Composition containing crocetin

Abstract

To provide a composition effective for the prevention, suppression of progression, or treatment of myopia. [Solution] A composition for the prevention, inhibition of progression, or treatment of myopia, comprising at least one component selected from the group consisting of crocetin and a pharmaceutically acceptable salt thereof, characterized by being used in combination with at least one component selected from the group consisting of atropine and a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to a composition used for the prevention, progression suppression or treatment of myopia or eye diseases. The present invention also relates to a method for searching for a treatment that enhances the myopia progression suppression effect of atropine.

Background Art

[0002] It has been reported that there are racial and regional differences in the frequency of myopia. Particularly in East Asian regions, the proportion of myopia is significantly higher compared to other regions, and the proportion of high-intensity myopia of -5.00 diopters (D) or more is also high. In recent years, myopia has been on the rise globally. Myopia also has a high incidence rate among the younger generation, and it is known that the increase in myopia among the younger generation is particularly significant in East Asian regions (Non-Patent Document 1).

[0003] Myopia is classified into refractive myopia, axial myopia, pseudomyopia and pathological myopia, but myopia progression in schoolchildren is mainly axial myopia. The human eye is hyperopic immediately after birth. As the eye axis elongates during the growth period, the degree of hyperopia decreases, and it becomes emmetropic when entering school age. The elongation of the eye axis after this emmetropization phenomenon directly leads to myopization, and the elongated eye axis length cannot return to its original state. Therefore, it is considered that suppression of eye axis elongation in childhood and school age is effective for the prevention or treatment of myopia progression (Non-Patent Document 2). Also, the eye axis elongates not only during the growth period but also in adults, and adult eye axis elongation is said to be a risk factor for various eye diseases (Non-Patent Document 3). High-intensity myopia, which is a result of excessive eye axis elongation, increases the risk of eye diseases such as cataract, glaucoma, retinal detachment, retinopathy, macular disease, choroidal neovascularization, posterior staphyloma and optic neuropathy as complications. Therefore, suppression of eye axis elongation can not only bring about an improvement in QOL by preventing myopia, but can also lead to the prevention of serious eye diseases that lead to blindness.

[0004] Various methods are being considered to suppress the progression of myopia. Representative examples include low-concentration atropine eye drops (e.g., Myopin®, Rejusea® Mini Eye Drops 0.025%), night-time orthokeratology lenses, multifocal soft contact lenses, progressive multifocal eyeglasses, and myopia progression suppression devices (e.g., Eyerising myopia treatment devices). However, challenges remain, such as side effects, cost burden, complexity of procedures, and limited effectiveness.

[0005] While atropine eye drops are effective in suppressing the progression of myopia in children, they are associated with dose-dependent side effects (more specifically, photophobia) and rebound after discontinuation. Although doses of 0.05% and 0.025% are considered particularly promising in terms of efficacy and safety, further long-term studies are needed to establish optimal treatment conditions (Non-Patent Literature 4). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Brien A. Holden et al., “Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050”, Ophthalmology Volume 123, Number 5, May 2016, 1036-1042 [Non-Patent Document 2] Fumio Inoue, "Factors in the Progression of Myopia in Childhood and Prevention," Kyoto Women's University Journal of the Department of Life and Welfare, No. 17, February 2022, pp. 31-37. [Non-Patent Document 3] Taiga Inooka et al., “Risk Factors for Adult Axial Length Elongation: A Five-Year Population-Based Cohort Study”, Ophthalmology Science, Articles in Press, 101011, November 17, 2025 [Non-Patent Document 4] Alberto Chierigo et al., “The Role of Atropine in Preventing Myopia Progression: An Update“ Pharmaceutics 2022, 14, 900 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide a composition effective for the prevention, inhibition of progression, or treatment of myopia. More specifically, to provide a composition that can be used in combination with atropine. Another object is to provide a screening method that can search for a treatment that exhibits an effective effect in preventing, inhibiting the progression, or treating myopia when combined with atropine. [Means for solving the problem]

[0008] Based on this background, the inventors conducted thorough research and, through experiments using myopic model mice, determined the concentration of atropine that exhibits a 50% effect. Then, while administering atropine eye drops at this concentration to the myopic model mice, they searched for components useful for preventing, inhibiting the progression of, or treating myopia.

[0009] The inventors then used this model to search for safe materials suitable for preventing, inhibiting, or treating myopia. As a result, they discovered that crocetin, which is widely used as a food ingredient, exhibits improved effects when used in combination with atropine compared to atropine alone, thus completing the present invention.

[0010] In other words, the present invention provides the following: [1] A composition for the prevention, inhibition of progression, or treatment of myopia, comprising at least one component selected from the group consisting of crocetin and a pharmaceutically acceptable salt thereof, characterized by being used in combination with at least one component selected from the group consisting of atropine and a pharmaceutically acceptable salt thereof. [2] The composition of [1], wherein the eye drops contain at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts, and the content of at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts in the eye drops is 0.01 to 0.5% (w / v). [3] A composition of [1] or [2] for use in children. [4] A composition [1] to [3] for suppressing a decrease in the refractive power of the eye. [5] A food composition, one of the compositions [1] to [4]. [6] A kit comprising a composition containing at least one component selected from crocetin and a pharmaceutically acceptable salt thereof, and a composition containing at least one component selected from atropine and a pharmaceutically acceptable salt thereof. [7] A method for identifying treatments that complement or enhance the myopia progression-inhibiting effect of atropine, including administering atropine eye drops at a concentration of 0.075-0.275% (w / v) once daily to myopic animal models (excluding humans), along with other treatments. [8] Another procedure is to administer a composition containing a candidate active ingredient to a myopic model animal, [7] the method. [Effects of the Invention]

[0011] The present invention provides a composition for the prevention, inhibition of progression, or treatment of myopia that exhibits improved effects when combined with atropine. Furthermore, the present invention provides a method for searching for other treatments that complement or enhance the effects of atropine in the prevention and inhibition of progression of myopia when combined with atropine. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows an image of the model mouse used in this embodiment. The joint allows for precise adjustment of the left and right lens frames. A -30D lens was applied to the right eye, while no lens was applied to the left eye. [Figure 2] Figure 2 is a graph showing the EC50 concentration of atropine in relation to changes in axial length, based on the embodiment of the present invention. Figure 2A: Linear scale, Figure 2B: Logarithmic scale [Figure 3] Figure 3 is a graph showing the change in axial length based on the embodiment of the present invention. Figure 3A: A graph showing the change in axial length of the right and left eyes of model mice treated with control (no treatment), crocetin only, atropine only, and crocetin and atropine. Figure 3B: A graph comparing the difference in axial length of both eyes of model mice that were fed a normal diet without atropine treatment, fed a crocetin diet, and fed a normal diet with atropine treatment, and fed a crocetin diet. *: p<0.05, **: p<0.01, ***: p<0.005, ****: p<0.001. [Figure 4] Figure 4 is a graph showing the change in refractive error based on the embodiment of the present invention. Figure 4A: A graph showing the change in refractive error of the right and left eyes of a model mouse treated with control (no treatment), crocetin only, atropine only, and crocetin and atropine. Figure 4B: A graph comparing the difference in refractive error between the two eyes of a model mouse that was fed a normal diet without atropine treatment and a crocetin diet, and a model mouse that was fed a normal diet with atropine treatment and a crocetin diet. *: p<0.05, **: p<0.01, ***: p<0.005, ****: p<0.001.

Mode for Carrying Out the Invention

[0013] In one embodiment, the present invention provides a composition for preventing, suppressing the progression of, or treating myopia, which contains at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts, and is used in combination with at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts.

[0014] The composition of the present invention is characterized by being used in combination with at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts.

[0015] In the present specification, atropine and its pharmaceutically acceptable salts include hydrates of atropine and its salts, organic solvent adducts of atropine and its salts, and mixtures of the hydrates and the organic solvent adducts.

[0016] Atropine salts include atropine sulfate or its hydrate. More specifically, the atropine salt is atropine sulfate hydrate.

[0017] Atropine sulfate hydrate is a compound represented by the following structural formula.

Chemical formula

[0018] When crystal polymorphs and crystal polymorph groups (crystal polymorph systems) exist in atropine or its salts, those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means not only the individual crystal forms obtained at each stage when the crystal form changes due to conditions and states such as the production, crystallization, and storage of those crystals, but also mixtures of crystal forms obtained at two or more stages.

[0019] Atropine or its salts can be manufactured according to conventional methods in the field of organic synthesis chemistry, or commercially available products can be used. For example, atropine sulfate hydrate is commercially available from Tokyo Chemical Industry Co., Ltd. (product code: A0550). Alternatively, commercially available pharmaceuticals containing atropine or its salts may be used. Examples of commercially available pharmaceuticals include Myopin® and Rejusea® Mini Eye Drops 0.025%.

[0020] In one embodiment, the eye drops contain at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts.

[0021] In one embodiment, the content of at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts contained in the eye drops is not particularly limited, but is preferably 0.5% (w / v) or less, for example 0.25% (w / v) or less, 0.1% (w / v) or less, 0.05% (w / v) or less, 0.025% (w / v) or less, 0.01% (w / v) or less, for example 0.001~0.5% (w / v), 0.0025~0.25% (w / v), 0.005~0.1% (w / v), 0.01~0.05% (w / v), 0.075~0.275% (w / v), 0.084~0.266% (w / v), and more specifically 0.01~0.1% (w / v).

[0022] The composition of the present invention contains at least one component selected from the group consisting of crocetin and pharmaceutically acceptable salts thereof.

[0023] Crocetin is a natural pigment and one of the components classified as a carotenoid. Crocetin is a component with strong antioxidant properties and can be extracted in high purity from the fruit of gardenia (Rubiaceae family, Gardenia genus; Gardenia augusta MERRIL var., grandiflora HORT., Gardenia jasminoides ELLIS) and the stigma of saffron (Iridaceae family, Crocus genus; Crocus sativus).

[0024] Crocetin is usually obtained by hydrolyzing crocin (digenthiobiose ester of crocetin), a carotenoid yellow pigment. Crocin is found in gardenia fruit, dried saffron stigmas, etc., but gardenia fruit is preferred as an industrial raw material for obtaining crocin.

[0025] The method for extracting crocin from plant sources is not particularly limited, and known methods can be used, such as extracting from crushed dried gardenia fruit with water or alcohol (e.g., methanol, ethanol, etc.), or a mixture thereof. When using a water-alcohol mixture, the extraction conditions are preferably 0 to 50°C for 1 to 18 hours, and more preferably 30 to 40°C for 2 to 4 hours. The extraction operation is usually repeated multiple times.

[0026] Industrially, hydrolysis of crocin is preferably carried out by alkaline hydrolysis. Hydrolysis may also be carried out under stirring and / or heating. Hydrolysis is preferably carried out under stirring at 20 to 70°C, and at 40 to 60°C for 1 to 24 hours, preferably 3 to 5 hours.

[0027] When crocin hydrolysis is performed by alkaline hydrolysis, after the hydrolysis is complete, an appropriate amount of an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as citric acid, is usually added to the reaction solution to bring the pH down to 4.0 or lower, preferably 1.0 to 3.0, thereby precipitating crocetin. Subsequently, the mixture containing the precipitated crocetin can be recovered as a paste-like solid by centrifugation or filtration.

[0028] The resulting crocetin usually has acids, neutralized salts, and impurities derived from the raw materials adhering to its solid surface; therefore, a washing treatment is performed to remove these impurities. This treatment may be carried out using known methods, such as washing the paste-like solid with a sufficient amount of water. Next, the washed solid can be dried, for example, using a shelf-type ventilated dryer or a vacuum dryer, preferably under a nitrogen gas atmosphere at a temperature not exceeding approximately 50°C, to remove any remaining water from the solid.

[0029] While the purity of crocetin is not limited as long as it contains enough crocetin to be effective, a purity of 50% by mass or higher, for example 75% by mass or higher, is preferable from the viewpoint of having fewer impurities. The purity of crocetin can be calculated based on the color value of pure crocetin. The color value can be calculated according to conventional methods, referring to the "Voluntary Standards for Food Additives Other Than Chemically Synthesized Products (Second Edition)," edited by the Japan Food Additives Association, and "Gardenia Yellow Pigment."

[0030] Crocetin can be obtained by hydrolyzing crocin, which is found in natural products such as plants, as described above, or it can be chemically synthesized. Alternatively, crocetin found in natural products such as gardenia fruit, gardenia extract, and saffron extract may be used. From the standpoint of safety and purity, it is more desirable to obtain crocetin from gardenia yellow pigment (example of food labeling).

[0031] Examples of pharmacologically acceptable salts of crocetin include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; and salts of pharmaceutically acceptable organic amino compounds such as pyridine, dimethylamine, diethylamine, and ethanolamine.

[0032] Examples of commercially available crocetin preparations include Crovit® manufactured by Riken Vitamin Co., Ltd. "Crovit P (product name)" is a powder containing 75% or more crocetin, while "Crovit 2.5WD (product name)" is a water-dispersible preparation containing 2.5% or more crocetin.

[0033] The qualitative and quantitative methods for crocetin or its pharmaceutically acceptable salts in the composition of the present invention are not particularly limited as long as they are scientifically valid. For example, the sample can be separated by high-performance liquid chromatography using an ODS column and a concentration gradient mobile phase (TFA aqueous solution → TFA aqueous-methanol solution), and the test substance can be qualitatively and quantitatively determined using a photodiode array detector with all-trans-crocetin or 13-cis-crocetin as standard substances.

[0034] The compositions of the present invention are for the prevention, suppression of progression, or treatment of myopia or eye diseases. Specific examples include reducing the risk of myopia or eye diseases, and improving symptoms.

[0035] As used herein, "myopia" is defined as the refractive state of the eye in which parallel light rays entering the eye in an unaccommodated state are focused in front of the retina. In this embodiment, "myopia" includes all known classifications and definitions of myopia, such as axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, very severe myopia, high myopia, moderate myopia, mild myopia, myopia with glaucoma (especially juvenile glaucoma), myopia at risk of developing glaucoma, myopia with high intraocular pressure, and more specifically, refractive myopia and / or axial myopia, and even more specifically, refractive myopia.

[0036] As used herein, "prevention" of myopia means preventing the onset of myopia, delaying the onset of myopia, or reducing the risk of developing myopia.

[0037] In a specific embodiment, myopia prevention means ensuring that the refractive power does not become a negative number, for example, by maintaining the refractive power within the range of 0 to 6 diopters.

[0038] In other specific embodiments, prevention of myopia means maintaining an axial length of 25 mm or less.

[0039] As used in this specification, "suppression of myopia progression" means slowing down the progression of myopia (delay in myopia progression) or reducing the progression of myopia (reduction in myopia progression).

[0040] In a specific embodiment, myopia progression suppression means preventing the refractive error from exceeding -6D, for example, preventing the refractive error from exceeding -5D, -3D, or -1D. In another embodiment, myopia progression suppression means that the change in the subject's refractive error before and after administration and / or ingestion is within the range of -1 to +1D, for example, -0.5 to +0.5D or +0.1 to +0.3D.

[0041] In other specific embodiments, myopia progression suppression means that the axial length of the eye does not exceed 27 mm, for example, that the axial length does not exceed 26.5 mm, 26 mm, 25.5 mm, or 25 mm. In other embodiments, myopia progression suppression means that the change in the subject's axial length before and after administration and / or ingestion is within the range of -1 to +1 mm, for example, -0.5 to +0.5 mm or -0.1 to +0.1 mm.

[0042] As used herein, “treatment” of myopia means any treatment or therapy of myopia or its associated symptoms, such as curing or improving myopia, especially refractive myopia and / or axial myopia, or alleviating or suppressing symptoms associated with myopia. It also includes preventing the recurrence of myopia.

[0043] The content of at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts in the composition of the present invention is not particularly limited, but it is preferable that the daily intake is 0.001 to 5000 mg / day, for example, 0.01 to 1000 mg / day or 0.1 to 500 mg / day. In other embodiments, the content of at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts in the composition of the present invention is 0.001 to 100 mg, for example, 0.01 to 50 mg, 0.1 to 20 mg, 0.5 to 15 mg, 1 to 7.5 mg, 1.5 to 2.5 mg, etc.

[0044] (subject) The target animals for administration and / or ingestion of the composition of the present invention are mammals, reptiles, birds, and other animals, specifically mammals such as humans, dogs, cats, rabbits, rats, mice, horses, cattle, and pigs. More specifically, the target is humans.

[0045] (Pharmaceutical composition) In one embodiment, the composition of the present invention is a pharmaceutical composition. The pharmaceutical composition of the present invention can be prepared by adding, for example, pharmaceutically acceptable excipients. The dosage form of the pharmaceutical composition of the present invention is not particularly limited, but it can be eye drops, oral preparations (solid preparations such as tablets, capsules, granules, fine granules, powders, chewables, lozenges, etc., or liquid preparations such as liquids, syrups, etc.), injections, etc. Of these, eye drops and oral preparations are preferred from the viewpoint of easily achieving the effects of the present invention. The pharmaceutical composition of the present invention may contain other additives other than the components described above, depending on the properties and uses of each.

[0046] The symptoms and diseases targeted by the pharmaceutical composition of the present invention are myopia, eye diseases, or eye symptoms, and are not particularly limited, but more specifically those related to the refractive error and / or elongation of the eye. Specific examples of myopia include refractive myopia and axial myopia. More specifically, myopia in children and young adults during their growth period, when onset and progression are more likely, is included. Specific examples of eye diseases include cataracts, glaucoma, retinal detachment, retinopathy, macular degeneration, choroidal neovascularization, posterior staphyloma, and optic neuropathy, and preferably cataracts, glaucoma, retinal detachment, macular hole, foveal spondylolysis, choroidal neovascularization, posterior staphyloma, myopic macular degeneration, and myopic neuropathy.

[0047] The pharmaceutical composition of the present invention is intended for people who need prevention or treatment of myopia or eye diseases, particularly children and young people in their growth period who are prone to the onset and progression of myopia, specifically children under 20 years of age and young people in their 20s and 30s, preferably children aged 2 to 15 years, more preferably children aged 6 to 12 years. It can also be suitably used in middle-aged and elderly people who are at high risk of age-related eye diseases such as cataracts, glaucoma, retinal detachment, macular hole, foveal schizophrenia, retinal edema, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic maculopathy, myopic macular degeneration, age-related macular degeneration, and myopic neuropathy, depending on the symptoms of each individual.

[0048] When the pharmaceutical composition of the present invention is used for close-up work and / or indoor work, it is not particularly limited to people who have risk factors for myopia progression or axial elongation, but it is intended for people who mainly do close-up work indoors, or people who mainly have little exposure to violet light (visible light of 360-400 nm) outdoors. In particular, it is preferred for children and schoolchildren who spend relatively long hours studying, reading, using personal computers, watching television, and playing video games, as well as elderly people who tend to have less outdoor activity.

[0049] (Eye drops) When using the composition of the present invention as an eye drop, the solubility and stability in water of at least crocetin or a pharmaceutically acceptable salt thereof should be considered, and the composition should be selected from aqueous eye drops, eye drops that dissolve immediately before use, suspension eye drops, oily eye drops, eye ointments, etc. For example, since crocetin has amphiphilic properties, possessing both a water-attracting structure and an oil-attracting structure, the dosage form of the composition of the present invention can usually be an aqueous eye drop or a suspension eye drop.

[0050] In addition to the above-mentioned components, eye drops may contain other active ingredients (pharmacologically active ingredients, physiologically active ingredients, etc.). The types of such ingredients are not particularly limited, and examples include decongestant ingredients, ocular muscle stimulant ingredients, anti-inflammatory ingredients, astringent ingredients, antihistamine ingredients, anti-allergic ingredients, vitamins, amino acids, antibacterial ingredients, sugars, high molecular weight compounds or their derivatives, cellulose or its derivatives, local anesthetic ingredients, glaucoma treatment ingredients other than those listed above, cataract treatment ingredients other than those listed above, etc.

[0051] In addition, eye drops may contain, in combination or in combination, one or more of various components and additives, selected appropriately according to their use and form, in accordance with conventional methods, as long as the effects of the present invention are not impaired. Examples of such components or additives include carriers, fragrances or cooling agents, preservatives, bactericides or antibacterial agents, pH adjusters, chelating agents, stabilizers, isotonic agents, buffers, viscosity modifiers, and other additives commonly used in the preparation of liquid formulations. Representative components used in eye drops are listed below, but are not limited to these.

[0052] Examples of carriers include aqueous solvents such as water and aqueous ethanol. If the various components are poorly soluble in the aqueous solvent, a solubilizer may be used. Examples of solubilizers include polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, povidone, and polysorbate 80.

[0053] Examples of fragrances or cooling agents include terpenes (specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, and bonito flakes, which may be d-, l-, or dl-isomers), and essential oils (fennel oil, cool mint oil, cinnamon oil, spearmint oil, peppermint water, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.).

[0054] Examples of preservatives, disinfectants, or antibacterial agents include polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride), and Glokill (a trade name of Rhodia Corporation).

[0055] Examples of pH adjusting agents include hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, and phosphoric acid.

[0056] Examples of chelating agents include ascorbic acid, tetrasodium edetate, sodium edetate, and citric acid.

[0057] Examples of stabilizers include sodium edetate hydrate, povidone, polysorbate 80, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, and glyceryl monostearate.

[0058] Examples of isotonic agents include potassium chloride, sodium chloride, concentrated glycerin, glucose, and D-mannitol.

[0059] Examples of buffering agents include sodium citrate hydrate, sodium acetate hydrate, sodium bicarbonate, trometamol, boric acid, borax, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate.

[0060] Examples of viscosity-concentrating agents include carboxyvinyl polymer, povidone, polyvinyl alcohol (partially saponified), hydroxyethylcellulose, hypromellose, methylcellulose, and glycerin.

[0061] The eye drops of the present invention preferably contain 0.001 to 1% by mass of a component such as crocetin or a pharmaceutically acceptable salt thereof, and more preferably 0.01 to 0.1% by mass. Other additives may be added to enhance the effects of the present invention or within a range that does not inhibit the effects of the present invention. The content is not particularly limited, but it is preferably about 0.001 to 1% by mass in the composition.

[0062] The pH of the eye drops should be between 3 and 10, with 4 to 9 being preferable from the viewpoint of usability, and 5 to 8.5 being more preferable from the viewpoint of usability.

[0063] Any known eye drop container can be used without limitation as a container for filling the eye drop solution of the present invention. Typically, an eye drop container can be used that has a shape that allows the eye drop solution to be dropped into the eye, for example, one that has a nozzle and a container opening at the tip of the nozzle. Furthermore, the eye drop container for the eye drop solution of the present invention may have a structure in which a nozzle, which is molded separately, is attached to the container, or a structure in which the nozzle part (liquid dispensing part) and the container body are integrally molded (for example, a single-use type eye drop solution).

[0064] The container for the eye drops of the present invention may be made of plastic. The material of the plastic container is not particularly limited, but examples include one of polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers thereof, or mixtures of two or more thereof. Polyethylene terephthalate, polyarylate, polyethylene naphthalate, copolymers thereof, or mixtures of two or more thereof are preferred, as they allow the effects of the present invention to be easily achieved by adjusting the extrusion process.

[0065] The eye drops of the present invention may be filled into a transparent container (a container with sufficient transparency to allow observation of foreign matter) made primarily of such a material, or into a light-shielded container. Light shielding may be achieved, for example, by adding a coloring agent to the transparent container material, or by covering the container with shrink film or an outer box. Furthermore, the capacity of the container is preferably about 0.5 to 50 mL, and more preferably about 3 to 20 mL, in order to further enhance the effects of the present invention through the degree of extrusion, etc.

[0066] Furthermore, the nozzle provided in the container for the eye drops of the present invention is not particularly limited in terms of its structure or constituent materials. The nozzle structure can be any structure commonly used for eye drop containers, and the constituent materials of the nozzle can be, for example, those similar to those used for the plastic container described above. From the viewpoint of further improving the liquid flow of the eye drops of the present invention and suppressing variations in the amount of drops dispensed, a nozzle containing polyethylene or polypropylene as a constituent material is preferred. Examples of polyethylene include high-density polyethylene and low-density polyethylene, but among these, a nozzle containing low-density polyethylene as a constituent material is preferred.

[0067] The eye drops of the present invention can be prepared by methods commonly used and known to those skilled in the art. For example, the components can be dispersed in a carrier such as water, a solubilizer can be added if necessary, the mixture can be heated as needed, homogenized, dissolved, or emulsified using a homogenizer or the like, and the pH can be adjusted with a pH adjuster. Furthermore, methods such as autoclaving or filtration sterilization can be selected as sterilization methods for the formulation.

[0068] The dosage and administration of the eye drops of the present invention may vary depending on the patient's symptoms, age, etc., but usually, it is sufficient to instill about 1 to 2 drops about 1 to 6 times a day.

[0069] (Oral medication: Solid dosage form) The composition of the present invention can be formed into solid formulations such as tablets, capsules, granules, and powders. Oral formulations have the advantage of being highly portable and allowing for easy administration of a consistent amount by mouth. The shape, weight, size, and color of oral formulations are designed with ease of handling and administration in mind. Depending on its use and form, solid formulations can contain one or more components and additives, selected appropriately according to conventional methods. In addition to antioxidant plant extracts or components derived therefrom, such as crocetin or its pharmaceutically acceptable salts, carotenoids, and polyphenols, these components or additives can include excipients, lubricants, binders, disintegrants, etc. Furthermore, preservatives, antioxidants, colorants, sweeteners, and other additives may be used as needed. The following are examples of typical components used in solid formulations, but are not limited to these.

[0070] Examples of excipients include sugar alcohols such as D-sorbitol, mannitol, and xylitol; sugars such as glucose, sucrose, lactose, and fructose; crystalline cellulose; carmellose sodium; croscarmellose sodium; calcium hydrogen phosphate; wheat starch; rice starch; corn starch; potato starch; dextrin; β-cyclodextrin; light anhydrous silicic acid; titanium dioxide; magnesium aluminometasilicate; talc; kaolin; and olive oil.

[0071] Examples of binders include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol alginate.

[0072] Examples of disintegrants include starch, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, and partially pregelatinized starch.

[0073] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax, bleached beeswax, and the like.

[0074] These additives can be incorporated within a range that does not impair the effects of the present invention.

[0075] The oral preparation (solid dosage form) of the present invention can be prepared by methods commonly used or known to those skilled in the art. Examples include a method of kneading a composition, forming an extruded granule by passing it through a screen, then crushing and sizing the granule; a method of adding kneading water to the composition and forming it with a vertical granulator, followed by stirring granulation, then crushing and sieving with a co-mill; a method of compressing the formulation composition with a roller compactor, then crushing and sieving with a roll granulator; and a method of stirring granulation followed by fluidized bed drying. Furthermore, for example, in the case of direct compression, the composition can be mixed and then directly fed into a tablet press for tableting.

[0076] (Oral medication: Liquid formulation) The composition of the present invention can also be in the form of a liquid formulation, such as a syrup or a drink. In addition to the components described above, the liquid formulation may contain solvents, solubilizers, suspending agents, isotonic agents, buffering agents, analgesics, etc. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed. These additives can be included within a range that does not impair the effects of the present invention.

[0077] Examples of solvents include water, alcohol, propylene glycol, macrogol, sesame oil, and corn oil.

[0078] Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0079] Examples of suspending and emulsifying agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and waxes such as shellac wax, beeswax, carnauba wax, whalebone wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin, lanolin wax, candelilla wax, Japanese wax, montan wax, shellac wax, and rice wax.

[0080] Examples of isotonic agents include sodium chloride, glycerin, and D-mannitol. Examples of buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates. Examples of analgesics include benzyl alcohol. Examples of preservatives include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of antioxidants include sulfites and ascorbic acid.

[0081] When the composition of the present invention is prepared as a liquid formulation, conventional methods can be used. When preparing a liquid formulation, the solubility and stability in water of at least crocetin or a pharmaceutically acceptable salt thereof should be considered. For example, since crocetin is a water-soluble carotenoid that possesses both a water-attracting structure and an oil-attracting structure, the dosage form of the liquid formulation can usually be an aqueous formulation or a suspension formulation.

[0082] The dosage of the oral preparation (solid dosage form, liquid dosage form) of the present invention can be appropriately set according to the target disease and condition, the severity of the disease and condition, the age and weight of the subject, etc. The amount of crocetin is 0.075 to 75 mg per day, more preferably 0.1 to 25 mg, and even more preferably 0.25 to 10 mg. The amount of extracts other than crocetin is 0.1 to 5000 mg per day, more preferably 1 to 1000 mg, and even more preferably 10 to 300 mg. The number of doses may be once per day, or multiple times, for example, two, three, or more times.

[0083] (food) The composition of the present invention can be provided as a food composition, either as is or mixed with other ingredients, or incorporated into food products to be provided in food form. Examples of such functional foods include beverages, supplements, health foods, foods with functional claims, health supplements, nutritional functional foods, foods for special dietary uses, foods for specified health uses, or ordinary foods. Because these foods contain the composition of the present invention, they can be suitably consumed according to the symptoms of individuals who need prevention or treatment of myopia or eye diseases, particularly children and young people in their growth period who are prone to the onset and progression of myopia, especially axial myopia, and middle-aged and elderly people who are at high risk of age-related eye diseases such as cataracts, glaucoma, retinal detachment, retinopathy, maculopathy, choroidal neovascularization, posterior staphyloma, and optic neuropathy. Furthermore, even in cases other than those mentioned above, the composition can be widely consumed with the expectation of improving symptoms and diseases caused by decreased refractive error or elongation of the eyeball, for the purpose of suppressing decreased refractive error or elongation of the eyeball.

[0084] These foods can take the form of liquids such as juices, soft drinks, energy drinks, and tea; solids such as biscuits, tablets, granules, powders, and capsules; and semi-liquids such as pastes, jellies, soups, seasonings, and dressings.

[0085] Specifically, examples include rice; various types of noodles including soba, udon, vermicelli, Chinese noodles, instant noodles, and cup noodles; beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, lactic acid drinks, and sports drinks; curry roux, stews, and various soups; frozen desserts such as ice cream, ice sherbet, and shaved ice; confectionery such as candy, cookies, gum, chocolate, tablets, snacks, biscuits, jelly, jam, cream, and other baked goods; processed seafood and livestock products such as kamaboko, hanpen, ham, and sausages; dairy products such as processed milk and fermented milk; oils and processed oils such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressings; seasonings such as sauces, dressings, miso, soy sauce, and tare; soups, stews, salads, prepared foods, furikake, and pickles; and various other forms of health and nutritional supplements.

[0086] Furthermore, foods that may be provided containing the composition of the present invention also include supplements (powder, granules, soft capsules, hard capsules, tablets, chewable tablets, fast-disintegrating tablets, syrups, liquids, etc.).

[0087] Furthermore, the composition of the present invention can be incorporated into animal feed, such as that for pets.

[0088] These foods can all be manufactured by adding crocetin or a pharmaceutically acceptable salt thereof, by methods known to those skilled in the art.

[0089] Foods may contain ingredients other than crocetin, as needed. Examples of such ingredients include sugars such as glucose, fructose, sucrose, maltose, lactose, and corn syrup; polysaccharides such as dextrin and oligosaccharides; sugar alcohols such as sorbitol and mannitol; and stevioside, rubusoside, and sucralose. 登録商標Sweeteners such as acesulfame potassium and aspartame; acids such as citric acid, sodium citrate, tartaric acid, malic acid, succinic acid, and lactic acid; antioxidants such as L-ascorbic acid, dl-α-tocopherol, and sodium erythorbate; softeners such as glycerin and propylene glycol; emulsifiers such as glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, and sorbitan fatty acid esters; thickening polysaccharides such as gum arabic, carrageenan, pectin, and agar; proteins such as casein and gelatin; vitamins such as vitamin C, B vitamins, vitamin E, nicotinamide, and calcium pantothenate; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; amino acids; oils and fats; fruit juice; dietary fiber; color fixatives; pigments; flavorings; and preservatives.

[0090] The food product in this invention may be labeled as having preventive, risk-reducing, or ameliorative effects on myopia or eye diseases (for example, posterior segment diseases such as cataracts, glaucoma, retinal detachment, macular hole, foveal spondylolysis, retinal edema, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic maculopathy, myopic macular degeneration, age-related macular degeneration, and myopic neuropathy). Furthermore, the food product in this invention may be labeled as being for children in their growth stage who are prone to developing and progressing myopia (specifically refractive myopia and / or axial myopia); for middle-aged and elderly people at high risk of age-related posterior segment diseases such as cataracts, retinal detachment, glaucoma, macular degeneration, and choroidal neovascularization; for symptoms and diseases caused by decreased refractive power or elongation of the eyeball; or for suppressing decreased refractive power or elongation of the eyeball.

[0091] In one embodiment, the present invention provides a composition containing at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts, and at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts. The form, subject, and content of the components of the composition are subject to all the conditions described above.

[0092] The compositions, pharmaceutical compositions (eye drops, oral preparations, etc.), foods, or food compositions (functional foods, foods for specified health uses, etc.) according to the present invention are effective for age groups in which myopia develops or progresses, particularly for children and young people during their growth period. In particular, they can suppress the decline in visual acuity (onset of myopia, progression of myopia), and mainly exert the effect of suppressing the decrease in refractive error or elongation of the axial length that is likely to occur in children under 20 years of age and young people in their 20s to 30s, preferably 2 to 15 years of age, more preferably 6 to 12 years of age during their growth period. They are also effective for middle-aged and elderly people who are at high risk of age-related posterior segment diseases such as cataracts, glaucoma, retinal detachment, retinopathy, macular degeneration, choroidal neovascularization, posterior staphyloma, and optic neuropathy.

[0093] In one embodiment, the composition of the present invention can enhance the effect of at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts. While not bound by theory, atropine is known to suppress the action of the parasympathetic nervous system and promote sympathetic dominance by competitively inhibiting acetylcholine receptors, while crocetin is known to activate the gene "EGR1 (Early Growth Response 1)" involved in myopia suppression. Because their mechanisms of action differ, it is thought that they exert additive or synergistic effects in preventing or inhibiting the progression of myopia without inhibiting the action of atropine. In particular, it is surprising that the combined effect of atropine and crocetin is more effective against changes in refractive error than against changes in axial length.

[0094] Therefore, in a more specific embodiment, the composition of the present invention is for suppressing a decrease in the refractive power of the eye.

[0095] In other specific embodiments, the compositions of the present invention are for enhancing ERG-1 expression. The effect of crocetin on ERG-1 expression is disclosed in detail in Japanese Patent No. 6502603, which is incorporated herein by reference. More specifically, since the enhancement of EGR-1 expression is thought to be related to the suppression of axial elongation, the compositions of the present invention can be suitably used as EGR-1 expression enhancing compositions in subjects at high risk of myopia, including growing children.

[0096] In one embodiment, the present invention provides a kit comprising a composition comprising at least one component selected from crocetin and a pharmaceutically acceptable salt thereof, and a composition comprising at least one component selected from atropine and a pharmaceutically acceptable salt thereof.

[0097] The form, target, and content of each composition included in the above kit are subject to all the conditions described above.

[0098] In the kit of the present invention, a composition comprising at least one component selected from crocetin and a pharmaceutically acceptable salt thereof and a composition comprising at least one component selected from atropine and a pharmaceutically acceptable salt thereof may be housed in separate containers within the same package, or they may be provided as a set of individually packaged components. Each composition may be filled into a single-dose or multi-dose container.

[0099] The kit of the present invention may include instructions for use (package insert) describing the method of using both compositions in combination, the order of administration, the interval between administrations, or the duration of administration. For example, an example of use is, but is not limited to, administering a composition containing at least one component selected from crocetin and a pharmaceutically acceptable salt thereof orally, while instilling a composition containing at least one component selected from atropine and a pharmaceutically acceptable salt thereof once daily into the eye. Furthermore, both compositions may be administered simultaneously or with a staggered period.

[0100] In one embodiment, the present invention provides a method for preventing, inhibiting the progression of, or treating myopia or eye disease, comprising administering at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts to a subject, including or excluding humans, before, concurrently with, or after administration of at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts. In another embodiment, the present invention provides the use of at least one component selected from the group consisting of crocetin and its pharmaceutically acceptable salts in combination with at least one component selected from the group consisting of atropine and its pharmaceutically acceptable salts to produce a drug for preventing, inhibiting the progression of, or treating myopia or eye disease. The above description also applies to embodiments of the method and embodiments of use.

[0101] In another embodiment, the present invention provides a method for searching for treatments that enhance the myopia progression inhibitory effect of atropine, which includes administering atropine eye drops at a concentration of 0.075-0.275% (w / v) once daily to a myopic model animal, along with other treatments.

[0102] Atropine has been shown to prevent elongation of the axial length of the eye when administered as 1% (w / v) eye drops. However, side effects such as photophobia are prominent at this concentration, and rebound effects upon discontinuation of administration are a concern. Therefore, 0.05% (w / v) and 0.025% (w / v) concentrations are considered more promising from the perspective of efficacy and safety. In addition, commercially available drugs for myopia progression control are 0.01% (w / v) and 0.025% (w / v), but their effect is less than that of 1% (w / v), and it is thought that combination with other effective treatments is necessary to obtain sufficient effect. For this reason, it is important to find a concentration of atropine that can produce a certain degree of effect, more specifically, a concentration that can produce about 50% effect.

[0103] As a result of diligent research, the inventors of this invention have determined the concentration at which atropine exerts a 50% effect through experiments using myopic model mice. More specifically, the concentration at which atropine exerts a 50% effect is 0.075-0.275% (w / v), and more specifically, 0.084-0.266% (w / v). Therefore, in a specific embodiment of the present invention, the search method involves administering atropine eye drops at the above concentration to myopic model animals once a day.

[0104] The myopia model animals used in the search method of the present invention are not particularly limited, but specifically, they are non-human animals capable of evaluating myopia progression, and include birds such as chickens or mammals such as mice, rats, guinea pigs, gerbils, hamsters, shrews, zebra lizards, rabbits, dogs, cats, marmosets, rhesus monkeys, green monkeys, and chimpanzees. Among these, mice, rats, or guinea pigs are preferred because changes in axial length and refractive error can be evaluated in a relatively short period of time. In one embodiment, these myopia model animals are individuals in which myopia has been induced by physical methods such as attaching negative lenses or occlusion, chemical methods such as myopia-inducing agents, or genetic methods.

[0105] In one embodiment, the negative lens used in the negative lens fitting is preferably a colorless, transparent spherical lens from the viewpoint of minimizing visual effects other than myopia induction. As for the power of the negative lens, from the viewpoint of sufficiently inducing pathological myopia, a D value of -15D or less is preferred, more preferably -20D or less, and even more preferably -30D or less. In one embodiment, the D value of the negative lens is, for example, -5D to -30D, -10D to -20D, and more specifically -30D.

[0106] In one embodiment, as a myopia inducer, animals may be administered one or more endoplasmic reticulum stress inducers such as tunicamycin, thapsigargin, dithiothreitol (DTT), and A23187, either individually or in combination (see, for example, Japanese Patent Application Publication No. 2020-023574). More specifically, the myopia inducer is preferably tunicamycin, thapsigargin, or a combination thereof.

[0107] In the search method of the present invention, "other treatments" refers to any treatment that, when used in combination with atropine eye drops, is expected to enhance the myopia progression inhibitory effect. Specific examples of such treatments include physical treatments, pharmacological treatments, environmental treatments, or genetic treatments.

[0108] Examples of physical treatments include irradiation with light of a specific wavelength and the application of lenses. Examples of pharmacological treatments include the administration of other compounds or physiologically active substances that act on eye tissue, and specifically include administering compositions containing candidate active ingredients to myopic model animals. These may be administered in any form, such as eye drops or oral administration.

[0109] In the search method of the present invention, by comparing a control group that receives only atropine eye drops with a test group that receives atropine eye drops in combination with other treatments, and by evaluating indicators such as axial length, refractive error, and morphological changes of the retina or choroid, it is possible to identify treatments that significantly enhance the myopia progression inhibitory effect of atropine. This method makes it possible to efficiently search for novel combination treatments that show a higher therapeutic effect than atropine monotherapy. [Examples]

[0110] Next, the present invention will be specifically described with reference to examples and test cases, but the present invention is not limited to the following examples and test cases.

[0111] (Mouse model) The model mouse described in Japanese Patent Application No. 2024-029565 was modified for testing. More specifically, three-week-old C57BL / 6J mice, shortly after weaning, were anesthetized with a three-drug mixture: Domitol (Nippon Zenyaku Kogyo Co., Ltd.), Betolfar (Meiji Seika Pharma Co., Ltd.), and Midazolam (Sandoz Inc.), and their skulls were exposed with scissors. A support post 1 was erected on the skull and fixed with dental cement (Super-Bond, Sun Medical Co., Ltd.). The support post has screw threads so that the adjustment device described later can be fixed with a nut.

[0112] The mice described above were fitted with a -30D negative contact lens (Rainbow Contact, Rainbow Optical Research Institute Co., Ltd.) in their right eye for three weeks using the fitting device shown in Figure 1. No lens was fitted to the left eye. To prevent the mice from damaging the lens with their forelegs, etc., a protector 4, which protrudes laterally, was attached to the frame at the bottom of the lens. Protector 4 prevented the mice from touching the lens, thus preventing damage. Note that -30D in mice is equivalent to -6D in humans.

[0113] An adjustment device 5 is attached to the frame above the lens to adjust the width and angle of the fitted lens as the mouse grows. The adjustment device 5 is bent into a "V" shape, with the lens attached to one end and an elongated hole 6 on the other end so that it can be attached to a support column 1 erected on the head. By passing the elongated hole 6 through the support column 1 and screwing it in with a nut 7, the lens can be fixed in close contact with the skin without compressing the edges of the mouse's eyes.

[0114] The adjustment mechanism, consisting of three parts—a support column (1), a nut (7), and an adjustment device (5)—allowed for adjustment of the width and angle to match the mouse's growth, ensuring the lens was positioned correctly at the mouse's eye. During rearing, the lens was removed from the mounting device and cleaned every three days, and its position was adjusted to ensure the correct angle and width relative to the mouse's eye axis.

[0115] (Searching for the EC50 concentration of atropine that provides 50% effectiveness) Using the mouse model described above, atropine eye drops were administered to both eyes once daily for three weeks at various concentrations (0%, 0.01%, 0.025%, 0.1%, 0.5%, and 1%). After three weeks, the difference in axial length between the two eyes was measured. Axial length was determined by imaging the entire eyeball using SD-OCT (Spectral-domain OCT, Envisu R4310, bioptigen Inc.). The results are shown in Figure 2. This study showed that the concentration at which a 50% effect was obtained compared to 1% atropine (EC50) was 0.175% (95% CI: 0.084~0.266%).

[0116] Based on the above results, the concentration at which atropine shows a 50% efficacy was determined. Although atropine is known to be highly effective at a 1% concentration, it has been forced to be used at low doses due to issues such as photophobia and rebound. However, even at low doses, its efficacy is limited. Now that the 50% effective concentration of atropine has been determined, it will be possible to search for ingredients or treatments that are effective in combination with atropine for the prevention, inhibition of progression, and / or treatment of myopia by conducting tests in combination with this concentration.

[0117] (Consideration of crocetin) Crocetin was investigated as an ingredient to be used in combination with atropine. Using the model mice described above, the axial length and refractive error of both eyes were measured immediately after the start of treatment and after 3 weeks in four groups: control group (no atropine eye drops or crocetin diet, PBS eye drops once daily), atropine group (0.2% atropine eye drops once daily), crocetin group (free access to diet containing 0.01% crocetin, PBS eye drops once daily), and atropine + crocetin group (0.2% atropine eye drops once daily, free access to diet containing 0.01% crocetin). Axial length was measured using the method described above, and refractive error was measured using a refractometer (Infrared photorefractor for mice, developed by Professor Schaeffel of Tubingen University).

[0118] (Axial length) In the control group, the axial length of the right eye with the lens implanted was significantly longer than that of the left eye. Both the crocetin group and the atropine group showed a tendency to suppress axial length elongation, but the crocetin + atropine group showed even greater suppression (Figure 3A). Furthermore, in terms of the difference in axial length elongation between the two eyes, both crocetin intake and atropine eye drops significantly suppressed axial length elongation, and the suppressive effect was strongest under the combined treatment condition, with almost no axial length elongation observed (Figure 3B).

[0119] (Refractive index) In the control group, the refractive error of the left eye (without lenses) was around 10D, while the refractive error of the right eye was -10D, showing a significant shift toward myopia. The crocetin group significantly suppressed myopia, with the right eye's refractive error remaining around 0D. The atropine group suppressed myopia more than the control group, but still showed a shift toward myopia. In the crocetin + atropine group, the change in refractive error was suppressed to the point where there was no significant difference between the right and left eyes (Figure 4A). Furthermore, in terms of the change in refractive error between the two eyes, both crocetin intake and atropine eye drops significantly suppressed the progression to myopia, with the suppressive effect being strongest under the combined use condition (Figure 4B).

[0120] Based on these results, while atropine and crocetin alone showed similar effects on axial length, combining crocetin and atropine further suppressed the elongation of the axial length. Furthermore, regarding refractive error, atropine suppressed it more effectively than the control group, but could not prevent it from becoming negative. Crocetin, while not causing it to become negative, only suppressed it to around 0D. In contrast, combining crocetin and atropine suppressed the progression of myopia until there was no significant difference in refractive error between the right and left eyes.

[0121] This confirmed that the combination of crocetin and atropine suppresses the progression of myopia in terms of both axial elongation and refractive error, particularly in terms of refractive error. [Industrial applicability]

[0122] The present invention makes it possible to provide compositions for the prevention, inhibition of progression, and / or treatment of myopia in combination with atropine. Furthermore, the present invention makes it possible to search for treatments, particularly compositions, for the prevention, inhibition of progression, and / or treatment of myopia that can be used in combination with atropine. Therefore, the present invention can be used in the medical field, veterinary field, food field, and the like. [Explanation of Symbols]

[0123] 1. Support post, 2. Negative lens, 3. Frame, 4. Protector, 5. Adjustment device, 6. Slotted hole, 7. Nut

Claims

1. A composition for the prevention, inhibition of progression, or treatment of myopia, comprising at least one component selected from the group consisting of crocetin and a pharmaceutically acceptable salt thereof, characterized by being used in combination with at least one component selected from the group consisting of atropine and a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, wherein the eye drops contain at least one component selected from the group consisting of atropine and pharmaceutically acceptable salts thereof, and the content of at least one component selected from the group consisting of atropine and pharmaceutically acceptable salts thereof in the eye drops is 0.01 to 0.5% (w / v).

3. The composition according to claim 1, for use in growing children.

4. The composition according to claim 1, for the purpose of suppressing a decrease in the refractive power of the eye.

5. The composition according to claim 1, which is a food composition.

6. A kit for the prevention, inhibition of progression, or treatment of myopia, comprising a composition comprising at least one component selected from crocetin and a pharmaceutically acceptable salt thereof, and a composition comprising at least one component selected from atropine and a pharmaceutically acceptable salt thereof.

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