A liquid composition comprising a carotenoid

Abstract

This invention discloses a liquid composition containing carotenoids, belonging to the field of eye care. The liquid composition comprises: carotenoids; and a mixed solvent; said mixed solvent comprises: perfluorocarbon as a first solvent; and semi-fluorinated alkane as a second solvent. In particular, liquid compositions containing carotenoids, represented by lutein, do not require the addition of pH adjusters, surfactants, or preservatives, thus avoiding eye irritation and damage, and exhibit excellent carotenoid stability.

Description

Technical Field

[0001] This invention belongs to the field of eye care, and more specifically, relates to an eye liquid composition containing carotenoids and a mixture of non-aqueous solvents. Background Technology

[0002] Blue light is ubiquitous in daily life, especially with the use of artificial light sources and the widespread use of display screens, leading to increased long-term exposure for many ordinary people. Blue light is a high-energy, short-wavelength light, with higher energy than red and green light. It can directly penetrate the cornea and lens to reach the retina. Studies have shown that blue light is associated with increased eye inflammation because exposure to blue light increases oxygen free radicals in the eye, accelerating the oxidation process in the macula. In severe cases, this can lead to progressive retinal degeneration and permanent vision damage.

[0003] In addition, when facing mobile phone and computer screens, people blink significantly less, increase the exposure time of the ocular surface, and increase the amount of tear evaporation, which can easily cause dry eyes. These problems are defined by the American Optometry Association as "computer vision syndrome", which directly or indirectly leads to the occurrence of dry eye syndrome.

[0004] To reduce the harmful effects of blue light on the eyes, various types of products have been launched, such as blue light blocking glasses, artificial tears, and eye washes containing specific ingredients.

[0005] Blue light blocking glasses work by reflecting harmful blue light through a coating on the lens surface (i.e., a blue light blocking film) or by absorbing harmful blue light through the addition of blue light blocking factors to the lens substrate. This effectively blocks blue light and reduces its continuous harmful effects on the eyes. At the same time, blue light blocking glasses can improve the contrast sensitivity of the eyes and enhance visual function. However, because blue light blocking glasses filter some blue light, due to color complementarity, images viewed while wearing them may appear slightly yellowish.

[0006] Artificial tears are medications used to relieve dry eye symptoms. They are primarily eye drops with added moisturizing agents such as sodium hyaluronate, polyvinyl alcohol, and polyethylene glycol. Artificial tears can be considered a form of "replenishing lost tears." However, artificial tears are not actual tears. The albumin, globulins, lysozyme, and immunoglobulins IgA, IgG, and IgE present in real tears are substances that artificial tear products cannot provide.

[0007] The main functions of eye wash are to cleanse the eyes, relieve eye fatigue, disinfect, keep the eyes moist, and promote blood circulation in the eyes. It is commonly used to prevent and reduce discomfort and dryness caused by wearing contact lenses or eye discharge; it can also be used to relieve eye fatigue after beauty treatments or swimming. Many existing water-based eye washes reduce the harmful effects of blue light on the eyes by adding specific ingredients such as lutein, zeaxanthin, taurine, houttuynia cordata, tea polyphenols, vitamin B6, and vitamin B12.

[0008] Lutein is a carotenoid widely found in green vegetables, egg yolks, and other foods, as well as in human blood plasma and the eye. Lutein possesses antioxidant activity and can absorb blue light, reducing light damage to the retina and thus preventing vision loss and blindness caused by age-related macular degeneration (AMD). Lutein can also improve visual function in individuals with prolonged screen exposure and adolescents. Studies have shown that lutein intervention can significantly improve tear film breakup time, visual persistence, and simple reaction time in individuals with prolonged screen exposure. Lutein can also regulate the GF-β / Smad signaling pathway, thereby inhibiting the EMT process in ARPE-19 cells and potentially inhibiting subretinal fibrosis. Furthermore, it can improve the survival rate of human retinal pigment epithelial cells and alleviate oxidative stress and inflammatory responses through the SIRT1 / NLRP3 signaling pathway.

[0009] However, lutein has poor chemical stability and is sensitive to oxygen, light, heat, metal ions, and pH, easily oxidizing and degrading into a series of alcohol and ketone compounds. Furthermore, lutein is insoluble in water, slightly soluble in oil, and readily soluble in acetone, chloroform, etc. These properties of poor stability and easy degradation limit the widespread application of lutein. Existing products mostly use lutein esters or water-soluble lutein.

[0010] Lutein esters are fatty acid esters of lutein, consisting of one or two fatty acid molecules bound to lutein. They possess strong light and heat stability. In the human small intestine, lutein esters require the combined action of bile and pancreatic lipases, as well as the hydrolysis of esters, to be converted into free lutein. Gastric acid and trypsin also promote the hydrolysis of lutein, converting it into lutein. This process is influenced by various factors, such as food processing methods and individual digestive capacity. The raw material used in lutein tablets is lutein ester.

[0011] Water-soluble lutein refers to lutein prepared into water-soluble microcapsules or nanobundles through methods such as microencapsulation and nanotechnology. The lutein used in various eye wash solutions is water-soluble lutein.

[0012] Lutein esters require a process of conversion and absorption by the human body before reaching the eyes to exert their effects, resulting in low bioavailability. While water-soluble lutein solves the solubility problem, the process of preparing water-soluble lutein from lutein is complex and difficult to control in terms of quality. Furthermore, due to the high surface tension and poor spreadability of water, each droplet volume is approximately 30–50 μL, exceeding the tear film's carrying capacity, causing overflow during use and wasting some of the medication.

[0013] Chinese patent document publication number CN114601798A discloses an ophthalmic nano-fat emulsion containing lutein and its preparation method. The nano-emulsion composition includes lutein, an oil solvent, an emulsifier, and water. The method involves dissolving lutein in an oil solvent, and then preparing the nano-emulsion with water in the presence of an emulsifier. This formulation and preparation process involve the preparation of a stable nano-emulsion. Because the emulsion is prone to instability such as coalescence and layering during storage, this method is complex to operate, difficult to control in terms of quality, and has high manufacturing costs.

[0014] Chinese patent document publication number CN117042753A discloses a water-soluble topical ophthalmic preparation containing lutein and its manufacturing method. This method uses a thickener to create a micellar solution of lutein, resulting in an extremely complex process. Furthermore, the manufacturing process involves heating, which can accelerate the degradation of lutein.

[0015] Chinese patent document publication number CN111494305A discloses a lutein liposome-based thermosensitive in-situ gel formulation for ophthalmic use and its preparation method. The gel comprises lutein liposomes, a thermosensitive substance, a thickener, and a preservative. This formulation uses a gel dosage form, which improves the retention time and bioavailability of lutein in the eye. Although this method encapsulates lutein in liposomes to prevent degradation, it does not completely solve the stability problem of lutein. The gel formulation needs to be stored in a light-protected refrigerator at 12°C; furthermore, the thermosensitive gel's use is limited to nighttime applications.

[0016] Chinese patent document publication number CN103845278A discloses a lutein ophthalmic nanoemulsion-temperature-sensitive in-situ gel and its preparation method, comprising lutein, emulsifier, vegetable oil, temperature-sensitive gel matrix, thickener, osmotic pressure regulator, antibacterial agent, antioxidant, and stabilizer. Its technical solution is similar to the aforementioned technologies, and its preparation method and disadvantages are basically the same.

[0017] Chinese patent document publication number CN104436156A discloses a lutein ophthalmic preparation for vision protection and its preparation process. This preparation is composed of water-soluble lutein, taurine, selenium, zinc, water-soluble vitamin A, and glutathione in a specific ratio. This formulation uses water-soluble lutein and other ingredients to prepare a water-soluble preparation. In addition to the disadvantages of aqueous formulations mentioned above, its formula also contains the preservative methylparaben. With long-term use, the addition of this preservative will inevitably cause damage to the eyes.

[0018] Chinese patent document publication number CN102210645A discloses a lutein ophthalmic nanocapsule in-situ gel formulation and its preparation method. This method improves the stability of lutein, prolongs its duration of action, and enhances its bioavailability by processing lutein into nanocapsules and then preparing an in-situ gel. However, this gel formulation also has limitations in its application scenarios, only allowing for nighttime use, which is a significant drawback.

[0019] Chinese patent document publication number CN102178925A discloses a novel vision-protecting ophthalmic formulation containing lutein. Its raw materials include water-soluble lutein, taurine, selenium, zinc, water-soluble vitamins, and glutathione. Excipients include diluents, humectants, isotonic adjusters, preservatives, and antioxidants. This formulation improves product stability by adding antioxidants. However, the formulation is complex and contains preservatives, meaning long-term use may still cause eye damage.

[0020] Chinese patent document publication number CN101420934A discloses a method for stabilizing oxidically unstable compositions. This method primarily stabilizes oxidically unstable drug components, such as lutein, by adding effective amounts of stabilizers such as silica, chitosan derivatives, and diethylenetriaminepentaacetic acid and its salts. Adding stabilizers to a system to improve product stability is a common industry practice. However, the addition of multiple excipients to a formulation increases the difficulty of product quality control and can also lead to certain toxic side effects. For example, the addition of stabilizers or preservatives may cause eye discomfort or other potential harm.

[0021] In summary, current solutions for improving the stability of lutein in aqueous eye drops mainly involve encapsulating lutein in liposomes, micelles, or nanocapsules to isolate it from water, or adding chemical stabilizers. Controlling the sterile environment is primarily achieved by adding preservatives. However, these existing solutions struggle to simultaneously address the issues of stable lutein, convenient application, and no harm to the eyes. Summary of the Invention

[0022] 1. The problem to be solved

[0023] Therefore, the purpose of this invention is to solve the problem in the prior art that lutein is difficult to dissolve and stabilize in aqueous solutions, and poses risks when applied to the eyes.

[0024] The first objective of this invention is to address the problem of poor stability of carotenoids, especially lutein, in the prior art. This invention provides a liquid composition that improves the stability of carotenoids, especially lutein, and enables the long-term stable preservation of lutein.

[0025] The second objective of this invention is to address the problem in the prior art that chemical stabilizers or antioxidants are added to ophthalmic compositions to stabilize carotenoids, especially lutein, which can lead to eye damage. This invention provides a liquid composition that does not contain chemical stabilizers or antioxidants, thus avoiding eye damage.

[0026] A third objective of the present invention is to provide a method for stabilizing carotenoids, based on the first objective, thereby further extending the stable storage time of carotenoids, particularly lutein, in liquid compositions.

[0027] 2. Technical Solution

[0028] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0029] [Liquid Composition]

[0030] The first aspect of the present invention provides a liquid composition comprising:

[0031] Carotenoids; and

[0032] Mixed solvents;

[0033] The mixed solvent comprises:

[0034] Perfluorinated carbon as the primary solvent; and

[0035] Semi-fluorinated alkane as a second solvent.

[0036] The above method does not contain preservatives or chemical stabilizers, yet it still maintains good storage stability of carotenoids.

[0037] As a preferred embodiment of any one of the first aspects of the present invention, the carotenoid is selected from one or more of lutein, α-carotene, β-carotene, γ-carotene, lycopene, zeaxanthin, astaxanthin, β-cryptoxanthin, and canthaxanthin, with lutein being particularly preferred.

[0038] Normally, because oxygen is more soluble in perfluorinated carbon than in water, it should theoretically not be used as a solvent for dissolving or dispersing lutein to avoid oxidative degradation. However, the inventors of this invention unexpectedly discovered that using a mixed solvent of perfluorinated carbon and semi-fluorinated alkane to dissolve or disperse carotenoids, particularly lutein, can avoid the problem of unstable storage of carotenoids, especially lutein, in aqueous liquid compositions, thus improving the storage stability of carotenoids, particularly lutein. Although oxygen is more soluble in perfluorinated carbon than in water, stability test results show that the stability of carotenoids, particularly lutein, is improved after dissolving or dispersing in the fluorocarbon mixed solvent of this invention compared to aqueous products. Therefore, using a fluorocarbon mixed solvent containing perfluorinated carbon as a solvent for dissolving or dispersing active ingredients can improve the storage stability of carotenoids, particularly lutein, in solvents.

[0039] As a preferred embodiment of any one of the first aspects of the present invention, the liquid composition is water-free. To maintain the stability of lutein, the liquid composition is water-free, both the first solvent and the second solvent are immiscible with water, and the mixed solvent composed of the first solvent and the second solvent can dissolve or stably disperse lutein, thus eliminating the need for water in the system.

[0040] As a preferred embodiment of any one of the first aspects of the present invention, the perfluorinated carbon is selected from one or more of perfluorotripropylamine, perfluorotributylamine, perfluorobromooctane, perfluoron-butyltetrahydrofuran, perfluorooctane, perfluoronaphthane, perfluoron-butylnaphthane, and perfluorophenanthrene. Perfluorobromooctane is preferred.

[0041] As a preferred embodiment of any one of the first aspects of the present invention, the semifluorinated alkane has the molecular formula C1. a H 2a+1 C b F 2b+1 , where a is selected from any integer value from 3 to 10, and b is selected from any integer value from 3 to 10;

[0042] Preferably, the semifluorinated alkane is selected from C5H. 11 C4F9 (perfluorobutylpentane), C6H 13 C4F9 (perfluorobutylhexane), C6H 13 C6F 13 (Perfluorohexylhexane), C8H 17 C6F 13 (Perfluorohexyloctane), C8H 17 C8F 17 (perfluorooctyl octane), C9H 19 C6F 13 (Perfluorohexylnonane), C 10 H21 C6F 13 One or more of (perfluorohexyldecane). Preferably C8H 17 C6F 13 (Perfluorohexyloctane).

[0043] As a preferred embodiment of the first aspect of the present invention, a liquid composition is provided, comprising:

[0044] Lutein; and

[0045] Mixed solvents;

[0046] The mixed solvent comprises:

[0047] Perfluorinated carbon as the primary solvent; and

[0048] Semi-fluorinated alkane as a second solvent;

[0049] The perfluorinated carbon is perfluorobromooctane, and the semifluorinated carbon is perfluorohexyloctane.

[0050] As a preferred embodiment of any of the first aspects of the present invention, the liquid composition does not contain preservatives. Since the mixed solvent is a non-aqueous system, microorganisms have difficulty multiplying in it, therefore, preservatives do not need to be added to the liquid composition.

[0051] As a preferred embodiment of any one of the first aspects of the present invention, the lutein content is 0-3% by weight of the total liquid composition, excluding 0%.

[0052] According to a preferred embodiment of any one of the first aspects of the present invention, the weight percentage of lutein relative to the total weight of the liquid composition is selected from any of the following ranges:

[0053] 0.001%–3%, 0.001%–2.5%, 0.001%–2%, 0.001%–1.5%, 0.001%–1%, 0.001%–0.5%, 0.001%–0.1%, 0.001%–0.05%, 0.001%–0.01%, 0.001%–0.005%, 0.001%–0.002%;

[0054] 0.002%–3%, 0.002%–2.5%, 0.002%–2%, 0.002%–1.5%, 0.002%–1%, 0.002%–0.5%, 0.002%–0.1%, 0.002%–0.05%, 0.002%–0.01%, 0.002%–0.005%;

[0055] 0.005%–3%, 0.005%–2.5%, 0.005%–2%, 0.005%–1.5%, 0.005%–1%, 0.005%–0.5%, 0.005%–0.1%, 0.005%–0.05%, 0.005%–0.01%;

[0056] 0.01%–3%, 0.01%–2.5%, 0.01%–2%, 0.01%–1.5%, 0.01%–1%, 0.01%–0.5%, 0.01%–0.1%, 0.01%–0.05%;

[0057] 0.02%–3%, 0.02%–2.5%, 0.02%–2%, 0.02%–1.5%, 0.02%–1%, 0.02%–0.5%, 0.02%–0.1%, 0.01%–0.05%;

[0058] 0.05%–3%, 0.05%–2.5%, 0.05%–2%, 0.05%–1.5%, 0.05%–1%, 0.05%–0.5%, 0.05%–0.1%;

[0059] 0.1%–3%, 0.1%–2.5%, 0.1%–2%, 0.1%–1.5%, 0.1%–1%, 0.1%–0.5%;

[0060] 0.2%–3%, 0.2%–2.5%, 0.2%–2%, 0.2%–1.5%, 0.2%–1%, 0.2%–0.5%;

[0061] 0.5%–3%, 0.5%–2%, 0.5%–1.5%, 0.5%–1%;

[0062] 1%–3%, 1%–2.5%, 1%–2%, 1%–1.5%;

[0063] 1.5%–3%, 1.5%–2.5%, 1.5%–2%;

[0064] 2%–3%, 2%–2.5%;

[0065] 2.5% to 3%.

[0066] As a preferred embodiment of any one of the first aspects of the present invention, the lutein has a mass percentage content of 0.001 to 0.1%.

[0067] As another preferred embodiment of any one of the first aspects of the present invention, the lutein has a mass percentage content of 0.1-3%.

[0068] As a preferred embodiment of any one of the first aspects of the present invention, the weight ratio of the first solvent to the second solvent in the mixed solvent is from 10:1 to 1:10. Preferably, the values ​​are selected from any of the following ranges:

[0069] 10:1 to 1:10; 8:1 to 1:8; 5:1 to 1:5; 3:1 to 1:3; 2:1 to 1:2; 1.5:1 to 1:1.5.

[0070] Most preferably, the weight ratio is 3:1 to 1:3.

[0071] The liquid composition of the present invention can be used as a medicine or as an eye care product.

[0072] As a preferred embodiment of any of the first aspects of the present invention, when the liquid composition is a drug, the lutein is the only active ingredient in the liquid composition.

[0073] As a preferred embodiment of any one of the first aspects of the present invention, the liquid composition further includes an inert gas dissolved in the mixed solvent, wherein the inert gas is preferably N2 or CO2, and particularly preferably CO2.

[0074] In this invention, the inventors discovered that perfluorocarbons in liquid compositions exhibit excellent solubility for nonpolar gases. Taking perfluorooctane as an example, perfluorooctane can dissolve a large amount of nonpolar gases at room temperature and pressure; the solubility of O2 in 100 mL of perfluorooctane can reach over 200 mL. Existing technologies mainly utilize the solubility of O2 in fluorocarbons. Research has found that the solubility of perfluorocarbons for gases decreases in the order of CO2 > O2 > N2, with a higher solubility for CO2 than for O2. Currently, there are no applications developed to utilize the solubility of perfluorocarbons in inert gases such as CO2 to achieve the desired purpose. In order to further improve the stability of lutein, this invention utilizes the characteristic of perfluorinated carbon. After dissolving lutein in a mixed solvent of perfluorinated carbon and semi-fluorinated alkane, especially a mixed solvent of perfluorobromooctane and perfluorohexyloctane, CO2 gas is introduced into the solvent to replace the oxygen in the solvent. By utilizing the high carbon dioxide solubility of fluorocarbon compounds, lutein is placed in a carbon dioxide-rich environment in the solvent, avoiding its oxidation reaction and further improving the stability of the product.

[0075] This invention has found that CO2 solubility varies in different ratios of perfluorocarbons / semifluoroalkanes. Taking perfluorobromooctane and perfluorohexyloctane as examples, the CO2 solubility is as follows:

[0076] Table 1. CO2 solubility in mixed solvents of different proportions of perfluorinated carbon / semifluorinated alkane

[0077]

[0078] Perfluorinated carbon (PFCA) has a higher CO2 solubility than hemifluorinated alkane (HMA). Therefore, in mixed solvents with different proportions, PFCA has the highest CO2 solubility, while HMA has the lowest. Thus, from the perspective of improving lutein stability, a higher proportion of PFCA in the mixed solvent is better.

[0079] However, it is well known that semi-fluorinated alkanes are another important component in mixed solvents due to their stabilizing effect on the tear film and their ability to improve eye problems. When the liquid composition provided by this invention is applied to the eye, the semi-fluorinated alkanes exhibit high gas solubility and low surface tension, allowing them to rapidly diffuse across the ocular surface and interact with the lipids on the tear film surface, thereby covering the tear film and providing long-lasting stabilization and preventing excessive tear evaporation. As a component of the liquid composition, semi-fluorinated alkanes can improve the bioavailability of lutein and enhance its stability and safety. However, direct application of semi-fluorinated alkanes to the eye results in poor eye comfort. Combining them with perfluorinated carbon improves the comfort of the semi-fluorinated alkanes in the eye. Furthermore, because perfluorinated carbon has high CO2 solubility, the CO2 content of the liquid composition after being infused with sufficient CO2 is higher than that of a liquid composition containing only semi-fluorinated alkanes. Therefore, compared to a liquid composition containing only semi-fluorinated alkanes without perfluorinated carbon, the mixed solvent liquid composition achieves improved lutein stability.

[0080] As a preferred embodiment of any one of the first aspects of the present invention, the amount of CO2 dissolved in the liquid composition is 0.1 mL / mL to 2 mL / mL, preferably selected from any of the following ranges:

[0081] 0.1mL / mL~2mL / mL, 0.1mL / mL~1.5mL / mL, 0.1mL / mL~1mL / mL, 0.1mL / mL~0.5mL / mL, 0.1mL / mL~0.2mL / mL;

[0082] 0.2mL / mL~2mL / mL, 0.2mL / mL~1.5mL / mL, 0.2mL / mL~1mL / mL, 0.2mL / mL~0.5mL / mL;

[0083] 0.5mL / mL~2mL / mL, 0.5mL / mL~1.5mL / mL, 0.5mL / mL~1mL / mL;

[0084] 1mL / mL~2mL / mL, 1mL / mL~1.5mL / mL;

[0085] 1.5 mL / mL~2 mL / mL.

[0086] As a preferred embodiment of any one of the first aspects of the present invention, the amount of CO2 dissolved in the liquid composition is preferably 1 mL / mL to 2 mL / mL.

[0087] The present invention has found that, before CO2 dissolution in a liquid composition reaches saturation concentration, the greater the amount of CO2 dissolved in the liquid composition, the more beneficial it is to the stability of lutein in the liquid composition.

[0088] As a preferred embodiment of any one of the first aspects of the present invention, the liquid composition further comprises one or more of cyclosporine A, dextran, taurine, aminocaproic acid, aspartic acid, and sodium hyaluronate.

[0089]

use

[0090] The second aspect of the present invention provides the use of the liquid composition according to any embodiment of the first aspect of the present invention in the preparation of ophthalmic drugs, or eye drops, or as a cleaning solution for the eye or eye tissues.

[0091] As a preferred embodiment of any of the second aspects of the present invention, the liquid composition is used to prepare an ophthalmic drug, or eye drops, for application to any area of ​​the cornea, conjunctiva, upper or lower eyelid margin, meibomian gland duct, eyelashes, or eye or eyelid anatomy, or as a cleansing solution for the eye or eye tissues.

[0092] Methods for stabilizing carotenoids / lutein

[0093] A third aspect of the present invention provides a method for stabilizing carotenoids, comprising dissolving, dispersing or suspending the carotenoids in a mixed solvent, said mixed solvent comprising perfluorinated carbon as a first solvent and semifluorinated alkane as a second solvent.

[0094] Preferably, the weight ratio of the first solvent to the second solvent in the mixed solvent is from 10:1 to 1:10, and more preferably, a value selected from any of the following ranges:

[0095] 10:1 to 1:10; 8:1 to 1:8; 5:1 to 1:5; 3:1 to 1:3; 2:1 to 1:2; 1.5:1 to 1:1.5.

[0096] Most preferably, the weight ratio is 3:1 to 1:3.

[0097] Preferably, the method further includes the step of introducing or pressurizing CO2 into the mixed solvent. Specifically, CO2 is introduced into the mixed solvent, for example, by using a carbon dioxide manufacturing device or by pressing bottled carbon dioxide through a 0.45 μm polyethersulfone gas filter into the bottom of the dispensing container.

[0098] Preferably, the step of introducing or pressurizing CO2 is performed first, followed by the step of dissolving, dispersing, or suspending carotenoids in the mixed solvent; or

[0099] First, perform the steps of dissolving, dispersing, or suspending carotenoids in a mixed solvent, and then perform the steps of introducing or pressurizing CO2.

[0100] A third aspect of the present invention also provides a method for stabilizing lutein, comprising dissolving, dispersing or suspending lutein in a mixed solvent, said mixed solvent comprising perfluorinated carbon as a first solvent and semifluorinated alkane as a second solvent.

[0101] As a preferred embodiment of any of the third aspects of the present invention, the perfluorocarbon is perfluorobromooctane, and the semi-fluorinated carbon is perfluorohexyloctane.

[0102] As a preferred embodiment of any of the third aspects of the present invention, the weight ratio of the first solvent to the second solvent in the mixed solvent is 10:1 to 1:10, preferably, a value selected from any of the following ranges:

[0103] 10:1 to 1:10; 8:1 to 1:8; 5:1 to 1:5; 3:1 to 1:3; 2:1 to 1:2; 1.5:1 to 1:1.5.

[0104] Most preferably, the weight ratio is 3:1 to 1:3.

[0105] As a preferred embodiment of any of the third aspects of the present invention, the method further includes the step of introducing or pressurizing N2 or CO2 into the mixed solvent, preferably CO2. Specifically, CO2 is introduced into the mixed solvent, for example, by using a carbon dioxide manufacturing device or by pressing bottled carbon dioxide through a 0.45 μm polyethersulfone gas filter into the bottom of the solution preparation container.

[0106] As a preferred embodiment of any of the third aspects of the present invention, the step of introducing or pressurizing N2 or CO2 is performed first, followed by the step of dissolving, dispersing or suspending lutein in a mixed solvent; or

[0107] First, perform the steps of dissolving, dispersing, or suspending lutein in a mixed solvent, and then perform the steps of introducing or pressurizing N2 or CO2.

[0108] 3. Beneficial effects

[0109] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0110] (1) Compared with the complex methods used in the prior art to solve the solubility and stability of carotenoids, especially lutein, such as preparing lutein and other related substances into nanoemulsions, micelle solutions or in-situ temperature-controlled gels, the liquid composition formulation provided by the present invention, which uses perfluorinated carbon and semifluorinated alkane as mixed solvents, is simple and effectively improves the stability of carotenoids, especially lutein, in liquid compositions.

[0111] (2) The mixed solvent in this invention has the characteristic of low surface tension, which can quickly spread and cover the ocular surface; at the same time, the vapor pressure of the mixed solvent is lower than that of water, thereby greatly increasing the residence time of lutein in the eye and improving bioavailability; in addition, the low surface tension makes the droplets of the liquid composition smaller, reducing drug loss during the administration process.

[0112] (3) This invention utilizes the high solubility of perfluorinated carbon in non-polar inert gases to place carotenoids, especially lutein, in an environment rich in non-polar inert gases, especially carbon dioxide, thus avoiding the oxidation reaction of lutein in the liquid composition and greatly improving the stability of the product; and data show that as the amount of carbon dioxide dissolved in the liquid composition increases, the stability of the product is improved.

[0113] (4) The liquid composition provided by the present invention does not contain pH adjusters, surfactants, preservatives, etc., thus avoiding irritation and damage to the eyes; and the liquid preparation does not require refrigeration and can be used day and night. Attached Figure Description

[0114] Figure 1 Bar chart showing the lutein content detection results of each embodiment and comparative example after 6 months of accelerated processing;

[0115] Figure 2 This is a schematic diagram of the production apparatus in Embodiments 5-10 of the present invention. Detailed Implementation

[0116] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0117] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0118] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable.

[0119] As used herein, the term "comprising" refers to the features of the component following "comprising" that are necessary to solve the corresponding technical problem. Those skilled in the art should understand that, unless specifically excluded, other components may be included in addition to the component following "comprising". For example, liquid compositions may also include other non-aqueous solvents or other active ingredients. Examples of other non-aqueous solvents include light liquid paraffin, liquid paraffin, soybean oil, corn oil, castor oil, sesame oil, anhydrous ethanol, isopropanol, acetone, medium-chain triglycerides, and polyoxyethylene 40 hydrogenated castor oil. These non-aqueous solvents can be used to dissolve and disperse active ingredients or to adjust the surface tension of liquid compositions. Examples of other active ingredients include cyclosporine A, dextran, taurine, aminocaproic acid, aspartic acid, and sodium hyaluronate.

[0120] Concentration, amount, and other numerical data may be presented in range format herein. It should be understood that such range format is used solely for convenience and brevity and should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges encompassed within the range, as if each value and subrange were explicitly stated. For example, a range of values ​​from about 1 to about 4.5 should be interpreted to include not only the explicitly stated limits of 1 to 4.5, but also individual numbers (such as 2, 3, 4) and subranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges that describe only a single value, such as “less than about 4.5,” which should be interpreted to include all the aforementioned values ​​and ranges. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0121] The present invention will be further described below with reference to specific embodiments.

[0122] Examples 1-3 (Liquid compositions without inert gases)

[0123] The preparation methods of the liquid compositions in Examples 1-3 are as follows:

[0124] (1) Weigh out lutein, perfluorobromooctane and perfluorohexyloctane according to the prescription in Table 2;

[0125] (2) Add perfluorohexyloctane to perfluorobromooctane and stir for 5 min to obtain a mixed solvent;

[0126] (3) Dissolve the lutein, then add the lutein to the mixed solvent and stir for 5 minutes;

[0127] (4) Filter the liquid composition using a filter membrane with a pore size of 0.22 μm.

[0128] Table 2. Content of main components in the liquid compositions of Examples 1-3

[0129] Liquid composition Prescription composition Example 1 Example 2 Example 3 - Lutein 4g 0.1g 0.1g First solvent Perfluorooctane 3kg 2kg 1kg Second solvent Perfluorohexyl octane 1kg 2kg 3kg inert gases none none none none Lutein content (wt%) - Approximately 0.1% Approximately 0.0025% Approximately 0.0025%

[0130] Example 4 (Liquid composition containing N2)

[0131] The preparation method of the liquid composition containing N2 is as follows:

[0132] (1) Weigh out lutein, perfluorobromooctane and perfluorohexyloctane according to the prescription amount in Example 1 in Table 2;

[0133] (2) Add perfluorohexyl octane to perfluorobromo octane and stir for 5 min;

[0134] (3) Dissolve the lutein, then add the lutein to the mixed solvent and stir for 5 minutes;

[0135] (4) Pass sufficient nitrogen gas into the solution;

[0136] (5) The liquid composition is obtained by filtering with a filter membrane with a pore size of 0.22 μm.

[0137] Examples 5-10 (Liquid Compositions Containing CO2)

[0138] The preparation methods of the CO2-containing liquid compositions in Examples 5-10 are as follows:

[0139] (1) Weigh out lutein, perfluorobromooctane and perfluorohexyloctane according to the prescription in Table 3;

[0140] (2) Add perfluorohexyloctane to perfluorobromooctane and stir for 5 min;

[0141] (3) Dissolve the lutein, then add the lutein to the mixed solvent and stir for 5 minutes;

[0142] (4) Pass sufficient carbon dioxide gas into the solution;

[0143] (5) Filter using a filter membrane with a pore size of 0.22 μm to obtain the liquid composition (e.g. Figure 2 (As shown).

[0144] The components and contents of the CO2-containing liquid compositions of Examples 5-10 are shown in the table below:

[0145] Table 3. Prescription composition of Examples 5-10

[0146]

[0147] Comparative Examples 1-4

[0148] The liquid compositions of Comparative Examples 1-4 are prepared by the following methods:

[0149] (1) Weigh each material according to the prescription in Table 4;

[0150] (2) Dissolve the lutein and then add the lutein to the solvent;

[0151] (3) Optional steps: Comparative Examples 1 and 3 do not perform the aeration step, while Comparative Examples 2 and 4 introduce sufficient carbon dioxide into the drug solution; (4) Filter using a filter membrane with a pore size of 0.22 μm to obtain the liquid composition.

[0152] Table 4. Prescription composition of Comparative Examples 1-4

[0153] Liquid composition Prescription composition Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 - Lutein 0.1g 0.1g 0.1g 0.1g First solvent Perfluorooctane none none 3kg 3kg Second solvent Perfluorohexyl octane 3kg 3kg none none inert gases <![CDATA[CO2 content]]> none 0.9 mL / mL none 1.9 mL / mL Lutein content - Approximately 0.0033% Approximately 0.0033% Approximately 0.0033% Approximately 0.0033%

[0154] Comparative Example 5

[0155] The preparation method of the aqueous liquid composition is as follows:

[0156] (1) Weigh each material according to the prescription in Table 5;

[0157] (2) Dissolve lutein (microcapsules, water-soluble, Xi'an Tianfeng) in purified water;

[0158] (3) Take a small amount of purified water, heat it to dissolve ethylparaben, and add menthol while stirring to dissolve;

[0159] (4) Combine the solutions from steps (2), (3) and (4), add sodium chloride and glycerol, and then add sodium sulfite;

[0160] (5) Adjust the pH to 7.0-7.4 with dilute hydrochloric acid / dilute sodium hydroxide solution, and filter through a 0.22μm filter membrane to obtain an aqueous liquid composition.

[0161] Table 5. Composition of prescriptions in Comparative Example 5

[0162] Prescription composition Comparative Example 5 Dosage Lutein Microcapsules 0.1g (calculated based on lutein) Ethylparaben 0.2g Menthol 0.01g Sodium chloride 0.9g Sodium sulfite 0.01g glycerin 10g Hydrochloric acid / sodium hydroxide Appropriate amount Purified water Up to 100mL

[0163] Test Example I (Stability Experiment)

[0164] Each example and comparative example was subjected to an accelerated test (40°C) for 6 months. After the experiment, the lutein content was measured, and the results are shown in the table below:

[0165] Table 6. Accelerated test (40°C) of the examples and comparative examples after 6 months of storage.

[0166]

[0167]

[0168] *The content of the lutein raw materials used has been calculated.

[0169] like Figure 1As shown, after 6 months of accelerated processing in Examples 5-10, lutein showed almost no degradation. In Examples 1-4, the lutein content decreased after 6 months of accelerated processing, indicating that the liquid composition containing CO2 has the best product stability compared to liquid compositions without inert gases or containing N2. Data from Example 4 shows that nitrogen in the liquid composition also has a certain protective effect on lutein, but the protective effect is relatively weak. Comparative Examples 1 and 3, compared with the aforementioned Examples 5-10, further demonstrate that CO2 contained in the liquid composition further improves product stability. Comparative Example 5 shows that adding the antioxidant sodium sulfite to the product is less effective in stabilizing lutein than using fluorocarbons as a solvent in Examples 1-4, and even less effective than adding CO2 to the formulation in Examples 5-10 to stabilize lutein.

[0170] Test Example II (Eye Comfort)

[0171] Ten volunteers were given instillation of Example 7 (left eye) and Comparative Example 2 (right eye), and their feelings were recorded.

[0172] Table 7 summarizes the volunteers' experiences with different prescription ophthalmic compositions instilled into both eyes.

[0173] Volunteer ID Left eye sensation Right eye sensation A No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. B No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. C No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. D No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. E No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. F No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. G No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. H No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. I No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort. J No irritation, no discomfort There was no irritation, but it felt like there was a sticky layer on the surface of my eyes, resulting in poor comfort.

[0174] Compared to Comparative Example 2, Example 7 increased the carbon dioxide carrying capacity, thus better ensuring product stability. Furthermore, Example 7 also improved patient comfort compared to Comparative Example 2. This is because perfluorohexyloctane, when instilled into the eye, forms a hydrophobic film that prevents tear evaporation. The addition of perfluorobromooctane to the prescription improves ocular permeability, thereby enhancing patient comfort.

[0175] The above description provides an illustrative overview of the present invention and its embodiments. This description is not restrictive, and the embodiments shown are merely one example of the invention's implementation. Actual implementations are not limited to these examples. Therefore, if those skilled in the art are inspired by this description and design similar implementations and examples without departing from the spirit of the invention, such designs should fall within the scope of protection of the present invention.

Claims

1. A liquid composition, characterized in that, Include: Carotenoids; and Mixed solvents; The mixed solvent comprises: Perfluorinated carbon as the primary solvent; and Semi-fluorinated alkane as a second solvent.

2. The liquid composition according to claim 1, characterized in that, The carotenoids are selected from one or more of lutein, α-carotene, β-carotene, γ-carotene, lycopene, zeaxanthin, astaxanthin, β-cryptoxanthin, and canthaxanthin.

3. The liquid composition according to claim 1 or 2, characterized in that, The perfluorinated carbon is selected from one or more of perfluorotripropylamine, perfluorotributylamine, perfluorobromooctane, perfluoron-butyltetrahydrofuran, perfluorooctane, perfluoronaphthane, perfluoron-butylnaphthane, and perfluorophenanthrene.

4. The liquid composition according to claim 1 or 2, characterized in that, The semifluorinated alkane has the molecular formula C0. a H 2a+ 1C b F 2b+1 , where a is selected from any integer value from 3 to 10, and b is selected from any integer value from 3 to 10; Preferably, the semifluorinated alkane is selected from C5H. 11 C4F9, C6H 13 C4F9, C6H 13 C6F 13 C8H 17 C6F 13 C8H 17 C8F 17 C9H 19 C6F 13 Or C 10 H 21 C6F 13 One or more of them.

5. A liquid composition, characterized in that, Include: Lutein; and Mixed solvents; The mixed solvent comprises: Perfluorinated carbon as the primary solvent; and Semi-fluorinated alkane as a second solvent; The perfluorinated carbon is perfluorobromooctane, and the semifluorinated carbon is perfluorohexyloctane.

6. The liquid composition according to any one of claims 2 to 5, characterized in that, The lutein content is 0-3% by weight of the total liquid composition, excluding 0%; preferably, the lutein content is 0.001-0.1% by weight; preferably, the lutein content is 0.1-3% by weight.

7. The liquid composition according to any one of claims 1 to 6, characterized in that, The weight ratio of the first solvent to the second solvent in the mixed solvent is 10:1 to 1:10, preferably 3:1 to 1:

3.

8. The liquid composition according to any one of claims 1 to 7, characterized in that, The liquid composition also includes an inert gas dissolved in the mixed solvent, preferably N2 or CO2.

9. The liquid composition according to claim 8, characterized in that, The solubility of N2 or CO2 in the liquid composition is 0.1 mL / mL to 2 mL / mL, preferably 1 mL / mL to 2 mL / mL.

10. The liquid composition according to claim 9, characterized in that, The liquid composition further comprises one or more of cyclosporine A, dextran, taurine, aminocaproic acid, aspartic acid, and sodium hyaluronate.

11. Use of the liquid composition according to any one of claims 1 to 10 in the preparation of ophthalmic drugs or eye drops, or as a cleansing solution for the eye or eye tissues; preferably, the liquid composition is used to prepare ophthalmic drugs or eye drops for application to the cornea, conjunctiva, upper or lower eyelid margin, meibomian gland duct, eyelashes, or any area of ​​the anatomy of the eye or eyelid, or as a cleansing solution for the eye or eye tissues.

12. A method for stabilizing carotenoids, characterized in that, This includes dissolving, dispersing, or suspending carotenoids in a mixed solvent, said mixed solvent comprising perfluorinated carbon as a first solvent and semifluorinated alkane as a second solvent.

13. The method according to claim 12, characterized in that, The weight ratio of the first solvent to the second solvent in the mixed solvent is 10:1 to 1:10, preferably 3:1 to 1:

3.

14. The method according to claim 12, characterized in that, It also includes the step of introducing or pressurizing an inert gas into the mixed solvent, wherein the inert gas is preferably N2 or CO2.

15. The method according to claim 14, characterized in that, First, perform the step of introducing or pressurizing an inert gas, then perform the step of dissolving, dispersing, or suspending carotenoids in a mixed solvent; or First, perform the steps of dissolving, dispersing, or suspending carotenoids in a mixed solvent, and then perform the steps of introducing or pressurizing an inert gas.

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