CN118388790B - A production process of thermoplastic polyurethane material for medical use - Google Patents
A production process of thermoplastic polyurethane material for medical use Download PDFInfo
- Publication number
- CN118388790B CN118388790B CN202410675871.7A CN202410675871A CN118388790B CN 118388790 B CN118388790 B CN 118388790B CN 202410675871 A CN202410675871 A CN 202410675871A CN 118388790 B CN118388790 B CN 118388790B
- Authority
- CN
- China
- Prior art keywords
- stirring
- polyurethane material
- thermoplastic polyurethane
- barium sulfate
- heparin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000004433 Thermoplastic polyurethane Substances 0.000 title claims abstract description 29
- 229920002803 thermoplastic polyurethane Polymers 0.000 title claims abstract description 29
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical group OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 28
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- 229920005749 polyurethane resin Polymers 0.000 claims abstract description 16
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims abstract description 13
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims abstract description 13
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Classifications
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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
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
-
- 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
-
- 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
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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
- C08G18/65—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
- C08G18/6659—Compounds of group C08G18/42 with compounds of group C08G18/34
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- 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
- C08K3/30—Sulfur-, selenium- or tellurium-containing compounds
-
- 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
- C08K9/00—Use of pretreated ingredients
- C08K9/04—Ingredients treated with organic substances
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- 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
- C08K9/00—Use of pretreated ingredients
- C08K9/08—Ingredients agglomerated by treatment with a binding agent
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- 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
- C08K3/30—Sulfur-, selenium- or tellurium-containing compounds
- C08K2003/3045—Sulfates
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
本发明公开了一种医疗用热塑性聚氨酯材料的生产工艺，属于医疗材料技术领域，先制备出一种聚氨酯树脂，其为带有羧基的聚碳酸酯型聚氨酯，发挥出聚碳酸酯型聚氨酯本身优异性能的同时引入了羧基，在4‑二甲氨基吡啶和二异丙基碳二亚胺的作用下羧基能够与肝素结构上的羟基反应进而能够将肝素接枝在材料表面，进而能够赋予该聚氨酯材料抗凝血效果，相比较现有的通过涂层方式涂覆游离的肝素，本申请以化学键合的方式接枝肝素，使得肝素结构与聚氨酯材料结合更加牢固，能够通过抗凝血酶Ⅲ介导的途径阻碍凝血酶的初始接触激活,因此具有更好的抗凝性能。The invention discloses a production process of a thermoplastic polyurethane material for medical use, belonging to the technical field of medical materials. A polyurethane resin is first prepared, which is a polycarbonate polyurethane with a carboxyl group. The carboxyl group is introduced while the excellent performance of the polycarbonate polyurethane itself is brought into play. Under the action of 4-dimethylaminopyridine and diisopropylcarbodiimide, the carboxyl group can react with the hydroxyl group on the heparin structure and then the heparin can be grafted on the surface of the material, thereby giving the polyurethane material an anticoagulant effect. Compared with the existing coating method of free heparin, the present invention grafts heparin in a chemically bonded manner, so that the heparin structure is more firmly combined with the polyurethane material, and the initial contact activation of thrombin can be hindered through the antithrombin III-mediated pathway, thereby having better anticoagulant performance.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a production process of a thermoplastic polyurethane material for medical use.
Background
With the development of medical science, materialology, biology, chemistry and other subjects, medical polymer materials are widely applied in the biomedical field; firstly, the high polymer material has excellent mechanical property and chemical stability, and is very suitable for medical use; and the polymer material has wide sources and low price, is suitable for being made into disposable medical supplies, and solves the problems of disinfection and cross infection caused by the fact that the traditional material products have to be used for many times due to high price.
Polyurethane (PU) is applied to materials for producing medical catheters for a long time, has stable chemical properties and good biocompatibility with low toxicity, no distortion effect and the like; meanwhile, the polyurethane material has good physical properties, easy processing of products and good product quality, so the polyurethane material has wide application in the medical field, can keep long-term stability of human implantation, can also be used on the production material of the indwelling needle, but the polyurethane has certain tissue compatibility and blood compatibility, and still can not completely meet the requirements of clinical practical application; for example, long term implantation of polyurethane medical articles in the body is prone to cause inflammatory reactions in the body, which inevitably produce varying degrees of clotting upon direct contact with blood; in addition, polyurethane medical insertion or implantation products may also be accompanied with problems such as bacterial infection, body injury, etc.
Disclosure of Invention
In order to solve the technical problems, the invention provides a production process of a thermoplastic polyurethane material for medical treatment.
The aim of the invention can be achieved by the following technical scheme:
A production process of a thermoplastic polyurethane material for medical treatment comprises the following steps:
firstly, adding polyhexamethylene carbonate dihydric alcohol into a flask, introducing nitrogen, heating to 75 ℃ and stirring at a constant speed until the mixture is melted, adding isophorone diisocyanate, preserving heat and magnetically stirring for 3 hours to obtain a prepolymer, then adding dimethyl carbonate to reduce the viscosity, continuously stirring and reacting for 1 hour, cooling to 60 ℃, adding dibutyl tin dilaurate and 2, 2-bis (hydroxymethyl) propionic acid, continuously stirring and reacting for 3 hours to obtain polyurethane resin, and controlling the dosage ratio of the polyhexamethylene carbonate dihydric alcohol to the isophorone diisocyanate to the dimethyl carbonate to the 2, 2-bis (hydroxymethyl) propionic acid to be 10-15 g:4-5 mL:25-30 mL:1.5-2 mL, wherein the dosage of the dibutyl tin dilaurate is 0.1-0.3% of the weight of the polyhexamethylene carbonate dihydric alcohol;
In the first step, poly (hexamethylene carbonate) dihydric alcohol is used as a soft segment, isophorone diisocyanate is used as a hard end, 2-bis (hydroxymethyl) propionic acid is used as a chain extender, and polycarbonate polyurethane is prepared under the action of a catalyst dibutyl tin dilaurate, the hydrogen bond between the poly (hexamethylene carbonate) dihydric alcohol and the hard segment is strong, the crystallization degree is high, so that the poly (hexamethylene carbonate) dihydric alcohol has better hydrolysis resistance, and compared with the existing polyether polyurethane carbonate group, the conjugation and molecular chain rigidity are higher than those of ether groups, the poly (hexamethylene carbonate) has better oxidation resistance, the complex water environment in a human body can be prevented from causing the oxidative degradation caused by uncontrollable hydrolysis of a thermoplastic polyurethane molecular chain, H + released by macrophages, enzyme, in-vivo free radical and other oxidation mediums, and a carboxyl structure is introduced, so that the next grafting reaction is facilitated;
Secondly, mixing the prepared polyurethane resin and modified barium sulfate, and then feeding the mixture into a double-screw extruder for extrusion and granulation to obtain a sample, wherein the rotating speed of a screw is controlled to be 100r/min, the extrusion temperature is 195 ℃, and the weight ratio of the polyurethane resin to the modified barium sulfate is 4-5:1;
Thirdly, adding the prepared sample into tetrahydrofuran, stirring at a constant speed, adding heparin, stirring for 15min, adding 4-dimethylaminopyridine and diisopropylcarbodiimide, stirring for 4h in an ice-water bath, transferring to room temperature, continuously stirring for 4h, filtering, and drying in vacuum to obtain the thermoplastic polyurethane material for medical use, wherein the weight ratio of the sample, heparin, 4-dimethylaminopyridine, diisopropylcarbodiimide and tetrahydrofuran is controlled to be 10-20:1:0.1-0.2:0.3-0.5:20-30.
In the third step, carboxyl introduced in the sample under the action of 4-dimethylaminopyridine and diisopropylcarbodiimide can react with hydroxyl on the heparin structure so as to graft heparin on the surface of the material.
Further, the modified barium sulfate comprises the following steps:
step S1, adding barium carbonate into deionized water, magnetically stirring at 45 ℃ and adding sodium sulfate, magnetically stirring for 30min, slowly adding an aqueous solution of polyethylenimine, uniformly stirring, transferring into a reaction kettle, heating to 150 ℃, preserving heat for reaction for 10h, filtering after the reaction is finished, respectively washing with deionized water and absolute ethyl alcohol for three times, and drying to obtain pretreated barium sulfate, wherein the weight ratio of the barium carbonate to the polyethylenimine to the deionized water is controlled to be 4.58-5.02 g:0.144 g:50 mL, and the molar ratio of the barium carbonate to the sodium sulfate is 1:1;
the aqueous solution of the polyethyleneimine is formed by mixing the polyethyleneimine and deionized water according to the dosage ratio of 0.144g to 10 mL.
In the step S1, barium carbonate reacts with sodium sulfate to generate barium sulfate precipitate, and polyethyleneimine is added to prepare pretreated barium sulfate, which is polyethyleneimine barium sulfate;
And S2, dispersing the prepared pretreated barium sulfate in absolute ethyl alcohol, adding bromohexane, magnetically stirring at room temperature and reacting for 12 hours, adding methyl iodide, continuously reacting for 12 hours, respectively washing three times by deionized water and absolute ethyl alcohol after the reaction is finished, drying at 55 ℃ to prepare modified barium sulfate, controlling the weight ratio of the pretreated barium sulfate, bromohexane and absolute ethyl alcohol to be 1:10:50, and controlling the molar ratio of methyl iodide to bromohexane to be 1:1.
The polyethylenimine barium sulfate is provided with a large amount of amino groups, part of amino groups can be converted into quaternary ammonium salts through alkylation modification of bromohexane, and then quaternary ammonium salt structures are connected to the barium sulfate, so that the antibacterial property of the barium sulfate is endowed, and further, the substrate is endowed with excellent antibacterial property, and unreacted amino groups can also react with carboxyl groups on heparin, so that the grafting rate of the heparin and the substrate is improved.
The invention has the beneficial effects that:
The application prepares a thermoplastic polyurethane material for medical treatment, first synthesizes a polycarbonate polyurethane with carboxyl, introduces carboxyl while exerting the excellent performance of polycarbonate polyurethane, can react with hydroxyl on the heparin structure under the action of 4-dimethylaminopyridine and diisopropylcarbodiimide to further graft heparin on the surface of the material, and further can endow the polyurethane material with anticoagulation effect, compared with the existing method of coating free heparin by a coating mode, the application grafts heparin by a chemical bonding mode, so that the heparin structure is more firmly combined with the polyurethane material, and the initial contact activation of thrombin can be blocked by an antithrombin III-mediated way, thereby having better anticoagulation performance;
In addition, the modified barium sulfate is added into the polyurethane material, so that on one hand, the contrast function of the barium sulfate can be exerted, on the other hand, after the quaternary ammonium salt is modified, the antibacterial property of the barium sulfate is endowed, and further, the excellent antibacterial property of the matrix is endowed, bacteria are prevented from adhering to the surface of the material, so that the problem of organism injury is caused by bacterial infection of a human body, and unreacted amino in the quaternary ammonium salt modified barium sulfate can also react with carboxyl on heparin, so that the grafting rate of heparin and the matrix is further improved, and the binding property of heparin and the matrix is improved.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A production process of a thermoplastic polyurethane material for medical treatment comprises the following steps:
Firstly, adding polyhexamethylene carbonate dihydric alcohol into a flask, introducing nitrogen, heating to 75 ℃ and stirring at a constant speed until the mixture is melted, adding isophorone diisocyanate, preserving heat and magnetically stirring for 3 hours to obtain a prepolymer, then adding dimethyl carbonate to reduce the viscosity, continuously stirring and reacting for 1 hour, cooling to 60 ℃, adding dibutyl tin dilaurate and 2, 2-bis (hydroxymethyl) propionic acid, continuously stirring and reacting for 3 hours to obtain polyurethane resin, and controlling the dosage ratio of the polyhexamethylene carbonate dihydric alcohol to the isophorone diisocyanate to the dimethyl carbonate to the 2, 2-bis (hydroxymethyl) propionic acid to be 10 g:4 mL:25 mL:1.5 mL, wherein the dosage of the dibutyl tin dilaurate is 0.1 weight of the polyhexamethylene carbonate dihydric alcohol;
Secondly, mixing the prepared polyurethane resin and modified barium sulfate, and then feeding the mixture into a double-screw extruder for extrusion and granulation to obtain a sample, wherein the rotating speed of a screw is controlled to be 100r/min, the extrusion temperature is 195 ℃, and the weight ratio of the polyurethane resin to the modified barium sulfate is 4:1;
Thirdly, adding the prepared sample into tetrahydrofuran, stirring at a constant speed, adding heparin, stirring for 15min, adding 4-dimethylaminopyridine and diisopropylcarbodiimide, stirring for 4h in an ice-water bath, transferring to room temperature, continuously stirring for 4h, filtering, and drying in vacuum to obtain the thermoplastic polyurethane material for medical use, wherein the weight ratio of the sample, heparin, 4-dimethylaminopyridine, diisopropylcarbodiimide and tetrahydrofuran is controlled to be 10:1:0.1:0.3:20.
The modified barium sulfate comprises the following steps:
step S1, adding barium carbonate into deionized water, magnetically stirring at 45 ℃ and adding sodium sulfate, magnetically stirring for 30min, slowly adding an aqueous solution of polyethylenimine, uniformly stirring, transferring to a reaction kettle, heating to 150 ℃, preserving heat for reaction for 10h, filtering after the reaction is finished, respectively washing with deionized water and absolute ethyl alcohol for three times, and drying to obtain pretreated barium sulfate, wherein the weight ratio of the barium carbonate to the polyethylenimine to the deionized water is controlled to be 4.58g to 0.144g to 50mL, and the molar ratio of the barium carbonate to the sodium sulfate is controlled to be 1:1;
the aqueous solution of the polyethyleneimine is formed by mixing the polyethyleneimine and deionized water according to the dosage ratio of 0.144g to 10 mL.
And S2, dispersing the prepared pretreated barium sulfate in absolute ethyl alcohol, adding bromohexane, magnetically stirring at room temperature and reacting for 12 hours, adding methyl iodide, continuously reacting for 12 hours, respectively washing three times by deionized water and absolute ethyl alcohol after the reaction is finished, drying at 55 ℃ to prepare modified barium sulfate, controlling the weight ratio of the pretreated barium sulfate, bromohexane and absolute ethyl alcohol to be 1:10:50, and controlling the molar ratio of methyl iodide to bromohexane to be 1:1.
Example 2
A production process of a thermoplastic polyurethane material for medical treatment comprises the following steps:
firstly, adding polyhexamethylene carbonate dihydric alcohol into a flask, introducing nitrogen, heating to 75 ℃ and stirring at a constant speed until the mixture is melted, adding isophorone diisocyanate, preserving heat and magnetically stirring for 3 hours to obtain a prepolymer, then adding dimethyl carbonate to reduce the viscosity, continuously stirring and reacting for 1 hour, cooling to 60 ℃, adding dibutyl tin dilaurate and 2, 2-bis (hydroxymethyl) propionic acid, continuously stirring and reacting for 3 hours to obtain polyurethane resin, and controlling the dosage ratio of the polyhexamethylene carbonate dihydric alcohol to the isophorone diisocyanate to the dimethyl carbonate to the 2, 2-bis (hydroxymethyl) propionic acid to be 12 g:4.5 mL:28 mL:1.8 mL, wherein the dosage of the dibutyl tin dilaurate is 0.2% of the weight of the polyhexamethylene carbonate dihydric alcohol;
Secondly, mixing the prepared polyurethane resin and modified barium sulfate, and then feeding the mixture into a double-screw extruder for extrusion and granulation to obtain a sample, wherein the rotating speed of a screw is controlled to be 100r/min, the extrusion temperature is 195 ℃, and the weight ratio of the polyurethane resin to the modified barium sulfate is 4:1;
Thirdly, adding the prepared sample into tetrahydrofuran, stirring at a constant speed, adding heparin, stirring for 15min, adding 4-dimethylaminopyridine and diisopropylcarbodiimide, stirring for 4h in an ice-water bath, transferring to room temperature, continuously stirring for 4h, filtering, and drying in vacuum to obtain the thermoplastic polyurethane material for medical use, wherein the weight ratio of the sample, heparin, 4-dimethylaminopyridine, diisopropylcarbodiimide and tetrahydrofuran is 15:1:0.1:0.4:25.
The modified barium sulfate comprises the following steps:
Step S1, adding barium carbonate into deionized water, magnetically stirring at 45 ℃ and adding sodium sulfate, magnetically stirring for 30min, slowly adding an aqueous solution of polyethylenimine, uniformly stirring, transferring into a reaction kettle, heating to 150 ℃, preserving heat for reaction for 10h, filtering after the reaction is finished, respectively washing with deionized water and absolute ethyl alcohol for three times, and drying to obtain pretreated barium sulfate, wherein the weight ratio of the barium carbonate to the polyethylenimine to the deionized water is 5g to 0.144g to 50mL, and the molar ratio of the barium carbonate to the sodium sulfate is 1 to 1;
the aqueous solution of the polyethyleneimine is formed by mixing the polyethyleneimine and deionized water according to the dosage ratio of 0.144g to 10 mL.
And S2, dispersing the prepared pretreated barium sulfate in absolute ethyl alcohol, adding bromohexane, magnetically stirring at room temperature and reacting for 12 hours, adding methyl iodide, continuously reacting for 12 hours, respectively washing three times by deionized water and absolute ethyl alcohol after the reaction is finished, drying at 55 ℃ to prepare modified barium sulfate, controlling the weight ratio of the pretreated barium sulfate, bromohexane and absolute ethyl alcohol to be 1:10:50, and controlling the molar ratio of methyl iodide to bromohexane to be 1:1.
Example 3
A production process of a thermoplastic polyurethane material for medical treatment comprises the following steps:
Firstly, adding polyhexamethylene carbonate dihydric alcohol into a flask, introducing nitrogen, heating to 75 ℃, stirring at a constant speed until the mixture is melted, adding isophorone diisocyanate, preserving heat and magnetically stirring for 3 hours to obtain a prepolymer, then adding dimethyl carbonate to reduce the viscosity, continuously stirring and reacting for 1 hour, cooling to 60 ℃, adding dibutyl tin dilaurate and 2, 2-bis (hydroxymethyl) propionic acid, continuously stirring and reacting for 3 hours to obtain polyurethane resin, and controlling the dosage ratio of the polyhexamethylene carbonate dihydric alcohol to the isophorone diisocyanate to the dimethyl carbonate to the 2, 2-bis (hydroxymethyl) propionic acid to be 15 g:5 mL:30 mL:2 mL, wherein the dosage of the dibutyl tin dilaurate is 0.3% of the weight of the polyhexamethylene carbonate dihydric alcohol;
Secondly, mixing the prepared polyurethane resin and modified barium sulfate, and then feeding the mixture into a double-screw extruder for extrusion and granulation to obtain a sample, wherein the rotating speed of a screw is controlled to be 100r/min, the extrusion temperature is 195 ℃, and the weight ratio of the polyurethane resin to the modified barium sulfate is 5:1;
Thirdly, adding the prepared sample into tetrahydrofuran, stirring at a constant speed, adding heparin, stirring for 15min, adding 4-dimethylaminopyridine and diisopropylcarbodiimide, stirring for 4h in an ice-water bath, transferring to room temperature, continuously stirring for 4h, filtering, and drying in vacuum to obtain the thermoplastic polyurethane material for medical use, wherein the weight ratio of the sample, heparin, 4-dimethylaminopyridine, diisopropylcarbodiimide and tetrahydrofuran is controlled to be 20:1:0.2:0.5:30.
The modified barium sulfate comprises the following steps:
Step S1, adding barium carbonate into deionized water, magnetically stirring at 45 ℃ and adding sodium sulfate, magnetically stirring for 30min, slowly adding an aqueous solution of polyethylenimine, uniformly stirring, transferring to a reaction kettle, heating to 150 ℃, preserving heat for reaction for 10h, filtering after the reaction is finished, respectively washing with deionized water and absolute ethyl alcohol for three times, and drying to obtain pretreated barium sulfate, wherein the weight ratio of the barium carbonate to the polyethylenimine to the deionized water is 5.02g to 0.144g to 50mL, and the molar ratio of the barium carbonate to the sodium sulfate is 1 to 1;
the aqueous solution of the polyethyleneimine is formed by mixing the polyethyleneimine and deionized water according to the dosage ratio of 0.144g to 10 mL.
And S2, dispersing the prepared pretreated barium sulfate in absolute ethyl alcohol, adding bromohexane, magnetically stirring at room temperature and reacting for 12 hours, adding methyl iodide, continuously reacting for 12 hours, respectively washing three times by deionized water and absolute ethyl alcohol after the reaction is finished, drying at 55 ℃ to prepare modified barium sulfate, controlling the weight ratio of the pretreated barium sulfate, bromohexane and absolute ethyl alcohol to be 1:10:50, and controlling the molar ratio of methyl iodide to bromohexane to be 1:1.
Biological tests were performed on the medical thermoplastic polyurethane materials prepared in examples 1-3;
1. acute systemic toxicity
The test is carried out on a test sample of 0.9% sodium chloride injection (SC) and cottonseed oil (CSO) according to the method of national standard GB/T16886.112011, medical instrument biology evaluation 11 part: systemic toxicity test.
Leaching the test sample using SC and CSO, and administering to the test animal by intraperitoneal Injection (IP); all animal status and number of dead animals were observed and recorded immediately after injection, 4h, 24h, 48h and 72h, respectively. All animals were weighed 24h, 48h and 72h after injection and recorded.
Under the test conditions, animals in the test group and the control group are not dead, all the test mice are not toxic, and the quality of the mice is increased. The test results show that the test solutions of the thermoplastic polyurethane materials of the examples 1-3 have no acute systemic effect on the test mice.
2. Cytotoxicity test
The test uses an in vitro cell culture method to evaluate toxicology risks. The test is carried out according to the MTT method of national standard GB/T16886.5-2017, medical appliance biology evaluation part 5, in vitro cytotoxicity test.
Sample test solution, a negative control, a positive control leaching solution and a medium control are respectively placed in a hole of a cell culture plate for 6L 929 mouse fibroblasts, the cells are cultured in a cell culture box with 5% CO 2 and 37 ℃, the morphological changes of the cells of the test sample group, the negative control group, the positive control group and the medium control group after being cultured are observed under a microscope after 24 hours, and the cell survival rate of each test sample group, the negative control group and the positive control group) relative to the medium control group is measured by an MTT method.
Under the test conditions, the cell viability of the test liquid of the thermoplastic polyurethane materials of the examples 1-3 is in the range of 81-90%, and the test liquid has no potential cytotoxicity. ( Reference standard: survival rates of less than 70% are potentially toxic )
3. Skin sensitization test
The test is based on the national standard GB/T16886.10-2017, medical instrument biology evaluation part 10, stimulation and skin sensitization test, and the maximum skin sensitization dosage test is carried out on the 0.9% sodium chloride injection (SC) and the cottonseed oil (CSO) test liquid of the test sample, so as to evaluate the potential of the test sample to cause guinea pigs to generate skin sensitization reaction under the test condition.
Test samples were leached using SC and CSO. Each test solution was injected intradermally and blocked in the shaved area of the back of guinea pigs in the test group to induce skin sensitization; after the induction period, the test liquid-impregnated filter paper sheet was closed and fixed to the abdominal shaved area of the test group animals for 24 hours. All animals were observed and recorded for skin conditions at the challenge site 24h and 48h after removal of the filter paper sheet, as described and graded according to Magnusson and K l i gman grading standards. Animals in the control group were operated in the same manner.
Under the test conditions, the test solutions of the thermoplastic polyurethane materials of examples 1 to 3 did not cause skin sensitization in guinea pigs.
4. Intradermal reaction test
The test uses rabbits to conduct an intradermal reaction test to evaluate the potential of a test sample to produce a stimulus response under test conditions. The test is carried out according to the specification of the national standard GB/T16886.10-2017, medical appliance biology evaluation part 10, stimulation and skin sensitization test.
Test samples were leached with 0.9% sodium chloride injection (SC) and cotton with oil (CSO) and a blank solution without test sample was prepared in the same way. The test solution and the blank control solution are injected intradermally at two sides of the home-use vertebra, erythema and edema at the injection site are scored at (24+/-2) h, (48+/-2) h and (72+/-2) h after injection, and the final score of the intradermal reaction of the test sample and the corresponding air-self control is calculated.
Under the test conditions, the final score of the thermoplastic polyurethane materials SC and CSO in the household care of the test liquid in the examples 1-3 is not more than 1.0, and meets the test requirements.
Comparative example 1
This comparative example was compared to example 3, with 1, 4-butanediol instead of 2, 2-bis (hydroxymethyl) propionic acid as chain extender, and the remainder was identical to example 3.
Comparative example 2
In this comparative example, the barium sulfate was not modified as in example 3, but the same as in example 3 was conducted.
Comparative example 3
This comparative example is a coating of heparin as a coating on the surface of TPU as disclosed in the examples of chinese patent No. CN 201811614127.7.
The properties of the polyurethane materials prepared in examples 1 to 3 and comparative examples 1 to 3 were examined, and the results are shown in Table 1 below:
Anticoagulation assay: including Activated Partial Thromboplastin Time (APTT) and Thrombin Time (TT).
The sample was first cut into small pieces of 0.5X0.5 cm 2 and soaked in PBS at 37℃for 30 minutes. Taking fresh whole blood of healthy rats, and centrifuging at4 ℃ for 15 minutes (2500 rpm) to obtain supernatant, namely Platelet Poor Plasma (PPP); the blood coagulation time test method is carried out according to the requirements of the corresponding kit, and comprises the following specific processes:
(1) APTT test
The material was placed in a 1.5mL centrifuge tube, 100. Mu.L PPP was added and incubated at 37℃for 30 minutes. Then sucking 50L of the co-incubated PPP, adding 50 mu L of APTT reagent, mixing uniformly, incubating for 3 minutes at 37 ℃, immediately adding 50 mu L of 0.025M CaCl 2 solution, mixing uniformly, timing, and recording the plasma coagulation time to obtain the APTT.
(2) TT test
The material was placed in a 1.5mL centrifuge tube, 150. Mu.L PPP was added and incubated at 37℃for 30 minutes, then 100. Mu.L of the incubated PPP was aspirated, and 100. Mu.L TT reagent was added and incubated for 3 minutes, and then the plasma clotting time was recorded as TT.
Antibacterial test: the model bacteria are selected from gram positive bacteria: staphylococcus aureus; gram-negative bacteria: coli; the operation method is as follows: activating and amplifying strains of staphylococcus aureus and escherichia coli, diluting the strains into bacterial suspension with the concentration of 5 multiplied by 10 5 CFU/mL, absorbing 200 mu L of the bacterial suspension by a sterile straw respectively, uniformly coating the bacterial suspension on the surfaces of all samples, and culturing for 24 hours at 37 ℃; then, bacteria on the surface of the samples are flushed by using an equal volume of culture medium, the samples are placed at 37 ℃ for further culture for 8 hours, the samples are spread on a flat plate after dilution, the colony numbers of the samples in each group are counted, and the bacteriostasis rate is calculated.
TABLE 1
From Table 1 above, it can be seen that the polyurethane materials prepared in examples 1 to 3 of the present invention have good anticoagulation performance and antibacterial property.
The foregoing is merely illustrative and explanatory of the principles of the invention, as various modifications and additions may be made to the specific embodiments described, or similar thereto, by those skilled in the art, without departing from the principles of the invention or beyond the scope of the appended claims.
Claims (7)
1. The production process of the thermoplastic polyurethane material for medical treatment is characterized by comprising the following steps of:
Firstly, adding polyhexamethylene carbonate dihydric alcohol into a flask, introducing nitrogen, heating to 75 ℃, stirring at a constant speed until the mixture is melted, adding isophorone diisocyanate, preserving heat, magnetically stirring for 3 hours to obtain a prepolymer, then adding dimethyl carbonate, continuously stirring and reacting for 1 hour, cooling to 60 ℃, adding dibutyl tin dilaurate and 2, 2-bis (hydroxymethyl) propionic acid, continuously stirring and reacting for 3 hours to obtain polyurethane resin;
secondly, mixing the prepared polyurethane resin and modified barium sulfate, and then sending the mixture into a double-screw extruder for extrusion and granulation to prepare a sample;
Thirdly, adding the prepared sample into tetrahydrofuran, stirring at a constant speed, adding heparin, stirring for 15min, adding 4-dimethylaminopyridine and diisopropylcarbodiimide, stirring for 4h in an ice water bath, transferring to room temperature, continuously stirring for 4h, filtering, and drying in vacuum to obtain the thermoplastic polyurethane material for medical use;
The modified barium sulfate comprises the following steps:
Step S1, adding barium carbonate into deionized water, magnetically stirring at 45 ℃ and adding sodium sulfate, magnetically stirring for 30min, slowly adding an aqueous solution of polyethylenimine, uniformly stirring, transferring into a reaction kettle, heating to 150 ℃, carrying out heat preservation reaction for 10h, filtering after the reaction is finished, washing with deionized water and absolute ethyl alcohol for three times respectively, and drying to obtain pretreated barium sulfate;
and S2, dispersing the prepared pretreated barium sulfate in absolute ethyl alcohol, adding bromohexane, magnetically stirring at room temperature, reacting for 12 hours, adding methyl iodide, continuously reacting for 12 hours, respectively washing with deionized water and absolute ethyl alcohol for three times after the reaction is finished, and drying at 55 ℃ to obtain the modified barium sulfate.
2. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein the amount ratio of the polyhexamethylene carbonate glycol, isophorone diisocyanate, dimethyl carbonate and 2, 2-bis (hydroxymethyl) propionic acid is controlled to be 10-15 g:4-5 mL:25-30 mL:1.5-2 mL in the first step, and the amount of dibutyltin dilaurate is controlled to be 0.1-0.3% by weight of the polyhexamethylene carbonate glycol.
3. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein the screw speed is controlled to be 100r/min, the extrusion temperature is 195 ℃, and the weight ratio of the polyurethane resin to the modified barium sulfate is 4-5:1.
4. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein in the third step, the weight ratio of the sample, heparin, 4-dimethylaminopyridine, diisopropylcarbodiimide and tetrahydrofuran is controlled to be 10-20:1:0.1-0.2:0.3-0.5:20-30.
5. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein in step S1, the weight ratio of barium carbonate, polyethylenimine and deionized water is controlled to be 4.58-5.02 g:0.144 g:50 mL, and the molar ratio of barium carbonate to sodium sulfate is controlled to be 1:1.
6. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein the aqueous solution of polyethyleneimine in step S1 is prepared by mixing polyethyleneimine and deionized water in a ratio of 0.144g to 10 mL.
7. The process for producing a thermoplastic polyurethane material for medical use according to claim 1, wherein in step S2, the weight ratio of the pretreated barium sulfate, bromohexane and absolute ethanol is controlled to be 1:10:50, and the molar ratio of methyl iodide to bromohexane is controlled to be 1:1.
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| CN104629058A (en) * | 2014-12-10 | 2015-05-20 | 胡学明 | Novel heparinized polyester film preparation method |
| CN106118198A (en) * | 2016-07-06 | 2016-11-16 | 西南交通大学 | The preparation method of carbon nano tube surface quaternized antibacterial in situ |
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| CN104629058A (en) * | 2014-12-10 | 2015-05-20 | 胡学明 | Novel heparinized polyester film preparation method |
| CN106118198A (en) * | 2016-07-06 | 2016-11-16 | 西南交通大学 | The preparation method of carbon nano tube surface quaternized antibacterial in situ |
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