CN115417963A

CN115417963A - Biocompatible polycarbonate polyurethane, preparation method and application

Info

Publication number: CN115417963A
Application number: CN202211134824.9A
Authority: CN
Inventors: 程荣恩; 钱成; 刘佳梅; 周静
Original assignee: Diascience Medical Co Ltd
Current assignee: Diascience Medical Co Ltd
Priority date: 2022-09-19
Filing date: 2022-09-19
Publication date: 2022-12-02
Also published as: WO2024060897A1

Abstract

The application relates to the field of medical polymer materials, and provides biocompatible polycarbonate polyurethane, a preparation method and application thereof. Wherein the biocompatible polycarbonate polyurethane comprises a reaction product of the directional polymerization of the following raw material components: the polyurethane polymer comprises (a) an isocyanate composition, (b) a component containing an isocyanate reactive group, (c) a hydroxyl or amino terminated compound, (d) a chain extender, (e) a modifying component and (f) a cross-linking agent, wherein a polyurethane chain segment obtained after the components (a), (b) and (d) are reacted contains an active site. The biocompatible polycarbonate polyurethane has good biocompatibility, and the sensor prepared by taking the biocompatible polycarbonate polyurethane as an outer membrane has excellent in-vitro test performance.

Description

Biocompatible polycarbonate polyurethane, preparation method and application

Technical Field

The application belongs to the field of medical polymer materials, and particularly relates to biocompatible polycarbonate polyurethane, a preparation method and application thereof.

Background

Polyurethanes (PU) are mainly obtained by addition reaction of diisocyanate compositions with polyether or polyester polyols as basic raw materials, and are produced in 1937 by otto bayer et al.

The polyurethane material has excellent mechanical property, fatigue resistance, biocompatibility and processability and is widely applied to the aspects of artificial organs, interventional catheters, tube wound dressings, medical adhesives and the like. The polyurethane material has the advantages of simple synthesis, designability of molecular structure, good stability and the like, and is widely applied to the field of biomedical materials, and the polycarbonate polyurethane material has better stability and biocompatibility than other types of polyurethane materials. Among polyester and polyether polyols, polycarbonate diol (PCDL) is the most excellent in overall performance, and studies on degradability and blood compatibility of a polycarbonate polyurethane material prepared therefrom have been drawing attention.

Polyurethane materials also have corresponding applications in the field of implantable medical devices for determining the presence and concentration of biological analytes, in which polyurethane is mainly present in the form of a film, the main function being to protect against its excellent biocompatibility, by modifying and/or physically doping the polyurethane so that the film of polyurethane is simultaneously rendered locally permselective for biological analytes such as: and the diffusion of glucose, lactic acid, uric acid, beta-hydroxybutyric acid and the like is controlled, so that the electrochemical detection is further completed. The conventional polyurethane is linear polyurethane, and the polyurethane film obtained through modification and/or physical doping is poor in stability and reproducibility, and along with long-time storage, the property of the polyurethane film is changed along with certain molecular migration, so that the test result deviation is caused.

This background is not intended to limit the scope of the claimed subject matter nor is it intended to limit the claimed subject matter to implementations that solve any or all of the disadvantages or problems noted above.

It should be noted that the above background section merely represents an understanding of the applicant's related art and does not constitute prior art.

Disclosure of Invention

In view of the problems of the prior art, it is an object of the present invention to provide a biocompatible polycarbonate polyurethane having good biocompatibility and performance stability.

To this end, as an aspect of the present application, there is provided a biocompatible polycarbonate polyurethane comprising the reaction product of the stereoregular polymerization of the following raw material components:

(a) An isocyanate composition, an isocyanate having at least two isocyanate groups,

(b) A component containing isocyanate-reactive groups selected from polycarbonate polyols,

optionally (c), a hydroxyl or amino terminated compound,

(d) A chain extender selected from a trifunctional or higher-functional polyamine, a trifunctional or higher-functional polyol, or a mixture thereof,

(e) A modifying component selected from a biocompatible compound, an amino-terminated hydrophilic compound, or mixtures thereof, and

optionally (f) a crosslinking agent, (f) being different from said (d).

Among them, the polyurethane segment obtained by the reaction of (a), (b) and (d) contains an active site, and more preferably, the active site is located on a branch in the polyurethane segment.

Wherein the active site is a reactive functional group such as an amino group and/or a hydroxyl group located on a branch chain in the polyurethane segment.

In accordance with the biocompatible polycarbonate polyurethane provided herein, preferably component (a) is one or more of a diisocyanate and/or a polyisocyanate, in particular toluene diisocyanate, diphenylmethane diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate, naphthalene diisocyanate, p-phenylene diisocyanate, lysine diisocyanate, 1,4-cyclohexane diisocyanate, methylcyclohexyl diisocyanate, norbornane diisocyanate, tetramethyl m-xylylene diisocyanate, cyclohexane dimethylene diisocyanate, trimethyl-1,6-hexamethylene diisocyanate, xylylene diisocyanate.

Similarly, the isocyanate composition in component (a) may be selected from the group consisting of derivatives of the above isocyanates, specifically 4,4' -methylenebis (phenyl isocyanate), dicyclohexylmethane 4,4' -diisocyanate, 4,4' -diphenylmethane diisocyanate, and the like.

According to the biocompatible polycarbonate polyurethane provided herein, preferably component (b) is a polycarbonate diol, in particular 1,6-hexanediol polycarbonate diol, caprolactone diol, butylene carbonate diol, cyclohexane dimethanol-1,6-hexanediol polycarbonate diol, 1,5 pentanediol-1,6-hexanediol polycarbonate diol, ethylene carbonate diol, propylene carbonate diol, 1,4 butanediol-1,6-hexanediol polycarbonate diol, or a mixture of at least two thereof.

According to the biocompatible polycarbonate polyurethane provided by the application, the raw material component preferably comprises optional (c), wherein the optional (c) is particularly dihydroxyl terminated polysiloxane, diamino terminated polysiloxane or a mixture thereof, and the molecular weight is preferably 1000-6000Da, and more preferably 1500-3000Da.

In accordance with the biocompatible polycarbonate polyurethane provided herein, preferably, component (d) is specifically tris (2-aminoethyl) amine, triethanolamine, 4,4',4 "-triaminotriphenylmethane, or a mixture of at least two thereof.

In accordance with the biocompatible polycarbonate polyurethane provided herein, component (e) is preferably a biocompatible compound, in particular 2-methacryloyloxyethyl phosphorylcholine, or a quaternary ammonium salt.

According to the biocompatible polycarbonate polyurethane provided herein, preferably, component (e) is an amino-terminated hydrophilic compound, in particular an amino-terminated polyethylene glycol; more preferably, the amino-terminated hydrophilic compound is an amino-terminated polyethylene glycol, and further, the prepared polycarbonate polyurethane has a network structure.

According to the biocompatible polycarbonate polyurethane provided by the application, the raw material component preferably comprises optional (f), and the optional (f) is specifically any one of glutaraldehyde, glutaric acid and carbodiimide.

As a second aspect of the present application, there is provided a method for preparing the above biocompatible polycarbonate polyurethane, the method comprising the steps of:

(1) Forming an isocyanate terminated polyurethane prepolymer A by reacting (a), (b) and optionally (c) in an organic solvent,

(2) Chain extending the polyurethane prepolymer A by the step (d) to obtain a polyurethane prepolymer B,

(3) Modifying a polyurethane prepolymer B with (e) and optionally (f), and

optionally, a separation and purification step.

According to the process for the preparation of a biocompatible polycarbonate polyurethane provided herein, preferably the molar amount of isocyanate groups in (a) is X and the molar total amount of hydroxyl and/or amino groups in (b) is Y, the ratio of X to Y is 1<X/Y ≦ 1.5.

According to the method for preparing the biocompatible polycarbonate polyurethane provided by the application, the organic solvent is preferably an organic solvent which does not contain active hydrogen groups in a molecule, and particularly is an organic solvent which is inactive to isocyanate groups or has lower activity than the active hydrogen groups of the components (a), (b), (c), (d), (e), (f) and the like.

For example, ketone solvents (acetone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (toluene, o-xylene, m-xylene, etc.), aliphatic hydrocarbon solvents (pentane, cyclopentane, methylcyclohexane, t-hexylcyclohexane, etc.), alcohol solvents (ethanol, t-butanol, etc.), ether solvents (diethyl ether, t-butyl methyl ether, tetrahydrofuran THF, 2-methyl tetrahydrofuran), ester solvents (ethyl acetate, butyl acetate, isobutyl acetate, etc.), glycol ether ester solvents (ethylene glycol ethyl ether acetate, propylene glycol methyl ether acetate, etc.), amide solvents (dimethylformamide, N-dimethylformamide DMF, dimethylacetamide, N-methyl-2-pyrrolidone, etc.), etc. may be used.

According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, the mass ratio of the organic solvent to the raw material components is preferably 100 (5-20).

According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, the polyurethane prepolymer B preferably contains active amino and/or hydroxyl.

According to the method for preparing the biocompatible polycarbonate polyurethane provided by the application, the content of (c) is preferably 0-30 wt% based on 100 wt% of the polyurethane prepolymer A.

According to the preparation method of the biocompatible polycarbonate polyurethane provided by the application, preferably, the ratio of the molar total amount of amino and/or hydroxyl in the (d) to the molar amount of isocyanate groups in the polyurethane prepolymer A is 0.8 to 1.2.

According to the method for preparing the biocompatible polycarbonate polyurethane provided by the present application, the content of (e) is preferably 10 to 20 wt% based on 100 wt% of the polyurethane prepolymer B.

According to the process for preparing a biocompatible polycarbonate polyurethane provided herein, preferably, the content of (f) is 0 to 10% by weight, based on 100% by weight of (e).

As a third aspect of the present application, there is provided the use of the biocompatible polycarbonate polyurethane described above. For example, after the separated and purified biocompatible polycarbonate polyurethane is dissolved in an organic solvent, a thin film is formed on the surface of a medical device, especially an implantable medical device, by coating methods such as blade coating, dot coating, dipping and the like, so that the compatibility of the medical device and organisms is improved.

According to the application of the biocompatible polycarbonate polyurethane provided by the present application, preferably, the components (a), (b), (c), (d), (e) and (f) are contained in the biocompatible polycarbonate polyurethane, and the film made of the biocompatible polycarbonate polyurethane has selective permeability, for example, can permeate biological metabolites such as glucose, lactic acid, uric acid and beta-hydroxybutyric acid, or has oxygen permeability, and can be used for an outer membrane of an implantable electrochemical sensor, for example.

Compared with the prior art, the technical scheme of the application has the following beneficial effects:

(1) The biocompatible polycarbonate polyurethane disclosed by the application realizes directional polymerization by adjusting the types of raw material components, and the sensor prepared by taking the biocompatible polycarbonate polyurethane as an outer membrane has excellent in-vitro test performance;

(2) The polycarbonate polyurethane is subjected to chain extension by introducing polyamine and/or polyhydroxy compound and the like as chain extenders, active sites such as active amino and/or hydroxyl are added on the chain segment of the polycarbonate polyurethane, and the polycarbonate polyurethane is further modified, for example, the biocompatibility of the polycarbonate polyurethane is increased;

(3) Unlike linear polyurethanes that use isocyanate as the rigid segment and polyether/polyester diol as the flexible segment in the prior art, the biocompatible polycarbonate polyurethane disclosed herein adds active sites for the branching reaction.

Drawings

FIG. 1 is a microphotograph of platelet adsorption of a polyurethane film prepared by the method of example 1 disclosed herein.

FIG. 2 is a microphotograph of platelet adsorption of the polyurethane film prepared by the procedure of comparative example 1 disclosed in the present application.

FIG. 3 is a graph of the response current of a glucose sensor prepared using the polyurethane disclosed in example 2 and comparative example 1 disclosed in the present application.

Fig. 4 is a response curve of sensor current versus oxygen content in a low oxygen environment when biocompatible polycarbonate polyurethane prepared in example 3 of the present application is applied to an electrochemical sensor in a thin film form.

Detailed Description

In order that the technical features and contents of the present application can be understood in detail, preferred embodiments of the present application will be described in more detail below. While the preferred embodiments of the present application have been described in the examples, it should be understood that the present application may be embodied in various forms and should not be limited by the embodiments set forth herein. Experimental methods without specifying specific conditions in the following examples of the present application, generally in accordance with conventional conditions, or according to the preparation

Conditions recommended by the manufacturer. The various chemicals used in the examples are commercially available.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

The term "isocyanate-reactive group" in the present application refers to a zerewitinov-active hydrogen-containing group, which is generally understood in the art to mean a hydroxyl group (OH), a carboxyl group (COOH), an amino group (NHx).

The term "optional" in this application means that in certain embodiments, the feedstock components or steps may be selected; in other embodiments, the feedstock components or steps may not be selected.

The term "and/or" in the present application refers to an association relationship describing an associated object, meaning that three relationships may exist, e.g., a and/or B, may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For numerical ranges, each range between its endpoints and individual point values, and each individual point value can be combined with each other to give one or more new numerical ranges, and such numerical ranges should be construed as specifically disclosed herein.

The room temperature or room temperature referred to in the following examples means a room temperature at about 25 ℃ and the glucose solution used was glucose buffer solutions (G-PBS) having different concentrations.

The present application will be described in detail with reference to specific examples.

Example 1

The method comprises the following specific steps:

(1) At normal temperature, 4g of polycarbonate 1,6-hexanediol glycol which is subjected to water removal and oxygen removal is dissolved in 50ml of N, N-dimethylformamide; heating to 40-60 deg.C;

(2) At normal temperature, 0.6g of 4,4' -diphenylmethane diisocyanate is dissolved in 50ml of N, N-dimethylformamide; slowly adding the prepolymer into the 1,6-hexanediol polycarbonate solution obtained in the step (1) for continuous reaction to obtain a prepolymer A;

(3) Adding 0.105ml of tri (2-aminoethyl) amine ((NH 2CH2CH 2) 3N) into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain prepolymer B;

(4) Adding 0.071g of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) into prepolymer B, cooling to 40-50 deg.C, and continuing until the reaction is finished.

Comparative example 1

The method comprises the following specific steps:

(3) And (3) adding 0.071g of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) into the prepolymer A, cooling to 40-50 ℃, and continuing until the reaction is finished.

The polyurethane film formed by the way of blade coating after the polyurethane prepared by the above steps is separated and purified, and fig. 1 and fig. 2 respectively show the platelet adsorption micrographs of the polyurethane film in the example 1 and the comparative example 1, and it is clear from the micrographs that the polycarbonate polyurethane is further grafted and modified by adding 2-Methacryloyloxyethyl Phosphorylcholine (MPC) on the basis that the active sites of the polycarbonate polyurethane are added by tris (2-aminoethyl) amine, so that the adsorption of the polycarbonate polyurethane on the platelets can be effectively reduced, and the effective service life of the film in vivo application can be prolonged.

The polyurethane film formed by the way of blade coating after separating and purifying the polyurethane prepared according to the above steps, and fig. 1 and fig. 2 show the platelet adsorption micrographs of the polyurethane film in example 1 and comparative example 1, respectively, and it is clear from the micrographs that the polyurethane film containing modified component MPC can effectively reduce the platelet adsorption and can improve the effective service life of the film in vivo application.

The platelet adsorption experiment procedure and parameters were as follows: a healthy human blood was taken, sodium citrate at a concentration of 3.8% was added as an anticoagulant, centrifugation was performed at 1000r/min for 10min, platelet Rich Plasma (PRP) in the upper layer was collected, diluted with physiological saline (platelet rich plasma/physiological saline = 1/4.5), and then a membrane sample (1 cm X1 cm) was placed in the above diluted solution, and the temperature was maintained at 37 ℃ for 0.5h. The sample was taken out, washed 3 times with phosphate buffer (PBS, pH = 7.4), and fixed with 2% glutaraldehyde solution at 4 ℃. After 24h, the platelets were dried at room temperature, observed for platelet adsorption under a light microscope (Motic) model DMBA400, and counted by using a photomicrograph technique.

Example 2

The method comprises the following specific steps:

(3) Adding 0.176ml of tri (2-aminoethyl) amine into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain a prepolymer B;

(4) And (3) adding 0.071g of 2-methacryloyloxyethyl phosphorylcholine to the prepolymer B, and cooling to 40-50 ℃ to obtain prepolymer C.

(5) And (3) adding 0.36g of diamino end-capped polyethylene glycol into the prepolymer C to 40-50 ℃, and reacting until the reaction is finished.

After the polycarbonate polyurethane prepared in the above example 2 and comparative example 1 was separated and purified, a thin film (outer film) was formed on the outer surface of the electrochemical biosensor by dip coating, and the response current curve of the test was performed in glucose solutions of different concentrations.

The electrochemical biosensor is a double-electrode electrochemical sensor disclosed in the prior art (CN 114767105A), wherein the working electrode is platinum iridium alloy, and the reference electrode is a silver/silver chloride electrode.

Fig. 3 shows response current curves of glucose sensors prepared by using different outer membranes (example 2 and comparative example 1), and it can be seen that the addition of the polyurethane membrane modified by diamino terminated polyethylene glycol in example 2 has a good diffusion-limiting effect on glucose, which is a small molecular substance to be detected, and the prepared sensor has excellent in-vitro linearity. The sensor prepared without any optimized polyurethane film in comparative example 1 had no glucose diffusion channel and could not be used for glucose detection.

In other embodiments, the glucose diffusion channel formed by modifying the polyurethane film with the diamino terminated polyethylene glycol or the amino terminated polyethylene glycol is also applicable to small molecules such as lactic acid, uric acid, ascorbic acid and the like. In other embodiments, the flux of small molecule diffusion can be varied by varying the amount of cross-linking agent and the amount of polyethylene glycol.

Example 3

The method comprises the following specific steps:

(1) At normal temperature, 2g of polycarbonate 1,6-hexanediol glycol subjected to water removal and oxygen removal is dissolved in 20ml of N, N-dimethylformamide; heating to 40-60 deg.C;

(2) Dissolving 5g of bis (3-aminopropyl) terminated poly (dimethyl siloxane) in 30ml of N, N-dimethylformamide at normal temperature, and adding the solution into 1,6-hexanediol polycarbonate solution obtained in the step (1);

(3) At normal temperature, 0.75g of 4,4' -diphenylmethane diisocyanate is dissolved in 50ml N, N-dimethylformamide; slowly adding the prepolymer into the solution obtained in the step (2), and continuously reacting to obtain a prepolymer A;

(4) Adding 0.131ml of tri (2-aminoethyl) amine into the prepolymer A, heating to 70-90 ℃, and continuously reacting to obtain a prepolymer B;

(5) And (3) adding 0.088g of 2-methacryloyloxyethyl phosphorylcholine to the prepolymer B, and cooling to 40-50 ℃ to obtain a prepolymer C.

(6) Adding 0.45g of diamino end-capped polyethylene glycol into the prepolymer C to 40-50 ℃, and reacting until the reaction is finished;

after the polycarbonate polyurethane prepared in the above example 3 was separated and purified, a thin film was formed on the surface of the electrochemical biosensor by dip coating, and the test was performed in a 20mmol/L glucose solution.

The test method is as follows: in a test environment, inert gas such as nitrogen or argon is continuously introduced into the glucose solution (20 mmol/L) to drive away oxygen in the glucose solution, and an oxygen analyzer is used for real-time monitoring, wherein a specific test result is shown in fig. 4.

Referring to fig. 4, the performance of the sensor is hardly affected by the oxygen content, and it can be seen that the introduction of silane into the biocompatible polycarbonate polyurethane disclosed in the present application can also improve the oxygen permeability of the polyurethane film layer, thereby ensuring that the electrochemical sensor requiring oxygen to participate in the reaction can also perform effective detection in a low-oxygen environment (0.6 to 0.9 mg/L) of a human body.

In other embodiments, a cross-linking agent such as glutaraldehyde, glutaric acid, EDC, etc. may be added to the composition of example 3 to promote the cross-linking reaction between the components.

While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of protection. Indeed, the various features and attributes disclosed herein may be combined in different ways to form additional embodiments, all of which are within the scope of the present application.

While this application provides certain preferred embodiments and applications, other embodiments that are apparent to those of ordinary skill in the art, including embodiments that do not provide all of the features and advantages described herein, are also within the scope of this application.

Claims

1. A biocompatible polycarbonate polyurethane, comprising the reaction product of the directional polymerization of the following raw material components:

(a) An isocyanate composition which is an isocyanate having at least two isocyanate groups,

(b) An isocyanate-reactive group containing component selected from a polycarbonate polyol, a polycarbonate polyamine, a polycarbonate polyacid, or mixtures thereof,

optionally (c), a hydroxyl or amino terminated compound,

optionally (f) a crosslinking agent, said (f) being different from said (d);

the polyurethane chain segment obtained after the reaction of the (a), (b) and (d) contains active sites.

2. The polycarbonate polyurethane of claim 1, wherein: the raw material components comprise the (c), and the (c) is selected from dihydroxy terminated polysiloxane, diamino terminated polysiloxane or a mixture thereof.

3. The polycarbonate polyurethane of claim 1, wherein: and (d) is selected from tris (2-aminoethyl) amine, triethanolamine, 4,4', 4' -triaminotriphenylmethane, tetraethylamine, or a mixture of at least two thereof.

4. The polycarbonate polyurethane of claim 1, wherein: said (e) is selected from said biocompatible compound selected from 2-methacryloyloxyethyl phosphorylcholine, or a quaternary ammonium salt.

5. The polycarbonate polyurethane of claim 1, wherein: the (e) is selected from the amino-terminated hydrophilic compound, and the amino-terminated hydrophilic compound is amino-terminated polyethylene glycol or amino-terminated polyethylene glycol with two ends.

6. The polycarbonate polyurethane of claim 5, wherein: the (e) is double-end amino-terminated polyethylene glycol, and the polycarbonate polyurethane has a network structure.

7. The polycarbonate polyurethane of claim 1, wherein: the raw material components comprise the (f), and the (f) is any one selected from glutaraldehyde, glutaric acid and EDC.

8. A process for preparing a polycarbonate polyurethane according to any of claims 1 to 7, wherein the preparation protocol comprises the steps of:

(1) Forming an isocyanate terminated polyurethane prepolymer A by reacting said (a), said (b) and optionally said (c) in an organic solvent,

(3) Modifying said polyurethane prepolymer B with said (e) and optionally said (f), and

optionally, a separation and purification step.

9. The method of claim 8, wherein: the molar weight of the isocyanate group in the (a) is X, the molar total amount of the hydroxyl group and/or the amino group in the (b) is Y, and the ratio of the X to the Y is 1<X/Y which is less than or equal to 1.5.

10. The method of claim 8, wherein: the polyurethane prepolymer B contains active amino and/or hydroxyl.

11. The method of claim 8, wherein: the content of (c) is 0 to 30 wt% relative to 100 wt% of the polyurethane prepolymer A.

12. The method of claim 8, wherein: the molar ratio of the total molar amount of the amino and/or hydroxyl in the step (d) to the molar amount of the isocyanate group in the polyurethane prepolymer A is 0.8-1.2.

13. The method for producing according to claim 8, characterized in that: the content of (e) is 10-20 wt% relative to 100 wt% of the polyurethane prepolymer B.

14. The method of claim 8, wherein: the content of (f) is 0 to 10% by weight with respect to 100% by weight of (e).

15. Use of a polycarbonate polyurethane according to any of claims 1 to 7, wherein: the polycarbonate polyurethane is applied to an implantable medical device in a thin film form.