WO2024060897A1 - 生物相容性聚碳酸酯聚氨酯及其制备方法和应用 - Google Patents

生物相容性聚碳酸酯聚氨酯及其制备方法和应用 Download PDF

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WO2024060897A1
WO2024060897A1 PCT/CN2023/113659 CN2023113659W WO2024060897A1 WO 2024060897 A1 WO2024060897 A1 WO 2024060897A1 CN 2023113659 W CN2023113659 W CN 2023113659W WO 2024060897 A1 WO2024060897 A1 WO 2024060897A1
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polyurethane
biocompatible
amino
terminated
polycarbonate
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PCT/CN2023/113659
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English (en)
French (fr)
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程荣恩
钱成
刘佳梅
周静
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苏州百孝医疗科技有限公司
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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
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—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
    • 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
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C08G18/12—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step using two or more compounds having active hydrogen in the first polymerisation step
    • 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
    • C08G18/44—Polycarbonates
    • 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
    • C08G18/61—Polysiloxanes
    • 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
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6633—Compounds of group C08G18/42
    • C08G18/6637—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6648—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38
    • C08G18/6651—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38 with compounds of group C08G18/3225 or polyamines of C08G18/38
    • 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
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • C08G18/7657—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings
    • C08G18/7664—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups
    • C08G18/7671—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups containing only one alkylene bisphenyl group
    • 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
    • C08G18/83—Chemically modified polymers
    • C08G18/836—Chemically modified polymers by phosphorus containing compounds

Definitions

  • This application belongs to the field of medical polymer materials, and specifically relates to a biocompatible polycarbonate polyurethane and its preparation method and application.
  • Polyurethane (PU) is mainly obtained through the addition reaction of a diisocyanate composition and polyether or polyester polyol as basic raw materials. It was produced by Otto Bayer and others in 1937.
  • Polyurethane materials have been widely used in artificial organs, interventional catheters, trauma dressings, medical adhesives, etc. due to their excellent mechanical properties, fatigue resistance, biocompatibility and processability.
  • Polyurethane materials have the advantages of simple synthesis, designable molecular structure and good stability, and are widely used in the field of biomedical materials.
  • Polycarbonate polyurethane materials have better stability and biocompatibility than other types of polyurethane materials. sex.
  • polycarbonate diol (PCDL) has the best comprehensive properties, and research on the degradability and blood compatibility of polycarbonate polyurethane materials prepared from it has attracted much attention.
  • Polyurethane materials also have corresponding applications in the field of implantable medical devices used to determine the presence and concentration of biological analytes.
  • polyurethane mainly exists in the form of films, and its main function is to take advantage of its excellent biocompatibility.
  • the polyurethane film can be selectively permeable to control the diffusion of biological analytes such as glucose, lactic acid, uric acid, ⁇ -hydroxybutyric acid, etc. , thereby further completing electrochemical detection.
  • Conventional polyurethanes are all linear polyurethanes.
  • Polyurethane films obtained through modification and/or physical doping have poor stability and poor reproducibility. With long-term storage, they will be accompanied by certain molecular migration, resulting in The properties of the polyurethane film change, causing deviations in test results.
  • the present application provides a biocompatible polycarbonate polyurethane, which has good biocompatibility and performance stability.
  • this application provides a biocompatible polycarbonate polyurethane, which includes the reaction product of the directional polymerization of the following raw material components:
  • isocyanate-reactive group-containing component which isocyanate-reactive group-containing component is selected from polycarbonate polyols;
  • chain extender is selected from trifunctional or higher functional polyamines, trifunctional or higher functional polyhydroxy compounds, or combinations thereof;
  • a modifying component selected from the group consisting of biocompatible compounds, amino-terminated hydrophilic compounds, or combinations thereof, and
  • the polyurethane segment obtained after the reaction of (a), (b) and (d) contains active sites.
  • the active sites are located on the side chains in the polyurethane segment;
  • the active site is a reactive functional group located on a branch in the polyurethane segment, which may be an amino group and/or a hydroxyl group, for example.
  • component (a) is diisocyanate and/or polyisocyanate, specifically selected from toluene diisocyanate, diphenylmethane diisocyanate, isophorone diisocyanate Isocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate, naphthalene diisocyanate, terephthalene diisocyanate, lysine diisocyanate, 1,4-cyclohexane diisocyanate, methylcyclohexyl diisocyanate, norborneol Alkane diisocyanate, tetramethylisoxylylene diisocyanate, cyclohexane dimethylene diisocyanate, trimethyl-1,6-hexamethylene diisocyanate or xylylene diisocyanate One or a combination of at least two.
  • the isocyanate composition in component (a) can also be selected from the derivatives of the above isocyanates, specifically 4,4'-methylenebis(phenyl isocyanate), dicyclohexylmethane 4,4'-diisocyanate or 4,4'-diphenylmethane diisocyanate.
  • component (b) is polycarbonate diol, specifically selected from polycarbonate 1,6-hexanediol diol, polyhexylene carbonate Diol, polycaprolactone carbonate diol, polybutylene carbonate diol, polycarbonate cyclohexanedimethanol-1,6-hexanediol ester diol, polycarbonate 1,5-pentanediol-1 ,6-hexanediol ester glycol, polyethylene carbonate glycol, polypropylene carbonate or polycarbonate One or a combination of at least two of the acid 1,4-butanediol-1,6-hexanediol ester diols.
  • the raw material component contains (c), and the (c) is selected from the group consisting of bis-hydroxyl-terminated polysiloxane and bis-amino-terminated polysiloxane.
  • component (d) is selected from tris(2-aminoethyl)amine, triethanolamine or 4,4',4"-triaminotriphenylmethane one or a combination of at least two.
  • component (e) is a biocompatible compound, specifically selected from 2-methacryloyloxyethylphosphocholine or quaternary ammonium salt.
  • component (e) is an amino-terminated hydrophilic compound, specifically an amino-terminated polyethylene glycol; more preferably, the amino-terminated The end hydrophilic compound is double-end amino-terminated polyethylene glycol; further, the prepared polycarbonate polyurethane has a network structure.
  • the raw material component contains (f), and the (f) is selected from any of glutaraldehyde, glutaric acid or carbodiimide A sort of.
  • this application provides a method for preparing the biocompatible polycarbonate polyurethane described in the first aspect, which includes the following steps:
  • separation and purification are performed after step (3).
  • the molar amount of the isocyanate group in (a) is calculated as X, and the total molar amount of hydroxyl and/or amino groups in (b) is The quantity is Y, where the ratio of X to Y is 1 ⁇ X/Y ⁇ 1.5.
  • the organic solvent described in step (1) is an organic solvent that does not contain active hydrogen groups in the molecule, specifically an inactive p-isocyanate group. , or an organic solvent whose hydrogen group activity is lower than that of the hydrogen groups in components (a), (b), (c), (d), (e), and (f).
  • the organic solvent may be, for example, a ketone solvent (acetone, methyl isobutyl ketone, etc.), an aromatic hydrocarbon Solvents (toluene, o-xylene, m-xylene, etc.), aliphatic hydrocarbon solvents (pentane, cyclopentane, methylcyclohexane, tert-hexylcyclohexane, etc.), alcoholic solvents (ethanol, tert-butanol, etc.) etc.), ether solvents (diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran), ester solvents (ethyl acetate, butyl acetate, isobutyl acetate, etc.), glycol ether ester solvents Solvent (ethylene glycol ethyl ether acetate, propylene glycol methyl ether acetate) or amide solvent (di
  • the mass ratio of the amount of organic solvent described in step (1) to the raw material components is 100: (5-20).
  • the polyurethane prepolymer B contains active amino groups and/or hydroxyl groups.
  • the content of (c) is 0-30% by weight.
  • the total molar amount of amino groups and/or hydroxyl groups in (d) is equal to the molar amount of isocyanate groups in the polyurethane prepolymer A.
  • the ratio is 0.8-1.2.
  • the content of (e) is 10-20% by weight.
  • the content of (f) is 0-10% by weight based on the weight of (e) being 100% by weight.
  • the present application provides an application of the biocompatible polycarbonate polyurethane described in the first aspect.
  • a layer of coating is formed on the surface of medical devices, especially implantable medical devices, through coating methods such as scraping, spot coating, and dipping.
  • a layer of film increases the compatibility between medical devices and living organisms.
  • the components of the biocompatible polycarbonate polyurethane include the above (a), (b), (c), (d) , (e), (f) components, the film made of them has selective permeability, for example, it can permeate biological metabolites such as glucose, lactic acid, uric acid or ⁇ -hydroxybutyric acid; or it has oxygen permeability, Can be used, for example, in the outer membrane of implantable electrochemical sensors.
  • the biocompatible polycarbonate polyurethane provided by this application can be adjusted by adjusting the types of raw material components.
  • the sensor prepared as an outer membrane has excellent in vitro test performance.
  • chain extenders By introducing polyamines and/or polyhydroxy compounds as chain extenders to extend the polycarbonate polyurethane, active sites are added to the chain segments, such as active amino groups and/or hydroxyl groups, which is beneficial to the It is further modified, for example, to increase its biocompatibility.
  • the biocompatible polycarbonate polyurethane provided by this application has added branched chains. active site for reaction.
  • Figure 1 is a photomicrograph of platelet adsorption of a polyurethane film prepared using the steps in Example 1.
  • Figure 2 is a photomicrograph of platelet adsorption of a polyurethane film prepared using the steps in Comparative Example 1.
  • Figure 3 is a response current curve of a glucose sensor prepared using the polyurethane provided in Example 2 and Comparative Example 1.
  • Figure 4 is a response curve of sensor current and oxygen content in a low-oxygen environment when the biocompatible polycarbonate polyurethane prepared in Example 3 is applied to an electrochemical sensor in a film form.
  • isocyanate reactive group in the present application refers to a group containing Zerevitinov-active hydrogen.
  • group containing Zerevitinov-active hydrogen is understood in the art to refer to a hydroxyl group (OH), a carboxyl group (COOH), and an amino group (NHx).
  • the normal temperature or room temperature mentioned in the following examples refers to the indoor temperature when the temperature is about 25°C, and the glucose solution used is glucose buffer solution (G-PBS) with different concentrations.
  • G-PBS glucose buffer solution
  • FIGS 1 and 2 show micrographs of platelet adsorption using the polyurethane film in Example 1 and Comparative Example 1, respectively. It can be clearly seen from the photo that on the basis of tris(2-aminoethyl)amine increasing the active sites of polycarbonate polyurethane, adding 2-methacryloyloxyethylphosphocholine (MPC) has a positive effect on polyurethane. Further grafting modification of carbonate polyurethane can effectively reduce the adsorption of platelets by polycarbonate polyurethane and improve the effective service life of the film layer in vivo.
  • MPC 2-methacryloyloxyethylphosphocholine
  • PRP platelet-rich plasma
  • platelet-rich plasma/physiological saline 1/4.
  • Example 2 After the polycarbonate polyurethane prepared in Example 2 and Comparative Example 1 was separated and purified, a thin film (outer film) was formed on the outer surface of the electrochemical biosensor by dip coating. Response current curve tested in .
  • the electrochemical biosensor in this embodiment is the one disclosed in the prior art (CN114767105A) A two-electrode electrochemical sensor in which the working electrode is a platinum-iridium alloy and the reference electrode is a silver/silver chloride electrode.
  • Figure 3 shows the response current curves of glucose sensors prepared using different outer membranes (Example 2 and Comparative Example 1). It can be seen that in Example 2, a polyurethane membrane modified with bis-amino-terminated polyethylene glycol is added for detection. The small molecule substance glucose has a good diffusion restriction effect, and the prepared sensor has excellent linear performance in vitro. However, the sensor prepared from the polyurethane membrane without any optimization in Comparative Example 1 has no channels for glucose diffusion and cannot be used for glucose detection.
  • the glucose diffusion channel formed by the polyurethane membrane modified with bis-amino-terminated polyethylene glycol or amino-terminated polyethylene glycol is also suitable for small molecules such as lactic acid, uric acid, and ascorbic acid.
  • the flux of small molecule diffusion can be changed by changing the amount of cross-linking agent and the amount of polyethylene glycol.
  • the electrochemical biosensor in this embodiment is a dual-electrode electrochemical sensor disclosed in the prior art (CN114767105A), in which the working electrode is a platinum-iridium alloy and the reference electrode is a silver/silver chloride electrode.
  • test method is as follows: continuously pass inert gases such as nitrogen or argon into the glucose solution (20mmol/L) in the test environment to remove the oxygen in the glucose solution, and use an oxygen analyzer for real-time Monitoring, the specific test results are shown in Figure 4.
  • inert gases such as nitrogen or argon
  • the oxygen content has almost no impact on the performance of the sensor. It can be seen that the introduction of silane into the biocompatible polycarbonate polyurethane provided by this application can also improve the oxygen permeability of the polyurethane film layer, thereby ensuring that the human body is hypoxic. In the environment (0.6-0.9mg/L), electrochemical sensors that require oxygen to participate in the reaction can also perform effective detection.
  • cross-linking agents such as glutaraldehyde, glutaric acid, and carbodiimide may be added to promote the cross-linking reaction between the components.

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Abstract

本申请提供了一种生物相容性聚碳酸酯聚氨酯及其制备方法和应用。所述生物相容性聚碳酸酯聚氨酯包括以下原料组分定向聚合的反应产物：(a)异氰酸酯组合物、(b)含异氰酸酯反应性基团组分、可选的(c)羟基或氨基封端化合物、(d)扩链剂、(e)修饰性组分和可选的(f)交联剂，其中，组分(a)、(b)和(d)反应后得到的聚氨酯链段中含有活性位点。本申请提供的生物相容性聚碳酸酯聚氨酯具有较好的生物相容性，将其作为外膜制备的传感器体外测试性能优良。

Description

生物相容性聚碳酸酯聚氨酯及其制备方法和应用 技术领域
本申请属于医用聚合物材料领域，具体涉及一种生物相容性聚碳酸酯聚氨酯及其制备方法和应用。
背景技术
聚氨酯(polyurethane，PU)主要是通过二异氰酸酯组合物与聚醚或聚酯类多元醇为基本原料通过加成反应获得，1937年由奥托·拜耳等制出此物。
聚氨酯材料以其优异的力学性能，耐疲劳性，生物相容性和可加工性在人工器官、介入导管、创伤敷料、医用粘合剂等方面得到了广泛的应用。聚氨酯材料具有合成简单、分子结构可设计性以及稳定性好等优点，被广泛应用于生物医用材料领域，而聚碳酸酯型聚氨酯材料比其他类型的聚氨酯材料具有更好的稳定性及生物相容性。在聚酯和聚醚类多元醇中，聚碳酸酯二元醇(PCDL)综合性能最为优异，由其制备的聚碳酸酯型聚氨酯材料的可降解性以及血液相容性的研究备受关注。
聚氨酯材料在用于确定生物分析物的存在和浓度的植入式医疗器械领域中也有相应的应用，在该领域中，聚氨酯主要是以薄膜的形式存在，主要作用是利用其优良的生物相容性起到保护作用，通过对聚氨酯改性和/或物理掺杂，让聚氨酯的薄膜同时具有选择透过性，实现对生物分析物如：葡萄糖、乳酸、尿酸、β-羟丁酸等扩散控制，从而进一步完成电化学检测。而常规的聚氨酯都是直链型聚氨酯，通过改性和/或物理参杂获得的聚氨酯薄膜稳定性差，重现性也比较差，并随着长时间储存，会伴随着一定的分子迁移，导致聚氨酯薄膜的性质发生变化，导致测试结果偏差。
需要指出的是，上述背景技术内容部分仅代表申请人对相关技术的理解，并不构成现有技术。
发明内容
本申请提供了一种生物相容性聚碳酸酯聚氨酯，所述聚碳酸酯聚氨酯具有较好的生物相容性和性能稳定性。
第一方面，本申请提供了一种生物相容性聚碳酸酯聚氨酯，其包括以下原料组分定向聚合的反应产物：
(a)异氰酸酯组合物，所述异氰酸酯组合物具有至少两个异氰酸酯基团的异氰酸酯；
(b)含异氰酸酯反应性基团组分，所述含异氰酸酯反应性基团组分选自聚碳酸酯多元醇；
可选的(c)，羟基或氨基封端化合物；
(d)扩链剂，所述扩链剂选自三官能团或更高官能团的多胺、三官能团或更高官能团的多羟基化合物、或其组合；
(e)修饰性组分，所述修饰性组分选自生物相容性化合物、氨基封端的亲水性化合物、或其组合，以及
可选的(f)交联剂，所述(f)不同于所述(d)；
其中，所述(a)、(b)和(d)反应后得到的聚氨酯链段中含有活性位点，作为更优选的实施方案，所述活性位点位于聚氨酯链段中的支链上；
其中，所述活性位点为位于聚氨酯链段中支链上的反应功能团，例如可以是氨基和/或羟基。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，组分(a)为二异氰酸酯和/或多异氰酸酯，具体选自甲苯二异氰酸酯、二苯基甲烷二异氰酸酯、异佛尔酮二异氰酸酯、六亚甲基二异氰酸酯、二环己基甲烷二异氰酸酯、萘二异氰酸酯、对苯二异氰酸酯、赖氨酸二异氰酸酯、1,4-环己烷二异氰酸酯、甲基环己基二异氰酸酯、降冰片烷二异氰酸酯、四甲基间苯二亚甲基二异氰酸酯、环己烷二亚甲基二异氰酸酯、三甲基-1,6-六亚甲基二异氰酸酯或苯二亚甲基二异氰酸酯中的一种或至少两种的组合。
类似地，作为优选的实施方案，组分(a)中异氰酸酯组合物还可以选自上述异氰酸酯的衍生物，具体为4,4'-亚甲基双(异氰酸苯酯)、二环己甲烷4,4'-二异氰酸酯或4,4'-二苯甲烷二异氰酸酯等。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，组分(b)为聚碳酸酯二醇，具体选自聚碳酸1,6-己二醇酯二醇、聚碳酸亚己酯二醇、聚碳酸己内酯亚己酯二醇、聚碳酸亚丁酯二醇、聚碳酸环己烷二甲醇-1,6-己二醇酯二醇、聚碳酸1,5戊二醇-1,6-己二醇酯二醇、聚碳酸亚乙酯二醇、聚碳酸亚丙二醇或聚碳 酸1,4丁二醇-1,6-己二醇酯二醇中的一种或至少两种的组合。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，所述原料组分中包含(c)，所述(c)选自双羟基封端聚硅氧烷、双氨基封端聚硅氧烷或两种的组合；所述(c)的分子量为1000-6000Da，优选为1500-3000Da。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，组分(d)选自三(2-氨基乙基)胺、三乙醇胺或4,4',4"-三氨基三苯甲烷中的一种或至少两种的组合。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，组分(e)为生物相容性化合物，具体选自2-甲基丙烯酰氧乙基磷酸胆碱或季铵盐。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，组分(e)为氨基封端的亲水性化合物，具体为端氨基封端聚乙二醇；更优选地，所述氨基封端的亲水性化合物为双端氨基封端聚乙二醇；进一步地，所制备的聚碳酸酯聚氨酯具有网络结构。
根据本申请提供的生物相容性聚碳酸酯聚氨酯，优选地，所述原料组分中包含(f)，所述(f)选自戊二醛、戊二酸或碳二亚胺中的任意一种。
第二方面，本申请提供了一种第一方面所述的生物相容性聚碳酸酯聚氨酯的制备方法，其包括如下步骤：
(1)通过使所述(a)、(b)和可选的(c)在有机溶剂中反应形成异氰酸酯封端的聚氨酯预聚体A；
(2)用所述(d)使所述聚氨酯预聚体A扩链得到聚氨酯预聚体B；
(3)用所述(e)和可选的(f)修饰所述聚氨酯预聚体B；以及
可选的，所述步骤(3)后进行分离提纯。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，所述(a)中的异氰酸酯基团摩尔量计为X，所述(b)中的羟基和/或氨基摩尔总量计为Y，其中，X与Y的比值为1<X/Y≤1.5。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，步骤(1)中所述的有机溶剂为分子内不含有活性氢基的有机溶剂，具体为非活性的对异氰酸酯基、或者氢基活性低于组分(a)、(b)、(c)、(d)、(e)、(f)中氢基的有机溶剂。
所述有机溶剂例如可以是，酮系溶剂(丙酮、甲基异丁基酮等)、芳族系烃 溶剂(甲苯、邻二甲苯、间二甲苯等)、脂肪族系烃溶剂(戊烷、环戊烷、甲基环己烷、叔己基环己烷等)、醇系溶剂(乙醇、叔丁醇等)、醚系溶剂(二乙基醚、叔丁基甲基醚、四氢呋喃、2-甲基四氢呋喃)、酯系溶剂(乙酸乙酯、乙酸丁酯、乙酸异丁酯等)、二醇醚酯系溶剂(乙二醇乙基醚乙酸酯、丙二醇甲基醚乙酸酯)或酰胺系溶剂(二甲基甲酰胺、N,N-二甲基甲酰胺、二甲基乙酰胺、N-甲基-2-吡咯烷酮等)。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，步骤(1)所述有机溶剂的用量与原料组分的质量比100:(5-20)。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，所述聚氨酯预聚体B含有活性氨基和/或羟基。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，以聚氨酯预聚体A的重量为100重量％计，所述(c)的含量为0-30重量％。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，所述(d)中氨基和/或羟基的摩尔总量与所述聚氨酯预聚体A中异氰酸酯基团的摩尔量比值为0.8-1.2。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，以聚氨酯预聚体B的重量为100重量％计，所述(e)的含量为10-20重量％。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的制备方法，优选地，以(e)的重量为100重量％计，所述(f)的含量为0-10重量％。
第三方面，本申请提供了一种第一方面所述的生物相容性聚碳酸酯聚氨酯的应用。例如，将经过分离提纯后的生物相容性聚碳酸酯聚氨酯溶于有机溶剂后，通过刮涂、点涂、浸渍等涂布方式，在医疗器械，尤其是植入式医疗器械的表面形成一层薄膜，增加了医疗器械与生物体的相容性。
根据本申请提供的生物相容性聚碳酸酯聚氨酯的应用，优选地，所述生物相容性聚碳酸酯聚氨酯的组分中包含上述(a)、(b)、(c)、(d)、(e)、(f)组分，将其制成的薄膜具有选择透过性，例如可以透过葡萄糖、乳酸、尿酸或β-羟丁酸等生物体代谢产物；或者具有透氧性，可用于例如植入式电化学传感器的外膜。
相对于现有技术，本申请具有如下的有益效果：
(1)本申请提供的生物相容性聚碳酸酯聚氨酯，通过调整原料组分的种类 来实现定向聚合，将其作为外膜制备的传感器体外测试性能优良。
(2)通过引入多胺和/或多羟基化合物等作为扩链剂来对聚碳酸酯聚氨酯进行扩链，在其链段上增加了活性位点，例如活性氨基和/或羟基，有利于对其进一步改性，例如，增加其生物相容性。
(3)有别于现有技术中以异氰酸酯为刚性链段、聚醚/聚酯二醇为柔性链段的直链型聚氨酯，本申请提供的生物相容性聚碳酸酯聚氨酯增加了支链反应的活性位点。
附图说明
图1为采用实施例1中步骤方法制备的聚氨酯膜的血小板吸附显微照片。
图2为采用对比例1中步骤方法制备的聚氨酯膜的血小板吸附显微照片。
图3为采用实施例2和对比例1提供的聚氨酯制备的葡萄糖传感器的响应电流曲线。
图4为将实施例3制备的生物相容性聚碳酸酯聚氨酯以薄膜状应用于电化学传感器，在低氧环境中传感器电流与氧含量的响应曲线。
具体实施方式
为了能够详细地理解本申请的技术特征和内容，下面将更详细地描述本申请的优选实施方式。虽然实施例中描述了本申请的优选实施方式，然而应该理解，可以以各种形式实现本申请而不应被这里阐述的实施方式所限制。本申请下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。
除非另有定义，本申请所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本申请。
本申请的术语“异氰酸酯反应性基团”是指含Zerevitinov-活性氢的基团，通常，含Zerevitinov-活性氢的基团在本领域中被理解为是指羟基(OH)、羧基(COOH)、氨基(NHx)。
本申请的术语“可选的”是指在某些方案中，可以选择该原料组分或步骤；在其他方案中，可以不选择该原料组分或步骤。
本申请的术语“和/或”，是指描述关联对象的关联关系，表示可以存在三种 关系，例如，A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
以下实施例中所涉及的常温或室温指温度为25℃左右时的室内温度，所采用的葡萄糖溶液为不同浓度的葡萄糖缓冲液(G-PBS)。
以下结合具体实施例来详细说明本申请。
实施例1
具体步骤如下：
(1)在常温下，取经除水除氧的聚碳酸1,6-己二醇酯二醇4g溶于50mLN,N-二甲基甲酰胺中；升温至40-60℃，备用；
(2)在常温下，取4,4'-二苯甲烷二异氰酸酯0.6g溶于50mL N,N-二甲基甲酰胺中；将其缓慢加入到步骤(1)的聚碳酸1,6-己二醇酯二醇溶液中，持续反应，得到预聚体A；
(3)向预聚体A中加入三(2-氨基乙基)胺0.105mL，升温至70-90℃，持续反应，得到预聚体B；
(4)向预聚体B中加入2-甲基丙烯酰氧乙基磷酸胆碱(MPC)0.071g，降温至40-50℃，持续至反应结束。
对比例1
具体步骤如下：
(1)在常温下，取经除水除氧的聚碳酸1,6-己二醇酯二醇4g溶于50mLN,N-二甲基甲酰胺中；升温至40-60℃，备用；
(2)在常温下，取4,4'-二苯甲烷二异氰酸酯0.6g溶于50mL N,N-二甲基甲酰胺中；将其缓慢加入到步骤(1)的聚碳酸1,6-己二醇酯二醇溶液中，持续反应，得到预聚体A；
(3)向预聚体A中加入2-甲基丙烯酰氧乙基磷酸胆碱(MPC)0.071g，降温至40-50℃，持续至反应结束。
将按照上述步骤方法制备的聚氨酯经分离提纯后、通过刮涂的方式形成的聚氨酯膜，图1和图2分别示出了利用实施例1和对比例1中聚氨酯膜的血小板吸附显微照片，从照片中可以清楚的看出，在三(2-氨基乙基)胺增加了聚碳酸酯聚氨酯活性位点基础上，再增加2-甲基丙烯酰氧乙基磷酸胆碱(MPC)对聚碳酸酯聚氨酯进一步接枝修饰，可以有效的减少聚碳酸酯聚氨酯对血小板的吸附，能够提高该膜层在体内应用有效使用寿命。
血小板吸附实验步骤及参数如下：取健康人血，加入浓度为3.8％的柠檬酸钠作为抗凝剂，在1000r/min的速率下离心10min，收集上层富血小板血浆(PRP)，用生理盐水稀释(富血小板血浆/生理盐水＝1/4.5)，然后将膜样品(1cm×1cm)置于上述稀释液中，37℃恒温0.5h。样品取出后用磷酸盐缓冲液(PBS，pH＝7.4)冲洗3次，在4℃下用浓度为2％的戊二醛溶液固定。固定24h取出后室温干燥，在DMBA400型光学显微镜(Motic)下观察血小板的吸附情况，并采用显微摄影技术对粘附的血小板进行统计计数。
实施例2
具体步骤如下：
(1)在常温下，取经除水除氧的聚碳酸1,6-己二醇酯二醇4g溶于50mLN,N-二甲基甲酰胺中；升温至40-60℃，备用；
(2)在常温下，取4,4'-二苯甲烷二异氰酸酯0.6g溶于50mL N,N-二甲基甲酰胺中；将其缓慢加入到步骤(1)的聚碳酸1,6-己二醇酯二醇溶液中，持续反应，得到预聚体A；
(3)向预聚体A中加入三(2-氨基乙基)胺0.176mL，升温至70-90℃，持续反应，得到预聚体B；
(4)向预聚体B中加入2-甲基丙烯酰氧乙基磷酸胆碱0.071g，降温至40-50℃，得到预聚体C。
(5)向预聚体C中加入双氨基封端聚乙二醇0.36g，至40-50℃，反应至结束。
将实施例2和对比例1中制得的聚碳酸酯聚氨酯经分离提纯后，通过浸涂的方式，在电化学生物传感器的外表面形成一层薄膜(外膜)，在不同浓度的葡萄糖溶液中进行测试的响应电流曲线。
本实施例中的电化学生物传感器为现有技术中(CN114767105A)所公开的 双电极电化学传感器，其中工作电极为铂铱合金，参比电极为银/氯化银电极。
图3示出利用不同的外膜(实施例2和对比例1)制备的葡萄糖传感器的响应电流曲线，可见，实施例2中增加经过双氨基封端聚乙二醇修饰过聚氨酯膜对需要检测的小分子物质葡萄糖有很好的限制扩散作用，制备的传感器体外线性性能优良。而对比例1中未经任何优化的聚氨酯膜制备的传感器没有葡萄糖扩散的通道，不能用于葡萄糖的检测。
在其他一些实施例中，经过双氨基封端聚乙二醇或氨基封端聚乙二醇修饰过聚氨酯膜所形成的葡萄糖扩散通道同样是适用于乳酸、尿酸、抗坏血酸等小分子。在其他一些实施例中，可以通过改变的交联剂用量及聚乙二醇的量可以改变小分子扩散的通量。
实施例3
具体步骤如下：
(1)在常温下，取经除水除氧的聚碳酸1,6-己二醇酯二醇2g溶于20mLN,N-二甲基甲酰胺中；升温至40-60℃，备用；
(2)在常温下，取双(3-氨丙基)封端的聚(二甲基硅氧烷)5g溶于30mL N,N-二甲基甲酰胺中，并加入到步骤(1)的聚碳酸1,6-己二醇酯二醇溶液中；
(3)在常温下，取4,4'-二苯甲烷二异氰酸酯0.75g溶于50mL N,N-二甲基甲酰胺中；将其缓慢加入到步骤(2)溶液中，持续反应，得到预聚体A；
(4)向预聚体A中加入三(2-氨基乙基)胺0.131mL，升温至70-90℃，持续反应，得到预聚体B；
(5)向预聚体B中加入2-甲基丙烯酰氧乙基磷酸胆碱0.088g，降温至40-50℃，得到预聚体C。
(6)向预聚体C中加入双氨基封端聚乙二醇0.45g，至40-50℃，反应至结束；
将上述制得的聚碳酸酯聚氨酯经分离提纯后，通过浸涂的方式，在电化学生物传感器的表面形成一层薄膜，在20mmol/L的葡萄糖溶液中进行测试。
本实施例中的电化学生物传感器为现有技术中(CN114767105A)所公开的双电极电化学传感器，其中工作电极为铂铱合金，参比电极为银/氯化银电极。
测试方法如下：在测试环境中向葡萄糖溶液(20mmol/L)中不断通入氮气或者氩气等惰性气体，以清除葡萄糖溶液中的氧气，并用氧气分析仪进行实时 监测，具体测试结果如图4所示。
参见图4，氧含量对的传感器的性能几乎没有影响，可见在本申请提供的生物相容性聚碳酸酯聚氨酯中引入硅烷，还可以提高聚氨酯膜层的透氧性，从而保证在人体低氧环境中(0.6-0.9mg/L)，需要氧气参与反应的电化学传感器还可以进行有效检测。
在其他实施例中，在实施例3的基础上，可以增加例如戊二醛、戊二酸、碳二亚胺之类交联剂，促进各组分之间的交联反应。
虽然已经描述了某些实施方案，但是这些实施方案仅作为示例呈现，并且不旨在限制保护范围。实际上，本申请中所公开的各特征和属性可以不同方式组合以形成另外的实施方案，所有这些都落入本申请的范围内。
尽管本申请提供了某些优选的实施方案和应用，但是对于本领域普通技术人员显而易见的其他实施方案，包括不提供本文所述的所有特征和优点的实施方案，也在本申请的范围内。

Claims (15)

  1. 一种生物相容性聚碳酸酯聚氨酯，其包括以下原料组分定向聚合的反应产物：
    (a)异氰酸酯组合物，所述异氰酸酯组合物为具有至少两个异氰酸酯基团的异氰酸酯；
    (b)含异氰酸酯反应性基团组分，所述含异氰酸酯反应性基团组分选自聚碳酸酯多元醇、聚碳酸酯多元胺、聚碳酸酯多元酸或其组合；
    可选的(c)，羟基或氨基封端化合物；
    (d)扩链剂，所述扩链剂选自三官能团或更高官能团的多胺、三官能团或更高官能团的多羟基化合物、或其组合，
    (e)修饰性组分，所述修饰性组分选自生物相容性化合物、氨基封端的亲水性化合物或其组合，以及
    可选的(f)交联剂，所述(f)不同于所述(d)；
    其中，所述(a)、(b)和(d)反应后得到的聚氨酯链段中含有活性位点。
  2. 根据权利要求1所述的生物相容性聚碳酸酯聚氨酯，其中，所述原料组分中包含所述(c)，所述(c)选自双羟基封端聚硅氧烷、双氨基封端聚硅氧烷或两种的组合。
  3. 根据权利要求1所述的生物相容性聚碳酸酯聚氨酯，其中，所述(d)选自三(2-氨基乙基)胺、三乙醇胺、4,4',4"-三氨基三苯甲烷、四乙胺中的一种或至少两种的组合。
  4. 根据权利要求1所述的生物相容性聚碳酸酯聚氨酯，其中，所述(e)选自所述生物相容性化合物，所述生物相容性化合物选自2-甲基丙烯酰氧乙基磷酸胆碱或季铵盐。
  5. 根据权利要求1所述的生物相容性聚碳酸酯聚氨酯，其中，所述(e)选自所述氨基封端的亲水性化合物，所述氨基封端的亲水性化合物为端氨基封端聚乙二醇或双端氨基封端聚乙二醇。
  6. 根据权利要求5所述的生物相容性聚碳酸酯聚氨酯，其中，所述(e)为双端氨基封端聚乙二醇，所述聚碳酸酯聚氨酯具有网络结构。
  7. 根据权利要求1所述的生物相容性聚碳酸酯聚氨酯，其中，所述原料组分中包含所述(f)，所述(f)选自戊二醛、戊二酸或碳二亚胺中的任意一种。
  8. 如权利要求1-7中任一项所述生物相容性聚碳酸酯聚氨酯的制备方法， 其包括如下步骤：
    (1)通过使所述(a)、所述(b)和可选的所述(c)在有机溶剂中反应形成异氰酸酯封端的聚氨酯预聚体A；
    (2)用所述(d)使所述聚氨酯预聚体A扩链得到聚氨酯预聚体B；
    (3)用所述(e)和可选的所述(f)修饰所述聚氨酯预聚体B；以及
    可选的，所述步骤(3)后进行分离提纯。
  9. 根据权利要求8所述的制备方法，其中，所述(a)中的异氰酸酯基团摩尔量计为X，所述(b)中的羟基和/或氨基摩尔总量计为Y，其中，X与Y的比值为1<X/Y≤1.5。
  10. 根据权利要求8所述的制备方法，其中，所述聚氨酯预聚体B含有活性氨基和/或羟基。
  11. 根据权利要求8所述的制备方法，其中，相对于所述聚氨酯预聚体A的重量为100重量％计，所述(c)的含量为0-30重量％。
  12. 根据权利要求8所述的制备方法，其中，所述(d)中氨基和/或羟基的摩尔总量与所述聚氨酯预聚体A中异氰酸酯基团的摩尔量比值为0.8-1.2。
  13. 根据权利要求8所述的制备方法，其中，相对于所述聚氨酯预聚体B的重量为100重量％计，所述(e)的含量为10-20重量％。
  14. 根据权利要求8所述的制备方法，其中，相对于所述(e)的重量为100重量％计，所述(f)的含量为0-10重量％。
  15. 如权利要求1-7中任一项所述生物相容性聚碳酸酯聚氨酯的应用，其中，所述聚碳酸酯聚氨酯以薄膜状应用于植入式医疗器械。
PCT/CN2023/113659 2022-09-19 2023-08-18 生物相容性聚碳酸酯聚氨酯及其制备方法和应用 WO2024060897A1 (zh)

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