Anisodine-loaded dopamine hydrogel as well as preparation method and application thereof

Abstract

The invention discloses anisodine-loaded dopamine hydrogel as well as a preparation method and application thereof. The anisodine-loaded dopamine hydrogel comprises a hydrogel matrix and anisodine loaded on the hydrogel matrix, the hydrogel matrix comprises a plurality of hyaluronic acid chains and dopamine bridging units, hydroxyl groups in at least one part of glucuronic acid units in the hyaluronic acid chains are converted into aldehyde groups, and the dopamine bridging units are connected with the hyaluronic acid chains. At least a part of the dopamine bridging units are respectively connected with different hyaluronic acid chains, so that the hydrogel matrix forms a cross-linked network structure. The anisodine dopamine hydrogel has good biocompatibility, stable release and continuous release of anisodine can be realized, the problem of unstable release of anisodine is solved, the action time of anisodine is effectively prolonged, the administration frequency is reduced, and the development of myopia and ocular axis extension can be remarkably inhibited. In addition, dopamine can be combined, the progress of myopia is more effectively controlled, and the method has wide application prospects in the field of biological medicine.

Description

Technical Field

[0001] The present application relates to the technical field of medical hydrogels, and in particular to anisodine-loaded dopamine hydrogel and a preparation method and application thereof. Background Art

[0002] In the field of myopia treatment, drug intervention is one of the important means. Among them, atropine eye drops, as a commonly used myopia control drug, have been widely used in clinical practice. However, atropine eye drops have significant limitations, mainly reflected in their short duration of action. Patients usually need to use them once or more per day to maintain effective drug concentrations. This frequent administration method causes many inconveniences to patients' daily lives, especially for children and adolescent patients. The long-term compliance with the use of atropine eye drops is poor, which greatly limits its application effect in myopia prevention and control.

[0003] Anisodine, an alkaloid, has been used in some reports to control myopia. Anisodine has anticholinergic effects, such as relieving smooth muscle spasms, dilating the pupil, and inhibiting salivary gland secretion. It can regulate vascular function throughout the eye and improve ocular blood supply, and is less toxic than atropine. However, the release of anisodine in the body can be affected by various factors, such as pH, temperature, and enzyme activity, leading to unstable release. Therefore, developing a novel drug delivery system that can effectively prolong the duration of drug action and reduce the number of dosing times is of great clinical significance for improving patient compliance and optimizing the effectiveness of myopia treatment. Summary of the Invention

[0004] Based on this, it is necessary to provide a dopamine hydrogel loaded with anisodine and a preparation method and application thereof.

[0005] The first aspect of the present application provides a kind of anisodine-loaded dopamine hydrogel, the anisodine-loaded dopamine hydrogel comprises a hydrogel matrix and anisodine loaded on the hydrogel matrix, wherein the hydrogel matrix comprises a plurality of hyaluronic acid chains and dopamine bridging units, the hydroxyl groups in at least a portion of the glucuronic acid units in the hyaluronic acid chains are converted into aldehyde groups, and at least a portion of the dopamine bridging units are respectively connected to different hyaluronic acid chains, so that the hydrogel matrix forms a cross-linked network structure. In some embodiments, the dopamine bridging unit is grafted to the carboxyl position of the glucuronic acid unit in the hyaluronic acid chain through an amide bond.

[0006] In some embodiments, the molecular weight of hyaluronic acid is 200,000 Da to 2,000,000 Da.

[0007] In some embodiments, the mass ratio of the hydrogel matrix to anisodine is (1-3):1.

[0008] The second aspect of the present application provides a method for preparing anisodine-loaded dopamine hydrogel, comprising the following steps:

[0009] The hyaluronic acid solution is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-2,5-pyrrolidinedione for activation, and dopamine is added for reaction to prepare dopamine-hyaluronic acid; and

[0010] The dopamine-hyaluronic acid is mixed with anisodine, and sodium periodate is added to prepare the anisodine-loaded dopamine hydrogel.

[0011] In some embodiments, the mass volume fraction of hyaluronic acid in the hyaluronic acid solution is 1% to 2%.

[0012] In some embodiments, the molecular weight of hyaluronic acid is 200,000 Da to 2,000,000 Da.

[0013] In some embodiments, the mass ratio of the hyaluronic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-2,5-pyrrolidinedione is (3-3.5):(1.5-2):1.

[0014] In some embodiments, the mass ratio of the hyaluronic acid to dopamine is (1-3):1.

[0015] In some embodiments, the conditions for adding dopamine to the reaction include: a temperature of 20° C. to 25° C., a stirring speed of 80-100 rpm, and a reaction time of 12 h to 16 h.

[0016] In some embodiments, after adding dopamine for reaction, the dopamine-hyaluronic acid in the resulting reaction system is purified and the solvent contained therein is removed.

[0017] In some embodiments, the purification method includes dialysis; the dialysis includes: placing the reaction system in a dialysis bag, then placing it in 1L~2L of water, dialyzing under magnetic stirring at 200rpm~400rpm, changing the water every 2h, 6h, 8h and 12h, and then changing the water every 12h.

[0018] In some embodiments, the removal of the contained solvent comprises freeze-drying.

[0019] In some embodiments, the dialysis time is 48 h to 50 h, and the freeze-drying time is 8 h to 10 h.

[0020] In some embodiments, the dopamine-hyaluronic acid and anisodine are mixed under the following conditions: magnetic stirring at 1000 rpm to 1500 rpm for 30 min to 40 min.

[0021] In some embodiments, the mass ratio of dopamine-hyaluronic acid to anisodine is (100-150):1.

[0022] In some embodiments, the mass ratio of dopamine-hyaluronic acid to sodium periodate is (5000-5500):1.

[0023] The third aspect of the present application provides the use of the anisodine-loaded dopamine hydrogel described in the first aspect of the present application in the preparation of any of the following drugs:

[0024] (a) drugs for controlling the progression of myopia;

[0025] (b) Drugs used to inhibit axial elongation.

[0026] The aforementioned anisodine-dopamine hydrogel exhibits excellent biocompatibility and enables stable and sustained release of anisodine, overcoming the problem of unstable anisodine release. This effectively prolongs the duration of anisodine's action, reduces the frequency of dosing, and significantly inhibits the progression of myopia and axial lengthening of the eye. Furthermore, it can be combined with dopamine to more effectively control the progression of myopia, demonstrating broad application prospects in the biomedical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions in the embodiments and examples of this application and to provide a more complete understanding of the application and its beneficial effects, the following briefly introduces the drawings required for use in the description of the embodiments or examples. Obviously, the drawings described below are only some embodiments of this application. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0028] Figure 1 This is a schematic diagram of the preparation and application process of anisodine hyaluronic acid-dopamine hydrogel in one embodiment of the present application;

[0029] Figure 2 The appearance and scanning electron microscope image of the dopamine hydrogel in one embodiment of the present application, wherein a is the appearance image of the dopamine hydrogel, and b is the scanning electron microscope image of the dopamine hydrogel;

[0030] Figure 3 This is an ultraviolet detection image of dopamine hydrogel in one embodiment of the present application;

[0031] Figure 4 Schematic diagram of the subconjunctival injection of anisodine-loaded dopamine hydrogel in guinea pigs according to one embodiment of the present application, wherein a is a schematic diagram before subconjunctival injection, and b is a schematic diagram of the subconjunctival injection of anisodine-loaded dopamine hydrogel;

[0032] Figure 5Figure 1 is a graph showing changes in refractive power and axial length in different form deprivation groups after 4 weeks in one embodiment of the present application, wherein a is a graph showing changes in refractive power in different form deprivation groups after 4 weeks, "Interocular Difference" indicates interocular difference, and "Refraction" indicates refraction; b is a graph showing changes in axial length in different form deprivation groups after 4 weeks, and "Axial Length" indicates axial length;

[0033] Figure 6 This is a scanning electron microscope image of the dopamine hydrogel in Comparative Example 1 of this application. DETAILED DESCRIPTION

[0034] To facilitate understanding of the present application, a more comprehensive description of the present application will be provided below with reference to the accompanying drawings. The accompanying drawings illustrate preferred embodiments of the present application. However, the present application may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the disclosure of the present application.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0036] In this application, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is independent unless otherwise specified and there are no contradictions or constraints.

[0037] In this application, "preferred", "better", "more preferred" and "suitable" are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute a limitation on the scope of protection of this application.

[0038] As used herein, the terms "having," "containing," "including," and "comprising" are synonymous and are inclusive or open-ended, not excluding additional, unrecited members or features. Examples of members or features include materials or components, structures, elements, and instruments. Non-limiting examples of members or features include actions, conditions for the occurrence of actions, timing, and states.

[0039] In this application, the technical features or technical solutions described in open language include closed technical features or technical solutions composed of the listed contents, and also include open technical features or technical solutions containing the listed contents.

[0040] In this application, when referring to the unit of a data range, if the unit is only after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same.

[0041] In this application, if a method flow involves multiple steps, unless otherwise specified herein, there is no strict order restriction on the execution of these steps, and they can be executed in an order other than the order described. Moreover, any step can include multiple sub-steps or multiple stages, and these sub-steps or stages do not necessarily need to be completed at the same time, but can be executed at different times, and their execution order is not necessarily sequential, but can be executed in turn, alternating, or simultaneously with other steps or parts of sub-steps or stages of other steps.

[0042] In this application, exemplary descriptions such as "in some embodiments (or examples)" and "in one embodiment (or example)" may include but are not limited to the following meanings: these solutions can be combined with other solutions in a suitable manner to form new technical solutions.

[0043] In this application, the terms "first," "second," and "third," etc., in "the first aspect," "the second aspect," "the third aspect," etc., are used for descriptive purposes only and should not be understood as indicating or implying relative importance or quantity, nor as implicitly indicating the importance or quantity of the technical features indicated. Furthermore, "first," "second," and "third," etc., are only used for non-exhaustive enumeration and description purposes and should be understood not to constitute closed-ended limitations on quantity.

[0044] In this application, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional numerical values ​​within the numerical interval is deemed to be continuous and includes the two numerical endpoints of the numerical interval (i.e., the minimum and maximum values), as well as every numerical value between these two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints, which is equivalent to directly listing every integer. When multiple numerical ranges are provided to describe a feature or characteristic, these numerical ranges can be combined. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all subranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, percentage, ratio, etc. "Numerical interval" allows for a broad range of numerical interval types including percentage intervals, ratio intervals, and ratio intervals.

[0045] In this application, the term "room temperature" generally refers to 4°C to 35°C, and may refer to 20°C ± 5°C. In some embodiments or examples of this application, room temperature refers to 20°C to 30°C.

[0046] As a potential drug for the treatment of myopia, anisodine has significant biological activity. However, its release process in physiological environments is unstable and its duration of action in the body is short.

[0047] Based on this, the embodiments of the present application at least provide a anisodine-loaded dopamine hydrogel and its preparation method and application.

[0048] In a first aspect of the present application, a dopamine-loaded anisodine hydrogel is provided, comprising a hydrogel matrix and anisodine loaded on the hydrogel matrix, wherein the hydrogel matrix comprises a plurality of hyaluronic acid chains and dopamine bridging units, the hydroxyl groups in at least a portion of the glucuronic acid units in the hyaluronic acid chains are converted into aldehyde groups, and at least a portion of the dopamine bridging units are respectively connected to different hyaluronic acid chains, so that the hydrogel matrix forms a cross-linked network structure.

[0049] In some embodiments, the dopamine bridging unit is grafted to the carboxyl position of the glucuronic acid unit in the hyaluronic acid chain via an amide bond.

[0050] In some embodiments, at least a portion of the hyaluronic acid chains have pendant dopamine units grafted onto the carboxyl positions of the glucuronic acid units.

[0051] In the present application, the term "suspended dopamine unit" means that the dopamine unit is only connected to one hyaluronic acid chain and does not participate in the cross-linking of the hyaluronic acid three-dimensional network.

[0052] In some embodiments, the molecular weight of the hyaluronic acid is 200,000 Da to 2,000,000 Da. In a non-limiting manner, the molecular weight of the hyaluronic acid can be, but is not limited to, 200,000 Da, 500,000 Da, 1,000,000 Da, 2,000,000 Da, or a value or range between any two of the above values.

[0053] In some embodiments, the mass ratio of the hydrogel matrix to anisodine is (1-3): 1. Without limitation, the mass ratio of the hydrogel matrix to anisodine can be, but is not limited to, 1:1, 2:1, 3:1, or a ratio or range between any two of the above ratios.

[0054] The above-mentioned anisodine-loaded dopamine hydrogel provides anisodine by loading it into the dopamine hydrogel, thereby enabling stable and sustained release of anisodine, overcoming the problem of unstable anisodine release, and slowing down the elongation of the axial line and the progression of myopia. Dopamine, as an important neurotransmitter, can act on the dopamine D2 receptor and also slow down the elongation of the axial line and the progression of myopia. Therefore, the above-mentioned anisodine-loaded dopamine hydrogel has a dual-target effect of controlling myopia.

[0055] In a second aspect of the present application, a method for preparing anisodine-loaded dopamine hydrogel is provided, comprising the following steps:

[0056] S100: mixing a hyaluronic acid solution with 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-2,5-pyrrolidinedione for activation, adding dopamine for reaction, and preparing dopamine-hyaluronic acid; and,

[0057] S200: dopamine-hyaluronic acid is mixed with anisodine, and sodium periodate is added to prepare anisodine-loaded dopamine hydrogel.

[0058] In some embodiments, the process of preparing anisodine-loaded dopamine hydrogel and its application are shown in the following diagram: Figure 1 shown.

[0059] In some embodiments, in step S100, the hyaluronic acid solution is prepared by mixing hyaluronic acid with 2-morpholineethanesulfonic acid, and the mass volume fraction of hyaluronic acid in the hyaluronic acid solution is 1% to 2%. Without limitation, the mass volume fraction of hyaluronic acid in the hyaluronic acid solution can be, but is not limited to, 1%, 1.5%, 2%, or a value or range between any two of the foregoing values.

[0060] In some embodiments, the molecular weight of hyaluronic acid is 200,000 Da to 2,000,000 Da.

[0061] In some embodiments, in step S100, the mass ratio of hyaluronic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and 1-hydroxy-2,5-pyrrolidinedione is (3-3.5):(1.5-2):1. Without limitation, the mass ratio of hyaluronic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and 1-hydroxy-2,5-pyrrolidinedione can be 3:1.5:1, 3:2:1, 3.5:1.5:1, 3.5:2:1, or a ratio or range between any two of the above ratios. In some embodiments, in step S100, the mass ratio of hyaluronic acid to dopamine is (1-3):1. Without limitation, the mass ratio of hyaluronic acid to dopamine can be, but is not limited to, 1:1, 2:1, 3:1, or a ratio or range between any two of the above ratios.

[0062] In some embodiments, in step S100, the conditions for adding dopamine to the reaction include: a temperature of 20°C to 25°C, a stirring speed of 80 rpm to 100 rpm, and a reaction time of 12 hours to 16 hours. In a non-limiting manner, the temperature may be, but is not limited to, 20°C, 23°C, 25°C, or a value or range between any two of the above values; the stirring speed may be, but is not limited to, 80 rpm, 85 rpm, 90 rpm, 95 rpm, 100 rpm, or a value or range between any two of the above values; and the reaction time may be, but is not limited to, 12 hours, 14 hours, 16 hours, or a value or range between any two of the above values.

[0063] In some embodiments, in step S100, after adding dopamine for reaction, the step further includes purifying the dopamine-hyaluronic acid in the resulting reaction system and removing the solvent contained therein.

[0064] In some embodiments, the purification method includes dialysis. Further, the dialysis includes: placing the reaction system in a dialysis bag, then placing it in 1L~2L of water, dialyzing under magnetic stirring at 200rpm~400rpm, changing the water every 2h, 6h, 8h and 12h, and then changing the water every 12h.

[0065] In some embodiments, the dialysis time is 48 hours to 50 hours. In a non-limiting manner, the dialysis time can be, but is not limited to, 48 hours, 49 hours, 50 hours, or a value or range between any two of the above values.

[0066] In some embodiments, the method for removing the contained solvent includes freeze drying. Further, the freeze drying time is 8 hours to 10 hours. Non-limitingly, the freeze drying time can be, but is not limited to, 8 hours, 9 hours, 10 hours, or a value or range between any two of the above values.

[0067] In some embodiments, in step S200, dopamine-hyaluronic acid and anisodine are mixed under magnetic stirring at 1000-1500 rpm for 30-40 minutes. In a non-limiting manner, the stirring speed may be, but is not limited to, 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm, or a value or range between any two of the foregoing values; and the stirring time may be, but is not limited to, 30 minutes, 32 minutes, 34 minutes, 36 minutes, 38 minutes, 40 minutes, or a value or range between any two of the foregoing values.

[0068] In some embodiments, in step S200, the mass ratio of dopamine-hyaluronic acid to anisodine is (100-150): 1. Without limitation, the mass ratio of dopamine-hyaluronic acid to anisodine can be, but is not limited to, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, or a ratio or range between any two of the above ratios.

[0069] In some embodiments, the mass ratio of dopamine-hyaluronic acid to sodium periodate is (5000-5500): 1. Without limitation, the mass ratio of dopamine-hyaluronic acid to sodium periodate can be, but is not limited to, 5000: 1, 5100: 1, 5200: 1, 5300: 1, 5400: 1, 5500: 1, or a ratio or range between any two of the above ratios.

[0070] In a third aspect of the present application, there is provided use of the above-mentioned anisodine-loaded dopamine hydrogel in the preparation of any of the following drugs:

[0071] (a) drugs for controlling myopia;

[0072] (b) Drugs used to inhibit axial elongation.

[0073] In this application, unless otherwise specified, "form deprivation" refers to the process of attaching a translucent eye mask to the skin around the eye, causing external light to produce a blurred image on the retina, thereby inducing the formation of myopia.

[0074] In this application, unless otherwise specified, "diopter" refers to the unit of measurement of the eye's refractive power. Myopia diopter is usually expressed as a negative number, with a larger value indicating a greater degree of myopia.

[0075] In this application, unless otherwise specified, "axial length" refers to the distance from the anterior surface of the cornea to the anterior surface of the retina and is an important indicator for assessing eye size. Axial length is closely related to refractive status; higher myopia is associated with a longer axial length.

[0076] Some examples are provided below.

[0077] The embodiments of the present application will be described in detail below with reference to the examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which the conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and may also be based on the experimental manuals or conventional conditions in this area, or on the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0078] In the following examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operating accuracy are allowed.

[0079] Example 1

[0080] 1. Preparation of hydrogel

[0081] 1. Add 100 mg of hyaluronic acid to 10 mL of 2-Morpholinoethanesulphonic acid (MES) and stir magnetically at 1300 rpm for 2 h to fully dissolve.

[0082] 2. Add 48.1 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 29.1 mg of 1-hydroxy-2,5-pyrrolidinedione (NHS) to the above system and stir magnetically at 1000 rpm for 20 min.

[0083] 3. Add 50 mg of dopamine to the above system and stir at 200 rpm at room temperature for 12 hours.

[0084] 4. Place the obtained reaction system in a dialysis bag, seal it, place the dialysis bag in 1 L of ultrapure water, stir it magnetically at 300 rpm, change the water at 2, 6, 8, and 12 hours, and then change the water every 12 hours.

[0085] 5. After 48 h, pour out the liquid in the dialysis bag, freeze it quickly in liquid nitrogen, and freeze-dry it (70°C, 0 KPa) for 8 h.

[0086] 6. The freeze-dried white solid was dissolved in Tris-HCl (pH 8.8) to a concentration of 10 mg / mL. Anisodine was added to a concentration of 0.1 mg / mL. After magnetic stirring at 1000 rpm for 30 min, 20 μL of 0.1 mg / mL sodium periodate was added per 1 mL. The mixture was magnetically stirred at 100 rpm for 2 h to obtain anisodine-loaded hyaluronic acid-dopamine black hydrogel.

[0087] 2. Characterization of anisodine-loaded dopamine hydrogel

[0088] 1. Characterization of anisodine-loaded dopamine hydrogel

[0089] like Figure 2 As shown in a in FIG, in terms of general appearance, the dopamine hydrogel prepared in the example is in the form of a gel block, has no fluidity, and is black. To further clarify its microscopic morphology, the dopamine hydrogel prepared in the example was subjected to SEM examination, and the results are shown in FIG. Figure 2 As shown in b, the hydrogel exhibits a typical porous structure with highly interconnected gaps.

[0090] 2. Characteristic UV absorption peak of anisodine-loaded dopamine hydrogel

[0091] The dopamine hydrogel prepared in Example was subjected to UV spectroscopy analysis, and the results were as follows: Figure 3 As shown, the characteristic absorption peak of dopamine appears in the wavelength range of 200-220 nm, where DA is dopamine, HA is hyaluronic acid, and HA-DA is dopamine hydrogel.

[0092] 3. Animal Experiments

[0093] 1. Subconjunctival injection of anisodine-loaded dopamine hydrogel

[0094] Two-week-old healthy male tricolor guinea pigs were selected and subjected to monocular form deprivation using an eye mask. The form deprivation eye mask was made of milky white translucent latex gloves and glued to the skin around the guinea pig's eye to ensure that the eye mask did not exert pressure on the covered eye and did not affect eye movement. Guinea pigs were injected with 20 µL of anisodine-loaded dopamine hydrogel subconjunctivally weekly. Figure 4 As shown in a and b.

[0095] 2. Changes in refractive power and axial length after 4 weeks of form deprivation

[0096] The experiment was divided into two groups: the form deprivation (FDM) group: the left eye served as a self-control, and the right eye was covered with an eye patch; the form deprivation combined with anisodine dopamine hydrogel treatment (FDM+A) group: the left eye served as a self-control, and the right eye was covered with an eye patch and a subconjunctival injection of anisodine dopamine hydrogel. After 4 weeks, the refractive error between the two eyes in the FDM group was -5.4D±1.2D, and the refractive error between the two eyes in the FDM+A group was -2.25D±0.86D. Figure 5 As shown in a, where * indicates p < 0.05; the difference in eye axis between the two eyes in the FDM group was 0.38 ± 0.10 mm, and the difference in refractive power between the two eyes in the FDM+A group was 0.15 ± 0.06 mm. Figure 5 As shown in b, where * indicates p < 0.05.

[0097] Comparative Example 1

[0098] The hydrogel was prepared by the same method as in Example 1, except that deactivated sodium periodate was used. The obtained hydrogel was subjected to SEM examination, and the results were as follows: Figure 6 As shown, the SEM ultrastructure showed a disordered structure and the hydrogel synthesis failed.

[0099] Comparative Example 2

[0100] The hydrogel was prepared by the same method as in Example 1, except that 20 μL of 0.01 mg / mL sodium periodate was added per 1 mL. The obtained hydrogel was subjected to SEM examination. The SEM ultrastructure showed a disordered structure, indicating that the hydrogel synthesis failed.

[0101] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0102] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art could make various modifications and improvements without departing from the spirit of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. A anisodine-loaded dopamine hydrogel, characterized in that: The anisodine-loaded dopamine hydrogel comprises a hydrogel matrix and anisodine loaded in the hydrogel matrix, wherein the hydrogel matrix comprises a plurality of hyaluronic acid chains and dopamine bridging units, the hydroxyl groups in at least a portion of the glucuronic acid units in the hyaluronic acid chains are converted into aldehyde groups, and at least a portion of the dopamine bridging units are respectively connected to different hyaluronic acid chains, so that the hydrogel matrix forms a cross-linked network structure.

2. The anisodine-loaded dopamine hydrogel according to claim 1, wherein Meet one or more of the following conditions: The dopamine bridging unit is grafted to the carboxyl position of the glucuronic acid unit in the hyaluronic acid chain through an amide bond; The molecular weight of the hyaluronic acid is 200,000 Da to 2,000,000 Da; The mass ratio of the hydrogel matrix to anisodine is (1-3):

1.

3. A method for preparing anisodine-loaded dopamine hydrogel, characterized in that: The following steps are involved: The hyaluronic acid solution is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-2,5-pyrrolidinedione for activation, and dopamine is added for reaction to prepare dopamine-hyaluronic acid; and The dopamine-hyaluronic acid is mixed with anisodine, and sodium periodate is added to prepare the anisodine-loaded dopamine hydrogel.

4. The method according to claim 3, wherein The hyaluronic acid solution is obtained by mixing hyaluronic acid with 2-morpholineethanesulfonic acid, wherein the mass volume fraction of hyaluronic acid in the hyaluronic acid solution is 1% to 2%; Optionally, the molecular weight of the hyaluronic acid is 200,000 Da to 2,000,000 Da.

5. The method according to claim 4, wherein The mass ratio of the hyaluronic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-2,5-pyrrolidinedione is (3-3.5): (1.5-2):

1.

6. The method according to claim 3, wherein The mass ratio of the hyaluronic acid to dopamine is (1-3):

1.

7. The method according to claim 6, wherein The conditions for adding dopamine to the reaction include: temperature of 20° C. to 25° C., stirring speed of 80 rpm to 100 rpm, and reaction time of 12 h to 16 h.

8. The method according to any one of claims 3 to 7, wherein After adding dopamine for reaction, the method further comprises purifying the dopamine-hyaluronic acid in the obtained reaction system and removing the solvent contained therein; Optionally, the purification method includes dialysis; further optionally, the dialysis includes: placing the reaction system in a dialysis bag, then placing it in 1L~2L of water, dialyzing under magnetic stirring at 200rpm~400rpm, changing the water every 2h, 6h, 8h and 12h, and then changing the water every 12h; Optionally, the removal of the contained solvent comprises freeze drying; Optionally, the dialysis time is 48h~50h, and the freeze-drying time is 8h~10h.

9. The method according to claim 3, wherein One or more of the following conditions are also met: The mixing conditions of the dopamine-hyaluronic acid and anisodine are as follows: magnetic stirring at 1000 rpm to 1500 rpm for 30 min to 40 min; The mass ratio of dopamine-hyaluronic acid to anisodine is (100-150):1; The mass ratio of dopamine-hyaluronic acid to sodium periodate is (5000-5500):

1.

10. Use of the anisodine-loaded dopamine hydrogel according to claim 1 or 2 in the preparation of any of the following medicines: (a) drugs for controlling myopia; (b) Drugs used to inhibit axial elongation.

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