CN117736359A - Phosphorylcholine antithrombotic polymer, coating, preparation method and application thereof - Google Patents
Phosphorylcholine antithrombotic polymer, coating, preparation method and application thereof Download PDFInfo
- Publication number
- CN117736359A CN117736359A CN202211124515.3A CN202211124515A CN117736359A CN 117736359 A CN117736359 A CN 117736359A CN 202211124515 A CN202211124515 A CN 202211124515A CN 117736359 A CN117736359 A CN 117736359A
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- Prior art keywords
- polymer
- solvent
- initiator
- solution
- phosphorylcholine
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- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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- Materials For Medical Uses (AREA)
Abstract
The invention discloses phosphorylcholine antithrombotic polymer, a coating, a preparation method and application thereof, and relates to the technical field of coating materials. The preparation method of the phosphorylcholine antithrombotic polymer comprises the following steps: polymerization stage: mixing a polymerization monomer and a styrene compound with a first solvent, reacting in the presence of an initiator, and separating a polymer after the reaction; crosslinking: and mixing the separated polymer with a crosslinking agent and a second solvent for reaction, and separating the crosslinked polymer after the reaction. The polymer obtained by polymerizing the polymerization monomer and the styrene compound in the presence of the initiator is crosslinked, so that the finally obtained polymer has good strength, the formed coating has good integrity, the stability in water is ideal, and the better anticoagulation effect is achieved.
Description
Technical Field
The invention relates to the technical field of coating materials, in particular to phosphorylcholine antithrombotic polymer, a coating, a preparation method and application thereof.
Background
Currently, there are a number of types of antithrombotic coatings that need to be applied to the interior surface of an aneurysm treatment device for this purpose, such as plasma deposited fluorine, plasma deposited glyme, phosphorylcholine, diamond-like carbon, fluorinated diamond-like carbon, polyvinylpyrrolidone, fluorinated ethylene propylene, polytetrafluoroethylene, polyvinylidene fluoride co-hexafluoropropylene, fluorophosphine, carboxybetaines, sulfobetaines, methacryloylated carboxybetaines, methacryloylated sulfobetaines, fluorosilanes, heparin or heparan molecules, hirudin, curcumin, thrombomodulin, prostacyclin, DMP 728 platelet GPIIb/IIIa antagonists, chitosan, sulfated chitosan, hyaluronic acid, tantalum doped titanium oxide, oxynitride, oxide layers, silicon carbide, and the like.
The Phosphorylcholine (PC) related part is mainly copolymerized with methacrylate compounds, and anchored to the surface to be coated through the hydrophobic region of phosphorylcholine, whereas the phosphorylcholine and methacrylate copolymerized coating has the problem of poor stability in aqueous phase.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide phosphorylcholine antithrombotic polymer and a preparation method thereof, which aim to improve the stability of a coating formed on a substrate by the polymer in a water phase.
The second object of the invention is to provide a phosphorylcholine antithrombotic coating and a preparation method thereof, aiming at improving the stability of the coating in an aqueous phase.
A third object of the present invention is to provide the use of the above phosphorylcholine antithrombotic coating for the preparation of blood contact devices.
The invention is realized in the following way:
in a first aspect, the present invention provides a method for preparing a phosphorylcholine antithrombotic polymer, comprising:
polymerization stage: mixing a polymerization monomer and a styrene compound with a first solvent, reacting in the presence of an initiator, and separating a polymer after the reaction;
crosslinking: and mixing the separated polymer with a crosslinking agent and a second solvent for reaction, and separating the crosslinked polymer after the reaction.
In an alternative embodiment, the styrenic compound is selected from at least one of styrene and divinylbenzene;
preferably, the polymeric monomer is selected from at least one of glycerophosphorylcholine, methacryloyl ethyl sulfobetaine and methacryloyl ethyl carboxybetaine;
preferably, the molar ratio of the polymerized monomer to the styrenic compound is (3-5): (5-7).
In an alternative embodiment, the method comprises:
polymerization stage: mixing a polymerization monomer, a styrene compound and a first solvent to obtain a first mixed solution, dissolving an initiator to obtain an initiator solution, dripping the initiator solution into the first mixed solution, reacting for 15-30h at 50-80 ℃, and mixing the solution with saline after cooling to separate out a polymer;
crosslinking: mixing the polymer obtained in the polymerization stage with a cross-linking agent and a second solvent to obtain a second mixed solution, reacting the second mixed solution at 70-90 ℃ for 15-30h, and mixing the second mixed solution with brine to precipitate the polymer after cooling;
preferably, the polymer is washed with water after precipitation of the polymer, both in the polymerization stage and in the crosslinking stage.
In an alternative embodiment, the first solvent and the second solvent are both mixed solvents of water and an organic solvent;
preferably, the first solvent is a mixed solvent formed by water and toluene, the volume ratio of the water to the toluene is 1 (4-8), and the total dosage of the first solvent for each gram of polymerized monomer is 15-20mL;
preferably, the second solvent is a mixed solvent formed by water, ethanol and toluene; the volume ratio of water to ethanol to toluene is 1 (5-9): 2-5, and the total dosage of the second solvent corresponding to each gram of polymer is 15-20mL.
In an alternative embodiment, the initiator used in the polymerization stage is selected from at least one of azobisisobutyronitrile and benzoyl peroxide;
preferably, the mass ratio of the initiator to the polymerized monomer is 0.5-2:100;
preferably, the initiator solution is obtained by dissolving an initiator in an organic solvent, wherein the concentration of the initiator in the initiator solution is 2-6mg/mL, and the dripping time of the initiator solution is 1-2h.
In an alternative embodiment, the crosslinking agent used in the crosslinking stage is selected from at least one of triethylamine and epichlorohydrin;
preferably, the cross-linking agent is used in a mass ratio to the polymer of (1-5): 100.
In a second aspect, the present invention provides a phosphorylcholine antithrombotic polymer prepared by the method of preparation of any of the preceding embodiments.
In a third aspect, the present invention provides a method for preparing a phosphorylcholine antithrombotic coating using the phosphorylcholine antithrombotic polymer of the foregoing embodiments;
preferably, phosphorylcholine antithrombotic polymer is mixed with a third solvent to obtain a coating solution with the mass fraction of 0.5-20%, and the coating solution is coated on the surface of a substrate and dried;
preferably, the third solvent is a mixed solution of water, ethanol and toluene.
In a fourth aspect, the present invention provides a phosphorylcholine antithrombotic coating prepared by the method of preparation of any of the preceding embodiments.
In a fifth aspect, the present invention provides the use of a phosphorylcholine antithrombotic coating according to the previous embodiments for the preparation of a blood contact device.
The invention has the following beneficial effects: the polymer obtained by polymerizing the polymerization monomer and the styrene compound in the presence of the initiator is crosslinked, so that the finally obtained polymer has good strength, the formed coating has good integrity, the stability in water is ideal, and the better anticoagulation effect is achieved.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides a preparation method of a phosphorylcholine antithrombotic coating, which utilizes phosphorylcholine antithrombotic polymer to form a coating on a substrate, wherein the phosphorylcholine antithrombotic polymer is prepared through two steps of polymerization and crosslinking. Specifically, the method comprises the following steps:
s1, polymerization stage
Mixing the polymerized monomer and the styrene compound with a first solvent, reacting in the presence of an initiator, and separating the polymer after the reaction. The double bond of the styrenic compound is opened under the action of an initiator to form a free radical, which then undergoes free radical polymerization, generally involving the processes of chain initiation, chain extension, chain transfer, and chain termination.
In the actual operation process, mixing a polymerization monomer, a styrene compound and a first solvent to obtain a first mixed solution, dissolving an initiator to obtain an initiator solution, dripping the initiator solution into the first mixed solution, reacting for 15-30h at 50-80 ℃, mixing the cooled initiator solution with saline water to separate out a polymer, and washing the obtained polymer with water to remove unreacted raw materials. The initiator is added dropwise, the temperature is controlled to 50-80 ℃, the dropwise addition is started, and the reaction is continued for 15-30h after the dropwise addition is completed.
Specifically, the reaction temperature may be 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃ and the like, and the reaction time may be 15h, 18h, 20h, 23h, 25h, 28h, 30h and the like.
In some embodiments, during the preparation of the first mixed solution, the raw materials and the first solvent are stirred while nitrogen is blown, so that the reaction is performed in an inert atmosphere, and free radical deactivation generated by the initiator is avoided.
In some embodiments, the styrenic compound is selected from at least one of styrene and divinylbenzene; the polymerization monomer is selected from at least one of glycerophosphorylcholine, methacryloyl ethyl sulfobetaine and methacryloyl ethyl carboxyl betaine; the molar ratio of the polymerized monomer to the styrene compound is (3-5): (5-7). The stability of the polymer forming coating is further improved by further controlling the raw materials and the dosage of the reaction.
Specifically, the molar ratio of the polymerized monomer to the styrene compound may be 3:5, 3:6, 3:7, 4:5, 4:6, 4:7, 5:5, 5:6, 5:7, etc., or may be any value between the above adjacent ratio values.
Further, the first solvent is a mixed solvent formed by water and an organic solvent, and the polymerization reaction can be smoothly performed by using the mixed solvent, and if water or the organic solvent is used alone, the polymerization reaction is difficult. In some embodiments, the first solvent is a mixed solvent of water and toluene in a volume ratio of 1 (4-8) (e.g., 1:4, 1:5, 1:6, 1:7, 1:8, etc.), and the total amount of the first solvent per gram of polymerized monomer is 15-20mL, e.g., 15mL, 16mL, 17mL, 18mL, 19mL, 20mL, etc.
In some embodiments, the initiator used in the polymerization stage is at least one selected from the group consisting of azobisisobutyronitrile and benzoyl peroxide, and is typically initiated by an initiator, with azobisisobutyronitrile or benzoyl peroxide being the initiator for the polymerization reaction to ensure the stability and effectiveness of the coating. The initiator solution is obtained by dissolving an initiator in an organic solvent, and the organic solvent used for dissolving the initiator is not limited, and may be tetrahydrofuran or the like.
Further, the mass ratio of the initiator to the polymerization monomer is 0.5-2:100, such as 0.5:100, 1.0:100, 1.5:100, 2.0:100, etc. The concentration of the initiator in the initiator solution is 2-6mg/mL, the dripping time of the initiator solution is 1-2h, and the reaction rate is better controlled by slowly dripping, so that a uniform polymer is obtained. The concentration of the initiator solution may be 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, etc., and the dropping time of the initiator solution may be 1h, 1.5h, 2.0h, etc.
S2, crosslinking stage
And mixing the separated polymer with a crosslinking agent and a second solvent for reaction, separating the crosslinked polymer after the reaction, and further crosslinking to obtain the polymer with the molecular weight meeting the requirement for forming the coating.
In the actual operation process, the polymer obtained in the polymerization stage is mixed with a cross-linking agent and a second solvent to obtain a second mixed solution, the second mixed solution is reacted for 15-30 hours at 70-90 ℃, and after the temperature is reduced, the second mixed solution is mixed with brine to separate out the polymer, and the obtained polymer can be washed with water to remove unreacted raw materials.
Specifically, the reaction temperature may be 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ and the like, and the reaction time may be 15h, 18h, 20h, 23h, 25h, 28h, 30h and the like. If the reaction temperature is too low, the reaction cannot proceed, and if the reaction temperature is too high, the polymerization degree of the obtained polymer is too high, and the polymer is difficult to dissolve and form a coating layer.
Further, the second solvent is a mixed solvent formed by water and an organic solvent, and the crosslinking reaction can be smoothly performed by using the mixed solvent, and if water or the organic solvent is used alone, the crosslinking reaction is difficult to react. In some embodiments, the second solvent is a mixed solvent formed by water, ethanol and toluene, the volume ratio of the water, the ethanol and the toluene is 1 (5-9): (2-5), the total dosage of the second solvent for each gram of polymer is 15-20mL, and the proportion and the dosage of the mixed solvent are controlled within the range, so that the polymer can be well dissolved.
Specifically, the volume ratio of water, ethanol and toluene is 1:5:2, 1:6:3, 1:7:4, 1:8:4, 1:9:5, etc.; the total amount of the second solvent per gram of polymer is 15mL, 16mL, 17mL, 18mL, 19mL, 20mL, etc.
In some embodiments, the crosslinking agent employed in the crosslinking stage is selected from at least one of triethylamine and epichlorohydrin; triethylamine and epichlorohydrin are used as cross-linking agents of the polymers to ensure the effectiveness and stability of the coating. The mass ratio of the cross-linking agent to the polymer is (1-5) 100, such as 1:100, 2:100, 3:100, 4:100, 5:100, etc.
S3, forming a coating
The phosphorylcholine antithrombotic polymer prepared by the method forms a coating on a substrate, and gives the antithrombotic effect to the material.
In the actual operation, the phosphorylcholine antithrombotic polymer is mixed with the third solvent to obtain a coating solution with a mass fraction of 0.5-20% (preferably, may be 0.5-2.0%), the coating solution is applied to the surface of the substrate, and the substrate is dried. The preparation of the coating can be completed by adopting a conventional coating process, and the prepared antithrombotic coating can be further applied to the preparation of blood contact devices, such as aneurysm treatment devices and the like.
In some embodiments, the third solvent is a mixed solution of water, ethanol and toluene, the ratio of water, ethanol and toluene is not limited, and the amount of the third solvent is not limited, so that the polymer can be well dissolved to facilitate forming the coating. The process of forming the coating layer is not limited to the mixed solvent, and a single water or organic solvent may be used, so that the polymer can be well dissolved.
Specifically, the drying mode is not limited, and a drying or baking mode may be adopted.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment provides a preparation method of a phosphorylcholine antithrombotic coating, which comprises the following steps:
(1) 0.8g of styrene was dissolved in 30mL of toluene, then a solution of glycerophosphorylcholine (2.0 g) dissolved in 5mL of water was added thereto, the temperature was raised and nitrogen gas was blown, 0.02g of azobisisobutyronitrile was dissolved in 5mL of tetrahydrofuran, and when the temperature reached 75 ℃, dropwise addition of azobisisobutyronitrile solution was started, after the completion of dropwise addition, nitrogen gas was stopped, and the temperature was maintained for reaction for 24 hours. After the reaction was completed and cooled to room temperature, the reaction solution was poured into a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(2) The washed polymer was added to a mixed solution of triethylamine, water, ethanol and toluene, wherein the volumes of ethanol, toluene and water were 20mL, 10mL and 3mL, respectively, and triethylamine was 0.1g. The temperature was raised to 80℃and the reaction was carried out for 24 hours. After the temperature is reduced to room temperature, pouring the mixture into salt water to precipitate a polymer, and cleaning the polymer.
(3) The crosslinked polymer was prepared as a 1.0% mass fraction solution consisting of water, ethanol and toluene (the volume ratio of water, ethanol and toluene was 1:6:3, the same applies below). And (3) coating the prepared solution on the surface of the material to be coated, and airing or drying.
Example 2
The embodiment provides a preparation method of a phosphorylcholine antithrombotic coating, which comprises the following steps:
(1) 0.9g of divinylbenzene was dissolved in 30mL of toluene, then a solution of glycerophosphorylcholine (2.0 g) dissolved in 5mL of water was added thereto, the temperature was raised and nitrogen gas was blown, 0.02g of azobisisobutyronitrile was dissolved in 5mL of tetrahydrofuran, and when the temperature reached 75 ℃, dropwise addition of azobisisobutyronitrile solution was started, after the completion of dropwise addition, nitrogen gas was stopped, and the temperature was maintained for reaction for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(2) The washed polymer was added to a mixed solution of triethylamine, water, ethanol and toluene, wherein the volumes of ethanol, toluene and water were 20mL, 10mL and 3mL, respectively, and the triethylamine was 5g. The temperature was raised to 80℃and the reaction was carried out for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(3) The crosslinked polymer was formulated as a 1.0% mass fraction solution consisting of water, ethanol and toluene. And (3) coating the prepared solution on the surface of the material to be coated, and airing or drying.
Example 3
The embodiment provides a preparation method of a phosphorylcholine antithrombotic coating, which comprises the following steps:
(1) 0.9g of divinylbenzene was dissolved in 30mL of toluene, then a solution of glycerophosphorylcholine (2.0 g) dissolved in 5mL of water was added thereto, the temperature was raised and nitrogen gas was blown, 0.03g of benzoyl peroxide was added to 5mL of tetrahydrofuran, and when the temperature reached 75 ℃, dropwise addition of the benzoyl peroxide solution was started, and after the completion of the dropwise addition, the nitrogen gas was stopped and the temperature was maintained for reaction for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(2) The washed polymer was added to a mixed solution of triethylamine, water, ethanol and toluene, wherein the volumes of ethanol, toluene and water were 20mL, 10mL and 3mL, respectively, and the triethylamine was 5g. The temperature was raised to 80℃and the reaction was carried out for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(3) The crosslinked polymer was formulated as a 1.0% mass fraction solution consisting of water, ethanol and toluene. And (3) coating the prepared solution on the surface of the material to be coated, and airing or drying.
Example 4
The embodiment provides a preparation method of a phosphorylcholine antithrombotic coating, which comprises the following steps:
(1) 0.9g of divinylbenzene was dissolved in 30mL of toluene, then a solution of glycerophosphorylcholine (2.0 g) dissolved in 5mL of water was added thereto, the temperature was raised and nitrogen gas was blown, 0.03g of benzoyl peroxide was added to 5mL of tetrahydrofuran, and when the temperature reached 75 ℃, dropwise addition of the benzoyl peroxide solution was started, and after the completion of the dropwise addition, the nitrogen gas was stopped and the temperature was maintained for reaction for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(2) The washed polymer was added to a mixed solution of epichlorohydrin, water, ethanol and toluene, wherein the volumes of ethanol, toluene and water were 20mL, 10mL and 3mL, respectively, and epichlorohydrin was 10g. The temperature was raised to 80℃and the reaction was carried out for 24 hours. After the completion of the reaction and cooling to room temperature, the reaction solution was poured into 200mL of a 1.0wt% sodium chloride solution to precipitate a polymer, and the polymer was washed with purified water.
(3) The crosslinked polymer was formulated as a 1.0% mass fraction solution consisting of water, ethanol and toluene. And (3) coating the prepared solution on the surface of the material to be coated, and airing or drying.
Example 5
The only difference from example 1 is that: styrene was replaced with an equimolar amount of divinylbenzene.
Example 6
The only difference from example 1 is that: the azobisisobutyronitrile was replaced with an equivalent amount of benzoyl peroxide.
Example 7
The only difference from example 1 is that: the triethylamine was replaced with an equal amount of epichlorohydrin.
Example 8
The only difference from example 1 is that: and (3) preparing the crosslinked polymer into a solution with the mass fraction of 0.5%.
Example 9
The only difference from example 1 is that: and (3) preparing the crosslinked polymer into a solution with the mass fraction of 2.0%.
Example 10
The only difference from example 1 is that: and (3) preparing the crosslinked polymer into a solution with the mass fraction of 5.0%.
Comparative example 1
The only difference from example 1 is that: styrene was replaced with an equimolar amount of butyl methacrylate.
Comparative example 2
The only difference from example 1 is that: styrene was replaced with an equimolar amount of lauryl methacrylate.
Comparative example 3
The only difference from example 1 is that: the azobisisobutyronitrile was replaced with an equivalent amount of potassium persulfate.
Comparative example 4
The only difference from example 1 is that: the azobisisobutyronitrile was replaced with an equivalent amount of cumene hydroperoxide.
Comparative example 5
The only difference from example 1 is that: triethylamine was replaced with an equivalent amount of triallyl cyanurate.
Comparative example 6
The only difference from example 1 is that: the triethylamine was replaced with an equal amount of dicumyl peroxide.
Comparative example 7
The only difference from example 1 is that: step (1) changes 75 ℃ to 55 ℃.
Comparative example 8
The only difference from example 1 is that: step (2) changes the temperature of 80 ℃ to 60 ℃.
Test example 1
The antithrombotic effect and stability of the coating materials obtained in example 1, example 5 and comparative examples 1 to 2 were tested, and the results are shown in Table 1.
The testing method comprises the following steps:
(1) Coating anticoagulation experimental protocol:
a) Coagulation time measurement
And (3) placing the coated short tube on a test tube rack, placing the test tube rack in a water bath at 37 ℃, then extracting fresh dog blood by using a syringe, adding the dog blood into the short tube within 1 minute, starting timing, and stopping timing when the blood is coagulated to obtain the coagulation time.
b) Partial Thromboplastin Time (APTT) assay
Fresh dog blood was collected into a vacuum tube containing 3.8% wt/vol sodium citrate anticoagulant. Centrifuging the collected whole blood in a centrifuge, centrifuging at 3000r/min at 4deg.C for 15min, repeatedly washing with PBS (pH=7.4) buffer solution for three times, and removing supernatant to obtain Platelet Poor Plasma (PPP);
1mL of the resin was immersed in 2mL of PBS buffer solution for 1 hour, after the PBS solution was pipetted off, 0.5mL of fresh PPP was added, and the resin was taken out after incubation at 37℃for 1 hour, and APTT was measured by a fully automatic coagulometer.
(2) Coating stability experiment: placing the coated short tube on a test tube rack, adding pure water or physiological saline, sealing, and placing into a shaking table for shaking, wherein the shaking table is set at 150rpm and 25 ℃ for 2 hours. After the oscillation was completed, the solution was taken for ultraviolet absorption, and the abscission rate was calculated from the absorption peak at 570nm (the absorption peak corresponding to 1mg/mL was 100%).
Table 1 examples and comparative examples the materials were tested for antithrombotic effect and stability
Note that: (1) the specific time is the experimental average value, and the error is 5min;
(2) unstable in water means that there is a coating falling off.
Therefore, the application selects styrene and divinylbenzene to polymerize with phosphorylcholine, the obtained polymer has better strength, better coating integrity and better stability.
This is probably due to the fact that the benzene ring is contained in the compound adopted in the embodiment of the application, so that the polymer has better strength, the copolymer can generate hydrophobic action, polymer adhesive force, intermolecular action force and other acting forces with the surface to be coated, and the copolymer can exist stably in a water phase and is not easy to fall off. The polymers obtained in comparative examples 1-2 were linear copolymers, the coating strength was weaker than that of crosslinking, and the hydrophobic anchoring effect was also easily broken by other forces, resulting in easy damage and even detachment of the coated coating.
Test example 2
The antithrombotic effect and stability of the coating materials obtained in example 1, example 6 and comparative examples 3 to 4 were tested, and the results are shown in Table 2.
Table 2 examples and comparative examples the materials were tested for antithrombotic effect and stability
| Sample numbering | Initiator(s) | Coagulation time | APTT | Shedding rate |
| Example 1 | Azo diisobutyl cyanide | 90min | ＞100s | 0 |
| Example 6 | Benzoyl peroxide | 90min | ＞100s | 0 |
| Comparative example 3 | Potassium persulfate | 3min | 10s | 85％ |
| Comparative example 4 | Cumene hydroperoxide | 3min | 15s | 80％ |
Therefore, the stability and the effectiveness of the coating can be ensured by adopting the azodiisobutyl cyanide and the benzoyl peroxide as the initiator of the polymerization reaction.
Test example 3
The antithrombotic effect and stability of the coating materials obtained in example 1, example 7 and comparative examples 5 to 6 were tested, and the results are shown in Table 3.
TABLE 3 antithrombotic effect and stability test results of materials obtained in examples and comparative examples
| Sample numbering | Crosslinking agent | Coagulation time | APTT | Shedding rate |
| Example 1 | Triethylamine | 90min | ＞100s | 0 |
| Example 7 | Epichlorohydrin | 90min | ＞100s | 0 |
| Comparative example 5 | Triallyl cyanurate | 20min | 20s | 85％ |
| Comparative example 6 | Dicumyl peroxide | 20min | 25s | 80％ |
Therefore, the triethylamine and the epichlorohydrin are selected as the cross-linking agents of the polymers, so that the effectiveness and the stability of the coating can be ensured.
Test example 4
The antithrombotic effect and stability of the coating materials obtained in examples 1 and 8 to 10 were tested, and the results are shown in Table 4.
Table 4 examples and comparative examples the antithrombotic effect and stability test results of the materials were obtained
| Sample numbering | Solubility of mass | Coagulation time | APTT | Shedding rate |
| Example 8 | 0.5％ | 90min | ＞100s | 0 |
| Example 1 | 1.0％ | 90min | ＞100s | 0 |
| Example 9 | 2.0％ | 90min | ＞100s | 0.5％ |
| Example 10 | 5.0％ | 70min | ＞100s | 2％ |
It can be seen that the effect of the coating is optimal when the mass solubility of the polymer solution is 0.5% -2.0%, and can be guaranteed to be consistent with or better than that of the original grinding.
Test example 5
The stability of the coating materials obtained in example 1 and comparative examples 7 to 8 was measured, and the results are shown in Table 5.
Table 5 examples and comparative examples stability test results of materials
| Sample numbering | Reaction temperature | Crosslinking temperature | Shedding rate |
| Example 1 | 75℃ | 80℃ | 0 |
| Comparative example 7 | 55℃ | 80℃ | 99％ |
| Comparative example 8 | 75℃ | 60℃ | 90％ |
When the reaction temperature is low, the energy supply is low, the initiator cannot be decomposed or the decomposition speed is low, the chain initiation or chain growth cannot be performed, and the polymer cannot be formed or the polymerization degree is low; when the crosslinking temperature is low, the polymer reacts with the crosslinking agent difficultly or slowly, so that a three-dimensional network structure of the polymer cannot be formed, and the mechanical strength is low. When the reaction temperature is 75 ℃ and the crosslinking temperature is 80 ℃, the effect of the coating is optimal, and the coating can be ensured to be consistent with or better than the original grinding.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing a phosphorylcholine antithrombotic polymer, comprising:
polymerization stage: mixing a polymerization monomer and a styrene compound with a first solvent, reacting in the presence of an initiator, and separating a polymer after the reaction;
crosslinking: and mixing the separated polymer with a crosslinking agent and a second solvent for reaction, and separating the crosslinked polymer after the reaction.
2. The production method according to claim 1, wherein the styrenic compound is selected from at least one of styrene and divinylbenzene;
preferably, the polymeric monomer is selected from at least one of glycerophosphorylcholine, methacryloyl ethyl sulfobetaine and methacryloyl ethyl carboxybetaine;
preferably, the molar ratio of the polymerized monomer to the styrenic compound is (3-5): (5-7).
3. The preparation method according to claim 1 or 2, characterized by comprising:
polymerization stage: mixing the polymerization monomer, the styrene compound and the first solvent to obtain a first mixed solution, dissolving an initiator to obtain an initiator solution, dripping the initiator solution into the first mixed solution, reacting for 15-30h at 50-80 ℃, and mixing the solution with saline after cooling to separate out a polymer;
crosslinking: mixing the polymer obtained in the polymerization stage with a cross-linking agent and the second solvent to obtain a second mixed solution, reacting the second mixed solution for 15-30h at 70-90 ℃, and mixing the second mixed solution with saline after cooling to separate out the polymer;
preferably, the polymer is washed with water after precipitation of the polymer, both in the polymerization stage and in the crosslinking stage.
4. The method according to claim 3, wherein the first solvent and the second solvent are mixed solvents of water and an organic solvent;
preferably, the first solvent is a mixed solvent formed by water and toluene, the volume ratio of the water to the toluene is 1 (4-8), and the total dosage of the first solvent for each gram of the polymerized monomer is 15-20mL;
preferably, the second solvent is a mixed solvent formed by water, ethanol and toluene; the volume ratio of water to ethanol to toluene is 1 (5-9): 2-5, and the total dosage of the second solvent for each gram of polymer is 15-20mL.
5. The process according to claim 3, wherein the initiator used in the polymerization stage is at least one selected from the group consisting of azobisisobutyronitrile and benzoyl peroxide;
preferably, the mass ratio of the initiator to the polymerized monomer is 0.5-2:100;
preferably, the initiator solution is obtained by dissolving the initiator in an organic solvent, the concentration of the initiator in the initiator solution is 2-6mg/mL, and the dripping time of the initiator solution is 1-2h.
6. A method of preparing according to claim 3, wherein the crosslinking agent used in the crosslinking stage is selected from at least one of triethylamine and epichlorohydrin;
preferably, the cross-linking agent is used in an amount to polymer mass ratio of (1-5): 100.
7. A phosphorylcholine antithrombotic polymer prepared by the preparation method according to any one of claims 1 to 6.
8. A method for preparing a phosphorylcholine antithrombotic coating, characterized in that it is prepared using the phosphorylcholine antithrombotic polymer according to claim 7;
preferably, the phosphorylcholine antithrombotic polymer is mixed with a third solvent to obtain a coating solution with the mass fraction of 0.5-20%, and the coating solution is coated on the surface of a substrate and dried;
preferably, the third solvent is a mixed solution of water, ethanol and toluene.
9. A phosphorylcholine antithrombotic coating prepared by the preparation method according to any one of claims 1 to 8.
10. Use of the phosphorylcholine antithrombotic coating according to claim 9 in the preparation of blood contact devices.
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| CN202211124515.3A CN117736359A (en) | 2022-09-15 | 2022-09-15 | Phosphorylcholine antithrombotic polymer, coating, preparation method and application thereof |
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| CN202211124515.3A CN117736359A (en) | 2022-09-15 | 2022-09-15 | Phosphorylcholine antithrombotic polymer, coating, preparation method and application thereof |
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