Preparation method of drug sustained-release modified starch hydrogel and application thereof

Abstract

The application discloses a preparation method of a drug sustained-release modified starch hydrogel and application thereof, and belongs to the field of starch chemical modification and biomedical materials. The method is characterized by a starch hydroxyl modification and modification through PAA micelle mediation and a starch gelatinization-network interweaving synergistic enhancement strategy. A CTS-PEG-600 composite solution and a PAA micelle modified starch dispersion liquid are prepared first, a dense three-dimensional network is constructed through compounding and cross-linking and high-temperature gelatinization, and a starch-based hydrogel material is obtained through post-processing. After fucoidan is loaded on the hydrogel, an oral sustained-release preparation can be prepared, long-acting and stable release of drugs is realized, non-alcoholic fatty liver disease is treated through targeted therapy, the hydrogel has excellent biocompatibility, mechanical stability and controllable sustained-release property, the process is green and environmentally friendly, the hydrogel is suitable for large-scale production, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the interdisciplinary field of starch chemical modification and biomedical materials, specifically to a method for preparing drug-release modified starch hydrogel and its application. Background Technology

[0002] Hydrogels, as a class of three-dimensional network materials formed by the physical or chemical cross-linking of hydrophilic polymer chains, occupy a core position in biomedical fields such as drug sustained release, tissue engineering scaffolds, and wound dressings due to their high water content, softness similar to human tissue, and excellent biocompatibility. In recent years, hydrogel materials based on natural polymers have gradually replaced some synthetic polymer hydrogels as a research hotspot due to their advantages such as biodegradability and non-immunogenicity. Among them, starch-based hydrogels have received particular attention from academia and industry due to their wide availability of raw materials, low cost, and high biosafety.

[0003] However, existing starch-based sustained-release hydrogels for drugs still face many technical challenges in practical applications. On the one hand, starch molecules are rich in hydroxyl groups, which easily form strong hydrogen bonds between molecules. This leads to severe aggregation of starch particles in the hydrogel matrix, making uniform dispersion impossible. Consequently, drug loading fluctuates greatly, and local drug concentrations are either too high or too low, affecting not only therapeutic efficacy but also potentially causing toxic side effects. Furthermore, aggregation disrupts the continuity of the hydrogel network, further reducing the material's mechanical stability. On the other hand, traditional starch-based hydrogels often rely on single physical or weak chemical cross-linking methods. The resulting network structure suffers from excessively high porosity and uneven pore size distribution. This not only leads to insufficient mechanical strength of the hydrogel, making it prone to swelling and rupture under physiological conditions and unable to maintain a long-term stable carrier morphology, but also allows the encapsulated drug to diffuse rapidly through the large pores, resulting in a significant burst release effect. The initial drug release far exceeds the therapeutic window, followed by a sharp drop in release rate, failing to meet the clinical needs for long-term, stable drug administration in chronic diseases.

[0004] Furthermore, existing methods for improving starch dispersibility mostly involve chemical modification, such as esterification and etherification. While these methods can reduce intermolecular hydrogen bonding in starch, the modification process requires the use of toxic chemical reagents, increasing process complexity and production costs, and leaving harmful impurities that impair the biocompatibility of the hydrogel. On the other hand, simply increasing the amount of crosslinking agent to improve mechanical properties can lead to an overly dense hydrogel network, reducing drug loading and swelling performance, thus limiting its sustained-release applications. Therefore, developing a preparation technology that achieves selective modification of starch hydroxyl groups under mild conditions and simultaneously addresses starch aggregation and hydrogel network enhancement is of great significance for promoting the clinical translation of starch-based drug sustained-release hydrogels. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing drug-release modified starch hydrogels and their applications. This invention utilizes PAA micelle-mediated starch hydroxyl modification technology and a starch gelatinization-network interweaving synergistic enhancement strategy to achieve mild modification and uniform dispersion of starch molecular chain hydroxyl groups. This solves the technical problems of starch agglomeration, poor mechanical properties, and burst drug release in traditional starch-based hydrogels. The resulting starch-based network-reinforced sustained-release hydrogel possesses excellent biocompatibility, mechanical stability, and controllable drug release, and can be effectively applied to the oral sustained-release treatment of chronic liver diseases such as non-alcoholic fatty liver disease.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for preparing a drug-release modified starch hydrogel includes the following steps:

[0008] S1: Preparation of composite solution:

[0009] Weigh 3-5g of chitosan (CTS) and 2-6g of polyethylene glycol 600 (PEG-600), add them to a mixed solvent consisting of 40-60mL of 1%-2% aqueous acetic acid solution and 20-30mL of anhydrous ethanol, place the system in a constant temperature water bath at 30-50℃, and stir at 400-600r / min for 1-3h until CTS and PEG-600 are completely dissolved to form a composite solution.

[0010] S2: Preparation of PAA micelle-modified starch dispersion:

[0011] Weigh 5-7g of corn starch by mass and add it to 40-60mL of deionized water. Disperse the starch by ultrasonication to form a starch suspension. Add 2-3g of polyacrylic acid (PAA, molecular weight 5000) to the starch suspension and stir until the PAA is completely dissolved. Then slowly add 20-30mL of anhydrous ethanol at a dropping rate of 1-2mL / min while stirring (300-400r / min). After stirring for 30-60min, the PAA forms micelles under the induction of ethanol and modifies the starch, resulting in a PAA micelle-modified starch dispersion.

[0012] S3: Composite cross-linking and starch gelatinization:

[0013] The PAA micelle-modified starch dispersion from step S2 was slowly added dropwise to the composite solution prepared in step S1. After the addition was complete, the mixture was stirred at 300-400 r / min for 30-40 min to ensure uniform dispersion. Then, 0.8-2.5 g of sodium alginate (crosslinking agent) and 0.05-0.3 g of calcium chloride (sodium alginate crosslinking accelerator) were added, and the mixture was kept at 30-40℃ for 0.5-1 h for initial crosslinking. Subsequently, the system was heated to 80-85℃ and stirred at a low speed of 100-200 r / min for 2-3 h to allow the anhydrous ethanol to fully evaporate. At the same time, PAA gradually dissolved as the ethanol evaporated. The PAA micelle-modified starch absorbed water, swelled, and gelatinized at high temperature. The starch molecular chains were uniformly dispersed in the sol and intertwined with the CTS-PEG network, filling the pores to form a CTS-PEG-600-starch three-dimensional cross-linked network structure.

[0014] S4: Post-processing:

[0015] The hydrogel precursor from step S3 was cooled to room temperature and then immersed in deionized water. The deionized water was changed every 4-5 hours for a total of 4-6 times to thoroughly remove unreacted crosslinking agents, PAA, and free drugs. The immersed hydrogel was then removed to obtain drug-release modified starch hydrogel.

[0016] The application of the drug-release modified starch hydrogel in the treatment of non-alcoholic fatty liver disease specifically includes the following operations:

[0017] S21. Drug load:

[0018] Fucoidan was selected as a specific drug for treating non-alcoholic fatty liver disease. A fucoidan aqueous solution with a mass concentration of 2 mg / mL was prepared. The starch-based sustained-release hydrogel prepared in step S4 was cut into small pieces of 1-2 mm and added to the above aqueous solution at a solid-liquid ratio of 1:20 (g / mL). The hydrogel was soaked at 25°C under light-protected conditions for 18 h to allow it to fully swell and adsorb the drug. After soaking, the hydrogel was removed and the residual drug solution on the surface was blotted dry with sterile filter paper to obtain fucoidan-supported starch-based sustained-release hydrogel.

[0019] S22. Preparation and administration of oral sustained-release formulations

[0020] The drug-loaded hydrogel was placed in a freeze dryer and freeze-dried under vacuum at -45°C for 15 hours. After pulverization, the hydrogel particles were collected by passing them through a 250-mesh sieve. The dosing regimen was 0.5g orally once daily. After entering the stomach, the microspheres remained structurally stable in the acidic environment of the stomach and did not release the drug. After entering the intestine, the microspheres absorbed water and swelled, slowly releasing the drug through the dense and loose composite network of the hydrogel. The drug was absorbed through the intestine and targeted to the liver, exerting the effects of regulating lipid metabolism and protecting hepatocytes.

[0021] Beneficial effects

[0022] (1) The PAA micelle-mediated starch hydroxyl modification strategy is adopted, which eliminates the need for complex chemical modification of starch: PAA forms micelles under ethanol induction and modifies starch, blocking the hydrogen bonding between starch molecules and avoiding aggregation; PAA is then dissolved and removed by ethanol evaporation, which ensures uniform starch dispersion and does not introduce residual impurities, simplifying the process and reducing costs.

[0023] (2) Synergistic enhancement of starch gelatinization and network construction: High-temperature gelatinization causes the PAA micelle-modified starch particles to break down and form molecular chains, which intertwine with the CTS-PEG network, fill the original pores, and construct a dense and loose composite network structure. This not only solves the problem of insufficient mechanical strength of traditional hydrogels, but also delays drug diffusion through the dense network, avoids burst release, and achieves long-term sustained release.

[0024] (3) Excellent biocompatibility and environmental friendliness: The raw materials are all biocompatible materials. Starch and chitosan can be completely biodegraded, with no toxic residues and a cell survival rate of ≥93%. The preparation process does not require high temperature and high pressure or toxic solvents. Only deionized water and anhydrous ethanol are used, which is green and environmentally friendly and suitable for large-scale production.

[0025] (4) Simple and controllable process: The parameters of each step are easy to adjust. The PAA micelle modified starch, cross-linking and gelatinization processes are connected in an orderly manner. The mechanical properties and sustained release period of the hydrogel can be flexibly adjusted by adjusting parameters such as starch dosage and gelatinization temperature to meet the needs of different medical scenarios. Attached Figure Description

[0026] Figure 1 This is a scanning electron microscope (SEM) image of the hydrogel prepared in Example 1;

[0027] Figure 2 (a)-(b) are SEM images of the hydrogels prepared in Comparative Example 1 and Comparative Example 2, respectively.

[0028] Figure 3 These are the Fourier transform infrared spectra of the hydrogels in Examples 1-3 and Comparative Example 1;

[0029] Figure 4 This is a photograph of the hydrogel prepared in Example 1;

[0030] Figure 5 These are the strain curves of Example 1, Comparative Example 1, and Comparative Example 2;

[0031] Figure 6 (a)-(c) are photographs of solutions of PAA dissolved in water, then anhydrous ethanol added, and then the anhydrous ethanol evaporated.

[0032] Figure 7These are the sustained-release curves of Example 1, Comparative Example 1, and Comparative Example 2;

[0033] Figure 8 (a)-(c) are images of mouse livers after application in Example 1, Comparative Example 1 and Comparative Example 2, respectively;

[0034] Figure 9 (a)-(c) are oil red O staining images of mouse livers after application in Example 1, Comparative Example 1 and Comparative Example 2, respectively.

[0035] Figure 10 (a)-(c) are staining images of mouse livers after application of hematoxylin and eosin (H&E) in Example 1, Comparative Example 1 and Comparative Example 2, respectively;

[0036] Figure 11 These are bar charts showing the cell survival experiments of the hydrogels prepared in Examples 1-3 and Comparative Example 1. Detailed Implementation

[0037] To make the above-mentioned objectives, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to examples. The following content is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, as long as they do not deviate from the concept of the invention, they should all fall within the protection scope of the present invention.

[0038] The preparation method of the present invention will be described below through specific embodiments and comparative examples.

[0039] Example 1

[0040] A method for preparing a drug-release modified starch hydrogel includes the following steps:

[0041] S1: Preparation of composite solution:

[0042] Weigh 3g of CTS and 2g of PEG-600, add them to a mixed solvent consisting of 40 mL of 1% acetic acid aqueous solution and 20 mL of anhydrous ethanol, place the system in a 30℃ constant temperature water bath, and stir at 400 r / min for 1 h to form a composite solution.

[0043] S2: Preparation of PAA micelle-modified starch dispersion:

[0044] Weigh 5g of corn starch according to the specified mass fraction, add it to 40mL of deionized water, and disperse it by ultrasonication to form a starch suspension; add 2g of PAA (molecular weight 5000) to the starch suspension, and stir until the PAA is completely dissolved; then slowly add 20mL of anhydrous ethanol at a dropping rate of 1mL / min while stirring (300r / min) and stirring for 30min to obtain a PAA micelle-modified starch dispersion;

[0045] S3: Composite cross-linking and starch gelatinization:

[0046] The PAA micelle-modified starch dispersion from step S2 was slowly added dropwise to the composite solution prepared in step S1. After the addition was complete, the mixture was stirred at 300 r / min for 30 min to ensure uniform dispersion. Then, 0.8 g of sodium alginate and 0.05 g of calcium chloride were added, and the mixture was cross-linked at 30 °C for 0.5 h to achieve initial cross-linking. Subsequently, the system was heated to 80 °C and stirred at a low speed of 100 r / min for 2 h to form a three-dimensional cross-linked network structure of "CTS-PEG-600-starch".

[0047] S4: Post-processing:

[0048] The hydrogel precursor from step S3 was cooled to room temperature and then immersed in deionized water. The deionized water was replaced every 4 hours for a total of 4 times to obtain a drug-release modified starch hydrogel.

[0049] Example 2

[0050] A method for preparing a drug-release modified starch hydrogel includes the following steps:

[0051] S1: Preparation of composite solution:

[0052] Weigh 4g of CTS and 4g of PEG-600, add them to a mixed solvent consisting of 30mL of 1.5% acetic acid aqueous solution and 25mL of anhydrous ethanol, place the system in a 40℃ constant temperature water bath, and stir at 500r / min for 2h to form a composite solution.

[0053] S2: Preparation of PAA micelle-modified starch dispersion:

[0054] Weigh 6g of corn starch according to the specified mass fraction, add it to 50mL of deionized water, and disperse it by ultrasonication to form a starch suspension; add 2.5g of PAA (molecular weight 5000) to the starch suspension and stir until the PAA is completely dissolved; then slowly add 25mL of anhydrous ethanol at a dropping rate of 1.5mL / min while stirring (350r / min) for 45min to obtain a PAA micelle-modified starch dispersion;

[0055] S3: Composite cross-linking and starch gelatinization:

[0056] The PAA micelle-modified starch dispersion from step S2 was slowly added dropwise to the composite solution prepared in step S1. After the addition was complete, the mixture was stirred at 350 r / min for 35 min to ensure uniform dispersion. Then, 1.5 g of sodium alginate and 0.18 g of calcium chloride were added, and the mixture was crosslinked at 35 °C for 0.7 h to achieve initial crosslinking. Subsequently, the system was heated to 82 °C and stirred at a low speed of 150 r / min for 2.5 h to form a three-dimensional cross-linked network structure of “CTS-PEG-600-starch”.

[0057] S4: Post-processing:

[0058] The hydrogel precursor from step S3 was cooled to room temperature and then immersed in deionized water. The deionized water was replaced every 4.5 hours for a total of 5 times to obtain the drug-release modified starch hydrogel.

[0059] Example 3

[0060] A method for preparing a drug-release modified starch hydrogel includes the following steps:

[0061] S1: Preparation of composite solution:

[0062] Weigh 5g of CTS and 6g of PEG-600, add them to a mixed solvent consisting of 60mL of 2% acetic acid aqueous solution and 30mL of anhydrous ethanol, place the system in a 50℃ constant temperature water bath, and stir at 600r / min for 3h to form a composite solution.

[0063] S2: Preparation of PAA micelle-modified starch dispersion:

[0064] Weigh 7g of corn starch according to the specified mass fraction, add it to 60mL of deionized water, and disperse it by ultrasonication to form a starch suspension. Add 3g of PAA (molecular weight 5000) to the starch suspension and stir until the PAA is completely dissolved. Then slowly add 30mL of anhydrous ethanol at a dropping rate of 2mL / min while stirring (400r / min). After stirring for 60min, the PAA forms micelles under the induction of ethanol and modifies the starch, resulting in a PAA micelle-modified starch dispersion.

[0065] S3: Composite cross-linking and starch gelatinization:

[0066] The PAA micelle-modified starch dispersion from step S2 was slowly added dropwise to the composite solution prepared in step S1. After the addition was complete, the mixture was stirred at 400 r / min for 40 min to ensure uniform dispersion. Then, 2.5 g of sodium alginate and 0.3 g of calcium chloride were added, and the mixture was cross-linked at 40 °C for 1 h to achieve initial cross-linking. Subsequently, the system was heated to 85 °C and stirred at a low speed of 200 r / min for 3 h to form a three-dimensional cross-linked network structure of “CTS-PEG-600-starch”.

[0067] S4: Post-processing:

[0068] The hydrogel precursor from step S3 was cooled to room temperature and then immersed in deionized water. The deionized water was changed every 5 hours for a total of 6 times to completely remove unreacted crosslinking agents, PAA, and free drugs. The immersed hydrogel was then removed to obtain drug-release modified starch hydrogel.

[0069] Comparative Example 1

[0070] Preparation of conventional hydrogels from PAA-free micelle-modified starch dispersions

[0071] Preparation of S1 composite solution

[0072] Weigh 3g of CTS and 2g of PEG-600, add them to a mixed solvent of 40mL of 1% acetic acid aqueous solution and 20mL of anhydrous ethanol, place the mixture in a 30℃ constant temperature water bath, and stir at 400r / min for 1h until completely dissolved to obtain a homogeneous and transparent composite solution.

[0073] S3 Crosslinking Reaction (without starch gelatinization step)

[0074] 0.8 g of sodium alginate and 0.05 g of calcium chloride were added directly to the above composite solution, and the mixture was stirred at 300 r / min for 30 min. Then, it was crosslinked at 30 °C for 0.5 h to form a hydrogel precursor. The system was heated to 80 °C and stirred at 100 r / min for 0.8 h to allow the anhydrous ethanol to evaporate completely, thus obtaining the ordinary CTS-PEG-600-sodium alginate hydrogel precursor.

[0075] S4 Post-processing

[0076] The hydrogel precursor was cooled to room temperature and then immersed in deionized water. The deionized water was changed every 4 hours for a total of 4 times. After being removed and drained, a starch-free ordinary hydrogel material was obtained.

[0077] Comparative Example 2

[0078] Preparation of ordinary starch hydrogels without PAA micelle modification

[0079] Except for step S2, where PAA is not added and PAA micelles cannot be used to modify starch, the rest of the operation is exactly the same as in Example 1.

[0080] application

[0081] The therapeutic effect of drug-release modified starch hydrogel on non-alcoholic fatty liver disease in mice.

[0082] (1) Construction of a mouse model of non-alcoholic fatty liver disease

[0083] Mice were randomly divided into a normal control group and a model group. The normal control group was fed a normal diet, while the model group was fed a high-sugar, high-fat diet for 12 consecutive weeks. After the model was established, mice in the model group were randomly selected, and liver tissue was taken for H&E staining to observe the pathological morphology of the liver tissue. If typical fatty liver features such as hepatocyte steatosis and ballooning degeneration were observed, the model was considered to have been successfully established.

[0084] (2) Grouping and administration

[0085] Mice that successfully established the model were randomly divided into 5 groups: Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, and Comparative Example 2 group. A normal control group (without modeling) and a model control group (without drug administration) were also set up.

[0086] Normal control group and model control group: each animal was administered 0.2 mL of physiological saline by gavage daily;

[0087] Examples 1-3 and Comparative Examples 1-2: 0.2 mL / animal of fucoidan-loaded hydrogel microsphere suspension was administered daily by gavage to the corresponding groups (based on a fucoidan dosage of 50 mg / kg / d).

[0088] All groups were administered the medication continuously for 8 weeks. During this period, the normal control group was fed a normal diet, while the other groups were fed a high-sugar, high-fat diet.

[0089] The following, in conjunction with the accompanying drawings, further demonstrates the innovative aspects of this invention:

[0090] The accompanying drawings of this invention visually verify the advancement of PAA micelle-modified starch technology and the starch gelatinization-network interweaving synergistic enhancement strategy from five dimensions: microstructure, chemical characterization, mechanical properties, sustained-release behavior, and biological effects, thus confirming the core innovation of this invention.

[0091] Figure 1 Example 1: Scanning electron microscope (SEM) image of the hydrogel; Figure 1 The results show that the hydrogel prepared in Example 1 exhibits a uniform, dense and interconnected three-dimensional network structure with no obvious starch aggregates.

[0092] Explanation of the principle: PAA forms micelles under ethanol induction and modifies starch, blocking hydrogen bonding between starch molecules and preventing starch aggregation. Subsequent high-temperature gelatinization allows the PAA-modified starch molecular chains to fully extend and tightly intertwine with the CTS-PEG-600 network, filling the network pores and forming a uniform and dense cross-linked structure. This directly proves that the PAA micelle-modified starch strategy of this invention can effectively solve the starch aggregation problem and overcome the network unevenness defects caused by aggregation in traditional starch-based hydrogels.

[0093] Figure 2 SEM images of the hydrogels of Comparative Example 1 and Comparative Example 2; Figure 2 In Comparative Example 1 (starch dispersion without PAA micelle modification), the hydrogel network exhibited large pores and a loose network structure. In Comparative Example 2 (starch without PAA micelle modification), numerous starch aggregates exceeding 20 μm in diameter were observed, with network breaks around the aggregates and a disordered pore distribution. Comparative Example 1, lacking starch molecular chain filling, exhibited a loose, single-network structure of CTS-PEG-sodium alginate. Comparative Example 2, without PAA micelle modification, showed starch molecules agglomerating through strong hydrogen bonds, disrupting network continuity. The comparison with Example 1 highlights the synergistic effect of PAA micelle modification and starch gelatinization, which is crucial for constructing a uniform and dense hydrogel network.

[0094] Figure 3 Fourier transform infrared (FT-IR) spectra of the hydrogels in Examples 1-3 and Comparative Example 1. Figure 3 The results show that intermolecular hydrogen bonds formed between the PAA-modified starch molecular chains and the chitosan-PEG network, achieving a tight interweaving of the network. The presence of characteristic peaks of starch glycosidic bonds proves that the PAA-modified starch is uniformly dispersed in the hydrogel matrix. From a chemical perspective, the molecular-level interweaving of the PAA-modified starch and the chitosan-PEG network is verified, proving the real existence of the CTS-PEG-600-starch three-dimensional cross-linked network structure constructed in this invention.

[0095] Figure 4 A photograph of the hydrogel prepared in Example 1; Figure 4 In Example 1, the hydrogel is a translucent, uniform, elastic block with a smooth, non-granular surface. Because the PAA micelle-modified starch in Example 1 is uniformly dispersed and interwoven with a network, forming a uniform and dense cross-linked structure, light can pass through uniformly, and the degree of cross-linking is moderate, exhibiting excellent elasticity. This clearly demonstrates that the hydrogel prepared by this invention possesses both good light transmittance and mechanical elasticity, solving the problem of high brittleness in traditional starch-based hydrogels.

[0096] Figure 5 Strain curves of hydrogels in Example 1, Comparative Example 1, and Comparative Example 2; Figure 5In the comparison, the hydrogel of Example 1 had a fracture strain of up to 350% and an elastic modulus of 12 kPa; the fracture strain of Comparative Example 1 was only 120% and the elastic modulus was 5 kPa; the fracture strain of Comparative Example 2 was about 180%, and the strain curve showed an obvious stress abrupt change (corresponding to the fracture of starch agglomerates).

[0097] Explanation of principle: The hydrogel of Example 1 has high fracture strain and moderate elastic modulus because the starch modified by PAA micelles is uniformly dispersed and the cross-linked network formed can withstand external forces uniformly. The loose network of Comparative Example 1 has weak resistance to deformation. In Comparative Example 2, because the starch was not treated with PAA micelles, the starch agglomerates became stress concentration points, resulting in stress abrupt changes.

[0098] Quantitative analysis demonstrates that the mechanical stability of the hydrogel of this invention is significantly superior to that of traditional hydrogels, verifying the enhancing effect of the PAA micelle-modified starch + starch gelatinization interweaving strategy on mechanical properties.

[0099] Figure 6 (a)-(c) are photographs of PAA dissolved in water, anhydrous ethanol added, and the anhydrous ethanol evaporated, respectively. Figure 6 (a) The PAA aqueous solution was initially completely transparent; (b) After adding ethanol, the solution exhibited the Tyndall effect (visible in the optical path), indicating the formation of PAA micelles; (c) After the ethanol evaporated, the solution became transparent again, and the micelles dissociated. This is because PAA is a water-soluble polymer and is molecularly dispersed in water; ethanol, as a poor solvent, reduces the solubility of PAA, promoting the aggregation of PAA molecules to form micelles, providing a structural basis for PAA micelle-modified starch; after the ethanol evaporated, the proportion of water in the system increased again, and the PAA micelles dissociated back into a molecular state. This demonstrates the principle of PAA micelle-modified starch in this invention: the micelles modify and disperse the starch, and the micelles dissociate after the ethanol evaporates, leaving no impurities.

[0100] Figure 7 These are the sustained-release curves for Example 1, Comparative Example 1, and Comparative Example 2. In Example 1, the cumulative drug release rate of the hydrogel within 160 minutes reached 16%, and the release curve was stable with no obvious burst release. In Comparative Example 1, the cumulative release rate of the hydrogel within 160 minutes reached 27%, and in Comparative Example 2, the cumulative release rate reached 39%. This demonstrates that the PAA micelle modification-starch gelatinization interweaving strategy can effectively control the pore size distribution of the hydrogel network, solving the technical pain point of burst drug release in traditional starch-based hydrogels and achieving long-lasting and stable sustained release.

[0101] Figure 8Images (a)-(c) show mouse livers after application in Examples 1, 1, and 2, respectively. The livers of mice in Example 1 showed near-normal morphology with no obvious inflammatory cell infiltration. The livers of mice in 1 and 2 showed steatosis with mild inflammatory cell infiltration. This demonstrates that the hydrogel prepared in this invention possesses excellent sustained-release targeting properties, which can improve therapeutic efficacy and reduce drug side effects through stable drug administration, overcoming the limitations of traditional formulations where unstable drug concentrations lead to poor therapeutic effects.

[0102] Figure 9 (a)-(c) show Oil Red O staining images after application in Example 1, Comparative Example 1, and Comparative Example 2, respectively. The liver tissue of mice in Example 1 showed the smallest area of ​​red lipid droplet staining, close to the normal control group; the liver tissue of mice in Comparative Example 1 and Comparative Example 2 showed larger areas of lipid droplet staining. This further verifies the drug delivery effectiveness of the hydrogel of this invention. Combined with the uniform network structure brought about by PAA micelle modification, it achieves precise and long-lasting drug action on the target site, significantly outperforming the therapeutic effect of traditional formulations.

[0103] Figure 10 Images (a)-(c) show H&E staining results after application in Examples 1, 1, and 2, respectively. In Example 1, mouse liver tissue cells were neatly arranged with no obvious pathological damage. In Comparative Examples 1 and 2, mouse liver tissues exhibited typical fatty liver pathological features such as hepatocyte edema and ballooning degeneration. This histopathological analysis verifies the clinical application value of the hydrogel of this invention, demonstrating its effective treatment of non-alcoholic fatty liver disease through controlled-release technology, and providing technical support for the clinical translation of natural polymer-based drug sustained-release formulations.

[0104] Figure 11 This is a bar chart showing the cell survival of the hydrogels prepared in Examples 1-3 and Comparative Example 1. The chart shows that after the hydrogel extracts from Examples 1-3 were applied to hepatocytes, the cell survival rate was ≥93%, and the survival rate was higher than that of Comparative Example 1. This indicates that the modified starch content can have better biocompatibility, and the cell survival rate did not decrease significantly with increasing PAA micelle-modified starch content. This demonstrates that the PAA micelle-mediated physical modification strategy does not require the use of toxic chemical reagents, solving the problem of poor biocompatibility caused by reagent residues in traditional chemically modified starch-based hydrogels, thus balancing the safety and functionality of the material.

Claims

1. A method for preparing a drug-controlled modified starch hydrogel, characterized in that, Includes the following steps: S1: Preparation of composite solution: Weigh 3~5g of chitosan CTS and 2~6g of PEG-600, add them to a mixed solvent consisting of 40~60mL of acetic acid aqueous solution with a mass fraction of 1%~2% and 20~30mL of anhydrous ethanol, place the system in a constant temperature water bath and stir until CTS and PEG-600 are completely dissolved to form a composite solution; S2: Preparation of PAA micelle-modified starch dispersion: Weigh 5-7g of corn starch and add it to 40-60mL of deionized water for dispersion. Disperse the starch using ultrasonication to form a starch suspension. Add 2-3g of polyacrylic acid (PAA) with a molecular weight of 5000 to the starch suspension and stir until the PAA is completely dissolved. Then slowly add 20-30mL of anhydrous ethanol dropwise while stirring. The dropwise rate is 1-2mL / min, the stirring speed is 300-400r / min, and the stirring time is 30-60min to obtain a stable PAA micelle-modified starch dispersion. S3: Composite crosslinking and starch gelatinization: The PAA micelle modified starch dispersion obtained in step S2 is slowly added dropwise to the composite solution prepared in step S1. After the addition is complete, the mixture is stirred. Sodium alginate and calcium chloride are added, and the mixture is crosslinked at a constant temperature. Then the system is heated and stirred at a low speed to obtain the hydrogel precursor. S4: Post-processing: Cool the hydrogel precursor obtained in step S3 to room temperature, immerse it in deionized water and replace the deionized water, and then take it out to obtain drug sustained-release modified starch hydrogel.

2. The preparation method according to claim 1, characterized in that, In step S1, the temperature of the constant temperature water bath is 30~50℃, the stirring speed is 400~600r / min, and the stirring time is 1~3h.

3. The preparation method according to claim 1, characterized in that, In step S3, the stirring speed after the droplet is 300~400 r / min, and the stirring time is 30~40 min.

4. The preparation method according to claim 1, characterized in that, In step S3, the amount of sodium alginate is 0.8~2.5g, the amount of calcium chloride is 0.05~0.3g, the constant temperature crosslinking temperature is 30~40℃, and the crosslinking time is 0.5-1h.

5. The preparation method according to claim 1, characterized in that, In step S3, the temperature after heating is 80~85℃, the stirring speed is 100~200r / min, and the stirring time is 2-3h.

6. The preparation method according to claim 1, characterized in that, In step S4, the deionized water is changed every 4 to 5 hours during the soaking process, and the number of times the water is changed is 4 to 6.

Images