Macromolecular injectable temperature-sensitive hydrogel as well as preparation method and application thereof
By polymerizing the crosslinking agent prepared by itaconic acid, polysuccinimide and amino acids with N-isopropyl acrylamide, a temperature-sensitive hydrogel with good biocompatibility and degradation performance is solved, and the problems of poor degradation performance of existing materials in vivo and the toxicity of crosslinking agents are achieved, and a temperature-sensitive hydrogel that can be reversibly transformed into a gel state at body temperature is achieved, with low viscosity injectability and safer and more effective drug release methods.
Patent Information
- Application Number
- CN202510182885.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-19
- Publication Date
- 2025-05-27
AI Technical Summary
The existing temperature-sensitive hydrogel materials have poor degradation performance in the body, long-term residues may be harmful, and crosslinking agents are toxic, affecting biocompatibility.
Itaconic acid, polysuccinimide and amino acids are used to prepare crosslinking agents, and radically polymerize with N-isopropylacrylamide to form a temperature-sensitive hydrogel with good biocompatibility and degradation properties.
It realizes a temperature-sensitive hydrogel that can be reversibly transformed into a gel state at body temperature, has low viscosity injectability, and provides a safer and more effective drug release method in the field of biomedical science.
Smart Images
Figure CN120037173A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of polymer materials, and conducts research on the preparation and properties of injectable thermosensitive hydrogel materials, specifically relating to a macromolecular injectable thermosensitive hydrogel and its preparation method and application. Background Art
[0002] Hydrogels have very good hydrophilicity and are widely used in many fields such as medicine and food. Among them, hydrogels with a three-dimensional structure have unique advantages. The voids inside them can efficiently load and encapsulate drugs, so they have become an extremely ideal drug carrier. Thermosensitive hydrogels belong to a branch of hydrogels, and their properties are very wonderful. When the external temperature changes, its own structure will also change accordingly. In a low-temperature environment, it presents a solution state. Once the temperature rises to the phase transition critical point, its structure will quickly transform and then gelate. Using this property, people fully mix drugs with a thermosensitive hydrogel solution at low temperature and then inject it. When it enters the human body, when the environmental temperature rises, the solution immediately turns into a gel, just like wrapping a "protective film" around the drug, thereby realizing the slow and continuous release of the drug and providing more long-term and stable drug efficacy support for treatment.
[0003] Polysuccinimide (PSI) is a synthetic polymer. Its molecular structure is mainly composed of succinimide units connected in series, and its chemical structure contains a five-membered cyclic imide structure. The imide groups in the polysuccinimide molecule can undergo various chemical modifications. By reacting with different functional groups, new properties can be imparted to polysuccinimide. Its linear structure gives it good mechanical strength and flexibility, and it can slowly degrade in the body, ensuring the stability during drug transportation and leaving no residue in the body. Polysuccinimide can be used as a drug carrier for cancer treatment. At the same time, using its hydrolysis characteristics and modifiability, drug molecules are encapsulated or connected to the polysuccinimide molecule. It gradually hydrolyzes in the body, releasing active ingredients such as drugs, and the hydrolysis products have relatively little irritation to organisms.
[0004] Amino acids, as the basic building blocks of living organisms, in addition to constructing proteins in the body, also participate in the body's metabolic processes and regulate physiological functions, etc. It has good biocompatibility. In the medical field, amino acids are used as raw materials or excipients for drugs. When it is introduced into a drug-loaded gel system, it can reduce the stimulation of the gel material to the human immune system. It can form a relatively stable bond with drug molecules, making the release of drugs in the gel slower and more controllable.
[0005] Itaconic acid is an unsaturated dicarboxylic acid with a carbon-carbon double bond and two carboxyl groups in its molecular structure. It is usually a white crystal or powder, slightly soluble in water, and easily soluble in organic solvents such as ethanol and acetone. At the same time, it is an important monomer for synthesizing various polymers. When synthesizing polymer materials, the double bond of itaconic acid can participate in the polymerization reaction and copolymerize with other monomers (such as styrene, acrylic acid, etc.) to generate polymers with special properties. In the medical field, itaconic acid and its derivatives have certain biological activities. Studies have found that itaconic acid can regulate the signal pathways inside cells and has potential regulatory effects on physiological processes such as inflammatory responses.
[0006] N-Isopropylacrylamide is a very important polymerization monomer. Due to the carbon-carbon double bond in its molecule, it can participate in various polymerization reactions. The synergistic effect of the isopropyl group and the amide group in its molecular structure makes the polymer formed by it have thermosensitive properties. In drug sustained release, taking advantage of its thermosensitivity, drugs are encapsulated in the hydrogel formed by the polymerization of N-isopropylacrylamide. When the environmental temperature approaches the human body temperature, the hydrogel undergoes a phase transition, thereby realizing the controlled release of drugs and improving the accuracy and effectiveness of drug treatment.
[0007] With the development of science and technology, now high molecular materials are more and more widely used in the medical field. Their good biocompatibility and biodegradability have great advantages in medical applications. However, the single performance of a single material cannot meet complex application scenarios. Therefore, high molecular materials can be modified by means such as compounding and grafting. The modified high molecular materials have multiple or unique properties, making them very suitable for specific applications. Summary of the Invention
[0008] Compared with the existing technology, the present invention uses itaconic acid, polysuccinimide, and amino acids to prepare a crosslinking agent containing an unsaturated double bond, which undergoes free radical polymerization with N-isopropylacrylamide for crosslinking to form a hydrogel. This hydrogel has good biocompatibility and biodegradability. It not only has temperature responsiveness and can transform into a gel state at body temperature, but also has a low viscosity and can be injected. Among them, itaconic acid and its derivatives have certain biological activities and have a certain anti-tumor effect, and can be used as an auxiliary component for tumor treatment.
[0009] Single N-isopropylacrylamide has poor degradation performance and will be harmful if it remains in the human body for a long time. And its crosslinking agent NN-methylenebisacrylamide (BIS) is toxic. Therefore, the crosslinking agent prepared with amino acids, itaconic acid, and polysuccinimide is used to replace BIS to reduce toxicity and increase its biocompatibility and degradation performance.
[0010] To achieve the above object, on the one hand, the present invention provides a macromolecular thermosensitive hydrogel material, the raw materials of which are poly(succinimide), amino acid, itaconic acid, and N-isopropylacrylamide, and the crosslinking agent is poly(succinimide)-amino acid-itaconic acid crosslinking agent, wherein the mass fraction ratio of poly(succinimide), amino acid, and itaconic acid is 1:0.5-1.5:0.7-2.0. Subsequently, the thermosensitive hydrogel is prepared by the reaction of amino acid-itaconic acid-poly(succinimide) crosslinking agent with N-isopropylacrylamide.
[0011] On the other hand, the present invention provides a preparation method of an amino acid thermosensitive hydrogel, and the method comprises the following steps:
[0012] (1) Dissolve poly(succinimide) in deionized water at 10°C - 50°C and stir evenly to obtain solution A with a concentration of 0.4 mol / L - 0.8 mol / L.
[0013] (2) Add amino acid to solution A to make the amino acid concentration 0.2 mol / L - 1.2 mol / L, keep the water bath heating at 30°C - 80°C, and react to obtain solution B.
[0014] (3) Add itaconic acid to solution B to make the itaconic acid concentration 0.3 mol / L - 1.2 mol / L, heat in a water bath at 20°C - 50°C to obtain a solution, and freeze-dry to obtain solid C.
[0015] (4) Dissolve solid C in deionized water and stir, add N-isopropylacrylamide and an initiator, and the ratio of solid C, N-isopropylacrylamide, and the initiator is 0.1-1:1-2:0.01-0.1. Stir and wait for the reaction for 2-4 h to obtain a poly(succinimide) / amino acid / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel.
[0016] In the above technical solution, further, the poly(succinimide) in step (1) is a white powder with a molecular weight of 7000 - 8000.
[0017] In the above technical solution, further, the amino acids in step (2) are lysine, histidine, and arginine, and the purity is not less than 98%.
[0018] In the above technical solution, further, the itaconic acid in step (3) has a purity of not less than 99%.
[0019] In the above technical solution, further, the N-isopropylacrylamide in step (4) has a purity of not less than 98% and is a pale yellow crystalline powder.
[0020] In the above technical solution, further, in the step (4), the stirring rate is 200 - 800 r / min, the water bath heating temperature is 50°C - 100°C, and the stirring time is 1 - 6 h.
[0021] In the above technical solution, further, the initiator in the step (4) is one of ammonium persulfate (APS), azobisisobutyronitrile (AIBN), and benzoyl peroxide (BPO).
[0022] In the present invention, the toxic cross - linker is replaced with a self - made poly(succinimide) / amino acid / itaconic acid cross - linker with good biocompatibility. Basic amino acids are introduced to enhance the biocompatibility and biodegradability of the hydrogel. The ring - opening reaction of poly(succinimide) with amino acids and the amide reaction with itaconic acid are used to introduce double bonds. Finally, it reacts with N - isopropylacrylamide to form a thermosensitive hydrogel.
[0023] The beneficial effects of the present invention are as follows:
[0024] Itaconic acid itself has good hydrophilicity, and its carboxyl group can form hydrogen bonds with water molecules. In the hydrogel, the presence of itaconic acid can increase the hydrophilicity of the hydrogel, enabling the hydrogel to absorb more water. Itaconic acid and its derivatives may have certain biological activities in the body. When the hydrogel is used in the biomedical field, this biological activity may affect cell behavior, such as promoting cell proliferation or regulating cell metabolism. The unsaturated double - bond structure of itaconic acid enables it to respond to some external stimuli (such as light, redox environment, etc.), providing the possibility for the intelligent responsive design of the hydrogel. Amino acids contain basic amino groups and can modify poly(succinimide). Poly(succinimide) can be used as a drug carrier to encapsulate drugs. Due to the existence of certain voids in its molecular structure, drug molecules can be entrapped therein. Moreover, poly(succinimide) has the property of being hydrolyzable. In the hydrogel environment, as the imide bond hydrolyzes, the drug can be slowly released. This slow - release property is very important for the long - term release of drugs and improving drug efficacy.
[0025] The preparation method of the present invention does not produce pollutants and harmful substances. Its production process is simple. The prepared polymer hydrogel material has good biocompatibility and degradability, and has temperature - sensitive properties, enabling phase transition at body temperature. The sol state of the hydrogel has a low viscosity, while the gel state has a high viscosity, which not only enables easy injection administration but also can be precisely fixed at the lesion site, realizing the expected use as a delivery for cancer drugs, providing convenience in medical treatment and further improving the treatment effect and safety. Description of the Drawings
[0026] Figure 1Infrared spectrum of the poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel prepared in Example 1;
[0027] Figure 2 Contact angle characterization diagrams of poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogels with different crosslinking degrees;
[0028] Figure 3 Contact angle characterization diagrams of poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogels with crosslinking degrees of 3%, 5%, 7.5%, 10%, and 20% in sequence;
[0029] Figure 4 Injection sample diagram of the poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel prepared in Example 1. Detailed implementation manners
[0030] The following examples facilitate a better understanding of the present invention, but do not limit the present invention. Additionally, in the following examples, unless otherwise specified, the materials, reagents, etc. used can be purchased from biological or chemical reagent companies.
[0031] Example 1
[0032] (1) Weigh poly(succinimide) with a molecular weight of 7000 - 8000, dissolve it in deionized water at 20 °C, stir for 30 min, and prepare a 0.4 mol / L poly(succinimide) solution;
[0033] (2) Subsequently, weigh lysine with a purity of 98% and add it to Step 1 to prepare a 0.4 mol / L lysine solution. React at 50 °C in a water bath for 24 h with a stirring rate of 500 r / min.
[0034] (3) Weigh itaconic acid with a purity of 99%, add it to the solution in Step 2, with the itaconic acid concentration being 0.4 mol / L. After reacting at 30 °C for 4 h, take it out and place it in a petri dish for freeze-drying.
[0035] (4) Take the freeze-dried product in Step 3 and add it to a three-necked flask containing 30 mL of deionized water with a concentration of 0.3%. After ultrasonic dissolution, add N-isopropylacrylamide with a total mass of 6% and ammonium persulfate as the initiator with a total mass of 0.1%. React at 80 °C under N 2 atmosphere for 2 h, and obtain the poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel after crosslinking reaction.
[0036] After the experiment, the infrared absorption of the hydrogel was measured by the potassium bromide tablet method, Figure 1Infrared spectrum of the poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel prepared for Example 1. It can be seen from it that Figure 1 The 1387 cm -1 and 1361 cm -1 The two peaks with the same intensity split from the isopropyl group are -CH 3 vibration peaks. The 1545 cm -1 is the C=O stretching vibration peak in the amide. The 1652 cm -1 is the bending vibration of N-H in the amide. The 2976 cm -1 is the stretching vibration peak of -OH in O=C-OH. The 3076 cm -1 is the C-H stretching vibration peak of C=C. The 3434 cm -1 is the bending vibration of -NH 2 . It can be seen from the above that poly(succinimide) has undergone an amidation reaction, indicating the success of the graft modification of the hydrogel.
[0037] Figure 2 and 3 are the contact angle characterization diagrams of the poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogels with different crosslinking degrees prepared. It can be seen from the figure that the contact angles of the hydrogels with crosslinking degrees of 3%, 5%, 7.5%, 10%, and 20% are 53.461°, 44.934°, 46.196°, 39.215°, and 50.488° respectively. The contact angles of the hydrogels are in the range of 39 - 54°, all less than 90°, indicating that the overall shows good hydrophilic properties.
[0038] Figure 4 The poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel prepared in Example 1 was injected into hot water at 37 ± 1°C. White strip-like substances could be seen during the injection, verifying that its thermosensitive performance is good and it can undergo a phase transition in the human body temperature range to achieve injectability.
[0039] Example 2
[0040] (1) Weigh poly(succinimide) with a molecular weight of 7000 - 8000 and dissolve it in deionized water at 10°C, stir for 60 min to prepare a 0.4 mol / L poly(succinimide) solution;
[0041] (2) Subsequently, weigh lysine with a purity of 98% and add it to step 1 to prepare a 0.2 mol / L lysine solution. React at 80°C in a water bath for 24 h with a stirring rate of 500 r / min.
[0042] (3) Weigh itaconic acid with a purity of 99% and add it to the solution in step 2. The concentration of itaconic acid is 0.3 mol / L. After reacting at 40 °C for 3 h, take it out and place it in a petri dish for freeze-drying.
[0043] (4) Take the product after freeze-drying in step 3 and add it to a three-necked flask containing 30 mL of deionized water with a concentration of 0.1%. After ultrasonic dissolution, add N-isopropylacrylamide with a total mass of 2% and ammonium persulfate as an initiator with a total mass of 0.02%. React at 60 °C under N 2 atmosphere for 4 h. After crosslinking reaction, a poly(succinimide) / lysine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel is obtained.
[0044] Example 3
[0045] (1) Weigh poly(succinimide) with a molecular weight of 7000 - 8000, dissolve it in deionized water at 50 °C, and stir for 5 min to prepare a 0.8 mol / L poly(succinimide) solution;
[0046] (2) Subsequently, weigh histidine with a purity of 98% and add it to step 1 to prepare a 1.2 mol / L histidine solution. Heat it in a water bath at 60 °C for 24 h with a stirring rate of 500 r / min.
[0047] (3) Weigh itaconic acid with a purity of 99% and add it to the solution in step 2. The concentration of itaconic acid is 0.8 mol / L. After reacting at 60 °C for 2 h, take it out and place it in a petri dish for freeze-drying.
[0048] (4) Take the product after freeze-drying in step 3 and add it to a three-necked flask containing 30 mL of deionized water with a concentration of 0.5%. After ultrasonic dissolution, add N-isopropylacrylamide with a total mass of 5% and azobisisobutyronitrile as an initiator with a total mass of 0.05%. React at 70 °C under N 2 atmosphere for 3 h. After crosslinking reaction, a poly(succinimide) / histidine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel is obtained.
[0049] Example 4
[0050] (1) Weigh poly(succinimide) with a molecular weight of 7000 - 8000, dissolve it in deionized water at 40 °C, and stir for 20 min to prepare a 0.6 mol / L poly(succinimide) solution;
[0051] (2) Subsequently, weigh arginine with a purity of 98% and add it to step 1 to prepare an 0.8 mol / L arginine solution. Heat it in a water bath at 60 °C for 24 h with a stirring rate of 500 r / min.
[0052] (3) Weigh itaconic acid with a purity of 99% and add it to the solution in Step 2. The concentration of itaconic acid is 1.2 mol / L. After reacting at 50 °C for 4 h, take it out and place it in a petri dish for freeze-drying.
[0053] (4) Take the freeze-dried product in Step 3 and add it to a three-necked flask containing 30 mL of deionized water with a concentration of 0.2%. After ultrasonic dissolution, add N-isopropylacrylamide with a total mass of 4% and benzoyl peroxide with a total mass of 0.02% as the initiator. React at 60 °C under a nitrogen 2 atmosphere for 3 h. After crosslinking reaction, a poly(succinimide) / arginine / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel is obtained.
[0054] The above-described embodiments are only the preferred embodiments of the present invention, and not all the feasible embodiments of the present invention. For those of ordinary skill in the art, any obvious modifications made without departing from the principle and spirit of the present invention should be considered to be included within the protection scope of the claims of the present invention.
Claims
1. A macromolecular injectable thermosensitive hydrogel, characterized in that: The raw materials are polysuccinimide, amino acid, itaconic acid and N-isopropylacrylamide. The crosslinking agent is polysuccinimide-amino acid-itaconic acid crosslinking agent, wherein the mass fraction ratio of polysuccinimide, amino acid and itaconic acid is 1:0.5-1.5:0.7-2.
0. Subsequently, the temperature-sensitive hydrogel is prepared by reacting the amino acid-itaconic acid-polysuccinimide crosslinking agent with N-isopropylacrylamide.
2. A method for preparing a macromolecular injectable thermosensitive hydrogel, characterized in that: The method comprises the following steps: (1) dissolving polysuccinimide in deionized water at 10° C. to 50° C. and stirring uniformly to obtain solution A; (2) Add amino acids to solution A and heat in a water bath at 30°C-80°C to obtain solution B; (3) adding itaconic acid to solution B, heating in a water bath at 20°C-50°C to obtain a solution, and freeze-drying to obtain solid C; (4) Dissolve solid C in deionized water and stir to a concentration of 0.1%-2%, add N-isopropylacrylamide and initiator, the ratio of solid C, N-isopropylacrylamide, and initiator is 0.1-1:1-2:0.01-0.1, stir and wait for the reaction for 2-4 hours to obtain polysuccinimide / amino acid / itaconic acid / N-isopropylacrylamide thermosensitive hydrogel.
3. The method for preparing the macromolecular injectable thermosensitive hydrogel according to claim 2, characterized in that: In the step (1), the polysuccinimide is a white powder with a molecular weight of 7000-8000.
4. The method for preparing the macromolecular injectable thermosensitive hydrogel according to claim 2, characterized in that: The amino acids in step (2) are lysine, histidine and arginine, and the purity is not less than 98%.
5. The method for preparing the macromolecular injectable thermosensitive hydrogel according to claim 2, characterized in that: The itaconic acid in step (3) has a purity of not less than 99%.
6. The method for preparing the macromolecular injectable thermosensitive hydrogel according to claim 2, characterized in that: The purity of N-isopropylacrylamide in step (4) is not less than 98%, and the product is a light yellow crystalline powder.
7. The method for preparing the macromolecular injectable thermosensitive hydrogel according to claim 2, characterized in that: In the step (4), the stirring rate is 200-800 r / min, the water bath heating temperature is 50° C.-100° C., and the stirring time is 1-6 h.
8. The method for preparing a macromolecular injectable thermosensitive hydrogel as claimed in claim 2, wherein the initiator in step (4) is any one of ammonium persulfate (APS), azobisisobutyronitrile (AIBN) and dibenzoyl peroxide (BPO).