Pharmaceutical composition for effectively delaying and treating myopia

Abstract

The invention relates to a pharmaceutical composition for effectively delaying and treating myopia, in particular to a method for treating myopia by using lipoic acid and / or lipoic acid choline ester. The pharmaceutical composition can effectively prevent and control myopia and / or delay myopia progression, is safe and does not have obvious side effects, and has a good clinical application prospect.

Description

A pharmaceutical composition for effectively delaying and treating myopia TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition for effectively delaying and treating myopia, in particular to a method for treating myopia by using lipoic acid or lipoic acid choline ester, a method and use for controlling the progression of myopia, and provides the corresponding drugs or preparations, belonging to the field of medicine. BACKGROUND

[0002] Myopia is the most common refractive error, which is a refractive state that the focus of parallel light falls in front of the retina after being refracted by the refractive system of the eye in the unaccommodated state. The pathogenesis of myopia is very complex, which involves multiple factors, including genetics, environment, age, eye intensity, and even eating habits. In the vast amount of research literature on the pathogenesis of myopia, many experimental conclusions related to myopia treatment or myopia induction are questioned by experts, and there are even cases of contradictory results under similar experimental conditions, especially in the study of molecular level targets of compound intervention in myopia. For example, in the negative lens-induced animal model, it was found that cAMP analog 8-Bromo-cAMP could effectively treat myopia (Rachel Ka Man Chun et al., Cyclic Adenosine Monophosphate Activates Retinal Apolipoprotein A1 Expression and Inhibits Myopic Eye Growth, Invest Ophthalmol Vis Sci., 2015 Dec;56(13):8151-7.), while another study also used cAMP analogs, which not only had no therapeutic effect on myopia but could induce myopia (Fuxin Zhao et al., Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression, Exp Eye Res., 2021 Nov;212:108758.). In actual experiments, it was found that using typical antioxidants such as vitamin C (ascorbic acid) could not obtain therapeutic effect in wild-type mouse myopia models, on the contrary, if in the retinal degeneration mouse (rd10) caused by gene mutation, vitamin C can inhibit form deprivation-induced myopia (Erica Landis et al., Ascorbic acid, and not L-DOPA, protects against form-deprivation myopia in retinal degeneration mouse models., IOVS, ARVO Annual Meeting Abstract, September 2016, Volume 57, Issue 12); Take the domestic atropine sulfate approved for listing as an example, in the treatment of human population and active ingredients are exactly the same, although the low and high concentration of atropine in the clinical administration process both have inhibitory effect on the occurrence and development of myopia, however, high concentration of atropine appears "rebound" phenomenon after drug withdrawal.These animal model data and clinical studies constantly remind researchers that it will be very difficult to predict the final myopia treatment efficacy results by trying to conduct experiments only through theoretical assumptions or speculation, because the mechanism of myopia is still unknown, and it is difficult to prevent and control.

[0003] In addition to the lack of basic research, it is also found that the cell biology mechanism involved in myopia is different from other tissues or organs. For example, as a key indicator in myopia treatment research, the collagen content in the sclera is up-regulated when the fibroblasts are transdifferentiated into myofibroblasts in other tissues of the body (Shan Jiang et al., Inhibition of TRPC6 suppressed TGFβ-induced fibroblast-myofibroblast transdifferentiation in renal interstitial NRK-49F cells., Exp Cell Res., 2022 Dec 1;421(1):113374. and Kazuya Kusama et al., PGE2 and Thrombin Induce Myofibroblast Transdifferentiation via Activin A and CTGF in Endometrial Stromal Cells., Endocrinology. 2021 Dec 1;162(12):bqab207.) while in the development of myopia, the appearance of this transdifferentiation is accompanied by a decrease in collagen (Hao Wu et al., Scleral hypoxia is a target for myopia control., Proc Natl Acad Sci U S A., 2018 Jul 24;115(30):E7091-E7100.). Therefore, in the attempt to treat myopia, it is difficult to draw lessons from the research results of other organs or other diseases, because the structure and function of different organs are quite different, and the cell signaling pathways of different diseases are quite different. In addition, due to the complex structure of the mammalian eye, such as the presence of cornea, sclera and other biological barriers, the development and use of myopia treatment drugs are a great challenge.

[0004] In addition, there are many types of myopia, and some complex myopia or myopia in different age groups, such as pathological myopia, myopia with diabetes mellitus or directly caused by hyperglycemia, presbyopia, high myopia, and myopia caused by lens or corneal diseases, etc. usually show different pathological changes or accompanied by other basic diseases affecting treatment. Therefore, the treatment method for complex myopia in clinic is also different from that for ordinary myopia. At present, there is still a lack of drugs with significant efficacy and safety for treating myopia, especially for controlling the progression of myopia in children and adolescents, so there is an unmet clinical need in this field.

[0005] Lipoic acid, usually refers to α-Lipoic acid, is an eight-carbon fatty acid with a disulfide bond (such as Formula I), which has both fat-soluble and water-soluble, and can be reduced to dihydrolipoic acid in vivo. Lipoic acid has two enantiomers, namely R (dextro)-lipoic acid and S (levo)-lipoic acid. Lipoic acid drug intermediates generally include granular lipoic acid, R-lipoic acid, lipoic acid aminobutyl triol salt and 6,8-dichlorooctanoic acid ethyl ester, etc. Among them, R-lipoic acid aminobutyl triol salt has strong stability and high bioavailability. LACE is a chemical synthetic derivative of α-lipoic acid, which can be further salified in eye preparations, as described in patent CN108135842A. Several lipoic acids, or their optical isomers or racemates, or their solvates, or their pharmaceutically acceptable salts or esters, or their prodrugs, or their metabolites, or their related compounds or extracts, or their crystal type compounds have been disclosed in the prior art. These substances can either increase the solubility of lipoic acid or increase the stability of lipoic acid, but are all considered to have the function of lipoic acid. Therefore, in this application, they are all considered to be able to treat myopia.

[0006] In the field of medicine, lipoic acid is mainly used for the treatment of diabetic peripheral neuropathy, nervous system complications and other diseases. In the field of presbyopia treatment in ophthalmology, lipoic acid can restore the elasticity of the lens of aging individuals, but LACE failed to achieve the primary endpoint of the mid-analysis of the Novartis IIb phase dose range study. In addition, due to its antioxidant capacity, there have been clinical trials of oral lipoic acid for the treatment of age-related macular degeneration in history, but its efficacy also failed to reach the clinical endpoint (Benjamin J Kim et al., Orally Administered Alpha Lipoic Acid as a Treatment for Geographic Atrophy: A Randomized Clinical Trial., Clinical Trial Ophthalmol Retina., 2020 Sep; 4(9): 889-898.). In the field of food and health care, lipoic acid has been reported as a promising anti-obesity drug.

[0007] SUMMARY

[0008] The present application unexpectedly discovered a new use of lipoic acid and proved through repeated experiments that lipoic acid and lipoic acid choline ester can treat myopia and control the occurrence and progression of myopia. That is, lipoic acid is not used as a supplement or auxiliary component in myopia treatment drugs to assist, accompany or assist other active substances for treating myopia to enhance (such as to make more drug main components reach the target cells for efficacy) the effect of the active substance in treating myopia; but as a direct active ingredient or main active ingredient for treating myopia.

[0009] The present application first proves that lipoic acid alone can have a significant inhibitory effect on the progression of myopia, and thus confirms that lipoic acid can effectively treat various types of myopia, including simple myopia or axial myopia (such as myopia in children and adolescents), mild or moderate myopia, etc. Compared with using lipoic acid to treat presbyopia in the elderly, or high myopia, or high myopia in the elderly, or pathological myopia, the effect of lipoic acid in treating myopia with continuous decrease in diopter (such as simple myopia, axial myopia, or axial simple myopia, or low and moderate myopia, or myopia in children and adolescents, or progressive myopia, etc.) will be significantly better.

[0010] Lipoic acid and lipoic acid choline ester can also be used for the prevention of various types of myopia, for example, using lipoic acid and lipoic acid choline ester for drug intervention during the progression of myopia can prevent and stop the occurrence of presbyopia in the elderly, high myopia, high myopia in the elderly and pathological myopia.

[0011] The application further studies the concentration, ratio and formula of lipoic acid or choline lipoate in the treatment of myopia drugs or preparations, as well as the related drug administration frequency, combination therapy and other medication methods. Among them, local (ocular) administration not only has good safety but also has better treatment effect than that of systemic administration.

[0012] The application provides the use of lipoic acid or choline lipoate, or an optical isomer 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 crystal type compound thereof, or a combination of these substances, which is one of the following or simultaneously satisfies two or more:

[0013] ① Prevent and / or treat myopia and its related symptoms, and / or myopia correction; or

[0014] ② Combine with orthokeratology lenses or other myopia treatment drugs to control the occurrence and development of myopia; or

[0015] ③ For myopic eye intervention treatment or delay of myopia progression; or

[0016] ④ Inhibit, slow down or reduce the increase of the axial length and / or vitreous chamber length (depth) of myopic individuals or individuals with a tendency to develop myopia; or

[0017] ⑤ Prevent, slow down, weaken or treat abnormal development of the eyeball related to visual impairment; or

[0018] ⑥ Make the individual obtain clearer distance vision without wearing glasses or relying on vision correction means than before using these glasses or means and / or without using these glasses or means; or

[0019] ⑦ Inhibit, delay or slow down the process or speed of negative diopter change of myopic individuals or individuals with a tendency to develop myopia; or

[0020] ⑧ For preparing a drug, preparation, composition or device for achieving at least one of the purposes of ①-⑦.

[0021] In some embodiments, the R-type optical isomer accounts for 50% and above (such as 99%) of the total lipoic acid, or its optical isomer or racemate thereof, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances, or less than 50%.

[0022] In some embodiments, the R optical isomer accounts for 50% or more (e.g., 99%) of the total lipoic acid choline ester, or its optical isomers or racemates thereof, or its solvates, or its pharmaceutically acceptable salts or esters thereof, or its prodrugs, or its metabolites, or its related compounds or extracts thereof, or its crystal type compounds, or combinations of these substances, or less than 50%.

[0023] In some embodiments, the lipoic acid is particulate lipoic acid.

[0024] In some embodiments, the specific content ratio or molar ratio of the two optical isomers affects the biological activity of lipoic acid, or its optical isomers or racemates thereof, or its solvates, or its pharmaceutically acceptable salts or esters thereof (e.g., lipoic acid choline ester), or its prodrugs, or its metabolites, or its related compounds or extracts thereof, or its crystal type compounds, or combinations of these substances, such as myopia treatment efficacy.

[0025] In some embodiments, the method of administration is systemic administration (e.g., oral administration), and / or local administration (e.g., eye drops, eye injection, eye implant, eye cream / eye ointment, or eye ointment), and / or parenteral administration (e.g., transmucosal administration, transdermal administration, microneedle administration), and / or non-invasive administration (e.g., eye spray). Preferably, the systemic administration refers to modified systemic administration.

[0026] In some embodiments, free lipoic acid can be detected in the blood of myopic individuals or individuals with a tendency to develop myopia after oral administration.

[0027] In some embodiments, the drug, preparation or composition can be an injection, tablet, lyophilized powder, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral solution, aerosol, nasal drops, external preparation, oral preparation, etc.; preferably, it is an eye preparation, including but not limited to eye drops (eye drops), eye ointment, eye spray, implant, eye gel, eye patch, eye microspheres, eye sustained-release preparation, periocular injection, intraocular injection; it can also be a regular solution, aqueous solution, unsaturated solution, oil-water mixture, suspension, liniment, lotion, cream, drops, infusion, spray, ointment, patch, paste, pill, suppository, emulsion, containing cellulose (e.g., methylcellulose), polyhydric alcohol, cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin), basic cosolvent, dendrimer, nanomaterial, sustained-release material, liposome or any combination thereof.

[0028] In some embodiments, the drug, formulation or composition contains distearoylphosphatidylcholine, soybean phospholipid, octadecylamine, poloxamer 188, sodium chloride, mannitol, mercaptoethanol, tromethamine, sodium sulfite, ethylenediamine, benzyl alcohol, arginine or any combination thereof. Of course, the drug, formulation or composition of the present application can also not contain any of the substances described in this paragraph.

[0029] In some embodiments, the myopic individual or the individual with a tendency to develop myopia is a child and / or a teenager, preferably a population of 2 to 30 years old, more preferably a population of 6 to 18 years old; or is a population of minors, preferably a population whose eyes (eyeballs) are still in the growth and development stage; or is a population of school age, preferably a population of students in grades one to twelve; or is a population whose parents are highly myopic; or is a population with insufficient hyperopic reserve.

[0030] In some embodiments, the myopia is myopia of refractive or axial; congenital myopia (born or preschool myopia), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), late-onset myopia (after adulthood); low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia; childhood and / or adolescent myopia (preferably a population aged 2-30 years old, more preferably a population aged 6-18 years old), minor myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; childhood and / or adolescent axial myopia (preferably a population aged 2-30 years old, more preferably a population aged 6-18 years old); school age and preschool population axial myopia; primary myopia, secondary myopia; childhood and / or adolescent primary myopia (preferably a population aged 2-30 years old, more preferably a population aged 6-18 years old); or childhood and / or adolescent progressive myopia (preferably a population aged 2-30 years old, more preferably a population aged 6-18 years old); curvature myopia, exponential myopia, astigmatic myopia, positional myopia, curvature myopia; axial myopia with continuously negative diopter; myopia caused by long-term close eye use, myopia and pseudomyopia caused by visual fatigue, negative diopter caused by adverse drug reactions, myopia caused by reading, myopia caused by using electronic products such as mobile phones, myopia caused by mismatch of refractive media (ingredients), refractive myopia, myopia caused by abnormal refractive development, myopia caused by eyeball overgrowth, myopia caused by unhygienic eye use, various reasons causing the imaging focus of distant objects to fall in front of the retina, myopia with poor or no effect on atropine treatment, non-complex myopia (such as non-progressive complex myopia with lipid peroxide oxidation POL disorder, non-senile myopia, or non-high myopia, or non-Nrf2 / HO-1 signal pathway related keratoconus myopia, etc.), myopia caused by insufficient outdoor exercise, accommodation tension myopia, childhood myopia, infant myopia, genetic myopia, myopia dominated by environmental factors.

[0031] In some embodiments, myopia mainly refers to myopia that is prevalent in healthy young individuals or in young population (patients do not have underlying diseases such as hypertension, hyperlipidemia, hyperglycemia, etc.) rather than high myopia or myopia in the elderly.

[0032] In some embodiments, myopia includes or excludes high myopia or myopia complications caused by high myopia, myopia caused by diabetes (hyperglycemia) or myopia complications thereof, myopia caused by lens lesions or myopia complications thereof, and / or myopia caused by keratoconus or myopia complications thereof.

[0033] In some embodiments, myopia-related symptoms include complications caused by myopia (especially high myopia), such as floaters, glaucoma, posterior scleral staphyloma, retinal lesions, retinal detachment, retinal tears, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or maculopathy, visual field defects, progressive or sudden decrease in vision (especially near vision), ocular acidosis and / or pain, night blindness, astigmatism, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent rubbing of the eyes, anisopia, blurred vision when looking at distant objects, the need to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye fatigue, difficulty concentrating due to myopia, difficulty driving, especially at night (night myopia), retinal atrophy degeneration (bleeding and tears), subretinal neovascularization, or ocular atrophy.

[0034] In some embodiments, myopia-related symptoms include or exclude myopia or myopia-related symptoms caused by hyperglycemia, such as choroidal neovascularization, retinal lesions, or macular degeneration in patients with hyperglycemia, etc.

[0035] In some embodiments, the drug, formulation, composition or device further comprises other drugs, compounds or ophthalmic agents, including but not limited to myopia treatment drugs (such as pirenzepine, muscarinic antagonists, robaxin, indoramine, timolol maleate, epinephrine, pirenzepine, pirenzepine, methanesulfonate, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, bromoepinephrine, tretinoin, ginsenoside, formononetin, etc.), prazosin, vinpocetine, bimatoprost, betimol, betaxolol, betaxolol, M receptor blockers (such as blockers or antagonists or inhibitors for M2 or M3 receptors), atropine or atropine sulfate, dibazol, polyunsaturated fatty acids (such as DHA, EPA), epinephrine, anisodamine (racemic), tropicamide, 7-methylxanthine, nicotinic acid, piracetam, danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), smooth muscle relaxants, anti-vasospasm drugs, non-selective adenosine antagonists, vasodilators, mydriatic components, hyperemia-removing components, ocular muscle (such as ciliary muscle) adjusting components, anti-inflammatory components, astringent components, antihistamine components, antiallergic components, collagen degradation inhibiting components, liver-protecting components (to avoid or reduce liver toxicity), blood-retinal barrier enhancing components (to make the compound more difficult to penetrate through the physiological barrier), amino acids, antibacterial components, antioxidant components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, amblyopia treatment components, glaucoma treatment components, cataract treatment components, phosphodiesterase inhibitors (specific or non-specific), miRNAs and their modifications, therapeutic components for ophthalmic diseases, ophthalmically compatible excipients, liver extract, propolis, bilberry (orange) extract, anthocyanins, nano-selenium, vitamin E, vitamin C, vitamin B, lutein, astaxanthin, mesalazine, pyridoxine (such as pyridoxine hydrochloride), lipoic acid, etc. Of course, the drug, formulation, composition or device of the present application can also not contain any of the substances described in this paragraph.

[0036] In some embodiments, lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal compound, or a combination of these substances, is formulated or designed into a continuous administration form, or a simultaneous administration form, or a sequential administration form, or an alternating administration form, or an interval administration form, or a separate administration form with one or more drugs for delaying myopia progression and / or myopia treatment drugs.

[0037] In some embodiments, lipoic acid related compounds include, but are not limited to: lipoic acid ester further formed salts, such as all the salt forms of lipoic acid choline ester in CN115279745A, including but 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 conjugates of said these substances are compounds in Figure 3 (Walter H. Moos et al., Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future., Biores Open Access., 2017 Dec 1; 6(1): 169-181.).

[0038] In some embodiments, lipoic acid and its related compounds include, but are not limited to, R (dextro)-lipoic acid, S (levorotatory)-lipoic acid (preferably R-alpha-lipoic acid), beta-lipoic acid, dihydrolipoic acid, halogenated or deuterated lipoic acid and dihydrolipoic acid, lipoic acid structural analogs such as CMX-2043, ester forms or derivatives or structural analogs of lipoic acid such as PMX500FI, various salts (such as sodium salt, lysine salt) or esters of lipoic acid (especially lipoic acid choline ester, such as EV06 or alpha-LACE or UNR844) or amide substances (such as Lipoamide), lipoic acid choline ester tosylate, lipoic acid choline ester 3, -dihydroxybenzoate, lipoic acid choline ester benzenesulfonate, lipoic acid choline ester iodide or lipoic acid choline ester chloride, derivatives of lipoic acid choline ester, other nanomaterials or biological macromolecules or drugs modified by lipoic acid, prodrugs of lipoic acid (such as lipoic acid choline ester or lipoic acid choline ester chloride), lipoic acid metabolites such as 6, 8-bis(methylthio)octanoic acid (BMOA), 4, 6-bis(methylthio)hexanoic acid (BMHA), 2, 4-bis(methylthio)butanoic acid (BMBA), bisnorlipoic acid (BNLA), tetranorlipoic acid (TNLA), beta-hydroxybisnorlipoic acid, etc.

[0039] In some embodiments, a derivative of lipoic acid choline ester can be understood as any compound or mixture of compounds formed from the reaction of lipoic acid choline ester with a non-aqueous pharmaceutically acceptable excipient other than lipoic acid and choline. In certain embodiments, the derivative is a product formed from the reaction of lipoic acid choline ester with propylene glycol. In certain embodiments, the derivative is a product formed from the reaction of lipoic acid choline ester with glycerol.

[0040] In some embodiments, a metabolite of lipoic acid or its pharmaceutically acceptable salts or esters is 6,8-bis(methylthio)octanoic acid (BMOA), 4,6-bis(methylthio)hexanoic acid (BMHA), 2,4-bis(methylthio)butanoic acid (BMBA), bisnorlipoic acid (BNLA), tetranorlipoic acid (TNLA), β-hydroxybisnorlipoic acid, tetranorlipoic acid, dimethylbisnorlipoic acid.

[0041] In one embodiment, the pharmaceutically acceptable salts or esters of lipoic acid of the present application are the compounds described in CN115279745A or CN113387923A, especially the compounds described in claims 1-21 of CN113387923A, which are believed to retain the essential function of lipoic acid. For example, the present application provides a lipoic acid choline ester tosylate salt having the following structure:

[0042] In some embodiments, the present application provides a (R) lipoic acid choline ester tosylate salt having the following structure:

[0043] having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% enantiomeric excess of the R isomer.

[0044] In one embodiment, the present application provides a lipoic acid choline ester benzenesulfonate salt having the following structure:

[0045] In some embodiments, the present application provides a (R) lipoic acid choline ester 3,4-dihydroxybenzoate salt having the following structure:

[0046] having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% enantiomeric excess of the R isomer.

[0047] In one embodiment, the present application provides a lipoic acid choline ester 3,4- dihydroxybenzoate salt having the following structure:

[0048] In some embodiments, the present application provides a (R) lipoic acid choline ester 3,4-dihydroxybenzoate salt having the following structure:

[0049] having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% enantiomeric excess of the R isomer.

[0050] In one embodiment, the lipoic acid related compounds of the present application are the compounds described in CN111315369A, especially the compounds described in claims 1-3 thereof, which are believed to retain the essential functions of lipoic acid. For example: the compound of Formula I, or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer, polymorph or prodrug thereof:

[0051] wherein X + represents,

[0052] In some embodiments, the compound is of Formula la, or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer, polymorph or prodrug thereof:

[0053] wherein X + is as defined in the foregoing.

[0054] In some embodiments, the compound is of Formula lb, or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer, polymorph or prodrug thereof:

[0055] wherein X + is as defined in the foregoing.

[0056] In some embodiments, the pharmaceutical, formulation or composition containing LACE has a counterion, including but not limited to chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (optical isomers or mixtures thereof), succinate, benzoate and glutamate anions, for example, WO 2018 / 055572 describes pharmaceutical compositions of LACE chloride and LACE iodide.

[0057] In some embodiments, LACE is a prodrug of lipoic acid, which is hydrolyzed and becomes lipoic acid after being applied to the eye. In certain embodiments, LACE can also be considered a derivative of lipoic acid.

[0058] In some embodiments, dihydrolipoic acid is a metabolite of lipoic acid, which can be further reduced to produce dihydrolipoic acid in the eye.

[0059] Lipoic acid and its related compounds can also be produced by organisms, so the components or media administered in myopia treatment also include microorganisms or mammalian cells that can produce or secrete lipoic acid, preferably, the microorganisms or mammalian cells are genetically edited or genetically engineered.

[0060] In fact, the above-mentioned lipoic acid-related compounds are all prior art, and have been proven to have the same basic effect as lipoic acid, except for solubility, corneal penetration ability, bioavailability, stability, etc. Those skilled in the art are also capable of preparing more other lipoic acid-related compounds with the function of lipoic acid.

[0061] In some embodiments, the formulation is a health product, food, dietary supplement, nutritional product, drink, or other oral product or cosmetic. The cosmetic can be one or a combination of regular solution, aqueous solution, unsaturated solution, oil-water mixture, suspension (agent), liniment, lotion, spray, cream, drop, infusion, ointment, paste, pill, suppository, emulsion, patch.

[0062] In some embodiments, the device is an instrument, equipment, consumables, system, medical device, health product or product that changes the appearance of the eye, such as a contact lens, glasses, intraocular lens, suture, OK lens cleaning (maintenance) system, eye patch, eye patch, beauty lens, microneedle, eye spray system, eye massager, eye fumigation instrument, ocular surface drug delivery device, intraocular drug delivery device, fundus drug delivery device, implant pump, wearable device, acupoint massage instrument, eye relaxation device, myopia treatment instrument or combination of drug and instrument for myopia prevention and control, which can release drugs or have drug delivery function or potential drug delivery ability.

[0063] In some embodiments, lipoic acid or lipoic acid choline ester, or an optical isomer thereof or a racemic 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 crystal type compound thereof, or a combination of these substances, as the only active ingredient or the main active ingredient or the direct active ingredient; or: the content or drug efficacy of lipoic acid or lipoic acid choline ester, or an optical isomer thereof or a racemic 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 crystal type compound thereof, or a combination of these substances accounts for 1% and below (such as a content of at least 0.15%) or more than 1%, more than 10%, more than 20%, more than 30%, more than 40%, or more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredients of the use; and / or: the content or drug efficacy of lipoic acid or lipoic acid choline ester, or an optical isomer thereof or a racemic 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 crystal type compound thereof, or a combination of these substances accounts for more than 20% (not including 20%) of the total raw material ingredients of the use; the percentage (%) can be mass ratio or molar ratio or potency ratio, or the contribution rate of drug efficacy to the use.

[0064] In some embodiments, the concentration of lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances in the drug, preparation, composition or device is 0.001 μM to 10 mM, preferably 0.01 μM to 1000 μM, preferably 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, more preferably 0.1 μM to 15 μM; 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 (such as about 46 mM, i.e. 0.94%); and / or: the concentration or proportion of lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances in the drug, preparation, composition or device is less than 25%, preferably less than 5%, preferably less than 1%, more preferably less than 0.01%, more preferably less than 0.001%; or more than 0.0005%, preferably more than 0.025%, preferably more than 0.05%, more preferably more than 0.1%, more preferably more than 1%; or not less than 0.0001%, preferably not less than 0.001%, preferably not less than 0.01%, more preferably not less than 0.1%, more preferably not less than 0.8%, the percentage (%) can be mass / volume concentration (grams per 100 milliliters) or mass percentage or molar (number) ratio.

[0065] The present application provides a drug, preparation, composition or device for ocular administration.

[0066] The present application also provides a pharmaceutical composition or compound preparation containing at least two active substances, including lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances and other active substances for treating myopia. Preferably, the added amount, concentration and / or efficacy of lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances is not less than that of any other active substance for treating myopia, in terms of myopia treatment or control of myopia progression.

[0067] The present application also provides a pharmaceutical composition or a compound preparation, which comprises lipoic acid or lipoic acid choline 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 crystal compound thereof, or a combination of these substances, and other active substances for treating myopia, which include or do not include one or more active substances such as propolis, bilberry extract, anthocyanin, beta-carotene, selenium or nano-selenium, vitamin E, vitamin C, lutein, taurine, astaxanthin, DHEA, grape seed extract, mesalazine, pyridoxine (such as pyridoxine hydrochloride), etc. In some embodiments, the proportion or concentration of lipoic acid or lipoic acid choline ester in the pharmaceutical composition or compound preparation is at least 0.5%, 0.15%, 0.05%, 0.005%, or 0.00001%.

[0068] The present application further provides an eye preparation or a drug, in which lipoic acid or lipoic acid choline 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 crystal compound thereof, or a combination of these substances, is used as a direct, unique, or main active ingredient.

[0069] In some embodiments, the preparation or drug includes, but is not limited to, eye drops (eye drops), eye ointments, eye sprays, implant tablets, eye gels, eye patches, eye microspheres, eye sustained-release preparations, periocular injections, or intraocular injections.

[0070] In some embodiments, the combination of two or more of lipoic acid or lipoic acid choline 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 crystal compound thereof, or a combination of these substances is administered simultaneously, such as administration at the same time or in sequence during a specific administration (treatment) process, on the same day, in the same week, in the same month, in the same year, or at intervals, such as 4-hour intervals, 12-hour intervals, alternate days, alternate weeks, alternate months, or alternate years, or:

[0071] Lipid extract of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances is administered simultaneously with one or more other drugs, such as a specific drug (treatment) process simultaneously or sequentially, on the same day, on the same week, on the same month, on the same year; or alternately at intervals, such as alternately at intervals of 4 hours, alternately at intervals of 12 hours, alternately every other day, alternately every other week, alternately every other month, alternately every other year; or:

[0072] Lipid extract of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances is used in combination with devices (such as contact lenses) and / or surgery (such as refractive surgery, myopia laser surgery, lens surgery).

[0073] In some embodiments, the preparation concentration or administration frequency of lipoic acid as the main active ingredient or the only active ingredient of the eye preparation is higher than that of lipoic acid choline ester as the main active ingredient or the only active ingredient of the eye preparation.

[0074] In some embodiments, the one or more other drugs are myopia prevention and / or myopia treatment drugs, such as atropine sulfate, dibazol, polyunsaturated fatty acids, DHA, fish oil, M receptor blockers, niacin, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), ambenonium, indoramin, timolol maleate, epinephrine, pyrazine, pifenzepine, pirenzepine, methamphetamine, chloroponamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, salidroside, formononetin, etc., vasodilators, smooth muscle relaxants, anti-vascular spasm drugs, collagen metabolism regulators, piracetam, antiallergics, liver protectants, gastrointestinal tract soothing drugs, propolis, bilberry extract, anthocyanins, beta-carotene, selenium or nano-selenium, vitamin E, vitamin C, lutein, taurine, astaxanthin, DHEA, grape seed extract, mesalazine, pyridoxine (such as pyridoxine hydrochloride), etc. Of course, the drugs, preparations, compositions or devices of the present application can also not contain any one or more of the substances described in this paragraph.

[0075] In some embodiments, the device is various glasses, OK glasses, frame glasses, eye patches, (myopia) acupoint massage instruments, eye relaxation devices, myopia treatment instruments, etc. instruments, devices, consumables, medical devices or health care products with the function of protecting vision or treating (correcting) myopia.

[0076] In some embodiments, the systemic administration dosage form (e.g., oral tablet) and the topical administration dosage form (e.g., eye drop) are used simultaneously, or in combination, or alternately, or separately, or sequentially in the course of achieving the use.

[0077] In some embodiments, the abnormal development of the eye is primarily due to genetic factors, including DNA encoded information and / or epigenetic characteristics.

[0078] In some embodiments, the abnormal development of the eye is a refractive development abnormality (e.g., abnormal development of the size of the eyeball in children and adolescents (e.g., 2-30 years old)) primarily induced by environmental factors, or primarily caused by human factors (e.g., long-term close-range reading, frequent use of electronic screens, lack of opportunities for distance vision, improper use of refractive glasses, drug side effects, obesity, trauma, poor learning environment lighting, lack of outdoor exercise), and is not related to genetic factors, or genetic factors are secondary factors, accompanying factors, or synergistic factors.

[0079] In some embodiments, the abnormal development or development abnormality includes an overlong axial length or an axial length elongation rate that does not match the refractive system, resulting in the imaging focal point of parallel light passing through the normal or abnormal refractive system of the eye being located in front of the retina. BRIEF DESCRIPTION OF DRAWINGS

[0080] Figure 1: Lipoic acid controls myopia progression. Comparison of the difference in diopter, vitreous cavity depth and axial length between the two eyes of the subjects in the lipoic acid treatment group and the negative control group before the experiment, 1 week after the experiment and 2 weeks after the experiment. A is the difference in diopter between the experimental eye and the contralateral eye; B is the difference in axial length between the experimental eye and the contralateral eye; C is the difference in vitreous cavity depth between the experimental eye and the contralateral eye. * represents p<0.05, ** represents p<0.01, *** represents p<0.001. Refraction: diopter; VCD: vitreous cavity depth; AL: axial length; n: sample size; Vehicle: solvent; lipoic acid: lipoic acid.

[0081] Figure 2: Effect of lipoic acid on anterior chamber depth (A), lens thickness (B), corneal curvature (C) and pupil diameter (D). ACD: anterior chamber depth; LT: lens thickness; RCC: corneal curvature; PD: pupil diameter; n: sample size; Vehicle: solvent; lipoic acid: lipoic acid.

[0082] Figure 3: Examples of lipoic acid and its related compounds.

[0083] Figure 4: Intervention effects of lipoic acid, mesalazine, pyridoxine, astaxanthin and bilberry extract on refractive power of myopic individuals. The difference in refractive power between the two eyes of the same subject was compared before the experiment, 1 week after administration and 2 weeks after administration in different administration groups. n: sample size. w: week. *P<0.05, **P<0.01, ***P<0.001.

[0084] Figure 5: Intervention effects of lipoic acid, mesalazine, pyridoxine, astaxanthin and bilberry extract on vitreous chamber depth and axial length of myopic individuals. The difference in axial length (A) and vitreous chamber depth (B) between the two eyes of the same subject was compared before the experiment, 1 week after administration and 2 weeks after administration in different administration groups. VCD: vitreous chamber depth. AL: axial length. n: sample size. w: week. *P<0.05, **P<0.01, ***P<0.001.

[0085] Figure 6: Effects of atropine, lipoic acid, mesalazine, pyridoxine, astaxanthin and bilberry extract on pupil size of test animals.

[0086] Figure 7: Intervention effects of lipoic acid as the main active ingredient or direct active ingredient on the progression of negative refractive power and elongation of the axial length of myopic individuals. The difference in refractive power (A) and axial length (B) between the two eyes of the same subject was compared before the experiment, 1 week after administration and 2 weeks after administration in different prescription ratio drug combinations. FD 2w refractive power Control VS. BFE (0.05%) + DL. ALA (1%) statistical P value = 0.0569. n: sample size. w: week. *P<0.05, **P<0.01.

[0087] Figure 8-1: Lipoic acid choline ester eye drops significantly treat myopia. The difference in refractive power (A) between the two eyes of the same subject was compared before the experiment, 1 week after administration and 2 weeks after administration in different concentrations of lipoic acid choline ester eye drops; the difference in axial length (B) between the two eyes of the same subject was compared before the experiment and 2 weeks after administration in different concentrations of lipoic acid choline ester eye drops. n: sample size. w: week. *P<0.05, **P<0.01, ***P<0.001.

[0088] Figure 8-2: Effects of different concentrations of lipoic acid choline ester on corneal curvature (A), anterior chamber depth (B) and lens thickness (C). ACD: anterior chamber depth; LT: lens thickness; RCC: corneal curvature; n: sample size.

[0089] Figure 9: Both lipoic acid optical isomers and dihydrolipoic acid can effectively treat negative lens-induced model myopia. The difference in refractive power between the two eyes of the same subject was compared before the experiment, 3 days after administration and 7 days after administration in different chiral lipoic acids or their metabolites. n: sample size. d: day. *P<0.05, **P<0.01.

[0090] Figure 10: Effect of lipoic acid optical isomers and dihydrolipoic acid on the crystalline thickness (A) and anterior chamber depth (B) of the LIM model.

[0091] Figure 11: Intervention effect of lipoic acid-containing pharmaceutical composition on the progression of negative refractive change and ocular axis elongation in myopic individuals. The difference in the change in diopter (A) and ocular axis length (B) between the two eyes of the same subject before the experiment, 1 week after administration, and 2 weeks after administration of a low-concentration atropine and lipoic acid compound preparation was evaluated. n: sample size. w: week. *P<0.05, **P<0.01, ***P<0.001.

[0092] Figure 12: Simple eye drop administration of lipoic acid choline ester can effectively increase the choroidal thickness of myopic individuals. ChT: choroidal thickness, n: sample size.

[0093] Figure 13: Both lipoic acid optical isomers and dihydrolipoic acid can effectively increase the choroidal thickness of myopic individuals. ChT: choroidal thickness, n: sample size, *P<0.05. DETAILED DESCRIPTION

[0094] The following will illustrate the embodiments of the present application by way of example. Although the present application has been described in connection with these specific embodiments, it should be understood that the application is not limited to the specific embodiments. On the contrary, the application is intended to cover all alternatives, modifications, substitutions, variations and equivalents as can be included within the spirit and scope of the application as defined by the appended claims.

[0095] The present application provides a method for preventing and treating myopia, which involves administering lipoic acid or lipoic acid choline ester, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts or esters, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystal type compounds, or combinations of these substances.

[0096] The present application further provides a drug for treating myopia and controlling myopia progression, which is topically applied to the eye and contains lipoic acid or lipoic acid choline ester as the only, or main, or direct active ingredient. In the prior art, lipoic acid is mainly in the form of tablets, capsules and injections, and is administered systemically. When lipoic acid or lipoic acid choline ester is used to treat myopia, if systemic administration is performed, it will be affected by the first-pass effect, blood-retinal barrier (BRB), etc., and a large dose of the drug needs to be given to ensure that the lipoic acid or its metabolites entering the eye reach the therapeutic concentration threshold. Such a treatment strategy has the potential risk of systemic adverse reactions, especially in low-age populations and requires long-term continuous administration. At the same time, systemic administration is affected by more individual differences, increasing the uncertainty of the efficacy of lipoic acid or lipoic acid choline ester in preventing and controlling myopia. Therefore, the present application develops a lipoic acid drug with better effectiveness and safety, which is topically applied to the eye. This drug development strategy is aimed at the use of lipoic acid and its related compounds (such as UNR844 Chloride) in the prevention and control of myopia in children and adolescents, and has the advantages of convenient medication for patients, high compliance, long-term administration (such as one month, half a year, one year, three years, five years, ten years), little impact on the growth and development of young individuals, safe and reliable eye preparations.

[0097] The present application also provides a method, which is to administer an effective dose of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances to a suitable subject.

[0098] The method or pharmaceutical composition of the present application can significantly inhibit the development of myopia, and can significantly inhibit, slow down the elongation of the eye axis and / or the increase of the vitreous cavity length of myopic individuals (including those who have not yet developed myopia but will develop myopia), and can increase the choroidal thickness of such population. Preferably, the population to which the method or pharmaceutical composition of the present application is applicable includes children and / or adolescents with myopia (preferably the population is aged 2-30 years, more preferably the population is aged 6-18 years), or early, intermediate myopia, or mild or moderate myopia, or non-pathological myopia, or simple axial myopia, or children and / or adolescents with axial myopia (preferably the population is aged 2-30 years, more preferably the population is aged 6-18 years), or children and / or adolescents with progressive myopia (preferably the population is aged 2-30 years, more preferably the population is aged 6-18 years), or primary myopia, or non-senile myopia, or juvenile myopia, or progressive myopia, or non-refractive myopia, the elongation of the eye axis and / or the increase of the vitreous cavity length of these myopic individuals (including those who have not yet developed myopia but will develop myopia) is inhibited or even terminated by the method, preparation or pharmaceutical composition of the present application.

[0099] The present application provides a method for treating, preventing or slowing down myopia and its related symptoms in a subject, comprising administering to the subject a therapeutically effective amount of lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances. Preferably, lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances is administered alone; preferably, lipoic acid or lipoic acid choline 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 crystal type compound thereof, or a combination of these substances is administered in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is prepared as an ophthalmic preparation; preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier; preferably, the carrier is an ophthalmically acceptable carrier.

[0100] The present application also provides a pharmaceutical composition for treating, preventing or slowing myopia and its related symptoms, said pharmaceutical composition comprising lipoic acid or lipoic acid choline 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 crystal form compound thereof, or a combination of these substances. The present application also provides the use of lipoic acid or lipoic acid choline 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 crystal form compound thereof, or a combination of these substances in the preparation of a pharmaceutical composition for treating, preventing or slowing myopia and its related symptoms. Preferably, the pharmaceutical composition is prepared into an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmically acceptable carrier, preferably, the carrier is an ophthalmically compatible carrier.

[0101] The present application also provides a myopia treatment (myopia progression inhibition) regimen in which lipoic acid or lipoic acid choline 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 crystal form compound thereof, or a combination of these substances is used in combination with, or is used alternately with, or is used separately from, other myopia prevention and control drugs (such as atropine) or optical prevention and control means (such as ok glasses, various forms of optical therapeutic instruments) or refractive surgery during the prevention, slowing and treatment of myopia.

[0102] The present application also provides a myopia treatment (myopia progression inhibition) regimen in which lipoic acid or lipoic acid choline 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 crystal form compound thereof, or a combination of these substances is used in combination with, or is used alternately with, or is used separately from, other myopia prevention and control drugs (such as atropine) or optical prevention and control means (such as ok glasses, various forms of optical therapeutic instruments) or refractive surgery during the prevention, slowing and treatment of myopia.

[0103] Terms and definitions

[0104] "myopia" refers to the condition in which parallel rays of light are brought to a focus in front of the retina after passing through the refractive structures of the eye. Myopia is usually manifested by a decrease in distance visual acuity with normal near visual acuity. The clinical concept of myopia is: static refraction ≥ -0.25 D. The clinical manifestations are blurred distance vision, good near vision, and initial myopia often has fluctuation in distance vision. Since accommodation is not used or less used when looking at near objects, the convergence function is correspondingly weakened, which easily causes exophoria or exotropia. In some paragraphs of this document, the term "myopia" and the term "myopic eye" represent the same concept and can be replaced by each other. Researchers in the field should correctly understand the meaning of "myopia" or "myopic eye" in this patent according to the context.

[0105] In the first aspect, there are four common classifications of myopia: (1) According to the size of the refractive error, it can be divided into mild (300 degrees or less), moderate (300 degrees to 600 degrees) and high (600 degrees or more than -6D); (2) According to whether the refractive component is abnormal, it can be divided into refractive myopia and axial myopia; (3) According to whether pathological changes occur, it can be divided into pathological myopia and simple myopia; (4) According to the cause, it can be divided into primary myopia and concurrent / secondary myopia.

[0106] In some embodiments, myopia or myopia complications can or can not include any one or more of the myopia categories or myopia complication types mentioned in this application, for example:

[0107] "Mild or moderate myopia", in addition to blurred distance vision, the patient has no other symptoms, that is, the main symptom is gradual decrease in distance visual acuity, blurred distance vision, normal near visual acuity, and usually no special changes in the eye except eye axis length.

[0108] "High myopia" (such as -6D), the patient's anterior chamber of the eye is deeper, the pupil is larger, and the eyeball appears slightly prominent due to the excessive length of the anterior and posterior axes. A white or gray-white crescent-shaped spot can be seen on the temporal side of the optic disc, known as the myopic crescent, which is due to the posterior elongation of the sclera, the detachment of the retinal pigment epithelium and choroid from the temporal edge of the optic disc, and the exposure of the sclera or part of the choroid and sclera. The posterior sclera continuously expands in the posterior pole, which can cause knee-like streaks and subretinal neovascularization in the macular region, and patchy atrophy of the nearby retina and choroid, leading to posterior scleritis staphyloma. There is often hyperpigmentation in the macular region, and even hemorrhage, forming an atrophic spot (Forster-Fuchs spot). Such patients are often accompanied by vitreous liquefaction and opacity, and a small number of them can also develop retinal detachment and concurrent cataract. In addition, high myopia often has poor distance and near vision due to refractive interstitial opacity and retinal and choroidal degeneration, and sometimes is accompanied by a black shadow floating in front of the eye. If such lesions occur, this type of myopia is no longer simple myopia.

[0109] "Refractive myopia", mainly due to corneal or lens curvature is too large, refractive power beyond the normal range, while the eye axis length is in the normal range.

[0110] "Axial myopia", is the eye axis length beyond the normal range, while the corneal and lens curvature is basically in the normal range. Axial myopia is the main type of myopia in children and adolescents.

[0111] "Pathological myopia", also known as degenerative myopia or malignant myopia, is a degenerative disease of the fundus. Patients with high myopia usually have high myopia (such as more than 600 degrees), and their visual function is significantly impaired, with poor distance vision, in addition to visual field, light perception, contrast sensitivity, etc. Often abnormal, often accompanied by night vision (night blindness), floaters, flashes, etc. The retinal pigment epithelium and choroid of the patient's fundus can be seen to be thin, often accompanied by retinal pigment epithelial atrophy, choroidal neovascularization and retinal detachment, macular degeneration and other symptoms, and the pathological changes of the fundus after development stop are still developing. This type of myopia can cause blindness.

[0112] "Simple myopia", refers to the development of myopia in the development period of the eyeball, and the myopia tends to be stable after the development stops, such as the onset of myopia in the school-age period, myopia less than 600 degrees, and the fundus is generally without obvious pathological changes. Also known as acquired myopia (eye). This type of myopia progresses, and the axial length of the eye also gradually increases. The visual acuity can be corrected to normal with appropriate lenses, and other visual function indicators are mostly normal. On the contrary, it is non-simple myopia. Examples of non-simple myopia include pathological myopia, high myopia, presbyopia, complex myopia, etc.

[0113] "Primary myopia", is the main type of myopia. "Primary" refers to a type of myopia whose cause and mechanism of occurrence cannot be determined using existing diagnostic techniques. In its development process, it shows specific pathological or physiological functional-structural changes of myopia, including congenital myopia and acquired simple myopia.

[0114] "Concurrent / secondary myopia", refers to a temporary or accompanying myopia caused by dysfunction of eye accommodation or abnormal refractive index due to internal and external factors, such as toxic myopia, drug-induced myopia, traumatic myopia, diabetic myopia, initial stage of cataract-induced myopia, myopia induced by lens oxidation, myopia induced by corneal damage or oxidation, and progressive complex myopia with lipid peroxide oxidation (POL) disorder. The characteristics of this type of myopia are that there are often clear inducing factors, and the degree of myopia can be alleviated or reversed when medical intervention is used to intervene in the inducing factors, so there is a visual fluctuation and recurrence in this type of myopia. This type of myopia is also common in the elderly.

[0115] “Axial simple myopia”, also sometimes referred to as simple axial myopia, belongs to simple myopia, which is characterized by simple myopia caused by elongation of the eye axis and / or increase in vitreous cavity depth. The ocular refraction tissue (such as the lens) of this myopia is basically normal, and is the most common type of myopia in children and adolescents, which is mostly found in people aged 2 to 30 years, especially in people aged 6 to 18 years (Paul N Baird, Nat Rev Dis Primers. 2020 Dec 17; 6(1): 99. and A J Adams, Am J Optom Physiol Opt. 1987 Feb; 64(2): 150-2 and Seang-Mei Saw, Ophthalmic Physiol Opt. 2005 Sep; 25(5): 381-91.).

[0116] “Curvature myopia” is myopia caused by an increase in the curvature of the cornea or lens.

[0117] “Index myopia” is mainly caused by an increase in the refractive power of the aqueous humor and lens, which belongs to refractive myopia.

[0118] “Progressive myopia” refers to myopia in which the diopter continuously decreases over time or with the increase in the age of the individual. If no intervention is taken or the patient is not yet of an age at which eye growth and development stops, this type of myopia will eventually develop into high myopia.

[0119] “Child and adolescent myopia” is a type of simple myopia caused by long-term close eye use. Most patients with this type of myopia do not develop pathological myopia. The eyeballs of children and adolescents are in the growth and development stage, have strong accommodation ability, and have relatively large scleral extension. When reading, writing, or other close work, the eyeball is in a defocus state, and over time, the anterior-posterior axis of the eyeball will become longer, which is prone to cause axial myopia in children and adolescents. If the eye use habits do not change or no medical intervention is taken for myopic eyes, the degree of myopia in children and adolescents will gradually increase, and the corresponding eye axis length will also further increase. Therefore, this type of myopia is in a dynamic state of increasing eye axis length and continuously negative diopter with the growth and development of children and adolescents and the tension of learning pace, which belongs to progressive myopia, rather than being in a static state like myopia in adults or the elderly. Therefore, the evaluation of the efficacy of drugs for the treatment of this type of myopia in clinical practice mainly takes the control of myopia progression and the inhibition of eye axis elongation as the main indicators.

[0120] "Myopia in the elderly" is usually quite complex, easily affected by aging of bodily organs and underlying diseases. It is often accompanied by symptoms such as changes in blood sugar, arteriosclerosis, insufficient blood supply, ocular microcirculation disorders, and oxidative stress. Furthermore, most patients receiving treatment clinically have high myopia. A significant characteristic of myopic patients in adults or the elderly is that the degree of myopia generally does not worsen with age. The main reason for this is that the growth and development of the eyes in these individuals has essentially ceased, and the axial length of the eye no longer changes due to prolonged close-range viewing. Therefore, myopia in the elderly (including adults) and myopia in children and adolescents (minors) are two distinct diseases, and these two indications need to be clearly distinguished in the treatment of myopia. Although the drugs or methods described in this application are suitable for treating various types of myopia, simple myopia, axial myopia, and myopia in children and adolescents are preferred, while myopia in the elderly, malignant myopia, pathological myopia, and other non-simple myopias are excluded. This is because the clinical intervention strategy for these myopic patients is no longer to inhibit axial elongation, but rather to prevent blindness caused by serious eye diseases, such as retinal detachment.

[0121] "Myopia-related symptoms" include complications caused by myopia, such as complications of high myopia, as well as floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular disease, visual field defects, progressive or sudden decrease in vision (especially near vision), eye strain and / or pain, poor night vision (such as night blindness), astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, flashes of light, frequent eye rubbing, blurred vision when looking at distant objects, needing to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye fatigue, and difficulty seeing while driving, especially when driving. Nocturnal myopia, retinal atrophy and degeneration (hemoptysis and tears), subretinal neovascularization, and phthisis bulbi; varying degrees of fundus changes may also occur, such as myopic lamina, macular hemorrhage, or subretinal neovascularization, which may result in irregularly shaped white atrophic spots or round black spots with pigmentation (Fuchs' spots), peripheral retinal lattice degeneration, cystic degeneration, vitreous liquefaction, opacity, and posterior vitreous detachment at a young age, and a higher risk of retinal tears and detachment than normal individuals. Often due to the longer anteroposterior diameter of the eyeball, the eyeball is more protruding, and the posterior part of the eyeball is extremely expanded, forming scleral staphyloma; choroidal atrophy, retinal diseases, and macular hemorrhage caused by myopia, especially high myopia.

[0122] "Complex myopia": also known as complex myopia. Compared with simple myopia, complex myopia is mainly manifested as complications caused by myopia, especially high myopia, which endanger vision (whether near vision or distance vision) or cause serious visual impairment (such as retinal detachment, blindness, etc.), and is no longer just simple refractive decline in myopia. Complex myopia is often seen in progressive complex myopia with lipid peroxide oxidation POL disorder, myopia in the elderly, myopia caused by high blood sugar (such as diabetic myopia), or high myopia, etc. On the contrary, it is non-complex myopia. Examples of non-complex myopia include myopia in children and adolescents, axial myopia, simple myopia, progressive myopia, mild myopia, and moderate myopia, etc.

[0123] "Accommodative tension myopia", due to excessive load of the eyeball for near vision, excessive accommodation of the ciliary muscle, etc., resulting in accommodative tension or accommodative spasm caused myopia.

[0124] "Astigmatic myopia", is a type of myopia caused by corneal damage or varying degrees of curvature, external light diffusing in all directions, and unable to form a focal point on the retina.

[0125] "Pseudomyopia", refers to the examination of refractive error after the use of cycloplegics, the myopia degree disappears, and appears as emmetropia or hyperopia.

[0126] "True myopia", i.e. the usual myopic eye, refers to the use of cycloplegics, the myopia refractive error does not decrease, or the decreased degree is less than 0.5D.

[0127] "Hybrid myopia", refers to the use of cycloplegics, the myopia refractive error decreases significantly, but does not recover to emmetropia.

[0128] Other types of myopia: traumatic myopia, toxic myopia, drug-induced myopia, diabetic myopia, instrumental myopia, spatial myopia, night myopia, other premature infant myopia, diving myopia, and hysteric myopia, as well as temporary myopia seen during menstruation, pregnancy, and various eye diseases and systemic diseases. Among them, "traumatic myopia" is mainly induced by blunt injury in eye trauma, and the refractive error is usually lower than -6.00D.

[0129] "Toxic myopia", a myopic reaction caused by acute or chronic poisoning of toxic substances such as organophosphorus pesticides.

[0130] "Drug-induced myopia", myopia induced by various drugs such as sulfonamides, diuretics, tetracyclines, adrenocorticotropic hormone, and contraceptives, etc.

[0131] "Diabetic myopia", a temporary myopia formed in diabetic patients.

[0132] "Instrumental myopia", myopia induced by long-term close-range operation of instruments or equipment.

[0133] “space myopia”, a kind of myopia phenomenon caused by lack of visual stimulation in normal environment when a person is in high altitude and gazes at the empty visual field around.

[0134] “night myopia”, a kind of myopia state of the human eye in a dark environment with reduced light.

[0135] In the second aspect, the intervention means for myopia can be divided into myopia correction and myopia treatment, wherein myopia treatment is characterized and aimed at inhibiting (controlling) the progression of myopia.

[0136] “myopia correction” is to correct or reduce myopia degree by optical method. Common correction means include wearing frame glasses, phacoemulsification, intraocular lens implantation, corneal laser surgery, etc. However, this means only corrects the refractive error of the individual and cannot delay the progression of myopia or reverse the long eye axis. That is to say, this kind of myopia intervention method usually does not stop or slow down the process of continuously negative refractive error, and cannot inhibit the progression of myopia. Therefore, myopia correction methods such as corneal laser surgery can compensate for the refractive error of patients, restore their distance vision, and are suitable for improving the vision of pathologic myopia, high myopia or elderly myopia population, but are not suitable for treating axial myopia or simple myopia, such as children or adolescent myopia, primary myopia, or mild to moderate myopia, etc. In fact, although the distance vision of axial myopia individuals is temporarily restored after wearing frame glasses, this correction method does not inhibit the further elongation of the eye axis or control the speed of myopia development, and without other drug treatment, the result is that the myopia degree will further increase, and the patient needs to replace the frame glasses with larger degree to continue to correct their vision every certain period of time.

[0137] “inhibiting (controlling) the progression of myopia” refers to delaying (slowing down) the deepening of myopia degree, slowing down the speed of refractive error becoming negative, controlling the development of myopia and inhibiting (controlling) the continuous elongation of the eye axis, which belongs to the treatment of etiology and is aimed at the underage population which is still in the development stage of the eye. For the treatment of children or adolescent myopia, slowing down, controlling or even stopping the continuous negative refractive error and inhibiting the corresponding increase in eye axial length are the primary goals of the development of myopia treatment drugs. That is, the treatment of myopia should achieve the effect of controlling or inhibiting the development of myopia for children or adolescent myopia, axial myopia, simple myopia and other types of myopia, rather than simply reversing or correcting this refractive error state.

[0138] Unless otherwise indicated, "treating (myopia)" in the present application means inhibiting (controlling) the progression of myopia, not correcting myopia. The terms "treatment," "slowing," "delaying," "inhibiting," or "controlling" as used herein refer to therapeutic treatment measures, which aim to slow down (alleviate) or stop the target condition or disorder. A subject's ophthalmic condition is successfully treated, for example, when the subject shows observable and / or measurable inhibition, slowing, reduction, and disappearance of one or more symptoms and signs of the ophthalmic condition, or slowing and delay of the progression of the ophthalmic condition, after receiving a therapeutic amount of a lipoic acid compound or a pharmaceutical composition containing the same according to the methods described herein.

[0139] It should also be understood that a drug capable of treating myopia often also has a "prevention" effect, i.e., is capable of preventing the occurrence and development of myopia, and therefore, "prevention and control" is often used herein to express the meaning of treatment and prevention.

[0140] The various modes of treatment or prevention of medical conditions described herein are intended to mean "significant," which includes complete treatment or prevention as well as less than complete treatment or prevention, where some biologically or medically relevant outcome is achieved. In some embodiments, "treatment" does not require 100% elimination of myopia or symptoms of myopia. In some embodiments, "treatment" of myopia or myopia-related symptoms according to the methods of the present application achieves prevention, alleviation, inhibition, prevention of, for example, at least about 5%, at least about 10%, or at least about 20% of the progression of myopia, as compared to the level observed in the absence of the compositions or methods of the present application (e.g., in a biologically matched control subject or specimen that has not been exposed to the compounds of the compositions or methods of the present application). In some embodiments, myopia or myopia-related symptoms are treated by at least about 30%, at least about 40%, at least about 50%, or at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more (about 100%) as compared to myopia or myopia-related symptoms in the absence of the compounds of the methods of the present application. Thus, one skilled in the art will appreciate that "treatment," "slowing," "delaying," "inhibiting," "controlling," or "prevention and control" are direct actions, and do not refer to means that indirectly benefit myopia treatment, such as eye health benefits or adjunctive treatment benefits, etc., such as enhancing ocular blood circulation, improving comfort upon ocular administration, etc.

[0141] The third aspect, the evaluation method of myopia treatment effect (efficacy) involves various factors, such as whether the selection of the sample population is scientific, whether an objective control is set, whether an effective dose is administered, etc. Specifically, if the sample population is mostly elderly people (eye development has stopped and may have underlying diseases such as arteriosclerosis, etc.), it is difficult to prove that the drug has a therapeutic effect on progressive myopia; if the efficacy is evaluated only by visual acuity test without designing any parallel control (such as a placebo group or the contralateral eye of the same person), it is also impossible to prove that the drug (such as lipoic acid) has a therapeutic effect on myopia. The present application uses two classical myopia disease models of sensory deprivation and negative lens induction in young animals whose eyes are still in the growth and development stage, which are usually used in the preclinical development stage of actual myopia drugs, and the scientific test standards in the field to evaluate the efficacy of compounds in preventing and controlling myopia, especially in preventing and controlling myopia and / or simple myopia in children and adolescents (D A Goss, Am J Optom Physiol Opt. 1981 Oct; 58(10): 859-69. and Hao Wu, Proc Natl Acad Sci U S A. 2018 Jul 24; 115(30): E7091-E7100. and Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083.).

[0142] "Efficacy": refers to the evaluation of the effect or comparison of the advantages and disadvantages of the therapeutic effect of a specific drug composition or preparation on myopia according to the requirements of drug registration application and in accordance with the relevant contents of the "Technical Guidelines for Clinical Research of Drugs for Controlling Myopia Progression" formulated by the China Drug Review Center, with diopter or diopter and eye axis parameter (length) as the judgment index. At the same time, the changes in corneal curvature, vitreous cavity depth, choroidal thickness, and eye axis length compared with the baseline can also be used as secondary efficacy indicators for evaluating myopia treatment. The evaluation method of efficacy or the calculation method of efficacy contribution rate can utilize the change value of diopter compared with the baseline, the change value of eye axis length compared with the baseline, the change value of vitreous cavity depth compared with the baseline, etc. The positive efficacy judgment standard can be a 50% reduction in the progression of refractive errors compared with the control, or a difference in diopter between groups of more than 0.75 D after 3 years of treatment, etc. For myopia treatment drugs containing two or more active ingredients, a scientific and reasonable design includes the evaluation of single and compound preparations of all active ingredients for myopia treatment, respectively, so as to obtain the efficacy contribution rate of each active ingredient and its role in the compound preparation (such as synergistic effect, stabilizer effect, absorption promoting effect, etc.). For the efficacy of preventing (preventing and controlling) myopia, inhibiting myopia progression, and correcting myopia, etc., the above-mentioned myopia treatment evaluation indicators, judgment standards, and active ingredient role evaluation methods can also be referred to to determine or obtain the efficacy of a specific compound (such as lipoic acid or lipoic acid choline ester) and its clinical use significance.

[0143] In the fourth aspect, other conventional terms are explained.

[0144] "Distance vision" also known as naked distance vision, medically refers to the distance of 5 meters in front of the normal eye, normal open to the front, without glasses and any auxiliary equipment (such as frame glasses, contact lenses, beauty lenses, pinhole lenses, etc.) that can increase vision.

[0145] "Local administration" refers to the direct administration of the body part to be affected or the administration method that can meet the local effect, including but not limited to: skin administration, inhalation administration, enema administration, eye administration, nasal administration.

[0146] "Systemic administration" also known as systemic administration, including intravenous administration, oral administration, intramuscular injection, subcutaneous injection and other administration methods. The drug can be transported and distributed throughout the body through the blood in the body.

[0147] "Improved systemic administration" refers to a safe, efficient and convenient systemic administration method that can use specific drug targeting technology to reduce the toxicity of systemic administration of drugs while enriching lipoic acid drugs in the eye.

[0148] "Direct active ingredient" also known as "(drug) active ingredient (Active pharmaceutical ingredient)", refers to the substance that has a direct therapeutic effect on the disease (such as myopia), which is the necessary condition for treating the disease or its administration dose, administration method and other parameters directly affect the treatment effect of the disease, and there is a clear causal relationship between the administration of the ingredient and the effect of treating the disease. For example, if the drug effect of the removed ingredient in the compound preparation is worse than that of the original formula preparation and there is a significant difference, then the removed ingredient is considered a direct active ingredient.

[0149] "Unique active ingredient" refers to the final product (such as a drug) that has only one ingredient to play a role, such as directly inhibiting, preventing and / or treating myopia.

[0150] "Main active ingredient" refers to an active ingredient whose amount, proportion, concentration or effect is not less than that of other active ingredients (such as myopia treatment effect) in the final product (such as a drug); or the content accounts for more than 50%, more than 60%, more than 70%, more than 80%, more than 90% of all active ingredients, the percentage is mass ratio or molar ratio.

[0151] "These substances" refer to lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound.

[0152] “Ophthalmically compatible” means formulations, polymers and other materials and / or dosage forms that are suitable for contact with the eye tissue of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate in severity with the reasonably foreseeable benefits to be received from its use.

[0153] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In addition, the term “or” as used herein is intended to encompass both the “inclusive-or” and “exclusive-or” senses of the term, unless the context clearly dictates otherwise.

[0154] As used herein, a reference to a range of values for a variable is intended to convey that the application can be practiced with a variable equal to any value within the range. Thus, for a variable that is inherently discrete, the variable can be equal to any integer value within the range, including the endpoints of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real value within the range, including the endpoints of the range. For example, a variable described as having a value between 0 and 2 can be 0, 1, or 2 for a variable that is inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for a variable that is inherently continuous.

[0155] “About” as used herein will be understood by one of ordinary skill in the art and will vary to some degree depending upon the context in which it is used. If the use of the term “about” is not clear to one of ordinary skill in the art, then in the context of the use of the term, “about” will mean values within 10% of the recited value, plus or minus.

[0156] As used herein, “administering” a compound, formulation, or drug to a subject includes any route of introducing or delivering the compound to the subject to perform its intended function. “Administering” can be performed by any suitable route, including oral, intraocular, ophthalmic, intranasal, parenteral (via intravenous, intramuscular, intraperitoneal, or subcutaneous), or topical (e.g., to the skin at a site surrounding the eye). “Administering” includes self- administration and administration by another person. When administered ocularly or periocularly, the compound can be administered to the affected eye, the unaffected eye, or both of a subject.

[0157] The term "effective amount" as used herein refers to an amount that is sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., to cause prevention or alleviation of a condition associated with an ophthalmic disorder. The amount of the composition administered to a subject will depend on the type and severity of the disease and on the properties of the individual, such as general health, age, body weight, and tolerability of drugs. The amount will also depend on the extent, severity, and type of disease. A person of ordinary skill will be able to determine appropriate dosages depending on these and other factors. The composition can also be administered in conjunction with one or more other therapeutic compounds. In the methods described herein, a lipoic acid compound or a pharmaceutical composition containing the same can be administered to a subject having one or more symptoms or signs of an ophthalmic disorder. For example, a "therapeutically effective amount" of lipoic acid or lipoic acid choline ester refers to the average level of pharmacological action that minimally alleviates an ophthalmic disorder.

[0158] The terms "formulation" and "composition" as used herein are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents and a carrier or other excipient. The composition can take almost any physical form, including a solid, a liquid (e.g., a solution), or a gas.

[0159] In addition, the term "dosage form" can include one or more formulations or compositions provided in a form for administration to a subject. For example, an injectable dosage form can be a formulation or composition prepared in a manner suitable for administration by injection.

[0160] The term "pharmaceutically acceptable" as used herein means approved by a regulatory agency of the Federal or a state government of China, the EMEA (Europe), and / or the FDA (US) and / or any other nationally recognized regulatory agency, e.g., a carrier, diluent, or vehicle, a concentration of a drug, or a form of a drug that is useful in animals, and more particularly in humans, e.g., a medicament.

[0161] The term "simultaneous" therapeutic application as used herein refers to administration of at least two active ingredients (compounds) by the same route and at the same time or substantially the same time.

[0162] The term "separate" therapeutic application as used herein refers to administration of at least two active ingredients (compounds) by different routes at the same time or substantially the same time.

[0163] The term "sequential" treatment application as used herein refers to the administration of at least two active ingredients at different times, either by the same or different routes of administration. More specifically, sequential application refers to the complete administration of one of the active ingredients before the administration of the other active ingredient is initiated. Thus, it is possible to administer one active ingredient several minutes, hours or days before the administration of the other active ingredient. No simultaneous treatment takes place in this case.

[0164] The term "preventing" a disorder or a condition as used herein refers to a compound reducing the occurrence of a disorder or condition in a treated sample relative to an untreated control sample, or delaying the occurrence of one or more symptoms of a disorder or condition or reducing the severity of one or more symptoms of a disorder or condition in a treated sample relative to an untreated control sample.

[0165] The term "related compound" as used herein includes any compound having the function of lipoic acid or lipoic acid choline ester, such as a derivative or an analogue. The skilled person is also aware of how to prepare various lipoic acid related compounds or lipoic acid choline ester related compounds which retain the function of lipoic acid or lipoic acid choline ester.

[0166] The term "derivative" or "analog" of a compound as used herein includes any molecule that is functionally and / or structurally related to the compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variant, or alkylated variant of the compound. The term derivative also includes structurally related compounds that have lost one or more substituents as listed above. Preferred derivatives of a compound are molecules that have a significant degree of similarity to the compound, as determined by known methods. Similar compounds together with their degree of similarity to the parent molecule can be found in a number of databases, such as PubChem (http: / / pubchem.ncbi.nlm.nih.gov / search / ) or DrugBank (http: / / www.drugbank.ca / ). In more preferred embodiments, the derivative should have a Tanimoto similarity index of more than 0.4, preferably more than 0.5, more preferably more than 0.6, even more preferably more than 0.7 to the parent drug. The Tanimoto similarity index is widely used to measure the degree of structural similarity between two molecules. The Tanimoto similarity index can be calculated by software available online, such as Small Molecule Subgraph Detector (http: / / www.ebi.ac.uk / thomton-srv / software / SMSD / ). Preferred derivatives should be related to the parent compound both structurally and functionally, i.e. they should also retain at least part of the activity of the parent drug. Furthermore, the term "derivative" also includes metabolites of a drug, e.g. a molecule that is typically produced from a (bio)chemical modification or processing of the drug upon administration to an organism, usually by specialized catalytic systems, and which shows or retains a biological activity of the drug. Furthermore, the term "derivative" also includes halogenated (such as fluorinated), protiated, deuterated, tritiated compounds of lipoic acid or its salt forms or combinations thereof.

[0167] A "derivative" of lipoic acid choline ester is any compound or mixture of compounds formed from the reaction of lipoic acid choline ester with a non-aqueous pharmaceutically acceptable excipient other than lipoic acid and choline. In some embodiments, the derivative is a product formed from the reaction of lipoic acid choline ester with propylene glycol. In certain embodiments, the derivative is a product formed from the reaction of lipoic acid choline ester with glycerol.

[0168] Salt forms of lipoic acid choline ester, including all salt forms of lipoic acid choline ester in CN115279745A, including but not limited to lipoic acid choline ester tosylate, lipoic acid choline ester benzenesulfonate, lipoic acid choline ester chloride, or lipoic acid choline ester iodide.

[0169] In particular embodiments, "metabolite" as used herein refers to a modified or processed drug that retains at least a portion of the activity of the parent drug, preferably has an inhibitory effect on phosphodiesterase activity or has a therapeutic, prophylactic or slowing effect on myopia and related symptoms. For example, in a living organism, lipoic acid can be reduced to dihydrolipoic acid or oxidized to beta-lipoic acid, i.e., a metabolite of lipoic acid.

[0170] "Extract" refers to a substance extracted or processed from a microorganism, plant or animal (e.g., a whole plant or a certain part of a plant) using appropriate chemical or physical methods, such as solvent extraction or pressing, which can be a pure substance, can contain a small amount of impurities, or can be a mixture.

[0171] "Ophthalmic composition" or "ophthalmic preparation" or "ophthalmic formulation" refers to an ophthalmic composition, or an ophthalmic pharmaceutical composition, or an ophthalmic pharmaceutical product; or a drug, preparation, cosmetic, health product, drug-device combination or device for the prevention and / or treatment of eye diseases, vision protection, maintenance, improvement, avoidance, slowing or reversal of vision impairment; or can be eye drops (eye drops), eye ointment, eye spray, implant, eye gel, eye patch, eye microspheres, eye sustained-release preparation, periocular injection, intraocular injection, etc.

[0172] "Fish oil" refers to lipid substances derived from higher animals, especially fish (such as cod, salmon), squid, seals, and in particular to polyunsaturated fatty acids therein, including but not limited to Omega-3 unsaturated fatty acids, DHA, EPA, DPA, ALA, nisinic acid, stearidonic acid, eicosatetraenoic acid or combinations thereof.

[0173] The active ingredients in the formulations or pharmaceutical compositions of the present application are added to water or other suitable solvents deoxygenated to less than 5 ppm with an inert gas, preferably the inert gas is nitrogen, and the preferred deoxygenation level is 2 ppm.

[0174] The administration route of lipoic acid and its related compounds can be eye drops, injection, infusion and oral administration.

[0175] In particular formulations, the ophthalmic formulation formula includes any of the following substances or combinations thereof: cyclodextrin (such as hydroxypropyl beta cyclodextrin), distearoylphosphatidylcholine, soybean phospholipid, octadecylamine, poloxamer 188, sodium chloride, mannitol, mercaptoethanol, tromethamine, sodium sulfite, ethylenediamine, benzyl alcohol, arginine.

[0176] lipoic acid also includes other active ingredients and pharmaceutical excipients in the myopia treatment formulation, such as: reducing agents (glutathione, N-acetyl peptides), glycerol, propylene glycol, ethyl pyruvate, semifluorinated alkanes, amino acids or their derivatives (such as alanine, methionine, cysteine and histidine), sugars or their metabolites (such as glucose-6-phosphate), oxygen scavengers (such as Oxy-Guard TM or StabilOx TM ), vitamins (vitamin B1, vitamin B2, vitamin C, vitamin E).

[0177] In the pharmaceutical composition or formulation containing lipoate choline, the lipoate choline has a counterion, including but not limited to chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (optical isomers or mixtures thereof), succinate, benzoate and glutamate anions; for example all the compositions mentioned in CN109906076A, especially the compositions mentioned in claims 1-9 thereof. In one embodiment, the pharmaceutical composition comprises 0.1-10% of a pharmaceutically acceptable salt of lipoate choline, 1-30% of cyclodextrin, 0.1-2% of a tonicity adjusting agent, 0.1-0.5% of a viscosity enhancer, 0.003-0.010% of a preservative, 0.05% to about 1.0% of a biochemical energy source and water for injection.

[0178] The present application discloses the identification of a compound, i.e. lipoic acid, for the treatment, prevention or slowing of myopia and its associated symptoms, to improve the myopia reduction or myopia slowing effect while avoiding or minimizing adverse side effects, such as those observed with atropine therapy.

[0179] The present application relates to a pharmaceutical composition or method for the treatment, prevention or slowing of myopia and its associated symptoms in an individual, such as a young child, school-aged child, teenager or younger adult. In some examples, the treatment, prevention or slowing of myopia and its associated symptoms can include the use of a therapeutically effective amount of a pharmaceutical composition or dosage form to a subject in need thereof.

[0180] The pharmaceutical composition or formulation comprises a therapeutically effective amount of lipoic acid or lipoate choline compound, or a salt thereof, or a related compound thereof.

[0181] In another aspect, the present application provides an ophthalmic device containing a pharmaceutical composition comprising lipoic acid or a therapeutically acceptable salt or derivative thereof, preferably wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner; preferably wherein the ophthalmic device delivers the pharmaceutical composition in a pulsatile manner.

[0182] We surprisingly found that lipoic acid or lipoic acid choline ester alone can significantly slow down the progression of refractive error in the myopia model of guinea pigs induced by form deprivation or lens, and even completely inhibit (terminate) the progression of refractive error in some individuals, and can significantly inhibit the elongation of the eye axis, based on which, it can be proved that lipoic acid compounds have the effect of preventing or treating, preventing or controlling the progression of myopia in animals, especially in humans, such as young children, school-age children, children and adolescents, minors, people aged 2 to 30 years old, or young adults.

[0183] In some embodiments, the subject to be treated by the technical solution of the present application is a child or an adolescent, aged 2-30 years old, preferably 6-18 years old, or 12-18 years old. In some embodiments, the subject to be treated by the technical solution of the present application is an adult, for example, aged 16-65 years old, preferably 16-26 years old.

[0184] In the local administration experiment, no discomfort or eye abnormalities were observed in all administered animals, and there was no weight loss, food intake reduction, or other toxic effects. Based on the existing clinical application of lipoic acid, one skilled in the art can expect that it will have good drug safety in the clinical treatment process of treating, preventing or improving myopia and its related symptoms.

[0185] The pharmaceutical composition of the present application has a significant technical effect of being superior to atropine in treating, preventing or slowing down myopia and its related symptoms, and no adverse reactions such as eye irritation, pupil dilation, inflammation or allergy were observed in the experiment.

[0186] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the patient is treated for a period of time of between about 1 month and 20 years, such as at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 7 years, or at least 9 years.

[0187] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a topical formulation, such as a topical ophthalmic composition, an eye gel formulation, an ophthalmic emulsion, an ophthalmic liposome, a nanodisc, a nanoparticle suspension, a salve or ointment or balm, such as an ophthalmic ointment (e.g., an eye salve), an oral formulation, such as a tablet or capsule or powder or syrup.

[0188] In other embodiments, the medicament, formulation, composition, device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the medicament, formulation, composition further comprises one or more other ophthalmically useful excipients and additives, including carriers, stabilizers, tonicity modifiers, preservatives, antioxidants, buffers, tonicity agents, thickening agents, or other excipients. In other embodiments, the tonicity modifier is sodium chloride. In other embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, sofradex, polyquatemium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or combinations thereof. In other embodiments, the buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof. In other embodiments, the tonicity agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, glucose, sucrose, urea, propylene glycol, glycerol, or combinations thereof. In other embodiments, the carrier is selected from, but not limited to: water, a mixture of water and a water-miscible solvent, vegetable or mineral oil containing 0.01% to 5% by weight of hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, acrylate, polyacrylamide, pectin, alginate, starch derivatives, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethylether, polyethylene oxide, cross-linked polyacrylic acid, carbapol, lecithin, polyethylene glycol stearate, polyhydroxy alcohol, acidic cosolvent, heptadecaethylene oxycetostearyl alcohol, or polyoxyethylene sorbitol monooleate.

[0189] In other embodiments, the medicament, formulation, composition, device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the medicament, formulation, composition, device, or method of treatment comprises a polyhydroxy alcohol and / or an acidic cosolvent, optionally hydroxypropyl-beta-cyclodextrin and citric acid or tartaric acid.

[0190] In other embodiments, the effect of lipoic acid or lipoic acid choline ester, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compounds or extracts, or its crystal type compound, or combinations of these substances, on the prevention and control (treatment) of myopia or the inhibition of axial length is not related to the gender, age, myopia type, myopia progression speed, and myopia severity of the subject to which the drug is administered.

[0191] In other embodiments, the pharmaceutical composition, ophthalmic device, or method of treatment according to any one of the above embodiments and any one or more of the other embodiments herein, wherein the pharmaceutical composition is a sustained release formulation or a subconjunctival depot; or the pharmaceutical composition is contained within an ophthalmic device, such as an eye patch, suture, contact lens; or the pharmaceutical composition is an ophthalmic composition and / or the ophthalmic composition is contained within an ophthalmic device; or the ophthalmic device is a contact lens, ocular insert, corneal overlay, corneal inlay, nanodisc, liposome, nanoparticle, punctal plug, or hydrogel matrix with microfluidic reservoir; or the ophthalmic device delivers the pharmaceutical composition in a sustained release manner; or the pharmaceutical composition is formulated as an ophthalmic composition for treatment of an ophthalmic disorder or condition; or the pharmaceutical composition is formulated as an ophthalmic composition for treatment of pre-myopia (or at risk of developing myopia), myopia, high myopia, moderate myopia, low myopia, true myopia, pseudo myopia, or progression of myopia; or the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device; or the ophthalmic device is contained within a contact lens blister pack, or wherein the pharmaceutical composition is immersed within the ophthalmic device within a contact lens blister pack.

[0192] Pharmaceutical formulation, mode of administration, and dosage: The cells, organs, or tissues can be contacted with lipoic acid or related compounds thereof using any method known to those of skill in the art. Suitable methods include in vitro methods, indirect in vivo methods, or in vivo methods. In vivo methods generally involve administering a lipoic acid compound of the application or a pharmaceutical composition containing the same to a mammal, preferably a human. When used in vivo for therapy, the lipoic acid compound or pharmaceutical composition containing the same can be administered to a subject in an effective amount, i.e., an amount that has the desired therapeutic effect. The dosage and administration regimen will depend on the extent of the ophthalmic disorder in the subject, the subject, and the subject's history.

[0193] Unlike brand new compounds, lipoic acid (or lipoic acid choline ester) is an old drug that has been used in the clinic for many years. Those skilled in the art can determine the "boundary" of the compound equivalent to lipoic acid (or lipoic acid choline ester) according to the prior art and the description, and have the ability to use the appropriate "its optical isomers or racemates thereof, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound" to achieve the purpose of the present application. For example, in terms of different forms of compounds, the salt formation of compounds is a routine technique in the art, and various salts of compounds are generally considered to have similar functions as the original compound (such as Ye Xuan et al., New Drug Development in Salt Case Analysis, Chinese Journal of New Drugs, 2019, Vol. 28, No. 19, pp. 2332-2335); the optical isomers or racemates thereof, or the crystal type compounds of the compound all have exactly the same molecular structure and composition as the compound, and in the absence of contrary evidence, it is also generally recognized that these compounds all have similar functions. For solvates, the specification exemplarily discloses lipoic acid (or lipoic acid choline ester) dissolved in physiological saline, DMSO, PEG, Tween as a solvent for treating myopia (see Example 1).

[0194] The compounds disclosed herein can also exist as prodrugs. Prodrugs of the compounds described herein are modified forms of the lipoic acid or its related compounds that are readily convertible in vivo into the lipoic acid under physiological conditions. In addition, prodrugs can be converted to the compound in an ex vivo environment using chemical or biochemical methods. For example, a prodrug can be slowly converted into the compound when placed in a transdermal patch reservoir with the appropriate enzymes or chemical reagents. Prodrugs are often useful because, in some situations, they can be easier to administer than the compound or parent drug. For example, they can be bioavailable by oral administration whereas the parent drug is not. The solubility of a prodrug in a pharmaceutical composition can also be enhanced compared to the parent drug. Many prodrug derivatives are known in the art, such as prodrug derivatives that rely on hydrolytic cleavage or oxidative activation for conversion to the parent drug. One non-limiting example of a prodrug is a compound that is administered as an ester (the "prodrug") but then metabolically hydrolyzes to the carboxylic acid (the active entity). For example, lipoic acid choline ester chloride is a prodrug of lipoic acid, chloride is a salt form, and choline ester can help the compound penetrate the cornea, and when lipoic acid choline ester chloride enters the cornea or after entering the cornea, lipoic acid choline ester chloride is hydrolyzed into choline and lipoic acid.

[0195] The compounds disclosed herein can exist as therapeutically acceptable salts. The application includes the compounds listed above in salt form, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are typically pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts can be of utility in the preparation and purification of the subject compounds. Base addition salts can also be formed, and are pharmaceutically acceptable.

[0196] As used herein, the term "therapeutically acceptable salt" means a salt or zwitterion form of the compounds disclosed herein that is water or oil-soluble or dispersible, and that is therapeutically acceptable, as defined herein. Salts can be prepared during the final isolation and purification of the compounds, or separately, by reacting the appropriate form of the compound with the appropriate acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisinate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, citrate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, the basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be employed to form therapeutically acceptable addition salts include inorganic acids (such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids) and organic acids (such as oxalic, maleic, succinic, and citric acids). Salts can also be formed by coordination of the compounds with alkali metals or alkaline earth metal ions. Thus, the application includes sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, among others.

[0197] The crystalline forms of lipoic acid include all the kinds known to man, such as the crystalline forms described by Samuel Golob in the literature (Samuel Golob, Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization, J Pharm Sci. 2016 Dec; 105(12): 3626-3633.).

[0198] Alkali addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with a suitable base such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salts of the cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines suitable for the formation of base addition salts include ethanolamine, diethanolamine, piperidine, and piperazine.

[0199] While it is possible that, for use in the application, a compound can be administered in the form of a crude chemical, it is also possible for them to be provided as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations comprising one or more certain compounds disclosed herein or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) is / are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient thereof. Proper formulation is dependent on the chosen route of administration. Any of the well-known techniques, carriers, and excipients can be used; see, e.g., Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be produced in any of the manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes; it can also be produced as a pharmaceutical brad.

[0200] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, ocular, intranasal, and intraaural) administration, the most suitable being dependent on the condition and disorder of the recipient. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. In general, such methods include the step of bringing into association the compound of the present application or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0201] Formulations of the compounds disclosed herein suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient can also be presented as a bolus, electuary or paste.

[0202] Pharmaceutical formulations that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a free-flowing form, such as a powder or granules, a mixture of the active ingredient with a binder, inert diluent, or lubricating, surface- active, or dispersing agent. Molding tablets can be made by molding in a mould a mixture of the powdered compound moistened with a liquid diluent. Tablets can optionally be coated or scored and can be formulated so as to provide a sustained, delayed, or controlled release of the active ingredient therein. The dosages of all formulations for oral administration should be adapted to the purpose of the prophylactic, therapeutic treatment to be reached. Push-fit capsules can contain the active ingredient in combination with filler (such as lactose), binder (such as starch), and / or lubricant (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active- compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, or liquid polyethylene glycol). In addition, stabilizers can be added. There are provided dragee cores. To this end, concentrated sugar solutions can be used which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carboxy- polymethylene gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound dosages.

[0203] Examples of fillers or diluents for oral pharmaceutical preparations, such as capsules and tablets, include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, com starch, pregelatinized starch, dextrates, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer (such as polyethylene oxide), methylcellulose, and hydroxypropyl methylcellulose. The filler can have complexed solvent molecules, such as where the lactose used is lactose monohydrate.

[0204] Examples of disintegrants for oral pharmaceutical preparations, such as capsules and tablets, include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crosscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0205] Additionally, glidants and lubricants can be used in oral pharmaceutical preparations to ensure uniform blending of excipients upon mixing. Examples of lubricants include, but are not limited to, calcium stearate, glycerol monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Examples of glidants include, but are not limited to, silicon dioxide (Si02), talc, com starch, and poloxamer. Poloxamer (or Pluronic® available from BASF Corporation) is an A-B-A block copolymer, where the A segment is a hydrophilic polyethylene glycol homopolymer and the B segment is a hydrophobic polypropylene glycol homopolymer.

[0206] Examples of tablet binders include, but are not limited to, acacia, alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copolyvidone, methyl cellulose, liquid glucose, maltodextrin, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.

[0207] The compound can be formulated for parenteral administration by injection, such as via bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage forms, for example, in ampoules or multi-dose containers with added preservatives. The composition may be in the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The formulation may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a lyophilized (freeze-dried) state, requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile pyrogen-free water, just before use. Ready-to-use injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types previously described. In a preferred embodiment, the pharmaceutical composition of this application is in the form of an injection, particularly a syringe. Preferably, the pharmaceutical composition is administered via intraocular injection, more preferably via intravitreal injection.

[0208] Formulations intended for parenteral administration include, but are not limited to: aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as methylcellulose, sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high-concentration solutions.

[0209] In addition to the aforementioned formulations, compounds such as thioctic acid mentioned in this patent can also be formulated into storage formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Therefore, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or formulated as slightly soluble derivatives, such as slightly soluble salts.

[0210] For oral or sublingual application, the composition may be in the form of tablets, lozenges, tablets, or gels formulated in a conventional manner. Such compositions may contain active ingredients, such as compounds like thioctic acid mentioned in this patent, within a flavored matrix (e.g., sucrose and gum arabic or tragacanth).

[0211] The compound can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter, polyethylene glycol or other glycerides.

[0212] In addition to the aforementioned formulations, the lipoic acid and other compounds mentioned in the present patent can be formulated into single-use formulations, devices, eye appearance-altering products, or medical consumables for topical application, such as single-use eye drops (containing only one therapeutically effective dose per package), individually packaged eye patches, contact lenses, and daily disposable contact lenses.

[0213] The lipoic acid and other compounds mentioned in the present disclosure can be applied topically, i.e., by non-systemic application. This includes applying the compounds disclosed herein to the exterior of the eye, skin, or oral cavity, and instilling such compounds into the ear, eye, and nose, such that the compound does not appreciably enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0214] Formulations suitable for topical application include liquid or semisolid formulations (such as gels, liniments, lotions, creams, ointments, or pastes) suitable for penetrating the skin to reach the site of action and formulations suitable for application to the eye, ear, or nose, such as drops, sprays. The active ingredient for myopia treatment can account for, for example, 0.0000001% to 99% w / w (by weight) of the total content of the formulation. In certain embodiments, the active ingredient can account for up to 50% w / w or more. In other embodiments, it can account for less than 1% w / w. In certain embodiments, the active ingredient can account for 0.01% w / w to 1% w / w. In other embodiments, it can account for 0.00001% to 0.001% w / w of the formulation. Alternatively, the active ingredient for topical application can account for, for example, 0.0000001% to 100% w / v (by weight to volume) of the formulation. Alternatively, in certain embodiments, the active ingredient can account for up to 50% w / v or more. In other embodiments, it can account for less than 1% w / v. In certain embodiments, the active ingredient can account for 0.01% w / v to 1% w / v. In other embodiments, it can account for 0.00001% to 0.001% w / v of the formulation.

[0215] The gel formulation form includes a formulation in which lipoic acid or its prodrug or its related compound is connected with a hydrogel, preferably the hydrogel connected with lipoic acid or its prodrug is a biodegradable hydrogel.

[0216] The hydrogel comprises, preferably consists of, at least one polymer, preferably selected from the group consisting of poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxypropylmethacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(imino carbonate), poly(N-isopropylacrylamide), poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(propylene fumarate), poly(organophosphocyan), poly(ortho ester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinyl amine), poly(vinyl methyl ether), poly(vinylpyrrolidone), a siloxane, a ribonucleic acid, a deoxyribonucleic acid, an albumin, an antibody and fragments thereof, a plasma protein, a collagen, an elastin, a fascin, a fibulin, a keratin, a polyaspartic acid, a polyglutamic acid, a prolamin, a transferrin, a cytochrome, a flavoprotein, a glycoprotein, a hemoprotein, a lipoprotein, a metalloprotein, a plant photosensory, a phosphoprotein, a visual protein, an agar, an agarose, an alginate, an arabinan, an arabinogalactan, a carrageenan, a cellulose, a carbomethyl cellulose, a hydroxypropyl methyl cellulose, and other carbohydrate-based polymers, a chitosan, a dextran, a dextrin, a gelatin, a hyaluronic acid and derivatives thereof, a mannan, a pectin, a rhamnogalacturonan, a starch, a hydroxyalkyl starch, a xylan, and copolymers and functionalized derivatives thereof.

[0217] Preferably, the hydrogel is a biodegradable polyethylene glycol (PEG)-based hydrogel.

[0218] Preferably, the polyethylene glycol (PEG) is a single molecular weight or a group of different molecular weights mixed in a certain ratio.

[0219] The hydrogel is in the shape of a shaped article, preferably in the shape of microparticles. More preferably, the hydrogel is in the shape of microparticle beads. Even more preferably, the microparticle beads have a diameter of 1-1000 μm, more preferably 5-500 μm, more preferably 10-100 μm, even more preferably 20-80 μm. The bead diameter is measured when the microparticle beads are suspended in an isotonic aqueous buffer. In a preferred embodiment, the hydrogel-linked lipoic acid or prodrug thereof is in the shape of a bead. More preferably, the hydrogel-linked lipoic acid or prodrug thereof is in the shape of a microparticle bead. Even more preferably, the microparticle beads have a diameter of 1-1000 μm, more preferably 5-500 μm, more preferably 10-100 μm, even more preferably 20-80 μm. The bead diameter is measured when the microparticle beads are suspended in an isotonic aqueous buffer. Such hydrogels can be polymerized in different ways, for example by free radical polymerization, ionic polymerization or complex formation reactions.

[0220] If the hydrogel is processed by free radical polymerization or ionic polymerization, at least two starting materials are a crosslinking macromonomer or crosslinking monomer (which is referred to as a crosslinker reagent) and a multifunctional macromonomer (which is referred to as a backbone reagent). The crosslinker reagent carries at least two functional groups that can be linked to each other, and the backbone reagent carries at least one functional group that can be linked to each other and at least one chemical functional group that is not used to participate in the polymerization step. Additional diluent monomers can or can not be present. Useful functional groups that can be linked to each other include, but are not limited to, free radically polymerizable groups such as vinyl, vinyl-phenyl, acrylate, acrylamide, methacrylate, methacrylamide, and ionically polymerizable groups such as oxetane, azetidine and oxirane. In an alternative method of preparation, the hydrogel is generated by a chemical complex formation reaction. In such reactions, the starting materials are at least one macromolecular starting material that has complementary functionality to perform a reaction such as a condensation or addition reaction. In one embodiment, only one macromolecular starting material is used, which is a heteromultifunctional backbone reagent, containing a number of polymerizable functional groups that can be the same or different.

[0221] In addition to the active ingredients, such as lipoic acid, the topical ocular, otic, and nasal formulations of the present application can also include excipients. Excipients commonly used in such formulations include, but are not limited to, isotonic agents, preservatives, chelating agents, buffering agents, and surfactants. Other excipients include solubilizing agents, stabilizing agents, comfort enhancers, polymers, demulcents, pH adjusting agents, and / or lubricants. Any of a variety of excipients can be used in the formulations of the present application, including water, mixtures of water and water-miscible solvents (such as C1-C7 alkanols), vegetable or mineral oils containing 0.5% to 5% of a non-toxic water-soluble polymer, natural products (such as alginic acid, pectin, tragacanth gum, gum karaya, guar gum, xanthan gum, carrageenan, agar, and gum arabic), starch derivatives (such as starch acetate and hydroxypropyl starch), and other synthetic products (such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, and mixtures of these products). The concentration of excipients is typically 1 to 100,000 times the concentration of the active ingredients. In preferred embodiments, excipients to be included in the formulations are generally selected for their inertness to the active ingredient composition of the formulation.

[0222] With respect to ocular, otic, and nasal formulations, suitable isotonicity adjusting agents include, but are not limited to, mannitol, dextrose, sodium chloride, glycerin, sorbitol, and the like. Suitable buffering agents include, but are not limited to, phosphates, citrates, borates, acetates, and the like. Suitable surfactants include, but are not limited to, ionic and non-ionic surfactants (although non-ionic surfactants are preferred), polysorbate 80, RLM 100, POE 20 cetylstearyl alcohol ethers (such as CS20), and poloxamers (such as F68). The formulations can contain substances that increase the viscosity of the solution or suspension, such as sodium carboxymethylcellulose, hypromellose, microcrystalline cellulose, sorbitol, or dextran. Optionally, the formulations can also contain suitable stabilizing agents or agents that increase the solubility of the compounds to enable the preparation of solutions of high concentration, including, but not limited to, ethanol, benzyl alcohol, polyethylene glycol, phenethyl alcohol, and glycerin.

[0223] The formulations presented herein can include one or more preservatives. Examples of such preservatives include benzalkonium chloride, parabens, sodium perborate, sodium chlorite, alcohols (such as chlorobutanol, benzyl alcohol, or phenethyl alcohol), guanidine derivatives (such as polyhexamethylene biguanide), sodium perborate, polyquatemium-1, amino alcohols (such as AMP-95), or sorbic acid. In certain embodiments, the formulation itself can be preservative, such that no preservative is needed. In certain embodiments, the formulation itself, although not preservative, can be packaged in a material or designed in a way that avoids drug deterioration (such as changes in physicochemical properties and / or biological effects), such that no preservative is needed.

[0224] For ocular, otic or nasal administration, the formulation can be a solution, suspension or gel. In a preferred aspect, the formulation for topical administration to the eye or ear in an aqueous solution or suspension is in the form of drops. The formulation for topical administration to the nose in an aqueous solution or suspension is in the form of drops, spray or aerosol. The term "aqueous" generally denotes an aqueous formulation in which the formulation contains >20%, >50%, more preferably >75% and in particular >90% water by weight. These drops can be delivered from single-dose eye drop bottles, which can preferably be sterile, thus enabling the formulation to be free of bacteriostatic components. Alternatively, the drops can be delivered from multi-dose eye drop bottles, which can preferably include a device to withdraw any preservative therefrom upon delivery of the formulation, such devices being known in the art. Solution and suspension formulations can be administered nasally using a nebulizer. Intranasal delivery of solutions, suspensions or dry powders can also be facilitated by propellant-based aerosol systems, including but not limited to hydrofluoroalkane-based propellants, or the active pharmaceutical ingredient can be delivered in the form of a dry powder.

[0225] For ocular disorders, the components of the present application can be delivered to the eye as a concentrated gel or similar vehicle or as a dissolvable insert placed under the eyelid.

[0226] In particular embodiments, the formulations of the present application are administered once daily. However, the formulations can also be formulated for administration at any frequency of administration, including once weekly, once every 5 days, once every 3 days, once every 2 days, twice daily, three times daily, four times daily, five times daily, six times daily, eight times daily, hourly, or at any higher frequency. Such frequency of administration is also maintained for varying durations depending on the treatment regimen. The duration of a particular treatment regimen can vary from a single administration to a regimen extending over months or years. The formulations are administered at varying dosages, but typical dosages are one to two drops per administration, or equivalent amounts of gel or other formulations (e.g., tablets, ointments) for the eye. One of ordinary skill in the art is familiar with how to determine a treatment regimen for a particular indication.

[0227] Gels for topical or transdermal administration can generally comprise a mixture of a volatile solvent, a non-volatile solvent, and water. In certain embodiments, the volatile solvent component of the buffered solvent system can include lower (C1-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The non-volatile solvent retards the evaporation of the volatile solvent and lowers the vapor pressure of the buffered solvent system. The amount of this non-volatile solvent component, as with the volatile solvent, is determined by the drug compound or drug being used. When there is too little non-volatile solvent in the system, the drug compound can crystallize due to evaporation of the volatile solvent, while too much can result in a lack of bioavailability due to poor release of the drug from the solvent mixture. The buffer component of the buffered solvent system can be selected from any of the commonly used buffers in the art; in certain embodiments, water is used. A common ingredient ratio is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. Several optional ingredients can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents can include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, galactomannan polymers (such as guar gum and its derivatives), and cosmetic agents.

[0228] Lotions include lotions suitable for application to the skin or the eye. Ophthalmic lotions can comprise sterile aqueous solutions optionally containing a bactericidal agent, and can be prepared in a manner similar to that for the preparation of drops. Lotions or liniments for application to the skin can also include agents to speed drying and cool the skin (such as alcohol or acetone) and / or moisturizers (such as glycerin) or oils (such as castor or peanut oil).

[0229] The pharmaceutical compositions of the present application can be creams, ointments (e.g., 3% ointment, soft paste) or pastes, which are semisolid preparations of the active ingredient for external application. They can be prepared by mixing the active ingredient in finely divided or powdered form, either alone or in solution or suspension in an aqueous or non-aqueous fluid, with an oleaginous or non-oleaginous base by means of suitable machinery. The base can include hydrocarbons such as petrolatum, hard, soft or liquid paraffin, glycerol, beeswax, metallic soaps; mucilages; oils of natural origin such as fish, apricot kernel, corn, groundnut, castor or olive oil; lanolin or derivatives thereof or fatty acids such as stearic or oleic acid together with an alcohol such as propylene glycol or macrocristalline glycol or lanosterol or dihydrolanosterol. The preparation can incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surface active agent such as sorbitan ester or its polyoxyethylene derivatives. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silica can also be included, as well as other ingredients such as lanolin, lanosterol.

[0230] Drops or sprays can comprise sterile aqueous or oily solutions or suspensions, and can be prepared by dissolving the active ingredient in the required amount of the appropriate solvent or solvent mixture, and if desired, adding a suitable bactericide and / or fungicide and / or any other appropriate preservative, and in certain embodiments, a surface active agent. The resulting solution can then be clarified by filtration, transferred to a suitable container and sealed, and sterilized by heat or by filtration. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of bactericides and fungicides which can be included in the drops are the azoles (e.g., econazole), phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohol and propylene glycol.

[0231] Formulations for topical application to the mouth (e.g., buccal cavity or sublingually) include lozenges comprising the active ingredient in a flavored base, such as sucrose and acacia or traganth, and pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0232] For administration by inhalation, the compounds mentioned in the present patent, such as lipoic acid, can be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering aerosol sprays. Pressurized packs can comprise a suitable propellant such as hydrofluorocarbon, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the application can take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs, from which the powder can be administered with the aid of an inhalator or insufflator.

[0233] A preferred unit dosage formulation is one which contains an effective dose, or an appropriate fraction thereof, of the active ingredient, as described herein.

[0234] It will be appreciated that, in addition to the ingredients particularly mentioned above, the formulations described above can include other agents conventional in the art, having regard to the type of formulation in question, for example, preservatives, flavoring agents, coloring agents, and the like.

[0235] The compounds can be administered orally or via injection at a dose of 0.001 to 200 mg / kg per day. The dose range for adults and the elderly is generally 5 mg to 1200 mg per day, with children or adolescents receiving a reduced or constant amount. Tablets or other presentations provided in discrete units can conveniently contain an amount of one or more compounds which is effective at such dosage or multiples of the dose, for example, 200 mg to 1200 mg, usually around 300 mg to 600 mg, preferably 400 mg.

[0236] The compounds mentioned in the present patent, such as lipoic acid, can be administered in various ways, for example, orally, topically, or by injection, either systemically or locally, or both systemically and locally, simultaneously or alternately. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition undergoing treatment. In addition, the route of administration can vary depending on the condition and its severity.

[0237] In certain instances, it can be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester or prodrug thereof) in combination with another therapeutic agent. As an example only, if one of the side effects experienced by a patient receiving one of the compounds described herein is hypotension, it can be appropriate to administer an anti-hypotensive drug in combination with the initial therapeutic agent. Or as an example only, the efficacy of one of the compounds described herein can be enhanced by administration of an anti-allergic drug (i.e., the anti-allergic drug can have only minimal therapeutic benefit by itself, but in combination with the therapeutic agent referred to herein, the overall therapeutic benefit to the patient is enhanced). Or as an example only, the benefit experienced by a patient can be enhanced by administration of one of the compounds described herein in combination with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. As an example only, in a myopia treatment involving administration of one of the compounds described herein, the therapeutic benefit can be enhanced by also providing the patient with another myopia treatment agent. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient can simply be additive of the two therapeutic agents, or the patient can experience a synergistic benefit.

[0238] The pharmaceutical composition, either in liquid or dry form, can be provided in the form of a single dose or a multiple dose pharmaceutical composition.

[0239] In one embodiment of the application, the liquid or dry pharmaceutical composition is provided in a single dose, which means that the container in which it is provided contains one pharmaceutical dose. Alternatively, the liquid or dry pharmaceutical composition is a multiple dose pharmaceutical composition, which means that the container in which it is provided contains more than one therapeutic dose, i.e., the multiple dose composition contains at least 2 doses. Such multiple dose compositions can be used for different patients as needed, or can be used for one patient, with the remaining doses being stored for later use after the first dose is applied.

[0240] In another aspect of the application, the pharmaceutical composition is in a container. Containers for liquid or dry pharmaceutical compositions are, for example, eye drop bottles, syringes, vials, vials with stoppers and seals, ampoules and cartridges. In particular, the liquid or dry pharmaceutical composition is provided in a syringe. If the pharmaceutical composition is a dry pharmaceutical composition, the container is preferably a dual chamber syringe. In this embodiment, the dry pharmaceutical composition is provided in the first chamber of the dual chamber syringe and the reconstitution solution is provided in the second chamber of the dual chamber syringe.

[0241] The dry composition is reconstituted prior to application to a patient in need thereof. Reconstitution can be performed in the container in which the dry composition is provided, for example, in an eye drop bottle, a syringe, a dual chamber syringe, an ampoule, and a cartridge. Reconstitution is performed by adding a predetermined amount of a reconstitution solution to the dry composition. The reconstitution solution is a sterile liquid such as water or a buffer, which can contain other additives such as preservatives and / or antimicrobial agents such as benzyl alcohol and cresol. Preferably, the reconstitution solution is sterile water. When the dry composition is reconstituted, it is referred to as a "reconstituted pharmaceutical composition" or a "reconstituted pharmaceutical composition" or a "reconstituted composition".

[0242] Ophthalmic formulations: The pharmaceutical compositions of the present application can be administered in the form of ophthalmic formulations, the ophthalmic formulations of the present application comprising an ophthalmically acceptable carrier.

[0243] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical composition will contain from about 0.1 to about 500 milligrams of active ingredient.

[0244] As used herein, an "ophthalmically acceptable carrier" is an ophthalmically acceptable solvent, suspending agent, or vehicle for a pharmaceutical composition to the eye of a subject. The carrier can be solid or liquid. The carrier is "ophthalmically acceptable" in the sense that the carrier is suitable for application to the eye without causing any major adverse reaction.

[0245] Typically, the ophthalmically acceptable carrier is or includes water. Typically, the ophthalmic formulation is in the form of an eye drop or a gel for application to the eye. Typically, the majority of the formulation is water. Typically, the formulation includes greater than 50% by weight (such as greater than 60%, 65%, 70%, 75%, 80%, 85%, or 90%) water, more typically greater than 95% by weight (such as 96%, 97%, 98%, or 99%) water.

[0246] In some embodiments, the ophthalmically acceptable carrier is an oil-in-water emulsion or an oil. In such embodiments, the ophthalmic formulation can be in the form of a cream for application to the eye. In such embodiments, the formulation can include greater than 10% by weight, more typically greater than 20% by weight, of an oily ingredient.

[0247] In other embodiments, the carrier can be a biodegradable polymer, such as a biodegradable polymer ocular implant for slow release of the compounds of the application and optionally other compounds. For example, a biodegradable, biocompatible polymer matrix. In one embodiment, the compound can be embedded in the polymer matrix while maintaining structural integrity. The polymer can be natural, such as a polypeptide, protein, or polysaccharide; or it can be synthetic, such as a poly-alpha-hydroxy acid. Examples include carriers made from, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, methyl cellulose, polysaccharides, fibrin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or polyglycolic acid copolymer (PGLA). Polymer matrices can be prepared and isolated in various forms and sizes, including microspheres and nanospheres.

[0248] In some embodiments, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound from rapid elimination from the body, such as a controlled release agent, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. These can be made using known techniques.

[0249] Excipients: Excipients suitable for use in the ophthalmic formulations of the application include, for example, demulcents, emollients, tonicity enhancing agents, preservatives, buffers or pH adjusting agents. Examples of suitable excipients include:

[0250] A. Demulcents: synthetic high molecular weight cross-linked acrylic acid polymers (such as carbomer 974 and carbomer 980); cellulose derivatives (such as hydroxypropyl methylcellulose ("HPMC" or "hypromellose"), hydroxyethylcellulose, methylcellulose, carboxymethylcellulose (carboxymethyl cellulose)) or sodium carboxymethylcellulose (sodium carboxymethyl cellulose)); dextrans (such as dextran 70); gelatin; polyols (such as glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, and propylene glycol); polyvinyl alcohol; povidone (polyvinylpyrrolidone); poloxamers; and hyaluronic acid (a disaccharide polymer) or its sodium or potassium salt.

[0251] B. Emollients: lanolin (such as anhydrous lanolin); oily ingredients (such as light mineral oil, mineral oil, paraffin, petrolatum, liquid paraffin, white ointment, white petrolatum, white wax, and yellow wax); and fish oil, castor oil.

[0252] C. Preservatives: benzalkonium chloride; sodium perborate; Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%); polyquaternium-1 (polymer of ethanol, 2,2',2"- nitrilotri- and 1,4-dichloro-2-butene and N,N,N',N'-tetramethyl-2-butene-1,4- diamine); silver sodium chloride; hexamethylene biguanide; oxydronate; and (sodium chlorite 0.005% m / v).

[0253] D. Ocular hypertonic agents: sodium chloride.

[0254] E. The ocular formulations of the present application can also contain a preservative that inhibits microbial growth and extends the shelf life of the formulation. Preservatives that can be used in the ocular formulations of the present application include, for example, benzalkonium chloride, sodium perborate, Oxyd (sodium chlorite 0.05%, hydrogen peroxide 0.01%), polyquaternium-1 (polymer of ethanol, 2,2',2"-nitrilotri- and 1,4-dichloro-2-butene and N,N,N',N'-tetramethyl-2-butene-1,4-diamine), silver sodium chloride, hexamethylene biguanide, oxydronate. Sodium chlorite (.005% m / v) is a broad-spectrum microbicide with antimicrobial activity and very low toxicity to mammalian cells, which protects the formulation during storage but ultimately dissociates into water, sodium ions, chloride ions, and oxygen after exposure to light. Because they are also found in natural tears, preservatives minimize the risk of ocular irritation and corneal damage induced by preservatives. Long term, sodium chlorite is safe and effective to use. This preservative has no side effects on epithelial cells in vitro or in vivo and is less disruptive to cell integrity than many other preservatives in use.

[0255] The ocular formulations of the present application can be prepared by any suitable method of preparing an ocular formulation. The ocular formulations are generally sterile, and thus the method can include a step of sterilizing the ocular formulation. Preferably, the ocular formulation is clear and has a reflectivity similar to that of tears, a suitable pH (typically buffered to about pH 7.5) to avoid severe corneal irritation and to prevent microorganisms. The formulations of the present application suitable for topical administration to the eye are preferably isotonic or slightly hypotonic so as to counteract any hyperosmolarity of the tears caused by evaporation and / or disease. This can require a tonicity agent to bring the osmolality of the formulation to or near the level of 210-320 milliosmoles per kilogram (mOsm / kg). The formulations of the present application generally have an osmolality in the range of 220-320 mOsm / kg, preferably in the range of 235-300 mOsm / kg. Surface tension values close to or below the surface tension values observed for the tear film are generally preferred. The ocular formulations are generally formulated as sterile aqueous solutions.

[0256] In certain ophthalmic embodiments, the compositions of the present application are formulated with one or more tear substitutes. Various tear substitutes are known in the art, including but not limited to: monomeric polyols such as glycerin, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl cellulose; dextran such as dextran 70; vinyl polymers such as polyvinyl alcohol; and carbomers such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P. The formulations or pharmaceutical compositions of the present application can be used with contact lenses, corneal contact lenses, or other ophthalmic products such as eyeglasses, orthokeratology devices.

[0257] The preferred formulations are prepared using a buffer system that maintains the pH of the formulation between about 4.5 and about 8. The most preferred formulations have a pH between 5.5 and 7.5. Alternative buffers are physiologically tolerated buffers that maintain the pH in the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate. Antacids such as Mg(OH)2or ZnCO3may also be used. The buffer capacity can be adjusted to match the conditions most sensitive to pH stability.

[0258] The ophthalmic formulations of the present application can also contain a cooling agent such as menthol, camphor, borneol, geraniol, eucalyptol, linalool, and the like. When a cooling agent is used, the concentration of the cooling agent is preferably between 0.0001 and 0.1 W / V %.

[0259] The ophthalmic formulations of the present application can also contain other ophthalmically common therapeutic ingredients such as decongestants (e.g., epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylphenidate hydrochloride, and the like), anti-inflammatory / constrictors (e.g., neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, berberine hydrochloride, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride, and the like), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate, and the like), water soluble vitamins (flavine mononucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, and the like), amino acids (e.g., L-aspartic acid potassium, L-aspartic acid magnesium, L-aspartic acid potassium-magnesium (equal mixture), aminomethyl benzoic acid, and the like), ingredients to relieve asthenopia and / or dryness of the eyes (e.g., taurine, vitamin A, hydroxypropyl methylcellulose, and vitamins E), polyunsaturated fatty acids (e.g., fish oil, omega-3 unsaturated fatty acids, DHA, EPA), piracetam, sulfonamides, niacin, tretinoin, and lutein, rhodiosin, formononetin, atropine, dibazol, M receptor blockers (e.g., blockers or antagonists or inhibitors of Ml receptors), and the like.

[0260] The content of active substances in the pharmaceutical composition of this application: When the drugs are mixed, the concentration of the therapeutically active compound can be selected according to the effective and suitable amount of each substance. Considering the irritation to the eyes, the stability of the formulation, etc., the therapeutically active compound (such as thioctic acid) in the pharmaceutical composition can be present in high, medium or low concentrations, for example, accounting for about 0.0000001-100%, about 0.00001-10%, about 0.001-20%, about 0.1-30%, about 1-40%, about 10-50%, or about 20-60% of the total amount of the pharmaceutical composition. About 30-70%, about 40-80%, about 50-90% (W / V), for example about 1 μM, about 0.1 μM, about 0.01 μM, about 5 μM, about 10 μM, about 15 μM, about 25 μM, about 50 μM, and / or at least as much as: about 0.0000001%, about 0.000001%, about 0.0001%, about 0.001%, about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 1%, or about 10% (W / V) of the total pharmaceutical composition.

[0261] Delivery of ophthalmic preparations: The ophthalmic preparations of this application may be delivered to the patient in the form of eye drops (in the form of single-dose or multi-dose droppers), ointments, gels, creams, or biodegradable polymeric ophthalmic implants (designed for sustained release) or by ophthalmic humidification (such as multi-dose sprays).

[0262] Packaging for ophthalmic preparations should be relevant to the retention or non-retention properties of the solution. Packaging methods such as molding-fill-encapsulation techniques, which integrate blow molding, aseptic filling, and sealing into a single process, are particularly suitable for packaging preservative-free preparations in single-dose containers. Typically, these single-dose containers are made of low-density polyethylene or polypropylene and include a screw-on cap.

[0263] The formulations and methods of this application have been used in any subject who may benefit from the formulations and methods of this application. Subjects are typically mammals, and more typically humans. However, this application is not limited to treating humans and may be applicable for veterinary use. Therefore, according to this application, the terms "subject," "patient," or "subject in need" include humans as well as non-human animals, such as farm animals like sheep, pigs, cattle, and horses; pet animals like dogs and cats; and laboratory animals like mice, rats, and rabbits. In a preferred embodiment, the mammal is a human.

[0264] In another aspect, lipoic acid or lipoic acid choline 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 form thereof, or a combination of these, is used for the treatment of myopia and its associated symptoms, or myopia correction, or delaying the progression of myopia, primarily by inhibiting the elongation of the eye axis, the increase in vitreous cavity depth and / or inhibiting the decrease in choroidal thickness in individuals with myopia or with a predisposition to develop myopia.

[0265] In another aspect, the present application provides an ophthalmic device comprising a pharmaceutical composition comprising lipoic acid or lipoic acid choline ester, or a therapeutically acceptable salt thereof or a derivative thereof or a combination thereof, preferably wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.

[0266] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition, e.g., as an ophthalmic composition for the treatment of an ophthalmic disorder or condition.

[0267] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device.

[0268] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition is administered to the eye of the patient; or the pharmaceutical composition is administered topically; or the pharmaceutical composition is administered to the eye in the form of an eye drop formulation, an eye spray formulation, or an eye gel formulation; or the pharmaceutical composition is administered to the eye in the form of an ophthalmic emulsion, an ophthalmic liposome, a nanodisc, a nanoparticle suspension, or an ophthalmic ointment; the pharmaceutical composition is administered ophthalmically to the eye of the patient.

[0269] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition is administered 1, 2, 3, 4, or 5 times per day.

[0270] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic formulation or an aqueous composition, such as an ophthalmic aqueous formulation, such as in the form of an eye drop. For example, the ophthalmic aqueous formulation as described herein can be packaged in an eye drop bottle and administered as a drop. In certain embodiments, the ophthalmic aqueous formulation can be administered as a single administration (i.e., a single dose), which can include one drop, two drops, three drops, or more drops instilled into the eye of the patient. In certain embodiments, one dose of the ophthalmic aqueous formulation described herein is one drop of the aqueous composition from the eye drop bottle.

[0271] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic gel formulation. For example, the ophthalmic gel formulation can be packaged in an eye dropper bottle and administered as drops. In certain embodiments, the ophthalmic gel formulation can be administered as a single administration (i.e., a single dose) which can include one drop, two drops, three drops, or more drops instilled into the eye of the patient. In certain embodiments, one dose of the ophthalmic gel described herein is one drop of the gel composition from the eye dropper bottle.

[0272] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic ointment formulation. For example, the ophthalmic ointment formulation can be packaged within a tube or other squeezable container having a dispensing nozzle through which an ointment strip is delivered. In certain embodiments, the ophthalmic ointment formulation can be administered as a single administration (i.e., a single dose) which can include one or more strips into the eye of the patient. In certain embodiments, one dose of the ophthalmic ointment is one strip of the ointment composition dispensed through the dispensing nozzle.

[0273] Treatment of a subject with a therapeutically effective amount of a therapeutic composition or formulation described herein can include a single treatment or a series of treatments.

[0274] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the method prevents, controls, or reduces, slows, or decreases myopia progression in the treated patient.

[0275] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the method controls, slows, decreases, delays, and / or reduces myopia progression in the treated patient in the range of about 5-95%, about 5-90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about 40-90%, about 50-90%, or about 75-90% relative to an untreated patient.

[0276] In certain embodiments of the pharmaceutical composition, formulation, ophthalmic device, or method of treatment disclosed herein, the use of the pharmaceutical composition, formulation, ophthalmic device, or method of treatment limits the magnitude of the change in refractive error of the eye of the subject being administered to about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D, and less than 1.0D.

[0277] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or treatment methods disclosed herein, the methods reverse myopia progression in the treated patient.

[0278] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or treatment methods disclosed herein, the methods prevent, control, slow, reduce, lessen, delay, and / or reverse axial (or longitudinal) growth of the eye, i.e., elongation of the ocular axis and / or increase in vitreous chamber length, of the treated patient.

[0279] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or treatment methods disclosed herein, the pharmaceutical compositions, ophthalmic devices, or treatment methods control, slow, lessen, reduce, delay, and / or reverse elongation of the ocular axis and / or increase in vitreous chamber length of the treated patient (e.g., a mild myope, a child or a young adult myope) by an amount relative to the untreated that is between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90%.

[0280] In certain embodiments of the pharmaceutical, formulation, composition, ophthalmic device, or treatment method disclosed herein, the methods control, halt, slow, reduce, delay, and / or lessen myopia onset, progression, increase choroidal thickness, and / or reduce axial (or longitudinal) growth rate, i.e., elongation of the ocular axis and / or increase in vitreous chamber length, of the eye (e.g., a myopic eye, a pre-myopic eye, or an eye at risk of developing myopia) of a patient diagnosed with myopia or at risk of developing myopia.

[0281] In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or treatment methods disclosed herein, the methods control, slow, reduce, delay, and / or lessen axial (or longitudinal) growth of the eye of the treated patient by an amount relative to the untreated that is between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90%.

[0282] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition, ophthalmic device, or method of treatment prevents, controls, slows, reduces, mitigates, alters, delays, and / or reverses myopia diopter in the eye of the treated patient.

[0283] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition, ophthalmic device, or method of treatment results in less severe adverse reactions relative to atropine monotherapy.

[0284] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition, ophthalmic device, or method of treatment produces less increase in pupil size or no effect on pupil size relative to atropine monotherapy.

[0285] In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the pharmaceutical composition, ophthalmic device, or method of treatment inhibits the degree of progression of the normal eye’s ocular axis or refractive diopter to myopia relative to atropine monotherapy.

[0286] Example 1, Preparation of the main formulation or pharmaceutical composition

[0287] Form-deprivation and lens-induced myopia in guinea pigs is a classic and well-recognized animal model of myopia in the art, which can be used for efficacy and safety evaluation of myopia treatment drugs, and its construction method is well known to those skilled in the art. The animal modeling and drug administration method in this application refers to the scientific literature published by the previous research group (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083.; Miaozhen Pan, Exp Eye Res. 2021 Jan; 202: 108332.).

[0288] The lipoic acid preparation is a pharmaceutical composition prepared by the inventors using only the compound lipoic acid as the effective pharmaceutical ingredient. Among them, the a-lipoic acid compound is purchased from MedChemExpress. Without adding other pharmaceutical adjuvants or other active ingredients, the 0.94% lipoic acid eye drop solution preparation components are as follows: DMSO (melt the required mass of lipoic acid compound): PEG300: physiological saline = 1:49:50 (volume ratio), wherein the 0.94 grams of a-lipoic acid is contained in 100 milliliters of the lipoic acid eye drop solution. At room temperature, the overall appearance of the lipoic acid preparation is clear, transparent, uniform and free of visible suspended matter.

[0289] R-Alpha Lipoic Acid (R.ALA) was purchased from Suzhou Fujilai Pharmaceutical Co., Ltd. The inventors dissolved R.ALA powder in DMSO to prepare a 100-fold stock solution, which was a clear, transparent, homogeneous, and stable yellow liquid at room temperature. The stock solution was then diluted to prepare the working solution in the following ratio: stock solution: PEG300: Tween 80: 0.9% physiological saline = 1:45:5:49. For example, if the final concentration of R.ALA used in the experiment was 0.4%, then the stock solution was prepared to be 40%.

[0290] S-Alpha Lipoic Acid (S.ALA) was purchased from Suzhou Fujilai Pharmaceutical Co., Ltd. S.ALA powder was dissolved in DMSO to prepare a 40% stock solution, which was then diluted with the following ratio: stock solution: PEG300: Tween 80: 0.9% physiological saline = 1:45:5:49 to prepare a working solution. The final concentration of the S.ALA preparation used was 0.4%.

[0291] Dihydrolipoic acid (DHLA) was purchased from MedChemExpress. First, DHLA powder was dissolved in DMSO to prepare a 40% stock solution. Then, a working solution was prepared according to the ratio of stock solution: PEG300: Tween 80: 0.9% physiological saline = 1:45:5:49. The final concentration of the DHLA preparation used in the experiment was 0.4%.

[0292] R-alpha-Lipoic Acid Choline Ester (LACE) was purchased from Suzhou Fujilai Pharmaceutical Co., Ltd. LACE powder was completely dissolved in 0.9% physiological saline to prepare alpha-lipoic acid choline ester eye drops of the required experimental concentrations, for example, 0.5%.

[0293] Emoxypine succinate (ES), purchased from MedChemExpress, was completely dissolved in 0.9% physiological saline to prepare a 0.37% solution.

[0294] Pyridoxol hydrochloride (PH) was purchased from Selleck. It was completely dissolved in 0.9% physiological saline to prepare a 0.3% solution.

[0295] Astaxanthin (ASTA), purchased from Selleck. ASTA powder was dissolved in the following mixed solvents, the final ratio of each solvent in the formulation was DMSO: PEG300: Tween80: 0.9% saline = 1:45:5:49, and the final concentration of ASTA used in the experiment was 0.87%.

[0296] Blueberry Fruit Extract (BFE), purchased from Selleck. BFE powder was dissolved in the following mixed solvents, the final ratio of each solvent in the formulation was DMSO: PEG300: Tween80: 0.9% saline = 1:45:5:49, and the final concentration of BFE used in the experiment was 6%.

[0297] Atropine sulfate (Atropine), purchased from MedChemExpress. After completely dissolved in 0.9% saline, a stock solution of 2mg / ml was prepared, and then diluted to the required concentration, for example 0.05%.

[0298] All working solutions (such as formulations containing lipoic acid, or its prodrugs or metabolites) used in all examples were divided and stored in a -80°C refrigerator, and a new tube was taken out from the refrigerator before each experiment to avoid repeated freezing and thawing. All preparation operations were carried out in a dark room.

[0299] Other formulations or pharmaceutical compositions described or used in the examples not mentioned in this application were prepared and stored according to the laboratory routine method or the standard well known to the skilled person. All preparations and pharmaceutical compositions may be prepared by heating, stirring, pH adjustment and other conventional physical and chemical means. No compound precipitation occurred during the administration of all formulations.

[0300] The examples of the present application used healthy guinea pigs (i.e. without underlying diseases such as hypertension, hyperglycemia, eye diseases or abnormalities, etc.) and both male and female were used. The animal experiments of the present application have been reviewed by the Experimental Animal Ethics Committee of Wenzhou Medical University.

[0301] Example 2, lipoic acid can effectively control the progression of guinea pig form deprivation myopia (FDM)

[0302] 3-week-old tricolor guinea pigs were selected after excluding individuals with obvious eye diseases or abnormalities, and after diopter (infrared eccentric photorefraction) and eye axis (A-mode ultrasound) tests. The animals with refractive power between 3-8 diopter (D) and a difference in refractive power between the two eyes of no more than 2D, and a difference in vitreous chamber depth and eye axis length of no more than 0.05mm were randomly divided into two groups: FD+solvent control group (1% DMSO+49% PEG300+50% normal saline, volume ratio) and FD+0.94% lipoic acid drug treatment group. The guinea pigs were subjected to form deprivation at 8 am on the first day of the experiment, using a mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). FD induction was performed throughout the lipoic acid efficacy experiment period, and the headgear was only temporarily removed for drug administration or ocular examination (such as diopter test). The position of the headgear was checked at 8 am, 12 noon, and 7 pm every day after the start of the efficacy experiment, and individuals with more than 3 times of headgear falling off during the drug administration period were eliminated. Starting on the day of modeling, the experimental eye was given the corresponding solvent or drug (lipoic acid preparation) subconjunctival injection at 9-10 am every day, with an injection volume of 100 μL, once a day for 2 weeks. The diopter and eye axis parameters of both eyes of all test individuals were tested at the start of the efficacy experiment, 1 week after drug administration, and after the last drug administration. All data collection and processing methods were the same as the published literature in the inventor's laboratory (Pan M, Zhao F, Xie B, et al. Dietary omega-3 polyunsaturated fatty acids are protective for myopia. Proc Natl Acad Sci U S A 2021 Oct 26; 118(43): e2104689118), and the difference between the experimental eye and the contralateral eye of the same test individual was used for statistical analysis. This efficacy experiment has been repeated in two batches of test animals before and after, and all experimental results are basically consistent and the conclusions are the same.

[0303] The experimental results show that the refractive power and eye axial parameter change trend of the solvent negative control group animals are consistent with the expected myopia model, proving that the myopia model in this experiment is successfully modeled and can be used for efficacy evaluation of lipoic acid myopia intervention. Compared with the solvent control group, the myopia inhibition rates of the lipoic acid drug group after 1 week and 2 weeks of treatment are 42.4% and 21.1%, respectively, and there are statistical differences between the lipoic acid drug group and the solvent negative control group, proving that lipoic acid can significantly inhibit and slow down the negative progression of refractive power of myopic individuals, that is, it can effectively delay and control the occurrence and development of myopia (Table 1). At the same time, compared with the solvent group, lipoic acid administration can also significantly inhibit the elongation of the eye axis of myopic individuals and slow down the increase of the vitreous cavity depth, and the indicators are statistically different from the negative control group (see Figure 1). The specific eye axial parameters are (mean ± SD): the mean difference in axial length of the same modeling individual's two eyes (myopia-induced eye and contralateral eye) of the lipoic acid treatment group and the solvent negative control group after 1 week of administration is 0.04364 ± 0.03295 mm and 0.09909 ± 0.01868, respectively, and the corresponding vitreous cavity depth difference is 0.0009091 ± 0.027 mm and 0.1164 ± 0.03075 mm, respectively; the mean difference in axial length of the same modeling individual's two eyes of the lipoic acid treatment group and the solvent negative control group after 2 weeks of administration is 0.06364 ± 0.03722 mm and 0.1236 ± 0.03042, respectively, and the corresponding vitreous cavity depth difference is 0.08545 ± 0.02067 mm and 0.06182 ± 0.03157 mm, respectively (Table 2). In addition, after administration of lipoic acid, no toxicity, eye irritation or obvious eye abnormalities were observed in the animals, and the related indicators such as the anterior chamber depth, lens thickness and corneal curvature of the test individuals were not affected by the drug (see Figures 2A, B, C). No mydriasis effect was observed in all lipoic acid drug treatment group animals during administration (Figure 2D).

[0304] The above results show that lipoic acid can treat myopia and delay the progression of myopia by inhibiting the elongation of the eye axis and / or the increase in the vitreous cavity depth of myopic or myopia-prone individuals.

[0305] Table 1 Lipoic acid can effectively control the negative progression of refractive power of myopia model

[0306] Table 2 Lipoic acid can effectively inhibit the deterioration of the eye axial parameters of the myopia model

[0307] Example 3, Lipoic acid can effectively inhibit the decrease in choroidal thickness of the myopic eye of the FDM guinea pig model

[0308] All animals in Example 2 were tested for choroidal thickness in all eyes using Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany) at 30-60 minutes after the last dose (solvent or lipoic acid), and the data collection and processing were the same as the published literature in the inventors' laboratory (Pan M, Zhao F, Xie B, et al. Dietary omega-3 polyunsaturated fatty acids are protective for myopia. Proc Natl Acad Sci U S A 2021; 118), and the statistics were based on the difference between the experimental eye and the fellow eye of the same individual.

[0309] In the solvent negative control group, the experimental eye was significantly thinner than the fellow eye of the same individual; the results showed that the use of lipoic acid alone (in eye drop form) can significantly inhibit the reduction of choroidal thickness in myopic eyes, and the choroidal thickness of some animals in the lipoic acid treatment group even completely maintained at the level of normal eyes (fellow eyes) after drug intervention. Experimental data showed that the choroidal thickness of the experimental eye was close to the choroidal thickness of the normal eye in the same individual after drug (lipoic acid) administration (the difference between the two decreased), and the statistical results showed that there was a significant difference between the lipoic acid drug group and the solvent group. In summary, lipoic acid can significantly inhibit the reduction of choroidal thickness in myopic individuals or individuals with a tendency to develop myopia and slow down the trend of choroidal thickness thinning. At the same time, the experimental results showed that lipoic acid can treat and correct myopia by inhibiting the thinning of choroidal thickness in myopic individuals or individuals with a tendency to develop myopia.

[0310] In myopic individuals, parallel light rays are refracted by the relaxed eye's refractive system, and the imaging focus falls in front of the retina. When lipoic acid increases the choroidal thickness of this myopic individual, the retina moves towards the lens, ultimately resulting in a shortening of the distance between the above-mentioned imaging focus and the retina in the myopic eye, or even a perfect fit between the two. In myopic individuals, the distance between the above-mentioned imaging focus and the retina is the degree of myopia. Lipoic acid can reduce the distance between the imaging focus and the retina and inhibit the increase in the distance between the two in myopic individuals, which itself reduces or controls the degree of myopia. Giving lipoic acid to myopic individuals will result in the drug-treated eye having better clear distance vision and its myopic refractive state being effectively improved (myopia is corrected, the degree of myopia is reduced), including its distance vision being improved by lipoic acid. Therefore, the myopia intervention and treatment (prevention and control) effect of lipoic acid in this application is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia or true myopia, and is unrelated to factors such as the age, gender, degree of myopia, speed of myopia progression, nationality, genetic background and age of myopia occurrence of the drug-treated subject, i.e. lipoic acid has a therapeutic and intervention effect on all types of myopia.

[0311] Example 4, Comparison of lipoic acid, mesoxalol, pyridoxine, astaxanthin, bilberry extract (anthocyanin) in the treatment of myopia

[0312] Using the guinea pig form deprivation model myopia treatment drug efficacy evaluation system consistent with that described in Example 2, the effects of mesoxalol, pyridoxine, astaxanthin, bilberry extract and lipoic acid on myopia prevention and control were compared. Among them, the administration method was subconjunctival injection, and the experimental group was set as 0.05% atropine sulfate group (positive control, Atropine), 0.37% mesoxalol succinate group (ES), 0.3% pyridoxine hydrochloride group (PH), 0.87% astaxanthin group (ASTA), 6% bilberry extract group (BFE), and 0.3% R-lipoic acid group (R.ALA). The 0.9% normal saline was the negative control group (Control).

[0313] The experimental results show that the diopter and axial parameter changes of the negative control group animals are consistent with the expectations of the myopia animal model, and the positive control drug atropine shows its expected efficacy in the experiment, which proves that the myopia model in this experiment is successful and can be used for efficacy evaluation of the tested drugs. As can be seen from Figure 4, lipoic acid has the best myopia treatment effect during the drug administration period (1 week of detection); at the end of the drug administration period, only atropine sulfate and R-lipoic acid show significant myopia treatment effect, and the other tested drugs and the solvent group have no statistical difference. Moreover, lipoic acid is significantly better than other comparative drugs such as pyridoxine, astaxanthin and bilberry extract in inhibiting the negative change of diopter of myopia individuals under the same experimental conditions. In terms of diopter index analysis alone, no myopia treatment effect was observed after local administration of bilberry extract, and even there was a tendency to induce myopia or aggravate myopia. The axial parameter results of each experimental group also support the above conclusion (see Figure 5), which shows that lipoic acid can effectively inhibit the elongation of the eye axis and the increase of the vitreous cavity depth of myopia individuals or individuals with a tendency to develop myopia. Among them, whether it is the axial length or the vitreous cavity depth, the myopia treatment effect of lipoic acid is significantly better than that of other comparative drugs at two detection time points after drug administration. Atropine can also effectively control the progression of myopia, but it causes obvious mydriasis after administration (Figure 6), which limits its clinical application. In summary, lipoic acid is significantly better than other comparative drugs in treating myopia. Therefore, compared with the prior art, lipoic acid is significantly better than the prior art in treating myopia and inhibiting the elongation of the eye axis of myopia individuals, which is unpredictable by those skilled in the art in advance.

[0314] Example 5, lipoic acid-containing pharmaceutical composition for myopia treatment

[0315] Using the guinea pig form deprivation model myopia treatment efficacy evaluation system consistent with that described in Example 2, the advantages and disadvantages of the compound preparation of bilberry extract + lipoic acid in different prescription proportions on myopia treatment effect were evaluated. Among them, the administration method is subconjunctival injection, and the experimental group has three groups, specifically bilberry extract (0.05%) + racemic lipoic acid (1%) group (0.05% BFE + 1% DL.ALA), bilberry extract (1%) + racemic lipoic acid (1%) group (1% BFE + 1% DL.ALA), and solvent negative control group (Control, the solvent of all test compositions in this experiment is 46 parts of PEG300 + 5 parts of Tween80 + 49 parts of 0.9% physiological saline). Racemic lipoic acid (DL-Alpha Lipoic Acid, DL.ALA) is purchased from Suzhou Fuji Lei Pharmaceutical Co., Ltd.

[0316] The experimental results show that the refractive diopter and eye axis parameter changes of the negative control group animals are consistent with the expectations of the myopia animal model, proving that the myopia model in this experiment is successful and can be used for the efficacy evaluation of the test drug composition. As can be seen from Figure 7, when the content of lipoic acid and bilberry extract in the drug composition is the same (lipoic acid: bilberry extract = 1:1), the drug composition only shows a trend of myopia treatment, but neither the refractive diopter index nor the eye axis length index has a statistical difference compared with the solvent control group; however, when the proportion of bilberry extract in the compound preparation is reduced under the condition of keeping the concentration of lipoic acid unchanged, i.e. lipoic acid as the main active ingredient or direct active ingredient of the drug composition (lipoic acid: bilberry extract = 20:1), the drug composition significantly inhibits the progression of negative refractive diopter and eye axis elongation of the myopia model. Compared with the case where the ratio of the two in the drug composition is 1:1, when lipoic acid is the main active ingredient or direct active ingredient of the drug composition (lipoic acid: bilberry extract > 1:1), the myopia treatment effect of the preparation is significantly enhanced, and the efficacy evaluation index has a statistical difference compared with the solvent control group.

[0317] The above results show that: compared with the drug composition in which lipoic acid is not the main active ingredient, the drug composition in which lipoic acid is the main active ingredient has better prevention and control effect on myopia. This is also an unexpected effect, i.e. by reducing the content of other main active ingredients in the drug composition, etc. to make lipoic acid the main active ingredient of the preparation, the prevention and control effect on myopia is not only not reduced, but also significantly improved. People did not know that lipoic acid could be used to treat myopia and could produce such a significant treatment effect, so they had no motivation to increase the content of lipoic acid in the drug composition to more than the content of other active ingredients, and thus there was no attempt or thinking to improve the treatment of myopia drug composition or improve the treatment of myopia drug combination by this method.

[0318] Example 6, lipoic acid choline ester eye drops (chloride form) for delaying the progression of myopia in young individuals

[0319] Using the guinea pig form deprivation model myopia treatment efficacy evaluation system consistent with that described in Example 2, the influence of different concentrations of R-lipoic acid choline ester eye drops (chloride form, LACE) on the prevention and control effect of myopia was systematically studied. Among them, the administration method of all groups of test animals was direct eye drop administration, twice a day (once in the morning and once in the afternoon), and each time 25uL. The test concentration of LACE was set to 0.5% and 0.15%, and 0.05% atropine sulfate group (positive control, Atropine) and 0.9% normal saline solvent group (negative control, Control) were used as controls.

[0320] The experimental results show that the diopter and axial parameter changes of the negative control group animals are consistent with the expected changes of the myopia animal model, and the positive control drug atropine shows its expected efficacy in the experiment, which proves that the myopia model in this experiment is successful and can be used for efficacy evaluation of the tested drug. As can be seen from FIG. 8-1, there is a positive correlation between the amount of lipoic acid choline ester and the treatment of form deprivation myopia. With the increase of the amount of drug, the myopia treatment effect is more satisfactory, and the axial elongation of myopia individuals also shows a stronger inhibition effect. Compared with the solvent control group, 0.5% lipoic acid choline ester can significantly inhibit the negative diopter change and the axial length elongation of form deprivation myopia during the entire drug administration period. At the same time, under the condition of eye drop administration, the comprehensive performance of 0.5% lipoic acid choline ester, as a prodrug of lipoic acid, in the treatment of myopia in young individuals is also better than that of the positive control atropine, especially in terms of inhibiting the negative diopter change process and the axial elongation of myopic eyes after a longer period of drug administration. During the entire drug administration period, the inventors did not observe mydriasis caused by the drug in the lipoic acid choline ester group animals, and there was no statistical difference in the anterior chamber depth, lens thickness, and corneal curvature between the lipoic acid choline ester group and the negative control group (FIG. 8-2).

[0321] The non-invasive administration of lipoic acid choline ester can effectively treat myopia and significantly inhibit the axial elongation of myopic individuals or individuals prone to myopia, and the drug efficacy increases with the increase of the concentration. It is well known that the excessive axial length of myopic individuals is the direct cause of various fundus lesions (such as complications of high myopia) and even complete loss of vision in this population, and the medical focus of myopia treatment is also to avoid excessive axial length of myopic eyes. The strong biological effect of lipoic acid choline ester in inhibiting axial elongation in the treatment of myopia proves its superiority and uniqueness as an effective drug for treating myopia in children and adolescents, simple myopia, primary myopia, progressive myopia, and axial myopia, and also suggests that individuals with myopia or myopia-prone individuals should use lipoic acid or lipoic acid choline ester as soon as possible to prevent and control the occurrence and development of myopia, so as to avoid irreversible damage to the vision of patients. In addition, lipoic acid choline ester has been prepared as an eye drop with a concentration of 1.5% as an active ingredient for the treatment of presbyopia, and clinical studies have found that it has good bioavailability and high safety. During the administration period of young individuals in this experiment, all lipoic acid choline ester group animals did not show any eye abnormalities or mydriasis. This result further proves that lipoic acid or its choline ester prodrug is safe and reliable for children or adolescents. At the same time, this study explores the minimum effective dose of lipoic acid choline ester eye drop administration for the treatment of myopia, which can provide necessary reference data for subsequent formulation development and clinical application of young population.

[0322] In summary, from the perspective of efficacy and safety evaluation, the risk-benefit ratio of lipoic acid or lipoic acid choline ester for the treatment of myopia is better than atropine sulfate (such as using lipoic acid or lipoic acid choline ester during the day will not cause photophobia similar to atropine mydriasis induced by myopia treatment), especially for delaying the occurrence and development of myopia in children and adolescents, and preventing and controlling myopia in school-age population.

[0323] Example 7, lipoic acid optical isomers and their metabolites can significantly inhibit and slow down the progression of guinea pig negative lens-induced model (LIM) myopia

[0324] After excluding individuals with eye diseases or eye abnormalities, healthy 3-week-old three-color guinea pigs (both male and female) were selected by diopter (infrared eccentric photography refraction instrument) and eye axis (A-mode ultrasound) detection, with refractive power between 3-8.5 diopter (D) and refractive disparity between both eyes not more than 2D, and also meeting the difference of vitreous cavity depth and eye axis length of both eyes not more than 0.05mm. The animals were randomly divided into the following 5 groups:

[0325] 1. Lens-induced + solvent control group (Control): single eye wearing -4D lens and 100 microliters of solvent (DMSO: PEG300: Tween80: 0.9% physiological saline = 1:45:5:49) was applied to the wearing eye every day for 1 week, sample size = 11;

[0326] 2. Lens-induced + R-lipoic acid experimental group (R.ALA): single eye wearing -4D lens and 100 microliters of 0.4% R-lipoic acid was applied to the wearing eye every day for 1 week, sample size = 15,

[0327] 3. Lens-induced + S-lipoic acid experimental group (S.ALA): single eye wearing -4D lens and 100 microliters of 0.4% S-lipoic acid was applied to the wearing eye every day for 1 week, sample size = 13,

[0328] 4. Lens-induced + dihydrolipoic acid experimental group (DHLA): single eye wearing -4D lens and 100 microliters of 0.4% dihydrolipoic acid was applied to the wearing eye every day for 1 week, sample size = 14;

[0329] 5. Lens-induced + positive control group (Atropine): single eye wearing -4D lens and 100 microliters of 0.05% atropine sulfate was applied to the wearing eye every day for 1 week, sample size = 13;

[0330] The difference between the negative control group (solvent control group) and other experimental groups is that it does not contain any active ingredients. On the day of modeling, the corresponding solvent or drug is administered to the experimental eye (wearing eye) at 9-10 am every day, subconjunctival injection is used for administration, the injection volume is 100 μL, and the administration is performed once a day for 1 week. All the parameters such as negative mirror induced modeling, subconjunctival injection administration, refractive power, and data processing of the test individual are the same as the previous use scheme (CN114796205B) of the research group. The refractive power of the test animal is detected at the beginning, 3 days of the experiment, and the end of the LIM model efficacy experiment, and the difference between the experimental eye (wearing eye) and the contralateral eye of the same test individual is used as the basis for statistics.

[0331] The experimental results show that the refractive power change of the animals in the negative control group is consistent with the expected LIM myopia model, and the positive control drug atropine shows the expected efficacy in the experiment, which proves that the myopia model in this experiment is successful and can be used for efficacy evaluation of the test drug. As can be seen from FIG. 9, all the test compounds show obvious myopia treatment effect during the entire administration period, that is, they all show a delaying effect on the refractive power decrease of myopia individuals, but the atropine group shows mydriasis. Among them, after the end of the administration period, the refractive power index difference between the R-lipoic acid group and the dihydrolipoic acid group is extremely significant compared with the solvent group. At 3 days of administration, the efficacy of the R-lipoic acid group and the S-lipoic acid group is basically the same, and both are better than the dihydrolipoic acid group, and even the average value is better than the positive control atropine group. At the same time, as can be obviously seen from FIG. 9, R-lipoic acid can have a very high inhibitory effect in the early stage of myopia, and can maintain such an inhibitory effect, that is, the excellent myopia prevention and control efficacy of lipoic acid is independent of the severity of myopia or the negative refractive power change speed. During the administration process, the optical isomers of lipoic acid and dihydrolipoic acid do not cause eye irritation, and do not affect the anterior chamber depth and lens thickness (FIG. 10).

[0332] It is generally believed that the main biological activity of lipoic acid is exhibited in the R form, and it is known that the reducing ability of dihydrolipoic acid is stronger than that of lipoic acid. However, the experimental results of our experiment prove that both chiral structures of lipoic acid can effectively treat myopia and have basically the same treatment efficacy in the treatment of myopia occurrence period, and overall, the efficacy of dihydrolipoic acid is inferior to that of R-lipoic acid, which indicates that the treatment of myopia by lipoic acid or its metabolites depends on a new mechanism of action that is unknown to people.

[0333] Example 8, Formulations Containing Lipoic Acid for Myopia Treatment

[0334] The therapeutic effect of the low concentration atropine + lipoic acid compound preparation on myopia was evaluated using the guinea pig form deprivation myopia treatment efficacy evaluation system consistent with the description in Example 2. Among them, the administration method was subconjunctival injection, and there were three groups in the experimental group, specifically 0.05% atropine sulfate group (Atropine, positive control), 0.01% atropine sulfate + 0.15% R-lipoic acid (0.01% atropine + 0.15% R.ALA), and solvent negative control group (Control, 0.9% normal saline). The preparation method of the above compound preparation is as follows: 15% R-lipoic acid stock solution (dissolved in DMSO) and 0.2% atropine sulfate stock solution (dissolved in normal saline) are added to the mixed solvent in the following proportion, the proportion of each component is 15% R-lipoic acid stock solution: 0.2% atropine sulfate stock solution: PEG300: Tween80: 0.9% normal saline = 1:5:45:5:44, so that the final concentration of the preparation is 0.01% atropine sulfate + 0.15% R-lipoic acid.

[0335] The experimental results show that the refractive and axial parameters of the negative control group animals change in line with the expectations of this myopia animal model, proving that the myopia model in this experiment is successful and can be used for efficacy evaluation of the test drug composition. As can be seen from Figure 11(A), when the test animals are given a low concentration of lipoic acid (0.15%) at the same time, the efficacy of 0.01% atropine in myopia treatment is comparable to that of 0.05% atropine (both groups have significant differences in refractive diopter compared with the solvent group, and the statistical difference of the 0.01% atropine + 0.15% R.ALA group is extremely significant), and even at the end of the administration, the refractive diopter index of the compound preparation is better than that of the 0.05% atropine sulfate group. The efficacy of myopia treatment benefits from the effective inhibition of the compound preparation on the elongation of the axial length of the myopic eye, as can be clearly observed from Figure 11(B) that the axial length of the myopic eye of the test animals is significantly inhibited by the atropine + lipoic acid compound preparation during the entire administration period.

[0336] Atropine sulfate is subject to its mydriatic, photophobia and withdrawal "rebound" and other adverse reactions, clinical treatment of myopia can only use a lower concentration, such as 0.01%, 0.02% and so on. However, due to the small amount of drug, the response rate of the drug at this concentration is low, and the prevention and control results of myopia are mostly not very satisfactory. If the therapeutic effect of atropine and other myopia prevention and control drugs can be effectively improved, while significantly avoiding the occurrence of adverse reactions, and thus overall reducing the drug risk of young or low age groups, it is the goal pursued by those skilled in the art. 0.01% atropine + 0.15% R. ALA (atropine + thioctic acid) can not only reduce the adverse reactions of atropine, but also increase its effectiveness in treating myopia. The prior art has never suggested or implied the existence of such a combination drug effect. We accidentally found that thioctic acid can increase the therapeutic effect of atropine and other M receptor inhibitors in the treatment of myopia in a drug synergistic manner, presumably because the two myopia treatment intervention targets are different, or the pharmacokinetic properties of the active ingredients in the eye are changed, or other unknown factors. In addition to the abnormally complex pathogenesis of myopia, the above phenomena need to be further studied. However, the potential synergistic effect of thioctic acid in combination with other myopia treatment drugs in the process of myopia prevention and control is worth focusing on and utilizing in the development of myopia drugs.

[0337] In summary, based on the myopia prevention and control effect of atropine co-administration in this experiment, and the fact that thioctic acid can effectively treat myopia through a new unknown mechanism, we believe that thioctic acid can also be used in combination with other myopia treatment drugs or prepared into a pharmaceutical composition for the treatment and prevention of myopia, especially for children or adolescents. The concentration, proportion or efficacy contribution rate of thioctic acid in the above pharmaceutical composition can be higher than, lower than, or the same as other active ingredients.

[0338] Example 9 Thioctic acid choline ester eye drop administration can effectively increase the choroidal thickness of myopic eyes

[0339] After the experiment, the choroidal thickness of the 2 control groups and the 0.5% thioctic acid choline ester eye drop administration group in Example 6 was detected (individual animals died during the measurement process due to non-drug reasons, so the corresponding samples were excluded). The detection and analysis method refers to the previously published literature (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083) by the research group.

[0340] As shown in Figure 12, compared with the negative control group, lipoic acid choline ester can effectively inhibit the thinning of the choroidal thickness of the model eye of the form deprivation model, and the treatment effect is better than that of the positive control atropine group. Therefore, lipoic acid choline ester has obvious inhibition and reversal effect on the thinning trend of the choroid of myopic individuals. In summary, the experimental results show that lipoic acid choline ester can treat and correct myopia by inhibiting the decrease in choroidal thickness of myopic individuals or individuals with a tendency to develop myopia.

[0341] Example 10 Lipoic acid optical isomers and dihydrolipoic acid can significantly inhibit the thinning of the choroidal thickness of myopic individuals

[0342] Using the test animals of Example 7, choroidal parameter detection was performed after the end of the experiment (a small number of animals died during the measurement process due to non-drug reasons, so this sample was excluded), specifically: the LIM myopia model animals were measured for choroidal thickness after 7 days of drug administration at the end of the experiment. The detection of choroidal thickness used a modified commercial OCTA (Spectralis HRA+OCT, OCTA, Heidelberg, Germany). Before detection, the guinea pigs were fully anesthetized, and after obtaining the OCTA image of the guinea pigs, the measurement results were quantified by a self-programming (MatLab R2017a, MathWorks) to realize real-time quantitative detection of the choroidal thickness of the guinea pigs (Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083).

[0343] As shown in Figure 13, compared with the solvent control group, lipoic acid optical isomers and dihydrolipoic acid can effectively inhibit the decrease in choroidal thickness of myopic individuals, and the positive control atropine also does so (the choroidal thickness of the experimental eye after drug intervention approaches the choroidal thickness level of the normal eye in the same individual, i.e. the difference between the two decreases). It is worth noting that whether it is lipoic acid optical isomers or dihydrolipoic acid, their inhibition efficiency on the thinning of the choroid of myopic individuals is better than that of the positive control atropine, especially R-lipoic acid can significantly increase the choroidal thickness of myopic eyes.

[0344] Regardless of the form deprivation model or the negative lens-induced model, the present application first reports that lipoic acid, lipoic acid choline ester and dihydrolipoic acid can increase the choroidal thickness of myopic eyes. In myopic individuals, parallel light is refracted by the relaxed refractive system of the eye, and the focus falls in front of the retina. When lipoic acid or its structural analogues increase the choroidal thickness of the myopic individual, the retina will move towards the lens, ultimately resulting in a decrease in the distance between the imaging focus and the retina in the above-mentioned myopic eye. The distance between the imaging focus and the retina is the degree of myopia, and lipoic acid or its structural analogues can shorten the distance between the two or inhibit the increase in the distance between the two in myopic individuals, which itself is to reduce the degree of myopia and treat myopia. Giving lipoic acid or its structural analogues to myopic individuals will result in better distance vision in the medicated eye, as well as effective reduction of the myopic refractive state, including improvement of distance vision. Therefore, the myopia treatment and intervention effect of lipoic acid or its structural analogues in the present application is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia or true myopia, and is also unrelated to factors such as the age, gender, myopia degree, myopia progression speed, nationality and myopia age of the medicated subject, i.e. lipoic acid optical isomers, or its prodrugs (such as lipoic acid choline ester) or its metabolites (such as dihydrolipoic acid) have therapeutic and intervention effects on all types of myopia.

[0345] From the long-term, continuous and continuous nature of myopia drug treatment, and the fact that most of the individuals taking the drug are in the growth and development stage, lipoic acid or lipoic acid choline ester is superior to other compounds in terms of effectiveness and safety. Our results demonstrate that lipoic acid and any one of its salt forms or ester forms (such as lipoic acid choline ester) can effectively treat myopia by inhibiting the elongation of the eye axis and slowing the increase in the depth of the vitreous cavity to control the progression of the refractive power of myopic individuals or individuals with a tendency to myopia. At the same time, lipoic acid and its pharmaceutically acceptable salts or esters (such as lipoic acid choline ester) can significantly increase the choroidal thickness of myopic individuals and reduce the degree of myopia. The dosage form of the above-mentioned lipoic acid and its pharmaceutically acceptable salts or esters (such as lipoic acid choline ester) in the treatment of myopia, intervention of myopia, correction of myopia and prevention and control of myopia can be eye drops, eye ointment, eye spray, eye injection or eye gel, or even oral dosage form; the present application proves that devices, preparations or pharmaceutical compositions containing such compounds (drugs) can be used to control the progression of myopia.

Claims

1. Use of lipoic acid or lipoic acid choline ester, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts or esters, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystal type compounds, or combinations of these substances; characterized in that, The use is one of the following or two or more of the following are met simultaneously: ① preventing and / or treating myopia and its associated symptoms, and / or myopia correction; or ② controlling the occurrence and development of myopia in combination with orthokeratology lenses or other myopia treatment drugs; or ③ for myopic eye intervention treatment or delay of myopia progression; or ④ inhibiting, slowing down, or reducing the elongation of the eye axis and / or the increase of the vitreous cavity depth of myopic individuals or individuals with a tendency to develop myopia, and increasing the choroidal thickness of myopic individuals or individuals with a tendency to develop myopia; or ⑤ preventing, slowing down, reducing, or treating abnormal development of children's and adolescents' eyes associated with refractive errors; or ⑥ enabling individuals to obtain clearer distance vision than before using these lenses or means and / or than without using these lenses or means, without wearing lenses or relying on vision correction means; or ⑦ inhibiting, delaying, or slowing down the process or speed of the negative diopter change of myopic individuals or individuals with a tendency to develop myopia; or ⑧ for the preparation of a drug, preparation, composition, or device for achieving at least one of the purposes of the preceding ①-⑦.

2. The use of claim 1, by means of systemic administration such as oral administration, and / or local administration (eye drops, eye injection, eye implantation, skin cream / eye cream, or eye ointment), and / or parenteral administration (such as by mucosal administration, transdermal administration, microneedle administration), and / or non-invasive administration (such as by using an eye spray).

3. The use of claim 1 or 2, wherein the drug, preparation or composition can be injection solution, tablet, lyophilized powder injection, capsule, effervescent tablet, chewable tablet, buccal tablet, granule, ointment, syrup, oral solution, aerosol, nasal drop, external preparation, oral preparation, etc.; preferably is an ophthalmic dosage form, including but not limited to eye drop (eye drops), eye ointment, eye spray, implant tablet, eye gel, eye patch, eye microsphere, eye sustained-release preparation, periocular injection, intraocular injection; can also be regular solution, aqueous solution, unsaturated solution, oil-water mixture, suspension, liniment, lotion, cream, drop, infusion, spray, ointment, patch, paste, pill, suppository, emulsion, containing cellulose (such as methyl cellulose), polyhydric alcohol, cyclodextrin (such as hydroxypropyl-β-cyclodextrin), reducing agent (such as glutathione, N-acetyl peptides), glycerol, liquid paraffin, vaseline, propylene glycol, ethyl pyruvate, semifluorinated alkane, amino acid or its derivative (such as alanine, methionine, cysteine and histidine), sugar or its metabolite (such as glucose-6-phosphate), oxygen scavenger (such as Oxy-Guard TM or StabilOx TM ), vitamin (such as vitamin B1, vitamin B2, vitamin C, vitamin E), NADPH, dendritic macromolecule, nanomaterial, sustained-release material, liposome or any combination thereof.​​​​ 4. The use of any one of the preceding claims, wherein the myopic individual or individual with a tendency to develop myopia is a person medically diagnosed as having myopia; or is a child and / or adolescent, preferably a person aged 2 to 30 years, more preferably a person aged 6 to 18 years; or is a minor, preferably a person whose eyes are still in the growth and development stage; or is a school-age person, preferably a person in grades one to twelve; or is a person whose parents are both or one of them highly myopic; or is a person with insufficient hyperopic reserve.

5. Use according to one of the preceding claims, the myopia being myopia of refraction or myopia of axis; congenital myopia (myopia since birth or preschool), early-onset myopia (before 14 years of age), late-onset myopia (between 16 and 18 years of age), late-onset myopia (after adulthood), low myopia (mild myopia), moderate myopia, high myopia (severe myopia), malignant myopia; pseudomyopia, true myopia; myopia of children and / or adolescents (preferably the population is aged between 2 and 30 years, more preferably the population is aged between 6 and 18 years), myopia of minors, myopia of adults, myopia of the elderly; simple myopia, pathological myopia, complex myopia; axial simple myopia, simple axial myopia; myopia of children and / or adolescents (preferably the population is aged between 2 and 30 years, more preferably the population is aged between 6 and 18 years), myopia of school-age and preschool populations; primary myopia, secondary myopia; myopia of children and / or adolescents (preferably the population is aged between 2 and 30 years, more preferably the population is aged between 6 and 18 years), or myopia of children and / or adolescents (preferably the population is aged between 2 and 30 years, more preferably the population is aged between 6 and 18 years); curvature myopia, index myopia, astigmatic myopia, positional myopia, flexural myopia; myopia of axis with a constant negative progression of dioptres; myopia caused by long periods of close eye work, myopia caused by visual fatigue and pseudomyopia, negative progression of dioptres caused by adverse drug reactions, myopia, myopia caused by reading, myopia caused by the use of electronic devices such as mobile phones, myopia caused by a mismatch of refractive media (components), myopia caused by abnormal refractive development, myopia caused by excessive eye growth, myopia caused by poor eye hygiene, imaging of distant objects with the focus falling in front of the retina for various reasons, myopia for which atropine treatment is ineffective, non-complex myopia, myopia caused by insufficient outdoor exercise, accommodative myopia, myopia of children, myopia of infants, genetic myopia, myopia dominated by environmental factors, mixed myopia, traumatic myopia, toxic myopia, drug-induced myopia, diabetic myopia, instrumental myopia, spatial myopia, night myopia, other myopia of premature babies, diving myopia, hysteric myopia, and temporary myopia observed during the menstrual period, during pregnancy and in various eye diseases and systemic diseases.

6. The use according to any of the preceding claims, wherein the myopia-related symptoms refer to complications caused by myopia or ocular axial length elongation, such as complications of high myopia, further such as floaters, glaucoma, posterior scleral staphyloma, retinal detachment, retinal tears, retinopathy, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or maculopathy, visual field defects, progressive or sudden decrease in vision, especially in near vision, ocular acidosis and / or pain, night blindness, astigmatism, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent rubbing of the eyes, anisometropia, blurred vision when looking at distant objects, the need to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye fatigue, concentration difficulties caused by myopia, difficulty in driving, especially at night (night myopia), retinal atrophy degeneration (hemorrhage and tears), subretinal neovascularization, or ocular atrophy.

7. The use according to any of the preceding claims, wherein the medicament, preparation, composition or device further comprises other drugs, compounds or ophthalmic preparations, including but not limited to myopia treatment drugs (such as pirenzepine, muscarinic antagonists, ambenonium, indoramin, timolol maleate, epinephrine, pyrazine, pibenzole, methylamine, chloroponamide, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, epi-nephrine, tretinoin, etc.), M receptor blockers (such as blockers or antagonists or inhibitors against M2 or M3 receptors), atropine or atropine sulfate, dibazol, polyunsaturated fatty acids (such as DHA, EPA), homatropine, anisodamine (racemic), scopolamine, tropicamide, 7-methyl xanthine, nicotinic acid, piracetam, salvia extract, safflower extract, bear bile extract, fish oil, adenosine triphosphate (ATP), smooth muscle relaxants, drugs to prevent vasospasm, non-selective adenosine antagonists, vasodilators, mydriatic components, components to remove hyperemia, components to regulate eye muscles (such as ciliary muscles), components of anti-inflammatory agents, components of astringents, components of antihistamines, components of antiallergics, components to inhibit collagen degradation, components of hepatoprotective agents (to avoid or reduce liver toxicity), components to enhance the blood-retinal barrier (to make it more difficult for compounds to penetrate through the physiological barrier), amino acids, components of antibacterial agents, components of antioxidants (such as vitamin C, tea polyphenols, glutathione, etc.), saccharides, polymers or derivatives thereof, cellulose or derivatives thereof, components of local anesthetics, components of amblyopia treatment, components of glaucoma treatment, miRNAs and their modifications, therapeutic components for ophthalmic diseases, excipients, etc.

8. The use of any of the preceding claims, wherein lipoic acid or choline ester of lipoic acid, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts or esters, or its prodrugs, or its metabolites, or its related compounds or extracts, or its crystal type compounds, or combinations of these substances are formulated or designed into continuous administration forms, or simultaneous administration forms, or sequential administration forms, or alternating administration forms, or interval administration forms, or separate administration forms with one or more myopia progression delaying drugs and / or myopia treatment drugs.

9. The use of any of the preceding claims, wherein the related compounds include but are not limited to: all the compounds listed in CN115279745A and CN 111315369 A, and salts formed by lipoic acid or lipoic acid ester, preferably the salt form of choline ester of lipoic acid, including but not limited to choline ester of lipoic acid toluenesulfonate, choline ester of lipoic acid benzenesulfonate, choline ester of lipoic acid chloride or choline ester of lipoic acid iodide; or conjugates of these substances are compounds in Figure 3; or 6-(benzylthio)-8-[(hydroxyphenylmethyl)thio]octanoic acid, lipoamide (1,2-dithiolane-3-pentanamide), 8-(ethyl disulfide)-6-(phenyl disulfide) octanoic acid, lipoic acid chloride, 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-thiaselenolani-5-yl)pentanoic acid, 5-(1,2-thiaselenolan-3-yl)pentanoic acid, 6,8-dimercaptooctanoic acid.

10. Use according to one of the preceding claims, characterized in that, The preparation is an oral preparation or a cosmetic product of health products, food, dietary supplements, nutritional products, drinks, etc.

11. Use according to one of the preceding claims, characterized in that, The device is an instrument, equipment, consumable, system, medical device, health care product or product changing the appearance of the eye, such as a contact lens, glasses, an intraocular lens, a suture, an OK lens cleaning (maintenance) system, an eye patch, an eye-care patch, a beauty lens, a microneedle, an eye spray system, an eye massager, an eye fumigator, an ocular surface drug delivery device, an intraocular drug delivery device, an ocular fundus drug delivery device, an implanted pump, a wearable device, an acupoint massager, an eye relaxation device, a myopia treatment device or a combination of a drug and a device for myopia prevention and control, which can release a drug or has a drug delivery function or potential drug delivery capability.

12. Use according to one of the preceding claims, characterized in that, Liponic Acid or Lipoic Acid Choline, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances, as the only active ingredient or main active ingredient or direct active ingredient; And / or: the content or efficacy of Lipoic Acid or Lipoic Acid Choline, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances, is less than 1% of the total active ingredients of the use, or more than 1%, 10%, 20%, 30%, 40%, or more than 50%, 60%, 70%, 80%, 90%, or 100%; And / or: the content, concentration or proportion of Lipoic Acid or Lipoic Acid Choline, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device is at least 0.001%, or at least 0.05%, or at least 0.15%; And / or: the efficacy of Lipoic Acid or Lipoic Acid Choline, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances is more than 20% of the total raw material ingredients or total active ingredients of the use, preferably more than 50%; The percentage (%) can be a mass ratio, or a molar ratio, or a mass-volume ratio, or a contribution rate to the efficacy of the use.

13. Use according to one of the preceding claims, characterized in that, The concentration of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device 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 (such as about 46 mM, i.e. 0.94%); and / or the concentration or proportion of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device is higher than 0.0005%, preferably higher than 0.025%, preferably higher than 0.05%, more preferably higher than 0.1%, more preferably higher than 1%, the percentage (%) can be mass / volume concentration (grams per 100 milliliters) or mass percentage or molar (number) ratio.

14. A topically-applied medicament, formulation, composition or device for myopia therapy or control of myopia progression, characterised in that, The concentration of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device 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; and / or: the concentration or proportion of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device is not less than 0.0001%, preferably not less than 0.001%, preferably not less than 0.01%, more preferably not less than 0.1%, more preferably not less than 0.8%, the percentage (%) can be mass / volume concentration (grams per 100 milliliters) or mass percentage or molar (number) ratio.

15. A pharmaceutical composition or a fixed combination comprising at least two active substances, characterized in that The concentration of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the drug, preparation, composition or device 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; 16. The pharmaceutical composition or combined preparation of claim 15, wherein The amount, concentration and / or efficacy of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances in the pharmaceutical composition or compound preparation is not less than the amount, concentration and / or efficacy of any other active substance for treating myopia and / or controlling the progression of myopia.

17. The pharmaceutical composition or the pharmaceutical preparation according to claim 15 or 16, characterized in that The preparation includes but is not limited to eye drops (eye drops), eye ointment, eye spray, implant sheet, eye gel, eye patch, eye microspheres, eye sustained-release preparation, periocular injection, or intraocular injection.

18. An ophthalmic formulation, characterized in that, The preparation includes but is not limited to eye drops (eye drops), eye ointment, eye spray, implant sheet, eye gel, eye patch, eye microspheres, eye sustained-release preparation, periocular injection, or intraocular injection.

19. The formulation of claim 18, wherein, The content of lipoic acid or lipoic acid choline ester, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt or ester, or its prodrug, or its metabolite, or its related compound or extract, or its crystal type compound, or a combination of these substances is a therapeutically effective amount.

20. The method of any of the above claims, wherein ​

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