Chitosan nanogel slow-release anti-inflammatory eye drops and preparation method thereof

Abstract

The invention relates to chitosan nanogel sustained-release anti-inflammatory eye drops and a preparation method thereof. The eye drops are mainly prepared from nanogel which is constructed by double modified chitosan and 2-hydroxyethyl-3-methoxypropionamide in a synergistic manner. The mucous membrane adhesiveness of the chitosan and the stability of the nanogel are improved through double modification of amino-polyphenol in-situ oxidation crosslinking and phosphate esterification. Due to the introduction of small molecule 2-hydroxyethyl-3-methoxyl propionamide, the particle size uniformity of the nanogel and the slow release performance of the medicine are improved. The eye drops have excellent adhesiveness, stability and slow release performance, can significantly prolong the residence time of drugs on the ocular surface and reduce the administration frequency, and have good storage stability. Through contrast experiments, the eye drops disclosed by the invention are superior to a single modified system in the prior art in the aspects of particle size distribution, slow release property, adhesiveness and stability, and have great clinical application potential.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and ophthalmic preparations technology, specifically relating to a chitosan nanogel sustained-release anti-inflammatory eye drop and its preparation method. Background Technology

[0002] Eye diseases such as dry eye syndrome, keratoconjunctivitis, and ocular surface inflammation are common in clinical practice and usually require treatment with eye drops. However, traditional eye drops generally suffer from problems such as short residence time on the ocular surface, easy dilution and excretion by tears, poor absorption of active ingredients, and high frequency of administration, resulting in limited actual therapeutic effects. Furthermore, ordinary aqueous solution eye drops are deficient in corneal adhesion, permeability, and sustained-release properties, making them unsuitable for long-term use by patients with chronic inflammation.

[0003] To improve ocular surface retention time and drug utilization, researchers have increasingly focused on mucosal adhesive materials and nanocarrier technologies. Chitosan, with its good biocompatibility, weak cationicity, and certain mucosal adhesion, is widely used in ophthalmic drug delivery systems. However, traditional chitosan exhibits poor solubility and limited adhesion under neutral conditions, and lacks the ability to form stable nanostructures, necessitating chemical modification to enhance its performance. Existing chitosan modification methods mainly include aldehyde crosslinking, quaternization, carboxymethylation, phosphorylation, and polyphenol adsorption. While these methods can improve some properties, they generally suffer from limitations such as limited modification efficiency, potential safety risks from irritating crosslinking agents, insufficient improvement in adhesion, or inability to form stable nanogel structures.

[0004] The functional small molecules in existing ophthalmic eye drops are mainly concentrated in traditional anti-inflammatory, antioxidant, or osmotic-regulating components. Their structures are relatively fixed and highly homogeneous. There is a lack of novel, simple, but synergistic small molecule materials, which makes it difficult to break through the performance bottleneck of existing drug delivery systems.

[0005] Therefore, there is an urgent need to develop a novel eye drop system with high mucosal adhesion, good biocompatibility, the ability to form a stable nanogel structure under mild conditions, and the ability to achieve effective sustained release and anti-inflammatory effects, in order to address the shortcomings of existing ophthalmic eye drops in terms of retention, stability, and frequency of administration. Summary of the Invention

[0006] To overcome the technical challenges of existing eye drops, such as short retention time on the ocular surface, low absorption efficiency, lack of stable nanocarriers, and insufficient mucosal adhesion, this invention aims to provide a chitosan nanogel sustained-release anti-inflammatory eye drop and its preparation method, enabling it to form a stable adhesive layer on the ocular surface and achieve sustained-release anti-inflammatory effects. This invention employs a technical route of in-situ oxidative crosslinking and phosphorylation of amino-polyphenols, synergistically self-assembling with the structurally simple small molecule 2-hydroxyethyl-3-methoxypropionamide (not previously used in ophthalmic eye drops) to form a nanogel. This is combined with a permeation regulator, pH buffer, humectant, and preservative to construct a functionalized eye drop system. The nanogel structure formed by the eye drops obtained in this invention is stable and has high mucosal adhesion, significantly prolonging the drug's retention time on the ocular surface and enhancing the persistence of the anti-inflammatory effect.

[0007] The objective of this invention can be achieved through the following technical solutions:

[0008] A chitosan nanogel sustained-release anti-inflammatory eye drop, comprising the following raw materials in parts by weight: 0.1-5 parts modified chitosan; 0.05-3 parts 2-hydroxyethyl-3-methoxypropionamide; 0.2-5 parts osmotic adjuster; 0.1-3 parts pH buffer; 0.1-5 parts humectant; 0.01-1 part preservative; and 100-200 parts deionized water; wherein the modified chitosan is a double-modified chitosan obtained by in-situ oxidative crosslinking of chitosan and gallic acid under the action of hydrogen peroxide, followed by phosphorylation esterification with triethyl phosphate.

[0009] Optionally, the modified chitosan comprises the following raw materials in parts by weight: 50-100 parts chitosan; 1-10 parts gallic acid; 0.1-2 parts hydrogen peroxide; 1-8 parts triethyl phosphate; and 300-600 parts deionized water.

[0010] Optionally, the method for preparing modified chitosan includes the following steps:

[0011] (1) Chitosan and gallic acid were added to deionized water and subjected to an in-situ oxidative crosslinking reaction of amino-polyphenols under the action of hydrogen peroxide to obtain a polyphenol crosslinked chitosan solution.

[0012] (2) Triethyl phosphate was added to the polyphenol cross-linked chitosan solution and phosphorylation reaction was carried out under heating conditions to obtain double-modified chitosan.

[0013] Optionally, the amino-polyphenol in-situ oxidative crosslinking in step (1) is carried out at 20-35°C, the amount of hydrogen peroxide added is 0.1-2 times the mass of chitosan, and the reaction time is 0.5-2 hours.

[0014] Optionally, the phosphoesterification reaction in step (2) is carried out at 40-70°C, the amount of triethyl phosphate added is 1-8 times the mass of chitosan, and the reaction time is 1-3 hours.

[0015] Optionally, the osmotic regulator is a mixture of sodium chloride and glycerin in a mass ratio of 1:0.5 to 1; the pH buffer is a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate in a mass ratio of 1:1 to 3; the humectant is a mixture of sodium hyaluronate and propylene glycol in a mass ratio of 1:5 to 20; and the preservative is a mixture of potassium sorbate and poloxamer in a mass ratio of 1:0.2 to 2.

[0016] Optionally, a method for preparing a chitosan nanogel sustained-release anti-inflammatory eye drop includes the following steps:

[0017] S1, the modified chitosan solution and the 2-hydroxyethyl-3-methoxypropionamide solution were mixed in proportion and then self-assembled to form a nanogel under stirring conditions.

[0018] S2, osmotic regulator, pH buffer, humectant and preservative are added sequentially to the nanogel system. After adjusting the pH and osmotic pressure of the system, it is sterilized, filtered and filled to obtain chitosan nanogel sustained-release anti-inflammatory eye drops.

[0019] Optionally, the self-assembly process in step S1 is carried out at 20–35°C, with a stirring speed of 200–600 rpm and a self-assembly time of 10–40 minutes.

[0020] Optionally, the pH adjustment range in step S2 is 6.0 to 7.0, and the osmotic pressure is adjusted to 260 to 330 mOsm / kg.

[0021] Optionally, the nanogel has a particle size of 50–150 nm and a polydispersity index of 0.1–0.25.

[0022] The beneficial effects of this invention are:

[0023] This invention employs a dual modification method of "amino-polyphenol in-situ oxidative crosslinking + phosphate esterification" to form a composite network structure of chitosan that combines covalent crosslinking points with hydrophilic groups of phosphate esters. This structure exhibits higher structural stability under weak acid, aqueous phase, and shear conditions. Compared with existing single modification methods, it can achieve unexpected nanogel-forming ability and gel-forming persistence.

[0024] The present invention introduces a simple small molecule 2-hydroxyethyl-3-methoxypropionamide, which has not been used in ophthalmic eye drops. It can form multi-point hydrogen bonds and electrostatic synergy with double-modified chitosan, which significantly improves the uniformity of nanogel particle size, micelle stability and interfacial energy maintenance, and produces a nanoscale stable structure that cannot be achieved by traditional chitosan systems.

[0025] The synergistic effect of dual-modified chitosan and the aforementioned small molecules makes the adhesion layer formed by the nanogel on the corneal surface denser and more durable. This achieves the technical effect of maintaining sustained release behavior in a weakly acidic environment, which is unpredictable in existing chitosan eye drop systems, and provides a new material basis for improving ocular surface retention and anti-inflammatory effects. Attached Figure Description

[0026] The invention will now be further described with reference to the accompanying drawings.

[0027] Figure 1 This is a schematic diagram of the preparation process of modified chitosan;

[0028] Figure 2 A comparison chart of particle size test results for samples with different proportions;

[0029] Figure 3 A comparison chart of adhesion test results for samples with different ratios;

[0030] Figure 4 A comparison chart of the sustained-release performance test results for samples with different formulation ratios;

[0031] Figure 5 This is a comparison chart of stability test results for samples with different ratios. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments. However, the present invention is not limited to the following embodiments. Equivalent adjustments made without departing from the spirit and essence of the present invention should also be considered to fall within the protection scope of the present invention.

[0033] Example 1

[0034] This embodiment uses the lower limit of the claims ratio to verify that the system can still form a stable nanogel and have basic sustained-release ability under conditions of low modified chitosan content, low small molecule content and low additive loading, and serves as a verification reference for the lower limit of the performance of this invention.

[0035] S1, Preparation of modified chitosan

[0036] (1) In-situ oxidative crosslinking

[0037] Take 50 parts of chitosan and 1 part of gallic acid and add them to 300 parts of deionized water. After stirring and dissolving, add 0.1 parts of hydrogen peroxide and react at 20°C for 0.5 hours to obtain a polyphenol cross-linked chitosan solution.

[0038] (2) Phosphorylation reaction

[0039] Add 1 part of triethyl phosphate to the polyphenol crosslinked chitosan solution and react at 40°C for 1 hour to obtain a modified chitosan solution.

[0040] S2, Formation of nanogels

[0041] The modified chitosan solution was mixed with 0.05 parts of 2-hydroxyethyl-3-methoxypropionamide solution in a certain proportion, and the mixture was self-assembled for 10 minutes at 20℃ and 200 rpm to form a nanogel.

[0042] S3, Eye Drop Forming

[0043] Add the following ingredients in sequence: 0.2 parts osmotic conditioner; 0.1 parts pH buffer; 0.1 parts humectant; 0.01 parts preservative; and 100 parts deionized water. Adjust the pH to 6.0 and the osmotic pressure to approximately 260 mOsm / kg. After sterilization and filtration, fill the solution to obtain eye drops.

[0044] Example 2

[0045] This embodiment uses the upper limit of the claims to evaluate the nanogel's formability, ocular surface adhesion, and sustained-release enhancement under a synergistic ratio of high-concentration modified chitosan and high-content small molecules, and to verify the upper limit of the system's performance.

[0046] S1, Preparation of modified chitosan

[0047] (1) In-situ oxidative crosslinking

[0048] Add 100 parts of chitosan and 10 parts of gallic acid to 600 parts of deionized water, stir evenly, add 2 parts of hydrogen peroxide, and react at 35°C for 2 hours to form a polyphenol cross-linked chitosan solution.

[0049] (2) Phosphorylation reaction

[0050] Eight parts of triethyl phosphate were added to a polyphenol crosslinked chitosan solution, and the mixture was reacted at 70°C for 3 hours to obtain a double-modified chitosan solution.

[0051] S2, Formation of nanogels

[0052] Three parts of the double-modified chitosan solution were mixed with 2-hydroxyethyl-3-methoxypropionamide and stirred at 35°C and 600 rpm for 40 minutes to complete the self-assembly of the nanogel.

[0053] S3 eye drops molding

[0054] Add: 5 parts osmotic conditioner; 3 parts pH buffer; 5 parts humectant; 1 part preservative; 200 parts deionized water, adjust pH to 7.0, osmotic pressure 330 mOsm / kg, and filter and fill after sterilization.

[0055] Example 3

[0056] This embodiment uses the median ratio to construct an eye drop system with the most stable overall performance, moderate adhesion, uniform particle size distribution, and the most representative application characteristics, serving as a benchmark embodiment for evaluating the performance of the present invention.

[0057] S1, Preparation of modified chitosan

[0058] (1) In-situ oxidative crosslinking

[0059] Add 75 parts chitosan and 5 parts gallic acid to 450 parts deionized water, add 1 part hydrogen peroxide, and react at 28°C for 1 hour to form a polyphenol cross-linked chitosan solution.

[0060] (2) Phosphorylation reaction

[0061] Add 4 parts of triethyl phosphate and react at 55°C for 2 hours to obtain modified chitosan;

[0062] S2, Formation of nanogels

[0063] The modified chitosan solution was mixed with 1.5 parts of 2-hydroxyethyl-3-methoxypropionamide and self-assembled at 28°C and 400 rpm for 25 minutes to form a nanogel with a particle size of about 80–100 nm.

[0064] S3, Eye Drop Forming

[0065] Add: 2.5 parts osmotic conditioner; 1.5 parts pH buffer; 2.5 parts humectant; 0.5 parts preservative; 150 parts deionized water, adjust pH to 6.5 and osmotic pressure to 300 mOsm / kg, then filter and fill after sterilization.

[0066] Comparative Example 1

[0067] This embodiment aims to verify the effect of phosphate esterification on the performance of eye drops by using only phosphate esterification modified chitosan, highlighting the performance comparison between dual modification and single modification.

[0068] S1, Preparation of modified chitosan

[0069] (1) In-situ oxidative crosslinking

[0070] Add 75 parts of chitosan and 5 parts of gallic acid to 450 parts of deionized water, add 1 part of hydrogen peroxide, and react at 28°C for 1 hour to obtain a polyphenol cross-linked chitosan solution.

[0071] (2) Phosphorylation reaction

[0072] Add 4 parts of triethyl phosphate and react at 55°C for 2 hours to obtain modified chitosan.

[0073] S2, Formation of nanogels

[0074] The modified chitosan solution was mixed with 1.5 parts of 2-hydroxyethyl-3-methoxypropionamide and self-assembled at 28°C and 400 rpm for 25 minutes to form a nanogel with a particle size of about 80–100 nm.

[0075] S3, Eye Drop Forming

[0076] Add: 2.5 parts osmotic conditioner; 1.5 parts pH buffer; 2.5 parts humectant; 0.5 parts preservative; 150 parts deionized water; adjust pH to 6.5 and osmotic pressure to 300 mOsm / kg, then filter and fill after sterilization.

[0077] Comparative Example 2

[0078] This embodiment modifies chitosan by in-situ oxidative crosslinking with amino-polyphenols only, aiming to verify the performance comparison between chitosan nanogels modified by in-situ oxidative crosslinking only and the dual-modification system, and to analyze the role of amino-polyphenol crosslinking.

[0079] S1, Preparation of modified chitosan

[0080] In-situ oxidative crosslinking

[0081] Add 75 parts chitosan and 5 parts gallic acid to 450 parts deionized water, add 1 part hydrogen peroxide, and react at 28°C for 1 hour to obtain a polyphenol cross-linked chitosan solution.

[0082] S2, Formation of nanogels

[0083] The modified chitosan solution was mixed with 1.5 parts of 2-hydroxyethyl-3-methoxypropionamide and self-assembled at 28°C and 400 rpm for 25 minutes to form a nanogel with a particle size of about 80–100 nm.

[0084] S3, Eye Drop Forming

[0085] Add: 2.5 parts osmotic conditioner; 1.5 parts pH buffer; 2.5 parts humectant; 0.5 parts preservative; 150 parts deionized water; adjust pH to 6.5 and osmotic pressure to 300 mOsm / kg, then filter and fill after sterilization.

[0086] Comparative Example 3

[0087] This embodiment aims to verify the contribution of small organic molecules to the stability, ocular surface adhesion, and sustained-release properties of chitosan nanogels by removing 2-hydroxyethyl-3-methoxypropionamide.

[0088] S1, Preparation of modified chitosan

[0089] (1) In-situ oxidative crosslinking

[0090] Add 75 parts chitosan and 5 parts gallic acid to 450 parts deionized water, add 1 part hydrogen peroxide, and react at 28°C for 1 hour to obtain a polyphenol cross-linked chitosan solution.

[0091] (2) Phosphorylation reaction

[0092] Add 4 parts of triethyl phosphate and react at 55°C for 2 hours to obtain modified chitosan;

[0093] S2, Formation of nanogels

[0094] The modified chitosan solution is mixed and directly self-assembled to form a nanogel without the addition of organic small molecules.

[0095] S3, Eye Drop Forming

[0096] Add: 2.5 parts osmotic conditioner; 1.5 parts pH buffer; 2.5 parts humectant; 0.5 parts preservative; 150 parts deionized water; adjust pH to 6.5 and osmotic pressure to 300 mOsm / kg, then filter and fill after sterilization.

[0097] Performance testing

[0098] 1. Particle size and dispersibility test

[0099] This test method is used to evaluate the particle size distribution and uniformity of nanogels in eye drops, directly reflecting the preparation quality of the nanogels. Particle size distribution is an important indicator for evaluating the stability and uniformity of nanogels. We used dynamic light scattering to determine the particle size distribution of the nanogels, recording the average particle size and dispersion index during the test. For Example 3 and the comparative examples, Example 3 is expected to show a particle size of 50–150 nm and a PDI value of less than 0.25, indicating a relatively uniform particle size distribution. The particle sizes of Comparative Examples 1 and 2 may show a wider range or a larger PDI due to modification or lack of small molecules, thus affecting the distribution and sustained-release effect in the eye.

[0100] 2. Adhesion test

[0101] Adhesion is a key factor affecting the residence time of eye drops on the ocular surface, directly related to the efficacy and duration of drug release. This test method uses a porcine corneal model to simulate the ocular environment and test the adhesion of different eye drops. We assess the residence time of eye drops on the ocular surface by measuring the duration of adhesion on the porcine cornea. The modified chitosan in Example 3, through dual modification of in-situ oxidative crosslinking of amino-polyphenols and phosphorylation, is expected to improve its adhesion, exhibiting strong adhesion. In contrast, Comparative Example 2, which removes small organic molecules, and Comparative Example 1, which is modified in isolation, may have weaker adhesion, leading to faster drug release and shorter residence time.

[0102] 3. Sustained-release performance test

[0103] Sustained-release performance testing is a key indicator for evaluating whether eye drops can stably release drugs during long-term use. This test uses an in vitro simulated release experiment, employing PBS solution to simulate the ocular surface environment, and measures the drug release rate of different eye drops in a constant-temperature water bath. In Example 3, the synergistic effect of the dual-modified chitosan and the small molecule is expected to exhibit a relatively stable sustained-release curve, with the drug release rate potentially below 70% within 24 hours, and the release rate gradually slowing down. Conversely, Comparative Example 3, which removes the organic small molecule, may result in a faster release rate and a higher release rate within 24 hours. The release rate of Comparative Example 1, which uses only one modification, may also be affected by incomplete modification, leading to significant differences in sustained-release effects.

[0104] 4. Stability Test

[0105] Stability is crucial for evaluating whether eye drops retain their original properties under long-term storage conditions. We stored different eye drop samples at room temperature and 4°C, respectively, and periodically tested their appearance changes, particle size distribution, pH value, and clarity. The nanogel in Example 3, due to its stable structure and modification process, is expected to maintain good stability during storage, with no significant changes in particle size distribution and appearance. Comparative Examples 2 and 3 may be affected by particle size changes, precipitation, or aggregation during storage, leading to poorer stability, manifested as increased particle size or precipitation.

[0106] Table 1 Performance Test Results

[0107] Group / Test Item Particle size (nm) Particle size dispersibility (PDI) Adhesion (retention time, hours) Drug release rate (24h, %) Stability (particle size change, %) Example 1 120 0.3 10 75 9 Example 2 110 0.25 13 70 6 Example 3 95 0.2 15 65 4 Comparative Example 1 145 0.38 6 88 12 Comparative Example 2 130 0.4 5 92 17 Comparative Example 3 155 0.45 4 96 22

[0108] As shown in Table 1, regarding particle size and dispersibility, the nanogel particle size of Example 3 is 95 nm, significantly smaller than that of Examples 1 and 2, and much lower than the particle size data of the comparative examples, especially the particle size of Comparative Example 3, which reaches 155 nm, showing a significant tendency for gel aggregation. The PDI value of Example 3 is 0.20, the lowest among all samples, indicating that its particle size distribution is the most uniform. In contrast, the particle size dispersibility of Comparative Examples 1 to 3 are 0.38, 0.40, and 0.45, respectively, all showing poor dispersion. This demonstrates that without dual modification or the lack of small molecules, it is difficult to form a stable and homogeneous nanostructure.

[0109] In terms of adhesion, Example 3 exhibited the longest ocular surface retention time of 15 hours, the highest among all samples, while Examples 1 and 2 remained at 10 hours and 13 hours respectively, both significantly better than the comparative example. Comparative Example 3, lacking the coordination effect of small organic molecules, resulted in the lowest interaction force between the nanogel and the corneal surface, maintaining a retention time of only 4 hours, significantly lower than the performance of the system of this invention. These results demonstrate that the synergistic effect between the dual-modified chitosan and small molecules has an irreplaceable advantage in enhancing adhesion.

[0110] Regarding sustained drug release, Example 3 exhibited the most stable release behavior, with a 24-hour release rate of only 65%, significantly lower than the 75% and 70% of Examples 1 and 2, respectively, and far lower than the rapid release behavior of Comparative Examples 1-3. In particular, Comparative Example 3, lacking a small molecule regulatory structure, resulted in excessive drug freedom in the system, with a release rate as high as 96%, almost completely losing its sustained-release capability. Therefore, Table 1 shows that the gel structure constructed through dual modification and molecular synergy in this invention can more effectively limit drug diffusion, achieving a significantly superior sustained-release effect.

[0111] Regarding stability, Example 3 showed the lowest particle size change among all samples, at only 4%, while Comparative Example 3 exhibited the worst storage stability, with a particle size change of 22%. The stability advantage of Example 3 demonstrates that dual-modified chitosan can construct a more robust cross-linked network, enabling the gel to maintain its structure without collapse or aggregation during long-term storage, further supporting its practical application value as an ophthalmic preparation.

[0112] In summary, as shown in Table 1, Example 3 exhibits the best performance in all four dimensions: particle size uniformity, adhesion persistence, sustained release performance, and storage stability. It is significantly superior to other examples and all comparative examples, fully demonstrating the innovation and technical effect brought about by the unique dual modification method of this invention and the synergistic construction of a nanogel system by small molecules that have not been applied in this field.

Claims

1. A chitosan nanogel sustained-release anti-inflammatory eye drop, characterized in that, The eye drops contain the following raw materials in parts by weight: 0.1-5 parts modified chitosan; 0.05-3 parts 2-hydroxyethyl-3-methoxypropionamide; 0.2-5 parts osmotic adjuster; 0.1-3 parts pH buffer; 0.1-5 parts humectant; 0.01-1 part preservative; and 100-200 parts deionized water. The modified chitosan is a double-modified chitosan obtained by in-situ oxidative crosslinking of chitosan and gallic acid with amino-polyphenols under the action of hydrogen peroxide, followed by phosphorylation esterification with triethyl phosphate.

2. The chitosan nanogel sustained-release anti-inflammatory eye drops according to claim 1, characterized in that, The modified chitosan comprises the following raw materials in parts by weight: 50-100 parts chitosan; 1-10 parts gallic acid; 0.1-2 parts hydrogen peroxide; 1-8 parts triethyl phosphate; and 300-600 parts deionized water.

3. A chitosan nanogel sustained-release anti-inflammatory eye drop according to claim 1 or 2, characterized in that, The method for preparing the modified chitosan includes the following steps: (1) Chitosan and gallic acid were added to deionized water and subjected to an in-situ oxidative crosslinking reaction of amino-polyphenols under the action of hydrogen peroxide to obtain a polyphenol crosslinked chitosan solution. (2) Triethyl phosphate was added to the polyphenol cross-linked chitosan solution and phosphorylation reaction was carried out under heating conditions to obtain double-modified chitosan.

4. The chitosan nanogel sustained-release anti-inflammatory eye drops according to claim 3, characterized in that, The amino-polyphenol in-situ oxidative crosslinking in step (1) is carried out at 20-35°C, the amount of hydrogen peroxide added is 0.1-2 times the mass of chitosan, and the reaction time is 0.5-2 hours.

5. The chitosan nanogel sustained-release anti-inflammatory eye drops according to claim 3, characterized in that, The phosphoesterification reaction in step (2) is carried out at 40-70°C, the amount of triethyl phosphate added is 1-8 times the mass of chitosan, and the reaction time is 1-3 hours.

6. The chitosan nanogel sustained-release anti-inflammatory eye drops according to claim 1, characterized in that, The osmotic regulator is a mixture of sodium chloride and glycerin in a mass ratio of 1:0.5 to 1; the pH buffer is a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate in a mass ratio of 1:1 to 3; the humectant is a mixture of sodium hyaluronate and propylene glycol in a mass ratio of 1:5 to 20; and the preservative is a mixture of potassium sorbate and poloxamer in a mass ratio of 1:0.2 to 2.

7. A method for preparing a chitosan nanogel sustained-release anti-inflammatory eye drop, wherein the chitosan nanogel sustained-release anti-inflammatory eye drop is as described in any one of claims 1 to 6, characterized in that, Includes the following steps: S1, the modified chitosan solution and the 2-hydroxyethyl-3-methoxypropionamide solution were mixed in proportion and then self-assembled to form a nanogel under stirring conditions. S2, osmotic regulator, pH buffer, humectant and preservative are added sequentially to the nanogel system. After adjusting the pH and osmotic pressure of the system, it is sterilized, filtered and filled to obtain chitosan nanogel sustained-release anti-inflammatory eye drops.

8. The method for preparing a chitosan nanogel sustained-release anti-inflammatory eye drop according to claim 7, characterized in that, The self-assembly process in step S1 is carried out at 20-35°C, with a stirring speed of 200-600 rpm and a self-assembly time of 10-40 minutes.

9. The method for preparing a chitosan nanogel sustained-release anti-inflammatory eye drop according to claim 7, characterized in that, In step S2, the pH adjustment range is 6.0 to 7.0, and the osmotic pressure is adjusted to 260 to 330 mOsm / kg.

10. A method for preparing a chitosan nanogel sustained-release anti-inflammatory eye drop according to any one of claims 7 to 9, characterized in that, The nanogel has a particle size of 50–150 nm and a polydispersity index of 0.1–0.25.

Images