Dual temperature-sensitive hydrogel drug carrier as well as preparation method and application thereof
By synergistically combining quaternized chitosan and polymethacrylamide Pluronic F127, a dual thermosensitive hydrogel drug carrier was prepared, solving the phase transition and biocompatibility problems of thermosensitive hydrogel materials in loading hydrophobic drugs. This achieved stable drug loading and rapid gelation, improving therapeutic efficacy and safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-10
- Publication Date
- 2026-04-10
AI Technical Summary
Existing thermosensitive hydrogel materials have problems in loading hydrophobic drugs, such as difficulty in balancing phase transition temperature range and kinetic parameters, insufficient biocompatibility, and insufficient mechanical properties and tissue adhesion after gelation. These issues affect the storage stability, injectability, and wound adhesion of the drug, resulting in poor treatment effects and safety risks.
A dual thermosensitive hydrogel drug carrier is formed by synergistic combination of quaternized chitosan and polymethacrylamide Pluronic F127 with physiological saline. It is in a gel state at 2-8℃ and 35-38℃ and in a sol state at 20-30℃. Combined with the biocompatibility and antibacterial properties of quaternized chitosan, stable drug loading and rapid gelation are achieved.
It achieves stable drug encapsulation and rapid gelation, improves drug retention time and release efficiency on the wound surface, reduces the toxic side effects and drug resistance risk of systemic administration, promotes tissue repair and anti-infection effects, and is suitable for local administration and postoperative anti-adhesion treatment.
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Figure CN121818521A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, and in particular to a dual thermosensitive hydrogel drug carrier, its preparation method, and its application. Background Technology
[0002] Infected wounds, especially complex tissue injuries caused by severe burns, pose a significant challenge in clinical treatment. These wounds are highly susceptible to bacterial infection, and the increasing prevalence of multidrug-resistant bacteria is significantly limiting the effectiveness of traditional treatments. Currently, wound management primarily employs a comprehensive approach combining debridement, local antibacterial dressings, and systemic antibiotic administration. However, traditional systemic antibiotic administration has significant limitations: it is difficult to achieve and maintain effective drug concentrations locally at the wound site, which not only affects treatment efficacy but also easily induces bacterial resistance and may cause systemic toxic side effects.
[0003] To overcome the drawbacks of systemic drug delivery, local drug delivery strategies have received widespread attention. Among these, Thermosensitive hydrogels exhibit promising application prospects due to their unique phase transition behavior and controllable release characteristics. Conventional thermosensitive hydrogels are liquid at low temperatures, facilitating drug mixing and storage; after injection into the wound, they rapidly transform into a gel state upon body temperature triggering, forming a physical barrier and enabling sustained local drug release. These materials not only significantly prolong drug retention time at the infection site and improve utilization efficiency, but also reduce systemic toxicity and the risk of drug resistance by decreasing the frequency of administration.
[0004] However, existing thermosensitive hydrogel materials still have significant shortcomings in loading hydrophobic drugs. First, their phase transition temperature range and kinetic parameters often fail to simultaneously meet the requirements of low-temperature stability, room-temperature injectability, and rapid gelation at body temperature, easily leading to burst release or precipitation of drugs in the early stages of injection, affecting efficacy and safety. Second, the biocompatibility and long-term safety of the material remain key considerations, as degradation products of some synthetic materials may cause adverse tissue reactions. In addition, existing thermosensitive systems often exhibit insufficient mechanical properties and tissue adhesion after gelation, making it difficult to fully adhere to irregular wound surfaces, easily causing barrier dysfunction and uneven drug release.
[0005] Therefore, there is an urgent need in this field to develop a novel drug carrier that possesses temperature-triggered controllable phase transition characteristics to ensure stability throughout the entire process from storage and injection to the formation of a drug reservoir in vivo, while also exhibiting good biocompatibility, broad drug loading capacity, and excellent wound adhesion and adaptability. Summary of the Invention
[0006] The purpose of this invention is to address the problems existing in the prior art by providing a dual thermosensitive hydrogel drug carrier, its preparation method, and its application. Through the synergistic combination of quaternized chitosan, polymethacrylamide Pluronic F127, and physiological saline, combined with its unique dual thermosensitive behavior, it exhibits significant beneficial effects in drug delivery and wound treatment.
[0007] To achieve the above objectives, the present invention provides a dual thermosensitive hydrogel drug carrier comprising quaternized chitosan and polymethacrylamide Pluronic F127. Hydrogel drug carriers have dual temperature-sensitive properties: they exhibit a gel state at 2-8℃ and 35-38℃, and a sol state at 20-30℃.
[0008] Preferably, the preparation method of quaternized chitosan includes the following steps: mixing chitosan solution and quaternizing reagent, and reacting to obtain quaternized chitosan.
[0009] Preferably, the quaternizing agent is selected from 2,3-epoxypropyltrimethylammonium chloride; the mass ratio of chitosan to the quaternizing agent is 1:1.2-1.6.
[0010] Preferably, the reaction temperature is 50-60℃ and the time is 16-20h.
[0011] Preferably, the preparation method of polymethacrylamide Pluronic F127 includes the following steps: (1) Pluronic F127, dichloromethane, triethylamine and acryloyl chloride were mixed and acrylated to obtain methacrylated Pluronic F127; (2) Mix methacrylamide Pluronic F127, water and initiator and carry out free radical polymerization to obtain polymethacrylamide Pluronic F127.
[0012] Preferably, in step (1), the temperature of the acrylation reaction is 2-6℃ and the time is 22-26h.
[0013] Preferably, in step (2), the temperature of the free radical polymerization reaction is 60-70℃ and the time is 10-14h.
[0014] The present invention also provides a method for preparing the aforementioned dual thermosensitive hydrogel drug carrier, comprising the step of dissolving quaternized chitosan and polymethacrylamide Pluronic F127 in physiological saline.
[0015] The present invention also provides the application of the aforementioned dual thermosensitive hydrogel drug carrier in the preparation of drugs for local drug delivery therapy.
[0016] The present invention also provides the application of the aforementioned dual thermosensitive hydrogel drug carrier in the preparation of medical devices for postoperative anti-adhesion or sustained-release therapy.
[0017] The dual thermosensitive hydrogel drug carrier provided by this invention, through the synergistic combination of quaternized chitosan, polymethacrylamide Pluronic F127, and physiological saline, combined with its unique dual thermosensitive behavior, exhibits significant beneficial effects in drug delivery and wound treatment, specifically in the following aspects: 1. The hydrogel drug carrier exists in a gel state at 2-8℃ and 35-38℃, and in a sol state at 20-30℃. This dual thermosensitive property enables it to stably encapsulate drugs and prevent precipitation during low-temperature storage; it maintains good fluidity when injected or applied at room temperature, facilitating clinical operation; and it rapidly gels upon contact with body temperature, forming a drug reservoir in situ at the wound site, achieving long-acting sustained release and local retention. This characteristic effectively solves the problem of traditional delivery systems struggling to balance storage stability, injectability, and in vivo retention.
[0018] 2. Using quaternized chitosan as the main material, it possesses excellent biocompatibility, biodegradability, and broad-spectrum antibacterial activity. It can not only serve as a drug carrier but also exert synergistic antibacterial effects with loaded hydrophobic drugs. Simultaneously, the three-dimensional network structure of the hydrogel can absorb wound exudate, maintain a moist healing environment, and provide a scaffold for fibroblast migration and angiogenesis, thereby actively promoting tissue repair while fighting infection.
[0019] 3. This hydrogel drug carrier, by utilizing the cationic properties carried by quaternized chitosan, can effectively load various types of hydrophobic drugs, including anionic, cationic, and neutral drugs, through electrostatic interactions, and has good versatility and dosage form adaptability.
[0020] 4. By administering the drug locally, it can accumulate in the wound area, significantly increasing the drug concentration at the site of infection and prolonging the duration of action. At the same time, it avoids the risks of rapid metabolism, large toxic side effects, and drug resistance caused by systemic administration. It is particularly suitable for postoperative anti-infection, anti-adhesion, and chronic wound treatment.
[0021] 5. The preparation method has clear steps, mild reaction conditions, widely available and cost-controllable raw materials, good process reproducibility, and good application potential.
[0022] In summary, the dual thermosensitive hydrogel drug carrier of the present invention is not only innovative in terms of material structure and thermosensitive properties, but also demonstrates comprehensive advantages in drug controlled release, wound repair and clinical applicability, providing a safe and efficient new material for infected wounds and other local drug delivery scenarios. Attached Figure Description
[0023] Figure 1 This is the rheological temperature scan of the dual thermosensitive hydrogel drug carrier in Example 1 of the present invention; Figure 2 This is the release performance curve of silver sulfadiazine in Experimental Example 3 of this invention; Figure 3 This is a diagram illustrating the antibacterial efficacy of the dual temperature-sensitive hydrogel drug carrier in Example 1 of this invention. Figure 3 In the diagram, 'a' represents the efficacy against Staphylococcus aureus. Figure 3 In the diagram, b represents the efficacy against E. coli. Detailed Implementation
[0024] This invention provides a dual thermosensitive hydrogel drug carrier comprising quaternized chitosan and polymethacrylamide Pluronic F127; Hydrogel drug carriers have dual temperature-sensitive properties: they exhibit a gel state at 2-8℃ and 35-38℃, and a sol state at 20-30℃.
[0025] In this invention, the preparation method of quaternized chitosan includes the following steps: mixing chitosan solution and quaternizing reagent, reacting to obtain quaternized chitosan.
[0026] In this invention, the method for preparing chitosan solution includes the following steps: dispersing chitosan in distilled water, then adding acetic acid, and continuously stirring until the chitosan is completely dissolved to obtain chitosan solution; the mass-volume ratio of chitosan, water and acetic acid is 2-3g: 80-120mL: 0.5-1.5mL.
[0027] In this invention, the degree of deacetylation of chitosan is greater than or equal to 95%, and the viscosity is 100-200 mPa·s.
[0028] In this invention, the quaternizing agent is selected from 2,3-epoxypropyltrimethylammonium chloride; the mass ratio of chitosan to the quaternizing agent is 1:1.2-1.6.
[0029] In this invention, the reaction is carried out in an oil bath with stirring, at a temperature of 50-60°C, for a time of 16-20 hours.
[0030] In this invention, after the reaction is completed, the reaction solution is purified by dialysis to remove unreacted small molecule impurities. Specifically, a dialysis bag with a molecular weight cutoff of 900-1100 Da is used, and the solution is dialyzed in deionized water for 44-52 hours, with the dialysis solution being replaced every 6-8 hours.
[0031] In this invention, the dialysis solution is freeze-dried to obtain quaternized chitosan. The freeze-drying process includes: first, pre-freezing the solution at -78 to -82°C for ≥4 hours, then transferring it to a freeze dryer and drying it for 22-26 hours at a cold trap temperature of -58 to -62°C and a vacuum degree of ≤20 Pa; then raising the temperature to 23-27°C for desorption drying for 5-7 hours to obtain quaternized chitosan, which is then sealed and stored at -20°C to -25°C.
[0032] In this invention, the preparation method of polymethacrylamide Pluronic F127 includes the following steps: (1) Pluronic F127, dichloromethane, triethylamine and acryloyl chloride were mixed and acrylated to obtain methacrylated Pluronic F127 (F127DA). (2) Mix methacrylamide Pluronic F127 (F127DA), water and initiator, and carry out free radical polymerization to obtain polymethacrylamide Pluronic F127.
[0033] In this invention, step (1) includes mixing: dissolving Pluronic F127 in dichloromethane to obtain a Pluronic F127 solution; and sequentially adding triethylamine and acryloyl chloride to the Pluronic F127 solution.
[0034] In this invention, the concentration of Pluronic F127 in the Pluronic F127 solution is 80-120 mg / mL, and the molar ratio of Pluronic F127, triethylamine and acryloyl chloride is 1:3-5:3-5.
[0035] In this invention, in step (1), the acrylation reaction is carried out under the conditions of ice-water bath and stirring, the temperature of the acrylation reaction is 2-6℃, and the time is 22-26h.
[0036] In this invention, in step (1), after the reaction is completed, the solvent is removed by rotary evaporation to obtain the crude product; the crude product is redissolved in water and then purified by dialysis: using a dialysis bag with a molecular weight cutoff of 3400-3600 Da, the solution is dialyzed in deionized water for 44-52 hours, and the dialysis solution is changed every 7-9 hours to completely remove unreacted small molecule reagents and byproducts to obtain a purified F127DA solution; finally, the purified F127DA solution is freeze-dried to obtain F127DA.
[0037] In this invention, the freeze-drying process includes: first, pre-freezing the solution at -78 to -82°C for ≥4 hours, then transferring it to a freeze dryer and drying it for 22-26 hours at a cold trap temperature of -58 to -62°C and a vacuum degree of ≤20Pa; then raising the temperature to 23-27°C for desorption drying for 5-7 hours to obtain F127DA.
[0038] In this invention, step (2) includes mixing: mixing F127DA and water to obtain an F127DA solution; adding an initiator to the F127DA solution to obtain a mixed solution.
[0039] In this invention, the mass fraction of F127DA in the F127DA solution is 3-7%; the initiator is selected from ammonium persulfate, and the concentration of the initiator in the mixed solution is 55-65 mmol / L.
[0040] In this invention, in step (2), the temperature of the free radical polymerization reaction is 60-70℃ and the time is 10-14h.
[0041] In this invention, in step (2), after the free radical polymerization reaction is completed, the reaction solution is purified by dialysis to remove unreacted small molecule impurities. Specifically, a dialysis bag with a molecular weight cutoff of 3400-3600 Da is used, and the solution is dialyzed in deionized water for 48-72 hours, and the dialysis solution is replaced every 11-13 hours.
[0042] In this invention, the dialysis solution is freeze-dried to obtain polymethacrylamide Pluronic F127. The freeze-drying process includes: first, pre-freezing the solution at -78 to -82°C for ≥4 hours, then transferring it to a freeze dryer and drying it for 22-26 hours at a cold trap temperature of -58 to -62°C and a vacuum degree of ≤20 Pa; then raising the temperature to 23-27°C for desorption drying for 5-7 hours to obtain polymethacrylamide Pluronic F127, which is then sealed and stored at -20°C to -25°C.
[0043] The present invention also provides a method for preparing the aforementioned dual thermosensitive hydrogel drug carrier, comprising the step of dissolving quaternized chitosan and polymethacrylamide Pluronic F127 in physiological saline.
[0044] In this invention, the physiological saline is a sodium chloride solution with a mass fraction of 0.9%; the mass-volume ratio of quaternized chitosan, polymethacrylamide Pluronic F127 and physiological saline is 1-2g: 4-6g: 80-120mL.
[0045] The present invention also provides the application of the aforementioned dual thermosensitive hydrogel drug carrier in the preparation of drugs for local drug delivery therapy.
[0046] The present invention also provides the application of the aforementioned dual thermosensitive hydrogel drug carrier in the preparation of medical devices for postoperative anti-adhesion or sustained-release therapy.
[0047] The present invention will be further described below with reference to embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.
[0048] In the following embodiments and comparative examples of the present invention, the degree of deacetylation of chitosan was 96%, the viscosity was 150 mPa·s, and it was purchased from Aladdin (item number: C105799-100g); Pluronic F127 was purchased from Aladdin (item number: P43442).
[0049] Example 1 This embodiment provides a method for preparing a dual thermosensitive hydrogel drug carrier, comprising the following steps: 2.7 g of chitosan was dispersed in 100 mL of distilled water, followed by the addition of 1.0 mL of acetic acid. The mixture was stirred until completely dissolved to obtain a chitosan solution. Under an oil bath at 55 °C, 2,3-epoxypropyltrimethylammonium chloride was added to the chitosan solution at a mass ratio of 1:1.425 (chitosan to 2,3-epoxypropyltrimethylammonium chloride), and the reaction was continuously stirred for 18 h. After the reaction, the reaction solution was dialyzed: using a dialysis bag with a molecular weight cutoff of 1000 Da, the solution was dialyzed in deionized water for 48 h, with the dialysate replaced every 7 h. Finally, the solution was freeze-dried: the dialyzed solution was pre-frozen at -80 °C for 4 h, then transferred to a freeze dryer and dried for 24 h under a cold trap temperature of -60 °C and a vacuum of 20 Pa; then heated to 25 °C for desorption drying for 6 h to obtain quaternized chitosan, which was then sealed and stored at -20 °C.
[0050] Pluronic F127 was dissolved in dichloromethane under 4°C ice-water bath conditions to obtain a 100 mg / mL Pluronic F127 solution; triethylamine and acryloyl chloride were slowly added dropwise to the Pluronic F127 solution in a molar ratio of 1:3.5:3.5, and the reaction was magnetically stirred for 24 h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was redissolved in distilled water and then purified by dialysis: using a dialysis bag with a molecular weight cutoff of 3500 Da, the solution was dialyzed in deionized water for 48 hours, with the dialysate being replaced every 8 hours to completely remove unreacted small molecule reagents and byproducts, resulting in a purified F127DA solution; the purified F127DA solution was pre-frozen at -80℃ for 4 hours, then transferred to a freeze dryer and dried for 24 hours at a cold trap temperature of -60℃ and a vacuum of 20 Pa; then heated to 25℃ for desorption and drying for 6 hours to obtain F127DA.
[0051] F127DA and water were mixed to obtain a 5% F127DA solution. Ammonium persulfate was added to the F127DA solution to obtain a mixed solution with an initiator concentration of 60 mmol / L. Free radical polymerization was carried out at 65 °C for 12 h. After the reaction, the reaction solution was purified by dialysis: a dialysis bag with a molecular weight cutoff of 3500 Da was used to dialyze in deionized water for 56 h, and the dialysate was replaced every 12 h. Finally, freeze-drying was performed: the dialyzed solution was pre-frozen at -80 °C for 4 h, then transferred to a freeze dryer and dried at a cold trap temperature of -60 °C and a vacuum of 20 Pa for 24 h. The temperature was then raised to 25 °C for desorption drying for 6 h to obtain polymethacrylamide Pluronic F127, which was sealed and stored at -20 °C.
[0052] 1.5g of quaternized chitosan and 5g of polymethacrylamide Pluronic F127 were dissolved in 100mL of physiological saline and vortexed to mix evenly to obtain a dual thermosensitive hydrogel drug carrier.
[0053] Example 2 This embodiment provides a method for preparing a dual thermosensitive hydrogel drug carrier, comprising the following steps: 2.7 g of chitosan was dispersed in 100 mL of distilled water, followed by the addition of 1.0 mL of acetic acid. The mixture was stirred until completely dissolved to obtain a chitosan solution. Under 50°C oil bath conditions, 2,3-epoxypropyltrimethylammonium chloride was added to the chitosan solution at a mass ratio of chitosan to 2,3-epoxypropyltrimethylammonium chloride of 1:1.2, and the reaction was continuously stirred for 16 h. After the reaction, the reaction solution was dialyzed: using a dialysis bag with a molecular weight cutoff of 1000 Da, the solution was dialyzed in deionized water for 48 h, with the dialysate replaced every 7 h. Finally, the solution was freeze-dried: the dialyzed solution was pre-frozen at -80°C for 4 h, then transferred to a freeze dryer and dried for 24 h under a cold trap temperature of -60°C and a vacuum of 20 Pa; then heated to 25°C for desorption drying for 6 h to obtain quaternized chitosan, which was then sealed and stored at -20°C.
[0054] Pluronic F127 was dissolved in dichloromethane under 2°C ice-water bath conditions to obtain a 100 mg / mL Pluronic F127 solution; triethylamine and acryloyl chloride were slowly added dropwise to the Pluronic F127 solution in a molar ratio of 1:3.5:3.5, and the reaction was magnetically stirred for 22 h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was redissolved in distilled water and then purified by dialysis: using a dialysis bag with a molecular weight cutoff of 3500 Da, the solution was dialyzed in deionized water for 48 hours, with the dialysate being replaced every 8 hours to completely remove unreacted small molecule reagents and byproducts, resulting in a purified F127DA solution; the purified F127DA solution was pre-frozen at -80℃ for 4 hours, then transferred to a freeze dryer and dried for 24 hours at a cold trap temperature of -60℃ and a vacuum of 20 Pa; then heated to 25℃ for desorption and drying for 6 hours to obtain F127DA.
[0055] F127DA and water were mixed to obtain a 5% (w / w) F127DA solution. Ammonium persulfate was added to the F127DA solution to obtain a mixed solution with an initiator concentration of 55 mmol / L. Free radical polymerization was carried out at 60 °C for 10 h. After the reaction, the reaction solution was purified by dialysis: a dialysis bag with a molecular weight cutoff of 3500 Da was used to dialyze in deionized water for 56 h, and the dialysate was replaced every 12 h. Finally, freeze-drying was performed: the dialyzed solution was pre-frozen at -80 °C for 4 h, then transferred to a freeze dryer and dried at a cold trap temperature of -60 °C and a vacuum of 20 Pa for 24 h; then heated to 25 °C for desorption drying for 6 h to obtain polymethacrylamide Pluronic F127, which was sealed and stored at -20 °C.
[0056] 1g of quaternized chitosan and 4g of polymethacrylamide Pluronic F127 were dissolved in 80mL of physiological saline and vortexed to obtain a dual thermosensitive hydrogel drug carrier.
[0057] Example 3 This embodiment provides a method for preparing a dual thermosensitive hydrogel drug carrier, comprising the following steps: 2.7 g of chitosan was dispersed in 100 mL of distilled water, followed by the addition of 1.0 mL of acetic acid. The mixture was stirred until completely dissolved to obtain a chitosan solution. Under an oil bath at 60 °C, 2,3-epoxypropyltrimethylammonium chloride was added to the chitosan solution at a mass ratio of 1:1.6 (chitosan to 2,3-epoxypropyltrimethylammonium chloride), and the reaction was continuously stirred for 20 h. After the reaction, the reaction solution was dialyzed: using a dialysis bag with a molecular weight cutoff of 1000 Da, the solution was dialyzed in deionized water for 48 h, with the dialysate replaced every 7 h. Finally, the solution was freeze-dried: the dialyzed solution was pre-frozen at -80 °C for 4 h, then transferred to a freeze dryer and dried for 24 h under a cold trap temperature of -60 °C and a vacuum of 20 Pa; then heated to 25 °C for desorption drying for 6 h to obtain quaternized chitosan, which was then sealed and stored at -20 °C.
[0058] Pluronic F127 was dissolved in dichloromethane under 6°C ice-water bath conditions to obtain a 100 mg / mL Pluronic F127 solution; triethylamine and acryloyl chloride were slowly added dropwise to the Pluronic F127 solution in a molar ratio of 1:3.5:3.5, and the reaction was magnetically stirred for 26 h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was redissolved in distilled water and then purified by dialysis: using a dialysis bag with a molecular weight cutoff of 3500 Da, the solution was dialyzed in deionized water for 48 hours, with the dialysate being replaced every 8 hours to completely remove unreacted small molecule reagents and byproducts, resulting in a purified F127DA solution; the purified F127DA solution was pre-frozen at -80℃ for 4 hours, then transferred to a freeze dryer and dried for 24 hours at a cold trap temperature of -60℃ and a vacuum of 20 Pa; then heated to 25℃ for desorption and drying for 6 hours to obtain F127DA.
[0059] F127DA and water were mixed to obtain a 5% F127DA solution. Ammonium persulfate was added to the F127DA solution to obtain a mixed solution with an initiator concentration of 65 mmol / L. Free radical polymerization was carried out at 70 °C for 14 h. After the reaction, the reaction solution was purified by dialysis: a dialysis bag with a molecular weight cutoff of 3500 Da was used to dialyze in deionized water for 56 h, and the dialysate was replaced every 12 h. Finally, freeze-drying was performed: the dialyzed solution was pre-frozen at -80 °C for 4 h, then transferred to a freeze dryer and dried for 24 h under a cold trap temperature of -60 °C and a vacuum of 20 Pa. The temperature was then raised to 25 °C for desorption drying for 6 h to obtain polymethacrylamide Pluronic F127, which was sealed and stored at -20 °C.
[0060] 2g of quaternized chitosan and 6g of polymethacrylamide Pluronic F127 were dissolved in 120mL of physiological saline and vortexed to obtain a dual thermosensitive hydrogel drug carrier.
[0061] Comparative Example 1 This comparative example provides a method for preparing a thermosensitive hydrogel drug carrier, which differs from Example 1 in that the step of reacting chitosan is omitted, and the quaternized chitosan is modified to be methacrylamide chitosan (EFL-S-CSMA-100K, Suzhou Yongqinquan Intelligent Equipment Co., Ltd.).
[0062] Comparative Example 2 This comparative example provides a method for preparing a thermosensitive hydrogel drug carrier, which differs from Example 1 in that the step of reacting Pluronic F127 is omitted, and polymethacrylamide Pluronic F127 is modified to Pluronic F127.
[0063] Comparative Example 3 This comparative example provides a method for preparing a thermosensitive hydrogel drug carrier, which differs from Example 1 in that: 1.5g of quaternized chitosan and 5g of polymethacrylamide Pluronic F127 are dissolved in 100mL of phosphate buffer solution and vortexed to mix evenly to obtain a dual thermosensitive hydrogel drug carrier.
[0064] Experimental Example 1 The hydrogel drug carriers prepared in Examples 1-3 and Comparative Examples 1-3 were placed at 4°C, 25°C, and 37°C, respectively, and their phase changes were observed and the gelation time was recorded. The results showed that Examples 1-3: Stable gels were formed within 10 minutes at both 4°C and 37°C; while at 25°C, they remained in a flowable sol state, exhibiting the expected dual thermosensitive properties. Comparative Example 1: Insufficient gelation ability; it was difficult to form stable gels at both 4°C and 37°C (fragile structure, easy to flow). Comparative Example 2: Only exhibited a single thermosensitive behavior, i.e., a sol state below 37°C and a gel state above 37°C, lacking the dual thermosensitive property of gelation at 4°C. Comparative Example 3: Only exhibited a single thermosensitive behavior, i.e., a gel state at 37°C, also lacking the dual thermosensitive property of gelation at 4°C.
[0065] Experiment Example 2 The dual-temperature-sensitive hydrogel drug carrier prepared in Example 1 was pre-equilibrated at 4°C to form an initial gel state. Subsequently, a rotational rheometer equipped with parallel plate clamps (25 mm diameter, 0.5 mm gap) was used to perform temperature scanning tests in oscillation mode (fixed strain and frequency). The temperature was increased from 4°C to 40°C at a heating rate of 2°C / min, and the changes in storage modulus (G′) and loss modulus (G″) as a function of temperature were recorded to obtain the rheological temperature scanning spectrum of the dual-temperature-sensitive hydrogel drug carrier in Example 1, as shown below. Figure 1 As shown. According to Figure 1 The results showed that in the low-temperature and body-temperature ranges of 2-8℃ and 35-38℃, G′ was significantly higher than G″, exhibiting a typical gel state; while in the 20-30℃ range, G″ was higher than G′, showing a sol state. This rheological behavior clearly verifies that the hydrogel has dual temperature-sensitive phase transition characteristics of "low temperature-body temperature".
[0066] Experimental Example 3 Using silver sulfadiazine (SSD) as a model drug, it was loaded into the dual thermosensitive hydrogel drug carrier prepared in Example 1 at a loading of 1% (w / w), and its release performance was determined in phosphate-buffered saline (PBS, pH 7.4). The release performance curve of silver sulfadiazine in Experiment 3 is shown in the figure below. Figure 2 As shown in the figure. The results show that its release curve exhibits typical biphasic characteristics: there is a slow release phase in the first hour, with a cumulative release rate of 3.5±0.13%, which is mainly attributed to the diffusion of the drug adsorbed on the surface and near-surface region of the hydrogel; then the release behavior turns into a near-linear continuous release phase, and follows an approximately zero-order kinetic mode for a smooth release in the following 70 hours, with a cumulative release rate of 80%±3% by 72 hours.
[0067] Experiment Example 4 To evaluate the antibacterial efficacy of the dual thermosensitive hydrogel drug carrier in Example 1, silver sulfadiazine (SSD) was used as a model drug. The inhibition zone method was employed to compare the inhibitory effects of the dual thermosensitive hydrogel drug carrier loaded with 0.1% (w / w) SSD (labeled QCS / CMFDA@AgSD(0.1%)) and a commercially available silver sulfadiazine cream (SSD content 1%, w / w) (labeled CC-AgSD 1%) on Staphylococcus aureus and Escherichia coli. After incubation at 37°C for 24 hours, the antibacterial efficacy of the dual thermosensitive hydrogel drug carrier in Example 1 was obtained, as shown in the figure. Figure 3 As shown; Figure 3 In the diagram, 'a' represents the efficacy against Staphylococcus aureus. Figure 3 Figure b represents the efficacy against *E. coli*. The results show that the inhibition zone diameters produced by the dual thermosensitive hydrogel drug carrier loaded with 0.1% SSD against both test bacterial species were comparable to those of the commercial cream group loaded with 1% SSD (the inhibition zone diameters against *Staphylococcus aureus* were both in the range of 12-13 mm). This result indicates that the hydrogel system of this invention achieves the same antibacterial effect with only one-tenth the drug loading of commercial products. This confirms that the system significantly improves drug utilization efficiency through the intelligent sustained-release properties of the hydrogel and the synergistic antibacterial effect of quaternized chitosan, providing a more optimized solution to reduce systemic toxicity and drug resistance risks while ensuring excellent local antibacterial performance.
[0068] Therefore, this invention, through the synergistic combination of quaternized chitosan, polymethacrylamide Pluronic F127 and saline, combined with its unique dual thermosensitive behavior, demonstrates significant beneficial effects in drug delivery and wound treatment.
[0069] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.
Claims
1. A dual-temperature-sensitive hydrogel drug carrier, characterized in that, Contains quaternized chitosan and polymethacrylamide Pluronic F127; Hydrogel drug carriers have dual temperature-sensitive properties: they exhibit a gel state at 2-8℃ and 35-38℃, and a sol state at 20-30℃.
2. The dual thermosensitive hydrogel drug carrier according to claim 1, characterized in that, The preparation method of quaternized chitosan includes the following steps: mixing chitosan solution and quaternizing reagent, reacting to obtain quaternized chitosan.
3. The dual thermosensitive hydrogel drug carrier according to claim 2, characterized in that, The quaternizing agent is selected from 2,3-epoxypropyltrimethylammonium chloride; the mass ratio of chitosan to the quaternizing agent is 1:1.2-1.
6.
4. The dual thermosensitive hydrogel drug carrier according to claim 2, characterized in that, The reaction temperature is 50-60℃ and the reaction time is 16-20h.
5. The dual thermosensitive hydrogel drug carrier according to claim 1, characterized in that, The preparation method of polymethacrylamide Pluronic F127 includes the following steps: (1) Pluronic F127, dichloromethane, triethylamine and acryloyl chloride were mixed and acrylated to obtain methacrylated Pluronic F127; (2) Mix methacrylamide Pluronic F127, water and initiator and carry out free radical polymerization to obtain polymethacrylamide Pluronic F127.
6. The dual thermosensitive hydrogel drug carrier according to claim 5, characterized in that, In step (1), the temperature of the acrylation reaction is 2-6℃ and the time is 22-26h.
7. The dual thermosensitive hydrogel drug carrier according to claim 5, characterized in that, In step (2), the temperature of the free radical polymerization reaction is 60-70℃ and the time is 10-14h.
8. The method for preparing the dual thermosensitive hydrogel drug carrier according to any one of claims 1-7, characterized in that, The process includes the step of dissolving quaternized chitosan and polymethacrylamide Pluronic F127 in physiological saline.
9. The use of the dual thermosensitive hydrogel drug carrier according to any one of claims 1-7 in the preparation of a drug for local drug delivery.
10. The use of the dual thermosensitive hydrogel drug carrier according to any one of claims 1-7 in the preparation of a medical device for postoperative anti-adhesion or sustained-release therapy.