Myopia-improving atropine sulfate local ophthalmic preparation and preparation method thereof

Abstract

The invention discloses a myopia-improving atropine sulfate local ophthalmic preparation and a preparation method thereof. The myopia-improving atropine sulfate local ophthalmic preparation is prepared from the following raw material components in percentage by mass and volume: 0.01-1% of atropine sulfate, 5-20% of a stabilizer, 0.5-8% of mannitol, 0.05-1% of a thickening agent, 0.05-1% of sodium chloride, 0.5-2% of a buffering agent and a solvent which is water for injection. Wherein the stabilizer is a temperature-sensitive block polymer material. The compound is good in water solubility, high in antibacterial activity, wide in antibacterial spectrum, safe, free of cytotoxicity to HEK-293T cells and free of hemolytic activity to mouse red blood cells, and has a wide application prospect. According to the invention, a treatment mode for delaying and controlling myopia of children and teenagers in the prior art is optimized; wherein the stability of the atropine sulfate is remarkably improved due to the use of the temperature-sensitive block polymer material, so that the atropine sulfate has a relatively long half-life period and can continuously and effectively release a medicine, the administration concentration and the administration frequency are greatly reduced, and the medication compliance of a patient is also remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a topical ophthalmic preparation of atropine sulfate for improving myopia and a preparation method thereof. Background Art

[0002] The prevalence of myopia has been increasing year by year. It is estimated that by 2050, 4.758 billion people globally will suffer from myopia, which will affect the visual health of nearly half of the world's population. Against the backdrop of such a high prevalence rate, various complications caused by myopia not only increase the disease burden but also exacerbate the socioeconomic burden. The prevention and treatment of myopia have become a major challenge for health care undertakings in various countries, especially in China, and it is also a key public health issue affecting the eye health of children and adolescents. The overall myopia rate among children and adolescents in China is 51.9%, and the myopia rate among high school students is as high as 81.2%. Therefore, preventing the occurrence of myopia in children and adolescents and delaying the progression of myopia are the top priorities of myopia prevention and control work.

[0003] In order to further improve the standardization level of myopia prevention and control and diagnosis and treatment and promote the development of myopia prevention and control work in China. The guidelines clearly state that low-concentration atropine eye drops are drugs that have been verified by evidence-based medicine to be effective in delaying the progression of myopia. Combining them with specially designed glasses or contact lenses can further enhance the myopia control effect. Among them, 0.01% low-concentration atropine sulfate eye drops were launched on March 5, 2024, for the prevention and control of myopia in children and adolescents.

[0004] Atropine (chemical formula C 17 H 23 NO 3) is a competitive muscarinic receptor (M-receptor) blocker. Its myopia control effect is closely related to the concentration: 1% high-concentration atropine sulfate eye drops have a myopia control effect as high as 60%-96%, but there are serious adverse reactions such as severe photophobia and decreased near vision, and a significant rebound effect may occur after drug withdrawal; while 0.01% low-concentration atropine sulfate eye drops show good effects in delaying myopia progression, with minimal adverse reactions and minimal rebound effect after drug withdrawal. Currently, the research on atropine sulfate eye drops involves multiple concentrations, including 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, and 0.5%. Studies have shown that no retinal function impairment or lens opacity has been found in atropine sulfate eye drops with concentrations of 0.01%, 0.1%, and 0.5%. However, after using atropine sulfate eye drops with concentrations higher than 0.01% and lower than 0.5%, patients may experience significant photophobia (17.8%) and decreased near vision (11.9%), while the adverse reaction rate of 0.01% low-concentration atropine sulfate eye drops is relatively low (6.3%). Based on the above research results, whether it is high concentration or low concentration, long-term use of traditional atropine sulfate eye drop formulations has varying degrees of adverse reactions and side effects, resulting in poor patient compliance and thus affecting the effect of myopia prevention and control.

[0005] In the prior art, atropine sulfate is highly soluble in water and may produce hydrolysis product tropic acid. Therefore, the preparation process of ordinary eye drops is usually used to prepare atropine sulfate eye drops. However, this traditional ophthalmic preparation has common defects: the residence time of the drug in the eye is short, the stability is poor, it is easily diluted by tears, resulting in low bioavailability, long treatment cycle, and high economic cost, bringing certain pressure to patients. Summary of the Invention

[0006] The object of the present invention is to overcome the defects of the prior art and provide a local ophthalmic preparation of atropine sulfate for myopia improvement.

[0007] Another object of the present invention is to provide a preparation method of the above-mentioned local ophthalmic preparation of atropine sulfate for myopia improvement.

[0008] The technical solution of the present invention is as follows:

[0009] A local ophthalmic preparation of atropine sulfate for myopia improvement is made from the following raw material components in mass-volume percentage:

[0010]

[0011] The solvent is injection water;

[0012] Among them, the stabilizer is a temperature-sensitive block polymer material, and the temperature-sensitive block polymer material is selected from at least one of polyethylene glycol-polycaprolactone-polypropylene glycol, polyethylene glycol-polycaprolactone-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly-N,N-diethylacrylamide, and polyethylene glycol-polycaprolactone-poly-N-ethylacrylamide.

[0013] In a preferred embodiment of the present invention, in the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone, and polypropylene glycol is 0.5:1:(0.1-15); in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and N-isopropylacrylamide is 0.1:0.5:(0.5-30); in the polyethylene glycol-polycaprolactone-poly-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N-isopropylacrylamide is 0.2:0.8:(1-10); in the polyethylene glycol-polycaprolactone-poly-N,N-diethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N,N-diethylacrylamide is 0.1:0.5:(0.2-12); in the polyethylene glycol-polycaprolactone-poly-N-ethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N-ethylacrylamide is 2:15:(3-20).

[0014] More preferably, in the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone, and polypropylene glycol is 0.5:1:0.1; in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and N-isopropylacrylamide is 0.1:0.5:0.5; in the polyethylene glycol-polycaprolactone-poly-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N-isopropylacrylamide is 0.2:0.8:1; in the polyethylene glycol-polycaprolactone-poly-N,N-diethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N,N-diethylacrylamide is 0.1:0.5:0.2; in the polyethylene glycol-polycaprolactone-poly-N-ethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone, and poly-N-ethylacrylamide is 2:15:3.

[0015] In a preferred embodiment of the present invention, the thickener is selected from at least one of hydroxypropyl methylcellulose, povidone, sodium hyaluronate, and glycerol; the buffer is selected from at least one of boric acid, citric acid, borax, sodium citrate, and sodium dihydrogen phosphate.

[0016] The preparation method of the above-mentioned myopia-improving atropine sulfate topical ophthalmic preparation comprises the following steps:

[0017] (1) Dissolve the atropine sulfate, mannitol and stabilizer in water for injection, and then perform lyophilization to obtain atropine sulfate lyophilized powder;

[0018] (2) Dissolve the thickener, sodium chloride and buffer in water for injection to prepare an isotonic buffer solution;

[0019] (3) Mix the atropine sulfate lyophilized powder prepared in step (1) and the isotonic buffer solution prepared in step (2) evenly before use to obtain the atropine sulfate topical ophthalmic preparation for myopia improvement.

[0020] Use of a thermosensitive block polymer material in the preparation of an atropine sulfate topical ophthalmic preparation for myopia improvement, wherein the thermosensitive block polymer material is used as a stabilizer and is selected from at least one of polyethylene glycol-polycaprolactone-polypropylene glycol, polyethylene glycol-polycaprolactone-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly-N,N-diethylacrylamide, and polyethylene glycol-polycaprolactone-poly-N-ethylacrylamide.

[0021] In a preferred embodiment of the present invention, in the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:(0.1-15); in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N-isopropylacrylamide is 0.1:0.5:(0.5-30); in the polyethylene glycol-polycaprolactone-poly-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly-N-isopropylacrylamide is 0.2:0.8:(1-10); in the polyethylene glycol-polycaprolactone-poly-N,N-diethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly-N,N-diethylacrylamide is 0.1:0.5:(0.2-12); in the polyethylene glycol-polycaprolactone-poly-N-ethylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly-N-ethylacrylamide is 2:15:(3-20).

[0022] Further preferably, in the polyethylene glycol - polycaprolactone - polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:0.1; in the polyethylene glycol - polycaprolactone - N - isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N - isopropylacrylamide is 0.1:0.5:0.5; in the polyethylene glycol - polycaprolactone - poly(N - isopropylacrylamide), the mass ratio of polyethylene glycol, polycaprolactone and poly(N - isopropylacrylamide) is 0.2:0.8:1; in the polyethylene glycol - polycaprolactone - poly(N,N - diethylacrylamide), the mass ratio of polyethylene glycol, polycaprolactone and poly(N,N - diethylacrylamide) is 0.1:0.5:0.2; in the polyethylene glycol - polycaprolactone - poly(N - ethylacrylamide), the mass ratio of polyethylene glycol, polycaprolactone and poly(N - ethylacrylamide) is 2:15:3.

[0023] In a preferred embodiment of the present invention, the raw materials of the myopia - improving atropine sulfate topical ophthalmic preparation further include atropine sulfate, mannitol, thickening agent, sodium chloride, buffer and injection water.

[0024] Further preferably, the thickening agent is selected from at least one of hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium hyaluronate and glycerol; the buffer is selected from at least one of boric acid, citric acid, borax, sodium citrate and sodium dihydrogen phosphate.

[0025] The beneficial effects of the present invention are as follows:

[0026] 1. The myopia - improving atropine sulfate topical ophthalmic preparation of the present invention optimizes the treatment method for delaying and controlling myopia in children and adolescents in the prior art; among them, the use of the thermosensitive block polymer material significantly improves the stability of atropine sulfate. In addition, the hydrophilic - hydrophobic structure of this material endows atropine sulfate with a sustained - release property, making it have a longer half - life and being able to continuously and effectively release the drug. This not only greatly reduces the administration concentration and frequency, but also significantly improves the patient's medication compliance.

[0027] 2. The thermosensitive block polymer raw materials used in the present invention are inexpensive, the preparation process is relatively simple, the preparation cost is low, it is convenient for industrial production, is conducive to large - scale popularization and application, and promotes the innovation of related technologies.

[0028] 3. The myopia - improving atropine sulfate topical ophthalmic preparation of the present invention overcomes the limitations of the existing ophthalmic preparations, prolongs the residence time of the drug in the eye, improves the bioavailability, reduces the use burden of patients, and enhances the medication compliance.

[0029] 4. The myopia - improving atropine sulfate topical ophthalmic preparation of the present invention has a significant positive effect on delaying and controlling the progression of myopia in children and adolescents. Description of the Drawings

[0030] Figure 1 Show the eutectic point curve of Example 3 of the present invention.

[0031] Figure 2 Show the lyophilization curve of Example 3 of the present invention.

[0032] Figure 3 Show the rheological properties of the lyophilized sample solution of Example 3 of the present invention and the atropine sulfate topical ophthalmic preparations prepared in Examples 7-10.

[0033] Figure 4 Show the rheological properties of the atropine sulfate lyophilized powder prepared in Comparative Example 1 of the present invention for comparison.

[0034] Figure 5 Show the pharmacokinetic results of the lyophilized sample solution of Example 3 of the present invention and the atropine sulfate topical ophthalmic preparation prepared in Example 10 in the rabbit eye retina. Detailed implementation manners

[0035] The technical solutions of the present invention will be further described and illustrated below through specific implementation manners in conjunction with the accompanying drawings.

[0036] Examples 1 to 6

[0037] The formulation compositions (mass / volume fraction) of Examples 1 to 6 are as follows: atropine sulfate 0.05%, stabilizer 5%-20%, mannitol 0.5%, and the solvent is water for injection. Specifically, as shown in Table 1, the unit is mg.

[0038] The preparation method includes: dissolving the formulated amounts of atropine sulfate, stabilizer, and mannitol shown in Table 1 in water for injection, stirring to make it uniformly mixed, and the stirring speed is 600 rpm; then placing it in a freeze dryer for freeze drying for 24 h to obtain atropine sulfate lyophilized powder.

[0039] The component ratios of the stabilizer in the atropine sulfate topical ophthalmic preparation are shown in Table 1, and the unit is mg.

[0040] Table 1

[0041] Component ratio of stabilizer Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Polyethylene glycol 0.5 0.1 0.2 0.1 1 2 Polycaprolactone 1 0.5 0.8 0.5 10 15 Polypropylene glycol 0.1 N-Isopropylacrylamide 0.5 Poly(N-isopropylacrylamide) 1 Poly(N,N-diethylacrylamide) 0.2 Poly(N-ethylacrylamide) 3

[0042] Measure the pH value before lyophilization and evaluate the stability after lyophilization of the materials prepared in Examples 1 to 6.

[0043] (1) Measurement of the pH value of the samples before lyophilization in Examples 1 to 6

[0044] The pH values of the sample solutions (volume: 1 mL) before lyophilization in Examples 1 - 6 were measured using a pH meter. There were almost no differences in the pH values of the sample solutions before lyophilization. See Table 2 for details.

[0045] Table 2

[0046]

[0047]

[0048] (2) Investigation of the stability of the samples after lyophilization in Examples 1 to 6

[0049] Detection method: The samples after lyophilization in Examples 1 to 6 were respectively placed under the conditions of 25 °C and 30 °C. One sample was taken on the 14th day, dissolved with 5 mL of isotonic buffer solution, and used as the test solution; 1 mL was precisely measured, placed in a 100 - mL volumetric flask, diluted to the mark with water, and shaken well to obtain the control solution. 50 μL of each of the above - mentioned solutions was precisely measured and sent into a high - performance liquid chromatography detector for detection, and data was collected.

[0050] Liquid chromatography conditions: C 18 chromatographic column, the mobile phase was phosphate buffer - acetonitrile (45:55), the column temperature was 30 °C, the flow rate was 1.0 mL / min, and the detection wavelength was 220 nm.

[0051] The results are shown in Table 3. After redissolving the sample after lyophilization in Example 3 after 14 days of storage, almost no related substances were detected under the condition of 25 °C.

[0052] Table 3

[0053]

[0054] Therefore, the sample after lyophilization in Example 3 was used as the test article to plot the eutectic point and the lyophilization curve.

[0055] (3) Determination of the eutectic point

[0056] Detection method: The sample solution before lyophilization in Example 3 was placed in a refrigerator at - 20 °C, and the temperature of the liquid medicine was measured with a Beckmann thermometer. It was recorded once every 0.5 min. The plateau period of the temperature - time curve was the eutectic point. The results showed that the eutectic point of the atropine sulfate lyophilized sample was about - 1 °C. See Figure 1 .

[0057] (4) Determination of the lyophilization curve

[0058] Lyophilization process: The sample solution before lyophilization in Example 3 was first placed in a refrigerator at -80°C for 8 hours of pre-freezing, then subjected to reduced-pressure freezing at -35°C for 2 hours and then heated to -25°C for 12 hours of sublimation drying, and then heated to 20°C for 2 hours of desorption drying. The data was recorded and a lyophilization curve was plotted. See Figure 2 .

[0059] Comparative Example 1

[0060] It was basically the same as Example 3, except that the corresponding stabilizer was not added, and atropine sulfate lyophilized powder for comparison was obtained.

[0061] Examples 7 to 10

[0062] Based on the formulation of Example 3, an isotonic buffer solution was prepared and the amount of the stabilizer was optimized. The preparation steps of the isotonic buffer solution were as follows: Sodium hyaluronate, a thickening agent with a formulation amount (mass / volume fraction) of 0.05%, was dissolved in injection water and stirred overnight to completely dissolve it; then sodium chloride with a formulation amount (mass / volume fraction) of 0.05% and borax, a buffer agent with a formulation amount of 1%, were added and stirring was continued for 10 minutes; finally, it was filtered through a 0.22-μm microporous membrane, dispensed, 5 mL per bottle. Then, the atropine sulfate lyophilized powder prepared in Example 3 with different stabilizer contents (corresponding to 5% - 20% of the stabilizer in Examples 1 to 6) corresponding to Examples 7 to 10 was mixed with the above isotonic buffer solution to obtain the atropine sulfate topical ophthalmic preparations of Examples 7 to 10.

[0063] The dosage ratios of the stabilizers in the atropine sulfate topical ophthalmic preparations prepared in Examples 7 to 10 are shown in Table 4.

[0064] Table 4

[0065] Polyethylene glycol-polycaprolactone-poly(N-isopropylacrylamide) Example 7 5％ Example 8 10％ Example 9 15％ Example 10 20％

[0066] The rheological evaluation was carried out on the solution obtained by reconstituting the lyophilized sample in Example 3 with injection water and the atropine sulfate topical ophthalmic preparations of Examples 7 to 10 using a TA Instrument AR 2000ex rheometer.

[0067] The test method was as follows:

[0068] A 20-mm measuring head was selected, the measurement temperature was set from 25°C to 45°C, and the change in shear stress at different shear rates was detected in the Flow mode and a curve was plotted. Compared with the solution obtained by reconstituting the lyophilized powder prepared in Comparative Example 1 with injection water, the solution obtained by reconstituting the lyophilized powder prepared in Example 3 with injection water and the atropine sulfate topical ophthalmic preparations prepared in Examples 7 - 10 all showed a temperature-sensitive gel system, while Comparative Example 1 was not a temperature-sensitive gel system in the temperature range of 25°C to 45°C. See Figure 3 and Figure 4。

[0069] Example 11

[0070] In this example, the lyophilized powder prepared in Example 3 and the lyophilized powder prepared in Comparative Example 1 were selected for preliminary stability characterization:

[0071] (1) High-intensity light irradiation test

[0072] Test method: Take the atropine sulfate lyophilized powder prepared in Example 3 and Comparative Example 1, and place it in a light box with an illuminance of 4500 Lx ± 500 Lx according to the marketed packaging. Samples were taken and measured on the 5th and 10th days of the test respectively.

[0073] (2) High-temperature test

[0074] Test method: Take the atropine sulfate lyophilized powder prepared in Example 3 and Comparative Example 1, and place it in a constant temperature incubator at 40°C ± 2°C and 60°C ± 2°C for 10 days. Samples were taken and detected on the 5th and 10th days of the test respectively, and the results were compared with those on the 0th day.

[0075] The results are shown in Table 5. The content of atropine sulfate in the atropine sulfate lyophilized powder obtained in Example 3 did not change significantly under high-temperature and light conditions, while the content of atropine sulfate in Comparative Example 1 decreased significantly, and the decrease was most significant on the 10th day at high temperature.

[0076] Table 5

[0077]

[0078] Example 12

[0079] In this example, the solution obtained by reconstituting the lyophilized powder prepared in Example 3 with injection water and the atropine sulfate topical ophthalmic preparation prepared in Example 10 were selected for rabbit eye retina pharmacokinetics characterization:

[0080] Test method:

[0081] Healthy rabbits were randomly divided into Group I and Group II by the complete random method. Group I was given the solution obtained by reconstituting the lyophilized powder prepared in Example 3 with injection water, and Group II was given the atropine sulfate topical ophthalmic preparation prepared in Example 10; 30 μL of the drug solution was aspirated with a pipette and injected into the eye, and both the left and right eyes were administered. At 5, 15, 30, and 60 min; 2, 4, 8, 12, 24, 36, and 48 h after administration; on the 4th day (72 h), 5th day (96 h), 6th day (120 h), and 7th day (144 h), the rabbits were sacrificed by injecting 10 mL of air into the marginal ear vein, and the retina samples were immediately collected and placed in a pre-weighed EP tube. After accurately weighing, the samples were placed in a -20°C refrigerator for frozen storage; the remaining 16 non-administered rabbits were used as blank retina samples.

[0082] Chromatographic and mass spectrometric conditions:

[0083] Chromatographic conditions: Mobile phase: methanol: 50 mmol·L -1 Ammonium acetate aqueous solution (60:40), flow rate 0.2 mL·min-1, column temperature 40 °C;

[0084] Chromatographic column: C 18 Chromatographic column (2.1×50 mm, 1.7 μm)

[0085] Mass spectrometric conditions: Ion source: electrospray ionization source (ESI source); Detection mode: positive ion detection; Scanning mode: MRM; Capillary voltage: 3.0 KV; Cone voltage: 50 V.

[0086] The results show that the drug concentration in the retina after a single administration of the freeze-dried powder prepared in Example 3 and the atropine sulfate topical ophthalmic preparation prepared in Example 10 can be maintained for at least 48 h or more. For the detailed results, see Figure 5 .

[0087] The above are only the preferred embodiments of the present invention, and thus the scope of implementation of the present invention cannot be limited thereby. That is, equivalent changes and modifications made according to the scope of the present invention patent and the content of the specification should still fall within the scope covered by the present invention.

Claims

1. A topical ophthalmic preparation of atropine sulfate for improving myopia, characterized in that: Made from the following raw material components in mass volume percentage: The solvent is water for injection; Among them, the stabilizer is a temperature-sensitive block polymer material, and the temperature-sensitive block polymer material is selected from at least one of polyethylene glycol-polycaprolactone-polypropylene glycol, polyethylene glycol-polycaprolactone-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly N,N-diethylacrylamide and polyethylene glycol-polycaprolactone-poly N-ethylacrylamide.

2. A topical ophthalmic preparation of atropine sulfate for improving myopia according to claim 1, characterized in that: In the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:(0.1-15); in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N-isopropylacrylamide is 0.1:0.5:(0.5-30); in the polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-isopropylacrylamide is 0.1:0.5:(0.5-30). The mass ratio of propyl acrylamide is 0.2:0.8:(1-10); in the polyethylene glycol-polycaprolactone-poly N,N-diethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N,N-diethyl acrylamide is 0.1:0.5:(0.2-12); in the polyethylene glycol-polycaprolactone-poly N-ethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-ethyl acrylamide is 2:15:(3-20).

3. A topical ophthalmic preparation of atropine sulfate for improving myopia as claimed in claim 2, characterized in that: In the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:0.1; in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N-isopropylacrylamide is 0.1:0.5:0.5; in the polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N -isopropyl acrylamide has a mass ratio of 0.2:0.8:1; in the polyethylene glycol-polycaprolactone-poly N,N-diethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N,N-diethyl acrylamide is 0.1:0.5:0.2; in the polyethylene glycol-polycaprolactone-poly N-ethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-ethyl acrylamide is 2:15:

3.

4. A myopia-improving atropine sulfate topical ophthalmic preparation according to any one of claims 1 to 3, characterized in that: The thickener is selected from at least one of hydroxypropyl methylcellulose, povidone, sodium hyaluronate and glycerol; the buffer is selected from at least one of boric acid, citric acid, borax, sodium citrate and sodium dihydrogen phosphate.

5. The method for preparing the topical ophthalmic preparation of atropine sulfate for improving myopia according to any one of claims 1 to 4, characterized in that: The steps include: (1) dissolving the atropine sulfate, mannitol and stabilizer in water for injection, and then freeze-drying to obtain atropine sulfate freeze-dried powder; (2) dissolving the thickener, sodium chloride and buffer in water for injection to prepare an isotonic buffer solution; (3) Before use, the atropine sulfate lyophilized powder prepared in step (1) and the isotonic buffer solution prepared in step (2) are mixed evenly to obtain the myopia-improving atropine sulfate topical ophthalmic preparation.

6. Use of a thermosensitive block polymer material in the preparation of a topical ophthalmic preparation for improving myopia with atropine sulfate, characterized in that: The temperature-sensitive block polymer material is used as a stabilizer and is selected from at least one of polyethylene glycol-polycaprolactone-polypropylene glycol, polyethylene glycol-polycaprolactone-N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, polyethylene glycol-polycaprolactone-poly N,N-diethylacrylamide and polyethylene glycol-polycaprolactone-poly N-ethylacrylamide.

7. The use according to claim 6, characterized in that: In the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:(0.1-15); in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N-isopropylacrylamide is 0.1:0.5:(0.5-30); in the polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-isopropylacrylamide is 0.1:0.5:(0.5-30). The mass ratio of propyl acrylamide is 0.2:0.8:(1-10); in the polyethylene glycol-polycaprolactone-poly N,N-diethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N,N-diethyl acrylamide is 0.1:0.5:(0.2-12); in the polyethylene glycol-polycaprolactone-poly N-ethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-ethyl acrylamide is 2:15:(3-20).

8. The use according to claim 7, characterized in that: In the polyethylene glycol-polycaprolactone-polypropylene glycol, the mass ratio of polyethylene glycol, polycaprolactone and polypropylene glycol is 0.5:1:0.1; in the polyethylene glycol-polycaprolactone-N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and N-isopropylacrylamide is 0.1:0.5:0.5; in the polyethylene glycol-polycaprolactone-poly N-isopropylacrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N -isopropyl acrylamide has a mass ratio of 0.2:0.8:1; in the polyethylene glycol-polycaprolactone-poly N,N-diethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N,N-diethyl acrylamide is 0.1:0.5:0.2; in the polyethylene glycol-polycaprolactone-poly N-ethyl acrylamide, the mass ratio of polyethylene glycol, polycaprolactone and poly N-ethyl acrylamide is 2:15:

3.

9. The use according to any one of claims 6 to 7, characterized in that: The raw materials of the myopia-improving atropine sulfate topical ophthalmic preparation also include atropine sulfate, mannitol, a thickener, sodium chloride, a buffer and water for injection.

10. The use according to claim 9, characterized in that: The thickener is selected from at least one of hydroxypropyl methylcellulose, povidone, sodium hyaluronate and glycerol; the buffer is selected from at least one of boric acid, citric acid, borax, sodium citrate and sodium dihydrogen phosphate.

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