A pharmaceutical composition that effectively delays and treats myopia.

Abstract

This application relates to a pharmaceutical composition for effectively delaying and treating myopia, and more particularly to a method for treating myopia using lipoic acid and / or lipoic acid choline ester. This pharmaceutical composition can not only effectively prevent and control myopia and / or delay its progression, but is also safe and has no apparent side effects, and is therefore expected to have good clinical use.

Claims

1. The use of lipoic acid or choline lipoic acid ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof, (1) To prevent and / or treat myopia and / or related symptoms, and / or to correct myopia, (2) To control the onset and progression of myopia in combination with orthokeratology lenses or other myopia treatment drugs, (3) To be used for interventional treatment of myopia or to delay the progression of myopia, (4) To suppress or delay the elongation of the axial length and / or the increase in the depth of the vitreous cavity of the eye in individuals who are myopic or who are prone to developing myopia, and to increase the choroidal thickness of individuals who are myopic or who are prone to developing myopia, (5) To prevent, delay, alleviate or treat abnormal eye development in children and adolescents related to refractive errors, (6) To enable an individual to acquire clearer distance vision without wearing lenses or relying on vision correction means than before using these lenses or means and / or without using these lenses or means, (7) Suppressing, postponing, or delaying the process or speed at which the refractive error of an individual who is myopic or prone to developing myopia becomes negative, (8) To use in the manufacture of a candy drug, preparation, composition or apparatus that realizes at least one of the uses described in (1) to (7) above. A use characterized by satisfying one of the above conditions, or two or more conditions simultaneously.

2. The use according to claim 1, which involves systemic administration such as oral administration, and / or local administration (eye drops, intraocular injection, intraocular implant, application of skin ointment / emulsion around the eye or application of eye ointment), and / or parenteral administration (e.g., transmucosal administration, transdermal administration, microneedle administration), and / or non-invasive administration (e.g., administration using spray eye drops).

3. The drug, formulation, or composition may be an injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, orally disintegrating tablet, granule, ointment, syrup, oral solution, aerosol, nasal spray, topical preparation, oral formulation, etc. Preferably, it includes, but is not limited to, eye drops, eye ointment, spray eye drops, implant, eye gel, eye pad, eye microsphere, ophthalmic sustained-release formulation, periorbital injection, and intraocular injection, and may also be a regular solution, aqueous solution, unsaturated solution, oil-water mixture, suspension, ointment, detergent, lotion, drop, powder, spray, ointment, patch, paste, pill, suppository, emulsion, or cellulose (e.g., methylcellulose), polyhydric alcohol, cyclodextrin (e.g., hydroxypropyl The use according to claim 1 or 2, which may be prepared by containing (e.g., 2-β-cyclodextrin), a reducing agent (e.g., glutathione, N-acetylcarnosine), glycerin, liquid paraffin, petrolatum, propylene glycol, ethyl pyruvate, semifluoroalkane, amino acids or their derivatives (e.g., alanine, methionine, cysteine, and histidine), sugars or their metabolites (e.g., glucose-6-phosphate), oxygen scavengers (e.g., Oxy-Guard® or StabilOx®), vitamins (e.g., vitamin B1, vitamin B2, vitamin C, vitamin E), NADPH, dendrimers, nanomaterials, sustained-release materials, liposomes, or any combination thereof.

4. The use according to any one of the claims, wherein the aforementioned myopic individual or individual prone to developing myopia is a person who has been medically diagnosed with myopia, or a child and / or adolescent, preferably a group of 2 to 30 years old, more preferably a group of 6 to 18 years old, or a minor, preferably a group in which the eyes are still growing and developing, or a school-age group, preferably a group of 1 to 12 years old, or a group in which one or both parents are highly myopic, or a group with insufficient reserve capacity for hyperopia.

5. The aforementioned myopia includes refractive myopia or axial myopia, congenital myopia (myopia present from birth or before school age), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), late-onset myopia (after adulthood), mild myopia, moderate myopia, high myopia, malignant myopia, pseudomyopia, true myopia, pediatric and / or juvenile myopia (preferably in the age group of 2-30 years, more preferably in the age group of 6-18 years), adolescent myopia, adult myopia, elderly myopia, simple myopia, pathological myopia, complex myopia, and axial myopia. Simple myopia, simple axial myopia, axial myopia in children and / or adolescents (preferably age group 2 to 30 years, more preferably age group 6 to 18 years), axial myopia in school-age and preschool groups, primary myopia, secondary myopia, primary myopia in children and / or adolescents (preferably age group 2 to 30 years, more preferably age group 6 to 18 years), or progressive myopia in children and / or adolescents (preferably age group 2 to 30 years, more preferably age group 6 to 18 years), and curvature myopia Myopia can be caused by various factors including visual acuity, exponential myopia, astigmatic myopia, positional myopia, curvature myopia, axial myopia (where refractive power is persistently negative), myopia caused by prolonged close-range eye use, myopia and pseudomyopia caused by eye strain, negative refractive power due to adverse drug events, myopia caused by reading, myopia caused by the use of electronic products such as mobile phones, myopia caused by unsuitable refractive media (components), myopia caused by abnormal refractive system development, myopia caused by excessive eye growth, myopia caused by unsanitary eye use, and various other causes of impaired focusing of distant objects. The use according to any one of the claims, wherein the point is located in front of the retina, and the myopia is poorly treated or ineffective with atropine, non-compound myopia, myopia caused by lack of outdoor exercise, accommodative spasmodic myopia, childhood myopia, infant myopia, hereditary myopia, myopia caused by environmental factors, mixed myopia, traumatic myopia, toxic myopia, drug-induced myopia, diabetic myopia, mechanical myopia, spatial myopia, nocturnal myopia, or premature infant myopia, diving myopia, psychogenic myopia, and temporary myopia occurring during menstruation, pregnancy, or various eye and systemic diseases.

6. The myopia-related symptoms are complications resulting from myopia or an excessively long axial length of the eye, for example, complications of high myopia, or floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, retinal lesion, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or maculopathy, visual field defects, progressive or sudden decline in visual acuity (especially near vision), swelling and / or pain of the eye, night blindness, astigmatism, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent rubbing of the eye, anisometropia, blurred vision when viewing distant objects, need to squint or partially close the eyelid to see distant objects clearly, headache due to eye strain, distractibility due to myopia, difficulty seeing while driving, especially at night (nocturnal myopia), retinal atrophy and degeneration (hemorrhage and tear), subretinal neovascularization, or ocular atrophy, as described in any one of the claims.

7. The drug, formulation, composition, or apparatus further comprises other drugs, compounds, or ophthalmic formulations, the drugs, compounds, or ophthalmic formulations include myopia treatments (e.g., pirenzepine, muscarinic antagonists, methocarbamol, indramin, timolol maleate, adrenaline, pyrazine, perlapine, methylamine, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, methylhomatropine bromide, tretinoin, etc.), M receptor blockers (e.g., blockers, antagonists, or inhibitors of M2 or M3 receptors), atropine or atropine sulfate, bendazole, polyunsaturated fatty acids (e.g., DHA, EPA), homatropine, raceanisodamine, scopolamine, tropicamide, 7-methylxanthine, nicotinic acid, piracetam, ta The use described in any one of the above claims includes, but is not limited to, ginseng extract, safflower extract, bear extract, fish oil, adenosine triphosphate (ATP), smooth muscle relaxants, vasospasmodics, non-selective adenosine antagonists, vasodilators, pupil dilating agents, decongestant agents, extraocular muscle (e.g., ciliary muscle) modulating agents, anti-inflammatory agents, astringent agents, antihistamine agents, anti-allergic agents, collagen degradation inhibitors, hepatoprotective (avoiding or weakening hepatotoxicity) agents, blood-retinal barrier strengthening agents (compounds that make it more difficult for the physiological barrier to penetrate), amino acids, antibacterial agents, antioxidant agents (e.g., vitamin C, tea polyphenols, glutathione, etc.), carbohydrates, polymers or their derivatives, cellulose or its derivatives, local anesthetic agents, amblyopia treatment agents, glaucoma treatment agents, miRNA and its modifications, ophthalmic disease treatment agents, additives, etc.

8. The use according to any one of the claims, wherein a drug and / or treatment for myopia that delays the progression of myopia, comprising lipoic acid or choline lipoic acid ester, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, or a metabolite thereof, or a related compound or extract thereof, or a crystalline compound thereof, or a combination thereof, is formulated or designed as a continuous dose, simultaneous dose, sequential dose, alternating dose, interval dose, or single dose.

9. The aforementioned related compounds include, but are not limited to, all the compounds listed in CN115279745A and CN111315369A, and salts further formed from lipoic acid or lipoic acid esters. Preferably, they include, but are not limited to, lipoic acid choline ester tosylate, lipoic acid choline ester benzenesulfonate, lipoic acid choline ester chloride, or lipoic acid choline ester iodide, or are salt forms of lipoic acid choline ester, or are complexes of these substances, which are the compounds shown in Figure 3, or 6-(benzylthio)-8-[(hydroxyphenylmethyl)thio]octanoic acid, lipoamide (1,2-dithiolan-3-pentanamide), 8-(ethyldisulfide)-6-(phenyldisulfide)octanoic acid, lipoyl chloride, 5-(1,2-10-dithiolan-3-yl)pentanoic acid (5-(1,2-10 (dithiolan-3-yl)pentanoic acid), 6,8-dimercaptooctanoic acid (dihydrolipoic acid), dihydrolipoate, 5-(1,2-dithiolan-3-yl)pentanoic acid, 5-(1,2-thiaselenolan-5-yl)pentanoic acid The use according to any one of the claims, wherein the acid is 5-(1,2-thiaselenolan-3-yl)pentanoic acid, or 6,8-dimercaptooctanoic acid.

10. The use according to any one of the above claims, characterized in that the preparation is an oral product such as a health food, food, nutritional supplement, nutritional food, beverage, or cosmetic.

11. The use according to any one of the above claims, characterized in that the apparatus is an instrument, device, consumable, system, medical device, health product or product that alters the appearance of the eye, capable of releasing a drug, having a drug delivery function, or having potential drug delivery capabilities, for example, a corneal contact lens, eyeglasses, intraocular lens, sutures, orthokeratology lens cleaning (maintenance) system, eye pads, eye patches for improving eye function, colored contact lenses, microneedles, eye spray systems, eye massagers, eye fumigation devices, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupressure massagers, eye relaxation devices, myopia treatment devices or combinations of drugs and devices for preventing or controlling myopia.

12. Lipoic acid or choline lipoic acid ester, or its optical isomer or racemate, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, may be used as the sole active ingredient, principal active ingredient, or direct active ingredient. And / or, the content or efficacy of lipoic acid or lipoic acid choline ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, shall be less than 1%, or 1%, 10%, 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90%, or 100% of the total active ingredient in the aforementioned use. And / or, the content, concentration, or proportion of lipoic acid or lipoic acid choline ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, in the drug, formulation, composition, or apparatus is at least 0.001%, or at least 0.05%, or at least 0.15%. And / or, the therapeutic effect of lipoic acid or lipoic acid choline ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof, accounts for more than 20%, preferably 50% or more, of the total raw material components or the total active ingredients in the aforementioned use. The use according to any one of the above claims, characterized in that the percentage (%) may be a mass ratio, a molar ratio, a mass-to-volume ratio, or a percentage contributing to the efficacy in the use.

13. The concentration of lipoic acid or choline lipoic acid ester, or its optical isomer or racemate, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof, in the drug, formulation, composition, or apparatus is 0.001 μM to 100 M, preferably 0.005 μM to 50 M, preferably 1 μM to 1 M, preferably 300 μM to 300 mM, more preferably 1 mM to 200 mM, more preferably 10 mM to 100 mM (e.g., about 46 mM, i.e., 0.94%) and / or lipoic acid or choline lipoic acid The use according to any one of the above claims, characterized in that the concentration or proportion of an ester, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, or a metabolite thereof, or a related compound or extract thereof, or a crystalline compound thereof, or a combination thereof, in the drug, formulation, composition, or apparatus is greater than 0.0005%, preferably greater than 0.025%, preferably greater than 0.05%, more preferably greater than 0.1%, and more preferably greater than 1%, wherein the percentage (%) may be expressed as mass / volume concentration (g / 100 mL), mass percentage, or mole ratio.

14. A topical drug, formulation, composition, or device for treating myopia or controlling the progression of myopia, The concentration of lipoic acid or choline lipoic acid ester, or its optical isomer or racemate, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof, in the drug, formulation, composition, or apparatus is 0.001 μM to 100 M, preferably 0.005 μM to 50 M, preferably 1 μM to 1 M, preferably 300 μM to 300 mM, more preferably 1 mM to 200 mM, and more preferably 10 mM to 100 mM. And / or, the concentration or proportion of lipoic acid or lipoic acid choline ester, or its optical isomer or racemate, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof, in the drug, formulation, composition, or apparatus is 0.0001% or more, preferably 0.001% or more, preferably 0.01% or more, more preferably 0.1% or more, and more preferably 0.8% or more, and the percentage (%) may be expressed as mass / volume concentration (g / 100 mL), mass percentage, or mole ratio, characterized in that the drug, formulation, composition, or apparatus is characterized in that

15. A pharmaceutical composition or compound formulation comprising at least two active substances, characterized by comprising lipoic acid or choline lipoic acid ester, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, or a metabolite thereof, or a related compound or extract thereof, or a crystalline compound thereof, or a combination thereof, and other myopia-treating active substances.

16. The pharmaceutical composition or compound formulation according to claim 15, characterized in that the amount, concentration and / or efficacy of lipoic acid or lipoic acid choline ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, in a pharmaceutical composition or compound formulation is no less than the amount, concentration and / or efficacy of any of the other myopia-treating active substances, and the efficacy refers to the treatment of myopia and / or the control of the progression of myopia.

17. The pharmaceutical composition or compound formulation according to claim 15 or 16, characterized in that the formulation includes, but is not limited to, eye drops, eye ointments, spray eye drops, implants, ophthalmic gels, eye pads, ophthalmic microspheres, ophthalmic sustained-release formulations, periocular injections, or intraocular injections.

18. It is an ophthalmic preparation, Lipoic acid or choline lipoate ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, is used as the direct, sole, or primary active ingredient for treating myopia, and the concentration of lipoic acid or choline lipoate ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or combination thereof, is 0.001 μM to 100 M, preferably 0.005 μM to 50 M, and preferably The concentration is 1 μM to 1 M, preferably 300 μM to 300 mM, more preferably 1 mM to 200 mM, more preferably 10 mM to 100 mM, and / or the concentration or proportion of lipoic acid or lipoic acid choline ester, or its optical isomer or racemic mixture, or its solvate, or a pharmaceutically acceptable salt or ester thereof, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, or a combination thereof is 0.0001% or more, preferably 0.001% or more, preferably 0.01% or more, more preferably 0.1% or more, more preferably 0.8% or more, and the percentage (%) may be expressed as mass / volume concentration (g / 100 mL), mass percentage, or mole ratio. A formulation characterized by the following features.

19. The preparation according to claim 18, characterized in that the preparation includes, but is not limited to, eye drops, eye ointments, spray eye drops, implants, ophthalmic gels, eye pads, ophthalmic microspheres, ophthalmic sustained-release preparations, periorbital injections, or intraocular injections.

20. The present invention is characterized in that the content of lipoic acid or choline lipoic acid ester, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, or a metabolite thereof, or a related compound or extract thereof, or a crystalline compound thereof, or a combination thereof, is a therapeutically effective amount.

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