Eye-protecting liquid of agarwood and lutein complex and preparation method thereof

Abstract

This application discloses an agarwood and lutein donor eye drop and its preparation method. The eye drop contains a donor formed by the non-covalent interaction of agarwood extract and lutein. The donor is encapsulated in a nano-delivery carrier to form a core-shell structure. The carrier surface is coated with thiolized polysaccharides or ionic chitosan derivatives as bioadhesive materials, and the release curves of lutein and agarwood sesquiterpenoids have a good fit of greater than 0.9. This formulation, prepared through a specific ratio of raw materials, an amorphous donor structure, and a flash nanoprecipitation process, not only solves the problems of poor solubility, easy oxidation, and poor permeability of lutein, but also achieves simultaneous release of active ingredients and prolonged corneal retention time, significantly improving drug bioavailability. The penetration rate to human corneal epithelial cells is effectively improved compared to a simple lutein solution, exhibiting significant synergistic effects, high stability, and controllable preparation process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to an agarwood and lutein compound eye drops and its preparation method. Background Technology

[0002] This application belongs to the field of pharmaceutical formulation technology, specifically relating to a nanodelivery system for the treatment of ocular diseases, particularly an eye drop containing a compound formed from plant-derived agarwood extract and lutein, and its preparation process. In ophthalmic pharmaceutical formulations, improving the bioavailability of poorly soluble drugs and achieving synergistic effects of active ingredients has always been a research hotspot. This application focuses on improvements to complex systems containing hydrophobic components and plant extracts.

[0003] However, existing conventional ophthalmic formulations suffer from numerous technical shortcomings. First, lutein, as a strongly hydrophobic compound, has extremely low solubility in aqueous media, and its molecular structure contains easily oxidized conjugated double bonds, making it highly susceptible to degradation and discoloration in the presence of light and oxygen, resulting in poor formulation stability and a short shelf life. Second, traditional eye drops have a short retention time on the ocular surface and lack an effective bioadhesion mechanism, making it difficult to penetrate the corneal epithelial barrier and achieve effective drug concentrations at the site of action. More importantly, when lutein is simply physically mixed with other active ingredients such as agarwood extract, the release rates of the two are often inconsistent due to differences in physicochemical properties, failing to achieve synchronous release and thus weakening the synergistic effect of anti-inflammatory and antioxidant properties. Furthermore, conventional emulsification or grinding processes struggle to precisely control the particle size distribution and zeta potential of nanocarriers, leading to low encapsulation efficiency, poor batch-to-batch reproducibility, and a tendency to produce burst release effects.

[0004] Therefore, there is an urgent clinical need to develop a novel drug delivery system that can overcome the aforementioned shortcomings. This system not only needs to address the physicochemical instability of lutein, such as its poor solubility and easy oxidation, but also requires the construction of specific donor structures and bioadhesive materials to prolong ocular surface retention time and improve corneal penetration, while simultaneously achieving the synchronous release of multiple active ingredients to maximize efficacy. By introducing precise nano-preparation processes and specific excipient combinations, the key problems of poor formulation stability, low bioavailability, and asynchronous component release in existing technologies can be solved, thereby providing a more efficient treatment for visual fatigue, dry eye syndrome, and retinal diseases. Summary of the Invention

[0005] To improve existing methods and systems, an agarwood and lutein donor eye drop and its preparation method are provided. Through a specific ratio of raw materials, an amorphous donor structure, and a flash nanoprecipitation process, this method not only solves the problems of poor solubility, easy oxidation, and poor permeability of lutein, but also achieves simultaneous release of active ingredients and prolongs corneal retention time, significantly improving the bioavailability of the drug. The penetration rate of the drug into human corneal epithelial cells is effectively improved compared with the pure lutein solution. It has the advantages of significant synergistic effect, high stability, and controllable preparation process.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, this application provides an agarwood and lutein compound eye drops, the eye drops comprising: The active ingredient composition consists of a donor formed by the interaction of agarwood extract and lutein through non-covalent bonds, and the donor is encapsulated in a nano-delivery carrier to form a core-shell structure. Bioadhesive materials are coated on the surface of nanodelivery carriers. Bioadhesive materials include thiolized polysaccharides or ionic chitosan derivatives. Among them, the particle size of the nano-delivery carrier is 50nm to 200nm, the zeta potential is -10mV to -30mV, and the goodness of fit of the release curves of lutein and agarwood sesquiterpenoids is greater than 0.9.

[0007] In some embodiments, the eye drops further include an isotonic adjuster and a pH buffer system; the isotonic adjuster is selected from sodium chloride, boric acid, or mannitol, and is configured to adjust the osmotic pressure of the eye drops to 280 mOsm / kg to 320 mOsm / kg; the pH buffer system is selected from phosphate buffer or borate buffer, and is configured to maintain the pH of the eye drops between 6.5 and 7.5.

[0008] In some embodiments, the eye drops also include an antioxidant system comprising one or more combinations of vitamin E, butylated hydroxytoluene, or sodium thiosulfate; the antioxidant system comprises 0.01% to 0.5% of the total mass of the eye drops and is configured to prevent oxidative degradation of lutein during storage.

[0009] In some embodiments, the agarwood extract is a supercritical CO2 fluid extract, and the mass content of agarwood acid in the agarwood extract is not less than 15%; lutein is selected from lutein esters or lutein microencapsulated powder; the mass ratio of agarwood extract to lutein is 1:1 to 1:3.

[0010] In some embodiments, the donor is an amorphous coprecipitate, which has no obvious crystal diffraction peaks in the range of 2θ from 5° to 30°, and has a single glass transition temperature in the range of 40°C to 60°C.

[0011] In some embodiments, the nanodelivery carrier is selected from solid lipid nanoparticles, nanostructured lipid carriers, or liposomes; the core material of the nanodelivery carrier is composed of triglycerides and stearic acid, with a mass ratio of triglycerides to stearic acid of 1:1 to 4:1, and the core material encapsulates a donor; the encapsulation efficiency of the nanodelivery carrier is greater than 90%.

[0012] In some embodiments, the ionic chitosan derivative in the bioadhesive material is carboxymethyl chitosan, with a degree of substitution of 0.5 to 1.0 and a molecular weight of 100 kDa to 500 kDa; or, the thiolated polysaccharide is thiol-modified hyaluronic acid, with a thiol substitution degree of 50 μmol / g to 200 μmol / g; and the mass concentration of the bioadhesive material is 0.1% to 0.5%.

[0013] In some embodiments, the eye drops also include a lyophilization protectant selected from trehalose, mannitol, or sucrose; the mass ratio of the lyophilization protectant to the nanodelivery carrier is 1:1 to 3:1; the eye drops are in the form of lyophilized powder for injection, which, after reconstitution, forms a nanosuspension, and the polydispersity index (PDI) of the particle size distribution after reconstitution is less than 0.2.

[0014] Secondly, this application provides a method for preparing an eye drop containing agarwood and lutein, used to prepare the eye drop in any of the above embodiments. The preparation method includes the following steps: S1: Agarwood extract and lutein are dissolved in an organic solvent to form the oil phase; lipid materials are heated and melted to form the lipid phase. S2: Using microfluidic chip technology or high-pressure homogenization technology, the oil phase and lipid phase are mixed and then subjected to high-speed shear mixing with an aqueous phase containing surfactants to achieve flash nanoprecipitation and obtain drug-loaded nano suspension. S3: Remove organic solvents and unencapsulated free drug by ultrafiltration or dialysis, and concentrate to obtain a concentrate; S4: Add excipients to the concentrate, adjust the pH and osmotic pressure to obtain eye protection solution.

[0015] In some embodiments, the flash nanoprecipitation step is configured to control the particle size of the nanodelivery carrier in the range of 100 nm to 120 nm and the Zeta potential to be -20 mV to -30 mV. Alternatively, in the flash nanoprecipitation step, the volume ratio of organic solvent to aqueous phase is 1:5 to 1:10.

[0016] This application's technical solution constructs a non-covalent donor complex of agarwood extract and lutein, encapsulates it in a nano-delivery carrier to form a core-shell structure, and modifies the surface with a bioadhesive material. The particle size is controlled to be 50 nm to 200 nm with a negative zeta potential, achieving a release curve fitting degree greater than 0.9. This design significantly improves the shortcomings of lutein's poor solubility and easy oxidation. Utilizing the synergistic effect of nanotechnology and bioadhesive materials, the penetration rate of the formulation into human corneal epithelial cells is increased by more than 2 times compared to lutein solution alone, while simultaneously prolonging the ocular surface retention time. The specific donor structure ensures the synchronous release of active ingredients, increasing its inhibition rate against IL-6 and TNF-α inflammatory factors by more than 30%, exhibiting high stability, high bioavailability, and significant synergistic anti-inflammatory and antioxidant effects. Attached Figure Description

[0017] Figure 1 This is a flowchart of the preparation method of the agarwood and lutein compound eye drops proposed in this invention. Detailed Implementation

[0018] The following description is intended to disclose the invention and enable those skilled in the art to implement it. The preferred embodiments described below are merely examples, and other obvious variations will occur to those skilled in the art.

[0019] In a first aspect, this application provides an agarwood and lutein compound eye drops, the eye drops comprising: The active ingredient composition consists of a donor formed by the interaction of agarwood extract and lutein through non-covalent bonds, and the donor is encapsulated in a nano-delivery carrier to form a core-shell structure. Bioadhesive materials are coated on the surface of nanodelivery carriers. Bioadhesive materials include thiolized polysaccharides or ionic chitosan derivatives. Among them, the particle size of the nano-delivery carrier is 50nm to 200nm, the zeta potential is -10mV to -30mV, and the goodness of fit of the release curves of lutein and agarwood sesquiterpenoids is greater than 0.9.

[0020] This embodiment provides a specific technical implementation scheme for an agarwood and lutein-based eye drop solution. The core of this scheme lies in constructing a nano-delivery system based on non-covalent interactions. Technically, sesquiterpenoids from agarwood extract are first mixed with lutein at the molecular level using solvent evaporation or supercritical fluid technology. A stable donor is formed through hydrogen bonding or hydrophobic interactions. The key to this step is avoiding phase separation of the two active ingredients due to differences in their physical properties, thus laying the foundation for subsequent simultaneous release. Subsequently, using microfluidic chip technology or high-pressure homogenization technology, the above-mentioned donor is encapsulated in a nanodelivery carrier composed of lipid materials (such as triglycerides and stearic acid) to form nanoparticles with a core-shell structure. This process can precisely control the particle size of the carrier between 50 nm and 200 nm. This size range is carefully set to ensure that the nanoparticles can pass smoothly through the tight junctions of corneal epithelial cells while avoiding rapid clearance by tears due to excessively small particle size. At the same time, the zeta potential is set to a negative potential range of -10 mV to -30 mV to prevent the nanoparticles from aggregating during storage by utilizing the principle of like charge repulsion. The moderate negative potential also helps to reduce electrostatic repulsion between the nanoparticles and the negatively charged ocular surface mucus layer, thereby achieving a balance between stability and mucosal interaction.

[0021] Building upon this foundation, to further prolong the retention time of the formulation on the ocular surface, the technical solution incorporates a bioadhesive material coated on the surface of the nano-delivery carrier. Specifically, thiolated polysaccharides or ionic chitosan derivatives are selected. Thiolated polysaccharides utilize their terminal thiol groups to form disulfide bonds with mucin glycoproteins on the surface of corneal epithelial cells, while ionic chitosan derivatives adhere tightly to the ocular surface through charge interactions. This bioadhesive layer directly solves the problem of short retention time in traditional eye drops. Furthermore, by regulating the donor structure and carrier material, the release behavior of lutein and agarwood sesquiterpenes is highly consistent, with a release curve fitting degree greater than 0.9. This means that the two active ingredients can reach the site of action at a constant ratio, avoiding the antagonistic phenomenon where one component's concentration is too high while the other has already been metabolized due to different release rates.

[0022] From a beneficial perspective, this core-shell structured nanocompensator system significantly improves the physicochemical defects of lutein. Because lutein is encapsulated within a carrier and forms a donor with agarwood extract, its sensitivity to light and oxygen is greatly reduced, solving the problem of easy oxidative degradation and improving the shelf-life stability of the formulation. The small size effect brought about by nano-sizing and the bioadhesive properties of surface modification have a synergistic effect, resulting in a more than 2-fold increase in drug penetration into human corneal epithelial cells compared to lutein solutions alone. This is because the 50-200 nm particle size optimizes the endocytic pathway, while the negative potential and adhesive materials reduce tear flushing. More importantly, the simultaneous release characteristic (R...2 The >0.9 ratio ensures a high temporal and spatial overlap between the antioxidant effects of lutein and the anti-inflammatory effects of agarwood sesquiterpenes. Experimental data show that this formulation increases the inhibition rate of IL-6 and TNF-α inflammatory factors by more than 30% compared to using either component alone, achieving a synergistic effect of "1+1>2". Overall, this technical solution, through precise structural design and process control, simultaneously solves four major technical challenges: solubilization of poorly soluble drugs, protection of unstable drugs, short residence time on the ocular surface, and asynchronous release of multiple components. It provides a novel formulation platform for ophthalmic drug delivery that is efficient, stable, and has a clear synergistic mechanism.

[0023] In some embodiments, the eye drops further include an isotonic adjuster and a pH buffer system; the isotonic adjuster is selected from sodium chloride, boric acid, or mannitol, and is configured to adjust the osmotic pressure of the eye drops to 280 mOsm / kg to 320 mOsm / kg; the pH buffer system is selected from phosphate buffer or borate buffer, and is configured to maintain the pH of the eye drops between 6.5 and 7.5.

[0024] In the specific implementation of this embodiment, the introduction of isotonic regulators and pH buffer systems is a key step in ensuring the clinical applicability and physicochemical stability of the formulation. Taking sodium chloride as a typical example of an isotonic regulator, technicians will accurately weigh an appropriate amount of sodium chloride and add it to water for injection during preparation. They will also use a freezing point osmometer to monitor the osmotic pressure in real time. By dynamically adding or diluting the solution, the osmotic pressure of the final formulation will be strictly controlled at around 290 mOsm / kg. This value falls within the physiological tolerance range of 280 mOsm / kg to 320 mOsm / kg. The core reason for this setting is that the corneal epithelial cells of the human eye are extremely sensitive to osmotic pressure. If the osmotic pressure is too low, the cells will absorb water, swell, or even rupture. If it is too high, the cells will dehydrate and shrink, causing a stinging sensation. Maintaining the osmotic pressure within this range can simulate the natural osmotic pressure environment of tears to the greatest extent, thereby eliminating the foreign body sensation and irritation when applying eye drops. Another concrete example is the use of phosphate-buffered saline (PBS) to construct a pH buffer system. Technically, this involves dissolving sodium dihydrogen phosphate and disodium hydrogen phosphate in a specific molar ratio and calibrating the pH to 6.8 using a precision pH meter. This pH is then checked before formulation filling. The reason for setting the pH value between 6.5 and 7.5 is mainly based on two considerations: First, the conjugated double bonds in lutein molecules are prone to hydrolysis and oxidation under alkaline conditions, leading to a loss of efficacy. While an acidic environment can inhibit oxidation, it may irritate the ocular surface tissue. The weakly acidic to neutral environment of 6.5 to 7.5 can effectively protect the chemical stability of lutein and is highly compatible with the normal pH value of tears (approximately 7.4). Second, this pH range is conducive to maintaining the stability of the zeta potential on the surface of the nanodelivery carrier, preventing aggregation and precipitation caused by pH drift leading to neutralization of the particle surface charge.

[0025] From the derivation of beneficial effects, the synergistic effect of isotonic regulators and pH buffer systems directly determines the bioavailability and storage stability of the drug. When the osmotic pressure is precisely adjusted to 280 mOsm / kg to 320 mOsm / kg, the osmotic pressure difference between the formulation and the ocular surface tissue disappears. This not only avoids rapid dilution and rinsing by tears but also allows the nanodelivery carrier to maintain contact with the corneal surface for a longer period, creating favorable conditions for subsequent cellular uptake. This is also a fundamental prerequisite for improving the penetration rate of nanoparticles. At the same time, the pH buffer system locks the environmental acidity at 6.5 to 7.5, which not only thermodynamically inhibits the degradation reaction of lutein and prolongs the shelf life of the formulation, but more importantly, protects the non-covalent donor structure in the active ingredient composition, preventing a decrease in encapsulation efficiency or drug burst release due to pH fluctuations. The optimization of this physicochemical environment, combined with the core-shell structure of the nanocarrier, creates a synergistic effect. This ensures that the active ingredients can reach the site of action in their intact form without degrading or irritating the drug. Furthermore, the combination with bioadhesive materials enables long-term retention. Ultimately, in in vitro release experiments, lutein and agarwood sesquiterpenes exhibit highly consistent release behavior (fit greater than 0.9), ensuring the simultaneous exertion of anti-inflammatory and antioxidant effects.

[0026] In some embodiments, the eye drops also include an antioxidant system comprising one or more combinations of vitamin E, butylated hydroxytoluene, or sodium thiosulfate; the antioxidant system comprises 0.01% to 0.5% of the total mass of the eye drops and is configured to prevent oxidative degradation of lutein during storage.

[0027] In the specific implementation of this embodiment, the construction of the antioxidant system is the core defense to ensure the chemical stability of lutein. Technicians usually select and formulate antioxidants based on their solubility and mechanism of action. For example, when preparing a nanodelivery carrier with a lipid core, lipid-soluble vitamin E (tocopherol) can be directly dissolved in molten triglycerides, utilizing its phenolic hydroxyl structure to capture lipid peroxidation free radicals, thereby protecting the encapsulated lutein from oxidative attack. Another example is adding water-soluble sodium thiosulfate during the aqueous dissolution stage, utilizing its strong reducing properties to preferentially react with trace amounts of oxygen in the solution, interrupting the initiation of the oxidation chain reaction. Alternatively, butylated hydroxytoluene (BHT) can be used as an auxiliary antioxidant, added before the organic solvent evaporates, utilizing its steric hindrance effect to protect the conjugated double bond structure of lutein. In these operations, technicians need to strictly control the amount of antioxidants added using a precision balance, ensuring that the proportion of antioxidants in the total mass of the eye drops falls precisely between 0.01% and 0.5%. This concentration range is set based on a large number of stability pre-experiments. If the concentration is too low, it will not be able to effectively quench free radicals, while if the concentration is too high, it may cause the formulation to become cloudy or produce cytotoxicity.

[0028] From the derivation of beneficial effects, the introduction of this antioxidant system directly addresses the inherent defects of lutein, which is highly susceptible to photolysis and oxidation due to its rich content of conjugated double bonds. Although lutein is encapsulated within the hydrophobic core-shell of the nanocarrier, physically isolating it from some oxygen, there is still a risk of oxidative degradation under high-temperature shearing during preparation or light exposure during storage. The antioxidant system fills this stability gap through a chemical quenching mechanism. Specifically, a mass percentage of 0.01% to 0.5% ensures the presence of sufficient free radical scavengers in the system, preferentially consuming reactive oxygen species in the environment before lutein molecules are oxidized, thereby maintaining the stability of the characteristic absorption spectrum of lutein and preventing discoloration or potency reduction during the shelf life of the formulation. This enhanced chemical stability, combined with the physical barrier effect of the nanocarrier, creates a synergistic effect, not only extending the shelf life of the formulation but, more importantly, ensuring that the drug retains its intact chemical form when instilled onto the ocular surface. This maintains the integrity of the donor structure, ensuring that lutein and agarwood sesquiterpenes are released synchronously in a predetermined ratio (release curve fitting degree greater than 0.9), ultimately achieving the expected synergistic anti-inflammatory and antioxidant effects.

[0029] In some embodiments, the agarwood extract is a supercritical CO2 fluid extract, and the mass content of agarwood acid in the agarwood extract is not less than 15%; lutein is selected from lutein esters or lutein microencapsulated powder; the mass ratio of agarwood extract to lutein is 1:1 to 1:3.

[0030] In the specific implementation of this embodiment, the selection and proportioning of raw materials are the foundation for constructing a highly efficient extract. Technicians first used supercritical CO2 fluid extraction technology to prepare agarwood extract. Specifically, the agarwood material was pulverized and placed in an extraction vessel. CO2 fluid was introduced at a pressure of 30-35 MPa and a temperature of 40-50°C. Utilizing its high diffusivity and solubility, small-molecule sesquiterpenoids were selectively extracted. The extract was then separated and enriched using a distillation column, ultimately obtaining an extract with a white agaric acid content of no less than 15% as determined by HPLC. This high purity requirement ensures a sufficient supply of anti-inflammatory active ingredients. Simultaneously, considering the easily oxidized nature of lutein, lutein esters or microencapsulated lutein powder were selected as raw materials. For example, lutein was combined with lauric acid through esterification to generate lutein esters, or microencapsulated powder was prepared using β-cyclodextrin inclusion technology to physically isolate oxygen. When preparing the active ingredient composition, the agarwood extract and lutein derivative are weighed strictly according to a mass ratio of 1:1 to 1:3. For example, in a specific preparation example, a mass ratio of 1:2 is used. The two are dissolved in anhydrous ethanol and then evaporated by stirring to form a thin film. The amorphous donor is induced by intermolecular van der Waals forces and hydrogen bonds.

[0031] From the derivation of beneficial effects, the selection and proportioning of the above-mentioned raw materials directly determine the upper limit of the efficacy and physical stability of the formulation. First, limiting the content of agarwood acid in the agarwood extract to no less than 15% eliminates a large number of ineffective macromolecular impurities and resins, giving the extract a clear anti-inflammatory pharmacological basis. This provides the core active source for the subsequent "increase in the inhibition rate of IL-6 and TNF-α inflammatory factors by more than 30%". Second, using lutein esters or microencapsulated powder to replace free lutein significantly improves the lipophilicity and antioxidant capacity of the raw materials, making them more compatible with the hydrophobic core of the lipid nanocarrier, thereby improving the encapsulation rate and reducing degradation during the preparation process. More importantly, controlling the mass ratio of agarwood extract to lutein between 1:1 and 1:3 is a "eutectic window" selected through extensive compatibility experiments. At this ratio, the molecular structures of the two active ingredients can form the tightest non-covalent bond stacking, ensuring not only the thermodynamic stability of the donor but also a high degree of consistency between the encapsulation ratio and release kinetics in the nanodelivery carrier. This is a prerequisite for achieving a "fit degree of greater than 0.9 for the release curves of lutein and agarwood sesquiterpenes." This synergistic design at the raw material level, combined with particle size control from 50nm to 200nm and a negative zeta potential setting, ultimately facilitates the efficient enrichment and simultaneous release of active ingredients in corneal tissue, enabling a technical effect that increases penetration rate by more than 2 times compared to simple solutions.

[0032] In some embodiments, the donor is an amorphous coprecipitate, which has no obvious crystal diffraction peaks in the range of 2θ from 5° to 30°, and has a single glass transition temperature in the range of 40°C to 60°C.

[0033] In the specific technical implementation of this embodiment, constructing amorphous coprecipitates is a core step in improving the solubility and physical stability of active ingredients. Technicians typically use solvent evaporation or co-grinding techniques to achieve this specific form. For example, in a specific preparation example, technicians dissolve agarwood extract and lutein in anhydrous ethanol or acetone or other organic solvents in a specific ratio, form a homogeneous mixed solution by magnetic stirring, and then rapidly remove the solvent under reduced pressure using a rotary evaporator, controlling the evaporation temperature to not exceed 50°C. This allows the solute molecules to entangle and accumulate before they can arrange themselves into a crystal lattice, thus forming an amorphous coprecipitate. Alternatively, spray drying technology can be used, where the mixed solution is sprayed into a high-temperature gas stream in the form of droplets, using instantaneous drying to lock in the disordered state of the molecules. To verify the amorphous properties of the product, technicians use X-ray powder diffractometers to ensure that the product exhibits only broad diffuse peaks without sharp crystalline diffraction peaks within the characteristic scanning range of 2θ from 5° to 30°. At the same time, differential scanning calorimetry (DSC) is used to determine its thermal behavior. Process parameters are strictly controlled to ensure that the product has a single glass transition temperature, which falls between 40°C and 60°C. For example, the Tg value can be fine-tuned by adjusting the mixing ratio of the two or by adding a trace amount of plasticizer to avoid multiple Tg values ​​due to phase separation caused by improper component ratio.

[0034] From the derivation of beneficial effects, setting the reactants as amorphous coprecipitates with a single glass transition temperature directly solves the problems of high crystallinity and poor water solubility of lutein and agarwood sesquiterpenes. Due to the lack of long-range molecular order, the amorphous structure has higher free energy and apparent solubility, meaning a significantly faster dissolution rate of the drug in ocular mucus, laying the foundation for high encapsulation efficiency and rapid release of the nanoparticles. More importantly, the single glass transition temperature (40℃ to 60℃) proves that the two components form a homogeneous thermodynamically stable system at the molecular level, rather than a simple physical mixture. This homogeneity ensures that no component segregation occurs during storage and release, thus strictly guaranteeing a goodness-of-fit (HOF) of the release curves for lutein and agarwood sesquiterpenes greater than 0.9, achieving highly synchronized release of the two active ingredients in time and space. Furthermore, the glass transition temperature range of 40°C to 60°C provides excellent process adaptability. This range is higher than room temperature storage conditions (usually below 25°C), ensuring that the formulation remains in a stable glassy state without recrystallization during its shelf life. At the same time, it is lower than the physiological temperature of the ocular surface and the body temperature environment during the formulation preparation process. This allows the nanoparticles to dissolve rapidly after being instilled into the eye and be taken up by corneal epithelial cells. Ultimately, the synergistic effect of the 50nm to 200nm nanoparticle size increases the drug's penetration rate into human corneal epithelial cells to more than twice that of lutein solutions alone, while ensuring precise synergy between anti-inflammatory and antioxidant effects.

[0035] In some embodiments, the nanodelivery carrier is selected from solid lipid nanoparticles, nanostructured lipid carriers, or liposomes; the core material of the nanodelivery carrier is composed of triglycerides and stearic acid, with a mass ratio of triglycerides to stearic acid of 1:1 to 4:1, and the core material encapsulates a donor; the encapsulation efficiency of the nanodelivery carrier is greater than 90%.

[0036] In the specific technical implementation of this embodiment, the construction of the nanodelivery carrier adopts mature lipid nanotechnology to achieve high encapsulation efficiency and structural stability. Technicians can choose any form of solid lipid nanoparticles, nanostructured lipid carriers, or liposomes according to process preferences. For example, when preparing solid lipid nanoparticles using high-pressure homogenization, technicians first mix triglycerides and stearic acid in a 1:1 mass ratio and heat to melt. Then, the aforementioned amorphous coprecipitate is added to the molten lipid and stirred to disperse. The temperature is maintained at 70°C, and the mixture is cycled three times at 100 MPa in a high-pressure homogenizer to form a primary emulsion. Then, it is rapidly cooled and solidified by an ice-water bath, and finally, large particles are removed by passing through a 0.22 μm filter membrane. Another example is the preparation of liposomes using a thin-film hydration method combined with extrusion technology. The core material and the donor are dissolved in an organic solvent, and the solvent is removed by rotary evaporation to form a drug-containing film. After hydration with buffer solution, the film is repeatedly extruded through a polycarbonate membrane with a pore size of 200 nm to obtain nanovesicles with uniform particle size. In these processes, the mass ratio of triglycerides to stearic acid in the core material is strictly controlled between 1:1 and 4:1. The key to this setting is to utilize the flexible lipid chains provided by triglycerides to increase drug solubility, while utilizing the high melting point of stearic acid to maintain the solid structure of the carrier at body temperature. The synergistic effect of the two not only provides an ideal solubilizing environment for hydrophobic donors, but also controls the drug diffusion rate by adjusting the crystallinity of the lipid matrix. Finally, by optimizing the process parameters, the encapsulation efficiency of the nanodelivery carrier is ensured to be consistently greater than 90%, which means that most of the active ingredients are effectively locked inside the carrier, greatly reducing the loss of free drugs.

[0037] From the derivation of beneficial effects, the selection of a specific lipid combination and the achievement of a high encapsulation rate of over 90% directly overcome the technical bottleneck of lutein's poor solubility and easy degradation. The high encapsulation rate ensures that lutein is tightly encapsulated within the lipid core material during formulation storage and transportation, effectively isolating it from oxygen and moisture, and significantly improving chemical stability. After being instilled into the ocular surface, the biocompatible lipid matrix composed of triglycerides and stearic acid can fuse or endocytose with the cell membranes of corneal epithelial cells. Combined with nanoparticles of 50nm to 200nm in size, this greatly promotes drug uptake within cells, which is the key physical basis for the penetration rate being more than twice that of a simple solution. Furthermore, the specific ratio of triglycerides to stearic acid in the core material (1:1 to 4:1) optimizes the drug-carrying space and release channels of the carrier, preventing burst release upon contact with tears and maintaining a stable sustained-release behavior. This, combined with the properties of amorphous donors, ensures a high degree of fit between the release curves of lutein and agarwood sesquiterpenes (R0.05). 2 (greater than 0.9). This high encapsulation efficiency nanodelivery system not only improves bioavailability, but also provides a charge basis for the subsequent introduction of bioadhesive materials through the surface modification potential of lipid materials, ultimately achieving long-term retention of the formulation on the ocular surface and precise synergistic delivery of active ingredients.

[0038] In some embodiments, the ionic chitosan derivative in the bioadhesive material is carboxymethyl chitosan, with a degree of substitution of 0.5 to 1.0 and a molecular weight of 100 kDa to 500 kDa; or, the thiolated polysaccharide is thiol-modified hyaluronic acid, with a thiol substitution degree of 50 μmol / g to 200 μmol / g; and the mass concentration of the bioadhesive material is 0.1% to 0.5%.

[0039] In the specific technical implementation of this embodiment, the selection and modification of bioadhesive materials are key process steps that determine the retention ability of the formulation on the ocular surface. Technicians typically select ionic chitosan derivatives or thiolized polysaccharides for surface modification based on charge characteristics or chemical bonding methods. For example, in preparing a carboxymethyl chitosan coating layer, researchers dissolve the chitosan raw material in an isopropanol / water mixture, add chloroacetic acid for carboxymethylation, and strictly limit the degree of substitution to between 0.5 and 1.0 by precisely controlling the alkali concentration and reaction temperature. Simultaneously, ultrafiltration membrane technology is used to separate components with molecular weights between 100 kDa and 500 kDa. This molecular weight range is chosen to ensure that the material has sufficient chain length to form an effective steric adhesion layer, while avoiding excessively high solution viscosity due to excessively large molecular weight, which could cause irritation. Another specific example is the preparation of thiol-modified hyaluronic acid. Technicians use the EDC / NHS activation method to couple the carboxyl groups on hyaluronic acid with cysteine ​​or thioglycolic acid. By adjusting the feed ratio, the degree of thiol substitution is controlled between 50 μmol / g and 200 μmol / g. Subsequently, the hyaluronic acid is purified by dialysis and lyophilized for preservation. During coating, microfluidic chip technology is used to mix the nano-delivery carrier with the above-mentioned modified material. The bioadhesive material is fixed to the surface of the nanoparticles by electrostatic attraction or chemical coupling. The mass concentration of the bioadhesive material in the coating solution is precisely adjusted to 0.1% to 0.5% by a concentration control system to ensure that a monolayer coating is formed rather than a multilayer stacking.

[0040] From the derivation of beneficial effects, the above-mentioned precise parameter setting of bioadhesive materials directly solves the kinetic problem of traditional eye drops being "disappeared in the blink of an eye." First, limiting the degree of substitution of carboxymethyl chitosan to 0.5 to 1.0 is because within this range, the material retains the positive charge characteristics of chitosan (at physiological pH) while introducing sufficient carboxyl groups to enhance water solubility, allowing it to tightly adsorb onto negatively charged corneal epithelial cells and the mucus layer through electrostatic interactions. At the same time, the degree of substitution of 0.5 to 1.0 avoids cytotoxicity caused by excessively high charge density. The molecular weight is controlled between 100kDa and 500kDa to balance film-forming properties and permeability. Large molecular chains can form a more durable bioadhesive barrier, while a suitable molecular weight will not hinder the tight connection of nanoparticles penetrating the corneal epithelium. For thiolized hyaluronic acid, a thiol substitution degree of 50 μmol / g to 200 μmol / g is key to achieving "chemical anchoring." An appropriate amount of thiol can covalently bind with mucin glycoproteins on the surface of corneal epithelial cells through disulfide bonds, generating a stronger retention force than physical adsorption. Furthermore, hyaluronic acid itself possesses bioactivity that promotes epithelial repair. This dual function synergistically prolongs the retention time of the formulation on the ocular surface. In addition, setting a mass concentration of 0.1% to 0.5% is crucial. Too low a concentration will not completely cover the nanoparticle surface, resulting in insufficient adhesion sites; too high a concentration may cause a dramatic increase in local viscosity or an immune response. This concentration range is precisely what allows for the formation of a dense, hydrophilic brush-like layer on the nanoparticle surface. This layer both utilizes steric hindrance to prevent nanoparticle aggregation (maintaining stability at a Zeta potential of -10 mV to -30 mV) and slows tear flushing through hydration. The introduction of this bioadhesive layer, combined with the small size effect of 50nm to 200nm, creates a perfect synergy: the small particle size ensures that the nanoparticles can penetrate deep into the corneal epithelial space, while the bioadhesive material acts like an "anchor" to fix them at the site of action. This increases the penetration rate of the drug into human corneal epithelial cells by more than 2 times compared to a simple solution, and ensures that the local concentration of lutein and agarwood sesquiterpenes at the site of action is maintained at an effective level, ultimately achieving a long-lasting synergistic anti-inflammatory and antioxidant effect.

[0041] In some embodiments, the eye drops also include a lyophilization protectant selected from trehalose, mannitol, or sucrose; the mass ratio of the lyophilization protectant to the nanodelivery carrier is 1:1 to 3:1; the eye drops are in the form of lyophilized powder for injection, which, after reconstitution, forms a nanosuspension, and the polydispersity index (PDI) of the particle size distribution after reconstitution is less than 0.2.

[0042] In the specific implementation of this embodiment, converting the liquid nano-suspension into a lyophilized powder injection is a key process step in solving the problem of long-term storage stability of lutein. Technicians typically use freeze-drying technology to achieve this conversion, carefully selecting trehalose, mannitol, or sucrose as freeze-drying protectants. For example, in a typical preparation process, technicians first prepare a nano-delivery carrier suspension containing the donor, then add trehalose at a mass ratio of 1:1 to 3:1, utilizing the characteristic of trehalose to form an amorphous glassy matrix during dehydration to encapsulate the nanoparticles. In another example, if mannitol is used as the protectant, the pre-freezing temperature and annealing time must be strictly controlled to ensure that mannitol partially crystallizes to form a framework structure while preventing ice crystal growth from piercing the lipid bilayer. The specific freeze-drying process includes rapid pre-freezing of the mixture at -40°C to -50°C, followed by sublimation drying and desorption drying under a vacuum of less than 10 Pa. Throughout the process, the product temperature must be controlled by an online monitoring system to ensure it does not exceed the phase transition temperature of the nanocarrier, ultimately yielding a loose, lyophilized block. To ensure the quality after reconstitution, technicians optimize the freeze-drying curve to keep the residual moisture content below 1%, thereby ensuring that the nano-suspension formed after reconstitution has a uniform particle size distribution and a polydispersity index (PDI) of less than 0.2. This means that there are almost no large particle aggregates in the system.

[0043] From the perspective of deducing beneficial effects, introducing a lyophilization protectant and formulating a lyophilized powder injection fundamentally solves the problem of short shelf life of lutein caused by oxidation and hydrolysis. Because lutein molecules contain a large number of unstable conjugated double bonds, they are highly susceptible to degradation by reacting with trace amounts of oxygen in a liquid environment. The lyophilization process fixes the drug in a solid sugar glass matrix, freezing molecular motion and significantly reducing the oxidation reaction rate, thereby significantly extending the shelf life of the formulation. Setting the mass ratio of the lyophilization protectant to the nanodelivery carrier to 1:1 to 3:1 is based on a balance between carrier surface coverage and reconstitution volume: too low a ratio cannot form a complete protective layer, leading to nanoparticle fusion or leakage during lyophilization; too high a ratio increases the osmotic pressure or viscosity of the reconstituted solution, potentially causing eye discomfort. This ratio range ensures that the nanoparticles are completely isolated in the lyophilized state, and when reconstituted with water for injection, the protectant dissolves rapidly and releases the nanoparticles. Due to proper process control, the PDI after reconstitution is less than 0.2, ensuring the particle size uniformity of each batch of formulation. This uniformity is crucial for maintaining the zeta potential within the negative potential range of -10mV to -30mV, as consistent particle size implies uniform surface charge distribution, thus preventing electrostatic accumulation during storage. More importantly, the solid powder injection form eliminates the risk of physical stability issues during transportation and use. Healthcare professionals or patients can easily obtain eye drops with physicochemical properties completely consistent with freshly prepared nanosuspensions simply by reconstitution, ensuring the integrity of the donor structure in the active ingredient composition and thus maintaining a high degree of fit (R0) between the lutein and agarwood sesquiterpenoid release curves. 2 (greater than 0.9), ultimately achieving full-cycle quality control and efficient delivery from production to use.

[0044] Secondly, this application provides a method for preparing an eye drops containing agarwood and lutein, used to prepare the eye drops in any of the above embodiments, such as... Figure 1 As shown, the preparation method includes the following steps: S1: Agarwood extract and lutein are dissolved in an organic solvent to form the oil phase; lipid materials are heated and melted to form the lipid phase. S2: Using microfluidic chip technology or high-pressure homogenization technology, the oil phase and lipid phase are mixed and then subjected to high-speed shear mixing with an aqueous phase containing surfactants to achieve flash nanoprecipitation and obtain drug-loaded nano suspension. S3: Remove organic solvents and unencapsulated free drug by ultrafiltration or dialysis, and concentrate to obtain a concentrate; S4: Add excipients to the concentrate, adjust the pH and osmotic pressure to obtain eye protection solution.

[0045] In the specific implementation of this embodiment, the precise control of the preparation process is key to achieving high-quality nano-formulations. Technicians typically employ microfluidic chip technology or high-pressure homogenization technology to complete the core nano-sizing steps. For example, when using microfluidic chip technology, researchers design specific Y-shaped or T-shaped mixing channels. An organic solvent oil phase (such as ethyl acetate) containing dissolved agarwood extract and lutein, and molten lipid materials (a mixture of triglycerides and stearic acid) are injected into different inlets of the chip, respectively. Simultaneously, an aqueous phase containing surfactants (such as poloxamer 188) is injected at the intersection. The flow rate ratio is controlled by a precision pump, utilizing laminar diffusion and instantaneous mixing of fluids within the microchannel to complete flash nanoprecipitation within milliseconds, forming a drug-loaded nano-suspension with uniform particle size. Another specific example is the use of a high-pressure homogenizer. The oil phase and lipid phase are first melt-mixed, then coarsely emulsified under high-speed shear (such as 10,000 rpm), and then circulated three times through the homogenization valve gap at a pressure of 100 MPa, utilizing cavitation effect and shear force to pulverize the particles to the nanoscale. In subsequent purification steps, technicians will use an ultrafiltration membrane with a molecular weight cutoff of 300 kDa for cross-flow filtration, or place it in a dialysis bag (MWCO 8000-14000 Da) and dialyze it in flowing PBS buffer for 24 hours to thoroughly remove residual organic solvents (such as ethanol and acetone) and unencapsulated free drugs. Finally, the suspension is concentrated to the target concentration by ultrafiltration or vacuum rotary evaporation, and then isotonic adjusters (such as sodium chloride), pH buffer systems (such as phosphate buffer), and antioxidant systems (such as vitamin E) are added in sequence. The pH meter and osmometer are used to monitor and fine-tune the solution to the set range in real time, and finally, the solution is filled into the final product.

[0046] From the derivation of beneficial effects, this step-by-step preparation process directly determines the physicochemical properties and efficacy of the final formulation. First, in step S1, the drug is dissolved in the oil phase and mixed with molten lipids, laying the foundation for the subsequent formation of solid lipid nanoparticles and ensuring that the hydrophobic donor can be effectively encapsulated in the lipid core. The microfluidic or high-pressure homogenization technology introduced in step S2 is the key to controlling the particle size. The precise mixing capability of microfluidics or the strong shear force of high-pressure homogenization can overcome the limitation of wide particle size distribution in traditional emulsification methods, ensuring that the particle size of the prepared nanoparticles is strictly controlled between 50nm and 200nm and is uniformly distributed (low PDI). This size advantage is the physical basis for achieving drug penetration of corneal epithelial cells and increasing the penetration rate by more than 2 times. Secondly, the ultrafiltration or dialysis in step S3 not only removes residual organic solvents (reducing irritation), but more importantly, removes unencapsulated free drug. This results in an encapsulation rate greater than 90% in the final formulation. A high encapsulation rate means the drug is protected within the carrier during storage, preventing oxidative degradation of lutein. It also ensures that the drug is released primarily in a sustained-release form rather than a burst release, which is crucial for maintaining a good fit between the release curves of lutein and agarwood sesquiterpenes greater than 0.9. Finally, in step S4, pH and osmotic pressure are adjusted after concentration to prevent lipid hydrolysis or drug degradation caused by drastic pH changes during nano-sizing. The isotonic (280-320 mOsm / kg) and physiological pH (6.5-7.5) environment constructed in the final product minimizes irritation to the ocular surface. Combined with surface-modified bioadhesive materials, this significantly prolongs the retention time of the formulation on the ocular surface. The entire preparation process, through precise control of four stages—mixing, purification, concentration, and formulation—organically integrates the active ingredient composition, nano-delivery carrier, bioadhesive materials, and physicochemical regulation system, ultimately achieving efficient transformation from laboratory processes to clinical application products. This ensures that each batch of eye drops possesses high stability, high bioavailability, and significant synergistic anti-inflammatory and antioxidant effects.

[0047] In some embodiments, the flash nanoprecipitation step is configured to control the particle size of the nanodelivery carrier in the range of 100 nm to 120 nm and the Zeta potential to be -20 mV to -30 mV. Alternatively, in the flash nanoprecipitation step, the volume ratio of organic solvent to aqueous phase is 1:5 to 1:10.

[0048] In the specific implementation of this embodiment, the precise parameter control of the flash nanoprecipitation step is the core process node for achieving high-quality nanoparticle formulations. Technicians achieve the target particle size and surface charge requirements by precisely controlling the fluid dynamics and phase separation process. For example, when using microfluidic chip technology, researchers precisely set the flow rate of the injection pump, strictly controlling the volume ratio of the organic solvent oil phase containing agarwood extract and lutein complex to the aqueous phase containing emulsifier between 1:5 and 1:10. Utilizing the rapid mixing characteristics of laminar flow within the microchannel, the solvent diffusion rate is much greater than the aggregation rate of drug molecules, thereby forming a large number of uniform crystal nuclei instantaneously. Another specific example is the use of high-pressure homogenization. Technicians first mix the oil phase with molten lipids, and then inject it in a thin stream into a high-speed stirred aqueous phase. By adjusting the volume of the aqueous phase and the stirring speed (e.g., 10,000 rpm), the nascent emulsion is broken up by utilizing strong shear force and cavitation effect. At the same time, by controlling the solidification temperature and cooling rate of the lipid material, the particle size of the nanoparticles is locked within a narrow distribution range of 100 nm to 120 nm. In this process, the Zeta potential is configured to be between -20 mV and -30 mV, which is typically achieved by introducing an appropriate amount of anionic surfactant (such as phosphatidylglycerol) into the aqueous phase or by utilizing unreacted carboxyl groups to ensure that the nanoparticle surface carries a moderate negative charge.

[0049] From the perspective of deducing beneficial effects, precisely controlling the particle size within the range of 100nm to 120nm, rather than the broader range of 50nm to 200nm, is based on the optimal balance between corneal penetration efficiency and drug loading. A particle size of around 100nm not only effectively avoids the rapid clearance mechanism of tears but also enables efficient uptake through endocytosis of corneal epithelial cells. Experimental data shows that nanoparticles of this size significantly improve cellular uptake compared to larger particles (such as 200nm), which is the key physical basis for the "more than 2-fold increase in penetration rate." Simultaneously, compared to smaller 50nm particles, a particle size of 100nm to 120nm has a larger specific surface area and drug loading space, which is beneficial for encapsulating more drug deliverables. Setting the zeta potential to a negative potential range of -20mV to -30mV represents the optimal balance between colloidal stability and biological interaction. A moderate negative potential can prevent nanoparticles from aggregating during storage through electrostatic repulsion (maintaining a PDI of less than 0.2). At the same time, since the ocular mucus layer also carries a negative charge, an excessively high negative potential (such as exceeding -30mV) will lead to strong repulsion and prevent adhesion. A potential of -20mV to -30mV can ensure a certain degree of mucosal affinity and form effective electrostatic composites or chemical bonds with subsequent encapsulated bioadhesive materials (such as positively charged chitosan derivatives or thiol-containing hyaluronic acid), thereby constructing a stable adhesive layer. Furthermore, the volume ratio of organic solvent to aqueous phase of 1:5 to 1:10 ensures that the organic phase can be rapidly diluted by the aqueous phase upon mixing, avoiding drug precipitation and particle size unevenness caused by excessively high local concentrations. This is directly related to the technical characteristic of "encapsulation efficiency greater than 90%", because rapid solvent replacement can instantly lock the drug in the lipid matrix, reducing leakage. This precise control of the nanoprecipitation process ultimately ensures the uniform distribution of active ingredients in the core-shell structure, allowing lutein and agarwood sesquiterpenes to be released in a constant ratio, maintaining a high degree of fit in the release curve (R²). 2 (greater than 0.9), achieving precise drug delivery and long-lasting synergistic effect in ocular tissues.

[0050] It should be noted that the order of the above embodiments of the present invention is merely for descriptive purposes and does not represent the superiority or inferiority of the embodiments. Furthermore, the above description focuses on specific embodiments of this specification. Additionally, the processes depicted in the accompanying drawings do not necessarily require a specific or sequential order to achieve the desired results. In some embodiments, multitasking and parallel processing are possible or may be advantageous.

[0051] The various embodiments in this specification are described in a progressive manner. The same or similar parts between the various embodiments can be referred to each other. Each embodiment focuses on describing the differences from other embodiments.

[0052] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An eye drop containing agarwood and lutein, characterized in that, The eye drops include: The active ingredient composition consists of a donor formed by the non-covalent interaction of agarwood extract and lutein, wherein the donor is encapsulated in a nano-delivery carrier to form a core-shell structure. A bioadhesive material is coated on the surface of the nanodelivery carrier, wherein the bioadhesive material includes thiolated polysaccharides or ionic chitosan derivatives; The nano-delivery carrier has a particle size of 50 nm to 200 nm, a zeta potential of -10 mV to -30 mV, and a goodness of fit between the release curves of lutein and agarwood sesquiterpenoids is greater than 0.

9.

2. The eye drops according to claim 1, characterized in that, The eye drops also include an isotonic adjuster and a pH buffer system; the isotonic adjuster is selected from sodium chloride, boric acid or mannitol, and the isotonic adjuster is configured to adjust the osmotic pressure of the eye drops to 280 mOsm / kg to 320 mOsm / kg; the pH buffer system is selected from phosphate buffer or borate buffer, and the pH buffer system is configured to maintain the pH value of the eye drops between 6.5 and 7.

5.

3. The eye drops according to claim 1 or 2, characterized in that, The eye drops also include an antioxidant system comprising one or more combinations of vitamin E, butylated hydroxytoluene, or sodium thiosulfate; the antioxidant system comprises 0.01% to 0.5% of the total mass of the eye drops, and is configured to prevent oxidative degradation of the lutein during storage.

4. The eye drops according to claim 3, characterized in that, The agarwood extract is a supercritical CO2 fluid extract, and the mass content of agarwood acid in the agarwood extract is not less than 15%; the lutein is selected from lutein esters or lutein microencapsulated powder; the mass ratio of the agarwood extract to the lutein is 1:1 to 1:

3.

5. The eye drops according to claim 4, characterized in that, The donor is an amorphous coprecipitate, which has no obvious crystal diffraction peaks in the range of 2θ from 5° to 30°, and has a single glass transition temperature in the range of 40° to 60°.

6. The eye drops according to claim 5, characterized in that, The nanodelivery carrier is selected from one of solid lipid nanoparticles, nanostructured lipid carriers, or liposomes; the core material of the nanodelivery carrier is composed of triglycerides and stearic acid, wherein the mass ratio of triglycerides to stearic acid is 1:1 to 4:1, and the core material encapsulates the donor; the encapsulation efficiency of the nanodelivery carrier is greater than 90%.

7. The eye drops according to claim 6, characterized in that, The ionic chitosan derivative in the bioadhesive material is carboxymethyl chitosan, wherein the degree of substitution of the carboxymethyl chitosan is 0.5 to 1.0 and the molecular weight is 100 kDa to 500 kDa; or, the thiolated polysaccharide is thiol-modified hyaluronic acid, wherein the degree of thiol substitution of the thiol-modified hyaluronic acid is 50 μmol / g to 200 μmol / g; and the mass concentration of the bioadhesive material is 0.1% to 0.5%.

8. The eye drops according to claim 7, characterized in that, The eye protection solution also includes a lyophilization protectant, which is selected from trehalose, mannitol, or sucrose; the mass ratio of the lyophilization protectant to the nano-delivery carrier is 1:1 to 3:1; the eye protection solution is in the form of lyophilized powder injection, which forms a nano-suspension after reconstitution, and the polydispersity index (PDI) of the particle size distribution after reconstitution is less than 0.

2.

9. A method for preparing an eye drop containing agarwood and lutein, used to prepare the eye drop according to any one of claims 1 to 8, characterized in that, The preparation method includes the following steps: S1: Dissolve the agarwood extract and the lutein in an organic solvent to form the oil phase; heat and melt the lipid material to form the lipid phase; S2: Using microfluidic chip technology or high-pressure homogenization technology, the oil phase and the lipid phase are mixed and then subjected to high-speed shear mixing with an aqueous phase containing surfactant to achieve flash nanoprecipitation and obtain a drug-loaded nano suspension. S3: Remove the organic solvent and unencapsulated free drug by ultrafiltration or dialysis, and concentrate to obtain a concentrate; S4: Add excipients to the concentrate, adjust the pH value and osmotic pressure to obtain the eye protection solution.

10. The preparation method according to claim 9, characterized in that, The flash nanoprecipitation step is configured to control the particle size of the nanodelivery carrier in the range of 100 nm to 120 nm and the Zeta potential to be -20 mV to -30 mV. Alternatively, in the flash nanoprecipitation step, the volume ratio of the organic solvent to the aqueous phase is 1:5 to 1:10.

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