Litamilast eye drops and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a litamilast eye drop and a preparation method thereof. The invention relates to a litamilast eye drop, which is prepared from the following raw materials in parts by weight: 3.5 to 4.5 parts of litamilast, 2 to 4 parts of poloxamer 407, 0.5 to 1.0 part of adhesive, 0.1 to 0.2 part of humectant, 1 to 3 parts of stabilizer, 2 to 4 parts of lipid carrier and 83.3 to 90.9 parts of water for injection, the lipid carrier is prepared from the following raw materials: a matrix, liquid fat, litamilast, vitamin E, sodium hyaluronate and trehalose. According to the present invention, the lidinafost is dissolved in the poloxamer 407, and is instantly gelled after the lidinafost is dropped into the conjunctival sac so as to resist the tear dilution; lipimilast in the lipid carrier slowly releases medicine through a corneal epithelial cell lipid channel, and then the slow release effect of the lipimilast is prolonged through cooperation of the adhesive.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical preparations, and in particular to a ristatin eye drop and a method for preparing the same. Background Technology

[0002] Rittal is a novel small molecule integrin inhibitor that antagonizes lymphocyte function-associated antigen-1 (LFA-1) and blocks its interaction with its homologous ligand intercellular adhesion molecule-1 (ICAM-1), interfering with the overexpression of ICAM-1 in the corneal and conjunctival tissues that cause dry eye disease. It is the first drug to treat the symptoms and signs of dry eye.

[0003] When listatin is formulated into eye drops, it is generally prepared as a solution due to its good water solubility. However, due to eyelid blinking and tear secretion, it can be diluted into a low concentration of the drug within minutes, requiring more frequent administration to improve the therapeutic effect. Therefore, ordinary listatin eye drops require frequent administration in clinical practice. At the same time, the fluctuation of local drug concentration in the eye caused by multiple administrations will affect the treatment effect of dry eye syndrome, resulting in a prolonged treatment time. In addition, multiple daily administrations can easily lead to missed medications by patients, resulting in poor clinical compliance. Summary of the Invention

[0004] To prolong the sustained-release effect of ristatin, this application provides a ristatin eye drop and a method for preparing the same.

[0005] In the first aspect, the listatin eye drops provided in this application adopt the following technical solution: A listatin eye drop, wherein the raw materials of the eye drop comprise the following components in parts by weight: listatin 3.5-4.5 parts, poloxamer 407 2-4 parts, adhesive 0.5-1.0 parts, moisturizer 0.1-0.2 parts, stabilizer 1-3 parts, lipid carrier 2-4 parts, and water for injection 83.3-90.9 parts; wherein the raw materials of the lipid carrier include matrix, liquid lipid, listatin, vitamin E, sodium hyaluronate, and trehalose.

[0006] By adopting the above technical solution, ristatin dissolves in poloxamer 407 and gels instantly after being instilled into the conjunctival sac, resisting tear dilution; ristatin in the lipid carrier slowly releases the drug through the lipid channels of corneal epithelial cells, and with the help of an adhesive, the sustained-release effect of ristatin is prolonged.

[0007] In one specific implementation, the method for preparing the lipid carrier includes the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristat are heated and mixed to obtain molten lipids; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate, and the mixture was heated and stirred to obtain the aqueous phase; Colostrum preparation: Molten lipids were added to the aqueous phase and homogenized to obtain the colostrum; Crystallization and drying: The colostrum is cooled and crystallized to obtain primary particles, then trehalose is added and freeze-dried to obtain the lipid carrier.

[0008] By adopting the above technical solution, the matrix, liquid lipid, and ristat are first heated and mixed to obtain molten lipid. Then, an aqueous phase is prepared, and the molten lipid is added to the aqueous phase and homogenized to obtain a colostrum. Finally, the colostrum is cooled and crystallized, trehalose is added, and the mixture is freeze-dried to obtain a lipid carrier.

[0009] In one specific implementation scheme, the weight ratio of the matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection is (4-5):(1-2):(0.4-0.6):(0.7-0.9):0.1:2:100.

[0010] In one specific implementation, the cooling crystallization temperature in the crystallization drying step is 3-5℃; the freeze-drying step involves first drying at -40℃ to -10℃ for 24-26 hours, followed by drying at 25℃ to 35℃ for 8-12 hours.

[0011] By adopting the above technical solution, the ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection, as well as the cooling crystallization temperature and freeze-drying conditions, were further defined, thereby improving the quality of the lipid carrier obtained.

[0012] In one specific embodiment, the adhesive comprises a mixture of succinyl chitosan and chitosan quaternary ammonium salt.

[0013] By adopting the above technical solution, succinyl chitosan binds to negatively charged mucins on the ocular surface, prolonging the retention time, and chitosan quaternary ammonium salt binds to the negatively charged cornea, prolonging the retention time, thereby extending the sustained-release effect of ristatin.

[0014] In one specific implementation, the moisturizer comprises sodium hyaluronate.

[0015] By adopting the above technical solution, sodium hyaluronate can not only moisturize, but also electrostatically crosslink with chitosan quaternary ammonium salt to form a gel network, thus synergistically releasing the hyaluronic acid.

[0016] In one specific implementation, the stabilizer comprises trehalose.

[0017] By adopting the above technical solutions, trehalose protects the corneal epithelium, reduces irritation, and enhances the stability of the formula.

[0018] Firstly, this application provides a method for preparing listatin eye drops, which adopts the following technical solution: A method for preparing ristatin eye drops includes the following steps: Poloxamer 407 was dissolved in a portion of water for injection at 4°C and stirred for 24 hours until clear. Then, an adhesive, humectant, and stabilizer were added and stirred to dissolve. Ritasul was then added, ultrasonically dispersed, and the pH was adjusted to 7.4 with an adjuster. Finally, a lipid carrier was added, magnetically stirred, and the remaining water for injection was added. The mixture was stirred, filtered, and sterilized to obtain ritasul eye drops.

[0019] By adopting the above technical solution, poloxamer 407 is first dissolved in a portion of water for injection at 4°C, then an adhesive, humectant, and stabilizer are added, followed by the addition of listatin, ultrasonic dispersion, pH adjustment, and finally the addition of a lipid carrier. The mixture is then magnetically stirred, the remaining water for injection is added, stirred, filtered, and sterilized to obtain listatin eye drops with good sustained-release effect.

[0020] In summary, this application includes at least one of the following beneficial technical effects: 1. In this application, ritalofi is dissolved in poloxamer 407 and gels instantly after being instilled into the conjunctival sac, resisting tear dilution; ritalofi in the lipid carrier slowly releases the drug through lipid channels of corneal epithelial cells, and with the help of an adhesive, the sustained-release effect of ritalofi is prolonged. 2. In this application, the matrix, liquid lipid, and ristat are first heated and mixed to obtain molten lipid. Then, an aqueous phase is prepared, and the molten lipid is added to the aqueous phase and homogenized to obtain a colostrum. Finally, the colostrum is cooled and crystallized, trehalose is added, and the mixture is freeze-dried to obtain a lipid carrier. 3. The method in this application involves first dissolving poloxamer 407 in a portion of water for injection at 4°C, then adding an adhesive, a moisturizer, and a stabilizer, followed by the addition of listatin, ultrasonic dispersion, pH adjustment, and finally the addition of a lipid carrier, magnetic stirring, the addition of the remaining water for injection, stirring, filtration, and sterilization to obtain listatin eye drops with good sustained-release effect. Detailed Implementation

[0021] The present application will be further described in detail below with reference to the embodiments.

[0022] All raw materials used in the examples were commercially available. Chitosan quaternary ammonium salt was provided by Nanjing Bermuda Biotechnology Co., Ltd.; the matrix was Precirol ATO 5 lipid; and vitamin E was TPGS.

[0023] Preparation Example Preparation Example 1 Preparation Example 1 provides a method for preparing a lipid carrier, comprising the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristatin were mixed by heating at 75°C to obtain molten lipids; wherein the liquid lipid was caprylic / capric triglyceride; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate. The mixture was heated and stirred at 75°C to obtain the aqueous phase. Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum was cooled and crystallized at 3°C ​​to obtain primary particles with a particle size of 70-90nm. Then, trehalose was added, and the mixture was dried at -40°C for 24h and then at 25°C for 12h to obtain the lipid carrier. The weight ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection was 4:1:0.4:0.7:0.1:2:100.

[0024] Preparation Example 2 Preparation Example 2 provides a method for preparing a lipid carrier, comprising the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristatin were mixed by heating at 75°C to obtain molten lipids; wherein the liquid lipid was caprylic / capric triglyceride; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate. The mixture was heated and stirred at 75°C to obtain the aqueous phase. Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum was cooled and crystallized at 3°C ​​to obtain primary particles with a particle size of 70-90nm. Then, trehalose was added, and the mixture was dried at -40°C for 24h and then at 25°C for 12h to obtain the lipid carrier. The weight ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection was 4.5:1.5:0.5:0.8:0.1:2:100.

[0025] Preparation Example 3 Preparation Example 3 provides a method for preparing a lipid carrier, comprising the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristatin were mixed by heating at 75°C to obtain molten lipids; wherein the liquid lipid was caprylic / capric triglyceride; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate. The mixture was heated and stirred at 75°C to obtain the aqueous phase. Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum was cooled and crystallized at 3°C ​​to obtain primary particles with a particle size of 70-90nm. Then, trehalose was added, and the mixture was dried at -40°C for 24h and then at 25°C for 12h to obtain the lipid carrier. The weight ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection was 5:2:0.6:0.9:0.1:2:100.

[0026] Preparation Example 4 Preparation Example 4 provides a method for preparing a lipid carrier, comprising the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristatin were mixed by heating at 75°C to obtain molten lipids; wherein the liquid lipid was caprylic / capric triglyceride; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate. The mixture was heated and stirred at 75°C to obtain the aqueous phase. Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum was cooled and crystallized at 4°C to obtain primary particles with a particle size of 70-90nm. Then, trehalose was added, and the mixture was dried at -25°C for 25h, followed by drying at 30°C for 10h to obtain the lipid carrier. The weight ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection was 4.5:1.5:0.5:0.8:0.1:2:100.

[0027] Preparation Example 5 Preparation Example 5 provides a method for preparing a lipid carrier, comprising the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristatin were mixed by heating at 75°C to obtain molten lipids; wherein the liquid lipid was caprylic / capric triglyceride; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate. The mixture was heated and stirred at 75°C to obtain the aqueous phase. Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum was cooled and crystallized at 5°C to obtain primary particles with a particle size of 70-90nm. Then, trehalose was added, and the mixture was dried at -10°C for 26 hours, followed by drying at 35°C for 8 hours to obtain the lipid carrier. The weight ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection was 4.5:1.5:0.5:0.8:0.1:2:100. Example

[0028] Example 1 Example 1 provides a method for preparing listatin eye drops, comprising the following steps: Dissolve 2g of poloxamer 407 in 45.45g of water for injection at 4°C and stir for 24h until clear. Then add 0.5g of binder, 0.1g of humectant, and 1g of stabilizer and stir to dissolve. Then add 3.5g of listatin and sonicate at 200W for 10min. Adjust the pH to 7.4 with a regulator. Finally, add 2g of the lipid carrier from Preparation Example 1 and stir magnetically at 4°C for 2h. Add 45.45g of water for injection, stir, filter through a 0.22μm PES membrane, and sterilize to obtain listatin eye drops. The binder is a mixture of succinyl chitosan and chitosan quaternary ammonium salt, with a weight ratio of 2:1. The humectant is sodium hyaluronate. The stabilizer is trehalose. The regulator is 0.1mol / L sodium hydroxide solution or 0.1mol / L hydrochloric acid solution.

[0029] Example 2 Example 2 provides a method for preparing listatin eye drops, comprising the following steps: Dissolve 3g of poloxamer 407 in 43.55g of water for injection at 4°C and stir for 24h until clear. Then add 0.75g of binder, 0.15g of humectant, and 2g of stabilizer, and stir to dissolve. Then add 4g of listatin and sonicate at 200W for 10min. Adjust the pH to 7.4 with a regulator. Finally, add 3g of the lipid carrier from Preparation Example 1, stir magnetically at 4°C for 2h, add 43.55g of water for injection, stir, filter through a 0.22μm PES membrane, and sterilize to obtain listatin eye drops. The binder is a mixture of succinyl chitosan and chitosan quaternary ammonium salt, with a weight ratio of 2:1. The humectant is sodium hyaluronate. The stabilizer is trehalose. The regulator is 0.1mol / L sodium hydroxide solution or 0.1mol / L hydrochloric acid solution.

[0030] Example 3 Example 3 provides a method for preparing listatin eye drops, comprising the following steps: 4g of poloxamer 407 was dissolved in 41.65g of water for injection at 4°C and stirred for 24 hours until clear. Then, 1g of binder, 0.2g of humectant, and 3g of stabilizer were added and stirred to dissolve. Next, 4.5g of listatin was added and ultrasonically dispersed at 200W for 10 minutes. The pH was adjusted to 7.4 with a regulator. Finally, 4g of the lipid carrier from Preparation Example 1 was added and magnetically stirred at 4°C for 2 hours. 41.65g of water for injection was added and stirred. The solution was filtered through a 0.22μm PES membrane and sterilized to obtain listatin eye drops. The binder was a mixture of succinyl chitosan and chitosan quaternary ammonium salt, with a weight ratio of 2:1. The humectant was sodium hyaluronate. The stabilizer was trehalose. The regulator was a 0.1mol / L sodium hydroxide solution or a 0.1mol / L hydrochloric acid solution.

[0031] Example 4 The difference between Example 4 and Example 2 is that 3g of poloxamer 407 was dissolved in 43.55g of water for injection at 4°C and stirred for 24 hours until clear; then 0.75g of binder, 0.15g of humectant, and 2g of stabilizer were added and stirred to dissolve; then 4g of ritaloflavone was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 3g of the lipid carrier from Preparation Example 2 was added, and the mixture was magnetically stirred at 4°C for 2 hours, then 43.55g of water for injection was added, stirred, filtered through a 0.22μm PES membrane, and sterilized to obtain ritaloflavone eye drops; the remaining steps were the same as in Example 2.

[0032] Example 5 The difference between Example 5 and Example 2 is that 3g of poloxamer 407 was dissolved in 43.55g of water for injection at 4°C and stirred for 24 hours until clear; then 0.75g of binder, 0.15g of humectant, and 2g of stabilizer were added and stirred to dissolve; then 4g of listatin was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 3g of the lipid carrier from Preparation Example 3 was added, and the mixture was magnetically stirred at 4°C for 2 hours, then 43.55g of water for injection was added, stirred, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 2.

[0033] Example 6 The difference between Example 6 and Example 2 is that 3g of poloxamer 407 was dissolved in 43.55g of water for injection at 4°C and stirred for 24 hours until clear; then 0.75g of binder, 0.15g of humectant, and 2g of stabilizer were added and stirred to dissolve; then 4g of listatin was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 3g of the lipid carrier from Preparation Example 4 was added, and the mixture was magnetically stirred at 4°C for 2 hours, then 43.55g of water for injection was added, stirred, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 2.

[0034] Example 7 The difference between Example 7 and Example 2 is that 3g of poloxamer 407 was dissolved in 43.55g of water for injection at 4°C and stirred for 24 hours until clear; then 0.75g of binder, 0.15g of humectant, and 2g of stabilizer were added and stirred to dissolve; then 4g of listatin was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 3g of the lipid carrier from Preparation Example 5 was added, and the mixture was magnetically stirred at 4°C for 2 hours, then 43.55g of water for injection was added, stirred, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 2.

[0035] Example 8 The difference between Example 8 and Example 6 is that the adhesive is succinyl chitosan; the remaining steps are the same as in Example 6.

[0036] Example 9 The difference between Example 9 and Example 6 is that the adhesive is chitosan quaternary ammonium salt; the remaining steps are the same as in Example 6.

[0037] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that 0.5g of binder, 0.1g of humectant, and 1g of stabilizer were added to 45.45g of water for injection and stirred to dissolve; then 3.5g of listatin was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 49.45g of water for injection was added, magnetically stirred for 2 hours, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 1.

[0038] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that 0.5g of adhesive, 0.1g of moisturizer, and 1g of stabilizer were added to 45.45g of water for injection and stirred to dissolve; then 3.5g of listatin was added and ultrasonically dispersed at 200W for 10min, and the pH was adjusted to 7.4 with a regulator; finally, 2g of the lipid carrier from Preparation Example 1 was added, and the mixture was magnetically stirred at 4°C for 2h, then 47.45g of water for injection was added, stirred, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 1.

[0039] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that 2g of poloxamer 407 was dissolved in 45.45g of water for injection at 4°C and stirred for 24 hours until clear; then 0.5g of binder, 0.1g of humectant, and 1g of stabilizer were added and stirred to dissolve; then 3.5g of listatin was added and ultrasonically dispersed at 200W for 10 minutes, and the pH was adjusted to 7.4 with a regulator; finally, 47.45g of water for injection was added, magnetically stirred for 2 hours, filtered through a 0.22μm PES membrane, and sterilized to obtain listatin eye drops; the remaining steps were the same as in Example 1.

[0040] Performance testing In vitro release experiment: The second method of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2020 edition was adopted. The products of Examples 1-9 and Comparative Examples 1-3 were placed in dialysis bags for in vitro release experiments. The dissolution medium was artificial tears (sodium chloride 0.67%, sodium bicarbonate 0.2%, calcium chloride dihydrate 0.008%). The medium volume was 250 mL, the medium temperature was 37 ± 0.5 °C, the sampling volume was 3 mL, and the apparatus was a modified small cup method with a rotation speed of 150 rpm. The release rates at cumulative release times of 15 min, 90 min, and 300 min in artificial tears were obtained.

[0041] Table 1. Performance test results of eye drops Combining Example 1 and Comparative Examples 1-3, the sustained-release effect of ristatin in the eye drops of Example 1 was the best. It can be seen that when preparing ristatin eye drops, poloxamer 407 and a lipid carrier were added to the raw materials. Ristatin dissolved in poloxamer 407 and gelled instantly after being instilled into the conjunctival sac, resisting tear dilution. Ristatin in the lipid carrier slowly released the drug through the lipid channels of corneal epithelial cells, and with the help of the adhesive, the sustained-release effect of ristatin was prolonged.

[0042] Based on Examples 1-3, it can be seen that when preparing ritaloflavone eye drops, following the raw material ratios in Examples 1-3 results in a better sustained-release effect.

[0043] Combining Examples 2, 4, and 5, the sustained-release effect of ristatin in the eye drops in Example 4 was the best. It can be seen that when preparing lipid carriers, the ratio of matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection in Preparation Example 2 was the best, resulting in a better lipid carrier effect.

[0044] Combining Examples 4, 6 and 7, the sustained-release effect of ristatin in the eye drops in Example 6 was the best. It can be seen that the preparation conditions in Example 4 were the best when preparing the lipid carrier, thus obtaining a better lipid carrier effect.

[0045] Combining Examples 6, 8, and 9, Example 6 showed the best sustained-release effect of ristatin in the eye drops. This indicates that when preparing ristatin eye drops, the preferred adhesive is a mixture of succinyl chitosan and chitosan quaternary ammonium salt, which results in a better sustained-release effect of ristatin in the eye drops.

[0046] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A listatin eye drop, characterized in that: The raw materials of the eye drops include the following components in parts by weight: 3.5-4.5 parts of listatin, 2-4 parts of poloxamer 407, 0.5-1.0 parts of adhesive, 0.1-0.2 parts of moisturizer, 1-3 parts of stabilizer, 2-4 parts of lipid carrier, and 83.3-90.9 parts of water for injection; the raw materials of the lipid carrier include matrix, liquid lipid, listatin, vitamin E, sodium hyaluronate, and trehalose.

2. The listatin eye drops according to claim 1, characterized in that: The preparation method of the lipid carrier includes the following steps: Preparation of molten lipids: The matrix, liquid lipid, and ristat are heated and mixed to obtain molten lipids; Aqueous phase preparation: Vitamin E was added to water for injection, followed by sodium hyaluronate, and the mixture was heated and stirred to obtain the aqueous phase; Colostrum preparation: Molten lipids are added to the aqueous phase and homogenized to obtain colostrum; Crystallization and drying: The colostrum is cooled and crystallized to obtain primary particles, then trehalose is added and freeze-dried to obtain the lipid carrier.

3. The listatin eye drops according to claim 2, characterized in that: The weight ratio of the matrix, liquid lipid, ristatin, vitamin E, sodium hyaluronate, trehalose, and water for injection is (4-5):(1-2):(0.4-0.6):(0.7-0.9):0.1:2:

100.

4. The listatin eye drops according to claim 2, characterized in that: In the crystallization drying step, the cooling crystallization temperature is 3-5℃; the freeze-drying step involves first drying at -40℃ to -10℃ for 24-26 hours, followed by drying at 25℃ to 35℃ for 8-12 hours.

5. The listatin eye drops according to claim 1, characterized in that: The adhesive comprises a mixture of succinyl chitosan and chitosan quaternary ammonium salt.

6. The listatin eye drops according to claim 1, characterized in that: The moisturizer includes sodium hyaluronate.

7. The listatin eye drops according to claim 1, characterized in that: The stabilizer includes trehalose.

8. A method for preparing listatin eye drops as described in any one of claims 1-7, characterized in that: Includes the following steps: Poloxamer 407 was dissolved in a portion of water for injection at 4°C and stirred for 24 hours until clear. Then, an adhesive, humectant, and stabilizer were added and stirred to dissolve. Ritasul was then added, ultrasonically dispersed, and the pH was adjusted to 7.4 with an adjuster. Finally, a lipid carrier was added, magnetically stirred, and the remaining water for injection was added. The mixture was stirred, filtered, and sterilized to obtain ritasul eye drops.

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