A flexible nano-lipid formulation of lipoic acid for presbyopia improvement and a preparation method thereof

Abstract

The present application relates to the technical field of medicine, in particular to a flexible lipoic acid nano ophthalmic preparation for improving presbyopia, the flexible lipoic acid nano ophthalmic preparation contains a substance with a core-shell structure, the shell layer of the substance covers the core layer, the core layer is lipoic acid nano liposome, and the shell layer is dendritic PAMAM; the flexible lipoic acid nano ophthalmic preparation includes the following 100% by weight of raw materials: 0.5-2.5% of lipoic acid, 1-6% of soybean phospholipid, 0.1-0.7% of cholesterol, 0.2-0.6% of dendritic PAMAM, 0.1-0.4% of chitosan mixture, 1-3% of isotonicity regulator, 0.1-0.3% of softener, and the balance is water for injection, and further includes a non-ionic pH regulator to adjust the pH value of the preparation to 6.0-7.5. The preparation has superior corneal permeability, cell compatibility and biodegradability, and has a long drug release time.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a flexible thioctic acid nano-ophthalmic formulation for improving presbyopia and its preparation method. Background Technology

[0002] As we age, the eye's accommodative ability gradually decreases due to the decline in the lens's ability to deform, naturally leading to a decline in near vision, a condition known as presbyopia. Presbyopia severely impairs near vision, often requiring the use of magnifying glasses or reading glasses; otherwise, it's impossible to see small print or close-up objects clearly. Therefore, how to safely and effectively improve the vision of presbyopic individuals has become a hot topic in ophthalmology. Currently, in addition to common methods like wearing reading glasses and contact lenses, presbyopia can also be corrected through surgery (such as corneal inlay implantation, multifocal intraocular lens implantation, or corneal refractive surgery). However, surgery is invasive and expensive, limiting its availability, while eyeglasses are not particularly convenient. Therefore, there is a need to find a simple, effective, safe, and economical method to improve presbyopia symptoms.

[0003] Presbyopia is caused by degenerative changes in the lens of the human eye as we age, including decreased lens elasticity and changes in lens size and shape. The increased formation of disulfide bonds between lens proteins with age is considered one of the main reasons for the decreased lens elasticity. Current technologies treat presbyopia with eye drops, but conventional eye drops and ophthalmic gels have drawbacks such as low bioavailability, frequent administration, and inaccurate dosage. Summary of the Invention

[0004] To address the technical problems of low bioavailability, frequent administration, and inaccurate dosage in existing eye drops, this invention provides a flexible lipoic acid nanoparticle ophthalmic formulation for improving presbyopia and its preparation method. This invention utilizes the therapeutic efficacy of lipoic acid in presbyopia and creatively employs a dendritic PAMAM-coated nanoliposome preparation technology to develop a lipoic acid-based nanoliposome ophthalmic formulation. The nanoliposome has a chitosan granulation inner layer and a dendritic PAMAM coating outer layer. The combined effect of these two components exhibits superior corneal permeability, cell compatibility, and biodegradability, allowing lipoic acid molecules to directly act on the lens to produce a therapeutic effect with a long release time.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0006] A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia, the flexible lipoic acid nano-ophthalmic formulation is a semi-solid formulation containing a core-shell structured substance, wherein the shell layer of the substance encapsulates the core layer, the core layer is a lipoic acid nanoliposome, and the shell layer is a dendritic PAMAM.

[0007] The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: lipoic acid 0.5-2.5%, soybean lecithin 1-6%, cholesterol 0.1-0.7%, dendritic PAMAM 0.2-0.6%, chitosan mixture 0.1-0.4%, isotonicity adjuster 1-3%, softener 0.1-0.3%, with the balance being water for injection. It also includes a non-ionic pH adjuster to adjust the pH of the formulation to 6.0-7.5.

[0008] Preferably, the flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: lipoic acid 0.8-2%, soybean lecithin 3%, cholesterol 0.4%, dendritic PAMAM 0.4%, chitosan 0.2%, isotonic adjuster 2-3%, softener 0.15-0.3%, and the balance being water for injection. It also includes a non-ionic pH adjuster to adjust the pH of the formulation to 6.0-7.5.

[0009] Further, the chitosan mixture is a mixture of chitosan and ethylene glycol chitosan in a mass ratio of 1:2-10; the dendritic PAMAM is an amino-terminated cationic PAMAM, including one or more of PAMAM G2-NH2, PAMAM G3-NH2, PAMAM G4-NH2, PAMAM G5-NH2, PAMAM G6-NH2, PAMAM G7-NH2, and PAMAM G8-NH2.

[0010] Furthermore, the isotonic regulator is mannitol; the softener is one or more of sodium deoxycholate, sodium cholate, and propylene glycol; and the nonionic pH regulator is tris(hydroxymethyl)aminomethane.

[0011] The preparation method of the above-mentioned flexible lipoic acid nano-ophthalmic formulation for improving presbyopia includes the following steps:

[0012] (1) Take the formula amount of soybean lecithin, cholesterol and lipoic acid, add them to chloroform in sequence and stir evenly. Evaporate under heating and reduced pressure to obtain lipid film.

[0013] (2) Take the formula amount of chitosan, isotonic regulator and softener and dissolve them in a portion of water for injection, stir evenly to obtain an aqueous solution;

[0014] (3) The aqueous solution is added dropwise to the lipid film and stirred to obtain a primary emulsion. The primary emulsion is then ultrasonically dispersed to obtain a solution containing lipoic acid nanoliposomes.

[0015] (4) Dissolve the formulated amount of dendritic PAMAM in a portion of water for injection to obtain a coating solution. Add the coating solution dropwise to the solution containing lipoic acid nanoliposomes. Add a non-ionic pH adjuster to adjust the pH of the system to 6.0-7.5. Then add the remaining water for injection. Stir magnetically at room temperature to obtain a flexible lipoic acid nano-ophthalmic preparation for improving presbyopia.

[0016] Furthermore, the heating conditions in step 1 are 35-45℃, using a constant temperature water bath, and the pressure reduction conditions are 0.04-0.06MPa.

[0017] Furthermore, the total mass concentration of the material in the aqueous solution in step 2 is at least 30%; the ultrasonic dispersion time in step 3 is 10-60 min; and the constant temperature magnetic stirring time in step 4 is 3-5 h.

[0018] Furthermore, the entire preparation process is carried out under sterile conditions.

[0019] Beneficial technical effects:

[0020] The active ingredient in the ophthalmic preparation for improving presbyopia in this invention is lipoic acid. After being absorbed by the long fiber cells of the lens, it can repair the fluid function of the long fiber cells of the lens, restore near vision, and reduce the core lens cytoplasmic modulus affected by disulfide cross-linking, thereby allowing the lens to restore better elasticity. This, in turn, enables the lens to have a higher deformation capacity during the eye's accommodation process, improves the dynamic refractive power of the user's lens, and achieves the purpose of treating presbyopia.

[0021] Because lipoic acid alone has insufficient permeability, considering its high lipid solubility, it is formulated into liposomes. These liposomes contain chitosan, which can be coated with terminal amino-cationic dendritic PAMAM to obtain a formulation. The combined use of chitosan and PAMAM can increase the permeability of the drug in the eye, increase the drug concentration, prolong the sustained-release effect, and improve bioavailability.

[0022] The formulation of this invention contains lipoic acid liposomes, which are chitosan-coated lipoic acid structures with a PAMAM coating on the outer layer. The combined effect of these two structures provides superior corneal permeability, cell compatibility, and biodegradability, allowing lipoic acid molecules to act directly on the lens to produce a therapeutic effect. The drug release time is long, reducing the dosing frequency from twice a day to once a day. The therapeutic effect is superior to that of ordinary formulations, with a smaller dosage and better long-term patient compliance. Attached Figure Description

[0023] Figure 1 The graphs show the penetration and accumulation of ophthalmic formulations from Example 1 and Comparative Example 1 onto isolated corneas. Detailed Implementation

[0024] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0025] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0026] Experimental methods not specified in the following examples are generally determined according to national standards; if there are no corresponding national standards, they are conducted according to general international standards or the standard requirements proposed by relevant enterprises.

[0027] Example 1

[0028] A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia, the flexible lipoic acid nano-ophthalmic formulation containing a core-shell structured substance, wherein the shell layer of the substance encapsulates the core layer, the core layer is a lipoic acid nanoliposome, and the shell layer is a dendritic PAMAM.

[0029] The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: 1% lipoic acid, 3% soybean lecithin, 0.4% cholesterol, 0.4% dendritic PAMAM (Sigmar-Aldrich, product number 536741, molecular weight 233373.9, PAMAM G8-NH2), 0.2% chitosan mixture (a mixture of chitosan and ethylene glycol chitosan at a mass ratio of 1:5), 2% isotonicity adjuster - mannitol, 0.1% softener - sodium deoxycholate and 0.1% propylene glycol, with the balance being water for injection. It also includes a nonionic pH adjuster - tris(hydroxymethyl)aminomethane to adjust the pH of the formulation to 6.2.

[0030] The preparation method of the above-mentioned flexible lipoic acid nano-ophthalmic formulation for improving presbyopia includes the following steps:

[0031] (1) Take the formula amount of soybean lecithin, cholesterol and lipoic acid, add them to an appropriate amount of chloroform and stir evenly. Evaporate in a constant temperature water bath at 40℃ under reduced pressure (0.05MPa) to obtain a lipid film.

[0032] (2) Take the formula amount of chitosan, isotonic regulator and softener and dissolve them in a portion of water for injection, stir evenly to obtain an aqueous solution, so that the total mass concentration of the materials in the aqueous solution is 50%.

[0033] (3) The aqueous solution is added dropwise to the lipid film and stirred to obtain a primary emulsion. The primary emulsion is ultrasonically dispersed for 30 min to obtain a solution containing lipoic acid nanoliposomes.

[0034] (4) Dissolve the formulated amount of dendritic PAMAM in a portion of water for injection to obtain a coating solution (mass concentration of 1%). Add the coating solution dropwise to the solution containing lipoic acid nanoliposomes. Add a non-ionic pH adjuster to adjust the pH of the system to 6.2. Then add the remaining water for injection and stir magnetically at room temperature for 4 hours to obtain a flexible lipoic acid nano-ophthalmic formulation for improving presbyopia. The entire process is carried out under sterile conditions and then sterilely packaged.

[0035] Example 2

[0036] A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia, the flexible lipoic acid nano-ophthalmic formulation containing a core-shell structured substance, wherein the shell layer of the substance encapsulates the core layer, the core layer is a lipoic acid nanoliposome, and the shell layer is a dendritic PAMAM.

[0037] The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: 1.2% lipoic acid, 4% soybean lecithin, 0.2% cholesterol, 0.3% dendritic PAMAM (Sigmar-Aldrich, product number 536741, molecular weight 233373.9, PAMAM G8-NH2), 0.2% chitosan mixture (a mixture of chitosan and ethylene glycol chitosan at a mass ratio of 1:2), 3% isotonicity adjuster - mannitol, 0.05% softener - sodium cholate, and 0.1% propylene glycol, with the balance being water for injection. It also includes a nonionic pH adjuster - tris(hydroxymethyl)aminomethane to adjust the pH of the formulation to 6.5.

[0038] The preparation method of the above-mentioned flexible lipoic acid nano-ophthalmic formulation for improving presbyopia includes the following steps:

[0039] (1) Take the formula amount of soybean lecithin, cholesterol and lipoic acid, add them to chloroform in sequence and stir evenly. Evaporate in a constant temperature water bath at 40℃ under reduced pressure (0.05MPa) to obtain a lipid film.

[0040] (2) Take the formula amount of chitosan, isotonic regulator and softener and dissolve them in a portion of water for injection, stir evenly to obtain an aqueous solution, so that the total mass concentration of the materials in the aqueous solution is 50%.

[0041] (3) The aqueous solution is added dropwise to the lipid film and stirred to obtain a primary emulsion. The primary emulsion is ultrasonically dispersed for 50 min to obtain a solution containing lipoic acid nanoliposomes.

[0042] (4) Dissolve the formulated amount of dendritic PAMAM in a portion of water for injection to obtain a coating solution (mass concentration of 1%). Add the coating solution dropwise to the solution containing lipoic acid nanoliposomes. Add a non-ionic pH adjuster to adjust the pH of the system to 6.5. Then add the remaining water for injection and stir magnetically at room temperature for 5 hours to obtain a flexible lipoic acid nano-ophthalmic formulation for improving presbyopia. The entire process is carried out under sterile conditions and then sterilely packaged.

[0043] Example 3

[0044] A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia, the flexible lipoic acid nano-ophthalmic formulation containing a core-shell structured substance, wherein the shell layer of the substance encapsulates the core layer, the core layer is a lipoic acid nanoliposome, and the shell layer is a dendritic PAMAM.

[0045] The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: lipoic acid 0.8%, soybean lecithin 3%, cholesterol 0.5%, dendritic PAMAM 0.5% (Sigmar-Aldrich, product number 536741, molecular weight 233373.9, PAMAM G8-NH2), chitosan mixture 0.2% (a mixture of chitosan and ethylene glycol chitosan at a mass ratio of 1:9), isotonic adjuster - mannitol 2.5%, softener - sodium deoxycholate 0.1% and propylene glycol 0.2%, with the balance being water for injection. It also includes a nonionic pH adjuster - tris(hydroxymethyl)aminomethane to adjust the pH of the formulation to 6.5.

[0046] The preparation method of the above-mentioned flexible lipoic acid nano-ophthalmic formulation for improving presbyopia includes the following steps:

[0047] (1) Take the formula amount of soybean lecithin, cholesterol and lipoic acid, add them to chloroform in sequence and stir evenly. Evaporate in a constant temperature water bath at 40℃ under reduced pressure (0.05MPa) to obtain a lipid film.

[0048] (2) Take the formula amount of chitosan, isotonic regulator and softener and dissolve them in a portion of water for injection, stir evenly to obtain an aqueous solution, so that the total mass concentration of the materials in the aqueous solution is 50%.

[0049] (3) The aqueous solution is added dropwise to the lipid film and stirred to obtain a primary emulsion. The primary emulsion is ultrasonically dispersed for 60 min to obtain a solution containing lipoic acid nanoliposomes.

[0050] (4) Dissolve the formulated amount of dendritic PAMAM in a portion of water for injection to obtain a coating solution (mass concentration of 1%). Add the coating solution dropwise to the solution containing lipoic acid nanoliposomes. Add a non-ionic pH adjuster to adjust the pH of the system to 6.5. Then add the remaining water for injection and stir magnetically at room temperature for 3 hours to obtain a flexible lipoic acid nano-ophthalmic formulation for improving presbyopia. The entire process is carried out under sterile conditions and then sterilely packaged.

[0051] Comparative Example 1

[0052] This comparative ophthalmic formulation comprises the following raw materials by weight percentage:

[0053] The formulation contains 1% thioctic acid, 0.2% chitosan mixture (same as in Example 1), 2% isotonicity regulator, 0.2% fabric softener (same as in Example 1), and the balance is water for injection. It also includes a nonionic pH adjuster, tris(hydroxymethyl)aminomethane, to adjust the pH of the formulation to 6.2.

[0054] Preparation method: Dissolve chitosan in a portion of water for injection. After dissolving evenly, add isotonicity regulator and softener, mix evenly, add non-ionic pH adjuster to adjust the pH of the preparation to 6.2, and add the remaining water for injection. The above is performed under aseptic conditions.

[0055] Comparative Example 2

[0056] This comparative ophthalmic formulation comprises the following raw materials by weight percentage:

[0057] The formulation contains 1% lipoic acid, 3% soybean lecithin, 0.4% cholesterol, 0.2% chitosan (same as in Example 1), 2% isotonic regulator - mannitol, 0.2% softener (same as in Example 1), and the remainder is water for injection. It also includes a nonionic pH adjuster - tris(hydroxymethyl)aminomethane to adjust the pH of the formulation to 6.2.

[0058] The preparation process is the same as in Example 1, except that step (4) is omitted, meaning that the comparative formulation does not contain any core-shell structured substances.

[0059] Test case

[0060] 1. Stability test

[0061] The ophthalmic formulations prepared in the above examples and comparative examples were stored under accelerated stability conditions (40℃±2℃, 25%RH±5%). Changes in the lipoic acid content, pH value, and osmotic pressure of the formulations under accelerated conditions were detected. The lipoic acid detection method involved diluting the nano-formulation with PBS solution, demulsifying it with an organic solvent, centrifuging it, and then performing HPLC analysis on the supernatant. The ratio of the detected value to the theoretical content was recorded. Stability data are shown in Table 1.

[0062] Table 1. Stability test results of examples and comparative examples.

[0063]

[0064]

[0065] As shown in Table 1, after six months of observation, there were no significant changes in any of the indicators in each example, and the quality was stable. It can be inferred that the formulation is stable after being stored at room temperature for 24 months.

[0066] 2. Corneal permeability test

[0067] Medium: Green's solution (compound sodium chloride solution);

[0068] Drugs: Experimental group: Formulation of Example 1; Control group: Formulation of Comparative Example 2;

[0069] Results: The experimental results are as follows Figure 1 As shown;

[0070] Procedure: A stereotactic rabbit cornea was fixed between the supply and receiving cells of the corneal permeation device, with the corneal endothelial layer facing the receiving cell. 5 ml of ursine solution was added to the receiving cell, followed by 5 ml of the drug to the sample cell. The device was placed in a magnetic stirrer at a constant temperature (35±1℃), while a mixture of CO2 and O2 (flow rate ratio 95:5) was simultaneously introduced. 50 μL samples were taken from the receiving cell at 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min, with an equal volume of ursine solution added. After demulsification and centrifugation with an organic solvent, the mass concentration of thioctic acid was determined by HPLC, and the cumulative permeate volume of thioctic acid was calculated.

[0071] The results are as follows Figure 1 As shown, the cumulative permeation of the lipoic acid liposome formulation coated with PAMAM in the experimental group to the isolated cornea was significantly higher than that in the uncoated control group. This indicates that the formulation prepared after PAMAM coating has significantly better permeability to the isolated cornea, and the higher permeability ensures an effective drug concentration and guarantees clinical efficacy.

[0072] 3. In vitro release study

[0073] Preparation of dissolution medium: Add 6.78g NaCl, 1.38g KCl, 2.18g NaHCH3, and 0.084g CaCl2·H2O to 1L of deionized water.

[0074] Procedure: In vitro release assays were performed using the dialysis bag method. 500 ml of artificial tears was used as the release medium. Ophthalmic formulations (prepared to achieve a lipoic acid content of 50 mg) from the examples and comparative studies were added to the dialysis bag. The dissolution apparatus was set at 40 rpm and 34 ± 0.5 °C. Samples (5 ml) were taken at 1, 2, 4, 8, 12, 16, 20, and 24 hours, with 5 ml of STF added each time. The content of the main component, lipoic acid, was measured, and the cumulative release percentage of the main component, lipoic acid, was calculated. The results are shown in Table 2.

[0075] Table 2. In vitro release data for examples and comparative examples.

[0076]

[0077] Table 2 shows the in vitro dissolution results. Examples 1, 2, and 3 released 16-20 wt% of the drug within 1 hour, and the cumulative release rate reached over 95 wt% within 16 hours, indicating complete drug release and meeting the visual needs of presbyopic patients. Comparative Examples 1 and 2 showed significantly faster drug release rates, especially Comparative Example 1, which achieved near-complete drug release within 4 hours, failing to achieve a sustained-release effect. These results demonstrate that the formulation of this invention contains lipoic acid liposomes. These liposomes are chitosan-coated lipoic acid structures with a PAMAM coating on the outer layer. The combined effect of these two components provides superior corneal permeability, cell compatibility, and biodegradability, allowing lipoic acid molecules to directly act on the lens to produce efficacy. The long-lasting release time and good sustained-release effect reduce the dosing frequency from twice daily to once daily, resulting in better therapeutic efficacy than conventional formulations. The lower dosage also improves patient compliance with long-term medication.

[0078] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia, characterized in that, The flexible lipoic acid nano-ophthalmic formulation contains a core-shell structured substance, wherein the shell layer of the substance encapsulates the core layer, the core layer is a lipoic acid nanoliposome, and the shell layer is a dendritic PAMAM. The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: lipoic acid 0.5-2.5%, soybean lecithin 1-6%, cholesterol 0.1-0.7%, dendritic PAMAM 0.2-0.6%, chitosan mixture 0.1-0.4%, isotonicity adjuster 1-3%, softener 0.1-0.3%, with the balance being water for injection. It also includes a non-ionic pH adjuster to adjust the pH of the formulation to 6.0-7.

5. The chitosan mixture is a mixture of chitosan and ethylene glycol chitosan in a mass ratio of 1:2-10; The dendritic PAMAM is a terminal amino cationic PAMAM, selected from one or more of PAMAM G2-NH2, PAMAM G3-NH2, PAMAM G4-NH2, PAMAM G5-NH2, PAMAM G6-NH2, PAMAM G7-NH2, and PAMAM G8-NH2; The fabric softener is one or more of sodium deoxycholate, sodium cholate, and propylene glycol; The nonionic pH adjuster is tris(hydroxymethyl)aminomethane; The preparation method includes the following steps: (1) Take the formula amount of soybean lecithin, cholesterol and lipoic acid, add them to chloroform in sequence and stir evenly. Evaporate under heating and reduced pressure to obtain lipid film. (2) Take the formula amount of chitosan mixture, isotonic regulator and softener and dissolve them in a portion of water for injection, stir evenly to obtain an aqueous solution; (3) The aqueous solution is added dropwise to the lipid film and stirred to obtain a primary emulsion. The primary emulsion is then ultrasonically dispersed to obtain a solution containing lipoic acid nanoliposomes. (4) Dissolve the formulated amount of dendritic PAMAM in a portion of water for injection to obtain a coating solution. Add the coating solution dropwise to the solution containing lipoic acid nanoliposomes. Add a non-ionic pH adjuster to adjust the pH of the system to 6.0-7.

5. Then add the remaining water for injection. Stir magnetically at room temperature to obtain a flexible lipoic acid nano-ophthalmic preparation for improving presbyopia.

2. The flexible lipoic acid nano-ophthalmic formulation for improving presbyopia according to claim 1, characterized in that, The flexible lipoic acid nano-ophthalmic formulation comprises the following raw materials in 100% by weight percentage: lipoic acid 0.8-2%, soybean lecithin 3%, cholesterol 0.4%, dendritic PAMAM 0.4%, chitosan mixture 0.2%, isotonicity adjuster 2-3%, softener 0.15-0.3%, and the balance being water for injection. It also includes a non-ionic pH adjuster to adjust the pH of the formulation to 6.0-7.

5.

3. A flexible lipoic acid nano-ophthalmic formulation for improving presbyopia according to claim 1 or 2, characterized in that, The isotonic regulator is mannitol.

4. The flexible lipoic acid nano-ophthalmic formulation for improving presbyopia according to claim 1, characterized in that, The heating conditions described in step 1 are 35-45℃, using a constant temperature water bath, and the pressure reduction conditions are 0.04-0.06MPa.

5. The flexible lipoic acid nano-ophthalmic formulation for improving presbyopia according to claim 1, characterized in that, The total mass concentration of the material in the aqueous solution in step 2 is at least 30%; the ultrasonic dispersion time in step 3 is 10-60 min; and the magnetic stirring time at room temperature in step 4 is 3-5 h.

6. The flexible lipoic acid nano-ophthalmic formulation for improving presbyopia according to claim 1, characterized in that, The preparation method is carried out under sterile conditions throughout the entire preparation process.

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