尔比为1:0.5的配比投入三口烧瓶中，加入0.5wt％氧化钙作为催化剂，在200℃下充分搅拌反应1～8h，直至反应物能够完全溶解于甲醇中，后滴加适量的磷酸终止反应。
在充满氮气的三口烧瓶中，加入30g改性豆油和20.0g的六亚甲基二异氰酸酯。在60℃下反应6h后，加入软硬段总质量0.03％的二丁基锡二月桂酸酯，继续反应0.5h，加入所述软段质量3％的2,2-二羟甲基丙酸，反应1h后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量20％的微米羟基磷灰石球形粒子、5％的纳米氧化锌粉末和10％的氧化铋粉末，并搅拌1.5h，再加入0.2g辛化亚锡，可得具生物活性、抗菌活性和X阻射性的目标可注射性医用生物材料。
实施例8 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入20g改性蓖麻油和20.0g的4,4'-二环己基甲烷二异氰酸酯。在70℃下反应6h后，加入软硬段总质量0.03％的二丁基锡二月桂酸酯，继续反应0.5h，加入所述软段质量2％的甘油，反应0.5h，然后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量10％的纳米羟基磷灰石棒状粒子、5％的纳米氧化锌粉末，并搅拌1.5h，再加入0.1g辛酸亚锡与0.1g三乙醇胺，可得具生物活性、抗菌活性的目标可注射性医用生物材料。
实施例9 本发明可注射医用生物材料的制备
改性椰子油的制备：在保护气氛下，将甘油与椰子油按羟基摩尔比为1:0.5的配比投入三口烧瓶中，加入3wt％环烷酸钙作为催化剂，在200℃下充分搅拌反应1～8h，直至反应物能够完全溶解于甲醇中，后滴加适量的磷酸终止反应。
在充满氮气的三口烧瓶中，加入20.0g改性椰子油和15.0g的赖氨酸二异氰酸酯。在90℃下反应4h后，加入软硬段总质量0.03％的二丁基锡二月桂酸酯，继续反应0.5h， 加入所述软段质量2％的聚乙二醇600，反应0.5h，然后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量30％的纳米羟基磷灰石球形粒子、10％的氧化铋粉末，并搅拌1.5h，再加入0.1g辛酸亚锡与0.05g三乙醇胺，可得具生物活性、X阻射性的目标可注射性医用生物材料。
实施例10 本发明可注射医用生物材料的制备
在充满氮气的三口烧瓶中，加入20.0g改性豆油和25.0g的赖氨酸二异氰酸酯。在60℃下反应8h后，加入软硬段总质量0.03％的辛酸亚锡，继续反应0.5h，加入所述软段质量2％的乙二胺，反应0.5h，然后冷却至室温后得到嵌段氨基甲酸酯预聚体，在氨基甲酸酯预聚体中复合总质量20％的纳米羟基磷灰石棒状粒子、5％的氧化锌粉末，并搅拌1.5h，再加入0.15g辛酸亚锡与0.15g三乙醇胺，可得具生物活性、抗菌活性的目标可注射性医用生物材料。

Claims (13)

  1. C 2～6多元醇与C 8～18脂肪酸形成的酯作为软段制备可注射聚氨酯的用途，其中，所述的酯含有两个以上羟基。
  2. 如权利要求1所述的用途，其特征是：满足以下至少一项：
    所述可注射聚氨酯的固化膨胀率≤0.5％；
    优选地，所述可注射聚氨酯的固化膨胀率≤0.1％；
    进一步优选地，所述可注射聚氨酯的固化膨胀率≤0.03％；
    所述酯的羟基值为10～500mg KOH/g；
    优选地，所述酯的羟基值为50～300mg KOH/g；
    进一步优选地，所述酯的羟基值为100～250mg KOH/g；
    所述C 2-6多元醇为甘油；
    所述的酯来源于植物油；
    优选地，所述植物油选自桐油、亚麻仁油、豆油、棉籽油、蓖麻油、脱水蓖麻油、椰子油中一种或两种以上；
    进一步优选地，所述植物油为蓖麻油。
  3. 如权利要求2所述的用途，其特征是：当植物油所含羟基数量小于2时，采用如下方法进行改性：取植物油，与C 2-6多元醇发生醇解反应，即得含有两个以上羟基的酯。
  4. 如权利要求3所述的用途，其特征是：所述改性满足以下至少一项：
    所述C 2-6多元醇为三羟甲基丙烷或甘油；
    优选地，所述C 2-6多元醇为甘油；
    所述C 2-6多元醇与植物油的质量比为1:(0.2～0.8)；
    优选地，所述C 2-6多元醇与植物油的质量比为1:(0.3～0.5)；
    于180～250℃进行醇解反应；
    醇解反应时间1～8h；
    醇解反应在保护气氛下进行；
    所述催化剂为氧化钙、氧化铅、环烷酸钙中一种或两种以上；
    优选地，所述催化剂为氧化钙或环烷酸钙；
    所述催化剂的用量为植物油与C 2-6多元醇总质量的0.01～10％；
    优选地，所述催化剂的用量为植物油与C 2-6多元醇总质量的0.01～5％。
  5. 可注射的聚氨酯，其特征是：包含如下组分的原料制备而成：
    预聚体：软段、脂肪族二异氰酸酯、催化剂和扩链剂制备而成，其中，所述的软段为C 2～6多元醇与C 8～18脂肪酸形成的酯，所述的酯含有两个以上羟基；和，
    固化剂：主要成分为催化剂；
    其中，所述脂肪族二异氰酸酯中异氰酸酯基：所述软段中羟基的摩尔比为(1.0～5.0):1；
    所述催化剂质量为软段和脂肪族二异氰酸酯总质量的0.01～0.5％；
    所述扩链剂质量为软段的1～12％；
    所述固化剂的质量为预聚体的0.1～3％。
  6. 如权利要求5所述的可注射的聚氨酯，其特征是：所述软段满足以下至少一项：
    所述软段的羟基值为10～500mg KOH/g；
    优选地，所述软段的羟基值为50～300mg KOH/g；
    进一步优选地，所述软段的羟基值为100～250mg KOH/g；
    所述C 2-6多元醇为甘油；
    所述软段来源于植物油；
    优选地，所述植物油选自桐油、亚麻仁油、豆油、棉籽油、蓖麻油、脱水蓖麻油、椰子油中一种或两种以上；
    进一步优选地，所述植物油为蓖麻油。
  7. 如权利要求5所述的可注射的聚氨酯，其特征是：所述脂肪族二异氰酸酯选自异佛尔酮二异氰酸酯、赖氨酸二异氰酸酯、4,4'-二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯中一种或两种以上；优选地，所述脂肪族二异氰酸酯为异佛尔酮二异氰酸酯。
  8. 如权利要求5所述的可注射的聚氨酯，其特征是：所述预聚体满足以下至少一项：
    脂肪族二异氰酸酯中异氰酸酯基：软段中羟基的摩尔比为(1.2～3.0):1；
    优选地，脂肪族二异氰酸酯中异氰酸酯基：软段中羟基的摩尔比为(1.5～2.0):1；
    所述催化剂为含锡催化剂；
    优选地，所述催化剂选自二丁基锡二月桂酸酯、辛酸亚锡、氯化亚锡中一种或两种以上；
    进一步优选地，所述催化剂为二丁基锡二月桂酸酯或辛酸亚锡；
    所述催化剂质量为软段和脂肪族二异氰酸酯总质量的0.02～0.05％；
    所述扩链剂选自多元醇、二元胺或其混合物；
    优选地，所述扩链剂选自1,4-丁二醇、1,6-己二醇、甘油、乙二胺、2,2-二羟甲基丙酸、聚乙二醇中一种或两种以上；
    进一步地，所述扩链剂选自2,2-二羟甲基丙酸、1，4-丁二醇、乙二胺、聚乙二醇中一种或两种以上；
    优选地，所述聚乙二醇的分子量为200～2000；
    进一步优选地，所述聚乙二醇的分子量为400～1000；所述扩链剂质量为软段的2～6％；
    所述预聚体的黏度为1000～20000mPa·s；
    优选地，所述预聚体的黏度为2000～15000mPa·s；
    进一步优选地，所述预聚体的黏度为2000～10000mPa·s；
    更优选地，所述预聚体的黏度为8400mPa·s。
  9. 如权利要求5所述的可注射的聚氨酯，其特征是：所述预聚体由下述方法制备得到：在保护气氛下，取所述软段与脂肪族二异氰酸酯共混反应，加入催化剂继续反应，再加入扩链剂反应，即得预聚体。
  10. 如权利要求9所述的可注射的聚氨酯，其特征是：满足以下至少一项：
    保持温度于40～90℃反应；
    优选地，保持温度于50～80℃反应；
    所述共混反应的时间为1～12h；
    优选地，所述共混反应的时间为4～6h；
    加入催化剂后反应0.5～4h；
    加入扩链剂后反应0.5～10h；
    优选地，加入扩链剂后反应20min～5h。
  11. 如权利要求5所述的可注射的聚氨酯，其特征是：所述固化剂满足以下至少一项：
    所述固化剂的质量为预聚体的0.1～1％；
    所述催化剂为含锡催化剂；
    优选地，所述催化剂选自二丁基锡二月桂酸酯、辛酸亚锡、氯化亚锡中一种或两种以上；
    进一步优选地，所述催化剂为二丁基锡二月桂酸酯或辛酸亚锡；
    还含有叔胺；
    所述叔胺选自N,N-二甲基环己胺、双(2-二甲氨基乙基)醚、N,N,N',N'-四甲基亚烷基二胺、三乙醇胺、二甲基乙醇胺中一种或两种以上；
    进一步优选地，所述叔胺为三乙醇胺；
    叔胺：催化剂的质量比为(0.5:1)～(4:1)；
    优选地，叔胺：催化剂的质量比为(0.8:1)～(3:1)。
  12. 如权利要求5～11任意一项所述的可注射的聚氨酯，其特征是：还含有功能性成分；优选地，所述功能性成分选自磷灰石、生物玻璃、抗菌剂、X射线阻射剂中一种或两种以上；优选地，含有占所述聚氨酯总质量5～40％的磷灰石和/或生物玻璃；进一步优选地，含有占所述聚氨酯总质量5～30％的磷灰石和/或生物玻璃；优选地，含有占所述聚氨酯总质量1～10％的抗菌剂；进一步优选地，含有占所述聚氨酯总质量3～8％的抗菌剂；优选地，含有占所述聚氨酯总质量3～20％的X射线阻射剂；进一步优选地，含有占所述聚氨酯总质量5～15％的氧化锆或氧化铋；最优选地，含有占所述聚氨酯总质量5～15％的氧化铋。
  13. 权利要求5～12任意一项所述可注射的聚氨酯的制备方法，其特征是：取预聚体，加入或不加入功能性成分，与固化剂混合，即可，所得可注射的聚氨酯可于室温固化。
PCT/CN2018/118990 2018-07-17 2018-12-03 可注射的聚氨酯及其制备方法 WO2020015276A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780867A (zh) * 2003-04-25 2006-05-31 陶氏环球技术公司 植物油基多元醇以及由它制造的聚氨酯
CN102741309A (zh) * 2008-06-12 2012-10-17 陶氏环球技术有限责任公司 基于天然油的多元醇的多元醇预聚物
CN103013094A (zh) * 2012-12-19 2013-04-03 四川大学 可注射型快速固化医用聚氨酯组合物及制备方法
CN107365408A (zh) * 2017-09-06 2017-11-21 厦门厦广安工贸有限公司 篦麻油基聚氨酯树脂及其制作

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3341272B2 (ja) * 1994-09-29 2002-11-05 日本ポリウレタン工業株式会社 二液型ポリウレタン結束材
JP3191610B2 (ja) * 1994-10-19 2001-07-23 日本ポリウレタン工業株式会社 ポリウレタン樹脂組成物並びに該組成物を用いた接着剤、シール剤及び結束剤
EP2195358A4 (en) * 2007-09-05 2012-12-19 Univ Vanderbilt ANTIBIOTIC RELEASE FROM BIODEGRADABLE POLYURETHANE INJECTABLE TUMORS FOR BETTER CONSOLIDATION OF BONE FRACTURES
US20100068171A1 (en) * 2008-05-27 2010-03-18 Vanderbilt University Injectable bone/polymer composite bone void fillers
ITTO20120669A1 (it) * 2012-07-27 2012-10-26 Torino Politecnico Poliuretani anfifilici termosensibili e soluzione acquosa iniettabile a base di tale materiale.
EP3368086A4 (en) * 2015-10-31 2019-12-04 Dermalink Technologies, Inc. SKIN ADHESIVES, ANTIMICROBIAL COMPOSITIONS, ARTICLES AND METHODS OF USE THEREOF
CN105999373B (zh) * 2016-05-30 2019-08-16 拓睿美（北京）医疗科技有限公司 一种聚氨酯/小肠粘膜下层(pu/sis)双组份可注射水凝胶
CN106632957A (zh) * 2016-09-20 2017-05-10 四川大学 自修复水性聚氨酯预聚物及其分散液和用途
CN107189746B (zh) * 2017-06-15 2020-06-23 广东药科大学 一种活性聚氨酯医用胶黏剂及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780867A (zh) * 2003-04-25 2006-05-31 陶氏环球技术公司 植物油基多元醇以及由它制造的聚氨酯
CN102741309A (zh) * 2008-06-12 2012-10-17 陶氏环球技术有限责任公司 基于天然油的多元醇的多元醇预聚物
CN103013094A (zh) * 2012-12-19 2013-04-03 四川大学 可注射型快速固化医用聚氨酯组合物及制备方法
CN107365408A (zh) * 2017-09-06 2017-11-21 厦门厦广安工贸有限公司 篦麻油基聚氨酯树脂及其制作

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG, LIBO ET AL.: "Thermoplastic Polyester Elastomer with Controllable Microstructure and Biodegradability", SCIENCE CHINA, vol. 46, no. 6, 31 December 2016 (2016-12-31), pages 579 - 585 *

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