Preparation method of polysorbate thymol ester-co-sorbate butenol ester hydrogel

Abstract

The invention belongs to the technical field of polymer hydrogel materials, and discloses a preparation method of polysorbate thymol ester-co-sorbate butenol ester hydrogel, which comprises the following steps: S1, synthesizing a sorbate thymol ester monomer TS; s2, synthesizing a butenol sorbate monomer BS; s3, synthesizing a polysorbate thymol ester-polysorbate butenol ester random copolymer PBS-ran-PTS (Poly ButyleneSulfonate-Poly Butenol Sulfonate) by virtue of copolymerization of the sorbate thymol ester monomer and the sorbate butenol ester monomer; and S4, mixing the random copolymer, 2-hydroxy-4 '-(2-hydroxyethoxy)-2-methyl propiophenone, acrylic acid AAC, acrylic acid N-hydroxysuccinimide ester AAC-NHS and tannic acid TA into tetrahydrofuran THF, performing ultrasonic stirring until the materials are fully dissolved, pouring the materials into a polytetrafluoroethylene mold, and performing curing to obtain organic gel. And placing the organic gel in deionized water for solvent exchange, and drying to obtain the finished product hydrogel. The hydrogel prepared by the invention has the advantages of high mechanical property, high adhesion, good stability and the like, the preparation method is simple and convenient, and the cost is low.

Description

Technical Field

[0001] The present invention belongs to the technical field of polymer hydrogel materials, and particularly relates to a preparation method of a poly(thymol sorbate)-co-(butenyl sorbate) hydrogel. Background Art

[0002] Trauma and bleeding are common events in daily life. Tissue adhesives, as materials for wound closure and promoting hemostasis, have received increasing attention. Currently, the most widely used adhesives in surgical operations include cyanoacrylate and fibrin. However, these tissue adhesives have limitations, such as low biocompatibility, slow adhesion formation, low mechanical strength, and weak adhesion strength on wet tissue surfaces in cases of acute bleeding.

[0003] Hydrogel is a material with a three-dimensional cross-linked network. Due to its porous structure and high water absorption, hydrogel has flexibility and biocompatibility, and to a certain extent, can be used as a substitute for biological tissues, especially in the field of hemostatic materials. In addition, the desired properties can be achieved and adjusted through material selection or cross-linking design. However, there are some problems with the hydrogel dressings in current research: 1. High production cost: Due to the relatively complex preparation method, the production cost is high, which limits its promotion and application in the market. 2. Poor stability: Since the hydrogel patch has certain water absorption and permeability, it is easily affected by factors such as environmental humidity and temperature, resulting in poor stability. 3. Low adhesion to the skin: Since the hydrogel patch itself does not have adhesion, it is easy to fall off or slip, and the adhesion needs to be enhanced during use. Summary of the Invention

[0004] In view of this, to solve the problems raised in the above background art, the purpose of the present invention is to provide a preparation method of a poly(thymol sorbate)-co-(butenyl sorbate) hydrogel.

[0005] To achieve the above purpose, the present invention provides the following technical solutions: A preparation method of a poly(thymol sorbate)-co-(butenyl sorbate) hydrogel, comprising the following steps: S1. Synthesize the thymol sorbate monomer; S2. Synthesize the butenyl sorbate monomer; S3. Copolymerize the thymol sorbate monomer and the butenyl sorbate monomer to synthesize a poly(thymol sorbate)-poly(butenyl sorbate) random copolymer; S4. Mix the random copolymer PBS-ran-PTS, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone Irgacure 2959, acrylic acid AAC, N-hydroxysuccinimide acrylate AAC-NHS and tannic acid TA into tetrahydrofuran THF, stir ultrasonically until fully dissolved, then pour it into a polytetrafluoroethylene mold, cure to obtain an organic gel, place the organic gel in deionized water for solvent exchange, and then dry to obtain the finished hydrogel.

[0006] Preferably, the synthesized sorbic acid thymol ester monomer includes: S11. Dissolve sorbic acid, thymol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane, react at room temperature and filter to obtain filtrate A; S12. Extract the filtrate A to obtain organic phase a, add anhydrous MgSO 4 to the organic phase a, stir and react, and filter to obtain filtrate B; S13. Rotavaporize the filtrate B to obtain crude product b; S14. Purify the crude product b by silica gel chromatography to obtain the sorbic acid thymol ester monomer.

[0007] Preferably, the mass ratio of sorbic acid, thymol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 11-12:12-13:20-21:2.

[0008] Preferably, in the step S12: use HCl aqueous solution, saturated NaHCO 3 solution and saturated NaCl solution to extract the filtrate A.

[0009] Preferably, the synthesized sorbic acid butenol ester monomer includes: S21. Dissolve sorbic acid, 3-buten-1-ol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane, react at room temperature and filter to obtain filtrate C; S22. Extract the filtrate C to obtain organic phase c, add anhydrous MgSO 4 to the organic phase c, stir and react, and filter to obtain filtrate D; S13. Rotavaporize the filtrate D to obtain crude product d; S14. Purify the crude product d by silica gel chromatography to obtain the sorbic acid thymol ester monomer.

[0010] Preferably, the mass ratio of sorbic acid, 3-buten-1-ol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 11-12:5-6:20-21:2.

[0011] Preferably, in the step S22: use HCl aqueous solution, saturated NaHCO3 Extract the filtrate C with the solution and saturated NaCl solution.

[0012] Preferably, the copolymerization in step S3 includes: S31. Under an argon atmosphere at room temperature, add the toluene standard solution of 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propene, the toluene standard solution of phosphazene ligand P4-tert-butyl, and toluene into the polymerization tube in sequence; S32. Dissolve the thymol sorbate monomer and the butenyl alcohol sorbate monomer in toluene solution and add them into the polymerization tube, and stir and react; S33. Add benzoic acid to the polymerization tube to terminate the reaction and obtain a polymerization solution; S34. Dialyze the polymerization solution to obtain a random copolymer of poly(thymol sorbate)-poly(butenyl alcohol sorbate).

[0013] Preferably, the molar ratio of the toluene standard solution of 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propene, the toluene standard solution of phosphazene ligand P4-tert-butyl, and toluene is 15:3:250.

[0014] Preferably, the molar ratio of the thymol sorbate monomer, the butenyl alcohol sorbate monomer, and the toluene solution is 12:18:5.

[0015] Preferably, in step S34: Dialyze the polymerization solution with a methanol solvent for 12 h, and then vacuum dry to obtain a random copolymer of poly(thymol sorbate)-poly(butenyl alcohol sorbate).

[0016] Preferably, the mass ratio of the random copolymer, Irgacure 2959, acrylic acid, N-hydroxysuccinimide acrylate, and tannic acid is 20:1:50:8-9:8-9.

[0017] Preferably, in step S4: After curing with ultraviolet light for 30 min to obtain an organic gel, place the organic gel in deionized water for solvent exchange for 10 min and then dry it in an oven at 37 °C for 10 min to obtain the finished hydrogel.

[0018] Compared with the prior art, the present invention has the following beneficial effects: For the hydrogel prepared by the present invention, since sorbic acid has a carboxyl group, it can introduce functional groups through classical esterification reactions to achieve the design of new monomers, reducing production costs. However, due to its conjugated diene structure, its polymerization is difficult. Group transfer polymerization can effectively solve this problem and can preserve the integrity of the side groups. A series of sorbic acid polymers with different structures and properties can be obtained after group polymerization. Sorbic acid and its derivatives are commonly used highly efficient and safe antiseptic and preservative agents. These compounds not only have the advantages of sorbic acid but also have stronger antibacterial ability and better stability, and can be applied to many interdisciplinary fields such as gene / drug carriers, antibacterial surfaces, etc. Thymol sorbate (TS) has hydrophobicity, and butenyl sorbate (BS) has a double bond side group that can be used as a crosslinking structure to crosslink the network. Group transfer polymerization is used to prepare polysorbates with different group functions. Since there are many crosslinking sites in the side groups of the polymer main chain, the strength and other properties of the hydrogel product can be improved well. This polymer is non-toxic and non-irritating. By introducing acrylic acid, N-hydroxysuccinimide acrylate, and tannic acid, the flexibility, strength, and adhesion of the hydrogel material can be effectively improved. Description of the Drawings

[0019] Figure 1 is the preparation flow chart of the hydrogel of the present invention; Figure 2 is the infrared spectrum of thymol sorbate monomer (TS) of the present invention; Figure 3 is the infrared spectrum of butenyl sorbate monomer (BS) of the present invention; Figure 4 is of the random copolymer of the present invention 1 1H NMR spectrum; Figure 5 is the infrared spectrum of polysorbate hydrogel (P-ANT) of the present invention; Figure 6 is the bar chart of the mechanical properties of hydrogels with different contents of AAC-NHS of the present invention; Figure 7 is the bar chart of the adhesion properties of hydrogels with different contents of AAC-NHS of the present invention. Detailed Embodiments

[0020] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0021] A preparation method of poly (thymol sorbate - co - butenyl sorbate) hydrogel, comprising: I. Synthesize thymol sorbate monomer; Put sorbic acid (373 mg, 3.33 mmol), thymol (417 mg, 2.78 mmol), dicyclohexylcarbodiimide (DCC) (687 mg, 3.33 mmol) and 4 - dimethylaminopyridine (DMAP) (67.8 mg, 0.556 mmol) into a 500 mL three - necked flask. Under nitrogen protection, add 200 mL of dichloromethane solvent to the three - necked flask, stir and react at room temperature for 12 h. After stopping the reaction, filter to obtain filtrate A; Extract the filtrate A with HCl aqueous solution, saturated NaHCO 3 solution and saturated NaCl solution respectively to obtain organic phase a; Add anhydrous MgSO 4 to the organic phase a, stir and react, and then filter to obtain filtrate B; Rotary evaporate the filtrate B to obtain crude product b; Purify the crude product b by silica gel column chromatography to obtain thymol sorbate monomer (TS).

[0022] II. Synthesize butenyl sorbate monomer; Put sorbic acid (624 mg, 5.55 mmol), 3 - buten - 1 - ol (333 mg, 4.61 mmol), dicyclohexylcarbodiimide (DCC) (1.14 g, 5.55 mmol) and 4 - dimethylaminopyridine (DMAP) (113 mg, 0.924 mmol) into a 500 mL three - necked flask. Under nitrogen protection, add 200 mL of dichloromethane solvent to the three - necked flask, stir and react at room temperature for 12 h. After stopping the reaction, filter to obtain filtrate C; Extract the filtrate C with HCl aqueous solution, saturated NaHCO 3 solution and saturated NaCl solution respectively to obtain organic phase c; Add anhydrous MgSO 4 to the organic phase c, stir and react, and then filter to obtain filtrate D; Rotary evaporate the filtrate D to obtain crude product d; Purify the crude product d by silica gel column chromatography to obtain butenyl sorbate monomer (BS).

[0023] III. Copolymerization reaction In an argon environment at room temperature, a toluene standard solution of 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propene (30 μL, 30 μmol), a toluene standard solution of phosphazene ligand P4-tert-butyl (60 μL, 6 μmol), and toluene (0.5 mL, 0.5 mmol) were successively added to a 10 mL polymerization tube; The monomer of thymol sorbate (293 mg, 1.2 mmol) and the monomer of butenyl sorbate (301 mg, 1.8 mmol) were dissolved in a toluene solution (0.5 mL, 0.5 mmol) and then added to the polymerization tube, and the mixture was stirred and reacted for 1 h; Benzoic acid was added to the polymerization tube to terminate the reaction, and a polymerization solution was obtained; The polymerization solution was dialyzed with a methanol solvent for 12 h, and then vacuum dried to obtain a random copolymer of poly(thymol sorbate)-poly(butenyl sorbate) (hereinafter referred to as random copolymer).

[0024] IV. Preparation of hydrogel The random copolymer (100 mg) was fully dissolved in tetrahydrofuran THF (445 mg, 0.5 mL, 6.17 mmol), and then Irgacure 2959 (5 mg, 22.3 μmol), acrylic acid AAC (250 mg, 0.24 mL, 3.50 mmol), acrylic acid N-hydroxysuccinimide ester AAC-NHS (42 mg, 492 μmol), and tannic acid TA (42 mg, 24.6 μmol) were successively added; after ultrasonic stirring until fully dissolved, the mixture was poured into a polytetrafluoroethylene mold, and an organic gel was obtained after ultraviolet curing for 30 min. The organic gel was placed in deionized water for solvent exchange for 10 min and then dried in an oven at 37 °C for 10 min to obtain the finished hydrogel.

[0025] In summary, the chemical formula for preparing the hydrogel in the present invention is as follows:

[0026] Among them, the process of preparing the hydrogel from the random copolymer is as Figure 1 shown.

[0027] During the overall preparation process: ① The synthesis of TS and BS was proved by attenuated total reflection Fourier transform infrared spectroscopy (ATR-IR). As Figure 2 and Figure 3 shown, the stretching vibration peak of -OH in thymol is at 3217 cm -1 ; the stretching vibration peak of -COOH in sorbic acid is at 2570 cm -1 ; in the infrared spectrum of the TS monomer shown in Figure 2 , both of these peaks disappeared, and at 1688 cm-1 The C=O peak at [location] shifted to 1707 cm -1 , and these results prove the successful synthesis of the TS monomer. Similarly, in Figure 3 the infrared spectrogram shown, the successful synthesis of the BS monomer was also proven.

[0028] ② Analyze the structural composition and sequence of the random copolymer through 1 1H NMR testing. As can be seen from Figure 4 , after the polymerization reaction, the peaks of H in the terminal methyl groups of the monomers at 1.8 - 1.9 ppm disappeared. Polymer peaks formed by the terminal methyl groups of the two monomers appeared at 0.8 - 11.2 ppm, and the characteristic H peaks of other parts of the two monomers also appeared in the polymer to form polymer peaks. This proves the successful synthesis of the random copolymer, and the polymer sequence PBS 59 -ran-PTS 40 was obtained through calculating the conversion rate and terminal analysis method.

[0029] ③ Prove the synthesis of the polysorbate hydrogel through attenuated total reflection Fourier transform infrared spectroscopy (ATR-IR). As Figure 5 shown, comparing with the infrared spectrogram of P-ANT, the C=C at 1632 cm -1 in the polymer (P), acrylic acid (AAC), and N-hydroxysuccinimide acrylate (AAC-NHS) weakened to almost disappear, indicating that the double bonds in these components were consumed and successfully participated in crosslinking. And in the infrared spectrogram of P-ANT, -OH peaks attributed to tannic acid, benzene ring C-H peaks of the polymer side groups, -COOH peaks in acrylic acid, and C=O peaks of the tertiary amide of N-hydroxysuccinimide acrylate were observed at 3333 cm -1 , 2926 cm -1 , 2650 cm -1 and 1733 cm -1 respectively. These results prove the successful synthesis of the polysorbate hydrogel.

[0030] ④ Use a film tensile tester to conduct tensile tests on the prepared hydrogel. The results are as Figure 6 shown, where the subscript numbers represent the mass ratio of the components in the whole system. On the premise of fixing the polymer and tannic acid TA content, adjust the AAC-NHS content, and finally obtain P-AN 12 T 12 . The tensile strength of the prepared hydrogel can reach 1.2 Mpa, and the breaking length can reach 123%.

[0031] ⑤ Apply the shear adhesion peel test to conduct pigskin adhesion on the prepared hydrogel. As Figure 7As shown, with the addition of N-hydroxysuccinimide acrylate AAC-NHS, the adhesiveness gradually increases, reaching 28.3 Kpa in the P-AN 12 T 12 group.

[0032] Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing polysorbate thymol-co-butylene sorbate hydrogel, characterized in that: The steps include: S1. Synthesis of thymol sorbate monomer; S2. Synthesis of butylene sorbate monomer; S3. Polysorbate thymol ester-polysorbate butylene glycol ester random copolymer PBS-ran-PTS is synthesized by copolymerizing sorbate thymol ester monomer and sorbate butylene glycol ester monomer; S4. The random copolymer PBS-ran-PTS, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone Irgacure 2959, acrylic acid AAC, acrylic acid N-hydroxysuccinimide ester AAC-NHS and tannic acid TA are mixed in tetrahydrofuran THF, ultrasonically stirred until fully dissolved, then poured into a polytetrafluoroethylene mold and solidified to obtain an organic gel. The organic gel is placed in deionized water for solvent exchange and then dried to obtain a finished hydrogel.

2. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 1, characterized in that: The synthetic thymol sorbate monomer comprises: S11. dissolving sorbic acid, thymol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane, reacting at room temperature and filtering to obtain filtrate A; S12. Extracting the filtrate A to obtain an organic phase a, adding anhydrous MgSO4 to the organic phase a, stirring the reaction and filtering to obtain a filtrate B; S13. Rotary evaporation of the filtrate B to obtain a crude product b; S14. Purify the crude product b by silica gel chromatography to obtain thymol sorbate monomer.

3. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 2, characterized in that: The mass ratio of the sorbic acid, thymol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 11-12:12-13:20-21:

2.

4. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 2, characterized in that: In the step S12: the filtrate A is extracted with HCl aqueous solution, saturated NaHCO3 solution and saturated NaCl solution.

5. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 1, characterized in that: The copolymerization synthesis in step S3 includes: S31. Under argon atmosphere at room temperature, a toluene standard solution of 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propylene, a toluene standard solution of phosphazene ligand P4-tert-butyl, and toluene were sequentially added to the polymerization tube; S32. The thymol sorbate monomer and the butylene sorbate monomer were dissolved in toluene solution and added to the polymerization tube, and the reaction was stirred; S33. Adding benzoic acid to the polymerization tube to terminate the reaction to obtain a polymerization solution; S34. Dialyze the polymerization solution to obtain polysorbate thymol-polysorbate butylene glycol random copolymer.

6. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 5, characterized in that: The molar ratio of the toluene standard solution of 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propylene, the toluene standard solution of the phosphazene ligand P4-tert-butyl, and toluene is 15:3:

250.

7. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 5, characterized in that: The molar ratio of the thymol sorbate monomer, the butylene sorbate monomer and the toluene solution is 12:18:

5.

8. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 5, characterized in that: In the step S34: the polymerization solution is dialyzed using methanol solvent for 12 hours, and then vacuum dried to obtain a polysorbate thymol-polysorbate butylene glycol random copolymer.

9. The method for preparing a polysorbate thymol-co-butylene sorbate hydrogel according to claim 1, characterized in that: The mass ratio of the random copolymer, Irgacure 2959, acrylic acid, acrylic acid N-hydroxysuccinimide ester and tannic acid is 20:1:50:8-9:8-9.

10. The method for preparing a polythymol sorbate-co-butylene sorbate hydrogel according to claim 9, characterized in that: In the step S4, the organic gel is obtained by ultraviolet curing for 30 minutes, and the organic gel is placed in deionized water for solvent exchange for 10 minutes and then dried in an oven at 37° C. for 10 minutes to obtain a finished hydrogel.

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