A nanomicellar drug for treating dry eye and a preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a nanomicelle drug for treating dry eye syndrome and its preparation method. This invention uses sodium caseinate as an excipient to construct a nano-formulation 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. Resveratrol focuses on anti-inflammatory, antioxidant, and neuroprotective effects, while curcumin excels at regulating the Nrf2 antioxidant pathway and promoting corneal repair and mucin secretion. This invention combines two natural active ingredients, resveratrol (RES) and curcumin (CUR), for the treatment of dry eye. These two components synergistically enhance each other, thereby effectively improving the efficacy of this nanomicelle drug for dry eye syndrome and alleviating dry eye symptoms.

Description

Technical Field

[0001] This invention belongs to the field of drug preparation technology, specifically relating to a nanomicelle drug for treating dry eye syndrome and its preparation method. Background Technology

[0002] Dry eye syndrome, a chronic ocular surface disease caused by multiple interacting factors, has shown a significant prevalence in my country in recent years. Epidemiological survey data shows that its incidence continues to rise among screen-dependent individuals, the elderly, and postoperative patients, making it the second most common ophthalmic disease after refractive errors. Its pathological characteristics are mainly manifested as tear film homeostasis imbalance and ocular surface microenvironment disturbance, with highly heterogeneous clinical manifestations: mild cases often complain of persistent dryness, foreign body sensation, and intermittent blurred vision; as the disease progresses, patients may experience typical symptoms such as congestive conjunctivitis, increased eyelid discharge, and difficulty opening their eyes in the morning; without timely intervention, complications such as punctate corneal epithelial abrasion and filamentous keratitis will significantly affect visual quality and even cause irreversible visual impairment. It is worth noting that recent studies have revealed that the inflammatory mechanism plays a pivotal role in the pathological network of dry eye disease. On the one hand, long-term exposure to changes in the microenvironment, such as hyperosmolar tears, oxidative stress, and neurogenic inflammation, can activate signaling pathways such as NF-κB and MAPK, promoting the cascade release of pro-inflammatory factors (such as IL-1β, TNF-α, and MMP-9), forming a vicious cycle of "inflammation-ocular surface damage-inflammation exacerbation." On the other hand, the inflammatory microenvironment can further damage goblet cell function, inhibit mucin secretion, and exacerbate tear film instability. This bidirectional vicious feedback mechanism makes anti-inflammatory treatment a key target for blocking disease progression.

[0003] In the current clinical treatment system, immunomodulators and anti-inflammatory drugs constitute the core treatment regimen. Cyclosporine A blocks T lymphocyte activation by inhibiting calcineurin activity, while tacrolimus inhibits IL-2 transcription by binding to the FKBP12 protein; both effectively regulate the ocular surface immune response. Glucocorticoids, with their broad-spectrum anti-inflammatory effects, can rapidly relieve acute inflammatory states. However, long-term use of these drugs faces serious challenges: the ocular irritation and fluctuating bioavailability of cyclosporine A may reduce patient compliance; although tacrolimus has low systemic absorption, it still carries the potential risk of nephrotoxicity; and glucocorticoids, due to their potential to induce complications such as glaucoma and accelerate cataract development, require strict monitoring of intraocular pressure changes during clinical use. In addition, problems such as frequent dosing due to inefficient drug delivery, limited drug penetration in patients with impaired corneal barrier function, and increased microbial resistance all highlight the limitations of existing treatment modalities. Summary of the Invention

[0004] (a) Technical problems to be solved

[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 syndrome and its preparation method, which solves the technical problems of low drug delivery efficiency and low drug bioavailability in the prior art.

[0006] (II) Technical Solution

[0007] In a first aspect, the present invention provides a nanomicelle drug for treating dry eye syndrome, wherein the nanomicelle drug uses casein or sodium caseinate as a carrier to co-encapsulate resveratrol and curcumin to form liquid nanomicelles, wherein 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, the present invention provides a method for preparing a nanomicelle drug for treating dry eye syndrome, comprising the steps of:

[0009] S1, Dissolve sodium caseinate in distilled water by stirring, then store at 4°C for 10-12 hours. The concentration of the sodium caseinate solution is 40-120 mg / mL.

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

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

[0012] S4, centrifuged for 15-25 min, the supernatant obtained was sodium caseinate nanomicelles loaded with resveratrol and curcumin, which were then freeze-dried.

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

[0014] Optionally, in step S2, the ultrasonic temperature is -4℃ to 0℃, and the ultrasonic time is 2-4 min.

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

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

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

[0018] (III) Beneficial Effects

[0019] This invention uses sodium caseinate as an excipient to construct a nano-formulation co-loaded with resveratrol (RES) and curcumin (CUR), and achieves synergistic delivery of the two drugs through co-encapsulation technology.

[0020] This invention uses sodium caseinate as an excipient to construct a nano-formulation 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 effects, while curcumin excels at regulating the Nrf2 antioxidant pathway and promoting corneal repair and mucin secretion. The two active ingredients have complementary mechanisms of action in the treatment of dry eye. Attached Figure Description

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

[0023] Figure 2 The results are obtained by transmission electron microscopy of the drugs in the embodiments and comparative examples of this invention.

[0024] Figure 3 The results are obtained by scanning electron microscopy of the drugs in the embodiments and comparative examples of this invention.

[0025] Figure 4 The results show the blood compatibility test results of the drugs in the embodiments and comparative examples of this invention.

[0026] Figure 5 The results show the oral compatibility test results of the drugs in the embodiments and comparative examples of this invention.

[0027] Figure 6 The results show the blood drug concentration detection results of the drugs in the embodiments and comparative examples of this invention.

[0028] Figure 7 The results show the detection of drug distribution in the whole eye tissue in the embodiments and comparative examples of the present invention.

[0029] Figure 8 This invention aims to evaluate the therapeutic effects of the drugs in the embodiments and comparative examples on ocular surface damage in dry-eye mice. Detailed Implementation

[0030] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0031] Resveratrol (RES) is a natural polyphenol compound widely found in grape skins, red wine, and blueberries. Its antioxidant, anti-inflammatory, and neuroprotective properties have demonstrated unique potential in the treatment of dry eye. Its pleiotropic mechanism of action encompasses inhibiting inflammatory responses, scavenging oxygen free radicals, and protecting ocular surface nerve function, thus improving dry eye symptoms from multiple dimensions. Studies show 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. Furthermore, this component exhibits a synergistic effect when used in combination with conventional therapeutic drugs, enhancing efficacy and reducing the risk of drug side effects. However, the oral bioavailability of resveratrol is less than 5%, mainly limited by its rapid metabolic elimination and low water solubility, making it difficult to maintain effective intraocular concentrations, posing a significant challenge to clinical application.

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

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

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

[0035] S1. Dissolve sodium caseinate (CSS) in distilled water by stirring, and then store 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 micelle structure.

[0036] S2, add resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjust the pH to 11.8-12.4, and then perform sonication in an ice bath; resveratrol and curcumin are both hydrophobic, and their solubility may be better under alkaline conditions, and a pH of 11.8-12.4 may help the drugs dissolve; the cavitation effect of ultrasound disrupts the casein micelle structure, exposes the hydrophobic regions, and promotes the re-assembly of the drugs after they enter; the ice bath helps to control the temperature.

[0037] S3, adjust 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, centrifuge for 15-25 min, the resulting supernatant is sodium caseinate nanomicelles loaded with resveratrol and curcumin, then freeze-dried. The centrifugation step removes unencapsulated resveratrol and curcumin.

[0039] The mechanism of action of resveratrol and curcumin in the synergistic treatment of dry eye syndrome in this invention is as follows:

[0040] Resveratrol and curcumin exhibit significant synergistic potential in the treatment of dry eye through multi-target effects. The core pathological mechanism of dry eye involves a vicious cycle of tear film homeostasis imbalance, ocular surface inflammation, and oxidative stress. These two natural polyphenolic compounds precisely intervene in these processes through complementary molecular pathways. Resveratrol primarily inhibits the NF-κB signaling pathway and activates SIRT1, reducing the release of pro-inflammatory factors (such as IL-1β and TNF-α) and the activation of the NLRP3 inflammasome. Curcumin, on the other hand, inhibits COX-2-mediated inflammatory mediator production by blocking the MAPK pathway and TLR4 / MyD88 signaling. The combination of these two compounds creates a "multi-point anti-inflammatory" effect, with results showing that their combined use further reduced IL-1β levels in the dry eye model compared to the single-drug group. At the antioxidant level, resveratrol activates the Nrf2 / ARE pathway to enhance the expression of endogenous antioxidant enzymes (such as SOD and GSH), while curcumin directly scavenge free radicals by inhibiting NOX4 and chelating metal ions, synergistically reducing the oxidative damage marker MDA. Furthermore, both promote goblet cell differentiation by activating the Wnt / β-catenin pathway and reduce meibomian gland fibrosis by inhibiting the TGF-β / Smad3 pathway, thereby increasing tear film mucin secretion and significantly restoring lipid layer stability. Nanoparticle co-loading technology (such as casein nanomicelles) further overcomes the bioavailability bottleneck; the co-loading system increases corneal drug concentration, restores tear secretion to normal levels, and exhibits excellent blood compatibility (hemolysis rate <2%). This synergistic mechanism of "anti-inflammatory-antioxidant-tear film repair," combined with the precise targeting characteristics of the delivery system, provides a novel, highly effective, and low-toxicity strategy for the treatment of dry eye.

[0041] Example 1

[0042] In this embodiment 1, sodium caseinate is used as a carrier to co-encapsulate resveratrol and curcumin to form nanomicelles. The mass ratio of resveratrol to curcumin is X, and it is labeled as RC@C.

[0043] Example 2

[0044] The method for preparing the nanomicelles includes the following steps:

[0045] S1, Sodium caseinate is dissolved in distilled water and then stored at 4°C for 11 hours. The concentration of the sodium caseinate solution is 100 mg / mL.

[0046] S2, add resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjust the pH to 12, and then perform ice bath sonication for 3 minutes.

[0047] S3, adjust the pH to 7;

[0048] S4, centrifuged for 20 min, the supernatant obtained was sodium caseinate nanomicelles loaded with resveratrol and curcumin, which were then freeze-dried.

[0049] Comparative Example 1

[0050] The nanomicelles in Comparative Example 1 were supported by sodium caseinate, but the micelles were blank hydrophobic regions, labeled as CSS.

[0051] Comparative Example 2

[0052] In Comparative Example 2, nanomicelles were formed by encapsulating resveratrol with sodium caseinate as a carrier, and labeled as R@C.

[0053] Comparative Example 3

[0054] Comparative Example 3 is an unencapsulated resveratrol formulation for the treatment of dry eye, labeled RES.

[0055] Comparative Example 4

[0056] Comparative Example 4 is an unencapsulated curcumin-based drug for treating dry eye syndrome, labeled CUR.

[0057] Comparative Example 5

[0058] Comparative Example 5 is an unencapsulated resveratrol combined with curcumin to form a drug for treating dry eye, labeled R+C.

[0059] Test case

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

[0061] The absorbance-concentration standard curves of the nanomicelle drugs at specific wavelengths (306 nm for resveratrol and 425 nm for curcumin) were pre-established using ultraviolet-visible spectrophotometry (UV-Vis).

[0062] In step S4 of the preparation method of the nanomicelles according to the present invention, the supernatant obtained after centrifugation is sodium caseinate nanomicelles loaded with resveratrol and curcumin. The amount of free drug in the precipitate after centrifugation is measured. Then, acetonitrile or methanol is added at a volume ratio of 1:1 to destroy the micelles, release the encapsulated drug, and calculate the total drug amount according to the following formula:

[0063] EE (%) = (Total drug content - Free drug content) / Total drug content × 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, ensuring suitable sample transmittance (laser signal intensity between 50–200 kcps). Place the sample in front of the DLS instrument's sample cell and allow it to stand for 5 minutes to equilibrate with the instrument's set temperature (typically 25°C). Set the parameters as follows: temperature 25°C, detection angle 90° (or backscatter 173°), solvent refractive index (e.g., 1.33 for water), and viscosity (0.8872 cP). Run three measurements, each with 10–20 scans, and record the average hydrodynamic diameter (Z-Average).

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

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

[0067] Figure 2 The images show the transmission electron microscopy (TEM) results of the drugs used in the embodiments and comparative examples of this invention. Specifically, they show the TEM results of Example 1 and Comparative Examples 1 and 2, respectively. Figure 2 The CSS itself has a filamentous network structure; the prepared R@C (Comparative Example 2) and RC@C (Example 1) have smaller hydrodynamic dimensions. R@C also has a slight filamentous state, but RC@C is almost completely separated, indicating that RC@C has the smallest nanoscale size.

[0068] Figure 3 The results are obtained by scanning electron microscopy of the drugs in the embodiments and comparative examples of this invention. Figure 3The results show that RES (Comparative Example 3) and CUR (Comparative Example 4) are both crystalline tubular structures. After being encapsulated by CSS, R@C (Comparative Example 2) and RC@C (Example 1) 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, 10min) to remove plasma and white blood cells, wash red blood cells 3 times with PBS, and prepare a 2% red blood cell suspension.

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

[0072] Centrifugation and analysis: Centrifuge at 1500×g for 10 min, and measure the absorbance (A) of the supernatant at 540 nm. Deionized water (completely hemolyzed) and PBS (non-hemolyzed) 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, the in vitro hemolysis experiments indicated that 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) were all less than 5%, and all had good blood compatibility.

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

[0076] 3. For example Figure 6 and Figure 7As shown, the blood concentrations of resveratrol and curcumin prepared from sodium caseinate nanomicelles of casein obtained in this invention (Example 1) and RES (Comparative Example 3) were measured respectively. As can be seen from the figure, the blood concentration of resveratrol in the nanomicelles of this invention was significantly increased, from the original 0.2 μg / mL to nearly 0.6 μg / mL. Sodium caseinate nanomicelles of resveratrol and curcumin obtained in this invention (Example 1), RES (Comparative Example 3), and CUR (Comparative Example 4) were introduced into the ocular tissue, and the distribution concentrations of resveratrol and curcumin in them were measured respectively. The resveratrol concentration in the whole ocular tissue increased from the original 0.05 μg / mL to nearly 0.4 μg / mL, and the curcumin concentration in the whole ocular tissue increased from the original 0.1 μg / mL to nearly 0.8 μg / mL. As can be seen from the figure, the distribution concentrations of resveratrol and curcumin in the whole ocular tissue of the nanomicelles were significantly increased. Therefore, the nanomicelles not only simultaneously enhance the oral bioavailability of resveratrol and curcumin, but also optimize the targeted distribution of the drugs in ocular tissues.

[0077] 4. Pharmacokinetic assays are crucial experiments for evaluating the dynamic processes of drug absorption, distribution, metabolism, and excretion (ADME) in vivo, and are essential for optimizing dosing regimens and predicting clinical efficacy. The following are standardized pharmacokinetic assays for casein nanomicelles co-loaded with resveratrol and curcumin; the results are shown in Table 1.

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

[0079]

[0080] As shown in the figure, in the pharmacokinetics of the nanomicelle drug of the present invention, the area under the curve (AUC) of the RC@C group is [missing information]. (0-4) The maximum plasma concentration (C) was increased by 3.01 times. max The time to peak concentration (T) increased by 3.44 times, and the time to peak concentration (T) was also increased by 3.44 times. max )constant.

[0081] 5. Dry Eye Syndrome Treatment Efficacy Test

[0082] A 0.10% benzalkonium chloride solution was instilled into the eyes of multiple mice, with 5 μL of benzalkonium chloride administered to each eye once daily for 14 consecutive days to induce a dry eye model. Simultaneously, drug treatment was administered via gavage at a dose of 50 mg / kg / mouse, with a volume of 100 μL / mouse. The control group received an equal volume of physiological saline orally, while the other groups of mice received equal volumes of the resveratrol and curcumin caseinate sodium nanomicelle drug (Example 1), R@C (Comparative Example 2), RES (Comparative Example 3), CUR (Comparative Example 4), and R+C (Comparative Example 5) obtained in this invention, respectively.

[0083] Dry eye treatment efficacy assessment: Fluorescein staining and phenol red suture test were used to measure the average tear secretion (unit: mm) of each group of mice. Corneal epithelial thickness and overall corneal thickness were also measured. Dry eye can cause epithelial cell damage and shedding, resulting in an irregular and indistinct corneal surface. Insufficient nutrition and moisture to the corneal epithelial cells can lead to reduced corneal thickness.

[0084] Figure 8 The results showed that in a benzalkonium chloride (BAC)-induced dry eye mouse model, oral administration of RC@C significantly reduced ocular surface damage, restored normal corneal structure, and increased tear secretion in dry eye mice. Its therapeutic effect was significantly better than oral administration of RES or CUR or a combination of oral administration of RES and CUR.

[0085] This invention utilizes sodium caseinate as an excipient to construct a nano-formulation 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 interaction mechanism: the two drugs competitively act on the same metabolic enzymes during intestinal absorption, effectively delaying the first-pass metabolic rate through a temporarily saturated metabolic enzyme system, thereby 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 the targeted distribution of the drugs in ocular tissues. Furthermore, the two active ingredients have complementary mechanisms of action in dry eye treatment—resveratrol focuses on anti-inflammation, anti-oxidation, and neuroprotection, while curcumin excels at regulating the Nrf2 antioxidant pathway and promoting corneal repair and mucin secretion. The multi-target synergistic effect achieved through nano-co-loading technology overcomes the limitations of single-drug efficacy, creating a synergistic effect in key pathological processes such as inhibiting the inflammatory cascade, repairing ocular surface damage, and stabilizing tear film function, thereby systematically improving the overall therapeutic effect of dry eye syndrome.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions 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 nanomicelle drug for treating dry eye syndrome, 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 resveratrol and curcumin-containing two-component nanomicelles in the preparation of drugs for treating dry eye syndrome.

3. A method for preparing a nanomicelle drug for treating dry eye as described in claim 1, characterized in that, Including the following steps: S1, Dissolve sodium caseinate in distilled water by stirring, then store at 4°C for 10-12 hours. The concentration of the sodium caseinate solution is 40-120 mg / mL. S2, add resveratrol and curcumin powder to the sodium caseinate solution obtained in step S1, adjust the pH to 11.8-12.4, and then perform sonication; S3, adjust the pH to 6.8-7.8; S4, centrifuged for 15-25 min, the supernatant obtained was sodium caseinate nanomicelles loaded with resveratrol and curcumin, which were then 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℃ to 0℃.

6. The preparation method according to claim 3, characterized in that, In step S2, the ultrasound 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 is 8000×g.

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