阅读说明：本技术 一种双交联聚硫氨酯及其作为水凝胶敷料的应用 (Double-crosslinking polythiourethane and application thereof as hydrogel dressing ) 是由 汤杰 于 2019-10-04 设计创作，主要内容包括：本发明属于新材料领域。一种双交联聚硫氨酯及其作为水凝胶敷料的应用,该方法以含环氧树脂、丙烯酸、壳聚糖、多元胺等为原料,分别经过壳聚糖的酰胺化反应、环氧树脂的开环与成环反应、巯基-烯点击反应等多步骤反应完成,通过分子结构设计,调整聚合物结构以及优化聚合工艺,合成了一种双交联聚硫氨酯。该双交联材料不仅有效解决目前聚硫氨酯材料亲水性差,力学性能不足的缺陷,同时兼具抗菌抑菌的效用,可大大拓宽其应用领域。(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.)

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

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

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.

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

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 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:

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.

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:

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.

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:

(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.

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.

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.