Composition for preventing, alleviating or treating ocular dysfunctions

Abstract

The present invention relates to a composition for preventing, alleviating, or treating eye dysfunctions. A racetam-based compound and / or the GABA-based compound of the present invention can effectively alleviate eye dysfunctions due to various causes such as aging, specifically diseases caused by abnormalities in pupillary adjustment, ocular muscle regulation, or optic nerve regulation, including presbyopia, myopia, glaucoma, and night vision adjustment disorder, and thus can be effectively used for the prevention, treatment or alleviation of eye dysfunctions.

Description

Composition for preventing, improving or treating eye dysfunction

[0001] The present invention relates to a composition for preventing, improving or treating eye dysfunction.

[0002] This invention was made possible with the support of the Korean government under the Ministry of SMEs and Startups' Project No. 1425157125, "Development of a Clinical Multi-Omics-Based Intractable Sarcopenia Treatment" (Research Period: October 1, 2021 - March 31, 2024).

[0003] The eye is a complex structure and function, each eye regulating the amount of incoming light, focusing on objects near and far, and generating a continuous stream of images that are instantly transmitted to the brain. The eye is composed of the orbit, a bony cavity that contains and protects the entire eye structure; the sclera, conjunctiva, and cornea, which serve as protective coverings; the pupil, through which light passes; the iris, which regulates the amount of light entering the eye; the lens, which focuses light on the retina; the retina, which detects light and creates visual images; and the optic nerve.

[0004] Ocular diseases can be categorized into eyelid disorders, conjunctival and scleral disorders, corneal disorders, refractive disorders, lens abnormalities, orbital disorders, retinal disorders, and optic nerve disorders. Common ocular dysfunctions include age-related pupillary control, muscle control, nerve control, and lens control disorders due to refractive disorders.

[0005] Presbyopia is a progressive loss of the eye's ability to accommodate, resulting in decreased near vision. It typically manifests in people over 40, making it difficult to see objects at close range (approximately 25-30 cm). The eye's lens thickens as we move from distant to near, allowing light to focus precisely on the retina. However, presbyopia occurs when the lens and surrounding muscles, which perform this accommodation, lose elasticity with age, impairing the ability to see up close.

[0006] Current treatments for presbyopia (decreased near vision) include lifestyle and environmental modifications, optical correction, and surgical procedures. Modern people spend a lot of time working at close range, such as on smartphones and computers, so the goal of treatment is to alleviate the discomfort caused by presbyopia. However, the effectiveness of these treatments is minimal. Furthermore, the most commonly used prescription glasses for near vision correction require constant wear and are not a fundamental treatment option. Furthermore, surgical treatments are often irreversible or require repeat surgery, and carry the risk of postoperative complications (side effects). Therefore, a more fundamental treatment approach is needed to address these shortcomings.

[0007] Oxiracetam, a racetam drug, is used to improve cognitive impairment caused by cerebrovascular diseases such as cerebral hemorrhage and cerebral ischemia. It is known to enhance brain metabolic function by stabilizing neural membranes, supplying energy to the brain, and increasing neurotransmitter activity, thereby improving memory, attention, and cognitive abilities. It is also known to be useful in preventing or treating sarcopenia.

[0008] Accordingly, the inventors of the present invention completed the present invention by conducting research to improve eye dysfunction such as presbyopia, myopia, glaucoma, and night vision accommodative disorder due to pupillary accommodation disorder, ocular muscle accommodation disorder, and ophthalmic nerve accommodation disorder based on a compound whose pharmacological activity related to eye diseases is not yet known.

[0009] One object of the present invention is to provide a pharmaceutical composition for preventing or treating eye dysfunction, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0010] Another object of the present invention is to provide an eye drop comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0011] Another object of the present invention is to provide a method for preventing or treating eye dysfunction, comprising administering the composition to a subject.

[0012] Another object of the present invention is to provide a health functional food for preventing or improving eye function disorders, comprising at least one compound selected from the group consisting of racetam compounds, GABA compounds, food-based salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0013] One aspect of the present invention provides a pharmaceutical composition for preventing or treating eye dysfunction, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0014] According to one specific example of the present invention, the racetam series compound may be a pyrrolidine-2-one compound represented by the following chemical formula 1:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1,

[0018] R 1 and R 2 are independent of each other -H, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5-C(O)-R 4 and -CHR 5 -C(O)-R 6is a substituent selected from the group consisting of, or

[0019] R 1 and R 2 is R 1 Nitrogen atom attached to and R 2 It forms a ring with the carbon atom attached to it -C 1-7 Alkylene-, -C 2-7 Alkenylene-, -C 2-7 Alkynylene-, -C(O)-C 1-6 Alkylene-, -C(O)OC 1-6 Alkylene-, -C(O)NH-C 1-6 Alkylene-, -C(O)N(C 1-6 alkyl)-C 1-6 Alkylene- and -C 1-3 Alkylene-R 7 -C 1-3 A substituent selected from the group consisting of alkylene;

[0020] R 3 -H, -F, -Cl, -Br, -I, -OH, -C 1-7 Alkylene-NH 2, -C 1-7 Alkylene-NH-C 1-6 Alkyl, -C 1-7 Alkylene-N(C 1-6 alkyl)2, -C 1-7 Alkylene-X, -C 2-7 Alkenylene-X2, -C 2-7 Alkynylene-X, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, -OCH2R 8 , -CN and -C6H3R 9 R 10 is any one substituent selected from the group consisting of;

[0021] X is any one substituent selected from the group consisting of -F, -Cl, -Br and -I;

[0022] R 4 , R 5 and R 6are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5, -C6H5, -C6H4-OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 -C containing 1 to 2 heteroatoms selected from alkyl)2, O or N 3-8 Heterocycloalkyl, -NH-C 1-6 Alkylene-NH2, -NH-C 1-6 Alkylene-NH-C 1-6 Alkyl and -NH-C 1-6 Alkylene-N(C 1-6 Any one substituent selected from the group consisting of alkyl)2;

[0023] R 7 -O-, -C(O)-, -C(O)O-, -C(O)NH-, -NH-, and -N(C 1-6 Any one substituent selected from the group consisting of alkyl);

[0024] R 8 , R 9 and R 10 are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C6H5, and -OR 11 is any one substituent selected from the group consisting of;

[0025] R 11 Silver -C 1-7 Alkyl, -C 3-8 -C containing 1 to 2 heteroatoms selected from cycloalkyl, O or N 3-8 Heterocycloalkyl, -C 6-12 -C containing 1 to 2 heteroatoms selected from aryl, O or N 3-8 Any one substituent selected from the group consisting of heteroaryl.

[0026] According to one specific example of the present invention, the racetam series compound may be any one compound selected from the group consisting of oxiracetam, piracetam, phenylpiracetam, aniracetam, levetiracetam, rolziracetam, fasoracetam, pramiracetam, brivaracetam, seletracetam, coluracetam, dimiracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, and rolipram.

[0027] According to one specific example of the present invention, the eye dysfunction may be an ocular muscle dysfunction, an eyelid disorder, a conjunctival and sclera disorder, a corneal disorder, a refractive disorder, a lens abnormality disorder, an orbital disorder, a retinal disorder, presbyopia, myopia, glaucoma, or a lack of night vision accommodation.

[0028] According to one specific example of the present invention, the eye dysfunction may be caused by one or more causes selected from the group consisting of excessive use of electronic devices, excessive close-up work, aging, inflammation, oxidative stress, long-term use of steroids, and other diseases.

[0029] According to one specific example of the present invention, the eye dysfunction may be a disorder of the eyelid, tear system and orbit, a disorder of the conjunctiva, a disorder of the sclera, cornea, iris and ciliary body, a disorder of the lens, a disorder of the choroid and retina, glaucoma, a disorder of the vitreous body and eyeball, a disorder of the eye muscle, binocular movement, accommodation and refraction, and other disorders of the eye and adnexa.

[0030] According to one specific example of the present invention, the steroid may be dexamethasone.

[0031] According to one specific example of the present invention, the other disease may be any one disease selected from the group consisting of diabetes, hypertension, thyroid disease, and peritonitis.

[0032] Another aspect of the present invention provides an eye drop comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0033] Another aspect of the present invention provides a method for preventing or treating ocular dysfunction comprising administering the composition to a subject.

[0034] Another aspect of the present invention provides a health functional food for preventing or improving eye function disorders, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, food-based salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0035] According to the composition for preventing, improving or treating eye dysfunction, the racetam series compound and / or the GABA series compound of the present invention can effectively improve eye dysfunction caused by various causes such as aging, specifically, diseases caused by pupillary accommodation abnormality, ocular muscle control abnormality or ocular nerve control abnormality such as presbyopia, myopia, glaucoma, and night vision accommodation disorder, and therefore can be usefully utilized for preventing, treating or improving eye dysfunction.

[0036] Figure 1 is a graph showing the measured Pupillary Constriction Time in the control group (Vehicle) and the dexamethasone (DEX) treatment group.

[0037] Figures 2 and 3 are graphs showing the measurement of the contraction time of the racetam compound treatment group in the dexamethasone-treated presbyopia-induced model.

[0038] Figure 4 is a photograph (top) showing the pupil size before irradiating light on a group of C57BL / 6N 2-month-old mice and a group of C57BL / 6J 18-month-old mice, and a graph (bottom) showing the measured dilated pupil diameter.

[0039] Figure 5 is a photograph (top) showing the pupil size of a 2-month-old C57BL / 6N mouse group and an 18-month-old C57BL / 6J mouse group before and after irradiation, and a graph (bottom) showing the measured pupillary constriction speed.

[0040] Figure 6 shows a photograph (top) of the pupil size before light exposure and a graph (bottom) showing the measured dilated pupil diameter after treating C57BL / 6J 18-month-old mice with oxiracetam and pilocarpine for 7 days.

[0041] Figure 7 is a graph showing the measurement of the contraction velocity after treating 18-month-old C57BL / 6J mice with oxiracetam and pilocarpine for 7 days.

[0042] Figure 8 shows photographs of the pupil size before and after miosis according to the treatment period of oxiracetam and pilocarpine in 18-month-old C57BL / 6J mice.

[0043] Figure 9 is a graph showing the measurement of the contraction velocity by treatment group according to the treatment period of oxiracetam and pilocarpine in 18-month-old C57BL / 6J mice.

[0044] Figure 10 is a graph showing the measurement of the eclampsia time according to the concentration of oxiracetam in 18-month-old C57BL / 6J mice.

[0045] Figure 11 is a graph showing the measurement of the contraction velocity according to the concentration of oxiracetam in 18-month-old C57BL / 6J mice.

[0046] Figure 12 is a graph showing ATP activity affecting muscle function according to treatment with GABAergic compounds in mouse muscle cells.

[0047] One aspect of the present invention provides a pharmaceutical composition for preventing or treating eye dysfunction, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0048] In the present invention, the racetam series compound refers to a group of drugs that structurally have a ring structure of pyrrolidone or pyrrolidine-2-one, such as oxiracetam, and are used as a therapeutic agent for increasing neurotransmitter activity, etc.

[0049] Racetams are widely used as nootropic drugs that are related to or influence the neurotransmitter GABAergic or GABAergic in molecular biology and physiology. They have been utilized as a type of brain nutritional supplement to improve memory or concentration, and as a treatment for neurodegenerative diseases such as Alzheimer's disease and epilepsy. However, there are no reports of a direct link with the regulation of ocular functions, including pupillary, ocular muscles, and ophthalmic nerves.

[0050] In the present invention, it was confirmed that racetam and / or GABAergic drugs can be used to prevent or treat eye function or myopia and presbyopia due to decreased pupillary control, ocular muscle control, and ocular nerve control functions by increasing eye function in an animal model of reduced ocular muscle function.

[0051] When referring to racetam compounds or GABA compounds, unless otherwise defined in the specification, it is used to mean stereoisomers including both racemates and enantiomers, and even salt forms that are pharmaceutically or food-wise acceptable.

[0052] The term "stereoisomer" as used herein refers to a compound of the present invention that has the same chemical formula or molecular formula but is sterically different. Such stereoisomers include R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers).

[0053] The racetam series compounds and GABA series compounds of the present invention can be used in the form of pharmaceutically or food-wise acceptable salts, and the salts can be acid addition salts formed by pharmaceutically or food-wise acceptable free acids. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0054] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the chemical formula 1 or a derivative thereof in an organic solvent such as methanol, ethanol, acetone, methylene chloride and / or acetonitrile, adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.

[0055] The term "eye function" used in the present invention generally refers to the eye's accommodative function for collecting visual information, specifically, "pupillary control, ocular muscle control, and ocular nerve control functions," and means that all structures of the eye, including the orbit, cornea, pupil, iris, lens, retina, and optic nerve, perform their functions. Various methods are used to measure eye function, that is, the accommodative function of the eye. Ophthalmic tests for diagnosing disorders arising in such pupillary control, ocular muscle control, and nerve control functions, that is, eye dysfunction, include visual field tests, visual acuity tests, color vision tests, ophthalmoscopy, slit-lamp tests, tonometry, angiography, electroretinography, ultrasound, corneal thickness measurements, optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI).

[0056] Clinically, age-related ocular dysfunction is diagnosed in adults aged 40 years or older. Clinically, age-related ocular dysfunction includes the most common form, near vision loss, but also includes retinal diseases (such as macular degeneration and retinal detachment), ptosis, cataracts, and glaucoma.

[0057] According to one specific example of the present invention, the racetam series compound may be a pharmaceutical composition for preventing or treating eye dysfunction, wherein the pharmaceutical composition is a pyrrolidin-2-one compound represented by the following chemical formula 1:

[0058] [Chemical Formula 1]

[0059]

[0060] In the above chemical formula 1,

[0061] R 1 and R 2 are independent of each other -H, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5-C(O)-R 4 and -CHR 5 -C(O)-R 6 is a substituent selected from the group consisting of, or

[0062] R 1 and R 2 is R 1 Nitrogen atom attached to and R 2 It forms a ring with the carbon atom attached to it -C 1-7 Alkylene-, -C 2-7 Alkenylene-, -C 2-7 Alkynylene-, -C(O)-C 1-6 Alkylene-, -C(O)OC 1-6 Alkylene-, -C(O)NH-C 1-6 Alkylene-, -C(O)N(C 1-6 alkyl)-C 1-6 Alkylene- and -C 1-3 Alkylene-R 7 -C 1-3 A substituent selected from the group consisting of alkylene;

[0063] R 3 -H, -F, -Cl, -Br, -I, -OH, -C 1-7 Alkylene-NH 2, -C 1-7 Alkylene-NH-C 1-6 Alkyl, -C 1-7 Alkylene-N(C 1-6 alkyl)2, -C 1-7 Alkylene-X, -C 2-7 Alkenylene-X2, -C 2-7 Alkynylene-X, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, -OCH2R 8 , -CN and -C6H3R 9 R10 is any one substituent selected from the group consisting of;

[0064] X is any one substituent selected from the group consisting of -F, -Cl, -Br and -I;

[0065] R 4 , R 5 and R 6 are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5, -C6H5, -C6H4-OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 -C containing 1 to 2 heteroatoms selected from alkyl)2, O or N 3-8 Heterocycloalkyl, -NH-C 1-6 Alkylene-NH2, -NH-C 1-6 Alkylene-NH-C 1-6 Alkyl and -NH-C 1-6 Alkylene-N(C 1-6 Any one substituent selected from the group consisting of alkyl)2;

[0066] R 7 -O-, -C(O)-, -C(O)O-, -C(O)NH-, -NH-, and -N(C 1-6 Any one substituent selected from the group consisting of alkyl);

[0067] R 8 , R 9 and R 10 are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C6H5, and -OR 11 is any one substituent selected from the group consisting of;

[0068] R 11 Silver -C 1-7 Alkyl, -C 3-8 -C containing 1 to 2 heteroatoms selected from cycloalkyl, O or N 3-8 Heterocycloalkyl, -C6-12 -C containing 1 to 2 heteroatoms selected from aryl, O or N 3-8 Any one substituent selected from the group consisting of heteroaryl.

[0069] In the present invention, "alkyl" means a straight-chain, branched-chain or cyclic aliphatic saturated hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. Specifically, such alkyl groups may include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a normal butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a normal pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group, a normal heptyl group, a normal octyl group, etc.

[0070] In the present invention, “alkylene” refers to a divalent group derived from an alkyl group, and may include, for example, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, a sec-butylene group, a tert-butylene group, etc.

[0071] In the present invention, "alkenyl" means an unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, and including a double bond, such as a vinyl group, an allyl group, a butadienyl group, etc., and includes both those having a substituent and those having no substituent.

[0072] In the present invention, “alkynyl” means an unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, and including a triple bond, such as an ethynyl group, and includes both those having and not having a substituent.

[0073] In the present invention, “alkenylene” refers to a divalent group derived from an alkenyl group, and “alkynylene” refers to a divalent group derived from an alkynylene group.

[0074] "Cycloalkyl" in the present invention refers to a saturated or partially saturated 3- to 10-membered aliphatic ring group. Such cycloalkyl groups may include, for example, a cyclopropyl group, a cyclohexyl group, a norbornyl group, and an adamantyl group.

[0075] In the present invention, “heterocycloalkyl” means a saturated or partially saturated 5- to 10-membered aliphatic ring group containing 1 to 2 heteroatoms selected from O and N. Such heterocycloalkyl groups may include, for example, a tetrahydrofuranyl group, a 2,3-dihydrofuranyl group, a 2,5-dihydrofuranyl group, a pyrrolidinyl group, a 2,3-dihydropyrrolidinyl group, a 2,5-dihydropyrrolidinyl group, a tetrahydro-2H-pyranyl group, a 3,4-dihydro-2H-pyranyl group, a 4H-pyranyl group, a piperidinyl group, a 1,2,3,4-tetrahydropyridinyl group, a 1,4-dihydropyridinyl group, a piperazinyl group, an N-protected piperazinyl, a morpholino group, etc. The N-protecting group of piperazinyl may typically include an alkyl group, an alkylcarbonyl group, or an alkylsulfonyl group.

[0076] In the present invention, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 12 carbon atoms. Specific examples of such aryl groups include a phenyl group, a naphthalenyl group, and the like.

[0077] "Heteroaryl" in the present invention means a monocyclic, bicyclic, or tricyclic aromatic ring group containing 1 to 2 heteroatoms selected from O and N and having 4 to 13 carbon atoms. Such heteroaryl may include a thiophenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolinyl group, a thiazolyl group, an isothiazolinyl group, a pyridinyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolinyl group, a benzothiazolinyl group, a benzisothiazolyl group, a quinolinyl group, an isoquinolinyl group, a phthalazizinyl group, a quinazolinyl group, and the like.

[0078] According to one specific example of the present invention, the racetam series compound may be any one compound selected from the group consisting of oxiracetam, piracetam, phenylpiracetam, aniracetam, levetiracetam, rolziracetam, fasoracetam, pramiracetam, brivaracetam, seletracetam, coluracetam, dimiracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, and rolipram.

[0079] According to one specific example of the present invention, the GABA series compounds are oxiracetam, gabaculine hydrochloride, 5-aminovaleric acid hydrochloride, (±)-nipecotic acid, 3-aminopropylphosphonic acid, cis-4-aminocrotonic acid, γ-acetylenic GABA, (±)-baclofen, CGP-7930, CGP-13501, SCH-50911, CGP 55845 hydrochloride, N-Methyl-β-carboline-3-carboxamide, isogubacin Isoguvacine hydrochloride, Guvacine hydrochloride, (+)-Hydrastine, Imidazole-4-acetic acid hydrochloride, Isonipecotic acid, NO-711 hydrochloride, 3-α,21-Dihydroxy-5-α-pregnan-20-one, Picrotoxin, Phaclofen, Pregnenolone sulfate sodium, 5α-Pregnan-3α-ol-20-one, SB 205384, It may be any one compound selected from the group consisting of (E)-4-amino-2-butenoic acid, SR-95531, THIP hydrochloride, TPMPA, and (±)-γ-vinyl GABA.

[0080] According to one specific example of the present invention, the eye dysfunction may be an ocular muscle dysfunction, an eyelid disorder, a conjunctival and sclera disorder, a corneal disorder, a refractive disorder, a lens abnormality disorder, an orbital disorder, a retinal disorder, presbyopia, myopia, glaucoma, or a lack of night vision accommodation.

[0081] According to one specific example of the present invention, the ocular muscle dysfunction may be strabismus, cognate gaze paralysis, or ophthalmoplegia.

[0082] According to one specific example of the present invention, the eyelid disorder may be entropion, ectropion, lagophthalmos, blepharoptosis, ptosis, or eyelid retraction.

[0083] According to one embodiment of the present invention, the conjunctival and scleral disorder may be conjunctivitis, pterygium, conjunctival adhesion, conjunctival edema, conjunctival relaxation, or scleritis.

[0084] According to one specific example of the present invention, the corneal disorder may be keratitis, corneal edema, corneal degeneration, keratoconus, corneal ectasia, or corneal epithelial endophytosis.

[0085] According to one specific example of the present invention, the refractive disorder may be hyperopia, myopia, astigmatism, anisometropia, ectropia, accommodative spasm or accommodative paraplegia.

[0086] According to one specific example of the present invention, the lens abnormality may be a cataract or dislocation of the lens.

[0087] According to one embodiment of the present invention, the orbital disorder may be inflammation, exophthalmos, deformation of the orbit, or enophthalmos.

[0088] According to one specific example of the present invention, the retinal disorder may be retinal detachment, retinal hole, retinal vascular occlusion, retinopathy, retinal degeneration, separation of retinal layers, retinal hemorrhage, retinal edema, retinal necrosis or retinal ischemia.

[0089] According to one specific example of the present invention, the eye dysfunction may be caused by one or more causes selected from the group consisting of excessive use of electronic devices, excessive close-up work, aging, inflammation, oxidative stress, long-term use of steroids, and other diseases.

[0090] According to one specific example of the present invention, the eye dysfunction may be, for example, a disorder of the eyelid, tear system and orbit, a disorder of the conjunctiva, a disorder of the sclera, cornea, iris and ciliary body, a disorder of the lens, a disorder of the choroid and retina, glaucoma, a disorder of the vitreous body and eyeball, a disorder of the eye muscle, binocular movement, accommodation and refraction, and other disorders of the eye and adnexa.

[0091] According to one specific example of the present invention, the steroid may be dexamethasone.

[0092] According to one specific example of the present invention, the other disease may be any one disease selected from the group consisting of diabetes, hypertension, thyroid disease, and peritonitis.

[0093] The term "eye dysfunction" or "pupillary, ocular muscle and ophthalmic nerve regulation dysfunction" used in the present invention refers to all ophthalmic diseases caused by eyelid disorders, conjunctival and sclera disorders, corneal disorders, refractive disorders (lens abnormalities), orbital disorders, related muscle and nerve disorders, etc., and means that the values ​​measured through various tests are lower or higher than those of normal people and are determined to be abnormal. Specifically, "eye dysfunction" may include ophthalmic diseases that present with symptoms such as decreased visual field and eyesight, and may be, for example, eye dysfunction due to aging.

[0094] The ocular dysfunction of the present invention, particularly presbyopia, which is an ocular dysfunction due to aging, includes cases in which the ocular function is lower than that of a normal person or in which the ocular function is reduced in the same individual, even if the condition is not diagnosed clinically.

[0095] The ocular dysfunction of the present invention may be caused by various factors, including presbyopia, which is a natural disorder of the pupil, ocular muscles, and ocular nerve control function that occurs with aging, as well as inflammation, oxidative stress, and other causes. If ocular dysfunction is severe, it may cause blurred vision, decreased vision, pain, and vision loss. Other causes that may cause ocular dysfunction include, but are not limited to, diabetes, high blood pressure, thyroid disease, cellulitis, and / or long-term use of steroids.

[0096] The ocular dysfunction of the present invention may be a disorder of the eyelids, the lacrimal system and the orbit, a disorder of the conjunctiva, a disorder of the sclera, the cornea, the iris and the ciliary body, a disorder of the lens, a disorder of the choroid and the retina, glaucoma, a disorder of the vitreous body and the eyeball, a disorder of the eye muscle, binocular movement, accommodation and refraction, and other disorders of the eye and ocular adnexa. Specifically, the disorder of the eyelids, the lacrimal system and the orbit may be an entropion, an ectropion, a lagophthalmos, a blepharoptosis, a ptosis, a squint, a retraction of the eyelid, a degenerative disorder of the eyelid or a laxity of the eyelid skin; the disorder of the conjunctiva may be an ocular adhesion or a conjunctival relaxation; the disorder of the sclera, the cornea, the iris and the ciliary body may be an scleritis, a keratitis, an edema of the cornea, a degeneration of the cornea, an ectasia of the cornea, an iris and a ciliary body, a degeneration of the iris and a ciliary body, or a pupillary membrane; The disorder of the above lens may be a cataract or dislocation of the retina; the disorder of the choroid and retina may be chorioretinitis, choroidal degeneration, choroidal detachment, retinal detachment, retinal tear or retinopathy; the disorder of the vitreous and eye may be vitreous prolapse, vitreous opacity, vitreous degeneration, endophthalmitis, degenerative myopia, ocular hypotension or ocular degenerative pathology; the disorder of the ocular muscles, binocular movement, accommodation and refraction may be strabismus, pupillary paralysis, hypoconstriction and hyperconstriction, internuclear ophthalmoplegia, hyperopia, myopia, astigmatism, anisometropia, presbyopia (presbyopia), accommodation disorder, internal ophthalmoplegia, accommodation paresis or accommodation spasm; the disorder of the other eye and adnexa may be nystagmus and other irregular eye movements, abnormality of pupillary function or eye pain.

[0097] As used in the present invention, the term "comprising as an active ingredient" means including in a dosage range that brings about the effect of preventing, improving, or treating eye dysfunction, and the dosage range can be appropriately selected depending on the severity and formulation, and the number of applications can also be appropriately selected and applied depending on the age, weight, and constitution of the subject.

[0098] The pharmaceutical composition of the present invention is administered in a "pharmaceutically effective amount." The term "pharmaceutically effective amount" as used herein means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical prevention, improvement, or treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, it can be 0.001 mg / kg to 1000 mg / kg, 0.01 mg / kg to 100 mg / kg, or 0.1 to 20 mg / kg, or 0.1 to 500 mg / kg, and the upper and lower limits of the quantity can be selected and implemented within an appropriate range by a person skilled in the art.

[0099] The term "prevention" used in the present invention means preventing the occurrence of symptoms of a disease in advance by administering, ingesting, or applying the pharmaceutical composition of the present invention to an individual without an eye dysfunction accompanied by a decrease in visual field and ocular muscle function, thereby suppressing or blocking the symptoms of a disease caused by the functional disorder.

[0100] The term "treatment" used in the present invention includes completely curing, partially curing, improving or alleviating the symptoms of a disease caused by the functional disorder by administering a pharmaceutical composition containing a racetam compound of the present invention to an individual with an eye dysfunction accompanied by visual field and pupillary control abnormality, ocular muscle control abnormality, and ophthalmic nerve control impairment.

[0101] The term "improvement" used in the present invention refers to alleviating or alleviating the symptoms of a disease caused by an eye dysfunction accompanied by a decrease in visual field and eye function by administering a pharmaceutical composition containing a racetam compound of the present invention to a subject having an eye dysfunction.

[0102] “Improvement in eye function disorder” or “improvement in pupil, ocular muscle and ocular nerve regulation function” by administration of a pharmaceutical composition comprising a racetam series compound and / or a GABA series compound of the present invention means an improvement in the visual function evaluation value between any two time points before and after administration of the pharmaceutical composition of the present invention, and improvement means an improvement in a statistically significant value, and specifically means an improvement in eye function disorder or an improvement in pupil, ocular muscle and ocular nerve regulation function of 1% or more, 5% or more, 10% or more or 15% or more after administration of the pharmaceutical composition of the present invention compared to before administration of the pharmaceutical composition of the present invention. For example, the two arbitrary time points may mean before and after administration of oxiracetam.

[0103] The dosage, number of administrations, and administration cycle of the effective ingredient that can improve the above-mentioned eye function disorder or improve the pupil, ocular muscle, and ocular nerve regulation function can be appropriately selected by a person skilled in the art depending on the subject to which the pharmaceutical composition of the present invention is administered.

[0104] The pharmaceutical composition comprising the racetam series compound and / or the GABA series compound of the present invention may be administered alone or in combination, or as a pharmaceutical composition.

[0105] The pharmaceutical composition according to the present invention may comprise an effective amount of a racetam series compound and / or a GABA series compound alone or in combination, or may comprise one or more pharmaceutically acceptable carriers, excipients or diluents.

[0106] Pharmaceutically acceptable carriers, excipients and / or diluents that may be included in the pharmaceutical composition according to the present invention may be substances that are physiologically acceptable and do not typically cause allergic reactions such as gastrointestinal disorders or dizziness or similar reactions when administered to humans. Examples of such carriers, excipients and / or diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.

[0107] The pharmaceutical composition according to the present invention can be formulated into various dosage forms for oral and parenteral administration during clinical administration.

[0108] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be formulated to contain, in addition to the active ingredient, a racetam series compound, at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be included. Liquid preparations for oral administration can include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included.

[0109] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may additionally include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0110] When the pharmaceutical composition of the present invention is administered parenterally, it can be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate it into such a dosage form, the racetam compound of the present invention or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. Additionally, it can be sterilized and can contain auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifying promoters, salts for osmotic pressure control, buffers, and / or other therapeutically useful substances, and can be formulated according to mixing, granulating, or coating methods commonly used in the art.

[0111] When the pharmaceutical composition of the present invention is administered parenterally, it can be administered directly to the eye as an eye drop.

[0112] Another aspect of the present invention provides an eye drop comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0113] The eye drop of the present invention contains a GABAergic compound, a racetam compound, or a pharmaceutically acceptable salt thereof as an active ingredient (pharmaceutical ingredient), and may further contain a pharmaceutically acceptable additive if necessary, and may be an aqueous composition. The form of the eye drop of the present invention may be, for example, a liquid such as a solution or suspension, and when the eye drop of the present invention is, for example, an aqueous composition, the aqueous solvent that can be used is not particularly limited as long as it contains water, and may be, for example, water, or a mixture of water and a water-soluble solvent such as alcohol, and preferably purified water.

[0114] The eye drops of the present invention can be manufactured with the amount of dissolved oxygen reduced as much as possible, and can be manufactured to be substantially free of dissolved oxygen. For example, dissolved oxygen in the eye drops can be removed or reduced by substitution with an inert gas such as nitrogen or argon.

[0115] The eye drops of the present invention may further include additives such as buffers, isotonic agents, pH adjusters, stabilizers, preservatives, solubilizers, and viscosity modifiers, as needed.

[0116] The eye drops of the present invention may also include buffers that can be used as additives to pharmaceuticals. For example, buffers such as phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, and trometamol may be included. Phosphates can be, for example, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.; borates can be, for example, borax, sodium borate, potassium borate, etc.; citrates can be, for example, sodium citrate, disodium citrate, etc.; acetates can be, for example, sodium acetate, potassium acetate, etc.; carbonates can be, for example, sodium carbonate, sodium bicarbonate, etc.; tartarates can be, for example, sodium tartrate, potassium tartrate, etc.

[0117] The concentration of the buffer in the eye drops of the present invention can be appropriately determined by those skilled in the art, taking into account the influence of the drug, other additives, and / or the osmotic pressure ratio. For example, the buffer is preferably included in an amount of 0.01 to 15 wt% based on the total weight of the eye drops, but is not limited thereto.

[0118] The eye drops of the present invention may further include a tonicity agent usable as an additive to a pharmaceutical. The tonicity agent may be, for example, an ionic tonicity agent or a non-ionic tonicity agent. The ionic tonicity agent may be, for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and the non-ionic tonicity agent may be, for example, glycerin, propylene glycol, sorbitol, mannitol, etc. The concentration of the tonicity agent in the eye drops of the present invention may be appropriately determined by a person skilled in the art in consideration of the influence of the drug, other additives, and / or osmotic pressure ratio. For example, the tonicity agent is preferably included in an amount of 0.01 to 3 wt% based on the total weight of the eye drops, but is not limited thereto.

[0119] The eye drops of the present invention may further include a pH adjuster usable as an additive to pharmaceuticals. Examples of pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like. For example, the pH of the eye drops of the present invention is preferably 7.0 to 9.5, but is not limited thereto.

[0120] The eye drops of the present invention may further include a stabilizer usable as an additive in pharmaceuticals. The stabilizer may be, for example, edetic acid, sodium edetate, sodium edetate hydrate, sodium citrate, a water-soluble polymer, etc. The water-soluble polymer may be, for example, povidone (polyvinylpyrrolidone), polyvinyl alcohol, carboxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium polyacrylate, etc. The concentration of the stabilizer in the eye drops of the present invention may be appropriately determined by a person skilled in the art in consideration of the influence of the drug, other additives, and / or osmotic pressure ratio. For example, the stabilizer is preferably included in an amount of 0.001 to 5.0 wt% based on the total weight of the eye drops, but is not limited thereto.

[0121] The eye drops of the present invention may further include a preservative usable as an additive to a pharmaceutical. The preservative may be, for example, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc. The concentration of the preservative in the eye drops of the present invention may be appropriately determined by those skilled in the art, taking into account the influence of the drug, other additives, and / or the osmotic pressure ratio. For example, the preservative is preferably included in an amount of 0.00005 to 0.01 wt% based on the total weight of the eye drops, but is not limited thereto.

[0122] The eye drops of the present invention may further include a solubilizing agent that can be used as an additive in a pharmaceutical. The solubilizing agent may be, for example, polysorbate 80, tyloxapol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene castor oil 35, poloxamer 188, poloxamer 407, macrogol 4000, etc. The concentration of the solubilizing agent in the eye drops of the present invention may be appropriately determined by a person skilled in the art in consideration of the influence of the drug, other additives, and / or osmotic pressure ratio. For example, the solubilizing agent is preferably included in an amount of 0.001 to 5.0 wt% based on the total weight of the eye drops, but is not limited thereto.

[0123] The eye drops of the present invention may further include a viscosity-modifying agent that can be used as an additive for pharmaceuticals. The viscosity-modifying agent may be, for example, polyvinyl alcohol, carmellose sodium, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, glucose, glycerin, polyethylene glycol, dextran, etc. The concentration of the viscosity-modifying agent in the eye drops of the present invention may be appropriately determined by a person skilled in the art in consideration of the influence of the drug, other additives, and / or osmotic pressure ratio. For example, the viscosity-modifying agent is preferably included in an amount of 0.001 to 5.0 wt% based on the total weight of the eye drops, but is not limited thereto.

[0124] The eye drop composition according to the present invention may additionally include other drugs applied to the eye, such as, but not limited to, GABA-based compounds, non-steroidal anti-inflammatory drugs, antihistamines, agents for treating herpes virus infectious eye diseases, or agents for treating cataracts.

[0125] Another aspect of the present invention provides a method for preventing or treating ocular dysfunction comprising administering the composition to a subject.

[0126] The pharmaceutical composition comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof of the present invention may be administered orally or parenterally, depending on the purpose, in an amount effective for the treatment or prevention of a subject or patient. It should be understood that the dosage for a specific subject or patient should be determined based on various related factors such as the patient's weight, age, race, sex, health condition, diet, administration time, administration method, and severity of the disease, and may be appropriately increased or decreased by a specialist. For example, a physician may start the dosage of the pharmaceutical composition of the present invention at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved, and may easily determine and prescribe the dosage as needed.

[0127] Another aspect of the present invention provides a health functional food for preventing or improving eye function disorders, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, food-based salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

[0128] To avoid excessive complexity due to unnecessary repetition in this specification, description of common items is omitted.

[0129] The racetam series compound, GABA series compound and / or food-wise acceptable salt of the present invention can be manufactured into a health functional food containing the same.

[0130] The racetam series compound and / or GABA series compound according to the present invention can be manufactured as a health functional food by adding it as it is to food or using it together with other food or food ingredients, and can be manufactured appropriately according to a method generally used in the art. The health functional food of the present invention can be manufactured in the form of the pharmaceutical composition described above, and in this case, the details of the pharmaceutical composition can be appropriately modified and used. The racetam series compound or food-wise acceptable salt, which is an active ingredient included in the health functional food, can be appropriately determined depending on the purpose of use (prevention or improvement) of the health functional food. For example, the amount of the racetam series compound included in the health functional food can be 0.1 to 90% by weight based on the total weight of the health functional food. However, in the case of long-term intake for the purpose of maintaining or regulating health, the amount can be less than the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount exceeding the above range.

[0131] The health functional food of the present invention may contain, in addition to the active ingredients, racetam series compounds, GABA series compounds and / or food-wise acceptable salts, various flavoring agents and / or natural carbohydrates as additional ingredients, like conventional beverages, but is not limited thereto. Natural carbohydrates may be, for example, conventional sugars such as monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.) and / or polysaccharides (e.g., dextrin, cyclodextrin, etc.), and sugar alcohols such as xylitol, sorbitol and / or erythritol. In addition, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and / or synthetic flavoring agents (e.g., saccharin, aspartame, etc.) may be further included as flavoring agents. The proportion of the natural carbohydrate may be, for example, about 1 to 20 wt%, preferably about 5 to 12 wt%, based on the total weight of the health functional food of the present invention, but is not limited thereto.

[0132] In addition, the health functional food of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, carbonating agents used in alcohol and / or carbonated beverages, etc. In addition, the health functional food of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice beverage, and / or vegetable beverage.

[0133] These ingredients can be used independently or in combination. The proportion of these additives is not particularly critical, but may be selected within the range of 0.1 to about 20% by weight based on the total weight of the health functional food of the present invention, but is not limited thereto.

[0134] The present invention will be described in more detail below through one or more examples. However, these examples are intended to exemplify the present invention and the scope of the present invention is not limited to these examples.

[0135]

[0136] Example 1. Confirmation of the presbyopia-improving effect of racetam compounds in a dexamethasone-induced presbyopia model.

[0137] 1-1. Creation of a presbyopia-induced model using dexamethasone

[0138] To confirm the presbyopia-inducing effect of dexamethasone, a presbyopia-inducing model was created by instilling 2.1% dexamethasone into the eye for 7 days, and then imaging was performed to measure the pupillary constriction time.

[0139] Specifically, the control group (Vehicle) was administered 2.1% dexamethasone dissolved in saline, and the dexamethasone treatment group (DEX) was administered 2 μl of 2.1% dexamethasone dissolved in saline directly into the right eye of the mice three times a day at 3-hour intervals. The miosis time was analyzed by photographing the eyes of the mice before and after light irradiation on the 0th day (day 0), 1st day after drug administration, and 7th day after drug administration.

[0140] As a result, it was confirmed that the eccentricity time was significantly reduced in the dexamethasone treatment group (DEX) compared to the control group (Vehicle) (Figure 1).

[0141]

[0142] 1-2. The anti-aging effect of racetam compounds

[0143] In the dexamethasone-treated glaucoma induction model prepared in Example 1-1, a racetam series compound was eyed to check whether glaucoma was improved.

[0144] Specifically, in the experimental group, oxiracetam, piracetam, phenylpiracetam, coluracetam, pramiracetam, levetiracetam and aniracetam were used. Oxiracetam was purchased from Tokyo Chemical Industry (Japan, product number: O0398, CASRN: 62613-82-5, purity: 96%), piracetam, phenylpiracetam, coluracetam and pramiracetam were purchased from Tokyo Chemical Industry (Japan, product numbers: P2880, P2604, C3689, P2061, purity: 96%), levetiracetam was purchased from Bide (China, product number: R025860, purity: 96%), and aniracetam was purchased from Luoen (China, product number: BD114391, purity: 96%) and used.

[0145] For the experimental group, 4.2% concentration of oxiracetam, piracetam, pramiracetam, levetiracetam dissolved in saline solvent, or 0.1% concentration of aniracetam, phenylpiracetam, coluracetam dissolved in DMOS (Dimethyl Sulfoxide, Biosesang, Product No.: DR1022-500-00, CAS No.: 67-68-5, Purity: 99.5%) solvent were administered intraocularly three times a day at 3-hour intervals for 7 days to the dexamethasone-treated presbyopia-induced model prepared in Example 1-1. Saline was used as the control group. On the 7th day of administration of racetam compounds, the eyes of the mice were imaged to measure the miosis time.

[0146] As a result, it was confirmed that the contraction time decreased in most of the racetam compound administration groups, including oxiracetam, piracetam, pramiracetam, levetiracetam, aniracetam, and phenylpiracetam, among the experimental groups. In particular, it was confirmed that the contraction time significantly decreased in the oxiracetam, piracetam, aniacetam, and phenylpiracetam administration groups compared to the dexamethasone-treated presbyopia-induced model (Figs. 2 and 3).

[0147] Through these results, it was confirmed that the effect of reducing the contraction time when racetam compounds such as oxiracetam were instilled in a dexamethasone-treated presbyopia-induced model was excellent.

[0148]

[0149] Example 2. Confirmation of the effect of racetam compounds on improving presbyopia in aged mice.

[0150] 2-1. Comparison of pupil size and miotic velocity between 18-month-old C57BL / 6J and 2-month-old C57BL / 6N mice.

[0151] We investigated whether presbyopia could be improved by instilling racetam-based compounds into aged mice.

[0152] Specifically, aged mice were prepared from 12-month-old C57BL / 6J mice (Orient Bio, Japan) after a 6-month acclimatization period and then used in the experiment at 18 months of age. Before light irradiation, the pupils of 18-month-old C57BL / 6J mice and 2-month-old C57BL / 6N mice were imaged to analyze the dilated pupil diameter, and the eyes of the mice were imaged before and after light irradiation to analyze the pupillary constriction speed. The pupillary constriction speed was derived by calculating it using the following formula.

[0153]

[0154] Speed ​​of rotation = (pupil diameter before rotation - pupil diameter after rotation) ÷ rotation time

[0155]

[0156] As a result, the pupil size before light irradiation was confirmed to be significantly smaller in 18-month-old C57BL / 6J mice compared to 2-month-old C57BL / 6N mice (Fig. 4), and the constriction velocity was also confirmed to be significantly slower in 18-month-old C57BL / 6J mice compared to 2-month-old C57BL / 6N mice (Fig. 5).

[0157]

[0158] 2-2. Confirmation of improvement in pupil size following oxiracetam topical application in 18-month-old C57BL / 6J mice.

[0159] Oxiracetam and pilocarpine (Tokyo Chemical Industry, Japan, product number: P0434) were instilled into the eyes of 18-month-old C57BL / 6J mice prepared in Example 2-1 for 7 days, and the pupil size before light exposure was checked on the 7th day.

[0160] Specifically, the experimental group was prepared by instilling 2 ㎕ of 4.2% oxiracetam dissolved in saline into the right eye of 18-month-old C57BL / 6J mice three times a day at 3-hour intervals for 7 days. As a positive control group, pilocarpine, which is conventionally used as a miotic, was used. The experimental group was prepared by instilling 2 ㎕ of 1.25% pilocarpine dissolved in saline into the right eye of 2-month-old C57BL / 6N mice twice a day at 6-hour intervals for 7 days.

[0161] As a result, it was confirmed that the pupil size of the oxiracetam-administered group was larger than that of the C57BL / 6J 18-month-old mouse group that was not administered the drug, and that the pupil size was similar to that of the C57BL / 6N 2-month-old mouse group. On the other hand, the pilocarpine-administered group was confirmed to show a smaller pupil size than the C57BL / 6J 18-month-old mouse group that was not administered the drug (Fig. 6).

[0162] Through these results, it was confirmed that the decrease in pupil size due to aging can be prevented and improved by oxiracetam.

[0163]

[0164] 2-3. Confirmation of improvement in miotic velocity following oxiracetam topical application in 18-month-old C57BL / 6J mice.

[0165] In Example 2-2, the eccentric velocity of 18-month-old C57BL / 6J mice that were administered oxiracetam or pilocarpine for 7 days was analyzed using the same method as in Example 2-1.

[0166] As a result, it was confirmed that the contraction speed was 36.1% faster in the oxiracetam-administered group compared to the 18-month-old C57BL / 6J mouse group that was not administered the drug, whereas the contraction speed was confirmed to be slowed in the pilocarpine-administered group (Fig. 7).

[0167] Through these results, we confirmed the improving effect of oxiracetam on eye function decreased due to aging.

[0168]

[0169] 2-4. Comparison of pupil size and miosis velocity according to the duration of oxiracetam eyedrop treatment in 18-month-old C57BL / 6J mice.

[0170] C57BL / 6J 18-month-old mice were treated with oxiracetam or pilocarpine for 7 days, and pupil size and miosis velocity were compared according to the duration of treatment.

[0171] Specifically, oxiracetam and pilocarpine were prepared in the same manner as in Example 2-1, and images were taken before administration (day 0), on day 1 after administration, and on day 7 after administration for C57BL / 6J 18-month-old mice, and the pupil size and miosis velocity of the mice were analyzed from the photographs before and after miosis.

[0172] As a result, it was visually confirmed that the constricted pupils observed in 18-month-old C57BL / 6J mice were maintained when oxiracetam was administered. On the other hand, when pilocarpine was administered, the pupil size before and after miosis was confirmed to be smaller on day 7 compared to day 0 of administration (Fig. 8). In addition, as a result of comparing and analyzing the miosis speed on day 0 and day 1, and day 0 and day 7 of administration by group, it was confirmed that the miosis speed was faster in the group administered oxiracetam (Figs. 9 and 10) and the miosis time was shortened (Fig. 11).

[0173] Through these results, it was confirmed that oxiracetam is more effective than pilocarpine, a miotic, in improving ocular dysfunction due to aging.

[0174]

[0175] Example 3. Confirmation of the muscle function activation effects of racetam compounds and GABAergic compounds in muscle cells.

[0176] Since the functional activity of muscle cells (myoblasts) must be preceded by the activity of ATP, which is the intracellular energy, the effect of increasing mitochondrial activity of GABAergic compounds, such as compounds related to or affecting the neurotransmitter GABA in molecular biology and physiology, on muscle cells was analyzed using a luminescence assay.

[0177] Specifically, 5 × 10 mouse muscle cells were seeded into each 96-well cell culture plate. 3 Cells were seeded per well, and 80% to 90% confluency was confirmed, then GABA-based compounds were treated, and luminescence analysis was performed 2 days later.

[0178] As a result, it was confirmed that muscle function was activated by increasing the production of ATP generated by mitochondrial activity according to treatment with GABA-based compounds (Fig. 12).

[0179]

[0180] The present invention has been described above, focusing on specific embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. A pharmaceutical composition for preventing or treating eye dysfunction, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

2. A pharmaceutical composition for preventing or treating eye dysfunction, wherein the racetam series compound in paragraph 1 is a pyrrolidine-2-one compound represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 are independent of each other -H, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5-C(O)-R 4 and -CHR 5 -C(O)-R 6 is a substituent selected from the group consisting of, or R 1 and R 2 is R 1 Nitrogen atom attached to and R 2 It forms a ring with the carbon atom attached to it -C 1-7 Alkylene-, -C 2-7 Alkenylene-, -C 2-7 Alkynylene-, -C(O)-C 1-6 Alkylene-, -C(O)OC 1-6 Alkylene-, -C(O)NH-C 1-6 Alkylene-, -C(O)N(C 1-6 alkyl)-C 1-6 Alkylene- and -C 1-3 Alkylene-R 7 -C 1-3 A substituent selected from the group consisting of alkylene; R 3 -H, -F, -Cl, -Br, -I, -OH, -C 1-7 Alkylene-NH 2, -C 1-7 Alkylene-NH-C 1-6 Alkyl, -C 1-7 Alkylene-N(C 1-6 alkyl)2, -C 1-7 Alkylene-X, -C 2-7 Alkenylene-X2, -C 2-7 Alkynylene-X, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, -OCH2R 8 , -CN and -C6H3R 9 R 10 is any one substituent selected from the group consisting of; X is any one substituent selected from the group consisting of -F, -Cl, -Br and -I; R 4 , R 5 and R 6 are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C 1-7 Alkylene-C6H5, -C6H5, -C6H4-OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 -C containing 1 to 2 heteroatoms selected from alkyl)2, O or N 3-8 Heterocycloalkyl, -NH-C 1-6 Alkylene-NH2, -NH-C 1-6 Alkylene-NH-C 1-6 Alkyl and -NH-C 1-6 Alkylene-N(C 1-6 Any one substituent selected from the group consisting of alkyl)2; R 7 -O-, -C(O)-, -C(O)O-, -C(O)NH-, -NH-, and -N(C 1-6 Any one substituent selected from the group consisting of alkyl); R 8 , R 9 and R 10 are independently of each other -H, -OH, -NH2, -C 1-7 Alkyl, -C6H5, and -OR 11 is any one substituent selected from the group consisting of; R 11 Silver -C 1-7 Alkyl, -C 3-8 -C containing 1 to 2 heteroatoms selected from cycloalkyl, O or N 3-8 Heterocycloalkyl, -C 6-12 -C containing 1 to 2 heteroatoms selected from aryl, O or N 3-8 Any one substituent selected from the group consisting of heteroaryl.

3. A pharmaceutical composition for preventing or treating eye dysfunction, wherein the racetam compound in claim 1 is any one compound selected from the group consisting of oxiracetam, piracetam, phenylpiracetam, aniracetam, levetiracetam, rolziracetam, fasoracetam, pramiracetam, brivaracetam, seletracetam, coluracetam, dimiracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam, and rolipram.

4. In the first paragraph, the GABA series compound is oxiracetam, gabaculine hydrochloride, 5-aminovaleric acid hydrochloride, (±)-nipecotic acid, 3-aminopropylphosphonic acid, cis-4-aminocrotonic acid, γ-acetylenic GABA, (±)-baclofen, CGP-7930, CGP-13501, SCH-50911, CGP 55845 hydrochloride, N-Methyl-β-carboline-3-carboxamide, isogubacin Isoguvacine hydrochloride, Guvacine hydrochloride, (+)-Hydrastine, Imidazole-4-acetic acid hydrochloride, Isonipecotic acid, NO-711 hydrochloride, 3-α,21-Dihydroxy-5-α-pregnan-20-one, Picrotoxin, Phaclofen, Pregnenolone sulfate sodium, 5α-Pregnan-3α-ol-20-one, SB 205384, A pharmaceutical composition for preventing or treating eye dysfunction, wherein the composition is any one compound selected from the group consisting of (E)-4-amino-2-butenoic acid, SR-95531, THIP hydrochloride, TPMPA, and (±)-γ-vinyl GABA.

5. A pharmaceutical composition for preventing or treating eye dysfunction in claim 1, wherein the eye dysfunction is an ocular muscle dysfunction, an eyelid disorder, a conjunctival and sclera disorder, a corneal disorder, a refractive disorder, a lens abnormality disorder, an orbital disorder, a retinal disorder, presbyopia, myopia, glaucoma, or night vision accommodative disorder.

6. A pharmaceutical composition for preventing or treating eye dysfunction, wherein the eye dysfunction in claim 1 is caused by one or more causes selected from the group consisting of excessive use of electronic devices, excessive close-up work, aging, inflammation, oxidative stress, long-term use of steroids, and other diseases.

7. A pharmaceutical composition for preventing or treating eye dysfunction, wherein the steroid is dexamethasone in claim 6.

8. A pharmaceutical composition for preventing or treating eye dysfunction, wherein the other disease in paragraph 6 is any one disease selected from the group consisting of diabetes, hypertension, thyroid disease, and vitreous cystitis.

9. An eye drop comprising at least one compound selected from the group consisting of racetam compounds, gabapentin compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

10. A method for preventing or treating eye dysfunction, comprising administering to a subject the composition of claim 1.

11. A health functional food for preventing or improving eye function disorders, comprising at least one compound selected from the group consisting of racetam compounds, GABAergic compounds, food-based salts thereof, hydrates thereof, solvates thereof, and isomers thereof.

Images