Hydrogel composites, methods of making the same, and ophthalmic drugs

Abstract

The application relates to the technical field of medical hydrogel materials, in particular to a hydrogel composite material, a preparation method thereof and an eye medicine. The hydrogel composite material comprises a hydrogel and EGCG loaded on the hydrogel; the hydrogel comprises methoxypolyethylene glycol amine and L-tyrosine-NCA. The hydrogel composite material provided in the application has no toxic side effects and has a relatively long ocular surface retention time.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical hydrogel materials, in particular to a hydrogel composite material, a preparation method thereof and an eye medication. BACKGROUND

[0002] Dry eye syndrome is a complex etiology and multiple ocular surface disease, with a variety of clinical symptoms, such as dryness, foreign body sensation, burning sensation, etc. which affect the quality of life of patients. Because the mechanism of dry eye syndrome is complex and the treatment cycle is long, it is becoming an important direction of ophthalmic drug research. The current clinical medication is mainly anti-inflammatory drugs and auxiliary treatment drugs for promoting ocular surface wetting.

[0003] At present, the drugs for relieving and treating dry eye syndrome mainly include artificial tears (PEG and polysaccharides such as hyaluronic acid and carboxymethyl cellulose) and biological function inhibitors / antagonists (immune cell or lymphocyte inhibitors / antagonists). However, artificial tears have a short ocular surface retention time and need to be used frequently; and long-term use of biological function inhibitors / antagonists can cause systemic toxic side effects to the human body. SUMMARY

[0004] Therefore, it is necessary to provide a hydrogel composite material capable of increasing ocular surface retention time and having no toxic side effects, a preparation method thereof and an eye medication.

[0005] In a first aspect, the present application provides a hydrogel composite material, comprising a hydrogel and EGCG loaded on the hydrogel.

[0006] The hydrogel comprises methoxypolyethylene glycol amine and L-tyrosine-NCA.

[0007] In some embodiments, in the hydrogel, the concentration of the EGCG is 0.25 mg / mL to 1.25 mg / mL.

[0008] In some embodiments, the mass ratio of the methoxypolyethylene glycol amine to the L-tyrosine-NCA is 1: (6-40).

[0009] And / or, the number average molecular weight of the methoxypolyethylene glycol amine is 2000-5000.

[0010] In a second aspect, the present application further provides a preparation method of the hydrogel composite material according to the first aspect, comprising the following steps:

[0011] Preparation of the hydrogel and an EGCG solution;

[0012] Mixing the hydrogel and the EGCG solution to prepare the hydrogel composite material.

[0013] In some embodiments, the mass ratio of EGCG in the EGCG solution to the hydrogel is 1:(1-9).

[0014] In some embodiments, the concentration of the EGCG solution is 0.25 mg / mL-1.25 mg / mL.

[0015] In some embodiments, the step of preparing the hydrogel comprises:

[0016] dissolving the methoxypolyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and performing ring-opening polymerization under a protective gas atmosphere to prepare a block copolymer;

[0017] mixing the block copolymer with a precipitant to prepare a precipitate, and freeze-drying the precipitate to prepare a gel powder;

[0018] dissolving the gel powder in water to prepare the hydrogel.

[0019] In some embodiments, the organic solvent comprises one or more of N,N-dimethylformamide and an alkane solvent.

[0020] In some embodiments, the precipitant comprises anhydrous diethyl ether and / or petroleum ether.

[0021] In some embodiments, the concentration of the gel powder in water is 10 mg / mL-30 mg / mL.

[0022] In some embodiments, the temperature for dissolving the gel powder in water is 4°C-37°C.

[0023] In some embodiments, after mixing the block copolymer with a precipitant, the method further comprises a step of dialyzing the mixed product with a dialysis bag to filter the precipitate.

[0024] In a third aspect, the present application further provides an eye medication comprising the hydrogel composite material of the first aspect.

[0025] The hydrogel composite material provided by the present application uses methoxypolyethylene glycol amine (mPEG-NH2) and L-tyrosine-NCA as raw materials to form a hydrogel, and loads epigallocatechin gallate (EGCG) in the hydrogel, thereby preparing a hydrogel composite material that can be used for dry eye syndrome, has a long ocular surface retention time, and has no toxic side effects. The polyamino acid hydrogel containing a PEG segment has excellent biocompatibility, can provide good moisturizing effect, and provides hydration protection for the ocular surface microenvironment. Moreover, compared with emulsions or aqueous solutions, the gel dosage form can further improve the retention time of the drug on the ocular surface.

[0026] Furthermore, EGCG, with its antioxidant properties, can be used to repair ocular surface damage. The biological cause of dry eye syndrome is primarily chronic inflammation resulting from oxidative stress, leading to ocular surface damage. The introduction of EGCG can prevent oxidative stress at its source, thereby reducing inflammation and repairing ocular surface damage. However, pure EGCG has poor antioxidant properties due to the presence of its phenolic structure. This application uses a hydrogel as a carrier for the antioxidant EGCG. Specifically, the phenolic structure in L-tyrosine-NCA and the phenolic structure in EGCG can form intermolecular hydrogen bonds and π-π forces, resulting in a stable and robust loading effect between the hydrogel and EGCG, enabling stable EGCG delivery. Moreover, the introduction of EGCG can reduce the gelation concentration of the hydrogel, enhance its gelation properties, and increase the retention time of the hydrogel composite material on the ocular surface. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0028] Figure 1 The 1H-NMR spectra of the block copolymers formed by amino acids and mPEG-NH2 in Examples 1-7 are shown.

[0029] Figure 2 The graph shows the rheological properties of the hydrogel composite materials prepared in Examples 3-5 and Comparative Example 1.

[0030] Figure 3 The figure shows the cytotoxicity evaluation results of the cell-level pure EGCG solution and the hydrogel composite material prepared in Example 3;

[0031] Figure 4 The graph shows the cytotoxicity evaluation results of the hydrogel (PY15) prepared in Example 3;

[0032] Figure 5 The figure shows the biocompatibility test results of the hydrogel composite material prepared in Example 3 during its use on the ocular surface.

[0033] Figure 6 The figure shows the repair effect of the hydrogel composite material prepared in Example 3 on corneal damage.

[0034] Figure 7 The image shows the therapeutic effect of the hydrogel composite material prepared in Example 3 on ocular surface damage in dry eye syndrome. Detailed Implementation

[0035] For the purposes of this application, a more complete understanding of the application can be obtained by reference to the following description in connection with the associated drawings. The drawings are intended to be illustrative only and are not intended to limit the application. The application can be implemented in numerous ways, including, but not limited to, the embodiments described herein. Rather, the application is intended to encompass all alternatives, modifications and equivalents of the embodiments described herein.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0037] Herein, the structural formulae of L-tyrosine-NCA and EGCG are shown as formula I and formula II, respectively:

[0038]

[0039] Traditional drugs for dry eye have the defects of short retention time, frequent use, and long-term use causing systemic toxic side effects to the human body. Therefore, the present application provides a hydrogel composite material for increasing ocular surface retention time and without toxic side effects, and a preparation method and an eye medication thereof.

[0040] In a first aspect, the present application provides a hydrogel composite material, comprising a hydrogel and EGCG loaded on the hydrogel.

[0041] The hydrogel comprises methoxypolyethylene glycol amine and L-tyrosine-NCA.

[0042] The hydrogel composite material provided by the present application is prepared by using methoxypolyethylene glycol amine (mPEG-NH2) and L-tyrosine-NCA as raw materials to form a hydrogel, and loading epigallocatechin gallate (EGCG) in the hydrogel, and can be used for dry eye and has a long ocular surface retention time and no toxic side effects. The polyamino acid hydrogel containing PEG segments has excellent biocompatibility and can provide good moisturizing effect and hydration protection for the ocular surface microenvironment. Moreover, compared with emulsion or water, the gel dosage form can further improve the retention time of the drug on the ocular surface.

[0043] And the EGCG with antioxidant effect can be used to repair the ocular surface damage. The main biological cause of dry eye syndrome is chronic inflammation caused by oxidative stress, which causes ocular surface damage. The introduction of EGCG can avoid the generation of oxidative stress from the source, thereby reducing the formation of inflammation and repairing the ocular surface damage. However, the simple EGCG has poor antioxidant property due to the presence of phenol structure. In the present application, the hydrogel is used as a carrier of the antioxidant EGCG. The phenol structure in the L-tyrosine-NCA and the phenol structure in the EGCG can form intermolecular hydrogen bonding and π-π interaction, so that the hydrogel and the EGCG can form a stable and firm loading effect, realizing the stable drug delivery of the EGCG. Moreover, the introduction of the EGCG can reduce the gelation concentration of the hydrogel, enhance the gelation property, and prolong the residence time of the hydrogel composite material on the ocular surface.

[0044] In some embodiments, the concentration of the EGCG in the hydrogel is 0.25 mg / mL to 1.25 mg / mL, for example, 0.30 mg / mL, 0.35 mg / mL, 0.40 mg / mL, 0.45 mg / mL, 0.50 mg / mL, 0.55 mg / mL, 0.60 mg / mL, 0.65 mg / mL, 0.70 mg / mL, 0.75 mg / mL, 0.80 mg / mL, 0.85 mg / mL, 0.90 mg / mL, 0.95 mg / mL, 1.00 mg / mL. By adjusting the concentration of the EGCG within this range, the antioxidant effect can be achieved without the precipitation of the EGCG. Preferably, the concentration of the EGCG is 1.25 mg / mL.

[0045] In the present application, the number average molecular weight of the methoxy polyethylene glycol amine is not limited, and any commercially available methoxy polyethylene glycol amine with a number average molecular weight known in the art can be selected. In some embodiments, the number average molecular weight of the methoxy polyethylene glycol amine is 2000 to 5000, for example, 2000 or 5000. Based on the principle of economic saving, the number average molecular weight of the methoxy polyethylene glycol amine is preferably 2000.

[0046] In some embodiments, the mass ratio of the methoxy polyethylene glycol amine to the L-tyrosine-NCA is 1:(6 to 40), for example, 1:6, 1:10, 1:15, 1:30, 1:40. Based on the segment length of the methoxy polyethylene glycol amine, the block length of the L-tyrosine-NCA is determined. Preferably, the mass ratio of the methoxy polyethylene glycol amine to the L-tyrosine-NCA is 1:15.

[0047] In the second aspect, the present application also provides a preparation method of the hydrogel composite material according to the first aspect, comprising steps S100-S200:

[0048] Step S100: preparing the hydrogel and the EGCG solution.

[0049] In some embodiments, the step of preparing the hydrogel comprises steps S101-S103:

[0050] Step S101: dissolving the methoxypolyethylene glycol amine and the L-tyrosine-NCA in an organic solvent and performing ring-opening polymerization under a protective gas atmosphere to prepare a block copolymer.

[0051] In the present application, the selection of the organic solvent is not limited, and a commonly used organic solvent in the field of hydrogel preparation can be selected to completely dissolve the methoxypolyethylene glycol amine and the L-tyrosine-NCA. In some embodiments, the organic solvent comprises one or more of N,N-dimethylformamide (DMF) and an alkane solvent, and preferably DMF. The alkane solvent comprises dichloromethane and / or trichloromethane.

[0052] In the present application, the protective gas is also not limited, and an inert gas and / or nitrogen can be selected. The inert gas comprises helium and / or argon.

[0053] It can be understood that the temperature of the ring-opening polymerization reaction can be room temperature, and the time can be 70-80 h.

[0054] Step S102: mixing the block copolymer with a precipitant to prepare a precipitate, and freeze-drying the precipitate to prepare a gel powder.

[0055] In the present application, the type of the precipitant and the mass ratio of the block copolymer to the precipitant are not limited, and a commonly used solvent in the field of precipitation can be selected to completely precipitate and separate the block copolymer. In some embodiments, the precipitant comprises anhydrous ether and / or petroleum ether, and preferably anhydrous ether.

[0056] In the present application, the conditions of freeze-drying are also not limited, and the water in the precipitate can be removed, and a uniformly dispersed powder can be formed. In some embodiments, the conditions of freeze-drying comprise:

[0057] The freeze-drying temperature is -40℃ to -50℃, and the time is 40-60 h.

[0058] It can be understood that in order to remove unreacted small molecules or solvents, after mixing the block copolymer with the precipitant, a step of using a dialysis bag to dialyze the mixed product to filter the precipitate is further included. The molecular weight cut-off of the dialysis bag can be 3000 Da, and the dialysis time can be 24-48 h.

[0059] Step S103: dissolving the gel powder in water to prepare the hydrogel.

[0060] In the present application, the method for observing whether the hydrogel is successfully gelled is not limited, and a method commonly used in the art can be selected, for example, the hydrogel can be observed by the small bottle inversion method.

[0061] In some embodiments, the concentration of the gel powder in water is 10 mg / mL to 30 mg / mL, for example, 12 mg / mL, 15 mg / mL, 20 mg / mL, 22 mg / mL, or 25 mg / mL. Controlling the concentration of the gel powder in this range can further ensure the gelling state of the hydrogel, so that it has strong gelling properties. Moreover, after the introduction of EGCG, the concentration of the gel powder can be reduced on the basis of improving the gelling properties of the hydrogel, and preferably, the concentration of the gel powder is 20 mg / mL.

[0062] In some embodiments, the temperature for dissolving the gel powder in water is 4°C to 37°C, for example, 4°C, room temperature (25°C), or 37°C; preferably, the temperature for dissolving the gel powder in water is 37°C.

[0063] It can be understood that the solvent in the EGCG solution can be water. After mixing the hydrogel with the EGCG solution, under the intermolecular hydrogen bonding and π-π interaction between the phenol structure in L-tyrosine-NCA and the phenol structure in EGCG, a stable and firm loading action is formed between the hydrogel and EGCG.

[0064] In some embodiments, the concentration of the EGCG solution is 0.25 mg / mL to 1.25 mg / mL.

[0065] Step S200: mixing the hydrogel with the EGCG solution to prepare the hydrogel composite material.

[0066] In some embodiments, the mass ratio of EGCG in the EGCG solution to the hydrogel is 1:(1-9). Preferably, the mass ratio of EGCG to the hydrogel is 1:3.

[0067] According to a specific embodiment, the method for preparing a hydrogel composite material comprises the following steps:

[0068] Step 1): dissolving the methoxypolyethylene glycol amine and the L-tyrosine-NCA in an organic solvent, and performing ring-opening polymerization under a protective gas atmosphere to prepare a block copolymer;

[0069] Step 2): mixing the block copolymer with a precipitant and dialyzing to prepare a precipitate, and freeze-drying the precipitate to prepare a gel powder;

[0070] Step 3): dissolving the gel powder in water to prepare the hydrogel;

[0071] Step 4): dissolving EGCG in water to prepare the EGCG solution; and

[0072] Step 5): mixing the hydrogel and the EGCG solution to prepare the hydrogel composite.

[0073] In a third aspect, the present application further provides an eye medication, which comprises the hydrogel composite according to the first aspect.

[0074] In the present application, the eye medication can be specifically a medication for treating dry eye, such as an eye drop.

[0075] The present application will be further described in detail below in combination with specific examples.

[0076] Example 1

[0077] Step 1): dissolving methoxy polyethylene glycol amine (mPEG-NH2) with a molecular weight of 2000 and L-tyrosine-NCA in N’N-dimethylformamide (DMF) at a mass ratio of 1:10, and performing a ring-opening polymerization reaction at room temperature under a nitrogen atmosphere for 72 h. Subsequently, adding anhydrous ether for precipitation, and then dialyzing with a dialysis bag with a molecular weight of 3000 Da for 48 h. Then, freeze-drying at -80 °C for 24 h to obtain a powder product;

[0078] Step 2): dissolving the powder product prepared in step 1) in water, and forming a hydrogel with a concentration of 30 mg / mL at 37 °C, which is denoted as PY10;

[0079] Step 3): dissolving EGCG in water to form an EGCG solution. Subsequently, mixing EGCG and PY10 at a mass ratio of 1:3 to form a hydrogel loaded with EGCG, which is denoted as EGCG@PY10. The final concentration of EGCG loaded in the hydrogel is 1.25 mg / mL. It can be observed by the small bottle inversion method that the gel transition temperature decreases after adding EGCG, indicating that the interaction between EGCG and the hydrogel increases the internal force of the hydrogel.

[0080] Example 2

[0081] The preparation method of Example 2 is basically the same as that of Example 1, except that in step 1), the mass ratio of mPEG-NH2 and L-tyrosine-NCA is 1:30; and in step 2), the concentration of the hydrogel is 10 mg / mL. The specific steps are as follows:

[0082] Step 1): mPEG-NH2 with a molecular weight of 2000 and L-tyrosine-NCA were dissolved in N,N-dimethylformamide (DMF) at a mass ratio of 1:30, and a ring-opening polymerization reaction was carried out at room temperature under a nitrogen atmosphere for 72 h. Subsequently, anhydrous ether was added for precipitation, and then dialysis was performed in a dialysis bag with a molecular weight of 3000 Da for 48 h. After that, freeze-drying was performed at -45 °C for 60 h to obtain a powder product;

[0083] Step 2): The powder product prepared in step 1) was dissolved in water to form PY30. Experiments showed that the powder product had poor solubility in water and could not form a hydrogel.

[0084] Example 3

[0085] The preparation method of Example 3 is basically the same as that of Example 1, except that in step 1), the mass ratio of mPEG-NH2 to L-tyrosine-NCA is 1:15; and in step 2), the concentration of the hydrogel is 20 mg / mL. The specific steps are as follows:

[0086] Step 1): mPEG-NH2 with a molecular weight of 2000 and L-tyrosine-NCA were dissolved in N,N-dimethylformamide (DMF) at a mass ratio of 1:15, and a ring-opening polymerization reaction was carried out at room temperature under a nitrogen atmosphere for 72 h. Subsequently, anhydrous ether was added for precipitation, and then dialysis was performed in a dialysis bag with a molecular weight of 3000 Da for 48 h. After that, freeze-drying was performed at -45 °C for 60 h to obtain a powder product;

[0087] Step 2): The powder product prepared in step 1) was dissolved in water to form a hydrogel with a concentration of 20 mg / mL at 37 °C, denoted as PY15;

[0088] Step 3): EGCG was dissolved in water to form an EGCG solution. Subsequently, EGCG and PY15 were mixed at a mass ratio of 1:3 to form a hydrogel loaded with EGCG, denoted as EGCG@PY15. The final concentration of EGCG loaded in the hydrogel was 1.25 mg / mL.

[0089] Example 4

[0090] The preparation method of Example 4 is basically the same as that of Example 3, except that in step 3), the final concentration of EGCG loaded in the hydrogel was 0.25 mg / mL.

[0091] Example 5

[0092] The preparation method of Example 5 is basically the same as that of Example 3, except that in step 3), the final concentration of EGCG loaded in the hydrogel was 0.75 mg / mL.

[0093] Example 6

[0094] The preparation method of Example 6 is basically the same as that of Example 1, except that in step 1), the mass ratio of mPEG-NH2 to L-tyrosine-NCA is 1:6; and the powder product prepared in step 1) is dissolved in water to form PY6. PY6 has almost no viscosity and cannot form a hydrogel.

[0095] Example 7

[0096] The preparation method of Example 7 is basically the same as that of Example 1, except that in step 1), the mass ratio of mPEG-NH2 to L-tyrosine-NCA is 1:40; and the powder product prepared in step 1) is dissolved in water to form PY40. Experiments show that the powder product has poor solubility in water and cannot form a hydrogel.

[0097] Example 8

[0098] The preparation method of Example 8 is basically the same as that of Example 1, except that in step 2), the temperature for forming the hydrogel is 0°C.

[0099] Example 9

[0100] The preparation method of Example 9 is basically the same as that of Example 1, except that in step 2), the temperature for forming the hydrogel is room temperature (25°C).

[0101] Comparative Example 1

[0102] The preparation method of Comparative Example 1 is basically the same as that of Example 3, except that step 3) is not performed, i.e., the hydrogel is not loaded with EGCG (the final concentration of EGCG loaded in the hydrogel is 0).

[0103] Comparative Example 2

[0104] The preparation method of Comparative Example 2 is basically the same as that of Example 3, except that L-phenylalanine-NCA is used instead of L-tyrosine-NCA.

[0105] Comparative Example 3

[0106] The preparation method of Comparative Example 3 is basically the same as that of Example 3, except that L-valine-NCA is used instead of L-tyrosine-NCA.

[0107] The raw materials and the ratio of the preparation methods of Examples 1-9 and Comparative Examples 1-3 are listed in Table 1 below:

[0108] Table 1

[0109]

[0110]

[0111] The hydrogel composite materials prepared in Examples 1-9 and Comparative Examples 1-3 were subjected to relevant performance tests.

[0112] 1) H-NMR spectra of the block copolymers formed by amino acids and mPEG-NH2 in Examples 1-3, 6, and 7 were tested, and the test results are shown in Figure 1 It can be seen from Figure 1 that the ring-opening polymerization reaction can occur by using the amino ring-opening in mPEG-NH2 and the lactone structure of L-tyrosine-NCA, to obtain the block copolymer. Moreover, according to the segment length of PEG, the amino acids with different segments used exhibit different assembly abilities. In addition, with the addition of EGCG, the interaction between EGCG and the hydrogel carrier enhances the stability of the polymerization system. At the same time, with the aid of the π-π interaction and intermolecular hydrogen bond interaction between L-tyrosine-NCA and the benzene ring in EGCG, EGCG can be stably loaded in the polytyrosine network.

[0113] 2) The hydrogel composite materials prepared in Examples 3-5 and Comparative Example 1 were subjected to rheological detection, and the test results are shown in Figure 2 It can be seen from Figure 2 that with the increase of EGCG, the storage modulus (G') of the drug-loaded gel increases, the intermolecular force is enhanced, thereby increasing the strength of the hydrogel.

[0114] 3) The hydrogel composite materials prepared in Examples 3-5 and Comparative Example 1 and pure EGCG solution (EGCG concentration of 1.25 mg / mL) were tested, and the test results show that the treatment effect of the hydrogel loaded with EGCG on dry eye is significantly better than that of pure EGCG aqueous solution and the hydrogel material prepared in Comparative Example 1. By adjusting the final concentration of EGCG loaded in the hydrogel, it can be known that if the final concentration of EGCG loaded in the hydrogel is too low, the expected treatment effect cannot be achieved, and if the concentration is too high, a precipitate will be separated out. The final concentration of EGCG loaded is preferably 1.25 mg / mL. At this concentration, the safety and sustained release of the hydrogel composite material are higher, the oxidation rate is slower, the loading stability of EGCG is better, and the required gelation concentration of the hydrogel is lower, the gelation performance is enhanced, and the ocular surface retention time is longer.

[0115] 4) At the cellular level, the cytotoxicity of pure EGCG solution (EGCG concentration of 1.25 mg / mL) and the hydrogel composite material prepared in Example 3 was evaluated, and the test results are shown in Figure 3As shown, EGCG, as a polyphenolic antioxidant, can exert its antioxidant-anti-inflammatory biological effects through the assistance of polyphenols; however, the polyphenol structure is easily oxidized, transforming into biotoxic quinones, thus limiting the drug-like potential of EGCG. Figure 3 It is understood that the EGCG-loaded hydrogel composite material provided in this application can not only achieve ocular hydration and increase ocular surface moisture through PEG, but also effectively bind EGCG to achieve stable EGCG loading. Moreover, the hydrogel composite material provided in this application has excellent biocompatibility.

[0116] 5) The hydrogel (PY15) prepared in Example 3 was subjected to cytotoxicity evaluation, and the test results are as follows: Figure 4 As shown. By Figure 4 It is known that, since the PEG segments and amino acids included in mPEG-NH2 are biomaterials with good biocompatibility, they still exhibit low cytotoxicity after polymerization to form a hydrogel system.

[0117] 6) Conduct animal experiments to evaluate the biocompatibility of the hydrogel composite material (Example 3), pure EGCG, and pure hydrogel PY15 provided in this application during ocular surface use. The specific steps are as follows:

[0118] Eight-week-old female C57BL mice were used as the research subjects. Fluorescein sodium solution, PY15, EGCG aqueous solution, and EGCG@PY15 were instilled into the eyes of the mice, respectively. The retention of the different substances in the eyes was observed under a slit lamp at 0 min, 5 min, 10 min, 20 min, and 30 min after instillation. The test results are as follows: Figure 5 As shown. By Figure 5 It is known that pure hydrogel PY15 and EGCG@PY15 loaded with EGCG have no significant toxicity to the ocular surface and will not cause damage to the cornea. Furthermore, by using sodium fluorescein for staining, it can be determined that EGCG@PY15 can increase the retention time of EGCG on the ocular surface (by 20 minutes), providing a more convenient condition for enhancing drug efficacy.

[0119] 7) Efficacy Evaluation: Eight-week-old C57BL female mice with benzalkonium chloride (BAC)-induced dry eye syndrome were used as an experimental model to verify the repair effect of the hydrogel composite material prepared in Example 3 on corneal damage and its therapeutic effect on ocular surface damage in dry eye syndrome. The specific methods are as follows:

[0120] In female mice, 2.5 mg / mL scopolamine hydrobromide was injected subcutaneously three times a day for 7 days to form a dry eye model. Then physiological saline, Xiidra, EGCG aqueous solution and EGCG@PY15 were administered three times a day for 4 days of treatment, respectively. Slit lamp photography was performed on the 0th, 2nd and 4th day of treatment, respectively, to observe the fluorescein sodium spot staining of the cornea and score it. The test results are shown in Figure 6 and Figure 7 It can be seen from Figure 6 that the hydrogel composite material provided in the present application has a more efficient and safer repair effect compared with the clinically known drug (Xiidra). It can be seen from Figure 7 that by comparing the hydrogel composite material prepared in Example 3 with the control group, the physiological saline group and free EGCG, the hydrogel composite material provided in the present application has the best treatment effect.

[0121] 9) The materials prepared in Example 1 and Comparative Examples 2-3 were subjected to rheological test, and the test results showed that other amino acids cannot form stable loading effect with EGCG, and it is difficult to improve the ocular surface retention time.

[0122] The technical features of the above-described embodiments can be combined arbitrarily. In order to make the description concise, all possible combinations of the technical features in the above-described embodiments are not described, but as long as the combinations of the technical features do not contradict, they should be considered as the scope of the present disclosure.

[0123] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as limiting the scope of the patent. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the scope of the patent protection of the present application should be subject to the appended claims, and the description and drawings can be used to explain the scope of the claims.

Claims

1. An ophthalmic medicament, characterized by comprising: The hydrogel composite comprises a hydrogel and epigallocatechin gallate (EGCG) loaded on the hydrogel. The raw material for preparing the hydrogel comprises methoxypolyethylene glycol amine (mPEG-NH2) and L-tyrosine-NCA. In the hydrogel composite, the concentration of the EGCG is 0.75 mg / mL to 1.25 mg / mL. The structural formula of the L-tyrosine-NCA is The mass ratio of the methoxypolyethylene glycol amine to the L-tyrosine-NCA is 1: (10~15); The method for preparing the hydrogel composite comprises the following steps: The hydrogel and an EGCG solution are prepared, the hydrogel is mixed with the EGCG solution, and the hydrogel composite is prepared, and the mass ratio of the EGCG in the EGCG solution to the hydrogel is 1: (1-9). The step of preparing the hydrogel comprises: The methoxypolyethylene glycol amine and the L-tyrosine-NCA are dissolved in an organic solvent, and ring-opening polymerization is performed under a protective gas atmosphere to prepare a block copolymer. The block copolymer is mixed with a precipitant to prepare a precipitate, and the precipitate is freeze-dried to prepare a gel powder. The gel powder is dissolved in water to prepare the hydrogel, and the concentration of the gel powder in water is 10 mg / mL to 30 mg / mL.

2. The ophthalmic pharmaceutical according to claim 1, wherein In the hydrogel composite, the concentration of the EGCG is 1.25 mg / mL.

3. The ophthalmic pharmaceutical according to claim 1, wherein The number-average molecular weight of the methoxypolyethylene glycol amine is 2,000 to 5,000.

4. The ophthalmic pharmaceutical according to claim 1, wherein The organic solvent comprises one or more of N,N-dimethylformamide and an alkane solvent.

5. The ophthalmic pharmaceutical according to claim 1, wherein The precipitant comprises anhydrous ether and / or petroleum ether.

6. The ophthalmic pharmaceutical according to claim 1, wherein The temperature for dissolving the gel powder in water is 4°C to 37°C.

7. The ophthalmic pharmaceutical according to claim 1, wherein After the block copolymer is mixed with a precipitant, the step of using a dialysis bag to dialyze the mixed product to filter the precipitate is further included.

8. An eye drop solution, characterized by, The eye medication comprises the hydrogel composite of any one of claims 1-7.

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