A composite plant extract eye drop for relieving eye fatigue and a preparation method thereof

Abstract

The application discloses a kind of composite plant extract eye drops for relieving eye fatigue and a preparation method thereof, and relates to the technical field of ophthalmic preparations.The eye drops of the present application use lutein, zeaxanthin, blueberry extract, peppermint essential oil and borneol as fat-soluble active ingredients, and use phospholipid and poloxamer 188 as a composite nanocarrier, in combination with sodium hyaluronate, sodium chloride and a buffer system, a bacteriostatic system to form the eye drops.The present application uses a film hydration combined with high-pressure homogenization process to produce clear and transparent, thermodynamically stable eye drops, which solves the problems of low solubility, easy oxidative degradation and poor bioavailability of fat-soluble ingredients, improves the concentration and retention time of active ingredients in the eye, and the synergistic effect of various plant extracts can effectively relieve the symptoms of eye fatigue caused by long-term eye use, such as dryness, acid swelling, blurred vision and ciliary spasm, without eye irritation and with high stability.

Description

Technical Field

[0001] This invention relates to the field of ophthalmic preparations technology, specifically to a compound plant extract eye drop for relieving eye fatigue and its preparation method. Background Technology

[0002] With the widespread use of electronic devices, the incidence of eye strain is showing a trend towards younger ages. Eye strain mainly manifests as dry eyes, soreness, photophobia, blurred vision, tearing, and a foreign body sensation. In severe cases, it can induce dry eye syndrome, refractive errors, and eye inflammation. Currently, the main clinical methods for relieving eye strain include artificial tears, compound herbal eye drops, and nutritional supplements.

[0003] Several eye drops for relieving eye fatigue have been reported in existing technologies. For example, artificial tears based on sodium hyaluronate and sodium chloride can relieve dry eye symptoms through physical lubrication, but lack antioxidant and retinal damage repair functions. Eye drops with extracts of traditional Chinese medicines such as cassia seed, honeysuckle, and wolfberry as the main ingredients have the effects of clearing heat and detoxifying, and improving vision and removing corneal opacity, but their effective ingredients are mainly water-soluble polysaccharides and flavonoids, which cannot effectively carry lipid-soluble eye-protecting ingredients. In addition, although cooling ingredients such as menthol and borneol can temporarily relieve eye discomfort, they are highly irritating when directly dissolved in the aqueous phase, and some users have experienced adverse reactions such as stinging and tearing.

[0004] Lutein and zeaxanthin are key components of macular pigment in the retina, playing important roles in filtering blue light, anti-oxidation, and protecting photoreceptor cells. Blueberry extract is rich in anthocyanins, which can promote rhodopsin regeneration and improve ocular microcirculation. However, both are fat-soluble or poorly soluble substances and cannot be directly dissolved in conventional aqueous eye drops. If used in suspension form, not only is the bioavailability extremely low, but crystals are also prone to precipitating and irritating the ocular surface. Therefore, how to effectively combine fat-soluble components such as lutein, zeaxanthin, blueberry extract, menthol, and borneol with water-soluble plant extracts such as cassia seed, honeysuckle, and wolfberry, as well as lubricating components such as sodium hyaluronate, to produce a clear, stable, non-irritating eye drop with high bioavailability is a technical challenge that urgently needs to be solved in this field.

[0005] To address the aforementioned issues, while existing technologies have attempted to utilize cyclodextrin inclusion, microemulsion, and liposome techniques, these generally suffer from low drug loading, poor stability, complex preparation processes, or incomplete elimination of irritation. Therefore, developing a nano-eye drop capable of simultaneously loading both lipid-soluble and water-soluble eye-protecting ingredients, while exhibiting high stability, low irritation, and excellent sustained-release effects, holds significant clinical importance and has broad market prospects. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a compound plant extract eye drop for relieving eye fatigue and its preparation method. This eye drop uses lutein, zeaxanthin, blueberry extract, peppermint oil, and borneol as lipid-soluble active ingredients, and phospholipids and poloxamer 188 as a composite nanocarrier, combined with sodium hyaluronate, sodium chloride, a buffer system, and an antibacterial system. This invention employs a thin-film hydration combined with high-pressure homogenization process to obtain a clear, transparent, and thermodynamically stable eye drop, solving the problems of low solubility, easy oxidation and degradation, and poor bioavailability of lipid-soluble ingredients. It improves the concentration and retention time of active ingredients in the eye. The synergistic effect of the various plant extracts effectively relieves symptoms of eye fatigue such as dryness, soreness, blurred vision, and ciliary muscle spasm caused by prolonged eye use, and is non-irritating to the eyes and highly stable.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: In one aspect, a compound plant extract eye drop for relieving eye fatigue, wherein, by weight, the components of the eye drop include:

[0008] Fat-soluble active ingredients: Lutein 0.001-0.1 parts, Zeaxanthin 0.01-0.5 parts, Blueberry extract 0.1-1.0 parts, Cassia seed extract 0.1-1.0 parts, Honeysuckle extract 0.1-1.0 parts, Goji berry extract 0.1-1.0 parts, Peppermint 0.05-0.5 parts, Borneol 0.05-0.5 parts;

[0009] Nanocarrier material: 0.5-5.0 parts phospholipid 5.0 portions;

[0010] Aqueous substrate: 0.1-1.0 parts sodium hyaluronate, 0.5-1.0 parts sodium chloride;

[0011] Buffer: 0.05-0.2 parts sodium dihydrogen phosphate and 0.1-0.4 parts disodium hydrogen phosphate, used to adjust the pH of the system to 5.5-7.5;

[0012] Antibacterial agent: 0.005 parts - 0.05 parts;

[0013] Water for injection: Balance.

[0014] Furthermore, in the nanocarrier material, the phospholipid is selected from one or more combinations of soybean lecithin, egg yolk lecithin, and hydrogenated soybean lecithin, and the mass ratio of phospholipid to poloxamer 188 is 1:(0.5-2).

[0015] Furthermore, among the fat-soluble active ingredients, the blueberry extract, cassia seed extract, honeysuckle extract, and wolfberry extract are all water-extracted alcohol precipitates with a polysaccharide content of ≥30%, the peppermint is natural peppermint essential oil, and the borneol is natural dextrorotatory borneol.

[0016] Furthermore, the sodium hyaluronate in the aqueous substrate is composed of high molecular weight sodium hyaluronate and low molecular weight sodium hyaluronate in a mass ratio of 1:(1-3), wherein the molecular weight of the high molecular weight sodium hyaluronate is 1000-2000kDa and the molecular weight of the low molecular weight sodium hyaluronate is 100-500kDa.

[0017] Furthermore, the antibacterial agent is selected from one of benzalkonium chloride, benzalkonium bromide, and ethylparaben;

[0018] When the antibacterial agent is benzalkonium chloride or benzalkonium bromide, the weight is 0.005-0.02 parts;

[0019] When the antibacterial agent is ethylparaben, the weight part is 0.02-0.05 parts.

[0020] Furthermore, the mass ratio of lutein to zeaxanthin is 1:1 to 1:10, the mass ratio of blueberry extract to wolfberry extract is 1:0.5 to 1:2, and the mass ratio of cassia seed extract to honeysuckle extract is 1:0.5 to 1:2.

[0021] On the other hand, a method for preparing compound plant extract eye drops to relieve eye fatigue includes the following steps:

[0022] S100 oil phase preparation: Add the prescribed amounts of lutein, zeaxanthin, blueberry extract, peppermint oil, and borneol to anhydrous ethanol, heat to 40-50℃, and stir until all components are completely dissolved to obtain a homogeneous oil phase solution.

[0023] S200 lipid film formation: Phospholipids and poloxamer 188 are added to the oil phase solution and stirred until completely dissolved. Then, the solution is transferred to a rotary evaporator and anhydrous ethanol is removed by rotary evaporation at 40-50°C and a vacuum of 0.08-0.09 MPa, forming a uniform, bubble-free lipid film on the inner wall of the container.

[0024] S300 aqueous phase preparation: Sodium hyaluronate, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and antibacterial agent are added to 80% of the prescribed volume of water for injection and stirred until completely dissolved to obtain a clear aqueous phase solution;

[0025] S400 coarse micelle hydration: Heat the aqueous solution to 40-50℃, add it to a container containing a lipid film, and stir and hydrate for 30-60 minutes at 40-50℃ and 100-200 r / min to completely detach and disperse the lipid film, thus obtaining a coarse micelle solution.

[0026] S500 High-Pressure Homogenization and Refinement: The coarse micelle solution is transferred to a high-pressure homogenizer and subjected to cyclic high-pressure homogenization treatment 3-5 times under a pressure of 60-100MPa to obtain a nano micelle solution.

[0027] S600 constant volume sterilization filling: Add water for injection to the nano micelle solution, stir evenly, and adjust the pH value to 5.5-7.5 again. Fill and seal in a clean environment to obtain the finished compound plant extract eye drops.

[0028] Furthermore, in S100, the amount of anhydrous ethanol used is 5-10 times the total mass of the fat-soluble active ingredient and the nanocarrier material.

[0029] Furthermore, in S200, the rotary evaporation time is 30-60 minutes, until there is no residual ethanol odor on the inner wall of the container and the lipid film is transparent.

[0030] Furthermore, the application of a compound plant extract nano-eye drop for relieving eye fatigue in the preparation of drugs or eye care products for relieving eye fatigue, improving tear film stability, or resisting ocular oxidative stress.

[0031] Compared with existing technologies, this compound plant extract eye drop for relieving eye fatigue and its preparation method have the following beneficial effects:

[0032] I. This invention uses phospholipids and poloxamer 188 as nanocarrier excipients. Through high-pressure homogenization technology, lipid-soluble components such as lutein, zeaxanthin, blueberry extract, menthol, and borneol are encapsulated in nano micelles or nanoemulsions to form a clear and transparent solution. This nano eye drop has good thermodynamic stability and shows no precipitation or crystallization after 12 months at room temperature, solving the problem that poorly soluble components such as lutein cannot be directly used in eye drops in the prior art.

[0033] II. The nanomicelles prepared by this invention can promote the uptake and transport of drugs by corneal epithelial cells, prolong the retention time of active ingredients on the ocular surface, and effectively reduce the ocular irritation of menthol and borneol: This invention encapsulates menthol and borneol in the hydrophobic core of nanomicelles, avoiding their direct exposure to the aqueous phase and contact with corneal nerve endings, thereby improving patient comfort and compliance.

[0034] Third, this invention organically combines fat-soluble antioxidant eye-protecting ingredients with water-soluble traditional Chinese medicine extracts for improving eyesight and moisturizing and lubricating ingredients. The components work synergistically to improve eye fatigue from multiple dimensions, including anti-oxidation, improved circulation, relief of spasms, and moisturization of the ocular surface. It is suitable for a wide range of people.

[0035] Other advantages, objectives and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination or study, or may be learned from the practice of the invention. Attached Figure Description

[0036] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are merely some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without any creative effort.

[0037] Figure 1 A flowchart illustrating the steps involved in preparing a compound plant extract eye drop for relieving eye fatigue.

[0038] Figure 2 This is a flowchart illustrating a method for preparing compound plant extract eye drops to relieve eye fatigue, as described in this invention. Detailed Implementation

[0039] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided below.

[0040] To address the limitations of existing eye drops for relieving eye fatigue, such as poor solubility of lipid-soluble components, low bioavailability, strong irritation from cooling components, poor stability, and limited functionality, etc. Figure 1 As shown, this invention proposes a method for preparing compound plant extract eye drops to relieve eye fatigue. The steps of this preparation method are as follows:

[0041] S100 oil phase preparation: Add the prescribed amounts of lutein, zeaxanthin, blueberry extract, cassia seed extract, honeysuckle extract, wolfberry extract, peppermint, and borneol to anhydrous ethanol, heat to 40-50℃, and stir until all components are completely dissolved to obtain a homogeneous oil phase solution.

[0042] S200 lipid film formation: Phospholipids and poloxamer 188 are added to the oil phase solution and stirred until completely dissolved. Then, the solution is transferred to a rotary evaporator and anhydrous ethanol is removed by rotary evaporation at 40-50°C and a vacuum of 0.08-0.09 MPa, forming a uniform, bubble-free lipid film on the inner wall of the container.

[0043] S300 aqueous phase preparation: Sodium hyaluronate, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and antibacterial agent are added to 80% of the prescribed volume of water for injection and stirred until completely dissolved to obtain a clear aqueous phase solution;

[0044] S400 coarse micelle hydration: Heat the aqueous solution to 40-50℃, add it to a container containing a lipid film, and stir and hydrate for 30-60 minutes at 40-50℃ and 100-200 r / min to completely detach and disperse the lipid film, thus obtaining a coarse micelle solution.

[0045] S500 High-Pressure Homogenization and Refinement: The coarse micelle solution is transferred to a high-pressure homogenizer and subjected to cyclic high-pressure homogenization treatment 3-5 times under a pressure of 60-100MPa to obtain a nano micelle solution.

[0046] S600 constant volume sterilization filling: Add water for injection to the nano micelle solution, stir evenly, and adjust the pH value to 5.5-7.5 again. Fill and seal in a clean environment to obtain the finished compound plant extract eye drops.

[0047] This invention constructs a nanocarrier system using composite phospholipids and poloxamer 188. Employing a thin-film hydration combined with high-pressure homogenization process, it encapsulates lipid-soluble active ingredients such as lutein, zeaxanthin, blueberry extract, peppermint oil, and borneol into nanomicelles. This is then combined with high and low molecular weight sodium hyaluronate, a buffer system, and an antibacterial system to produce a clear, transparent, and thermodynamically stable eye drop solution. This results in a comprehensive plant extract eye drop solution solution that combines high drug loading capacity, low irritation, long retention time, and multi-target synergistic eye protection.

[0048] This invention is primarily applied in the fields of ophthalmic preparations and eye care, targeting symptoms of eye fatigue such as dryness, soreness, blurred vision, and ciliary muscle spasm caused by prolonged eye use. Traditional artificial tears only provide physical lubrication and lack antioxidant and retinal protection effects. Herbal eye drops are difficult to load with lipid-soluble eye-protecting ingredients, and direct addition of menthol and borneol can easily cause stinging and discomfort. Lipid-soluble nutrient suspensions are prone to crystallization and have low bioavailability. Existing nano-drug delivery technologies suffer from complex processes and insufficient stability. This invention achieves efficient solubilization and gentle delivery of poorly soluble active ingredients through nano-micelle carrier design, compounding of lipid-soluble and water-soluble components, optimization of process parameters, and precise pH control. This improves the retention time and bioavailability of ocular surface. The product remains stable at room temperature for 12 months without precipitation or irritation. It can improve eye fatigue from multiple dimensions, including antioxidant, microcirculation improvement, spasm relief, and ocular surface moisturization, making it suitable for daily eye care and industrial production.

[0049] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. The raw materials used in the embodiments of the present invention are all commercially available conventional products, wherein: lutein purity ≥90%, zeaxanthin purity ≥90%; blueberry extract, cassia seed extract, honeysuckle extract, and wolfberry extract are all water-extracted alcohol precipitates with a polysaccharide content ≥30%; peppermint is natural peppermint essential oil, and borneol is natural dextrorotatory borneol; high molecular weight sodium hyaluronate has a molecular weight of 1500kDa, and low molecular weight sodium hyaluronate has a molecular weight of 300kDa; the phospholipid used is soybean lecithin; and the antibacterial agent used is benzalkonium chloride.

[0050] All embodiments and comparative examples of this invention were evaluated using the following standardized and repeatable testing methods. All experiments included three parallel samples, and data are expressed as mean ± standard deviation. Specifically, the methods included:

[0051] Appearance inspection: Take 10 mL of the test sample and place it in a colorless transparent glass colorimetric tube. Observe it with the naked eye under natural light and record whether it is clear and transparent, whether there is any sediment, suspended matter, layering, or odor.

[0052] pH value determination: To verify whether the pH value of the system meets the requirements of ophthalmic preparations, the pH meter was calibrated with standard buffer solutions (pH 4.00, pH 6.86, pH 9.18), and the pH value of the test sample was measured at 25℃±1℃. The measurement was performed in parallel for 3 times and the average value was taken.

[0053] Osmolality determination: To evaluate the isotonicity of eye drops and avoid ocular osmotic irritation, use a STY-2 osmolality analyzer. Take an appropriate amount of the test sample and determine the osmolality according to the instrument's operating procedures. Perform three parallel measurements and take the average value. The required osmolality is 280-320 mOsmol / kg.

[0054] Average particle size, polydispersity index (PDI), and zeta potential: To evaluate the particle size uniformity and colloidal stability of nanomicelles, the test sample was diluted to a suitable concentration (absorbance 0.1-0.3) with water for injection filtered through a 0.22 μm microporous membrane. The average particle size, PDI, and zeta potential were measured at 25℃±1℃ and a scattering angle of 90°. The measurements were performed in triplicate, and the average value was taken.

[0055] Encapsulation efficiency of active ingredients: To evaluate the loading capacity of the nanocarrier for lipid-soluble active ingredients, ultrafiltration centrifugation was used. 1 mL of the test sample was added to an ultrafiltration centrifuge tube and centrifuged at 4000 r / min for 30 minutes. The lower filtrate was collected, and the free lutein content was determined by HPLC. Separately, 1 mL of the test sample was added to anhydrous ethanol to break the emulsion, and the volume was adjusted to 10 mL. The total lutein content was determined by HPLC.

[0056] Stability study: To verify the long-term storage stability and accelerated stability of the eye drops, the test sample was sealed and placed in a constant temperature and humidity chamber at 40℃±2℃ and relative humidity of 75%±5% for 3 months. Samples were taken at 0, 1, 2 and 3 months to test the appearance, pH value, average particle size, PDI and lutein content, and to observe whether there was any precipitation, crystallization or stratification.

[0057] For the long-term stability test, the test sample was sealed and placed in a constant temperature and humidity chamber at 25℃±2℃ and relative humidity of 60%±5% for 12 months. Samples were taken at 0, 3, 6, 9 and 12 months and the same indicators were tested to evaluate the long-term stability.

[0058] In vitro release assay: To evaluate the sustained-release effect of the nanomicelles, the dialysis bag method was used. The release medium was simulated tears. 2 mL of the test sample was placed in a dialysis bag, sealed at both ends, and placed in a dissolution vessel containing 200 mL of release medium. The mixture was stirred at a constant temperature of 37℃±0.5℃ and 50 r / min. 5 mL samples were taken at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours, and an equal amount of isothermal release medium was added simultaneously. The lutein content in the sample was determined by HPLC, the cumulative release rate over 24 hours was calculated, and the release curve was plotted.

[0059] Tear film stability test: To evaluate the effect of eye drops on improving tear film stability, healthy white rabbits, half male and half female, were used as experimental animals. Before administration, 1% sodium fluorescein solution was instilled into each eye. The basal tear film breakup time (BUT) of both eyes was measured under a slit lamp. Each eye was measured 3 times and the average value was taken. 50 μL of the test sample was instilled into each eye, and the BUT was measured at 0.5, 1, 2, 4 and 6 hours after administration.

[0060] Tear film stability: Tear film breakup time (BUT) determination in rabbits.

[0061] Eye fatigue relief effect: In a mouse model of ciliary muscle spasm, the ciliary muscle contractility and retinal superoxide dismutase (SOD) activity were measured.

[0062] Example 1

[0063] This embodiment uses a composite carrier ratio of phospholipids and poloxamer 188 (1:1 mass ratio), a lutein to zeaxanthin ratio of 1:5 mass ratio, a blueberry extract to wolfberry extract ratio of 1:1 mass ratio, a cassia seed extract to honeysuckle extract ratio of 1:1 mass ratio, and intermediate parameters of the thin-film hydration-high-pressure homogenization process to prepare eye drops. This is used to verify the comprehensive performance of the core technical solution of this invention and serves as the benchmark sample for all comparative experiments.

[0064] Formula composition

[0065] Lutein 0.05 parts, Zeaxanthin 0.25 parts, Blueberry Extract 0.5 parts, Cassia Seed Extract 0.5 parts, Honeysuckle Extract 0.5 parts, Goji Berry Extract 0.5 parts, Peppermint 0.25 parts, Borneol 0.25 parts, Soy Lecithin 2.0 parts, Poloxamer 188 2.0 parts, High Molecular Weight Sodium Hyaluronate 0.125 parts, Low Molecular Weight Sodium Hyaluronate 0.375 parts, Sodium Chloride 0.75 parts, Sodium Dihydrogen Phosphate 0.125 parts, Disodium Hydrogen Phosphate 0.25 parts, Benzalkonium Chloride 0.01 parts, Water for Injection to 100 parts.

[0066] like Figure 2 As shown, the preparation process of this compound plant extract eye drop for relieving eye fatigue is as follows:

[0067] S100 oil phase preparation: Weigh out lutein, zeaxanthin, blueberry extract, cassia seed extract, honeysuckle extract, wolfberry extract, peppermint, and borneol according to the above prescription. Add 7.5 times the total mass of anhydrous ethanol, heat to 45°C, and stir at 200 r / min until all components are completely dissolved to obtain a homogeneous and transparent oil phase solution.

[0068] S200 lipid film formation: Add the prescribed amount of soybean lecithin and poloxamer 188 to the above oil phase solution, continue stirring until completely dissolved, and then transfer to the eggplant flask of a rotary evaporator. Rotate and evaporate for 45 minutes at 45°C and a vacuum of 0.085MPa until there is no residual ethanol odor on the inner wall of the eggplant flask, forming a uniform, transparent, bubble-free lipid film.

[0069] S300 aqueous phase preparation: Weigh high molecular weight sodium hyaluronate, low molecular weight sodium hyaluronate, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and benzalkonium chloride according to the prescription amount, add them to 80 parts of water for injection, stir at room temperature for 2 hours until completely dissolved, and obtain a clear aqueous phase solution.

[0070] S400 coarse micelle hydration: Heat the aqueous solution to 45°C and slowly add it to a flask containing a lipid film. Hydrate for 45 minutes at 45°C and 150 r / min to completely detach the lipid film and disperse it evenly to obtain a coarse micelle solution.

[0071] S500 High-Pressure Homogenization and Refinement: The coarse micelle solution is transferred to a high-pressure homogenizer and homogenized 4 times under a pressure of 80MPa to obtain a nano micelle solution with uniform particle size.

[0072] S600 constant volume sterilization filling: Add water for injection to the nano micelle solution to 100 parts, stir evenly, adjust the pH of the system to 6.5 with sodium dihydrogen phosphate or disodium hydrogen phosphate, sterilize through a 0.22μm microporous membrane, fill and seal in sterile eye vials in a Class A clean environment to obtain the finished product.

[0073] The eye drops prepared in this embodiment are clear, transparent, pale yellow liquids, free of precipitation, suspended matter, and odor. The average particle size of the nanomicelles is 28.6 nm, the polydispersity index (PDI) is 0.102, and the zeta potential is -23.5 mV. After accelerated stability testing (40℃ / 75%RH, 3 months) and long-term stability testing (25℃ / 60%RH, 12 months), there was no change in appearance, the particle size change rate was <5%, and no crystal precipitation occurred. The tear film breakup time (BUT) was extended by 125% compared to the control group, and the retinal SOD activity was increased by 82%, demonstrating the best overall performance.

[0074] Example 2

[0075] In this embodiment, the mass ratio of phospholipid to poloxamer 188 was adjusted to 1:0.5. All other formulations and preparation process parameters were exactly the same as in Example 1. This was used to investigate the effect of the lower limit of the carrier material ratio on the nanomicelle particle size distribution, system stability and drug loading.

[0076] Formula composition

[0077] Except for adjusting the soybean lecithin to 3.0 parts and the poloxamer 188 to 1.5 parts, the other ingredients and dosages are exactly the same as in Example 1.

[0078] Preparation method

[0079] It is exactly the same as Example 1.

[0080] The eye drops prepared in this embodiment are clear and transparent liquids with an average nanomicelle particle size of 35.2 nm, a PDI of 0.138, and a Zeta potential of -21.2 mV. Accelerated stability testing showed no significant changes after 3 months, and long-term stability testing showed a particle size change rate of 7.2% after 12 months, with no precipitation or crystallization. Eye irritation testing showed no abnormalities, tear film break-through (BUT) was prolonged by 118%, and retinal SOD activity increased by 79%. The results indicate that the lower limit of the carrier ratio still meets the stability and efficacy requirements of the eye drops, with only a slight increase in particle size.

[0081] Example 3

[0082] In this embodiment, the mass ratio of phospholipids to poloxamer 188 was adjusted to 1:2, and all other formulations and preparation process parameters were exactly the same as in Example 1. This was used to investigate the effect of the upper limit of the carrier material ratio on the drug loading capacity, eye irritation, and sustained-release effect of the nanomicelles.

[0083] Formula composition

[0084] Except for adjusting the soybean lecithin to 1.5 parts and the poloxamer 188 to 3.0 parts, the other ingredients and dosages are exactly the same as in Example 1.

[0085] Preparation method

[0086] It is exactly the same as Example 1.

[0087] The eye drops prepared in this embodiment are clear and transparent liquids with an average nanomicelle particle size of 24.8 nm, a PDI of 0.095, and a Zeta potential of -25.7 mV. After 12 months of stability testing, the particle size change rate was <3%, indicating superior stability. However, the cumulative release rate of the active ingredient over 24 hours was 12% higher than in Example 1, resulting in a slight decrease in sustained-release effect. The tear film break-time (BUT) was prolonged by 121%, and retinal SOD activity was increased by 77%. These results indicate that the upper limit of the carrier ratio can further reduce irritation, but the sustained-release performance is slightly weakened.

[0088] Example 4

[0089] In this embodiment, the mass ratio of lutein to zeaxanthin was adjusted to 1:1, and all other formulations and preparation process parameters were exactly the same as in Example 1. This was used to investigate the effect of the lower limit of the active ingredient ratio on the antioxidant capacity, blue light filtering effect and eye fatigue relief of the eye drops.

[0090] Formula composition

[0091] Except for lutein being adjusted to 0.1 parts and zeaxanthin being adjusted to 0.1 parts, the other ingredients and dosages are exactly the same as in Example 1.

[0092] Preparation method

[0093] It is exactly the same as Example 1.

[0094] The eye drops prepared in this embodiment are clear and transparent liquids with an average nanomicelle particle size of 29.1 nm, a PDI of 0.105, and good stability. No abnormalities were observed in the eye irritation test. Retinal SOD activity was increased by 91%, and the antioxidant capacity was superior to that of Example 1. Tear film break-through time (BUT) was prolonged by 122%, and the ciliary muscle spasm relief rate was basically consistent with that of Example 1. The results indicate that increasing the proportion of lutein can enhance the antioxidant effect without affecting other core properties.

[0095] Example 5

[0096] In this embodiment, the mass ratio of high molecular weight sodium hyaluronate to low molecular weight sodium hyaluronate was adjusted to 1:1. All other formulations and preparation process parameters were exactly the same as in Example 1. This was used to investigate the effect of the sodium hyaluronate compounding ratio on the moisturizing effect, ocular surface retention time, and spreadability of the eye drops.

[0097] Formula composition

[0098] Except for adjusting the high molecular weight sodium hyaluronate to 0.25 parts and the low molecular weight sodium hyaluronate to 0.25 parts, the other components and dosages are exactly the same as in Example 1.

[0099] Preparation method

[0100] It is exactly the same as Example 1.

[0101] The eye drops prepared in this embodiment have an average particle size of 28.9 nm, a PDI of 0.103, and good stability. The viscosity is slightly lower than in Example 1, resulting in better spreadability on the ocular surface and no sticky feeling after application. The tear film withstand time (BUT) is extended by 98%, and the moisturizing duration is approximately 4 hours, 1.5 hours shorter than in Example 1. The antioxidant and ciliary muscle spasm-relieving effects are comparable to those in Example 1. These results indicate that adjusting the sodium hyaluronate formulation ratio can optimize the user experience and meet the needs of different user groups.

[0102] Example 6

[0103] In this embodiment, the high-pressure homogenization process parameters were adjusted to 3 cycles of homogenization at 60 MPa pressure. All other formulations and preparation process parameters were exactly the same as in Example 1. This was used to investigate the effect of the lower limit of process parameters on the uniformity of nanomicelle particle size, long-term stability and encapsulation efficiency of active ingredients.

[0104] Formula composition

[0105] It is exactly the same as Example 1.

[0106] Preparation method

[0107] Except for step S500, which is changed to cyclic homogenization at 60MPa pressure for 3 times, the other steps are exactly the same as in Example 1.

[0108] The eye drop nanomicelles prepared in this embodiment have an average particle size of 32.7 nm, a PDI of 0.142, and a slightly wider particle size distribution. The encapsulation efficiency of the active ingredient is 92.3%, which is 3.1% lower than that in Example 1. Accelerated stability testing showed no change after 3 months, while long-term stability testing showed a particle size change rate of 8.5% after 12 months. Tear film break-through time (BUT) was prolonged by 120%, and retinal SOD activity was increased by 78%. These results indicate that the lower limit of the process parameters meets the requirements for industrial production, reducing production costs.

[0109] Comparative Example 1

[0110] This comparative example omits phospholipids and poloxamer 188 nanocarrier materials, while retaining the same formulation as Example 1. It was prepared using a direct stirring and mixing method to compare and verify the core role of nanocarriers in the solubility, stability, and bioavailability of lipid-soluble active ingredients.

[0111] Formula composition

[0112] Except for the removal of soy lecithin and poloxamer 188, the remaining ingredients and dosages are exactly the same as in Example 1.

[0113] Preparation method

[0114] All ingredients were added directly to 100 parts of water for injection, stirred at room temperature for 30 minutes, the pH was adjusted to 6.5, and the mixture was sterilized by passing it through a 0.22μm microporous membrane before filling and sealing.

[0115] The sample prepared in this comparative example was a yellow suspension. After standing for 24 hours, obvious precipitation and stratification occurred, and it could not be completely reconstituted after shaking. After filtration, the lutein content in the filtrate was only 12% of the initial amount, and the zeaxanthin content was 15%. The lipid-soluble components were almost insoluble. The tear film transition time (BUT) was only prolonged by 28%, and the retinal SOD activity was increased by 17%, with almost no antioxidant or eye fatigue relief effects. The results indicate that without a nanocarrier, the lipid-soluble active components cannot be effectively dissolved, and the product stability is extremely poor.

[0116] Comparative Example 2

[0117] This comparative example omits poloxamer 188 and adjusts the amount of soybean lecithin to 4.0 parts (the total carrier mass is the same as in Example 1). The remaining formulation and preparation process are exactly the same as in Example 1. This is used to compare and verify the advantages of composite nanocarriers over single phospholipid carriers in terms of particle size uniformity and long-term stability.

[0118] Formula composition

[0119] Except for the removal of poloxamer 188 and the adjustment of soy lecithin to 4.0 parts, the remaining ingredients and dosages are exactly the same as in Example 1.

[0120] Preparation method

[0121] It is exactly the same as Example 1.

[0122] The eye drops prepared in this comparative example were a slightly yellow, semi-transparent liquid with an average nanomicelle size of 126.5 nm and a PDI of 0.327, exhibiting extremely uneven particle size distribution. Slight opalescence appeared after one month of accelerated stability testing, and significant stratification occurred after three months. Crystallization occurred after six months of long-term stability testing. Tear film break-through time (BUT) was prolonged by 72%, and retinal SOD activity increased by 45%. These results indicate that nanomicelles prepared with a single phospholipid carrier have large particle sizes, poor stability, and significantly reduced efficacy.

[0123] Comparative Example 3

[0124] This comparative example omits soybean lecithin and adjusts the amount of poloxamer 188 to 4.0 parts (the total carrier mass is the same as in Example 1). The remaining formulation and preparation process are exactly the same as in Example 1. This is used to compare and verify the advantages of the composite nanocarrier over the single poloxamer carrier in terms of drug loading and sustained release effect.

[0125] Formula composition

[0126] Except for the removal of soy lecithin and the adjustment of poloxamer 188 to 4.0 parts, the remaining ingredients and dosages are exactly the same as in Example 1.

[0127] Preparation method

[0128] It is exactly the same as Example 1.

[0129] The eye drops prepared in this comparative example were clear and transparent liquids with an average nanomicelle particle size of 18.3 nm and a PDI of 0.089. However, the encapsulation efficiency of the active ingredient was only 68.5%, a decrease of 26.9% compared to Example 1. The cumulative release rate of the active ingredient after 24 hours reached 92%, with no significant sustained-release effect. The tear film break-time (BUT) was prolonged by 85%, and retinal SOD activity was increased by 52%, but the duration of efficacy was only 2 hours. The results indicate that the single poloxamer carrier has low drug loading and poor sustained-release effect, and cannot achieve a long-lasting effect.

[0130] Comparative Example 4

[0131] In this comparative example, peppermint and borneol were added directly to the aqueous phase during the volume adjustment step without nano-encapsulation. The rest of the formulation and preparation process were exactly the same as in Example 1. This was used to compare and verify the effect of nano-encapsulation technology on reducing eye irritation of cooling ingredients.

[0132] Formula composition

[0133] It is exactly the same as Example 1.

[0134] Preparation method

[0135] In step S100, only lutein, zeaxanthin, blueberry extract, cassia seed extract, honeysuckle extract, and wolfberry extract are added to prepare the oil phase; in step S600, water for injection is added and the pH is adjusted, then peppermint and borneol are added, stirred evenly, and then sterilized and filled.

[0136] The eye drops prepared in this comparative example were clear and transparent liquids with an average nanomicelle particle size of 29.0 nm and a PDI of 0.104. No significant changes were observed after 12 months of accelerated and long-term stability testing. Tear film break-through time (BUT) was prolonged by 115%, and retinal SOD activity was increased by 78%, with efficacy similar to that of Example 1. The results indicate that nano-encapsulation technology does not affect the efficacy of the cooling and active ingredients.

[0137] Comparative Example 5

[0138] This comparative example uses a commercially available conventional artificial tear formula that does not contain lipid-soluble active ingredients or nanocarriers, and is used to compare and verify the comprehensive advantages of the eye drops of this invention in relieving eye fatigue in multiple dimensions compared with traditional artificial tears.

[0139] Formula composition

[0140] 0.5 parts high molecular weight sodium hyaluronate, 0.75 parts sodium chloride, 0.125 parts sodium dihydrogen phosphate, 0.25 parts disodium hydrogen phosphate, 0.01 parts benzalkonium chloride, and water for injection to a total of 100 parts.

[0141] Preparation method

[0142] Add all ingredients to water for injection and stir to dissolve. Adjust the pH to 6.5, sterilize, and then fill and seal.

[0143] The artificial tears prepared in this comparative example are clear and transparent liquids with no irritation; the tear film break-through time (BUT) is extended by 65%, and it can only temporarily relieve dry eye symptoms through physical lubrication; it has no antioxidant or blue light filtering effects, cannot improve ciliary muscle spasm and retinal damage, and the duration of eye fatigue relief is less than 1 hour.

[0144] To visually compare the core performance differences between the embodiments of this invention and the comparative examples, the results of the nanocarrier performance, stability, and efficacy tests of all the above samples are summarized in the table below. All data are the average values ​​of three parallel experiments:

[0145] Sample number Average particle size (nm) PDI 12 months of stability BUT elongation rate (%) SOD activity enhancement rate (%) Example 1 28.6 0.102 No change 125 82 Example 2 35.2 0.138 No sediment 118 79 Example 3 24.8 0.095 No change 121 77 Example 4 29.1 0.105 No change 122 91 Example 5 28.9 0.103 No change 98 80 Example 6 32.7 0.142 No sediment 120 78 Comparative Example 1 - - Large amount of sediment 28 17 Comparative Example 2 126.5 0.327 Crystallization 72 45 Comparative Example 3 18.3 0.089 No change 85 52 Comparative Example 4 29.0 0.104 No change 115 78 Comparative Example 5 - - No change 65 0

[0146] The performance test results above show that the composite plant extract eye drops prepared in each embodiment of the present invention have uniform nanomicelle particle size, excellent long-term stability, significant tear film improvement effect, and outstanding ocular antioxidant capacity. The average particle size of each embodiment is controlled within the range of 24.8 nm to 35.2 nm, the polydispersity index (PDI) is less than 0.15, and the system is uniformly dispersed. In the 12-month long-term stability test, no precipitation or crystallization occurred, meeting the stability requirements of ophthalmic preparations. The tear film breakup time extension rate is not less than 98%, and the retinal SOD activity enhancement rate is not less than 77%. It can simultaneously achieve long-lasting moisturizing, enhance tear film stability, improve ocular oxidative stress, and relieve eye fatigue from multiple dimensions.

[0147] The comparative examples differ significantly from the embodiments of the present invention. The sample without the addition of nanocarriers cannot form a stable system, and obvious stratification and precipitation occur, resulting in a significant decrease in efficacy. The sample using a single nanocarrier has defects such as uneven particle size, poor stability, low drug loading or no sustained-release effect. Conventional artificial tears only have a short-term lubricating effect and have no antioxidant or eye fatigue relief effect.

[0148] In summary, the present invention utilizes a phospholipid and poloxamer 188 composite nanocarrier, combined with multi-component plant extracts, to effectively solve the problems of poor solubility, insufficient stability, and low bioavailability of fat-soluble active ingredients. The resulting eye drops exhibit high stability, definite efficacy, and superior overall performance.

[0149] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A compound plant extract eye drop for relieving eye fatigue, characterized in that, The components of this eye drop, by weight, include: Fat-soluble active ingredients: Lutein 0.001-0.1 parts, Zeaxanthin 0.01-0.5 parts, Blueberry extract 0.1-1.0 parts, Cassia seed extract 0.1-1.0 parts, Honeysuckle extract 0.1-1.0 parts, Goji berry extract 0.1-1.0 parts, Peppermint 0.05-0.5 parts, Borneol 0.05-0.5 parts; Nanocarrier material: 0.5-5.0 parts phospholipid 5.0 portions; Aqueous substrate: 0.1-1.0 parts sodium hyaluronate, 0.5-1.0 parts sodium chloride; Buffer: 0.05-0.2 parts sodium dihydrogen phosphate and 0.1-0.4 parts disodium hydrogen phosphate, used to adjust the pH of the system to 5.5-7.5; Antibacterial agent: 0.005 parts - 0.05 parts; Water for injection: Balance.

2. The compound plant extract eye drops for relieving eye fatigue according to claim 1, characterized in that, In the nanocarrier material, the phospholipid is selected from one or more combinations of soybean lecithin, egg yolk lecithin, and hydrogenated soybean lecithin, and the mass ratio of phospholipid to poloxamer 188 is 1:(0.5-2).

3. The compound plant extract eye drops for relieving eye fatigue according to claim 1, characterized in that, Among the fat-soluble active ingredients, blueberry extract, cassia seed extract, honeysuckle extract and wolfberry extract are all water-extracted alcohol precipitates with a polysaccharide content of ≥30%, peppermint is natural peppermint essential oil, and borneol is natural dextrorotatory borneol.

4. The compound plant extract eye drops for relieving eye fatigue according to claim 1, characterized in that, The sodium hyaluronate in the aqueous substrate is composed of high molecular weight sodium hyaluronate and low molecular weight sodium hyaluronate in a mass ratio of 1:(1-3), wherein the molecular weight of the high molecular weight sodium hyaluronate is 1000-2000kDa and the molecular weight of the low molecular weight sodium hyaluronate is 100-500kDa.

5. The compound plant extract eye drops for relieving eye fatigue according to claim 1, characterized in that, The antibacterial agent is selected from one of benzalkonium chloride, benzalkonium bromide, and ethylparaben; When the antibacterial agent is benzalkonium chloride or benzalkonium bromide, the weight is 0.005-0.02 parts; When the antibacterial agent is ethylparaben, the weight part is 0.02-0.05 parts.

6. The compound plant extract eye drops for relieving eye fatigue according to claim 1, characterized in that, The mass ratio of lutein to zeaxanthin is 1:1 to 1:10, the mass ratio of blueberry extract to wolfberry extract is 1:0.5 to 1:2, and the mass ratio of cassia seed extract to honeysuckle extract is 1:0.5 to 1:

2.

7. A method for preparing a compound plant extract eye drop for relieving eye fatigue, applicable to the compound plant extract eye drop for relieving eye fatigue as described in any one of claims 1-6, characterized in that, The preparation method involves the following steps: S100 oil phase preparation: Add the prescribed amounts of lutein, zeaxanthin, blueberry extract, cassia seed extract, honeysuckle extract, wolfberry extract, peppermint, and borneol to anhydrous ethanol, heat to 40-50℃, and stir until all components are completely dissolved to obtain a homogeneous oil phase solution. S200 lipid film formation: Phospholipids and poloxamer 188 are added to the oil phase solution and stirred until completely dissolved. Then, the solution is transferred to a rotary evaporator and anhydrous ethanol is removed by rotary evaporation at 40-50°C and a vacuum of 0.08-0.09 MPa, forming a uniform, bubble-free lipid film on the inner wall of the container. S300 aqueous phase preparation: Sodium hyaluronate, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and antibacterial agent are added to 80% of the prescribed volume of water for injection and stirred until completely dissolved to obtain a clear aqueous phase solution; S400 coarse micelle hydration: Heat the aqueous solution to 40-50℃, add it to a container containing a lipid film, and stir and hydrate for 30-60 minutes at 40-50℃ and 100-200 r / min to completely detach and disperse the lipid film, thus obtaining a coarse micelle solution. S500 High-Pressure Homogenization and Refinement: The coarse micelle solution is transferred to a high-pressure homogenizer and subjected to cyclic high-pressure homogenization treatment 3-5 times under a pressure of 60-100MPa to obtain a nano micelle solution. S600 constant volume sterilization filling: Add water for injection to the nano micelle solution, stir evenly, and adjust the pH value to 5.5-7.5 again. Fill and seal in a clean environment to obtain the finished compound plant extract eye drops.

8. The method for preparing a compound plant extract eye drop for relieving eye fatigue according to claim 7, characterized in that, In S100, the amount of anhydrous ethanol is 5-10 times the total mass of the fat-soluble active ingredient and the nanocarrier material.

9. The method for preparing a compound plant extract eye drop for relieving eye fatigue according to claim 7, characterized in that, In S200, the rotary evaporation time is 30-60 minutes until there is no residual ethanol odor on the inner wall of the container and the lipid film is transparent.

10. The use of the composite plant extract nano eye drops for relieving eye fatigue according to any one of claims 1-6 in the preparation of drugs or eye care products for relieving eye fatigue, improving tear film stability, or resisting ocular oxidative stress.

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