CN110628031A

CN110628031A - Double-crosslinking polythiourethane and application thereof as hydrogel dressing

Info

Publication number: CN110628031A
Application number: CN201910946329.XA
Authority: CN
Inventors: 汤杰
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-10-04
Filing date: 2019-10-04
Publication date: 2019-12-31

Abstract

The invention belongs to the field of new materials. The method takes epoxy resin, acrylic acid, chitosan, polyamine and the like as raw materials, and is finished by multi-step reactions such as amidation reaction of chitosan, ring opening and cyclization reaction of epoxy resin, sulfydryl-alkene click reaction and the like respectively, and the double-crosslinking polythiourethane is synthesized by molecular structure design, adjustment of polymer structure and optimization of polymerization process. The double-crosslinking material not only effectively overcomes the defects of poor hydrophilicity and insufficient mechanical properties of the conventional polythiourethane material, but also has antibacterial and bacteriostatic effects, and can greatly widen the application field of the double-crosslinking material.

Description

Double-crosslinking polythiourethane and application thereof as hydrogel dressing

Technical Field

The invention relates to double-crosslinking polythiourethane and application thereof as hydrogel dressing. The invention belongs to the field of new materials.

Background

Polyurethanes refer to a class of polymers containing a large number of urethanes in the molecular structure, also known as polyurethanes, abbreviated by PU. The basic raw materials comprise isocyanate, polyol, a catalyst, a chain extender and the like. Isocyanates form the hard segment structure in PU, and aromatic MDI and TDI, alicyclic IPDI, aliphatic HDI and the like are commonly used. The polyols form the elastic part of the PU structure, and are usually polyether polyols and polyester polyols, and the content of the polyols determines the hardness, flexibility and rigidity of the prepared PU. PU has many excellent properties, such as: excellent elasticity, toughness and processability.

The Polyurethane (PU) is a macromolecule with excellent biological performance, and the derivative polythiourethane has no toxic or side effect, excellent biocompatibility, better mechanical performance, processability and the like, and meets the medical requirements. Meanwhile, the polythiourethane structure contains a large amount of sulfur elements, so that the polythiourethane has higher refractive index and has great application prospect on artificial corneas.

In view of the defects that most products of the prior polythiourethane have poor hydrophilicity and insufficient mechanical strength, and the synthesis method of polyurethane is mostly adopted, the reaction of sulfydryl and isocyanate is accompanied with high preparation cost. Therefore, the preparation of the polythiourethane material with excellent mechanical properties has important significance.

Disclosure of Invention

The invention aims to overcome the defects of poor hydrophilicity, insufficient mechanical strength and high preparation cost in the prior art, and provides a double-crosslinking polythiourethane and a preparation method thereof.

The technical scheme adopted by the invention for solving the technical problems is as follows:

the structural formula of the double-crosslinking polythiourethane is shown as follows:

wherein: x is 1-3, y is 10-15, m is 3-6, n is 10-40; chitosan average molecular weight 5 kDa; r₁Is butyl, cyclohexyl, hexyl or ethyl.

A double-crosslinking polyurethane and a preparation method thereof comprise the following steps:

step 1): performing amidation reaction on acrylic acid and chitosan to obtain acrylic acid modified chitosan, which is marked as A;

step 2): ring-opening cyclization reaction of epoxy resin and carbon disulfide to obtain five-membered thiocarbonate, which is marked as B;

step 3): ring-opening reaction of pentabasic thiocarbonate B and polyamine to obtain polythiourethane, which is marked as C;

step 4): performing sulfydryl-alkene click reaction on polythiourethane C and acrylic acid modified chitosan A to obtain chitosan modified polythiourethane, and marking as D;

step 5): and (3) carrying out a sulfydryl-alkene click reaction on the chitosan modified polythiourethane D and acrylic acid to obtain the double-crosslinked polythiourethane, which is marked as F.

All expressed as mole fraction of reactive functional groups

Preferably, the step 1) is specifically:

adding 0.1-0.3 part of acrylic acid into 0.1 wt% of a mixed solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, activating carboxyl for 4h at 4 ℃ in an ice bath, then placing the solution into an acetic acid solution dissolved with 1 part of chitosan, reacting for 10-24h at 4 ℃, standing for 10-24h at room temperature, and carrying out suction filtration and vacuum drying on a reaction product for multiple times to obtain acrylic acid modified chitosan, wherein the mark is A;

the mass ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide is 5:1, the concentration of the acetic acid is 0.1mol/L, and the molar ratio of the acrylic acid to the chitosan according to the carboxyl group/amino group is 0.1-0.3.

Preferably, the step 2) is specifically:

dissolving 1 part of epoxy resin, 2-4% of catalyst and 1-1.1 parts of carbon disulfide in 40 parts of organic solvent a, carrying out ice bath, and stirring for 2 hours. Stirring at room temperature for 4-24h, carrying out reduced pressure distillation and concentration, adding 30 parts of deionized water, oscillating, adding 40 parts of organic solvent B, extracting, separating, drying with anhydrous sodium sulfate, and filtering to obtain a yellow product solution, which is marked as B;

the dosage of the catalyst is 2-4% of the mole number of the epoxy resin.

Preferably, the step 3) is specifically:

1.0 to 1.2 parts of polyamine is added to 1 part of B and stirred at room temperature for 0.5 to 2 hours, distilled under reduced pressure and dried in vacuum to obtain a yellow product which is marked as C.

Preferably, the step 4) is specifically:

adding 0.05-0.15 part of A and 0-3 wt% of photoinitiator PI into 1 part of C, uniformly mixing, and placing under UV illumination for 0.5-5min to initiate the click reaction of mercapto-alkene to obtain a target product, which is marked as D;

the dosage of the photoinitiator is 0-3 wt% of the mass of the A.

Preferably, the step 5) is specifically as follows:

adding 0.9-1.0 part of acrylic acid and 0-3 wt% of photoinitiator PI into 1 part of D, uniformly mixing, and placing under UV illumination for 0.5-5min to initiate the click reaction of mercapto-alkene to obtain a target product, which is marked as F;

the dosage of the photoinitiator is 0-3 wt% of the mass of the acrylic acid.

Preferably, the epoxy resin is 711, CY-183, 6206, or 6269.

Preferably, the catalyst is sodium iodide, lithium bromide or lithium chloride.

Preferably, the organic solvent a is tetrahydrofuran, N-dimethylformamide, acetone or acetonitrile; the organic solvent b is ethyl acetate, butyl acetate, hexane or chloroform.

Preferably, the photoinitiator PI is 184, 1173, BP, 2959, TPO or ITX.

The preparation method of the double-crosslinking polythiourethane dressing comprises the following steps:

(1) placing the polythiourethane material in an organic solvent c, washing for 3-5 times, filtering and drying; washing with deionized water for 3-5 times, filtering, and drying;

(2) and (3) preparing 10 wt% of aqueous solution of the polythiourethane material from the dried product, and carrying out freeze-drying treatment at-20 to-4 ℃ for 10 to 24 hours to obtain the polythiourethane material hydrogel dressing.

Preferably, the organic solvent c is tetrahydrofuran, N-dimethylformamide, acetone or butanone.

The preparation process of the double-crosslinking polythiourethane material provided by the invention is as follows:

the invention has the beneficial effects that:

(1) the invention provides a double-crosslinking polyurethane, which is prepared by molecular design, adjustment of polymer structure, epoxy resin as a raw material through epoxy ring-opening hybridization, sulfydryl-alkene click reaction and the like, overcomes the defect of insufficient performance of the traditional polyurethane or polysulfide single material, and has the performance advantages of wear resistance, tear resistance and high strength of polysulfide of polyurethane. And meanwhile, the use of a toxic isocyanate structure is avoided, the reaction is used as a biological material, and the whole reaction process is safe and environment-friendly.

(2) The invention provides a preparation method of double-crosslinking polyurethane, which adopts epoxy resin to provide rigid groups and improve mechanical strength; on the other hand, the generated ether bond provides a flexible group, and finally, effective matching of rigidity and flexibility is achieved.

(3) The invention provides a preparation method of double-crosslinking polyurethane, which adopts chitosan as one of raw materials, wherein firstly, the chitosan is a natural polymer widely existing in nature and has wide source; secondly, the chitosan structure provides a large amount of hydroxyl and ether bonds in a molecular chain, and hydrogen bonds can be formed; finally, the chitosan has natural antibacterial property, the acylation degree of about 15 percent is ensured to ensure the antibacterial property, and the biocompatibility is good.

(4) The invention provides a preparation method of double-crosslinking polythiourethane, which adopts polyamine as one of raw materials, wherein on one hand, the polyamine provides a chemical crosslinking point; on the other hand, the balance between the mechanical strength and elasticity can be adjusted according to the rigidity and toughness of the system.

(5) The invention provides a preparation method of double-crosslinking polythiourethane, which introduces a mercapto-alkene reaction system through molecular design, and firstly introduces the defects of high efficiency, simplicity, no volume shrinkage and no oxygen inhibition of mercapto-alkene reaction; secondly, a small amount of photoinitiator is added in the reaction process, and the reaction can still be carried out even in the absence of the photoinitiator; finally, the introduction of S atoms enhances the toughness of the system to a certain extent, increases the biocompatibility of the material and can still provide weak hydrogen bonds of S-H.

(6) The invention provides a double-crosslinking polythiourethane, which is prepared by molecular design, polymer structure adjustment and high-efficiency sulfydryl-alkene click reaction, and introduces hydroxyl, carboxyl and other hydrophilic groups while forming a double-crosslinking body, so that the defects of insufficient mechanical property, poor hydrophilicity, high preparation cost and the like of the polythiourethane material are overcome, the double-crosslinking polythiourethane material has antibacterial and bacteriostatic effects, has a great application prospect in the fields of biological materials (including hydrogel) and the like, and can be expected to meet a wide market space.

The specific implementation mode is as follows:

the present invention will be described in detail with reference to examples. It is to be understood, however, that the following examples are illustrative of embodiments of the present invention and are not to be construed as limiting the scope of the invention.

Example 1

Step 1) adding 0.1 part of acrylic acid into a 0.1 wt% mixed solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, activating carboxyl for 4h in an ice bath at 4 ℃, then placing the solution into an acetic acid solution dissolved with 1 part of chitosan, reacting for 10h at 4 ℃, standing for 10h at room temperature, and carrying out suction filtration and vacuum drying on the reaction product for multiple times to obtain acrylic acid modified chitosan (IR: 1641cm^-1、811cm^-1: c is generated; 3400cm^-1: O-H, N-H becomes broader and weaker; 1657.92cm^-1: N-H is weakened), is marked as A;

the mass ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide is 5:1, the acetic acid concentration is 0.1mol/L, and the carboxyl/amino molar ratio of the acrylic acid to the chitosan is 0.1.

Step 2) dissolving 1 part of epoxy resin 6206, 2% lithium chloride (LiCl) and 1 part of carbon disulfide in 40 parts of Tetrahydrofuran (THF), carrying out ice bath, stirring for 2 hours, stirring at room temperature for 24 hours, carrying out reduced pressure distillation and concentration, adding 30 parts of deionized water, oscillating, adding 40 parts of chloroform for extraction, separating, drying with anhydrous sodium sulfate, and filtering to obtain a yellow product solution (IR: 910cm^-1: disappearance of epoxy group) as B;

the amount of LiCl was 2% by mole of the epoxy resin 6206.

Step 3) 1.2 parts of cyclohexanediamine was added to 1 part of B and stirred at room temperature for 0.5h, distilled under reduced pressure, purified to give a yellow product (IR: 2562cm^-1: -SH generation; 3335cm^-1: -generation of N-H; 701cm^-1: -C-S generation), denoted C.

And step 4) adding 0.05 part of A and 3 wt% of photoinitiator 184 into 1 part of C, uniformly mixing, placing under UV illumination for 0.5min, and initiating a mercapto-alkene click reaction to obtain a target product (IR: 2562cm^-1: -reduction of SH; 1641cm^-1、811cm^-1: c disappears) and is denoted as D;

the photoinitiator 184 was used in an amount of 3 wt% based on the mass of A.

And step 5) adding 1.0 part of acrylic acid and 3 wt% of photoinitiator 184 into 1 part of D, uniformly mixing, and placing under UV illumination for 0.5min to initiate the click reaction of mercapto-alkene, so as to obtain a target product (IR: 2562cm^-1: -SH disappearance; 1641cm^-1、811cm^-1: c disappears) and is denoted as D;

the photoinitiator 184 was used in an amount of 3 wt% based on the mass of A.

Examples 2-8, otherwise identical to example 1, differ as set forth in the following table:

the double-crosslinking polythiourethane material obtained in the specific example 1 is used as a base material of an application example, and is processed into the hydrogel dressing of the double-crosslinking polythiourethane material.

Application example 1

The preparation method of the double-crosslinking polythiourethane hydrogel dressing comprises the following steps:

(1) placing the polythiourethane material in tetrahydrofuran, washing for 5 times, filtering and drying; washing with deionized water for 5 times, filtering, and drying;

(2) and (3) preparing 10 wt% of aqueous solution of the polythiourethane material from the dried product, and carrying out freeze-drying treatment at-20 ℃ for 10 hours to obtain the polythiourethane material hydrogel dressing.

Application examples 2 to 5 were conducted in the same manner as in application example 1 except for the differences shown in the following Table

Practical example comparative example 1

preparing 10 wt% aqueous solution of the double-crosslinked polythiourethane material, and carrying out freeze-drying treatment at-20 ℃ for 10h to obtain the double-crosslinked polythiourethane material hydrogel dressing.

Practical example comparative example 2

(2) and (3) preparing 10 wt% aqueous solution of the polythiourethane material from the dried product, and carrying out freeze-drying treatment at-80 ℃ for 10 hours to obtain the polythiourethane material hydrogel dressing.

Practical example comparative example 3

(2) and (3) preparing 10 wt% aqueous solution of the polythiourethane material from the dried product, and carrying out air drying treatment at 50 ℃ for 10 hours to obtain the polythiourethane material hydrogel dressing.

Physical properties including porosity, equilibrium water content, air permeability, water loss rate, tensile strength and bacteriostatic rate of the chitosan-cellulose composite dressings prepared in application examples 1 to 5 and application examples 1 to 3 of the present invention were measured, respectively, and the results are shown in the following table.

The test method comprises the following steps:

1. and (3) porosity determination:

1) the sample was cut into a circle of diameter D and weighed, and m1 was noted;

2) measuring the thickness of the sample by a micrometer, and recording H;

3) the samples are respectively put into 10mL of absolute ethyl alcohol, and after 24 hours, the samples are taken out, the ethyl alcohol on the surface is wiped off, and the samples are weighed and recorded as m 2.

The porosity calculation formula is as follows:

porosity ═ 100% (m2-m1)/(ρ ethanol × V) —, where V ═ pi × (D/2)²×H。

2. Equilibrium Water Content (EWC) test: shearing hydrogel with a certain size, slightly sucking free water on the surface of the hydrogel with dust-free filter paper, weighing the mass W at saturated water content_sThen the mixture is put into a baking oven with the temperature of 100 ℃ to be dried to constant weight, taken out and cooled to room temperature, and the dry mass W is weighed_dThe equilibrium water content W of the hydrogel was calculated by the following equation_t％。

W_t％＝(W_s-W_d)÷ W_s × 100％ (1)

3. Determination of air Permeability

1) And (3) filling a certain amount of deionized water in the wide-mouth bottle, sealing the mouth of the wide-mouth bottle by using a material to be detected, and standing at room temperature for 24 hours.

The air permeability calculation formula is as follows:

air permeability is 24h water loss/control water loss x 100%.

4. Determination of Water loss

The water vapor transmission rate test of hydrogel films was measured according to ASTM E96-00 published by the U.S. Bureau of standards. The prepared hydrogel film was placed in a cylindrical plastic cup (diameter 36mm) containing 10ml of water, the rim of the cup being sealed with teflon tape to prevent any water vapor loss from the rim of the cup. The plastic cups were then placed in a desiccator containing a saturated solution of ammonium sulfate (relative humidity 79%) at 37 ℃. The slope of the weight loss as a function of the time between measurements was calculated. The Water Vapor Transmission Rate (WVTR) is calculated as follows from the slope:

water Vapor Transmission Rate (WVTR) (g/m2/day) slope × 24/a;

a in the formula represents the surface area of the test sample.

Wherein, the anhydrous gel covers: 3369 + -143 g/m 2/day;

water loss rate is the water vapor transmission rate of the hydrogel/water vapor transmission rate of the anhydrous gel coverage.

5. Measurement of tensile Strength, elongation at Break and elastic modulus

1) The material was cut to the same specification (length: 25mm, width: 2.5mm, thickness: 2mm) were placed on a universal tester for testing and data on tensile strength, elongation at break and elastic modulus were recorded.

6. And (3) antibacterial and bacteriostatic test:

according to GB4789.2-2010 food safety national standard food microbiology test colony total number determination, escherichia coli antibacterial and bacteriostatic experiments are carried out on the chitosan-cellulose composite dressing prepared in application examples 1-5 and application examples 1-3.

In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims

1. The double-crosslinking polyurethane is characterized by having a structural formula as follows:

2. A preparation method of double-crosslinking polythiourethane is characterized by comprising the following steps: all expressed as mole fraction of reactive functional groups

3. The method of claim 2, wherein the method comprises the steps of: the step 1) is specifically as follows:

the mass ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide is 5:1, the acetic acid concentration is 0.1mol/L, and the carboxyl/amino molar ratio of the acrylic acid to the chitosan is 0.1-0.3, preferably 0.2.

4. The method of claim 2, wherein the method comprises the steps of: the step 2) is specifically as follows:

dissolving 1 part of epoxy resin, 2-4% of catalyst and 1-1.1 parts of carbon disulfide in 40 parts of organic solvent a, carrying out ice bath, stirring for 2 hours, stirring for 4-24 hours at room temperature, carrying out reduced pressure distillation and concentration, adding 30 parts of deionized water, oscillating, adding 40 parts of organic solvent B, extracting, separating liquid, drying with anhydrous sodium sulfate, and filtering to obtain a yellow product solution, which is marked as B;

the dosage of the catalyst is 2-4% of the mole number of the epoxy resin.

5. The method of claim 2, wherein the method comprises the steps of: the step 3) is specifically as follows:

6. The method of claim 2, wherein the method comprises the steps of: the step 4) is specifically as follows:

adding 0.05-0.15 part of A and 0-3 wt% of photoinitiator PI into 1 part of C, uniformly mixing, and placing under UV illumination for 0.5-5min to initiate a mercapto-alkene click reaction to obtain chitosan modified polythiourethane, which is marked as D;

the dosage of the photoinitiator is 0-3 wt% of the mass of the A;

the photoinitiator PI is 184, 1173, BP, 2959, TPO or ITX.

7. The method of claim 2, wherein the method comprises the steps of: the step 5) is specifically as follows:

the dosage of the photoinitiator is 0-3 wt% of the mass of the acrylic acid.

8. The method of claim 4, wherein the method comprises the steps of: the epoxy resin is 711, CY-183, 6206 or 6269; the catalyst is sodium iodide, lithium bromide or lithium chloride; the organic solvent a is tetrahydrofuran, N, N-dimethylformamide, acetone or acetonitrile; the organic solvent b is ethyl acetate, butyl acetate, hexane or chloroform.

9. A preparation method of the double-crosslinking polyurethane hydrogel dressing comprises the following steps:

10. The method for preparing a bis-crosslinked polythiourethane hydrogel dressing according to claim 9, wherein: the organic solvent c is tetrahydrofuran, N-dimethylformamide, acetone or butanone.