CN116333217B

CN116333217B - Preparation method of amino-containing polymer, polymer product and application

Info

Publication number: CN116333217B
Application number: CN202310632018.2A
Authority: CN
Inventors: 请求不公布姓名
Original assignee: Shanghai Weimi Medical Technology Co ltd
Current assignee: Shanghai Weimi Medical Technology Co ltd
Priority date: 2023-05-31
Filing date: 2023-05-31
Publication date: 2023-08-15
Anticipated expiration: 2043-05-31
Also published as: WO2024245021A1; CN116333217A

Abstract

The application relates to the field of blood contact medical instrument coatings, in particular to a preparation method of an amino-containing polymer, a polymer product and application. The structural formula of the polymer prepared by the preparation method is as follows:wherein R is ₁ And R is ₂ Is CH ₃ ；A ₁ Is O, B ₁ An amino hydrochloride segment containing 2, 4 or 5 carbon atoms; a is that ₂ Is NH, B ₂ Is an amino hydrochloride chain segment containing 3-5 carbon atoms; m, n and k are the repetition numbers of the structural units, and the ratio of m/n/k is 7:1:2. The polymer represented by the structural formula is obtained by random copolymerization of 2-methacryloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride, has good reactivity, platelet adhesion resistance, platelet activation resistance and fibrinogen adhesion resistance, can be efficiently and chemically fixed on the surface of a medical instrument, and plays an anticoagulant advantage.

Description

Preparation method of amino-containing polymer, polymer product and application

Technical Field

The application relates to the field of blood contact medical instrument coatings, in particular to a preparation method of an amino-containing polymer, a polymer product and application.

Background

Blood contact-type medical devices have been widely used in clinics including intravenous catheters, implantable coronary stents, intracranial blood flow guiding devices, prosthetic heart valve or ventricular assist devices, hemodialysis and extracorporeal circulation devices, membrane oxygenators, and other internal and external devices. In the use of such medical devices, it is often desirable to improve the blood compatibility of the materials from which such medical devices are made in order to prevent thrombosis and avoid complications that may lead to failure of such medical devices. The blood compatibility is mainly the phenomenon that when the biological material is contacted with blood, coagulation and platelet adhesion aggregation are not caused and the existing components in the blood are not destroyed. Numerous studies indicate that natural cell membranes are highly effective against the adhesion and activation of blood proteins and platelets by virtue of their specific phospholipid structure, thus exhibiting excellent antithrombotic properties. Therefore, the polymer imitating the natural cell membrane structure is constructed, so that the polymer has both antithrombotic performance and reactivity, and can be widely applied to the surface modification of blood contact medical instruments.

The prior art (CN 112316218B) discloses a zwitterionic polymer and heparin composite coating and a preparation method and application thereof, the reactive functional group of the zwitterionic polymer protected by the patent is carboxyl, and as the reactivity of the carboxyl is not high, when the zwitterionic polymer is introduced to the surface of a medical apparatus, an additional catalyst or activator is usually required to be added, so that the modification cost is increased, and the small-molecular catalyst or activator is not easy to completely remove, so that the zwitterionic polymer has potential biotoxicity.

The prior art (CN 103596996B) discloses a process for the preparation of polymers by reacting an epoxy-containing phosphorylcholine polymer with a small molecule 2-Aminoethanethiol (AET) to produce an amino-containing phosphorylcholine polymer, notably that the epoxy group can react not only with the thiol group but also with the amino group with a relatively high reactivity. The preparation method inevitably has side reactions, so that the content of amino groups in the polymer cannot be expected.

The prior art (CN 109796616B) discloses a bionic polymer, a method for manufacturing a durable double bionic polymer coating and application thereof, and the ternary polymer structure provided by the patent comprises a zwitterionic group, an amino reactive group and a quaternary ammonium cationic group. However, the amino reactive group-containing monomer has higher activity and can undergo Michael addition reaction with other double bond-containing monomers. While this patent does not protect the amino groups, it is likely that the resulting terpolymer lacks sufficient amino reactive groups. At the same time, the patent lacks data that characterize the amino groups in the terpolymer qualitatively, limiting its use.

Therefore, in order to solve the problems, the application provides a novel preparation method of an amino-containing polymer and a prepared polymer product, and the novel amino-containing polymer is applied to the field of blood contact medical instruments.

Disclosure of Invention

In order to solve the above problems, the first aspect of the present application provides a method for producing the above amino group-containing polymer, comprising the steps of: (1) Dissolving 2-methacryloyloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent according to a proportion to obtain an initiator solution; (3) Mixing the monomer mixed solution obtained in the step (1) with the initiator solution obtained in the step (2) according to a proportion, regulating the pH value of the solution to be 1-6 by using acid liquor, removing water and deoxidizing, controlling the temperature to react for 6-72 hours under the protection of inert gas, and purifying to obtain the amino-containing polymer.

As a preferable scheme, the reaction temperature in the step (3) is 30-100 ℃.

As a further preferable scheme, the reaction temperature in the step (3) is 45-60 ℃.

According to the application, the reaction temperature and the pH value in the polymer reaction process and the molar ratio of the three monomers are regulated, so that the molecular weight of the polymer can be effectively improved within a proper range, the higher polymer yield of the reaction is further ensured, and the generation of side reactions is obviously reduced. In the actual reaction research process, the inventor finds that in the ternary random polymerization reaction, the proportion of three monomers, the regulation and control of pH value and the setting of reaction temperature can effectively control the whole reaction process, if the proportion of three monomers, the pH value and the reaction temperature are unsuitable, the polymerization reaction is easy to fail or the anticoagulation effect of the obtained polymer is poor, so that the proportion of three monomers, the pH value and the reaction temperature play an important role in achieving the expected anticoagulation effect of the polymer. For the ternary random copolymerization reaction, the ratio of monomers, pH and reaction temperature are also important reaction conditions, so that a preferred anticoagulant material is obtained.

As a preferable embodiment, the acrylic monomer of the amino hydrochloride is at least one of 2-aminoethyl methacrylate hydrochloride, 2-aminobutyl methacrylate hydrochloride and 2-aminopentyl methacrylate hydrochloride.

As a preferred embodiment, the acrylic monomer of the amino hydrochloride is 2-aminoethylmethacrylate hydrochloride.

As a preferred embodiment, the acrylamide monomer of the amino hydrochloride is at least one of N- (3-aminopropyl) methacrylamide hydrochloride, N- (4-aminobutyl) methacrylamide hydrochloride and N- (5-aminopentyl) methacrylamide hydrochloride.

As a preferred embodiment, the acrylamide monomer of the amino hydrochloride is N- (3-aminopropyl) methacrylamide hydrochloride.

As a preferable scheme, the reaction solvent is at least one of water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, N-hexane, toluene, N-dimethylformamide and tetrahydrofuran.

As a preferable scheme, the reaction solvent is at least one of water, methanol, ethanol and isopropanol.

As a preferred embodiment, the initiator is a peroxide and/or azo.

As a preferred embodiment, the initiator is at least one of azobisisobutyronitrile, azodicyanovaleric acid, azodiisoheptonitrile, azoi Ding Qingji formamide, azodiisobutylamidine hydrochloride, dimethyl azodiisobutyrate, benzoyl peroxide, ammonium persulfate, potassium persulfate, tertiary butyl benzoyl peroxide and 2-butanone peroxide.

As a preferable scheme, the acid liquid is at least one of phosphoric acid, sulfuric acid, carbonic acid, hydrochloric acid, lactic acid, citric acid and benzoic acid solution of corresponding reaction solvents.

As a preferable scheme, the molar ratio of the 2-methacryloxyethyl phosphorylcholine monomer, the acrylic monomer of amino hydrochloride and the acrylamide monomer of amino hydrochloride is 7:1:2.

according to the application, by mixing the three monomers, the anticoagulation performance of the product is effectively improved. 2-amino ethyl methacrylate hydrochloride and N- (3-amino propyl) methacrylamide hydrochloride, along with the preparation process in the application, the specific proportion of the two monomers is compounded to show more reactive groups, so that the reaction efficiency of the polymer is improved and the probability of free radical reaction is increased.

In addition, 2-methacryloyloxyethyl phosphorylcholine has good anticoagulation (platelet adhesion, fibrinogen adsorption), and on one hand, since the surface of the Phosphorylcholine (PC) terminal group is inert to blood cells, platelets are not adsorbed and activated, and hemolysis of red blood cells is not caused; on the other hand, the PC end group has equivalent positive and negative charges, so that the PC end group can be firmly hydrated with the travel of water molecules, the interaction with protein is weakened, and the adsorption of the protein is basically reversible, so that the adsorbed protein can maintain the natural conformation of the protein. The substrate grafted with the amino-containing PC polymer has a significantly better anticoagulation effect. There is no necessarily or significant correlation between platelet adhesion and protein adsorption rates and polymer molecular weight, as well as amino content, and its anti-adhesion effect is largely determined by the enrichment and uniformity of PC end groups successfully grafted to the substrate surface.

As a preferred scheme, the mass ratio of the total monomer to the reaction solvent is 10:60.

as a preferable scheme, the mass ratio of the initiator to the acrylic ester monomer of the amino hydrochloride is 0.05-10: 90-99.5.

As a preferable scheme, the mass ratio of the initiator to the acrylic monomer of the amino hydrochloride is 1:99.

as a preferable scheme, the mass ratio of the monomer mixed solution to the initiator solution is 65-99: 1-35.

As a preferable scheme, the mass ratio of the monomer mixed solution to the initiator solution is 70:30.

the application provides an amino-containing ternary random polymer obtained by the preparation method, which has the structural formula:

，

wherein R is ₁ And R is ₂ Is CH ₃ ；A ₁ Is O, B ₁ An amino hydrochloride segment containing 2, 4 or 5 carbon atoms; a is that ₂ Is NH, B ₂ Is an amino hydrochloride chain segment containing 3-5 carbon atoms; m, n and k are the repetition numbers of the structural units, and the ratio of m/n/k is 7:1:2.

As a preferred embodiment, the polymer is a random polymer; the random polymer is obtained by random copolymerization of 2-methacryloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride.

As a preferable scheme, the weight average molecular weight of the polymer is 4000-90000 Da.

In the application, the change of the molecular weight is determined by the selection and addition of the reaction monomer and the initiator, and the like, and the change range of the molecular weight is also within the adjustable range of the free radical polymerization of the compounds such as 2-methacryloyloxyethyl phosphorylcholine. The inventors have found during the investigation of the technical scheme that when 2-methacryloyloxyethyl phosphorylcholine monomer is polymerized with an amino-containing acrylate monomer, the 2-methacryloyloxyethyl phosphorylcholine also utilizes its own reactive group (double bond) to synthesize homopolymers, such as poly 2-methacryloyloxyethyl phosphorylcholine, so that in some examples the polymer molecular weight is increased without a significant increase in amino content. The purpose of designing amino groups in the compound is to promote the grafting ratio of PC and the substrate and to improve the grafting effect. Although it is generally believed that the higher the amino content, the more readily PC can be grafted onto the substrate, related experiments have shown that PC can reach "graft saturation" after grafting a certain amount onto the substrate, and simply increasing the amino group content of the polymer is not sufficient to increase its grafting yield. Therefore, even if the molecular weight is not very high (4000-7000 Da), even grafting of the amino-containing polymer to the surface of the substrate can be realized in some embodiments, and a good anticoagulation effect is achieved; however, if the substrate surface cannot be grafted with more amino-containing polymer, a certain space-occupying effect occurs, and poor results of surface grafting and anticoagulation occur. The technical scheme of the application can realize a wider molecular weight selection range, and can meet the use requirements of the characteristic polymer in the medical field to a greater extent.

In a third aspect, the application provides the use of an amino group-containing polymer as described above in a blood contact medical device surface coating.

The beneficial effects are that:

1. the application provides a preparation method of an amino-containing ternary random polymer, which is prepared by copolymerizing 2-methacryloyloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride; the structure has good chemical reactivity and anticoagulation performance, and can be chemically fixed on the surface of a medical instrument to increase the anticoagulation performance.

2. The application provides a preparation method of an amino-containing polymer, which can effectively improve the moldability and anticoagulation performance of the polymer by regulating and controlling the process in the preparation process of the polymer, and a ternary random polymer obtained by copolymerizing 2-methacryloyloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride with proper proportions can form a good branched chain structure, and has the advantages that: on one hand, the ternary random polymer can regulate the quantity of reactive groups, and ensure good reaction sites and corresponding branched chain spaces; on the other hand, the ternary random polymer contains enough reactive sites, and besides being fixed on the surface of a medical apparatus, the ternary random polymer can be further grafted with an anticoagulant drug, a polypeptide targeting endothelial cells and a fluorescent dye, so that various biological activities are obtained.

3. The application provides an amino-containing polymer, which can realize the selective design of the molecular weight of the polymer and effectively improve the application effect of the polymer in the field of blood contact medical devices.

Drawings

FIG. 1 is a graph of nuclear magnetic data of a polymer prepared in example 1 of the present application.

FIG. 2 is a graph showing the data of the molecular weight test of the polymer prepared in example 1 of the present application.

FIG. 3 is a graph showing the data of the molecular weight test of the polymer prepared in comparative example 1 of the present application.

FIG. 4 is a graph showing the data of the molecular weight test of the polymer prepared in comparative example 2 according to the present application.

FIG. 5 is a graph showing the data of the molecular weight test of the polymer prepared in comparative example 3 according to the present application.

FIG. 6 is a graph showing the results of an amino quantitative fluorescence test for the polymer prepared in example 1 of the present application.

FIG. 7 is a graph showing the results of an anti-platelet adhesion test for the polymer prepared in example 1 of the present application.

FIG. 8 is a graph of nuclear magnetic data for the polymer prepared in comparative example 4 of the present application.

Detailed Description

Example 1

In a first aspect, the present embodiment provides a method for preparing the amino group-containing polymer, which includes the following steps: (1) Dissolving three monomers of 2-methacryloxyethyl phosphorylcholine, 2-amino ethyl methacrylate hydrochloride (acrylic ester monomer of amino hydrochloride) and N- (3-amino propyl) methacrylamide hydrochloride (acrylamide monomer of amino hydrochloride) in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent according to a proportion to obtain an initiator solution; (3) Mixing the monomer mixed solution obtained in the step (1) with the initiator solution obtained in the step (2) according to a proportion, regulating the pH value of the solution to 3.5 by using acid liquor, removing water and deoxidizing, controlling the temperature under the protection of inert gas, reacting for 24 hours, and purifying to obtain the catalyst.

The reaction temperature in step (3) was 55 ℃.

The reaction solvent is methanol; the initiator is dimethyl azodiisobutyrate; the acid solution is a methanol solution of phosphoric acid.

The molar ratio of 2-methacryloyloxyethyl phosphorylcholine, 2-aminoethyl methacrylate hydrochloride to N- (3-aminopropyl) methacrylamide hydrochloride in step (1) is 7:1:2.

the mass ratio of the total monomer to the reaction solvent in the step (1) is 10:60.

the mass ratio of the initiator to the acrylic monomer of the amino hydrochloride in the step (3) is 1:99.

in the step (3), the mass ratio of the monomer mixed solution to the initiator solution is 70:30.

the reaction yield was 89%.

In a second aspect of this embodiment, there is provided a method of preparing an amino-containing terpolymer according to the above method, wherein the resulting polymer has the structural formula:

wherein the ratio of m/n/k is 7:1:2.

The polymer had a peak molecular weight Mp of 82615 Da and a weight average molecular weight Mw of 78561 Da.

Example 2

The polymer prepared in the embodiment 1 is coated on the surface of a blood contact medical device, and the results of the anti-protein and anti-platelet adhesion experimental evaluation show that the polymer can improve the anti-protein adhesion and the anti-platelet adhesion of the surface of the blood contact medical device and improve the blood compatibility.

Comparative example 1

The specific embodiment of comparative example 1 is the same as example 1 except that: the three monomers are respectively 2-methacryloxyethyl phosphorylcholine, 2-amino ethyl methacrylate hydrochloride (acrylic ester monomer of amino hydrochloride) and N- (4-amino butyl) methacrylamide hydrochloride (acrylamide monomer of amino hydrochloride), and the molar ratio of the three monomers is 8:3:3, in the step (3), the reaction temperature is 45 ℃, the pH value is adjusted to 5 by acid liquor, the reaction solvent is water, the initiator is azodicyanovaleric acid, the acid liquor is carbonic acid aqueous solution, and the reaction yield is 76%.

The structural formula of the obtained polymer is as follows:

wherein the ratio of m/n/k is 8:3:3.

the polymer obtained had a peak molecular weight Mp of 9370 Da and a weight average molecular weight Mw of 11259 Da.

Comparative example 2

The specific embodiment of comparative example 2 is the same as example 1, except that: the three monomers are respectively 2-methacryloxyethyl phosphorylcholine, 2-amino ethyl methacrylate hydrochloride (acrylic ester monomer of amino hydrochloride) and N- (5-amino amyl) methacrylamide hydrochloride (acrylamide monomer of amino hydrochloride), and the molar ratio is 8:1:1, the reaction temperature in the step (3) is 60 ℃, the pH value is adjusted to 6 by acid liquor, the reaction solvent is isopropanol, the initiator is azobisisobutyronitrile, and the reaction yield is 65%.

The structural formula of the obtained polymer is as follows:

wherein the ratio of m/n/k is 8:1:1.

the peak molecular weight Mp of the resulting polymer was 4302 Da and the weight average molecular weight Mw was 5442 Da.

Comparative example 3

The embodiment of comparative example 3 is the same as example 1, except that: the three monomers are respectively 2-methacryloxyethyl phosphorylcholine, 2-aminoethyl methacrylate hydrochloride (acrylic ester monomer of amino hydrochloride) and N- (4-aminobutyl) methacrylamide hydrochloride (acrylamide monomer of amino hydrochloride), and the molar ratio is 4:3:3, the reaction temperature in the step (3) is 50 ℃, the pH value is adjusted to 4.5 by acid liquor, the reaction solvent is water, the initiator is azobisisobutyltidine hydrochloride, and the reaction yield is 43%.

Wherein the ratio of m/n/k is 4:3:3.

the polymer obtained had a peak molecular weight Mp of 7073, da and a weight average molecular weight Mw of 7808, da.

Comparative example 4

Comparative example 4 a first aspect provides a process for the preparation of the above amino group containing polymer comprising the steps of: (1) Dissolving 2-methacryloyloxyethyl phosphorylcholine and 2-aminoethyl methacrylate hydrochloride monomer (acrylic ester monomer of amino hydrochloride) in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent according to a proportion to obtain an initiator solution; (3) Mixing the monomer mixed solution and the initiator solution according to a proportion, adjusting the pH value to 3.5 by using acid liquor, removing water and deoxidizing, controlling the temperature to react for 24 hours under the protection of inert gas, and purifying to obtain the catalyst.

The reaction temperature in step (3) was 55 ℃.

The molar ratio of 2-methacryloyloxyethyl phosphorylcholine to 2-aminoethyl methacrylate hydrochloride in step (1) was 8:2.

in the step (3), the mass ratio of the monomer mixed solution to the initiator solution is 50:1.

The reaction yield was 81%.

In a second aspect of this comparative example, there is provided a process as described above for preparing an amino group-containing binary polymer, the resulting polymer having the structural formula:

wherein the ratio of m/n is 8:2.

the weight average molecular weight Mw of the resulting polymer was 5042 Da.

Comparative example 5

The embodiment of comparative example 5 is the same as comparative example 4, except that: the reaction temperature in the step (3) is 80 ℃, and the pH is adjusted to 6 by acid liquor.

The weight average molecular weight Mw of the resulting polymer was 5017 Da.

Comparative example 6

The embodiment of comparative example 6 is the same as comparative example 4, except that: the molar ratio of the 2-methacryloyloxyethyl phosphorylcholine to the 2-aminoethyl methacrylate hydrochloride is 1:1.

The structural general formula of the obtained polymer was the same as that of comparative example 4, in which the ratio of m/n was 1:1.

the weight average molecular weight Mw of the resulting polymer was 9563 Da.

Comparative example 7

The embodiment of comparative example 7 is the same as comparative example 4, except that: the mass ratio of the initiator to the acrylic monomer of the amino hydrochloride is 5:95.

The weight average molecular weight Mw of the resulting polymer was 40000 Da.

Performance testing

1. The results of the nuclear magnetic resonance, molecular weight, amino group characterization and anti-platelet adhesion tests on the polymer prepared in example 1 and the nuclear magnetic resonance test on the polymer prepared in comparative example 4 are shown in fig. 1, 2, 6, 7 and 8, respectively: bruce 400M H-NMR was used.

2. The molecular weight of comparative example 1, comparative example 2 and comparative example 3 is measured, and the results are respectively recorded in fig. 3-5; molecular weight testing, GPC gel permeation chromatography testing was used.

3. Amino content, platelet adhesion, platelet activation, fibrinogen adsorption rate test:

amino qualitative test: firstly, preparing a fluorescamine acetone solution with the concentration of 3 mg/mL, and refrigerating in a dark place for later use. Subsequently, the polymer of example 1 was accurately weighed and dissolved in Phosphate Buffered Saline (PBS) to prepare a 1.Mg/mL polymer solution. 1mL of the polymer solution is accurately removed, 3 mL fluorescamine acetone solution is added, the mixture is uniformly mixed and is reacted for 10 min at room temperature in a dark place, and finally, under the excitation of excitation light with the wavelength of 380 nm, whether fluorescence is generated or not is observed.

Amino group quantitative test: firstly, preparing a fluorescamine acetone solution with the concentration of 3 mg/mL, and refrigerating in a dark place for later use. Subsequently, glycine was accurately weighed and dissolved in Phosphate Buffered Saline (PBS) to prepare a glycine solution of 1.mg/mL. Accurately transferring 1mL of glycine solution, adding into 3 mL fluorescamine acetone solution, mixing and shaking uniformly to obtain fluorescamine-glycine reaction derivative mother solution. The mother liquor was then diluted with PBS to a series of solutions ranging in concentration from 0.1 to 3 nmol/mL, and the fluorescence intensity of the series of solutions was then measured at excitation wavelength 380 nm to yield a standard curve of amino concentration in glycine versus fluorescence intensity. The amino content of the different examples and comparative examples was tested according to a standard curve.

Quantitative measurement of platelet adhesion rate: the amino-containing polymer prepared according to the present application was first immobilized on the surface of a titanium plate, followed by adding a Platelet Rich Plasma (PRP) solution, and after incubation at 37℃for 2 hours, PRP was removed. According to the requirement of a kit (lactate dehydrogenase (LDH) activity detection kit, solarbio/Soliebao), an antibody for activating blood platelets and a developing solution are added, and an enzyme-labeled instrument is used for measuring absorbance at a wavelength of 450 nm. Platelet adhesion rates for the different examples and comparative examples were tested and calculated according to standard curves.

Platelet activation rate quantification test: firstly, fixing the prepared amino-containing polymer on the surface of a titanium plate, then adding a Platelet Rich Plasma (PRP) solution, incubating for 2 hours at 37 ℃, removing the PRP, adding an antibody and a developing solution for activating blood platelets according to the requirements of a kit (beta-TG ELISA kit, mlbrio/ELISA organism), and measuring the absorbance value of the kit under a given wavelength by using an enzyme-labeled instrument. Platelet activation rates for the different examples and comparative examples were tested and calculated according to standard curves.

Adsorption quantification test of fibrinogen (Fg): the amino-containing polymer prepared by the method is firstly fixed on the surface of a titanium sheet, then Fg solution is added, and Fg is removed after incubation for 2 hours at 37 ℃. The antibody and developing solution of Fg were added according to the requirements of the kit (BCA protein quantification kit, cwbio/kang century), and absorbance at 562nm was measured using an enzyme-labeled instrument. Fibrinogen adsorption rates were tested and calculated according to standard curves for the different examples and comparative examples.

In Table 1 "/" indicates that no relevant test was performed, the platelet adhesion (%) data in Table 1 are preferentially compared, and the amino content is a conventional test item for the product, and does not directly indicate the final application properties of the product.

TABLE 1

From the examples, comparative examples and table 1 show that the amino-containing ternary random polymer prepared by the preparation method provided by the application, the polymer with the structure prepared by the example 1 has good reactivity, platelet adhesion resistance, platelet activation resistance and fibrinogen adhesion resistance. Is favorable for being stably and efficiently chemically fixed on the surface of the medical instrument and plays an anticoagulant advantage. Meanwhile, due to the unique group structure, the anti-coagulation drug can be effectively grafted, and the endothelial cell polypeptide and the fluorescent dye can be targeted, so that various biological activities can be obtained, and the anti-coagulation drug is suitable for popularization in the field of medical instruments.

Claims

1. A process for the preparation of an amino group-containing polymer, characterized in that: comprises the following steps: (1) Dissolving 2-methacryloyloxyethyl phosphorylcholine, acrylic ester monomers of amino hydrochloride and acrylamide monomers of amino hydrochloride in a reaction solvent to obtain a monomer mixed solution; (2) Mixing an initiator into a reaction solvent according to a proportion to obtain an initiator solution; (3) Mixing the monomer mixed solution obtained in the step (1) with the initiator solution obtained in the step (2) according to a proportion, regulating the pH value of the solution to be 1-6 by using acid liquor, removing water and deoxidizing, controlling the temperature to react for 6-72 hours under the protection of inert gas, and purifying to obtain an amino-containing polymer;

the reaction temperature in the step (3) is 30-100 ℃;

the mass ratio of the total monomer to the reaction solvent in the step (1) is 10:60;

the mass ratio of the initiator to the acrylic monomer of the amino hydrochloride in the step (3) is 0.05-10: 90-99.5;

the mass ratio of the monomer mixed solution to the initiator solution in the step (3) is 65-99: 1-35;

the acrylic monomer of the amino hydrochloride is at least one of 2-amino ethyl methacrylate hydrochloride, 2-amino butyl methacrylate hydrochloride and 2-amino amyl methacrylate hydrochloride; the acrylamide monomer of the amino hydrochloride is at least one of N- (3-aminopropyl) methacrylamide hydrochloride, N- (4-aminobutyl) methacrylamide hydrochloride and N- (5-aminopentyl) methacrylamide hydrochloride;

the molar ratio of the 2-methacryloxyethyl phosphorylcholine to the acrylic acid ester monomer of the amino hydrochloride to the acrylic acid amide monomer of the amino hydrochloride in the step (1) is 7:1:2.

2. the method for producing an amino group-containing polymer according to claim 1, wherein: the reaction solvent in the step (1) and the reaction solvent in the step (2) are each independently selected from at least one of water, methanol, ethanol, isopropanol, dimethyl sulfoxide, ethyl acetate, toluene, N-dimethylformamide, tetrahydrofuran.

3. The method for producing an amino group-containing polymer according to claim 2, characterized in that: the initiator is peroxide and/or azo.

4. A process for the preparation of an amino group containing polymer according to claim 3, characterized in that: the acid liquid is at least one of phosphoric acid, sulfuric acid, carbonic acid, hydrochloric acid, lactic acid, citric acid and benzoic acid solution of corresponding reaction solvents.

5. An amino group-containing polymer produced by the process for producing an amino group-containing polymer according to any one of claims 1 to 4, characterized in that: the weight average molecular weight of the amino-containing polymer is 4000-90000 Da.

6. Use of an amino group containing polymer according to claim 5, characterized in that: the amino-containing polymer is applied to the surface coating of blood contact medical instruments.