Preparation method and application of thermally reversible self-repairing micromolecular gel material
A thermally reversible self-healing hydrogel is developed using pyridine-2,6-diaminohydrazide modification to address mechanical weaknesses and acidic instability in traditional hydrogels, offering rapid self-healing and effective drug release.
Patent Information
- Application Number
- CN202510466711.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-14
- Publication Date
- 2025-07-15
AI Technical Summary
The existing hydrogels have poor mechanical properties, low self-repair efficiency and insufficient stability in acidic environments, making them difficult to effectively apply in biological bodies.
Pyridine-2,6-diformylhydrazide is used as the reaction substrate to prepare pyridine-2-formaldehyde compounds by reacting with pyridine-2-formaldehyde to form a thermally reversible self-healing small molecule gel material. It dissolves and gels by heating and cooling to form a stable three-dimensional network structure in an acidic environment.
It has achieved a gel material with thermal reversibility, rapid self-repair ability and excellent drug sustained release performance in an acidic environment. It is suitable for drug carriers and has good biocompatibility and drug controlled release effect.
Smart Images
Figure CN120309535A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of material chemistry and relates to biomedical materials. Specifically, it relates to a preparation method of a thermally reversible self-healing supramolecular hydrogel based on dynamic hydrazone bonds and its applications in the fields of drug sustained release, biomedical materials, etc. Background Art
[0002] Supramolecular hydrogel is a gel material with high water hydration ability. It is a three-dimensional network structure formed by non-covalent interactions between water-soluble polymers and water molecules, such as hydrogen bonds, van der Waals forces, and electrostatic interactions. This structure allows water molecules to form a three-dimensional network structure similar to a gel therein, forming a gel-like substance. The characteristics of supramolecular hydrogel include high water absorbency, reversibility, and controllability. It can absorb a large amount of water molecules and maintain the gel state, and at the same time has good stability and mechanical properties. Due to its special structure and properties, supramolecular hydrogel has wide applications in many fields, such as drug delivery, tissue engineering, biosensors, etc.
[0003] The performance of supramolecular hydrogel can be adjusted by regulating its composition and structure. For example, the network density, pore size, and mechanical strength can be adjusted, which makes it have great potential in the medical and biological fields and has also received extensive attention and research in nanotechnology and material science.
[0004] Self-healing supramolecular hydrogel materials have the ability of self-repair. Such gel materials can quickly restore their mechanical functions and structures after being damaged or destroyed, and realize the repair process under certain conditions (such as light, heating, adjusting pH, etc.). As a new type of intelligent material, self-healing gel materials are becoming a hot spot in current scientific research. Traditional hydrogels have defects such as poor acid resistance and insufficient firmness, are not easily degraded, and cause greater harm to organisms. Summary of the Invention
[0005] (1) Technical Problems to be Solved
[0006] The present invention provides a method for preparing a thermoreversible self-healing small molecule gel material and its application. Selecting 2,6-pyridinedicarbohydrazide as the reaction substrate and modifying it with pyridine-2-carboxaldehyde to obtain a pyridine acylhydrazone compound (PDA-CN2) gelator. Heating it to dissolve in an acidic aqueous solution, cooling and then gelating to finally obtain a thermoreversible self-healing small molecule gel material. The method provided by the present invention has a simple operation process, is safe and environmentally friendly, and solves the problems of poor mechanical properties, low self-healing efficiency and insufficient stability in an acidic environment of existing hydrogels. The gel material of the present invention can form a stable three-dimensional network structure in an acidic solution with pH = 0.5 - 1.5, has thermoreversibility, rapid self-healing ability and excellent drug slow-release performance, can be used as a drug carrier in vivo, and has great application prospects.
[0007] (II) Technical solution
[0008] To achieve the above object, the present invention provides the following technical solution. A method for preparing a thermoreversible self-healing small molecule gel material includes the following steps:
[0009] Step a: Preparation of 2,6-pyridinedicarbohydrazide: First, weigh a certain amount of methyl 2,6-pyridinedicarboxylate and absolute ethanol in a flask, heat and stir, then add hydrazine hydrate, heat under reflux for a period of time, after the reaction is completed, cool and filter by suction, and finally rinse with methanol and dry under vacuum to obtain the white product 2,6-pyridinedicarbohydrazide;
[0010] Step b: Preparation of the thermoreversible self-healing small molecule gel material: Secondly, weigh a certain amount of 2,6-pyridinedicarbohydrazide, absolute ethanol and pyridine-2-carboxaldehyde in a flask, then add an acidic solution, heat under reflux for a period of time, cool and filter by suction, purify by recrystallization with DMSO and water after drying under vacuum, and then weigh a certain amount of the purified pyridine acylhydrazone derivative (PDA-CN2) in an acidic aqueous solution, heat to completely dissolve PDA-CN2, and let it stand for a period of time after cooling to room temperature to obtain a stable thermoreversible self-healing small molecule gel material.
[0011] As a preferred scheme, in the step a, methyl 2,6-pyridinedicarboxylate is roughly dissolved in ethanol.
[0012] As a preferred scheme, in the step a, control the reaction temperature at 80 - 90 °C in an oil bath and carry out condensation reflux for 24 h.
[0013] As a preferred scheme, in the step a, the vacuum drying temperature is 60 - 80 °C and the vacuum drying time is 5 - 6 h.
[0014] As a preferred embodiment, in step b, pyridine-2,6-dicarbohydrazide reacts with pyridine-2-carboxaldehyde in a molar ratio of 1:2, and the aldehyde is in excess; the dissolution temperature of the gelator is 80-90 °C.
[0015] As a preferred embodiment, in step b, the acidic substance in the acidic solution acts as a catalyst, preferably an acetic acid solution, and the dropping amount is 1.5-2.0 mL of acetic acid solution corresponding to every 200 mL of the reaction system.
[0016] As a preferred embodiment, in step b, the obtained gel material can be stably maintained in 1.0 mL of an HCl aqueous solution with a pH of 1.0 for 14 months, and has good acid resistance, so it can be used for drug controlled release in an acidic environment.
[0017] As a preferred embodiment, the gel material is mainly composed of a pyridinecarbohydrazide-based gelator PDA-CN2 and a hydrochloric acid solution, and presents a lamellar structure after freeze-drying.
[0018] As a preferred embodiment:
[0019] S1: First, weigh 6.0 g (about 30 mmol) of methyl pyridine-2,6-dicarboxylate into a flask, add 150-170 mL of anhydrous methanol, add a magnetic stir bar to the flask and mix evenly, heat at 75-85 °C, wait for a while, the ester is roughly dissolved in ethanol, add 45.0 mL of 80% hydrazine hydrate, control the reaction temperature at 80-90 °C in an oil bath with reflux condensation for 24 h. After the reaction is completed, it needs to be cooled and filtered, rinsed with methanol, and dried in vacuo at 60-80 °C to obtain white pyridine-2,6-dicarbohydrazide for standby; Subsequently, weigh pyridine-2,6-dicarbohydrazide into a flask, add 200.0 mL of anhydrous ethanol, pyridine-2-carboxaldehyde (reacting in a molar ratio of 1:2 and the aldehyde is in excess), and then add 1.5 mL of acetic acid as a catalyst. Control the temperature at 80-90 °C in an oil bath with reflux condensation for 24 h, cool and filter by suction, and dry in vacuo to obtain the white solid crude product of N2,N6-bis(2-pyridylcarbonyl)pyridine-2,6-dicarbohydrazide (PDA-CN2), and then recrystallize and purify it with DMSO and water. Add the gelator PDA-CN2 to an aqueous solution with a certain pH, heat to completely dissolve PDA-CN2 in it, and let the dissolved and clarified system stand and cool at room temperature to obtain a stable thermoreversible self-healing small molecule hydrogel material;
[0020] S2: Add an appropriate amount of pyridinehydrazone derivative gelator to an aqueous solution system of HCl and heat to dissolve it into a clear solution, cool down to form a stable gel, add an excessive amount of sodium hydroxide solution to the gel system, and mix the system evenly. The white gel will turn into a yellow solution, and then add a certain amount of aqueous HCl solution to form a white gel;
[0021] S3: Shake the prepared hydrogel well and stir it into a flowing state, and the hydrogel collapses; let the collapsed hydrogel system stand at room temperature for a period of time. It can be found that the original flowing system re-heals into a stable gel, and the sample bottle will not fall off even when it is inverted. A rheometer was used to perform a time scan on the gel and a "destruction-repair" cycle was carried out on the gel; the concentration of the gelator was 20.0 g / L, the solvent was an HCl solution with pH = 1.0, the initial elastic modulus of the formed gel was about 533 Pa, and it could recover to an elastic modulus of about 260 Pa after being destroyed for five minutes, and it could maintain self-repairing to 260 Pa after multiple cycles, indicating that the gel of this system has good self-healing ability.
[0022] S4: Load VB12 into this self-healing gel material at concentrations of 200.0 mg / L, 300.0 mg / L, and 400.0 mg / L respectively. Take the upper buffer solution at regular intervals and test it by ultraviolet-visible spectrophotometry. The results show that the sustained release rate of VB12 reaches more than 80%;
[0023] (III) Beneficial effects
[0024] The present invention can be used as a drug carrier for special purposes. Benefiting from the natural three-dimensional hydrophilic network, it can also be used as a wound dressing to provide a moist and airtight microenvironment, promote oxygen exchange and support the penetration of nutrients for tissue regeneration. Compared with traditional drug carriers, it has the following three advantages: First, the thermoreversible self-healing hydrogel of the present invention can adapt to special environments such as acidic environments and can be used for drug controlled release applications in special parts such as the stomach; Second, the material of the present invention can be used as a precisely controllable drug release system and can release drugs continuously and sequentially; Finally, the material of the present invention is easy to degrade, has small side effects, causes little burden on organisms, has various sizes and various delivery routes, and can be targeted at different parts and types of diseases. Description of the drawings
[0025] Figure 1 It is a synthetic route diagram of the gelator of a thermoreversible self-healing small molecule gel material of the present invention.
[0026] Figure 2 It is a schematic diagram of the formation process of a thermoreversible self-healing small molecule gel material of the present invention.
[0027] Figure 3 It is a scanning electron microscope photograph of the dry gel of a thermoreversible self-healing small molecule gel material of the present invention.
[0028] Figure 4 It is a picture of the acid-base responsiveness result of a thermoreversible self-healing small molecule gel material of the present invention.
[0029] Figure 5This is the result diagram of the self-healing performance study of a thermoreversible self-healing small molecule gel material of the present invention.
[0030] Figure 6 This is the drug controlled release effect diagram of a thermoreversible self-healing small molecule gel material of the present invention on VB12. Detailed implementation manners
[0031] To make the objectives, technical solutions and advantages of the present invention clearer, so that those skilled in the art can better understand the present invention, the following further elaborates on the implementation manners of the present invention in conjunction with the accompanying drawings and embodiments.
[0032] Example 1
[0033] Weigh 6.0 g (about 30 mmol) of methyl pyridine-2,6-dicarboxylate and add it to a pear-shaped flask. Add 150.0 mL of absolute ethanol, heat and stir. Wait for a while until the ester is roughly dissolved in ethanol. Then add 45.0 mL of 80% hydrazine hydrate, control the reaction temperature at 80 - 90 °C in an oil bath, carry out reflux condensation for 24 h, cool and then filter by suction, and dry in vacuum to obtain the white solid product pyridine-2,6-dicarbohydrazide. Leave it for later use. Weigh 0.9750 g (5 mmol) of pyridine-2,6-dicarbohydrazide into a flask, add 200.0 mL of absolute ethanol, 1.20 g of pyridine-2-carboxaldehyde (about 11 mmol, react in a molar ratio of 1:2 and the aldehyde is in excess), and then add 1.5 mL of acetic acid as a catalyst. Control the temperature at 80 - 90 °C in an oil bath, carry out reflux condensation for 24 h, cool and filter by suction, and dry in vacuum to obtain the white solid crude product N2,N6-bis(2-pyridinecarbonyl)pyridine-2,6-dicarbohydrazide (PDA-CN2), and then purify it by recrystallization with DMSO and water. The above reaction process is shown by Figure 1 It can be seen.
[0034] Load VB12 into the 20.0 g / L PDA-CN2 gel system at concentrations of 200.0 mg / L, 300.0 mg / L, and 400.0 mg / L respectively. Take the upper buffer solution at regular intervals and examine the slow release effect by ultraviolet-visible spectrophotometry.
[0035] Perform stability analysis on a thermoreversible self-healing small molecule gel material prepared as above, and obtain the results as Figure 2 shown. It can be seen from the figure that this gel material has thermoreversibility.
[0036] Perform acid-base responsiveness analysis on a thermoreversible self-healing small molecule gel material prepared as above, and obtain the results as Figure 3 shown. It can be seen from this that this gel material has good acid resistance.
[0037] Perform self-healing performance analysis on a thermoreversible self-healing small molecule gel material obtained by the above preparation, and obtain Figure 4 the results shown in the figure. From this, it can be seen that the gel material has good self-healing performance.
[0038] Perform microscopic morphology analysis on the xerogel of a thermoreversible self-healing small molecule gel material obtained by the above preparation, and obtain as Figure 5 shown in the figure. It can be seen from the figure that the gel material after freeze-drying is mainly in a lamellar structure.
[0039] Perform drug controlled release research on a thermoreversible self-healing small molecule gel material obtained by the above preparation, and obtain as Figure 6 shown in the figure. It can be seen from the figure that vitamin VB12 reaches a sustained release equilibrium at about 60 h, and the sustained release rate reaches 80%, indicating that the gel material has a good sustained release effect on vitamin VB12.
[0040] The above-described embodiments are only for further description of the present invention. However, the present invention is not limited thereto. Any modifications, equivalent substitutions, or improvements made without departing from the core of the present invention shall be included within the protection scope of the present invention.
Claims
1. A preparation method of a thermoreversible self-healing small molecule hydrogel, characterized in that The following steps are involved: Step a: Preparation of pyridine-2,6-dicarboxylic acid hydrazide: First, weigh a certain amount of methyl pyridine-2,6-dicarboxylate and anhydrous ethanol in a flask, heat and stir, then add hydrazine hydrate, heat and reflux for a period of time, cool and filter after the reaction is completed, finally rinse with methanol, and vacuum dry to obtain a white product pyridine-2,6-dicarboxylic acid hydrazide; Step b: Preparation of thermally reversible self-healing small molecule gel material: Secondly, weigh a certain amount of pyridine-2,6-dicarboxylic acid hydrazide, anhydrous ethanol and pyridine-2-carboxaldehyde into a flask, add acidic solution, heat and reflux for a period of time, cool and filter, vacuum dry and then recrystallize and purify with DMSO and water to obtain a stable thermally reversible self-healing small molecule gel material.
2. The preparation method of a thermoreversible self-healing small molecule gel material according to claim 1, characterized in that: In the step a, methyl pyridine-2,6-dicarboxylate is substantially dissolved in ethanol.
3. The preparation method of a thermally reversible self-healing small molecule gel material according to claim 1, characterized in that: In the step a, the reaction temperature is controlled at 80-90° C. in an oil bath and condensed under reflux for 24 hours.
4. A method for preparing a thermoreversible self-healing small molecule gel material according to claim 1, characterized in that: In the step a, the vacuum drying temperature is 60-80° C., and the vacuum drying time is 5-6 hours.
5. The preparation method of a thermally reversible self-healing small molecule gel material according to claim 1, characterized in that: In the step b, pyridine-2,6-dicarboxylic acid hydrazide and pyridine-2-carboxaldehyde react at a molar ratio of 1:2, and the aldehyde is in excess; the dissolution temperature of the gel factor is 80-90°C.
6. The preparation method of a thermally reversible self-healing small molecule gel material according to claim 1, characterized in that: In the step b, the acidic substance in the acidic solution plays a catalytic role, preferably an acetic acid solution, and the amount of the acetic acid solution added is 1.5-2.0 mL per 200 mL of the reaction system.
7. A method for preparing a thermally reversible self-healing small molecule gel material according to claim 1, characterized in that: In the step b, the obtained gel material can be stably maintained in 1.0 mL of HCl aqueous solution with pH = 1.0 for 14 months and has good acid resistance, so that drug controlled release can be performed in an acidic environment.
8. A preparation method of a thermoreversible self-healing small molecule gel material according to claim 1, characterized in that: The gel material is mainly composed of pyridine hydrazide gel factor PDA-CN2 and hydrochloric acid solution, and has a lamellar structure after freeze-drying.
9. Application of a thermally reversible self-healing small molecule gel material according to claim 1: S1: First, weigh 6.0 g (about 30 mmol) of methyl pyridine-2,6-dicarboxylate into a flask, add 150 - 170 mL of anhydrous methanol, add a magnetic stirrer to the flask and mix well. Heat at 75 - 85 °C, wait for a while, the ester is roughly dissolved in ethanol, add 45.0 mL of 80% hydrazine hydrate, control the reaction temperature at 80 - 90 °C in an oil bath, reflux for 24 h. After the reaction is completed, cool and filter, wash with methanol, and dry in vacuo at 60 - 80 °C to obtain white pyridine-2,6-dicarbohydrazide for later use. Subsequently, weigh pyridine-2,6-dicarbohydrazide into a flask, add 200.0 mL of anhydrous ethanol, pyridine-2-carboxaldehyde (reacting in a molar ratio of 1:2 with an excess of aldehyde), and then add 1.5 mL of acetic acid as a catalyst. Control the temperature at 80 - 90 °C in an oil bath, reflux for 24 h, cool and filter by suction, and dry in vacuo to obtain the white solid crude product of N2,N6-bis(2-pyridinecarbonyl)pyridine-2,6-dicarbohydrazide (PDA-CN2), and then recrystallize and purify it with DMSO and water. Add the gelator PDA-CN2 to an aqueous solution of a certain pH, heat to completely dissolve PDA-CN2 in it, The dissolved and clarified system is allowed to stand and cool at room temperature, thereby obtaining a stable thermally reversible self-healing small molecule hydrogel material; S2: Add an appropriate amount of pyridylhydrazone derivative gel factor to an aqueous solution of HCl, heat and dissolve into a clear solution, cool down to form a stable gel, add an excess of sodium hydroxide solution to the gel system, and mix the system evenly, the white gel will turn into a yellow solution, and then add a certain amount of HCl aqueous solution to form a white gel; S3: The prepared hydrogel was fully shaken and stirred into a fluid state, and the hydrogel collapsed; the collapsed hydrogel system was left to stand at room temperature for a period of time, and it was found that the original fluid system healed into a stable gel again, and the sample bottle would not fall down when it was inverted. The gel was time-scanned using a rheometer, and the gel was subjected to a "destruction-repair" cycle; the gel factor concentration was 20.0g / L and the solvent was HCl solution with a pH of 1.
0. The initial elastic modulus of the gel was about 533pa, and it could be restored to an elastic modulus of about 260pa after being destroyed for five minutes, and it could maintain self-repair to 260pa after multiple cycles, which shows that the system gel has good self-repair ability. S4: Load VB12 into this self-healing gel material at concentrations of 200.0 mg / L, 300.0 mg / L, and 400.0 mg / L respectively. Take the upper buffer solution at regular intervals and test it by ultraviolet-visible spectrophotometry. The results show that the sustained-release rate of VB12 reaches over 80%.