Nano-micelle medicine for treating xerophthalmia and preparation method thereof

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a nano-micelle medicine for treating xerophthalmia and a preparation method of the nano-micelle medicine. According to the invention, sodium caseinate is adopted as an auxiliary material to construct the nano preparation co-loaded with resveratrol RES and curcumin CUR, so that the oral bioavailability of resveratrol and curcumin is synchronously enhanced, and the targeting distribution of drugs in eye tissues can be optimized. Resveratrol focuses on anti-inflammatory, anti-oxidation and neuroprotection, and curcumin is good at regulating an Nrf2 anti-oxidation pathway and promoting corneal repair and mucoprotein secretion. According to the invention, the two natural active components, namely the resveratrol RES and the curcumin CUR, are combined for treating the dry eye, and the two components can achieve a synergistic effect, so that the curative effect of the nano-micelle medicine on the dry eye syndrome is effectively improved, and the dry eye symptom is relieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and in particular relates to a nano-micelle drug for treating dry eye and a preparation method thereof. Background Art

[0002] Dry eye, a chronic ocular surface disease caused by the interaction of multiple factors, has shown a significant epidemic trend in my country in recent years. According to epidemiological survey data, the incidence of this disease continues to rise in screen-dependent people, the elderly, and postoperative patients, and has become the second most common ophthalmic disease after refractive error. Its pathological characteristics are mainly manifested in the imbalance of tear film homeostasis and the disorder of the ocular surface microenvironment. The clinical manifestations are highly heterogeneous: patients with mild symptoms often complain of persistent dry eyes, foreign body friction, intermittent blurred vision and other discomforts; as the disease progresses, patients may experience typical symptoms such as congestive conjunctival inflammation, increased eyelid secretions, and difficulty opening the eyes in the morning; if not intervened in time, complications such as corneal epithelial punctate exfoliation and filamentary keratitis will significantly affect visual quality and even cause irreversible vision damage. It is worth noting that recent studies have revealed that inflammatory mechanisms occupy a pivotal position in the pathological network of dry eye. On the one hand, long-term exposure to microenvironmental changes such as hyperosmotic tears, oxidative stress and neurogenic inflammation can activate signaling pathways such as NF-κB and MAPK, prompting the cascade release of proinflammatory factors (such as IL-1β, TNF-α, MMP-9), forming a vicious cycle of "inflammation-ocular surface damage-exacerbated inflammation"; on the other hand, the inflammatory microenvironment will further destroy goblet cell function, inhibit mucin secretion, and aggravate tear film instability. This bidirectional vicious feedback mechanism makes anti-inflammatory treatment a key target for blocking the disease progression.

[0003] In the current clinical treatment system, immunomodulators and anti-inflammatory drugs constitute the core treatment options. Cyclosporine A blocks T lymphocyte activation by inhibiting calcineurin activity, while tacrolimus inhibits IL-2 transcription by binding to the FKBP12 protein. Both can effectively regulate the immune response on the ocular surface. Glucocorticoids, with their broad-spectrum anti-inflammatory effects, can rapidly alleviate acute inflammatory states. However, the long-term use of these drugs faces severe challenges: cyclosporine A's ocular irritation and fluctuating bioavailability may reduce patient compliance; while tacrolimus, despite low systemic absorption, still carries the potential risk of nephrotoxicity; and because glucocorticoids may induce complications such as glaucoma and accelerated cataract development, strict monitoring of intraocular pressure changes is required during clinical use. Furthermore, issues such as frequent dosing due to inefficient drug delivery, limited drug penetration in patients with impaired corneal barrier function, and increased microbial resistance highlight the limitations of current treatment models. Summary of the Invention

[0004] (1) Technical issues to be resolved

[0005] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a nanomicelle drug for treating dry eye and a preparation method thereof, which solves the technical problems of low drug delivery efficiency and low drug bioavailability in the prior art.

[0006] (2) Technical solution

[0007] In a first aspect of the present invention, a nanomicelle drug for treating dry eye is provided. The nanomicelle drug uses casein or sodium caseinate as a carrier to co-encapsulate resveratrol and curcumin to form liquid nanomicelles. The concentration of resveratrol in the liquid nanomicelles is 4.8-5.2 mg / mL, the concentration of curcumin is 4.8-5.2 mg / mL, and the concentration of casein or sodium caseinate is 40-120 mg / mL.

[0008] In a second aspect of the present invention, the present invention provides a method for preparing a nano-micelle drug for treating dry eye, comprising the steps of:

[0009] S1, stirring sodium caseinate in distilled water until dissolved, and then storing at 4°C for 10-12 hours. The concentration of sodium caseinate solution is 40-120 mg / mL;

[0010] S2, adding resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjusting the pH to 11.8-12.4, and then performing sonication;

[0011] S3, adjust pH to 6.8-7.8;

[0012] S4, centrifugation for 15-25 minutes, and the obtained supernatant is sodium caseinate nanomicelles loaded with resveratrol and curcumin, which is freeze-dried.

[0013] Optionally, in step S2, the pH is adjusted to 12.

[0014] Optionally, in step S2, the ultrasonic temperature is -4°C-0°C, and the ultrasonic time is 2-4 minutes.

[0015] Optionally, in step S3, the pH is adjusted to 7.

[0016] Optionally, in step S4, the centrifugal force of the centrifugation is 8000×g.

[0017] In a third aspect of the present invention, the present invention provides use of sodium caseinate-loaded resol and curcumin dual-component nanomicelles in the preparation of a drug for treating dry eye.

[0018] (3) Beneficial effects

[0019] The present invention adopts sodium caseinate as an excipient to construct a nanoformulation co-loaded with resveratrol RES and curcumin CUR, and realizes the coordinated delivery of the two drugs through co-encapsulation technology.

[0020] The present invention adopts sodium caseinate as an excipient to construct a nanoformulation co-loaded with resveratrol RES and curcumin CUR, which not only simultaneously enhances the oral bioavailability of resveratrol and curcumin, but also optimizes the targeted distribution of the drugs in ocular tissues.

[0021] Resveratrol focuses on anti-inflammatory, antioxidant, and neuroprotective properties, while curcumin excels at regulating the Nrf2 antioxidant pathway, promoting corneal repair and mucin secretion. These two active ingredients have complementary mechanisms of action in the treatment of dry eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is to identify the encapsulation efficiency and size characteristics of the drugs in the examples and comparative examples of the present invention.

[0023] Figure 2 The figures are the transmission electron microscopy results of the drugs in the examples of the present invention and the comparative examples.

[0024] Figure 3 The figures are the scanning electron microscopy results of the drugs in the examples of the present invention and the comparative examples.

[0025] Figure 4 The blood compatibility test results of the examples and comparative examples of the present invention are shown.

[0026] Figure 5 The figures are the oral compatibility test results of the examples and comparative examples of the present invention.

[0027] Figure 6 The blood drug concentration test results of the examples and comparative examples of the present invention are shown.

[0028] Figure 7 The diagram shows the distribution of the drugs of the examples and comparative examples in the whole ocular tissues.

[0029] Figure 8 This is an evaluation of the therapeutic effects of the examples and comparative examples of the present invention on ocular surface damage in dry eye mice. DETAILED DESCRIPTION

[0030] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below through specific implementation methods in conjunction with the accompanying drawings.

[0031] Resveratrol (RES) is a natural polyphenol compound that is widely found in plants such as grape skins, red wine and blueberries. With its antioxidant, anti-inflammatory and neuroprotective properties, it shows unique potential in the treatment of dry eye. Its pleiotropic mechanisms of action include inhibiting inflammatory responses, scavenging oxygen free radicals and protecting ocular surface nerve function, which can improve dry eye symptoms from multiple dimensions. Studies have shown that resveratrol significantly alleviates the inflammatory microenvironment of the eye by specifically regulating inflammatory pathways, and may also promote the repair and regeneration of damaged nerves. In addition, this ingredient exhibits a synergistic effect when used in combination with conventional therapeutic drugs, which can enhance efficacy and reduce the risk of drug side effects. However, the oral bioavailability of resveratrol is less than 5%, mainly due to its rapid metabolic elimination characteristics and low water solubility, which makes it difficult to maintain an effective concentration in the eye, posing a major challenge in clinical application.

[0032] Curcumin (CUR) is a natural polyphenolic active substance extracted from the rhizome of Curcuma longa. Its unique chemical structure endows it with multi-target regulatory capabilities, holding great promise for the treatment of dry eye. This compound exerts its therapeutic effects by inhibiting the release of ocular surface inflammatory factors, alleviating oxidative stress damage, and restoring the stability of the tear film lipid layer. In particular, it enhances the body's endogenous antioxidant defense system by activating the Nrf2 signaling pathway. Furthermore, curcumin can promote the migration and proliferation of corneal epithelial cells, accelerate ocular surface tissue repair, and improve tear film adhesion by increasing mucin secretion. These properties make it particularly suitable for dry eye subtypes characterized by chronic inflammation as the core pathology. Its natural origin also reduces the risk of systemic toxicity, but its bioavailability still needs to be optimized through innovative formulation technologies.

[0033] Casein is the main protein in milk and is composed of subtypes such as α, β, and κ. In solution, casein molecules form nanoscale micelles (about 50-500nm in diameter) through hydrophobic interactions and calcium phosphate bridges. The interior of the micelle is a hydrophobic region (mainly composed of hydrophobic amino acid residues of β-casein), and the outside is a hydrophilic region (containing phosphate groups and sugar groups). This structure may be used to encapsulate hydrophobic molecules. Resveratrol and curcumin are both hydrophobic. The hydrophobic cavity of casein can encapsulate resveratrol and curcumin, which can significantly improve their solubility, stability and bioavailability.

[0034] The method for preparing the nanomicelles of the present invention comprises the following steps (including the functions of each step):

[0035] S1. Sodium caseinate CSS is stirred in distilled water until dissolved, and then stored at 4°C for 10-12 hours. The concentration of the sodium caseinate solution is 40-120 mg / mL; this may allow the CSS to be fully hydrated and form a micellar structure.

[0036] S2, adding resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjusting the pH to 11.8-12.4, and then performing ice bath sonication; resveratrol and curcumin are both hydrophobic and may have better solubility under alkaline conditions, and pH 11.8-12.4 may facilitate drug dissolution; using the cavitation effect of ultrasound to destroy the casein micelle structure, expose the hydrophobic area, and promote re-self-assembly after the drug enters; the ice bath helps to control the temperature.

[0037] S3, adjusting the pH to 6.8-7.8; this step lowers the pH to neutral (i.e., the micelle stability zone), promoting micelle reorganization and encapsulation of the drugs resveratrol and curcumin.

[0038] S4, centrifugation for 15-25 minutes, the resulting supernatant is the sodium caseinate nanomicelles loaded with resveratrol and curcumin, which is freeze-dried. The centrifugation step can remove unencapsulated drugs resveratrol and curcumin.

[0039] The mechanism of the synergistic treatment of dry eye by resveratrol and curcumin of the present invention is as follows:

[0040] Resveratrol and curcumin demonstrate significant synergistic potential in the treatment of dry eye disease through multi-target synergistic effects. The core pathological mechanism of dry eye disease involves a vicious cycle of tear film homeostasis, ocular surface inflammation, and oxidative stress. These two natural polyphenols precisely intervene in this process through complementary molecular pathways. Resveratrol primarily inhibits the NF-κB signaling pathway and activates SIRT1, reducing the release of proinflammatory cytokines (such as IL-1β and TNF-α) and activation of the NLRP3 inflammasome. Curcumin, on the other hand, inhibits COX-2-mediated production of inflammatory mediators by blocking the MAPK pathway and TLR4 / MyD88 signaling. The combined effect of these two agents produces a "multi-point anti-inflammatory" effect. Results show that their combined use further reduces IL-1β levels in a dry eye model compared to either agent alone. Regarding antioxidant activity, resveratrol activates the Nrf2 / ARE pathway, enhancing the expression of endogenous antioxidant enzymes (such as SOD and GSH), while curcumin directly scavenges free radicals by inhibiting NOX4 and chelating metal ions, synergistically reducing the oxidative damage marker MDA. In addition, the two promote goblet cell differentiation by activating the Wnt / β-catenin pathway, and inhibit the TGF-β / Smad3 pathway to reduce meibomian gland fibrosis, thereby increasing the secretion of tear film mucin and significantly restoring the stability of the lipid layer. Nano-co-delivery technology (such as casein nano-micelles) further breaks through its bioavailability bottleneck. The co-delivery system increases the corneal drug concentration, restores the tear secretion volume to normal levels, and has excellent blood compatibility (hemolysis rate <2%). This "anti-inflammatory-antioxidant-tear film repair" trinity synergistic mechanism, combined with the precise targeting characteristics of the delivery system, provides a new strategy for the treatment of dry eye with high efficiency and low toxicity.

[0041] Example 1

[0042] The nanomicelles of Example 1 use sodium caseinate as a carrier to co-encapsulate resveratrol and curcumin to form nanomicelles. The mass ratio of resveratrol to curcumin is X, and is marked as RC@C.

[0043] Example 2

[0044] The method for preparing the nano micelles comprises the steps of:

[0045] S1, sodium caseinate was stirred in distilled water until dissolved, and then stored at 4°C for 11 h. The concentration of sodium caseinate solution was 100 mg / mL;

[0046] S2, adding resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjusting the pH to 12, and then performing ice bath sonication for 3 minutes;

[0047] S3, adjust pH to 7;

[0048] S4, centrifugation for 20 min, the obtained supernatant is sodium caseinate nanomicelles loaded with resveratrol and curcumin, and freeze-dried.

[0049] Comparative Example 1

[0050] The nanomicelles of Comparative Example 1 use sodium caseinate as a carrier, but the micelles have a blank hydrophobic region, which is marked as CSS.

[0051] Comparative Example 2

[0052] The nanomicelles of Comparative Example 2 use sodium caseinate as a carrier to encapsulate resveratrol to form nanomicelles, which are marked as R@C.

[0053] Comparative Example 3

[0054] Comparative Example 3 is a drug for treating dry eye disease formed by unencapsulated resveratrol, which is marked as RES.

[0055] Comparative Example 4

[0056] Comparative Example 4 is a drug for treating dry eye formed by unencapsulated curcumin, which is marked as CUR.

[0057] Comparative Example 5

[0058] Comparative Example 5 is a drug for treating dry eye formed by unencapsulated resveratrol and curcumin, marked as R+C.

[0059] Test example

[0060] 1. Determination of Encapsulation Efficiency (EE) and Hydrodynamic Size

[0061] Ultraviolet-visible spectrophotometry (UV-Vis) was used to pre-establish an absorbance-concentration standard curve of the nanomicelle drug at a specific wavelength (306 nm for resveratrol and 425 nm for curcumin).

[0062] According to step S4 of the method for preparing nanomicelles of the present invention, the supernatant obtained after centrifugation is the sodium caseinate nanomicelles loaded with resveratrol and curcumin, and the amount of free drug in the precipitate after centrifugation is measured; then, acetonitrile or methanol is added in a volume ratio of 1:1 to destroy the micelles, releasing the encapsulated drug, and the total drug amount is calculated according to the following formula:

[0063] EE (%) = (total drug amount - free drug amount) / total drug amount × 100

[0064] Dilute the sodium caseinate nanomicelle solution loaded with resveratrol and curcumin with ultrapure water to a concentration of 0.1–1 mg / mL. Ensure the sample has appropriate transmittance (laser signal intensity between 50–200 kcps). Place the sample in front of the DLS instrument sample cell and allow it to equilibrate to the instrument's set temperature (typically 25°C) for 5 minutes. Set the following parameters: temperature 25°C, detection angle 90° (or backscattering angle 173°), solvent refractive index (e.g., 1.33 for water), and viscosity (0.8872 cP). Run three measurements, each with 10–20 scans, and calculate the average hydrodynamic diameter (Z-Average).

[0065] like Figure 1 As shown, the encapsulation efficiency of the sodium caseinate nanomicelle drug of resveratrol and curcumin (Example 1) of the present invention and the drug of Comparative Example 2 reached 95% and 80%, respectively; it can be seen that the encapsulation efficiency of the sodium caseinate nanomicelle drug prepared by the present invention is improved to a certain extent.

[0066] The hydrodynamic sizes of Example 1, Comparative Examples 1 and 2 were measured respectively. The sodium caseinate nanomicelles of resveratrol and curcumin (Example 1) of the present invention were only about 100 nm, thus having the smallest nanometer size.

[0067] Figure 2 The transmission electron microscopy results of the examples and comparative examples of the present invention are shown in FIG1 , FIG2 and FIG3 are transmission electron microscopy results of the examples and comparative examples of the present invention, respectively. Figure 2 The results show that CSS itself has a network structure connected into filaments; the prepared R@C (Comparative Example 2) and RC@C (Example 1) have smaller hydrodynamic sizes, among which R@C is still slightly connected into filaments, but RC@C is almost completely separated, indicating that RC@C has the smallest nanometer size.

[0068] Figure 3 The figures are the scanning electron microscopy results of the drugs in the examples of the present invention and the comparative examples. Figure 3It shows that RES (Comparative Example 3) and CUR (Comparative Example 4) are both crystalline tubular structures, and after being encapsulated by CSS, R@C (Comparative Example 2) and RC@C (Example 1) will become spherical nanomicelles.

[0069] 2. Determination of blood compatibility and oral compatibility

[0070] Preparation of red blood cell suspension: Take fresh human or animal anticoagulated whole blood, centrifuge (1500×g, 10 min) to remove plasma and leukocytes, wash red blood cells three times with PBS, and prepare 2% red blood cell suspension.

[0071] Sample treatment: The nanomicelle solution was mixed with the red blood cell suspension in a volume ratio of 1:1 (final concentration gradient: 0.1–1 mg / mL) and incubated at 37°C for 1–4 hours.

[0072] Centrifugation and analysis: Centrifuge at 1500×g for 10 min, take the supernatant and measure the absorbance A at 540 nm. Deionized water (complete hemolysis) and PBS (no hemolysis) were used as controls.

[0073] Calculate the hemolysis rate: Hemolysis rate (%) = (A 样品 -A PBS ) / (A 水 -A PBS )×100%

[0074] like Figure 4 As shown, according to the above in vitro hemolysis experiment, the hemolysis rates of RC@C (Example 1), CSS (Comparative Example 1), R@C (Comparative Example 2), RES (Comparative Example 3), CUR (Comparative Example 4) and R+C (Comparative Example 5) are all less than 5%, and all have good blood compatibility.

[0075] The sodium caseinate nanomicelle drug of resveratrol and curcumin obtained in the present invention (Example 1) was subjected to acute toxicity test with R@C (Comparative Example 2), RES (Comparative Example 3), CUR (Comparative Example 4) and R+C (Comparative Example 5). A single high dose (e.g., 80 mg / kg) was intravenously injected into the mouse animal model and observed for 14 days. ALT, AST (a marker of liver damage) and core renal function indicators (CREA and UREA) were tested. Figure 5 As shown, the ALT of Example 1 of the present invention and Comparative Examples 2-5 was about 30 U / L; the AST was about 120 U / L. The core renal function indicators (CREA and UREA) of Example 1 of the present invention and Comparative Examples 2-5 were CREA less than 30 μmol / L; and UREA less than 8 mmol / L.

[0076] 3. If Figure 6 and Figure 7As shown, the blood concentrations of resveratrol and curcumin prepared by the sodium caseinate nanomicelle drugs of resveratrol and curcumin obtained by the present invention (Example 1) and RES (Comparative Example 3) were respectively measured. It can be seen from the figure that the blood concentration of resveratrol in the nanomicelles of the present invention is greatly improved, from the original 0.2 μg / mL to nearly 0.6 μg / mL; the sodium caseinate nanomicelles of resveratrol and curcumin obtained by the present invention (Example 1) and RES (Comparative Example 3) and CUR (Comparative Example 4) entered the eyeball tissue, and the distribution concentrations of resveratrol and curcumin therein were respectively measured. The resveratrol in the whole eyeball tissue increased from the original 0.05 μg / mL to nearly 0.4 μg / mL, and the curcumin in the whole eyeball tissue increased from the original 0.1 μg / mL to nearly 0.8 μg / mL. It can be seen from the figure that the distribution concentrations of resveratrol and curcumin in the whole eyeball tissue of the nanomicelles are greatly improved. Therefore, the nanomicelles not only enhance the oral bioavailability of resveratrol and curcumin simultaneously, but also optimize the targeted distribution of the drugs in ocular tissues.

[0077] Pharmacokinetic testing is a key experiment to evaluate the dynamic processes of drug absorption, distribution, metabolism, and excretion (ADME) in the body. It is crucial for optimizing dosing regimens and predicting clinical efficacy. The following is a standardized pharmacokinetic test of casein nanomicelles co-loaded with resveratrol and curcumin. The results are shown in Table 1.

[0078] Table 1 Pharmacokinetic test results of casein nanomicelles co-loaded with resveratrol and curcumin

[0079]

[0080] As can be seen from the figure, in the pharmacokinetics of the nanomicelle drug of the present invention, the area under the drug-time curve (AUC (0-4) ) increased by 3.01 times, and the maximum blood concentration (Maximum Concentration, C max ) increased by 3.44 times, and the time to peak concentration (Time to Maximum Concentration, T max )constant.

[0081] 5. Dry eye treatment effect test

[0082] Benzalkonium chloride solution with a mass concentration of 0.10% was dripped into the eyes of multiple mice, and 5 μL of benzalkonium chloride was given to each eye once a day for 14 consecutive days to induce a dry eye model. While the dry eye model was being established, drug treatment was carried out, and the administration method was gavage, with a dosage of 50 mg / kg / only and a dosage volume of 100 μL / time / only. The control group was orally administered with an equal volume of normal saline, while the other groups of mice were orally administered with an equal volume of resveratrol and curcumin sodium caseinate nanomicelles (Example 1) obtained by the present invention and R@C (Comparative Example 2), RES (Comparative Example 3), CUR (Comparative Example 4) and R+C (Comparative Example 5) drugs.

[0083] To assess the effectiveness of dry eye treatment, sodium fluorescein staining and a phenol red cotton thread test were performed to measure the average tear volume (unit: mm) in each group of mice. The corneal epithelial thickness and overall corneal thickness were also measured. Dry eye can cause epithelial cell damage and shedding, resulting in irregularities and blurred corneal texture. Lack of nutrition and water in corneal epithelial cells may lead to a reduction in corneal thickness.

[0084] Figure 8 It was shown that in the benzalkonium chloride (BAC)-induced dry eye mouse model, oral administration of RC@C could significantly reduce ocular surface damage, restore the normal structure of the cornea, and increase tear secretion in dry eye mice. Its therapeutic effect was significantly better than oral administration of RES or CUR or the combined oral administration of RES and CUR.

[0085] This invention uses sodium caseinate as an excipient to construct a nanoformulation co-loaded with resveratrol (RES) and curcumin (CUR), achieving synergistic delivery of the two drugs through co-encapsulation technology. The core advantage of this design lies in leveraging their drug-drug interaction mechanism: the two drugs competitively target the same metabolic enzymes during intestinal absorption. By temporarily saturating the metabolic enzyme system, their first-pass metabolism rate is effectively slowed, significantly improving the efficiency of intestinal absorption into the bloodstream. This characteristic not only simultaneously enhances the oral bioavailability of resveratrol and curcumin but also optimizes their targeted distribution within ocular tissues. Furthermore, the two active ingredients have complementary mechanisms of action in dry eye treatment—resveratrol focuses on anti-inflammatory, antioxidant, and neuroprotective effects, while curcumin excels at regulating the Nrf2 antioxidant pathway, promoting corneal repair, and promoting mucin secretion. The multi-target synergistic effect achieved through nanoco-loading technology can overcome the therapeutic limitations of single drugs, creating synergistic effects in key pathological pathways such as inhibiting the inflammatory cascade, repairing ocular surface damage, and stabilizing tear film function, thereby systematically enhancing the overall therapeutic efficacy of dry eye.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A nano-micelle drug for treating dry eye, characterized in that: The nanomicelle drug uses casein or sodium caseinate as a carrier to co-encapsulate resveratrol and curcumin to form liquid nanomicelles. The concentration of resveratrol in the liquid nanomicelles is 4.8-5.2 mg / mL, the concentration of curcumin is 4.8-5.2 mg / mL, and the concentration of casein or sodium caseinate is 40-120 mg / mL.

2. Application of sodium caseinate-loaded resol and curcumin dual-component nanomicelles in the preparation of drugs for the treatment of dry eye.

3. A method for preparing the nano-micelle drug for treating dry eye according to claim 1, characterized in that: Including steps: S1, stirring sodium caseinate in distilled water until dissolved, and then storing at 4°C for 10-12 hours. The concentration of sodium caseinate solution is 40-120 mg / mL; S2, adding resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjusting the pH to 11.8-12.4, and then performing sonication; S3, adjust pH to 6.8-7.8; S4, centrifugation for 15-25 minutes, and the obtained supernatant is sodium caseinate nanomicelles loaded with resveratrol and curcumin, which is freeze-dried.

4. The preparation method according to claim 3, characterized in that In step S2, the pH is adjusted to 12.

5. The preparation method according to claim 3, characterized in that In step S2, the ultrasonic temperature is -4°C to 0°C.

6. The preparation method according to claim 3, characterized in that In step S2, the ultrasonic time is 2-4 minutes.

7. The preparation method according to claim 3, characterized in that In step S3, the pH is adjusted to 7.

8. The preparation method according to claim 3, characterized in that In step S4, the centrifugal force of the centrifugation is 8000×g.

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