Methods and pharmaceutical compositions for treating myopia

Abstract

The present application relates to methods and pharmaceutical compositions for treating myopia. The pharmaceutical compositions or methods of the present application can effectively prevent and control myopia, and are safe without obvious side effects, and have good clinical application prospects.

Description

[0001] This application is a divisional application of the patent application with the application date of 2022.04.29, the Chinese patent application number of 202210472306.1, and the invention patent application name of "Method and pharmaceutical composition for treating myopia".

[0002] Related Applications

[0003] The disclosure of this application claims priority to Chinese patent application number 202110485864.7, filed on April 30, 2021, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0004] The present application relates to a method and a pharmaceutical composition for treating myopia, and belongs to the field of medicine. BACKGROUND

[0005] Myopia has many hazards. In addition to causing blurred vision at a distance, myopia, especially high myopia, can also cause serious complications such as glaucoma, cataract, retinal detachment, retinal tear, posterior scleral staphyloma, macular hemorrhage or myopic maculopathy, choroidal neovascularization, etc., which can damage the quality of life related to vision, increase the difficulty of vision-related work, cause vision damage, and even blindness (Chen-Wei Pan, Ophthalmic Physiol Opt. 2012 Jan;32(1):3-16. and Seang-Mei Saw, Ophthalmic Physiol Opt. 2005 Sep;25(5):381-91.). SUMMARY

[0006] In view of the above technical problems, the present application provides the use of benzaldehyde lysine or benzaldehyde acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or its derivative, or its crystal type compound, or a combination of these substances, characterized in that the use is one or simultaneously satisfies at least two of the following:

[0007] (a) for preventing and / or treating myopia and its related symptoms;

[0008] (b) for delaying, weakening or treating abnormal development of the eyeball associated with refractive errors;

[0009] (c) for an individual to obtain clearer distance vision without the aid of or changing glasses (such as myopic frame glasses or OK glasses) or relying on other vision correction means (such as refractive surgery);

[0010] (d) for controlling, inhibiting, delaying or slowing down the process (speed) of the refractive power of myopic individuals or individuals with a tendency to develop myopia becoming more negative;

[0011] (e) for use in preventing and / or treating myopia and its associated symptoms in conjunction with surgical procedures (e.g. refractive surgery, myopic laser keratotomy, lens surgery) or other vision correction means (e.g. contact lenses);

[0012] (f) for use in preventing and / or treating myopia and its associated symptoms in conjunction with one or more other drugs;

[0013] (g) for use in reducing the distance between the retina and the lens, preferably in myopic individuals or individuals with a tendency to develop myopia;

[0014] (h) for use in reducing myopia, or treating myopic eye, or myopic eye treatment, or controlling myopia progression, or myopia correction, or alleviating myopia, or prevention of myopia in adolescents;

[0015] (i) for use in inhibiting or treating myopia caused by lens pathology;

[0016] (j) for use in the manufacture of a pharmaceutical composition, preparation or device for at least one of the uses described in (a) to (i) above.

[0017] In some embodiments, the benzoxaborole or benzoxaborole acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or its derivative, or its crystal form compound, or a combination of these substances, is used as the only active ingredient or the main active ingredient.

[0018] In some embodiments, the only active ingredient or the main active ingredient is in an amount of more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredients, and the percentage is a mass ratio or a molar ratio.

[0019] In some embodiments, the substances or their combinations and the one or more other drugs are 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.

[0020] In some embodiments, the abnormal development of the eyeball associated with refractive error is mainly induced by environmental factors or mainly caused by human factors (such as long-term close reading, frequent use of electronic screens, lack of myopic opportunities for distance vision, improper use of refractive correction glasses, drug side effects, obesity, trauma, poor learning environment lighting, lack of outdoor exercise) during the early stage of the individual (such as 2-28 years old in humans), and genetic factors are secondary factors, accompanying factors, synergistic factors, or the abnormal development of refractive development is completely unrelated to genetic factors, and the main feature is that the focal point of parallel light passing through the refractive system of the eye falls in front of the retina in the accommodation relaxation state.

[0021] In some embodiments, the drug is administered by systemic administration (such as oral administration, intravenous infusion), or local administration (such as eye drops, intravitreal injection, skin ointment or cream application), or parenteral administration (such as transmucosal administration, transdermal administration, microneedle administration), or non-invasive administration (such as applying eye ointment to the cornea or squeezing into the capsule formed by stretching the lower eyelid), or non-invasive administration (such as using an eye spray).

[0022] In some embodiments, the skin ointment or cream application is applied by 3% skin ointment or eye ointment.

[0023] In some embodiments, the above administration methods (such as eye drops, oral administration) are used simultaneously, or in combination, or alternately, or interval, or alone, or one of them is selected.

[0024] In some embodiments, the preparation used for local administration includes but is not limited to aqueous, oily or suspension agents, which can be added with ingredients with pharmacological activity and / or physiological activity, such as mydriatic components, decongestant components, ocular muscle (such as ciliary muscle) adjusting components, anti-inflammatory agent components, astringent components, antihistamine components, antiallergic components, hepatoprotective components (to avoid or reduce liver toxicity), blood-retinal barrier enhancing components (to make the compound more difficult to penetrate through the physiological barrier), vitamins, amino acids, antibacterial agent components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, glaucoma treatment components, cataract treatment components, etc.

[0025] In some embodiments, the concentration or proportion of these substances or combinations thereof in the pharmaceutical composition, preparation or device is at least not less than 0.01%, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more preferably 0.1%; or the concentration or proportion of these substances or combinations thereof is less than 0.01%, and the percentage is expressed as mass / volume concentration (ratio) or mass ratio or molar (number) ratio.

[0026] In some embodiments, the pharmaceutical composition or preparation can be an injection, a tablet, a lyophilized powder injection, a capsule, an effervescent tablet, a chewable tablet, a buccal tablet, a granule, an ointment, a syrup, an oral solution, an aerosol, a nasal drop, a topical preparation, an oral preparation, etc.; preferably 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 or intraocular injection; and can also be a free solution, an oil-water mixture, a suspension, a liniment, a lotion, a cream, a drop, a bolus, a spray, a paste, a patch, a paste, a pill, a suppository or an emulsion.

[0027] In some embodiments, the myopic individual or the individual with a tendency to develop myopia is a human, who can be a child, a teenager, a middle-aged person or an elderly person, preferably a human aged 3 to 26 years old, more preferably a human aged 6 to 18 years old; or an adult, or a minor, preferably a human whose eye (eyeball) is still in the growth and development stage; or a school-age human, preferably a human in grades one to twelve.

[0028] In some embodiments, the myopia is refractive myopia or axial myopia; 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, semi-true semi-pseudomyopia (mixed) myopia; childhood and / or adolescent myopia (preferably a human aged 3-26 years old, more preferably a human aged 6-18 years old), minor myopia, adolescent myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; childhood and / or adolescent axial myopia (preferably a human aged 3-26 years old, more preferably a human aged 6-18 years old); school-age and preschool-age axial myopia; primary myopia, secondary myopia; childhood and / or adolescent primary myopia (preferably a human aged 3-26 years old, more preferably a human aged 6-18 years old); childhood and / or adolescent progressive myopia (preferably a human aged 3-26 years old, more preferably a human aged 6-18 years old); curvature myopia, index myopia, positional myopia, curvature myopia; 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, myopia caused by insufficient outdoor exercise, accommodative stress myopia, childhood myopia, environment factor dominant myopia.

[0029] In some embodiments, the myopia-related symptoms include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior scleral staphyloma, 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, aniseikonia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent rubbing of the eyes, aniseikonia, 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 seeing while driving, especially at night (night myopia), retinal atrophic degeneration (hemorrhage and tears), subretinal neovascularization, and ocular atrophy.

[0030] In some embodiments, the pharmaceutical composition, formulation, or device further comprises a medical preparation or drug, including but not limited to myopia treatment drugs (such as atropine, dibazol, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), ambenonium, echothiophate, timolol maleate, epinephrine, pirenzepine, pyrazine, pirenzepine, pirenzepine, pirenzepine, methylamine, chloroponamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as blockers or antagonists or inhibitors against M3 receptors), benzodiazole or various salt forms thereof, benzodiazole lysine or various salt forms thereof, polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, epinephrine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamin, adenosine triphosphate (ATP), non-selective adenosine acid antagonist, vasodilator, mydriatic, smooth muscle relaxant, anti-vasospasm drug, collagen metabolism regulator, antiallergic drug, anti-inflammatory drug, hepatoprotective drug, therapeutic component for ophthalmic disease, topical ophthalmic anesthetic, or ophthalmic preparation.

[0031] In some embodiments, the one or more other drugs include, but are not limited to, myopia treatment drugs (such as atropine, dibazol, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, ambenonium, phentolamine, timolol maleate, epinephrine, pyrazine, pindolol, piperphenidol, pirenzepine, methylamine, chloroponamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, tretinoin, etc.), M receptor blockers (such as blockers or antagonists or inhibitors against M3 receptors), benzalkonium chloride or various salt forms thereof, benzalkonium lactate or various salt forms thereof, polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, epinephrine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, danshen extract, safflower extract, fish oil, bear bile extract, vitamin, adenosine triphosphate (ATP), non-selective adenosine acid antagonists, vasodilators, smooth muscle relaxants, drugs to prevent vasospasm, drugs to regulate collagen metabolism, antiallergic drugs, anti-inflammatory drugs, liver-protecting drugs, therapeutic components for ophthalmic diseases, topical ophthalmic anesthetics, mydriatics, or ophthalmic preparations or drugs.

[0032] In some embodiments, the preparation can also be an oral preparation or a cosmetic product of health products, food, dietary supplements, nutritional products, drinks, etc.; wherein the cosmetic product can be one or a combination of free solutions, oil-water mixtures, suspensions, liniments, lotions, sprays, creams, drops, punches, ointments, pastes, pills, suppositories, emulsions, patches.

[0033] In some embodiments, the device is an instrument, equipment, consumables, system, medical device, health product, or product for 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, a vision-improving patch, a beauty lens, a microneedle, an eye spray system, an eye massager (myopia massager), an eye fumigation instrument, 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 massage instrument, an eye relaxation device, a myopia treatment instrument, or a combination of a drug and a medical instrument for myopia prevention and control, which can release drugs or has a drug delivery function or potential drug delivery capability. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 : Benzalkonium lactate controls the progression of myopia.

[0035] Figure 2 : Safety of benzalkonium lactate eye drops treatment.

[0036] Figure 3 : Different concentrations of benzalkonium lactate eye drops for myopia prevention and control.

[0037] Figure 4 Safety of different concentrations of benzydamine hydrochloride treatment.

[0038] Figure 5 Benzydamine hydrochloride increases choroidal thickness in myopic individuals.

[0039] Figure 6 Therapeutic effect of benzydamine hydrochloride eye drops and bendazac ophthalmic ointment eye application.

[0040] Figure 7 Safety of benzydamine hydrochloride eye drops and bendazac ophthalmic ointment eye application.

[0041] wherein, Figures 1-5 Among them, the statistical difference of benzydamine hydrochloride (bendazac) administration group and negative control group. The statistical difference of atropine administration group and negative control group. * represents p<0.05, ** represents p<0.01, *** represents p<0.001, # represents p<0.05, ## represents p<0.01, ### represents p<0.001. Figure 6 and Figure 7 Among them, * the difference between benzydamine hydrochloride eye drops and normal saline group, # the statistical difference between atropine administration group and normal saline group, $ the difference between bendazac ophthalmic ointment and normal saline group. * represents p<0.05, *** represents p<0.001, # represents p<0.05, ## represents p<0.01, $ represents p<0.05.

[0042] Figure 8 Simple lysine cannot treat myopia, # the difference between BDL and normal saline solvent group, # represents p<0.05, ## represents p<0.01, ### represents p<0.001.

[0043] Figure 9 Simple bendazac eye drops have the same myopia treatment effect as benzydamine hydrochloride eye drops. Among them, # the difference between BDL and normal saline solvent group, * the difference between bendazac and vehicle solvent group. * represents p<0.05, *** represents p<0.001, ## represents p<0.01, ### represents p<0.001.

[0044] Figure 10 Safety of simple bendazac treatment.

[0045] Figure 11 Safety of simple lysine treatment.

[0046] Figure 12 Bendazac inhibits the decrease of choroidal thickness in myopic individuals, * represents p<0.05.

[0047] Figure 13: Sorbinil and Zopolrestat did not treat myopia.

[0048] Figure 14 : Safety evaluation of aldose reductase inhibitor administration.

[0049] Figure 15 : Methylhydroxybenzylamine did not treat myopia. The statistical difference between atropine administration group and negative control group, ## represents p < 0.01. DETAILED DESCRIPTION

[0050] The embodiments of the technical scheme of the present application will be described in detail below with reference to the accompanying drawings. The following examples are only used to more clearly illustrate the technical scheme of the present application, and therefore only serve as examples, and cannot limit the protection scope of the present application.

[0051] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0052] Myopia is the most common refractive error, which is defined as a refractive state where parallel rays of light are brought to focus in front of the retina in the unaccommodated state. There are four common classifications of myopia: (1) According to the size of the refractive error, myopia can be classified as mild (low), moderate, and high (severe); (2) According to the abnormality of refractive components, myopia can be classified as refractive myopia and axial myopia; (3) According to the presence of pathological changes, myopia can be classified as pathological myopia and simple myopia; (4) According to the cause of myopia, myopia can be classified as primary myopia and concurrent / secondary myopia. Regardless of the type of myopia, the mismatch between the components of the refractive system (i.e., refractive media, including cornea, lens, and vitreous) is the key to the formation and severity of myopia. For example, in the case of refractive myopia, if the corneal curvature of an individual is abnormal, the focal point of parallel light after passing through the cornea will deviate from the original position on the retina, causing a change in refractive error, which is commonly caused by keratoconus; for example, changes in the refractive index of the lens caused by certain diseases will directly affect the projection of parallel light on the retina, and if the focal point of parallel light falls in front of the retina, it is called myopia caused by lens disease; the mismatch of refractive components also includes the posterior displacement of the retina caused by the enlargement of the vitreous cavity, which causes the focal point of the distant object to fall in front of the retina, resulting in a negative refractive error. As mentioned above, the classification of myopia may be further subdivided in clinical practice according to specific circumstances. However, the refractive error is recognized as the only indicator for determining all types of myopia, measuring its severity, and evaluating the effectiveness of myopia treatment. According to the 'Guidelines for Clinical Research on Drugs for Controlling Myopia Progression' and the consensus view of the academic community, the most common type of myopia in children and adolescents (especially 6-18 years old) is axial simple myopia (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.), and the main part of the axial elongation is in the posterior pole of the eyeball. Consistent with the myopia in humans, axial elongation, scleral thinning, and scleral collagen fiber thinning have been found in long-term experimental myopia models of mammalian animals (such as tree shrews, marmosets, and guinea pigs) (Neville A McBrien, Prog Retin Eye Res. 2003 May;22(3):307-38.).In the actual preclinical development stage of drugs, researchers almost all use two classic myopia disease models of form-deprivation (FD) or lens induced (LI) to evaluate the efficacy of myopia prevention and control (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.), and the compounds with both therapeutic and preventive effects on the two myopia models are considered to have the most drug potential.

[0053] The pathogenesis of myopia is still not fully understood. It is currently believed that environmental factors are the main inducements for the high prevalence of myopia, affecting the prevalence and severity of myopia, while genetic myopia cases are relatively rare. Environmental factors include over accommodation, peripheral retinal hyperopic defocus, lighting (abnormal light), form deprivation, etc. The specific mechanism of these factors inducing myopia may be that after the retina recognizes the near visual information, these signals are transmitted to the sclera through the choroid, causing changes in the extracellular matrix components of the sclera cells, ultimately triggering a decrease in refractive power until the refractive power becomes negative, forming myopia. This can also be simply summarized as optical defocus triggers defocus-specific signals, thereby regulating the refractive development of the eye (Wen-Yi Wang, Biomed Pharmacother. 2021 Jan;133:111092. and Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov;40(11):833-852. and David Troilo, Invest Ophthalmol Vis Sci. 2019 Feb 28;60(3):M31-M88.). In normally developing individuals, the size of the eye also grows along with other parts of the body. Humans, like other mammals, are hyperopic at birth and during early childhood. During the subsequent growth stage, with the further development of each refractive component in the eyeball and the moderate elongation of the eye axis, the imaging focus of parallel light and the retina overlap (i.e., the focus falls on the retina), turning into emmetropia. If there is a long-term continuous near visual information during this development process, a series of refractive component mismatches including excessive elongation of the eye axis will occur, causing the imaging focus of parallel light to fall in front of the retina, forming myopia. Therefore, how to ensure that each refractive component of the eyeball matches during the development process and prevent the eyeball from growing too much is the key to the prevention and control of myopia. Previous studies have found that refractive development abnormalities in myopic individuals are related to the loss of scleral tissue caused by decreased synthesis of connective tissue and increased degradation of collagen type I (COL1), and dopamine, insulin, nitric oxide or are involved.

[0054] Currently, frame glasses are the main way to correct myopia in children and adolescents, and adult patients can use laser surgery to correct myopia. Although myopia can be corrected by glasses, contact lenses or refractive surgery in most cases, it cannot delay its progression. Once any type of myopia develops into high myopia, it will be a particularly dangerous vision problem, because there is a high risk of complications of the retina, choroid and sclera. Therefore, myopia correction cannot be simply understood as myopia treatment. Clinically, myopia treatment mainly manifests as inhibition or slowing of myopia progression, which involves both optical and pharmacological methods. Orthokeratology lenses can delay myopia progression in children and adolescents, but the effect varies greatly between individuals, and requires close assistance from professional optometrists (Jinhai Huang, Ophthalmology. 2016 Apr; 123 (4): 697-708.); the pharmacological options for myopia control are very limited (Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov; 40 (11): 833-852.), for example, atropine eye drops have shown myopia treatment effects in many studies, but clinical observations have shown that the degree of myopia rebounds after stopping the drug, and the use process is accompanied by mydriasis and photophobia and other serious side effects (Prema Ganesan, Expert Rev Ophthalmol. 2010 Dec 1; 5 (6): 759-787.), and it has not been approved for use in China by the National Medical Products Administration; 7-methylxanthine is another drug being developed to control myopia, and its safety and effectiveness still need more data to support (Klaus Trier, J Ocul Biol Dis Infor. 2008 Dec; 1 (2-4): 85-93. and Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov; 40 (11): 833-852.). Therefore, there is currently a lack of drugs with clear efficacy and safety for controlling myopia progression, and there is an unmet clinical need in this disease area.

[0055] Bendazac lysine (BDL) or bendazac is known to have analgesic and antipruritic effects, anti-cell necrosis, choleretic and treatment of dyslipidemia. Clinically, bendazac lysine treats cataracts by preventing lens protein denaturation.

[0056] The inventors unexpectedly found that bendazac or bendazac lysine can have a therapeutic, preventive or slowing effect on myopia and its related symptoms, which manifests as the compound being able to effectively control, inhibit, delay or slow down the progression of myopia, ultimately for the preparation of preparations or pharmaceutical compositions for the prevention and treatment of myopia, and the compound has the advantages of high drug safety and few adverse reactions.

[0057] In view of the above findings, the present application provides the use of benzydamine hydrochloride or benzydamine acid, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analogue thereof or a derivative thereof, or a crystalline compound thereof, or a combination of these, characterized in that said use is one or simultaneously satisfies at least two of the following:

[0058] (a) for preventing and / or treating myopia and its associated symptoms;

[0059] (b) for inhibiting, slowing down the elongation of the ocular axis and / or the increase of the vitreous chamber length (depth) of a myopic individual or of an individual having a predisposition to develop myopia;

[0060] (c) for increasing the choroidal thickness and / or inhibiting the decrease of the choroidal thickness of a myopic individual or of an individual having a predisposition to develop myopia;

[0061] (d) for delaying, reducing or treating the abnormal development of the eye associated with refractive errors;

[0062] (e) for providing an individual with clearer distance vision without the aid of or the change of lenses (such as myopic frame glasses or OK lenses) or without the reliance on other vision correction means (such as refractive surgery);

[0063] (f) for controlling, inhibiting, delaying or slowing down the progression (speed) of the refractive error of a myopic individual or of an individual having a predisposition to develop myopia;

[0064] (g) for preventing and / or treating myopia and its associated symptoms in combination with surgery (such as refractive correction surgery, myopic corneal laser surgery, lens surgery) or other vision correction means (such as contact lenses);

[0065] (h) for preventing and / or treating myopia and myopia associated symptoms in combination with one or more other drugs;

[0066] (i) for reducing the distance between the retina and the lens, preferably in a myopic individual or in an individual having a predisposition to develop myopia;

[0067] (j) for reducing myopia, or treating myopic eye, or myopic eye treatment, or controlling myopia progression, or myopia correction, or alleviating myopia, or prevention of myopia in young people;

[0068] (k) for inhibiting or treating myopia caused by lens pathology;

[0069] (l) for maintaining refractive stability in an individual whose eyeball is in a developmental stage, in particular, controlling the speed of ocular axial elongation to maintain the matching between them, preferably, the matching can keep emmetropia or keep emmetropia as much as possible;

[0070] (m) for maintaining refractive stability in an individual whose eyeball is in a developmental stage, in particular, controlling the speed of ocular axial elongation to maintain the matching between them, preferably, the matching can avoid the occurrence of myopia or inhibit the increase of myopia degree;

[0071] (n) for preparing a pharmaceutical composition, preparation or device to achieve at least one of the uses of (a) to (m) above.

[0072] In some embodiments, the benzoxamide or benzoxal acid, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or its derivative, or its crystal type compound, or a combination of these substances, is used as the only active ingredient or the main active ingredient.

[0073] In some embodiments, the only active ingredient or the main active ingredient is more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredients, and the percentage is mass ratio or molar ratio.

[0074] In some embodiments, these substances or their combinations 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 the one or more other drugs.

[0075] In some embodiments, the abnormal development of the eyeball associated with refractive errors is an abnormality of refractive development in an individual in the early stage of life (such as 2-28 years old in humans), which is mainly induced by environmental factors or mainly caused by human factors (such as long-term close reading, frequent use of electronic screens, lack of opportunity to see far in near vision, improper use of refractive glasses, drug side effects, obesity, trauma, poor learning environment lighting, lack of outdoor exercise), while genetic factors are secondary factors, accompanying factors, synergistic factors, or the abnormal development of refractive development is completely unrelated to genetic factors, and the main feature is that in the accommodation relaxation state, the focal point of parallel light after being refracted by the refractive system of the eye falls in front of the retina.

[0076] In some embodiments, the analogues or derivatives of benzoxamide or benzoxal acid are one of the following compounds (a) to (c):

[0077] (a) wherein R1is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; and R2is H, P (Protium), D (Deuterium), T (Tritium), K, or Na.

[0078] (b) wherein R1is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; and R2is H, P (Protium), D (Deuterium), T (Tritium), K, or Na.

[0079] (c) wherein R1is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; and R2is H, P (Protium), D (Deuterium), T (Tritium), K, or Na.

[0080] In some embodiments, the administration is by systemic administration (e.g., oral, intravenous drip), or local administration (e.g., eye drop, intravitreal injection, skin ointment or cream, preferably, 3% skin ointment or eye cream), or parenteral administration (e.g., by mucosal administration, transdermal administration, microneedle administration), or non-invasive administration (e.g., by applying eye cream to the cornea or squeezing into the pocket created by stretching the lower eyelid), or non-invasive administration (e.g., by using an eye spray).

[0081] In some embodiments, the administration is by systemic administration (e.g., oral, intravenous drip), or local administration (e.g., eye drop, intravitreal injection, skin ointment or cream, preferably, 3% skin ointment or eye cream), or parenteral administration (e.g., by mucosal administration, transdermal administration, microneedle administration), or non-invasive administration (e.g., by applying eye cream to the cornea or squeezing into the pocket created by stretching the lower eyelid), or non-invasive administration (e.g., by using an eye spray).

[0082] In some embodiments, the formulation used for local administration includes, but is not limited to, aqueous, oily, or suspension formulations, which can include ingredients with pharmacological and / or physiological activity, such as mydriatic components, decongestant components, ocular muscle (e.g., ciliary muscle) modulating components, anti-inflammatory components, astringent components, antihistamine components, antiallergic components, hepatoprotective (to avoid or reduce liver toxicity) components, components to enhance the blood-retinal barrier (to make the compound more difficult to penetrate through this physiological barrier), local anesthetic components, glaucoma treatment components, cataract treatment components, etc.

[0083] In some embodiments, the concentration or proportion of these substances or combinations thereof in the pharmaceutical composition, preparation or device is at least no less than 0.01%, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more preferably 0.1%; or the concentration or proportion of these substances or combinations thereof is less than 0.01%, the percentage being expressed as mass / volume concentration (ratio) or mass ratio or molar (number) ratio, preferably the concentration is the use concentration or storage concentration.

[0084] In some embodiments, the concentration of these substances or combinations thereof is, for example, 0.01%-0.05%, 0.05%-0.1%, 0.1%-0.5%, the percentage being expressed as mass / volume concentration (ratio), preferably the concentration is the use concentration or storage concentration.

[0085] In some embodiments, the pharmaceutical composition or preparation can be an injection, a tablet, a lyophilized powder injection, a capsule, an effervescent tablet, a chewable tablet, a buccal tablet, a granule, an ointment, a syrup, an oral solution, an aerosol, a nasal drop, a topical preparation, an oral preparation, etc.; preferably an ophthalmic dosage form, 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 or intraocular injection; and can also be a free solution, an oil-water mixture, a suspension, a liniment, a lotion, a cream, a drop, a bolus, a spray, a paste, a patch, a paste, a pill, a suppository or an emulsion.

[0086] In some embodiments, the myopic individual or individual with a tendency to develop myopia is a human, which can be a child, a teenager, a middle-aged person or an elderly person, preferably a human aged 3 to 26 years old, more preferably a human aged 6 to 18 years old; or an adult, or a minor, preferably a human whose eye (eyeball) is still in the growth and development stage; or a school-age human, preferably a human in grades one to twelve.

[0087] In some embodiments, the myopia is myopia or axial myopia; congenital myopia (born or preschool myopia), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), late-onset myopia (adult), low myopia (mild myopia), moderate myopia, high myopia (severe myopia), pseudomyopia, true myopia, semi-true and semi-pseudomyopia (mixed myopia), childhood and / or adolescent myopia (preferably the population age is 3-26 years old, more preferably the population age is 6-18 years old), juvenile myopia, adolescent myopia, adult myopia, elderly myopia, simple myopia, pathological myopia, axial simple myopia, simple axial myopia, childhood and / or adolescent axial myopia (preferably the population age is 3-26 years old, more preferably the population age is 6-18 years old), school-age and preschool population axial myopia, primary myopia, secondary myopia, childhood and / or adolescent primary myopia (preferably the population age is 3-26 years old, more preferably the population age is 6-18 years old), childhood and / or adolescent progressive myopia (preferably the population age is 3-26 years old, more preferably the population age is 6-18 years old), curvature myopia, index myopia, positional myopia, curvature myopia, myopia caused by long-term close-up eye use, myopia and pseudomyopia caused by visual fatigue, negative diopter caused by adverse drug reactions, myopia, 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 causes of imaging focus of distant objects falling in front of the retina, myopia with poor or no effect on atropine treatment, myopia caused by lack of outdoor exercise, accommodative myopia, childhood myopia, myopia dominated by environmental factors.

[0088] In some embodiments, the aforementioned myopia includes or excludes myopia or symptoms of myopia caused by lens lesions.

[0089] In some embodiments, the myopia-related symptoms or signs include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior scleral staphyloma, 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, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent eye rubbing, 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, difficulty seeing while driving, especially at night (night myopia), retinal atrophy degeneration (hemorrhage and tears), subretinal neovascularization, and eyeball atrophy.

[0090] In some embodiments, the pharmaceutical composition, formulation or device also comprises a medical preparation or drug, including but not limited to myopia treatment drugs (such as atropine, dibazol, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), ambenonium, echothiophate, timolol maleate, epinephrine, pirenzepine, pyrazinamide, pindolol, pirenzepine, pimozide, methamphetamine, chloroponamide, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, tretinoin, etc.), M receptor blockers (such as blockers or antagonists or inhibitors against M3 receptors), polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, danshen extract, safflower extract, fish oil, bear bile extract, vitamin, adenosine triphosphate (ATP), non-selective adenosine acid antagonists, vasodilators, mydriatics, smooth muscle relaxants, drugs to prevent vasospasm, drugs to regulate collagen metabolism, antiallergics, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, topical ophthalmic anesthetics, or ophthalmic preparations.

[0091] In some embodiments, the pharmaceutical composition, formulation or device also comprises a medical preparation or drug, including benzydamine or various salt forms thereof, or benzydamine hydrochloride or various salt forms thereof. This means that, in these pharmaceutical compositions, formulations or devices, a combination of "benzydamine or various salt forms thereof" and benzydamine, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound, or a combination of "benzydamine hydrochloride or various salt forms thereof" and benzydamine, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound is ultimately formed; or a combination of "benzydamine or various salt forms thereof" and benzydamine, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound, or a combination of "benzydamine hydrochloride or various salt forms thereof" and benzydamine, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound is ultimately formed.

[0092] In some embodiments, the medical preparation or drug can also be administered simultaneously with the pharmaceutical composition, formulation or device, such as simultaneous or sequential administration in a specific drug (treatment) process, administration on the same day, administration in the same week, administration in the same month, administration in the same year; or interval alternating administration, such as interval of 4 hours alternating administration, interval of 12 hours alternating administration, alternating administration every other day, alternating administration every other week, alternating administration every other month, alternating administration every other year.

[0093] In some embodiments, the one or more other drugs include, but are not limited to, myopia treatment drugs (such as atropine, dibazol, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, ambenonium, phentolamine, timolol maleate, epinephrine, pyrazine, pindolol, piperphenidol, pirenzepine, methylamine, chloroponamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, tretinoin, etc.), M receptor blockers (such as blockers or antagonists or inhibitors against M3 receptors), polyunsaturated fatty acids (such as DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, danshen extract, safflower extract, fish oil, bear bile extract, vitamin, adenosine triphosphate (ATP), non-selective adenosine acid antagonists, vasodilators, smooth muscle relaxants, drugs to prevent vasospasm, drugs to regulate collagen metabolism, antiallergic drugs, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, topical ophthalmic anesthetics, mydriatics, or ophthalmic preparations or drugs.

[0094] In some embodiments, the one or more other drugs can also include benzydamide or various salt forms thereof, or benzydamide lysine or various salt forms thereof. This means that, when these substances of the present application are used in combination with these drugs, they can finally be used in the form of "benzydamide or various salt forms thereof" in combination with benzydamide lysine, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound; or they can finally be used in the form of "benzydamide lysine or various salt forms thereof" in combination with benzydamide, or its optical isomers or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog or its derivative, or its crystal compound.

[0095] In some embodiments, the combination use is that the one or more other drugs are administered at the same time, such as simultaneously or sequentially in a specific drug (treatment) process, on the same day, in the same week, in the same month, in the same year; or are administered 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.

[0096] In some embodiments, the preparation can also be an oral preparation or a cosmetic product of health products, food, dietary supplements, nutritional products, drinks, etc.; wherein the cosmetic product can be one or a combination of free solutions, oil-water mixtures, suspensions (agents), liniments, lotions, sprays, creams, drops, punches, ointments, pastes, pills, suppositories, emulsions, patches.

[0097] In some embodiments, the device is an instrument, apparatus, consumable, system, medical device, healthcare product, or an eye appearance-altering product, such as a contact lens, eyeglasses, intraocular lens, suture, OK lens cleaning (maintenance) system, eye patch, vision-improving patch, cosmetic contact lens, microneedle, eye spray system, eye massager (myopia massager), eye fumigator, ocular surface drug delivery device, intraocular drug delivery device, fundus drug delivery device, implantable pump, wearable device, acupoint massager, eye relaxation device, myopia treatment device, or a combination of a drug and a device for myopia prevention and control, that can release a drug or has a drug delivery function or potential drug delivery capability. In some embodiments, the device can be referred to as an ophthalmic device.

[0098] Terms and Definitions

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of this application; the description and claims of this application as well as the above discussion of the background of the application and the above description of the drawings herein are not to be taken as limiting the present application; the terms "including" and "comprising" and any variations thereof herein are intended to cover both the inclusive and exclusive cases.

[0100] Reference herein to "one or more of something" means that at least one of the element is present; there can be a plurality of such elements present unless otherwise expressly specified.

[0101] In the description of the application, the term "and / or" is merely used to describe an associated relationship between associated objects, which means that there can be three relationships, for example, A and / or B, which can represent the three cases of A alone, A and B together, and B alone. In addition, the character " / " herein generally represents an "or" relationship between the front and rear associated objects.

[0102] Reference herein to "an embodiment" or "embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiment (or "embodiments") can be included in at least one embodiment (or "embodiment") of the present application. The appearance of the phrase in the specification does not necessarily mean the same embodiment (or "embodiment") at each location, nor does it mean that the other embodiments (or "embodiments") are mutually exclusive or alternative embodiments (or "embodiments") to each other. It is explicitly and implicitly understood by those skilled in the art that the embodiments (or "embodiments") described herein can be combined with other embodiments (or "embodiments").

[0103] 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 means "and / or," unless otherwise indicated.

[0104] As used herein, a reference to a range of values for a variable is intended to convey that the application can be practiced with variables that are 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.

[0105] "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 the term is used. If the use of the term "about" is not clear to one of ordinary skill in the art, "about" will mean values that are within 10% of the stated value or within the range of values plus or minus the range of values.

[0106] The term "individual," "subject" includes humans as well as non-human animals, e.g., including farm animals such as sheep, pigs, cows, and horses; pet animals such as dogs and cats; and animals in laboratories such as mice, rats, and non-human primates. In preferred embodiments, the mammal is a human.

[0107] As used herein, "administering" a compound, formulation, test article, 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 appropriate route including, but not limited to, oral, intraocular, intranasal, parenteral (by intravenous, intramuscular, intraperitoneal, or subcutaneous), or topical administration. "Administering" includes self- administration and administration by another.

[0108] In the administration methods herein, "used alone" means that only one administration method is used at each stage of the entire administration process, and the administration method can be changed (but not alternated) at different stages of the administration process.

[0109] In the administration methods herein, "used alternatively" means that only one administration route is used throughout the entire administration process, and the administration route is not changed.

[0110] The term "amino acid" as used herein includes naturally occurring amino acids and synthetic amino acids as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, such as those amino acids found in the protein products of genes. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an alpha-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homo-serine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but otherwise function in a manner similar to the naturally occurring amino acids. Amino acid mimetics refers to chemical compounds that have structures different from the general structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. NATURALLY OCCURRING AMINO ACIDS

[0111] 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 reduction 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, diet, ethnic origin, degree of myopia, rate of myopia progression, and tolerance for drugs. The amount will also depend on the degree, severity, and type of disease, as well as the treatment protocol determined by a medical practitioner. A skilled artisan will be able to determine appropriate dosages depending on these and other factors. The pharmaceutical composition can also be administered in conjunction with one or more other therapeutic compounds, biologies, and therapeutic molecules, such as polypeptides. In the methods described herein, a benzydamide, a benzydalysine 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 a benzydalysine refers to the average level of physiological effect that minimally reduces an ophthalmic disorder, preferably the average level of physiological effect that minimally controls myopia progression.

[0112] The terms "formulation," "pharmaceutical composition," and "composition" as used herein are used interchangeably and can refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms "formulation," "pharmaceutical composition," and "composition" can be used to refer to a mixture of one or more active agents (active ingredients) with a carrier or other excipients. The composition can take almost any physical form, including a solid, a liquid (e.g., a solution), or a gas.

[0113] The term "dosage form" can include one or more formulations or compositions provided in a form for administration to a subject. For example, an injection dosage form can be a formulation or composition prepared in a manner suitable for administration by injection.

[0114] The term "pharmaceutically acceptable" as used herein means approved by a regulatory agency such as the CFDA (China), EMEA (Europe), and / or FDA (US) and / or any other national regulatory agency, for use in animals, and more specifically in humans.

[0115] As used herein, "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 it is suitable for administration to the eye without causing any major adverse reaction.

[0116] The term "simultaneously" as used herein means that at least two active ingredients are administered at the same time or at essentially the same time by the same or different routes (e.g., orally and as eye drops) or that administration and surgery are performed at the same time or at essentially the same time or that administration and application of a therapeutic device are performed at the same time or at essentially the same time.

[0117] The term "separately" as used herein means that at least two active ingredients are administered at the same time or at essentially the same time, but only one way or one substance is limited, e.g., only one active ingredient is administered.

[0118] The term "sequentially" as used herein means that at least two active ingredients are administered at different times, the administration routes being the same or different. More specifically, "sequential application" means that one of the active ingredients is administered completely before the administration of the other active ingredient is started. Thus, one active ingredient can be administered several seconds, minutes, hours or days before the administration of the other active ingredient.

[0119] The terms "treat," "control," "inhibit," "delay," "reduce," "prevent," or "slow," as used herein refer to therapeutic treatment measures and prophylactic or preventative measures, wherein the object is to slow down (lessen) or stop (eliminate or reverse) the target condition or disorder. A subject is successfully treated for an ophthalmic condition, for example, if the subject exhibits observable and / or measurable avoidance, reduction, and elimination of one or more symptoms and signs of the ophthalmic condition, or a slowing of the progression of the ophthalmic condition, after receiving a therapeutic amount of a benzaldehyde amino acid compound or a pharmaceutical composition containing the same according to the methods described herein. It is also to be understood that the various modes of treatment or prophylaxis of medical conditions described herein are intended to mean "substantial," which includes total treatment or prevention as well as less than total treatment or prevention such that there is some biological or medical relevant result. For example, in some embodiments "treatment" does not require 100% elimination or prevention of myopia or myopia symptoms. In some embodiments, "treatment" of myopia or myopia-related symptoms according to the methods of the present application is reduced, inhibited, prevented, and / or reversed by, for example, at least about 5%, at least about 10%, or at least about 20% 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, individual, or specimen that has not been exposed to the compositions or compounds of the 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%) compared to myopia or myopia-related symptoms in the absence of the compounds of the methods of the present application.

[0120] The term "myopia-prone (individual)," as used herein, can be a case where the refractive level has already decreased, but has not yet become negative; can be a case where the individual is susceptible to myopia or is at high risk as predicted or considered by an authority or a professional physician; can be a case where the individual has a family history of myopia; can include a case where the individual receives more near vision information but lacks the opportunity to see far; can refer to a case where the myopia incidence rate or the severity of myopia is not less than the average level once myopia occurs; can refer to a case where the adverse reactions after taking the drug or the risk after surgery is performed include a decrease in refractive power; or can refer to a case where the individual will develop myopia or the refractive power will decrease to 0 or below if no intervention is performed using a drug or other myopia treatment (prevention) means.

[0121] An "ophthalmic composition" or "ophthalmic formulation" or "ophthalmic preparation" refers to an ophthalmic composition, or an ophthalmic pharmaceutical composition, or an ophthalmic pharmaceutical product; or a pharmaceutical, formulation, cosmetic, nutraceutical, drug-device combination, or device for the prevention and / or treatment of ocular diseases, vision protection, maintenance, improvement, avoidance, slowing, or reversal of vision impairment.

[0122] "Fish oil" refers to lipid material derived from higher animals, especially fish (e.g., cod, salmon), squid, seals, and in particular to polyunsaturated fatty acids, including but not limited to Omega-3 unsaturated fatty acids, DHA, EPA, DPA, ALA, nisinic acid, stearidonic acid, eicosatetraenoic acid, or combinations thereof.

[0123] "Analogue" refers to a structural derivative of a parent compound (e.g., bendazac or bendazac lysine as referred to in the present application) which differs from the parent compound by only one element (including an isotope).

[0124] The term "derivative" of a compound as used herein includes any molecule which is functionally and / or structurally related to the compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variant or alkylated (C1-C6) variant, halogenated, deuterated, etc. of the compound. The derivative shall 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 with 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 / thornton-srv / software / SMSD / ). Preferred derivatives shall be related to the parent compound both structurally and functionally, i.e. they shall also retain at least part of the activity of the parent drug, for example the bendazac lysine derivatives or analogues described in the reference Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010), more preferably they shall have a modulating effect on the refractive development. Furthermore, "derivative" also includes metabolites of a drug, e.g. a molecule which is usually produced by (bio-)chemical modification or processing of the drug upon administration to an organism, typically by specialized catalytic systems, and which shows or retains the biological activity of the drug. Metabolites have been disclosed to be responsible for the majority of the therapeutic effect of the parent drug.

[0125] As used herein, "metabolite" means a modified or processed drug that retains at least some of the activity of the parent drug, preferably inhibits the activity of Aldose Reductase (AR) or has a therapeutic, prophylactic or slowing progression effect on myopia and related symptoms.

[0126] As used herein, the term "therapeutically acceptable salt" means a salt or zwitterion form of a compound 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 and can be prepared separately from the appropriate free base form of the compound by reacting the latter 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, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, the basic groups of the compounds disclosed herein can be quaternized with such agents as 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 be formed by coordination of the compounds with alkali or alkaline earth metal ions. Thus, the present application includes sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, among others.

[0127] References herein to "the substance" means benzalkonium hydrochloride or benzalkonium acid, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or analogues or derivatives thereof, a crystalline form thereof.

[0128] "myopia" refers to the condition where parallel rays of light are brought to a focus in front of the retina after passing through the refractive system of the eye in the unaccommodated state. It is classified into myopic refractive and axial myopia according to the refractive cause, and their clinical manifestations are both blurred distance vision and good near vision. In the early stage of myopia, there is often fluctuation of distance vision, and because accommodation is not used or less used when looking at near objects, the convergence function is correspondingly weakened, which easily causes exophoria or exotropia. Myopia-related symptoms also include poor night vision, floaters, flashes of light, etc., and can also cause varying degrees of changes in the fundus, such as myopic arcuate chink, macular hemorrhage or formation of subretinal neovascular tumor, irregular white atrophic spots, or pigment deposition in the form of round black spots (Fuchs spots), retinal peripheral lattice degeneration, cystic degeneration, vitreous liquefaction, turbidity and posterior vitreous detachment at a young age, and a higher risk of retinal breaks and detachment than normal, often due to the length of the anteroposterior diameter of the eye, the protrusion of the eye, the extreme expansion of the posterior part of the eye, the formation of scleral staphyloma, and the like. Those with the above-mentioned clinical symptoms are referred to as pathological myopia.

[0129] Myopia can be a serious debilitating disease of the eye. The underlying defect (risk) of myopia is that the eye is slightly elongated, causing the eye lens to focus light from distant objects slightly in front of the retina. Thus, myopia is often referred to as near vision shortening or near vision dependence. In severe cases, this elongation of the eye stretches and thins certain internal parts of the eye, which increases the risk of retinal detachment, cataracts, glaucoma, blindness, and the like. Thus, myopia is much more than just near vision shortening.

[0130] Myopia exists as an axial elongation of the eye, affecting a large portion of the population. Myopia onset typically occurs during elementary school age and develops until the growth of the eye is complete. Despite the use of corrective lenses, the development of myopia can still lead to increased visual impairment. The present disclosure recognizes the importance of pharmaceutical compositions and therapies for treating, preventing, managing, controlling, inhibiting, slowing, retarding, reducing, delaying, and / or mitigating the onset and progression of myopia, particularly pharmaceutical compositions that facilitate administration or implementation, reduce potential side effects, and provide therapeutic benefits, or combinations thereof, devices containing or delivering the same, and methods of their use.

[0131] A variety of causes of myopia have been discussed and researched in the academic community, such as genetic predisposition, prolonged book work or screen time, insufficient exposure to bright light, and the like. Regardless of the underlying cause of myopia in a given case, which can be one or more of the above-listed causes, the elongated eye associated with myopia weakens for all individuals affected by this condition. Because the eye grows during childhood and school age, myopia typically occurs in school-aged children and adolescents and can persist with these individuals for their entire lives. Thus, active pharmaceutical intervention treatment of individuals, such as school-aged children and adolescents, can improve the quality of life for these individuals when they are young and for the rest of their lives.

[0132] A "myopic individual" or "myopic-prone individual" is a child, an adolescent, a middle-aged person or an elderly person, preferably a person aged 3 to 26 years, more preferably a person aged 6 to 18 years; or is a minor, preferably a person whose eye (eyeball) is still in the growth and development stage; or is a school-aged person, preferably a person in grades one to twelve.

[0133] In the present text, the terms "myopia" and "myopic eye" are not distinguished and can be used interchangeably. The person skilled in the art will understand the meaning of "myopia" or "myopic eye" in the present application according to the context in which it is used.

[0134] The specific types of "myopia" include refractive myopia or axial myopia; congenital myopia (myopia since birth or before school age), early-onset myopia (before the age of 14), late-onset myopia (between the ages of 16 and 18), and 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 person aged 3 to 26 years, more preferably a person aged 6 to 18 years), minor myopia, adult myopia, elderly myopia; simple myopia, pathological myopia; axial simple myopia, simple axial myopia; childhood and / or adolescent axial myopia (preferably a person aged 3 to 26 years, more preferably a person aged 6 to 18 years); school-aged and preschool-aged axial myopia; primary myopia, secondary myopia; childhood and / or adolescent primary myopia (preferably a person aged 3 to 26 years, more preferably a person aged 6 to 18 years); or childhood and / or adolescent progressive myopia (preferably a person aged 3 to 26 years, more preferably a person aged 6 to 18 years); myopia caused by long-term close eye use, myopia caused by visual fatigue and pseudomyopia, and myopia caused by adverse drug reactions.

[0135] "Axial myopia" refers to myopia in which the anteroposterior diameter of the eyeball is too long (the axial length exceeds the normal range, causing it to be mismatched with other refractive components), while the refractive power (the refractive performance of other refractive components such as the cornea and the lens) is basically within the normal range.

[0136] "Refractive myopia" refers to myopia in which the axial length is basically within the normal range, but the refractive power is mainly caused by changes in the refractive performance of the refractive components.

[0137] "Pathological myopia" is also known as degenerative myopia, which is a degenerative disease of the fundus. Patients usually have high myopia diopter (usually more than 600 degrees), and visual function is significantly impaired, with poor distance vision. In addition, visual field, light perception, contrast sensitivity and other abnormalities are also common, often accompanied by poor night vision (night blindness), floaters, flashes and other symptoms. This type of myopia is characterized by significant pathological changes, including thinning and atrophy of the retinal pigment epithelium, choroidal neovascularization and retinal detachment, macular degeneration and other symptoms in patients with fundus, which can cause blindness.

[0138] "Simple myopia" refers to myopia that occurs mainly in school age, and gradually stabilizes with development, with myopia degree below 600 degrees, and no obvious pathological changes in the fundus. It is also called acquired myopia (eye). This type of myopia progresses and can be corrected to normal vision with appropriate lenses, and other visual function indicators are generally normal.

[0139] "Primary myopia" refers specifically to a type of myopia whose cause and mechanism of occurrence cannot be determined using existing diagnostic techniques. During its development, it exhibits specific non-temporary functional-structural changes, including congenital myopia and acquired simple myopia.

[0140] "Concurrent / secondary myopia" refers to temporary 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, and initial cataract myopia). This type of myopia is characterized by a clear inducing factor and repeated fluctuations in vision. This type of myopia is common in the elderly.

[0141] "Axis simple myopia" is also known as simple axis myopia, which belongs to simple myopia. Its characteristic is simple myopia caused by elongation of the eye axis and / or increased vitreous cavity depth, which causes the imaging focus to be located in front of the retina. This type of myopia has normal ocular refractive tissue (such as corneal curvature), and is the most common type of myopia in children and adolescents, mainly occurring in people aged 2 to 30 years.

[0142] "Progressive myopia" refers to a type of myopia in which the diopter continues to decrease over time or with increasing age. If not intervened, this type of myopia will eventually develop into high myopia.

[0143] "Moderate myopia" usually refers to myopia with a diopter of 300 degrees or more but less than 600 degrees.

[0144] "Curvature myopia" is a type of myopia caused solely by an increase in corneal or lens curvature.

[0145] "Index myopia" is mainly caused by an increase in the refractive index of the aqueous humor and lens, leading to an increase in refractive power. It belongs to refractive myopia.

[0146] "accommodative hypermetropia" is a kind of myopia caused by over-accommodation of ciliary muscle and other accommodation organs due to overloading of near vision.

[0147] "lens lesion-induced myopia" refers to a kind of myopia caused by changes in the structure parameters or internal structure of the lens due to protein denaturation of the lens, accompanied by changes in some physical properties such as thickness, hardness, and refractive index, and then causing parallel light to converge in front of the retina after passing through the lens lesion.

[0148] "distance visual acuity" is also known as naked eye distance visual acuity, which refers to the visual acuity measured at a horizontal distance of 5 meters from the visual acuity table, with normal eyes open and staring straight ahead, without wearing glasses or any auxiliary equipment that can increase visual acuity (such as frame glasses, contact lenses, beauty lenses, pinhole lenses, etc.).

[0149] "myopia-related symptoms" include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior scleral staphyloma, retinal detachment, retinal tears, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field defects, progressive or sudden decrease in visual acuity (especially near vision), ocular acid swelling and / or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent eye blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, the need to squint or partially close the eyelids to see distant objects clearly, headache caused by eye fatigue, difficulty driving, especially at night (night myopia), retinal atrophy degeneration (hemorrhage and tear), subretinal neovascularization, and eyeball atrophy.

[0150] "abnormal development of the eyeball" refers to abnormal development of the eyeball in children and adolescents (such as 3-26 years old), which is mainly characterized by excessive length of the eye axis, causing parallel light to form an image in front of the retina after passing through the normal refractive system of the eye; or mainly induced by environmental factors, or mainly caused by human factors (such as long-term close reading, frequent use of electronic screens, lack of distant vision opportunities for near vision, improper use of refractive corrective glasses), while genetic factors are secondary factors, accompanying factors, synergistic factors, or the abnormal development is completely unrelated to genetic factors.

[0151] "Benzyl lysine", chemical name: L-lysine (1-benzyl-1H-indazole-3-oxyl) acetate, molecular formula: C6H 14 N2O2•C 16 H 14 N2O3, molecular weight: 428.49, structural formula as follows:

[0152]

[0153] (I)

[0154] "Bendazac" has the following structure:

[0155]

[0156] (II)

[0157] "Derivatives of bendazac or bendazolic acid" include optical isomers or racemates thereof or metabolites thereof (such as 5-hydroxybendazac), etc., and can specifically include, but are not limited to, those listed by Hong Shen et al. (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010). Commercially available eye drops containing bendazolic acid (such as State Drug Standard Code H20063847) can be used, and processes well known to those skilled in the art can be used to prepare bendazolic acid and its derivatives. An exemplary preparation method includes the following steps: In the first step of synthesis, phenylhydrazine is used as a starting material, and a benzyl group is introduced by benzylization reaction with benzyl chloride to obtain α-benzylphenylhydrazine. In the second step of synthesis, α-benzylphenylhydrazine is reacted with urea under high temperature conditions to form a ring to obtain 3-hydroxy-1-benzylindazole. In the third step of synthesis, 3-hydroxy-1-benzylindazole is subjected to carboxymethylation reaction with chloroacetic acid to obtain bendazac, i.e., α-[(1-benzyl-1H-indazol-3-yl)oxy]acetic acid. In the fourth step of synthesis, bendazac is subjected to salt formation reaction with L-lysine in tetrahydrofuran, and then recrystallized in ethanol to obtain the final product bendazolic acid.

[0158] "Analogues or derivatives of bendazolic acid or bendazac" include, for example, (a)-(c):

[0159] (a) wherein R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; and R2 is H, P (Protium), D (Deuterium), T (Tritium), K or Na;

[0160] (b) wherein R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; and R2 is H, P (Protium), D (Deuterium), T (Tritium), K or Na;

[0161] (c) wherein R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, m-F, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K or Na.

[0162] “Formulation” is an oral product or cosmetic product, such as a health product, food, dietary supplement, nutritional product, drink, etc.; wherein the cosmetic product can be one or a combination of free solution, oil-water mixture, suspension, liniment, lotion, spray, cream, drop, infusion, ointment, paste, pill, suppository, emulsion, patch.

[0163] “Device” is an instrument, equipment, consumable, system, medical device, health product, or product for changing the appearance of the eye, such as a contact lens, glasses, intraocular lens, suture, OK lens cleaning (maintenance) system, eye patch, eye-care patch, beauty lens, microneedle, eye spray system, eye massager (myopia massager), eye fumigation instrument, ocular surface drug delivery device, intraocular drug delivery device, fundus drug delivery device, implant pump, wearable device, or combination of drug and equipment for myopia prevention and control.

[0164] The present application refers to “the only active ingredient or the main active ingredient” as meaning that, in addition to benzydamine hydrochloride or benzydamine acid, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, or its analogues or derivatives, or its crystal type compounds, or combinations of these substances, there is no or only a small amount of other active substances for treating myopia. For example, the content of benzydamine hydrochloride or benzydamine acid, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, or its analogues or derivatives, or its crystal type compounds, or combinations of these substances is more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% of the total active ingredients; or benzydamine hydrochloride or benzydamine acid, or its optical isomers or its racemates, or its solvates, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites, or its analogues or derivatives, or its crystal type compounds, or combinations of these substances contribute more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or 100% to the efficacy of myopia treatment during medication.

[0165] Drug combination therapy is a widely used and powerful strategy in medicine, aiming to achieve synergistic therapeutic effects, reduce dosage and toxicity, and minimize or delay the induction of drug resistance (Chou TC. "Drug combination studies and their synergy quantification using the Chou-Talalay method," Cancer Res. (2010) 70:440-6). The present application discloses the identification of compounds, such as benzbromaric acid, for the treatment, prevention or slowing of myopia and its related symptoms, to improve the effect of myopia (degree) reduction or myopia (progress) slowing, while avoiding or minimizing adverse side effects, such as those observed by atropine therapy. The drug combination of the present application has a significant technical effect in treating, preventing or slowing myopia and its related symptoms, which is superior to atropine, and no adverse reactions such as photophobia and pupil dilation are observed in experiments in addition to improvement in diopter indicators. In the experiments, no discomfort or eye abnormalities were observed in all animals administered, and further based on the existing clinical application of benzbromaric acid or benzbromaric acid, it can be considered that it will have good drug safety in the clinical treatment process of using it to treat, prevent or improve myopia and its related symptoms.

[0166] Through experiments, we unexpectedly found that benzbromaric acid and benzbromaric acid can significantly slow down the progression of negative diopter in form deprivation guinea pigs and negative lens-induced guinea pig myopia models, and can significantly inhibit the elongation of the eye axis, based on which it can be confirmed that benzbromaric acid and its salt form compounds have therapeutic, preventive or control effects on myopia in animals, especially humans, such as school-age children, adolescents or young adults, and can slow down the progression of myopia.

[0167] The present application provides a method for treating or preventing myopia and its related symptoms in a subject, comprising administering to the subject a therapeutically effective amount of benzbromaric acid, benzbromaric acid and / or their therapeutically acceptable salts and derivatives thereof. Preferably, the benzbromaric acid or benzbromaric acid is administered alone, preferably, the benzbromaric acid and / or benzbromaric acid is administered simultaneously or sequentially with other drugs, preferably, the benzbromaric acid and / or benzbromaric acid is administered in the form of a drug combination, preferably, the drug combination is prepared into an ophthalmic preparation, preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmically acceptable carrier.

[0168] The present application also provides a method for inhibiting the progression of axial myopia by inhibiting the elongation of the axial length, comprising administering to a subject a therapeutically effective amount of benzbromarone, benzbromarone lysine and / or their therapeutically acceptable salts and derivatives thereof. Preferably, the benzbromarone or benzbromarone lysine is administered alone, preferably, the benzbromarone and / or benzbromarone lysine is administered simultaneously or sequentially with other drugs, preferably, the benzbromarone and / or benzbromarone lysine is administered in the form of a pharmaceutical composition, 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.

[0169] The present application also provides a method for reducing the myopia degree, comprising administering to a subject a therapeutically effective amount of benzbromarone, benzbromarone lysine and / or their therapeutically acceptable salts and derivatives thereof. Preferably, the benzbromarone or benzbromarone lysine is administered alone, preferably, the benzbromarone and / or benzbromarone lysine is administered simultaneously or sequentially with other drugs, preferably, the benzbromarone and / or benzbromarone lysine is administered in the form of a pharmaceutical composition, 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.

[0170] The present application also provides a hyperopic improving agent for myopic individuals, which can improve the hyperopia of myopic individuals by reducing the distance between the imaging focus of a distant object and the retina. The hyperopic improving agent contains benzbromarone, benzbromarone lysine and / or their therapeutically acceptable salts and derivatives thereof. Preferably, the myopic individual is refractive myopia. Preferably, the myopic individual is axial myopia.

[0171] The present application also relates to a pharmaceutical composition or method for treating, preventing or controlling myopia and its related symptoms in an individual, such as a young child, a school-age child, a teenager or a young adult. In some embodiments, the subject of the treatment of the technical solution of the present application is a teenager, aged 6-28 years old, preferably 6-18 years old, most preferably 12-18 years old. In some embodiments, the subject of the treatment of the technical solution of the present application is an adult. In some examples, the treatment, prevention or control of myopia and its related symptoms can include the use of a therapeutically effective amount of a pharmaceutical composition or dosage form in a subject in need thereof.

[0172] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a benzbromarone compound or its salt and derivative thereof, such as hydrogen, deuterium, tritium substituent.

[0173] In other embodiments, for any one or more of the pharmaceutical compositions, devices, or methods of treatment, wherein the pharmaceutical composition contains at least one of benzydamide or a therapeutically acceptable salt thereof (e.g., benzydamine hydrochloride) or a derivative thereof; or, the pharmaceutical composition comprises benzydamine hydrochloride or a therapeutically acceptable salt thereof or a derivative thereof; preferably, both benzydamide and benzydamine hydrochloride; preferably, both benzydamine hydrochloride and benzydamine calcium phosphate; preferably, benzydamine calcium phosphate; preferably, further comprising a pharmaceutically acceptable carrier; preferably, wherein the device delivers the pharmaceutical composition in a sustained release manner.

[0174] In certain embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the subject (patient) is treated for a period of time between about 0.5 months 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 9 years, or at least 13 years.

[0175] In other embodiments, the pharmaceutical compositions, devices, or methods 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 an aqueous composition, preferably, the aqueous composition has an osmolarity similar to or identical to that of tear fluid; or the pharmaceutical composition is an ophthalmic composition (e.g., an ophthalmic topical composition) or an ophthalmic formulation, preferably, the ophthalmic formulation is an ophthalmic aqueous formulation, an ophthalmic gel formulation, an ophthalmic emulsion, an ophthalmic liposome, an ophthalmic ointment (preferably, the ophthalmic ointment is an ophthalmic ointment containing petrolatum or liquid paraffin); or the pharmaceutical composition is a drop formulation, an eye spray formulation, a topical formulation, a nanoparticle suspension, or a nanodisc, a sustained release formulation, or a subconjunctival depot, etc.

[0176] In certain embodiments, a pharmaceutical composition as disclosed herein can be an ophthalmic aqueous formulation, such as in the form of eye drops. For example, an ophthalmic aqueous formulation as described herein can be packaged in an eye drop bottle and administered as drops. In certain embodiments, an 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 a patient. In certain embodiments, one dose of an ophthalmic aqueous formulation described herein is one drop of the aqueous composition from the eye drop bottle.

[0177] 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 a patient. In certain embodiments, one dose of the ophthalmic gel described herein is one drop of the gel composition from the eye dropper bottle.

[0178] In certain embodiments, the pharmaceutical composition as disclosed herein can be an ophthalmic ointment formulation. For example, the ophthalmic ointment formulation can be packaged in 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 a patient. In certain embodiments, one dose of the ophthalmic ointment is one strip of the ointment composition dispensed through the dispensing nozzle.

[0179] In other embodiments, the pharmaceutical composition is an ocular pharmaceutical composition contained within a contact lens blister pack.

[0180] In other embodiments, the pharmaceutical composition is administered by a non-invasive route of administration.

[0181] In other embodiments, the pharmaceutical 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 device is preferably an ophthalmic device, e.g., it can be understood to mean an object placed on or present in the eye. The device can provide optical correction. Devices include, but are not limited to, beauty lenses, contact lenses, ocular inserts, corneal onlays, corneal inlays, nanowafers, liposomes, nanoparticles, punctal onlays, or hydrogel matrices with microfluid reservoirs.

[0182] In other embodiments, the pharmaceutical composition is a sustained release formulation contained within a device.

[0183] In other embodiments, the pharmaceutical composition is contained within a device.

[0184] In other embodiments, the pharmaceutical composition is an ophthalmic composition and the ophthalmic composition is contained within a device.

[0185] In other embodiments, the device contains or is capable of delivering the pharmaceutical composition to the respective target tissue for myopia treatment.

[0186] In other embodiments, the device delivers the pharmaceutical composition in a sustained release manner.

[0187] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of an ophthalmic disorder or condition.

[0188] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of pre-myopia, myopia (eye) or myopia progression.

[0189] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of high myopia, moderate myopia or low myopia.

[0190] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of axial myopia or refractive myopia.

[0191] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of an individual (patient) diagnosed with pre-myopia (or at risk of developing myopia or having a predisposition to myopia).

[0192] In other embodiments, the pharmaceutical composition is substantially uniformly distributed throughout the device.

[0193] In other embodiments, the device is contained within a contact lens blister pack.

[0194] In other embodiments, the pharmaceutical composition is immersed within the device within a contact lens blister pack.

[0195] The cells, organs or tissues can be contacted with the compound, such as benzydamine or benzydamine lysine, 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 benzydamine or / and benzydamine lysine compound of the application, or a pharmaceutical composition containing the same, to a mammal, preferably to a human. When used in vivo for treatment, the benzydamine or / and benzydamine lysine compound, or a pharmaceutical composition containing the same, can be administered to the 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.

[0196] The compounds disclosed herein can also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VCHA, Zurich, Switzerland 2003). A prodrug of a compound described herein is a modified form of the compound that is susceptible to facile chemical change under physiological conditions to yield the compound. Further, a prodrug can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be gradually converted to the compound when placed in a transdermal patch reservoir with the appropriate enzyme or chemical reagent. 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 over the parent drug. Many prodrug derivatives are known in the art, such as prodrugs that rely on hydrolytic cleavage or oxidative activation. One non-limiting example of a prodrug is a compound that is administered as an ester (“prodrug”) but then metabolically hydrolyzes to the carboxylic acid (the active entity).

[0197] The compounds disclosed herein can exist as therapeutically acceptable salts, including acid addition salts. Suitable salts include those formed with organic and inorganic acids, such acid addition salts are generally pharmaceutically acceptable; base addition salts can also be formed, and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0198] Base 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 the hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts 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 that are useful include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0199] While it is possible that, for use in accordance with the application, a compound can be administered as a raw chemical, it is possible to present them 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) must be "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 upon 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 manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or compression processes.

[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 intraocular) administration, the most suitable of which depending on, e.g., the condition and disorder of the recipient. Formulations can conveniently be presented in unit dosage form and can be prepared by any methods known in the art of pharmacy. In general, such methods include the step of bringing into association a compound of the 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

[0201] Formulations of a compound disclosed herein suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets; 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, syrup, elixir, or a paste.

[0202] Orally administrable pharmaceutical preparations include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, a surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, 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 or controlled release of the active ingredient therein. The dosages of all preparations for oral administration should be suited to the administration. The push-fit capsules can contain the active ingredient in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds 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. Provide a sugar-coated pill core with a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or sugar-coated pill coating for identification or to characterize different combinations of active compound doses.

[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, corn starch, pregelatinized starch, dextrates, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer (e.g., polyethylene oxide), and hydroxypropyl methylcellulose. The filler can have complexed solvent molecules, such as where 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 glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0205] Additionally, flow agents 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, glycerol 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 flow agents include, but are not limited to, silicon dioxide (Si02), talc, corn starch, and poloxamer. Poloxamer (or KOLLIPHARM® available from BASF Corporation) is an A-B-A block copolymer in which 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, carboxymethylcellulose sodium, 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 compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Formulations can be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. In one preferred embodiment, the pharmaceutical composition of the present application is in the form of an injection, in particular a syringe. Preferably, the pharmaceutical composition is administered into the vitreous by intraocular injection, more preferably by intravitreal injection into the vitreous.

[0208] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions of the active compound(s) which can contain anti-oxidants, buffers, bactericides and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension also can contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0209] In addition to the formulation of the foregoing, the compounds can be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated in suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as sparingly soluble salts.

[0210] For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions can contain the active ingredient in a flavored, e.g. sucrose and acacia or tragacanth, base.

[0211] The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0212] Certain compounds disclosed herein can be administered topically, i.e., non-systemically, by application directly to the eye, skin, external mucosal surfaces, ear, and / or nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0213] The active ingredient can comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation for topical administration. In certain embodiments, the active ingredient can comprise up to 10% w / w. In other embodiments, it can comprise less than 5% w / w. In certain embodiments, the active ingredient can comprise from 2% w / w to 5% w / w. In other embodiments, it can comprise from 0.1% w / w to 2% w / w, preferably 0.1%-0.5% w / w, of the formulation. In certain embodiments, it can comprise 0.01% w / w, 0.05% w / w, 0.1% w / w, 0.25% w / w, 0.5% w / w of the formulation.

[0214] In some embodiments, the active ingredient for topical administration can comprise, for example, 0.001% to 10% w / v (weight / volume, units: g / 100 ml) of the formulation. In certain embodiments, the active ingredient can comprise up to 10% w / v. In other embodiments, it can comprise less than 5% w / v. In certain embodiments, the active ingredient can comprise 0.2% to 0.5% w / v. In other embodiments, it can comprise 0.1% to 2% w / v, preferably 0.1% to 0.5% w / v, of the formulation. In certain embodiments, it can comprise 0.01% w / v, 0.05% w / v, 0.1% w / v, 0.25% w / v, 0.5% w / v of the formulation.

[0215] In preferred aspects, the formulation for topical administration in an aqueous solution or suspension to the eye or ear 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, sprays or aerosols. The term "aqueous" generally denotes an aqueous formulation in which the formulation contains > 50%, more preferably > 75% and especially > 90% by weight of water. These drops can be delivered from a single dose ampoule which can preferably be sterile, thus enabling the formulation to be free of bacteriostatic components. Alternatively, the drops can be delivered from a multi-dose bottle which can preferably include a device to withdraw any preservative from the bottle at the point of 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. Alternatively the active pharmaceutical ingredient can be delivered in the form of a dry powder.

[0216] In particular embodiments, the formulations of the application are administered 2 times per day. However, the formulations can also be formulated for administration at any frequency of administration, including once per week, once every 5 days, once every 3 days, once every 2 days, once per day, three times per day, four times per day, five times per day, six times per day, eight times per day, hourly administration or at any higher frequency. Depending on the treatment regimen, such dosing frequencies are also maintained for varying lengths of time. The duration of a particular treatment regimen can vary from a single dose to a regimen extending for months or years.

[0217] Formulations for topical administration in the mouth (e.g. buccal or sublingual) include lozenges comprising active ingredients in a flavored base, such as sucrose and acacia or tragacanth gum and pastilles comprising the active ingredient in a base such as gelatin and glycerin, or sucrose and acacia.

[0218] For administration by inhalation, the compounds can be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. 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.

[0219] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction of the effective dose, of the active ingredient as herein described.

[0220] 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 those suitable for oral or intranasal administration can include flavouring agents.

[0221] The compounds can be administered in a dose of 0.01 to 300 mg / kg orally or via injection. The dose range for adults is generally 0.1 mg to 50 mg per day. Tablets or other present forms 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, 0.05 mg to 100 mg, generally about 1 mg to 50 mg, and preferably 5 mg.

[0222] The compounds can be administered in various modes of administration, e.g., orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. Specific dose levels for any particular patient will depend upon a variety of factors, including the activity of the particular compound employed, the age, body weight, general health condition, 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.

[0223] 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. For example only, if one of the side effects experienced by a patient who is receiving one of the compounds described herein is liver damage, it can be appropriate to administer a liver-protecting agent in combination with the initial therapeutic agent. Or for example only, the efficacy of one of the compounds described herein can be enhanced by administration of an adjuvant (i.e., the adjuvant itself can have only minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or for 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. For example only, in a treatment for myopia 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, such as atropine. 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.

[0224] The pharmaceutical composition, either in dry or liquid form, can be provided in the form of a single-dose or a multi-dose pharmaceutical composition.

[0225] 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 multi-dose pharmaceutical composition, which means that the container in which it is provided contains more than one therapeutic dose, i.e. the multi-dose composition contains at least 2 doses. Such multi-dose compositions can be used for different patients in need thereof, or can be used for one patient, wherein the remaining doses are stored after application of the first dose for use when needed.

[0226] In another aspect of the application, the pharmaceutical composition is in a container. Containers for liquid or dry pharmaceutical compositions are, for example, 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.

[0227] The dry composition is reconstituted prior to administration to a patient in need thereof. Reconstitution can be performed in the container in which the dry composition is provided, for example, in a vial, 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, for example, 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".

[0228] The pharmaceutical compositions of the present application can be administered in the form of ophthalmic preparations, the ophthalmic preparations of the present application comprising an ophthalmically acceptable carrier.

[0229] 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

[0230] The active substance content of the pharmaceutical compositions of the present application. When the drugs are mixed, the concentration of each drug can be selected as an effective suitable amount of each drug.

[0231] The formulations and methods of the present application have application in any subject that can benefit from the formulations and methods of the present application. The subject is typically a mammal, more typically a human. However, the present application is not limited to treatment of humans and can have application to veterinary uses.

[0232] In another aspect, the present application provides a device containing a pharmaceutical composition comprising bendazac or a therapeutically acceptable salt thereof (such as bendazac lysine) or a derivative thereof, preferably wherein the device delivers the pharmaceutical composition in a sustained release manner.

[0233] In certain embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the device delivers the pharmaceutical composition in a sustained release manner, preferably wherein the sustained release is circadian.

[0234] In certain embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition, for example, as an ophthalmic composition for treatment of an ophthalmic disorder or condition.

[0235] In certain embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of pre-myopia, myopia, or myopia progression.

[0236] In certain embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of high myopia, moderate myopia, or low myopia.

[0237] In certain embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition for treatment of a patient diagnosed with pre-mydriasis (or at risk of developing mydriasis or having a predisposition for mydriasis to occur).

[0238] In certain embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is ophthalmically administered to the eye of the patient, preferably the myopic eye.

[0239] In certain embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is administered topically.

[0240] In certain embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is ophthalmically administered to the eye of the patient by a device.

[0241] In certain embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is administered 1, 2, 3, 4, or 5 times per day.

[0242] The amount of a therapeutic agent that will therapeutically effect patients can be determined from standard pharmaceutical procedures, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Compounds exhibiting high therapeutic indices are preferred. While compounds that can elicit toxic side effects can be used, it is desirable to design a delivery system that targets such compounds to the site of action to minimize potential damage to non-targeted cells or tissues.

[0243] The data obtained from the animal studies can be used in formulating a range of dosage for use in humans. The dosage can vary depending upon the type of formulation used, the route of administration utilized, and the condition of the patient. A series of dosage can be formulated in animal models to achieve a circulating blood concentration range that includes the lowest effective concentration, the circulating blood concentration range after single and multiple dosing, and the drug exposure. Such results can be used to more accurately determine useful dosages in humans by scaling based on body surface area.

[0244] Those skilled in the art will recognize that certain factors can influence the dosage and timing required to treat a subject effectively, including but not limited to the severity of the disease or disorder, the overall health status of the subject, whether the subject is in a state of complete compliance with treatment, previous treatments, health status, and / or age and other diseases present in the subject. Moreover, treatment of a subject with a therapeutically effective amount of a therapeutic composition described herein can include a single treatment or a series of treatments.

[0245] The methods of the present application control, slow, reduce, delay, and / or slow the progression of myopia in a 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.

[0246] The use of the pharmaceutical composition, device, or method of treatment limits the magnitude of the change in the refractive error of the eye of the subject 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.

[0247] In some embodiments, the methods of the present application halt or reverse the progression of myopia in a treated patient. These patients have high myopia, moderate myopia, or low myopia; or the patient is pre-myopic (or at risk of developing myopia).

[0248] In some embodiments, the methods of the present application prevent, control, slow, delay, retard, and / or slow the axial (or longitudinal) growth of the eye of a treated patient.

[0249] In some embodiments, the methods of the present application control, slow, reduce, delay, and / or slow the progression of myopia in a patient diagnosed with myopia or at risk of developing myopia, increase the choroidal thickness (ChT) of the eye (e.g., myopic eye, pre-myopic eye, or eye at risk of developing myopia) of said patient, and / or reduce the axial (or longitudinal) growth rate of the eye (e.g., myopic eye, pre-myopic eye, or eye at risk of developing myopia) of said patient.

[0250] In some embodiments, the application of the methods of the present application reduces the axial (or longitudinal) growth of the eye of the treated patient relative to the untreated control by 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%.

[0251] In some embodiments, the application of the methods of the present application results in less increase in pupil size or no mydriasis relative to atropine monotherapy.

[0252] In some embodiments, the oral preparation is a solid preparation such as a tablet, a capsule, a granule, and a powder preparation, and a liquid preparation such as a syrup and a beverage preparation; optionally (a) in the solid preparation, an excipient, a lubricant, a binder, a disintegrant, etc. can be formulated, preferably, a preservative, an antioxidant, a coloring agent, and a sweetening agent can be formulated, more preferably, an additive is used; optionally (b) in the liquid preparation, a solvent, a dissolution aid, a suspending agent, and an isotonic agent are included, preferably, an agent, a buffer, an analgesic, etc. can be mixed, more preferably, an additive such as a preservative, an antioxidant, a coloring agent, a sweetening agent, etc. is used.

[0253] In some embodiments, the drug can be an injection, a tablet, a lyophilized powder injection, a capsule, an effervescent tablet, a chewable tablet, a sublingual tablet, a granule, an ointment, a syrup, an oral solution, an aerosol, a nasal drop, a topical preparation, an oral preparation, etc.; preferably, an ophthalmic dosage form, including but not limited to an eye drop (eye drops), an eye ointment, an eye spray, an implant tablet, an eye gel, an eye patch, an eye microsphere, an eye sustained-release preparation, a periocular injection, an intraocular injection; and can also be a free solution, an oil-water mixture, a suspension, a liniment, a lotion, a cream, a drop, a decoction, a spray, a paste, a patch, a paste, a pill, a suppository, an emulsion.

[0254] In some embodiments, the "ophthalmic preparation or drug" is administered simultaneously with the pharmaceutical composition or preparation of the present application, such as administration at the same time or sequentially during a specific administration (treatment) process, on the same day, in the same week, in the same month, in 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.

[0255] The specific embodiments of the present application will be described in detail hereinafter. 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.

[0256] Methods and sources of preparation of the main reagents or formulations (pharmaceutical compositions) of Example 1

[0257] The preparation of bengamide includes two types: the commercialized drug and the pharmaceutical composition prepared by the inventors using only bengamide compound as the effective pharmaceutical ingredient. The bengamide drug (BDL(S)), i.e. the 0.5% bengamide eye drops commercially available in China (GMP H20063847), is directly used for local administration in the eyes of guinea pig myopia model; the bengamide compound is purchased from MedChemExpress. The bengamide compound powder is directly completely dissolved in 0.9% normal saline to prepare a 5 mg / ml (11.669 mM) preparation (BDL) without adding other pharmaceutical excipients or other compounds. The whole appearance of the preparation is clear, transparent, uniform and free of visible suspended substances at room temperature, and it is directly administered locally in the eyes of the test subjects or diluted with 0.9% normal saline before administration according to the required dose.

[0258] The preparation of benzydamide includes two types: the commercialized drug and the preparation prepared by the inventors using only benzydamide compound. Among them, the commercialized drug is 3% benzydamide ointment, which is purchased from Japan Iwaki Pharmaceutical Co., Ltd.; the benzydamide compound is purchased from MedChemExpress. The benzydamide is completely dissolved in DMSO to prepare a 330 mg / ml (1166.9 mM) stock solution, which is stored at -20 degrees. Before the experiment, the working solution is prepared according to the ratio of stock solution: PEG300: Tween80: 0.9% normal saline = 1:45:5:49, and the final concentration of benzydamide preparation is 3.3 mg / ml (11.669 mM). All preparation operations are carried out in a dark room.

[0259] Lysine is purchased from MedChemExpress, which can be completely dissolved in 0.9% normal saline to prepare a 1.7 mg / ml (11.669 mM) test preparation.

[0260] M-hydroxy-methylaniline is purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd. Hydroxy-methylaniline is completely dissolved in 0.9% normal saline to prepare a 250 mM stock solution, which is stored at -20 degrees. Before the experiment, it is diluted with 0.9% normal saline, and the final concentration of hydroxy-methylaniline preparation used in the example is 5 mM. All preparation operations are carried out in a dark room.

[0261] Aldose Reductase Inhibitor (ARI) Sorbinil, purchased from MedChemExpress. Sorbinil powder was dissolved in DMSO to make a 4.8 mg / ml (20 mM) stock solution, stored at -20 degree. Diluted with 0.9% normal saline before experiment, the final concentration of Sorbinil used in the examples was 24 μg / ml (100 μM), all operations were performed in a dark room.

[0262] Aldose Reductase Inhibitor Zopolrestat, purchased from MedChemExpress. Zopolrestat powder was dissolved in DMSO to make a 84 mg / ml (1 M) stock solution, stored at -20 degree. Diluted with normal saline before experiment, the final concentration of Zopolrestat used in the examples was 420 μg / ml (1 mM), all operations were performed in a dark room.

[0263] Atropine powder was purchased from Stanford Chemicals, dissolved in 0.9% normal saline to make a 1 mg / ml, i.e. 0.1% preparation (positive control). All operations were performed in a dark room.

[0264] All other preparations or pharmaceutical compositions not mentioned were prepared and stored according to the laboratory routine methods and standards. All preparations may be prepared using heating, stirring, pH adjustment and other conventional physical and chemical solubilization aids as appropriate, and no compound precipitation occurred before administration of all preparations.

[0265] Example 2 Construction of animal models and experimental methods

[0266] Form deprivation and lens-induced guinea pig myopia models are classic and recognized myopia animal models in the art, which can be used for efficacy and safety evaluation of myopia treatment drugs, and their construction methods are well known to those skilled in the art. Guinea pig form deprivation myopia (FDM) and lens-induced myopia (LIM) modeling, drug administration and data analysis were performed according to the published literature in the laboratory of the inventors. 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 approved by the Experimental Animal Ethics Committee of Wenzhou Medical University. The construction methods of the form deprivation and lens-induced guinea pig myopia models used in Example 3 below are as follows:

[0267] Three-week-old guinea pigs were raised in the experimental animal house of Wenzhou Medical University, under a 12-hour light (400-500 lux) / 12-hour dark environment, with free access to water and food. The myopia model was established by monocular form deprivation (FD) and lens-induced (LI) methods. For form deprivation, a special eye patch with a light transmission rate of 1% was used to completely cover the right eye of the animals, and the left eye (left eye) received normal vision. For lens-induced, a -4D lens was fixed in front of the right eye of the animals, and the left eye received normal vision. The lens was cleaned twice a day to prevent it from becoming cloudy. Drug administration was performed from 9:00 to 9:30 am every day. At the time of administration, the control and experimental animals were taken off the eye patch or lens under red light, and 0.1 ml of solvent control or 5 mg / mL test drug or positive control was injected subconjunctivally into the right eye. After injection, the animals were confirmed to be successfully administered without trauma and immediately restored the eye patch and lens. The administration process of each animal was controlled within 10 seconds. Administration began on the day of modeling, and the form-deprived animals were administered once a day for 2 weeks, while the lens-induced animals were administered once a day for 1 week.

[0268] Animal grouping

[0269] 1. Form-deprived group:

[0270] Form-deprived plus solvent injection group: single eye wearing an eye patch and injecting solvent saline into the wearing eye for 2 weeks, sample size = 11.

[0271] Form-deprived plus drug injection group: single eye wearing an eye patch and injecting benzalkonium chloride (0.5 mg / day) into the wearing eye for 2 weeks, sample size = 14.

[0272] Form-deprived plus positive control group: single eye wearing an eye patch and injecting 0.1% atropine into the wearing eye for 2 weeks, sample size = 12.

[0273] 2. Lens-induced group:

[0274] Lens-induced plus solvent injection group: single eye wearing a -4D lens and injecting solvent saline into the wearing eye for 1 week, sample size = 14.

[0275] Lens-induced plus drug injection group: single eye wearing a -4D lens and injecting benzalkonium chloride (0.5 mg / day) into the wearing eye for 1 week, sample size = 14.

[0276] Measurement of animal eye parameters

[0277] All animals were measured in the same time period for the same model pharmacodynamic experiment. The first measurement was taken at 3 weeks of age. Refractive and axial parameters were measured in all animals before the experiment, 1 week after the experiment and 2 weeks after the experiment (only for FD). Refractive measurements were taken using an eccentric infrared photoretinoscope (EIR) built in our laboratory. Each eye was measured 3 times and the average was taken as the final result. Axial measurements were taken using the A-mode probe of the Cinescan A / B ultrasound diagnostic instrument (Quantel Medical, Aviso, France). The ultrasound frequency was 11 MHz and the ultrasound propagation velocities were set at 1557.5 m / s for the anterior chamber, 1723.3 m / s for the lens and 1540 m / s for the vitreous chamber. The measurements included anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD) and axial length (AL). The animals were topically anesthetized with 0.5% proparacaine hydrochloride eye drops (Alcon, Belgium) 2 minutes before the measurements. Each eye was measured 6 times and the average was taken as the final result.

[0278] Example 3: In vivo therapeutic effect of benzalkonium chloride

[0279] The experimental animals were 3-week-old trichromic guinea pigs, which were divided into two groups: form deprivation (FD) and lens-induced (LI). The FD group was further divided into three subgroups: the negative control group was injected with 100 μΐ of saline around the model eye each day, the experimental group was injected with 100 μΐ of 0.5 mg benzalkonium chloride around the model eye each day and the positive control group was injected with 100 μΐ of 0.1% atropine around the model eye each day. The LI group was further divided into two subgroups: the negative control group was injected with 100 μΐ of saline around the model eye each day and the experimental group was injected with 100 μΐ of 0.5 mg benzalkonium chloride around the model eye each day. Refractive, vitreous chamber and axial parameters were measured in all animals before the first administration, 1 week after the administration and 2 weeks after the administration (only for FD).

[0280] Results:

[0281] The myopia induced by the saline injection group was -3.75±1.76D after one week of administration, and -6.17±1.52D after two weeks of administration, while the myopia induced by the benzalkonium chloride injection group was -2.15±1.09D after one week of administration, which was 42.6% lower than that of the saline injection group, and the myopia induced by the 0.1% atropine was -2.98±1.54D, which was 20.5% lower than that of the saline injection group; the myopia induced by the benzalkonium chloride injection group was -3.46D after two weeks of administration, which was 43.9% lower than that of the saline injection group, and the myopia induced by the 0.1% atropine was -3.93D, which was 36.4% lower than that of the saline injection group. The elongation of the vitreous cavity depth and the axial length were inhibited by the benzalkonium chloride (see Figure 1 ). In summary, compared with the saline injection group, the benzalkonium chloride administration group significantly inhibited the refractive power of the guinea pigs with form deprivation myopia, the elongation of the vitreous cavity depth, and the elongation of the axial length.

[0282] The myopia induced by the saline injection group was -4.42±0.95D after one week of administration, while the myopia induced by the benzalkonium chloride injection group was -3.49±1.15D after one week of administration, which was 21.0% lower than that of the saline injection group. Figure 1 It can be seen that, compared with the saline injection group, the benzalkonium chloride administration group significantly inhibited the refractive power of the guinea pigs with lens-induced myopia, and the elongation of the vitreous cavity depth and the axial length were also inhibited by the benzalkonium chloride.

[0283] In addition, no eye abnormalities were observed in all benzalkonium chloride treatment group animals during the entire experimental period, and no individual toxicity reactions were observed, and the corneal curvature (RCC), anterior chamber depth (ACD), and lens thickness (LT) related indicators were not affected by the test drug (see Figure 2 ).

[0284] The above experiments show that benzalkonium chloride can significantly slow down the progression of refractive power in myopic individuals, and can significantly inhibit the elongation of the axial length, and can significantly improve the myopia-related symptoms of form deprivation and lens-induced guinea pigs, suggesting that it can be applied to the prevention and control of myopia, especially to the treatment, prevention or improvement of refractive myopia or axial myopia and related symptoms. The above experimental results of the present application prove that benzalkonium chloride has good prevention, slowing down and treatment effects on myopia in humans, especially in children and adolescents.

[0285] Example 4, Commercial Benzalkonium Chloride Eye Drops (0.5%, BDL(S)) Inhibit Myopia Progression

[0286] Healthy 3-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, underwent refractive power (infrared eccentric radiography) and axial length (A-scan) measurements. Animals with refractive power between 3 and 8 diopters (D) and binocular anisometropia not exceeding 2D were randomly divided into the following 5 groups: form deprivation (FD) + solvent control (NS) group, FD + 0.5% benzyldamine lysine eye drops (BDL(S)) group, FD + 0.1% atropine, lens induction (LI) + solvent control (NS) group, and LI + 0.5% benzyldamine lysine (BDL(S)) group. On the first day of the experiment, form deprivation (FD) or lens induction (LI) myopia modeling was initiated in the guinea pigs starting at 8:00 AM. The form deprivation myopia model used the mask method. The headgear was made by the inventor using a 10-inch milky white non-toxic latex balloon. The right eye of the guinea pig model was covered by the headgear (experimental eye), while the left eye was not covered (contralateral eye). The lens-induced myopia model used a -4D lens purchased from Wenzhou Xinshijie Technology Co., Ltd., with the following parameters: central power -4D, base curve 16mm, and diameter 11.8mm. The lens was fixed in front of the guinea pig's right eye (experimental eye), while the left eye remained untreated (contralateral eye). FD and LI induction were performed continuously throughout the entire benzyldamine lysine efficacy experiment period, with the headgear or lens only briefly removed during drug administration or ocular examinations (such as refractive power measurement). The headgear position was checked or the lens wiped daily at 8:00 AM, 12:00 PM, and 7:00 PM, and before drug administration, and individuals whose headgear or lens fell off more than three times were discarded. Starting from the day of model establishment, the corresponding solvent or drug for the FDM model experimental eye was administered daily between 9:00 AM and 10:00 AM via subconjunctival injection, with an injection volume of 100 μl, once daily for two consecutive weeks. At the start of the pharmacodynamic experiment, and at 1 and 2 weeks, the refractive error and axial length parameters of the test animals were measured. All data collection and processing methods were identical to those used in the literature published by the inventor's laboratory. The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. For the lens-induced myopia model, starting from the day of modeling, individuals in the lens-induced group were given either the solvent (negative control) or the drug (benzyldenafil) daily between 9 and 10 a.m., via subconjunctival injection, with an injection volume of 100 μl, once daily for one week. Refractive error and axial length parameters of all subjects were measured at the beginning and end of the experiment. All data collection and processing methods were the same as in the form deprivation group. All efficacy experiments were repeated at least twice. In this embodiment, the test drug (0.5% benzyldenafil eye drops, National Drug Approval Number H20063847) and the solvent control (negative control group) were manufactured and provided to the inventors by the same commercial benzyldenafil eye drops manufacturer.

[0287] The results show: consistent with the conclusion of Example 3. The diopter and axial length parameters of the negative control group animals changed as expected in the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment, which proved that the two myopia models in this experiment were successful and could be used for drug efficacy evaluation. The commercially available 0.5% brimonidine tartrate eye drops can significantly inhibit and slow down the progression of myopia in the form deprivation myopia model and the negative lens-induced myopia model (development of negative diopter in myopic individuals is successfully delayed and effectively controlled by brimonidine tartrate eye drops. Even in individual animals in the brimonidine tartrate treatment group, the inventors found that the progression of myopia was almost completely stopped by the test drug. In terms of FDM group diopter indicators, 0.5% brimonidine tartrate eye drops were more effective than 0.1% atropine eye drops in treating myopia after 1 week of treatment, but there was no statistical difference between the two; after 2 weeks of treatment, 0.5% brimonidine tartrate eye drops were similar to 0.1% atropine eye drops in treating myopia, and the efficacy of both was significantly different from the negative control group. In the LIM group, brimonidine tartrate also effectively prevented the progression of myopia, and the diopter of the drug intervention group animals was significantly slower than the control group, and there was a significant difference in diopter between the two at the end of the experiment, and brimonidine tartrate also effectively treated the myopia induced by negative lenses. The specific results are that under the same myopic visual information input conditions (-4D), at the same detection time point (1 week after drug administration), the diopter of the drug intervention group was greater than that of the solvent group (all negative values, the mean diopter of the negative control group reached -4D, and the drug intervention group did not), indicating that brimonidine tartrate can effectively control the progression of myopia. At the same time, the increase in vitreous cavity depth (VCD) and the lengthening of the axial length (AL) of animals treated with brimonidine tartrate in the above two classic myopia research models were also effectively inhibited (statistically different from the negative control group), and the above corresponding indicators at two detection time points in the form deprivation experiment were better in the brimonidine tartrate group than in the atropine group. In addition, all animals in the brimonidine tartrate treatment group did not observe eye abnormalities and individual toxicity reactions during the entire experimental period, and the corneal curvature (RCC), anterior chamber depth (ACD), and lens thickness (LT) related indicators were also not affected by the test drug. Animals in the positive control group developed pupil dilation after atropine administration.

[0288] In summary, under the premise that no obvious adverse drug reactions occur, the commercialized benzalkonium chloride eye drops can effectively prevent and treat myopia in mammals (including humans), especially can slow down and control the deepening of myopia, and can significantly improve the related symptoms of the myopia disease model, which is manifested that benzalkonium chloride can effectively reduce (inhibit) the elongation of the eye axis length of individuals with myopia or myopia tendency and can effectively reduce (inhibit) the increase of the vitreous cavity depth, suggesting that it can be applied to the prevention and control of myopia, whether it is applied to the treatment, prevention or improvement of refractive myopia or axial myopia and related symptoms. Therefore, the commercialized benzalkonium chloride eye drops can be used for myopia (eye) treatment, especially can control the progression speed of the disease to reduce the complications and blindness risk caused by high myopia, especially in the intervention treatment of children and adolescents.

[0289] Example 5, Dose-effect relationship experiment of different concentrations of benzalkonium chloride for myopia treatment (0.01%, 0.05%, 0.1% and 0.5%)

[0290] After removing individuals with obvious eye diseases or abnormalities, healthy 3-week-old three-color guinea pigs were selected by diopter (infrared eccentric photography refraction instrument) and eye axis (A-mode ultrasound) detection, and the refractive power of the animals was between 3-8 diopter (D) and the refractive difference between the two eyes was not more than 2D. The animals were randomly divided into the following 6 groups: FD+saline group (negative control), FD+0.01% benzalkonium chloride, FD+0.05% benzalkonium chloride, FD+0.1% benzalkonium chloride, FD+0.5% benzalkonium chloride (experimental group, referring to the administration of 0.5% benzalkonium chloride to FDM model individuals), FD+0.1% atropine (positive control). In order to be more intuitive, the percentage was converted into milligram units when drawing. The guinea pigs were subjected to form deprivation (FD) myopia modeling at 8 am on the first day of the experiment. The form deprivation myopia model used a mask method, and the headgear was made by the inventor using a 10-inch white latex balloon. The right eye of the guinea pig modeling individual was covered with the headgear (experimental eye), and the left eye was not covered with the headgear (contralateral eye). FD induction was continued throughout the benzalkonium chloride efficacy experiment period, and the headgear was only temporarily removed for drug administration or eye examination (such as diopter detection). 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 were eliminated. The corresponding solvent (negative control) or drug was administered to the experimental eye of the FDM model at 9-10 am every day after the modeling day. The administration method was subconjunctival injection, and the injection volume was 100 μl. The administration was once a day, and the administration was continued for 2 weeks. The refractive power and eye axis parameters of the test animals were detected at the start of the model efficacy experiment, 1 week and 2 weeks. All data collection and processing methods were the same as those in the published literature of the inventor's laboratory , statistical basis for the same test eye and contralateral eye of the individual difference. All the above pharmacodynamic experiments were repeated at least three times, and the betaxolol hydrochloride preparation was prepared by the inventors using normal saline.

[0291] The experimental results showed that the refractive and axial parameters of the negative control group animals changed as expected in the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment, which proved that the myopia model was successfully established and could be used for the evaluation of the efficacy of betaxolol hydrochloride. Compared with the negative control group, betaxolol hydrochloride (without other pharmaceutical excipients except 0.9% normal saline as a solvent) showed a dose-dependent slowing of the progression of myopia in the test subjects. As the dose of betaxolol hydrochloride increased, the myopia inhibition rate (calculated formula: (drug group diopter - solvent group diopter) / solvent group diopter) as an indicator of diopter also increased, indicating that the more betaxolol hydrochloride was administered, the better the prevention and control effect of myopia (eye). In terms of the diopter indicator, the efficacy of the betaxolol hydrochloride preparation prepared by the inventors using normal saline was consistent with that of the betaxolol hydrochloride commercial drug, i.e., 0.5% betaxolol hydrochloride was more effective than 0.1% atropine in treating myopia after one week of administration, but there was no statistical difference between atropine and betaxolol hydrochloride. After two weeks of administration, 0.5% betaxolol hydrochloride had similar efficacy to 0.1% atropine eye drops in treating myopia, and both drugs were significantly different from the negative control group. This indicates that betaxolol hydrochloride as the main or only active ingredient can have a therapeutic and preventive effect on myopia. Statistically, 0.05% and 0.1% betaxolol hydrochloride preparations also showed significant therapeutic effects (effective inhibition of the progression of negative diopter) on myopia. The 0.01% betaxolol hydrochloride group had similar results to the negative control group in terms of diopter at one week, and slightly better results at two weeks, but there was no statistical difference. Betaxolol hydrochloride at concentrations of 0.05%, 0.1%, and 0.5% also inhibited the increase in vitreous cavity depth (VCD) and the elongation of axial length (AL) in myopic individuals. Except for the 0.01% betaxolol hydrochloride group, the other higher concentration betaxolol hydrochloride and atropine could effectively inhibit the elongation of the posterior segment of the eye (vitreous cavity depth and axial length) and effectively control, inhibit, delay, or slow down the progression of negative diopter in myopic individuals or individuals with a tendency to develop myopia, with significant differences between the above-mentioned inhibition effects and the solvent group or extremely significant differences between the two (see Figure 3 ). No eye irritation or any abnormal eye phenomena were observed in all betaxolol hydrochloride groups during the administration period, and the anterior chamber depth, lens thickness, and pupil were not affected by betaxolol hydrochloride administration. Pupil dilation was observed in all animals in the atropine group after administration, and there was a statistical difference between the atropine group and the solvent group (see Figure 4 ), which is consistent with the adverse reactions reported in clinical trials.

[0292] The results of this example prove that benzydamine hydrochloride alone can be used to prevent and treat myopia (eye), or benzydamine hydrochloride can be used to prepare a preparation or a pharmaceutical composition which can be used for the prevention and treatment of myopia (eye). Preferably, the concentration of benzydamine hydrochloride in the above preparation or pharmaceutical composition is not less than 0.01%, which can be 0.05%-1% of benzydamine hydrochloride. Considering the three aspects of FDA's (Food and Drug Administration) consideration of the possible serious liver toxicity of benzydamine hydrochloride to the human body, the long-term continuous use of myopia treatment drugs and the special requirements of regulatory authorities for the safety of pediatric drugs, the inventors believe that 0.1%-0.25% concentration of benzydamine hydrochloride eye drops is a reasonable formula for clinical myopia prevention, that is, the concentration of benzydamine hydrochloride in the preparation or pharmaceutical composition is preferably 0.1% to 0.25%. At the same time, in addition to increasing the concentration of benzydamine hydrochloride in the preparation of benzydamine hydrochloride, the ways to achieve or improve the myopia prevention effect of benzydamine hydrochloride for myopia population or people with myopia tendency include increasing the ocular bioavailability of benzydamine hydrochloride, increasing the frequency of drug administration, using other myopia treatment drugs in combination, and optimizing the formulation of benzydamine hydrochloride preparation, etc. In summary, the above-mentioned benzydamine hydrochloride preparation or pharmaceutical composition can effectively reduce (inhibit) the elongation of the axial length of the eye of myopic or myopic-prone individuals and effectively reduce (inhibit) the increase in vitreous cavity depth of myopic or myopic-prone individuals; the benzydamine hydrochloride preparation or pharmaceutical composition can treat (prevent) myopia, especially for myopia treatment for people aged 6 to 18 years.

[0293] Example 6, benzydamine hydrochloride can significantly increase choroidal thickness

[0294] (I) Benzydamine hydrochloride effectively inhibits the decrease in choroidal thickness of FDM and LIM guinea pig models

[0295] 3-week-old three-color guinea pigs were selected after removing individuals with obvious eye diseases or abnormalities, and after diopter (infrared eccentric photography refraction instrument) and eye axis (A-mode) detection, animals with refractive power between 3-8 diopter (D) and binocular refractive disparity of not more than 2D were randomly divided into the following 4 groups: form deprivation (FD) + solvent control (NS) group, FD + 0.5% benzalkonium chloride eye drops (BDL(S)) group, lens induction (LI) + solvent control (NS) group, and LI + 0.5% benzalkonium chloride (BDL(S)) group. On the first day of the experiment at 8 am, the guinea pigs were subjected to form deprivation (FD) or lens induction (LI) myopia modeling. The form deprivation myopia model used a mask made of a 10-inch white latex balloon. The right eye of the guinea pig was covered with the mask (experimental eye), and the left eye was not covered with the mask (contralateral eye). The -4D lens was purchased from Wenzhou Xinsijie Technology Co., Ltd., and the specific parameters were: center power -4D, base arc 16 mm, and diameter 11.8 mm. The lens was fixed in front of the right eye of the guinea pig (experimental eye), and the left eye was not treated (contralateral eye). FD and LI induction were continued throughout the benzalkonium chloride efficacy experiment period, and the mask or lens was only temporarily removed for drug administration or choroidal thickness detection. The mask position or lens was checked at 6 am, 12 pm, and 6 pm every day after the start of the efficacy experiment, and individuals with more than 3 times of mask or lens falling off were eliminated. From the day of modeling, the FDM model experimental eye was given the corresponding solvent or drug at 9-10 am every day for 2 weeks. The drug administration method was subconjunctival injection of the experimental eye with a volume of 100 μl. For lens-induced myopia models, from the day of modeling, the lens-induced group was given solvent (negative control) or drug (benzalkonium chloride) at 9-10 am every day for 1 week. The drug administration method was subconjunctival injection of the experimental eye with a volume of 100 μl. The above two types of myopia models were detected for choroidal thickness using Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) 30-60 min after the last administration. All data collection and processing methods were the same as those in the published literature by the inventors . The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject, and the statistical method was independent sample T test. All the above efficacy experiments were repeated at least twice. The test drug (0.5% benzalkonium chloride eye drops) and solvent control (negative control group) were produced by the same commercial benzalkonium chloride eye drop manufacturer and provided to the inventors.

[0296] The results show that: compared with the solvent control group, benzyl daidzein can effectively increase the choroidal thickness of guinea pigs in FDM and LIM models, and there is a statistical difference between the two (LIM model solvent control group and drug group difference is extremely significant), the specific drug effect is that the experimental eyes of guinea pigs in FDM and LIM model solvent groups appear smaller choroidal thickness, and benzyl daidzein can inhibit the decrease of choroidal thickness in myopic eyes. In the FDM model, the average difference between the experimental eye and the contralateral eye of the choroidal thickness is-17.51 microns, while the average difference between the experimental eye and the contralateral eye of the choroidal thickness of the myopic individual after benzyl daidzein intervention is-9.20 microns, indicating that the experimental eye choroidal thickness is closer to the choroidal thickness level of the normal eye in the same individual after drug intervention (the difference between the two is reduced); in the LIM model, the average difference between the experimental eye and the contralateral eye of the choroidal thickness is-23.38 microns, while the average difference between the experimental eye and the contralateral eye of the choroidal thickness of the myopic individual after benzyl daidzein intervention is-6.31 microns, and the experimental eye choroidal thickness in individual animals even completely recovers to the level of the normal eye (see Figure 5 ). Corneal curvature (RCC), anterior chamber depth (ACD) and lens thickness (LT) indicators are also not affected by the test drug. In summary, benzyl daidzein can significantly inhibit the decrease of choroidal thickness and slow down the trend of choroidal thickness thinning in myopic individuals or individuals with myopia tendency.

[0297] In myopic individuals, parallel light passes through the relaxed refractive system of the eye and is focused in front of the retina. When benzyl daidzein increases the choroidal thickness of the myopic individual, it will move the retina towards the lens, ultimately causing the distance between the imaging focus and the retina in the myopic eye to shorten or even coincide. The distance between the imaging focus and the retina is the degree of myopia, and benzyl daidzein can shorten the distance between the two or inhibit the increase of the distance, which itself is to reduce the degree of myopia. Giving benzyl daidzein to myopic individuals will result in better distance vision in the treated eye and effectively reduce the myopic refractive state (treat myopia, reduce the degree of myopia), including improving distance vision. Therefore, the myopia treatment (prevention and control) effect of benzyl daidzein in this application is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia or true myopia, and is also unrelated to the age, gender, myopia degree, myopia progression speed, nationality and myopia age of the drug object, that is, benzyl daidzein has a treatment and prevention effect on all types of myopia.

[0298] Example 7, treatment effect of using benzyl daidzein eye drop eye drop and benzyl daidzein ointment eye application (non-invasive or non-invasive drug administration)

[0299] 3-week-old three-color guinea pigs were selected after removing individuals with obvious eye diseases or abnormalities, and after diopter (infrared eccentric photography refraction instrument) and eye axis (A-mode ultrasound) detection, animals with refractive power between 3-8 diopter (D) and binocular refractive disparity not more than 2D were selected and randomly divided into three groups: FD+saline group, FD+0.5% benzalkonium hydrochloride eye drops (self-prepared), FD+0.1% atropine. The guinea pigs were subjected to form deprivation at 8 am on the first day of the experiment, using the mask method, the right eye was covered (experimental eye), and the left eye was not covered (contralateral eye). FD induction was continued throughout the benzalkonium hydrochloride efficacy experiment period, and the headgear was only temporarily removed for drug administration or eye examination (such as diopter detection). The position of the headgear was checked every day at 8 am, 12 noon, and 7 pm after the start of the efficacy experiment, and individuals with more than 3 times of headgear falling off were eliminated. Starting on the day of modeling, the experimental eye was given the corresponding solvent or drug every day from 9 am to 10 am, directly instilled, and the second instillation was performed from 2:30 pm to 3:30 pm in the afternoon, i.e., twice a day, with a volume of 25 μl each time, for 2 consecutive weeks. The diopter and eye axis parameters of the test animals were detected at the start of the model efficacy experiment, 1 week, and 2 weeks, and all data collection and processing methods were the same as those in the published literature by the inventors' laboratory, and the statistical basis was the difference between the experimental eye and the contralateral eye of the same individual. All the above efficacy experiments were repeated at least twice.

[0300] Because of the modeling method, the eye structure of guinea pigs (the eyeball is relatively convex compared to humans and does not actively close the eyes), and normal blinking of animals, the actual effective treatment dose of the drug obtained by each test eye was lower than the amount of peribulbar injection of the same volume, and the total volume of eye drops administered to the test animals per day was also smaller than the injection volume in Example 5. Therefore, whether it was benzalkonium hydrochloride eye drops or 0.1% atropine, the efficacy of the eye drop directly instilled in this example was poorer than the treatment effect of peribulbar injection on myopia. The changes in diopter and eye axis parameters of the negative control group animals were consistent with the expected changes in the myopia model, and the positive control drug atropine showed the expected efficacy in the experiment, which proved that the myopia model in this experiment was successful and could be used for benzalkonium hydrochloride efficacy evaluation. In terms of eye axis parameters, compared with the saline solvent group, benzalkonium hydrochloride and 0.1% atropine can significantly inhibit the elongation of the eye axis of the form deprivation myopia model (there is a statistical difference), and both can inhibit the increase in the eye axis length and the increase in the vitreous cavity depth of myopia individuals; the myopia inhibition rates of benzalkonium hydrochloride eye drops for 1 week and 2 weeks were close to those of the 0.1% atropine instillation group (35.5% VS. 28.1% and 33.9% VS. 36.9%, respectively, and both had statistical differences with the negative control solvent group) (see Table 2). Figure 6), but the atropine group had adverse reactions of pupil dilation, while the brimonidine group had no obvious eye abnormalities. Neither atropine nor brimonidine myopia intervention affected the corneal curvature, anterior chamber, and lens-related indicators of the test subjects (see Figure 7 ). In the laboratory of the inventors, 0.01% atropine eye drops, which are commonly used in the current clinical trial concentration, were used under the same administration conditions as in this embodiment (the myopia model, administration method, administration frequency, and administration volume were kept the same), and no therapeutic effect was observed on the guinea pig myopia model, whether in terms of diopter indicators or eye axis parameter indicators, which may be related to the short time the eye drops remain on the surface of the eyeball after animal eye drop administration. Therefore, from the perspective of efficacy and safety evaluation, the risk-benefit ratio of brimonidine for myopia treatment is superior to that of atropine (such as the use of brimonidine during the day without the photophobia phenomenon caused by atropine mydriasis), especially for children and adolescents, and is suitable for myopia treatment and prevention in school-age populations.

[0301] For the test drug ointment dosage form, this embodiment did not set up a control group because the 3% brimonidine ointment used is a domestic commercial product, and the inventors cannot obtain a formulation without brimonidine corresponding to this product. Atropine ointment containing the same excipients is also excluded for the same reason. However, for the evaluation of the efficacy of brimonidine ointment for myopia treatment, the inventors can still refer to the indicators of the same batch of the same model control group in the non-invasive administration experiment of this application. The specific experimental process is as follows: the brimonidine ointment is applied to the corneal surface and the skin around the eye of the guinea pig form deprivation myopia model test eye (experimental eye) described in this application, and the eyelids are manually closed quickly for 10 times, but due to the slow absorption of the ointment and the covering of the eye mask and the normal blinking of the animal, the inventors found that there was also a certain amount of brimonidine ointment residue on the inner surface of the eye mask at the next administration. The dose of brimonidine ointment for each administration is 18 mg ± 2 mg, and the deprived eye is administered at 9-10 am every day starting on the day of modeling, and the second administration is at 2:30-3:30 pm, that is, twice a day, for 2 consecutive weeks. The refractive diopter and eye axis parameters of the test animals were detected at the beginning of the model efficacy experiment, 1 week, and 2 weeks, and all data collection and processing methods were the same as those in the published literature in the laboratory of the inventors , and the statistics were based on the difference between the experimental eye and the contralateral eye of the same test subject.

[0302] 3% of benzidate ointment administration 1 week and 2 weeks of myopia inhibition rate were 17.7% and 25.9%, the treatment effect was worse than the same batch of 0.5% benzidate lysine or 0.1% atropine, but much better than the same batch of form deprivation myopia model untreated group. Possible reasons are the model of the mask affects the eye absorption of benzidate in ointment, or due to the dosage form is mainly for human skin administration route, so the benzidate drug bioavailability of guinea pig eye is not reasonable formula. However, benzidate (ointment) still shows effective prevention and control of myopia, in addition to the inhibition of myopia individual diopter negative process, the increase of vitreous cavity depth and the extension of eye axis length of myopia individual after administration are also inhibited, specifically, the vitreous cavity depth extension mean of 0.09 mm and the eye axis length extension mean of 0.09 mm of benzidate ointment myopia treatment group after 2 weeks of administration, and the corresponding indexes of the same batch of myopia non intervention group are 0.13 mm and 0.12 mm (see Figure 6 ). It can be seen that the extension of eye axis of myopia individual is mainly caused by the increase of vitreous cavity depth, and benzidate can reduce the increase of vitreous cavity depth and the extension of eye axis length of myopia individual. After administration of benzidate, no obvious eye abnormalities were found in animals, and the pupil, corneal curvature, anterior chamber and lens related indexes of the test individual were not affected by the drug (see Figure 7 ).

[0303] In summary, in addition to eye injection administration, benzidate and its salt form (such as lysine salt) can also effectively treat and prevent myopia when using other non-invasive (non-invasive) administration methods, and delay the negative process of diopter of myopia individual or myopia prone individual. Specifically, using benzidate lysine eye drops for direct eye administration or benzidate ointment for eye administration to treat myopia, inhibit the extension of eye axis of myopia individual or myopia prone individual and reduce the increase of vitreous cavity depth.

[0304] Example 8, the effect of simple lysine and simple benzidate eye drops on myopia

[0305] 3-week-old three-color guinea pigs were selected after removing individuals with obvious eye diseases or abnormalities, and after diopter (infrared eccentric photography refraction instrument) and eye axis (A-mode ultrasound) detection, animals with refractive power between 3-8 diopter (D) and refractive disparity of both eyes not more than 2D were randomly divided into 5 groups: FD+normal saline group (NS), FD+lysine (L-lysine), FD+0.5% benzalkonium lysine (BDL), FD+DMSO (solvent control group for bendazic acid, vehicle), and FD+bendazic acid (experimental group, referring to the administration of bendazic acid to FDM model individuals, bendazac). On the first day of the experiment at 8 am, guinea pigs were subjected to form deprivation, using a mask method, the right eye was covered (experimental eye), and the left eye was not covered (contralateral eye). FD induction was continued throughout the efficacy experiment period, and the headgear was only temporarily removed for drug administration or eye detection (such as diopter detection). After the start of the efficacy experiment, the headgear position was checked at 8 am, 12 noon, and 7 pm every day, and individuals with more than 3 times of headgear falling off were eliminated. Starting on the day of modeling, the experimental eye was given the corresponding solvent or drug at 9-10 am every day, subconjunctival injection, injection volume was 100 μl, once a day for 2 weeks of continuous administration. Diopter and eye axis parameters were detected at the start of the efficacy experiment, 1 week and 2 weeks of the experiment, and all data collection and processing methods were the same as the published literature in the inventor's laboratory , and the statistics were based on the difference between the experimental eye and the contralateral eye of the same individual. All the above efficacy experiments were repeated at least three times, and the drug preparations were prepared by the inventor.

[0306] The experimental results showed that the changes in diopter and eye axis parameters of animals in the normal saline or DMSO solvent negative control group were consistent with the expected myopia model, and the positive control drug 0.5% benzalkonium lysine showed the expected efficacy in the experiment, which proved that the myopia model in this experiment was successful and could be used for efficacy evaluation of bendazic acid and lysine. The use of lysine alone with the same molar as 0.5% benzalkonium lysine had no inhibitory effect on the progression of myopia, whether it was diopter becoming negative or vitreous cavity depth and eye axis length extension. The diopter index at 1 week and 2 weeks during the drug administration showed that the myopia degree of the lysine intervention group was even higher than that of the normal saline group, while the same molar benzalkonium lysine could effectively inhibit the progression of diopter becoming negative in the drug administration individuals and showed statistical difference with the normal saline group (see Figure 8 ). Therefore, lysine does not have any efficacy for the treatment or prevention of myopia, and the efficacy of benzalkonium lysine for the treatment of myopia is not directly related to the lysine component in its molecule, and any pharmaceutically acceptable salt of bendazic acid can be used for the treatment and prevention of myopia.

[0307] The myopia inhibition rate of simple benemid compared with its DMSO solvent control group was 33.4% and 30.1% at 1 week and 2 weeks, and the myopia treatment effect was consistent with the same batch of equal molar benemid lysine positive control group, and both were statistically different from the corresponding negative control, which proved that benemid was the key and only part of benemid lysine molecules in the treatment of myopia, which could effectively inhibit and slow down the process of myopia individual diopter variable negative. Compared with the DMSO solvent group, the eye axis elongation of the myopia individual can also be significantly inhibited after the administration of benemid, and the increase of the vitreous cavity depth is slowed down, and there is a statistical difference with the negative control group, and the effect is similar to the same batch of equal molar benemid lysine experimental group (see Figure 9 ).

[0308] After the administration of benemid lysine, benemid or lysine, no obvious eye abnormalities were found in animals, and the pupil, corneal curvature, anterior chamber depth and lens thickness related indicators of the test individual were not affected by the drug (see Figures 10-11 ).

[0309] In the above experiment, the choroidal thickness was detected at 2 weeks after the administration of benemid and its corresponding solvent negative control according to the scheme described in the application, the results showed that the simple use of benemid (eye drops) can inhibit the decrease of choroidal thickness of myopic eye, the mean difference of choroidal thickness between the experimental eye and the contralateral eye of myopic individual is-18.82 microns, and the mean difference of choroidal thickness between the experimental eye and the contralateral eye of myopic individual after the intervention of benemid is-8.47 microns, there is a statistical difference between the benemid drug group and the DMSO solvent group (see Figure 12 ). Therefore, benemid and benemid lysine show consistency in inhibiting the decrease of choroidal thickness of myopic individual or myopic tendency individual, and benemid can significantly inhibit the decrease of choroidal thickness of myopic individual or myopic tendency individual and slow down the trend of choroidal thickness thinning.

[0310] The above results prove that: benemid and any one of its salt forms (such as benemid lysine) can effectively treat myopia, which can slow down the process of myopic individual or myopic tendency individual diopter variable negative by inhibiting the elongation of eye axis and slowing down the increase of vitreous cavity depth. At the same time, benemid and its pharmaceutically acceptable salts (such as benemid lysine) can effectively increase the choroidal thickness and reduce the myopia degree. The dosage form of the above benemid and its pharmaceutically acceptable salts (such as benemid lysine) in the treatment and prevention of myopia can be eye drops, eye ointment, eye spray, eye injection and eye gel; the device, preparation or pharmaceutical composition containing such compounds (drugs) can be used to control the progression of myopia.

[0311] Example 9, Treatment effect of Sorbinil and Zopolrestat on guinea pig form deprivation myopia model

[0312] 3-week-old tricolor guinea pigs were selected after excluding those with obvious eye diseases or abnormalities. The refractive power (infrared eccentric photography refraction instrument) and eye axis (A-mode ultrasound) were detected, and animals with refractive power between 3-8 diopter (D) and a difference of no more than 2D between the two eyes were selected and randomly divided into 3 groups: FD+DMSO, FD+Sorbinil, and FD+Zopolrestat. According to the compound database information, the IC 50 of zopolrestat was 3.1 nM, and the IC 50 of sorbinil was 3.14 ± 0.02 μM. The actual concentration of the zopolrestat preparation used in the inventor's experiment was 1 mM, and the final concentration of the sorbinil preparation was 100 μM. The guinea pigs were subjected to form deprivation myopia modeling at 8 am on the first day of the experiment. The form deprivation myopia model used a mask method. The headgear was made by the inventor using a 10-inch white latex balloon. The right eye of the guinea pig modeling individual was covered with the headgear (experimental eye), and the left eye was not covered with the headgear (contralateral eye). FD induction was performed continuously throughout the entire benzyl lysine drug efficacy experiment period, and the headgear was only temporarily removed for drug administration or ocular examination (such as refractive power detection). After the start of the drug efficacy experiment, the headgear position was checked at 8 am, 12 noon, and 7 pm every day, and individuals with more than 3 times of headgear falling were eliminated. Starting on the day of modeling, the experimental eye of the FDM model was given the corresponding solvent or drug from 9 am to 10 am every day. The drug administration frequency was once a day, and the administration method was subconjunctival injection with a volume of 100 μl. The administration was continuous for 2 weeks. The refractive power and eye axis parameters of the test animals were detected at the start of the model drug efficacy experiment, 1 week, and 2 weeks. All data collection and processing methods were the same as those in the published literature of the inventor's laboratory . The statistics were based on the difference between the experimental eye and the contralateral eye of the same test individual. All the above drug efficacy experiments were repeated at least 3 times. The test drugs and solvent controls (negative control group) in this example were prepared by the inventor.

[0313] The results showed that Sorbinil and Zopolrestat had no myopia treatment effect after administration and could not control the progression of myopia. These two aldose reductase inhibitors could not inhibit the progression of refractive power becoming negative and slow down the progression of eye axis elongation in FD-induced myopia individuals. At each detection time point during the entire experimental period, there was no significant difference between Sorbinil and Zopolrestat and the solvent group in terms of refractive power and eye axis parameters Figure 13 . In addition, Sorbinil and Zopolrestat had no effect on the corneal curvature, anterior chamber depth, and lens thickness related indicators of the test individuals (see Figure 14 ). In summary, aldose reductase is not a target for the development of myopia treatment drugs, and not all aldose reductase inhibitors have the efficacy of myopia prevention and control.

[0314] Example 10, Therapeutic effect of m-hydroxy-methylaniline on guinea pig form-deprivation myopia model

[0315] The guinea pig form-deprivation myopia model described in this application was used to evaluate the efficacy of the drug. After the refractive diopter and eye axis were detected, all individuals were randomly divided into 3 groups: FD+0.9% normal saline (NS), FD+m-hydroxy-methylaniline (compound A), and FD+0.1% atropine (positive control). The guinea pigs were subjected to form deprivation at 8 am on the first day of the experiment, using the mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). From the day of modeling, the experimental eye was given the corresponding solvent or drug from 9 am to 10 am every day, and the drug was administered by subconjunctival injection with a volume of 100 μl, once a day for 1 week. The refractive diopter and eye axis parameters were detected at the beginning and end of the efficacy experiment, and all data collection and processing methods were the same as those in other examples of this application. The statistics were based on the difference between the experimental eye and the contralateral eye of the same individual.

[0316] The changes in refractive diopter and eye axis parameters of the negative control group animals in this experiment were consistent with the expected myopia model, and the positive control drug atropine showed the expected efficacy in the experiment, which proved that the myopia model in this experiment was successful and could be used for efficacy evaluation of the test drug. The results of the experiment are shown in Figure 15 . After administration of m-hydroxy-methylaniline, neither the refractive diopter became negative nor the increase in vitreous cavity depth or eye axis length was inhibited. This indicates that m-hydroxy-methylaniline has no myopia prevention or treatment effect. After administration of m-hydroxy-methylaniline, the eye axis parameters and refractive diopter of the test individuals showed no statistical difference from the negative control group. This drug had no inhibitory effect on the elongation of the eye axis of myopic individuals, and it also had no effect on slowing down the increase in vitreous cavity depth. In this example, atropine showed normal myopia treatment effect, but all test animals in this group had pupil dilation, and the anterior chamber depth and lens thickness were not affected after drug intervention Figure 15 . In summary, the experimental results prove that not all compounds (drugs) with cataract treatment effects can be used to treat myopia; and not all compounds with antioxidant activity or reduced BLOA (Biological Liquid Oxidant Activity) have myopia prevention and control efficacy.

[0317] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that the technical solutions recorded in the foregoing embodiments can still be modified, or some or all of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application, and they should be covered in the scope of the claims and the description of the present application. In particular, as long as there is no structural conflict, each technical feature mentioned in each embodiment can be combined in any way. The present application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

[0318] References:

[0319]

Claims

1. The use of benzyldaza lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, as the sole active ingredient in the preparation of a pharmaceutical composition, formulation, or apparatus, characterized in that, The use of the pharmaceutical composition, formulation, or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and related symptoms; the myopia does not include myopia caused by lens disease; the related symptoms are selected from anisometropia, elongation of axial length, increase of vitreous cavity depth, decrease of choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat abnormal development of the eyeball associated with refractive errors, the main characteristic of which is that, in a relaxed state of accommodation, parallel light rays, after refraction by the eye's refractive system, focus in front of the retina; (c) Controlling, inhibiting, delaying or slowing the process and / or speed of negative refractive power in the eye, wherein myopia does not include myopia caused by lens disease; (d) Used to reduce the distance between the retina and the lens; (e) For the prevention of myopia-related symptoms; the related symptoms are selected from posterior staphyloma, retinal detachment, retinal tear, retinal atrophy and degeneration, subretinal neovascularization, macular hemorrhage, macular degeneration or macular disease, vitreous liquefaction, progressive or sudden loss of near vision, visual field defects, blindness and phloroplasty, choroidal neovascularization, and choroidal atrophy caused by high myopia. The pharmaceutical composition, formulation, or device is intended for use in individuals with myopia or those prone to developing myopia, wherein the individuals are mammals.

2. The use of benzyldane, or a pharmaceutically acceptable salt thereof, or a combination of these substances with one or more other pharmaceutical products, characterized in that, The composition is intended for use in the preparation of a pharmaceutical composition, formulation, or device, and the use of the pharmaceutical composition, formulation, or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and related symptoms; the myopia does not include myopia caused by lens disease; the related symptoms are selected from anisometropia, elongation of axial length, increase of vitreous cavity depth, decrease of choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat abnormal development of the eyeball associated with refractive errors, the main characteristic of which is that, in a relaxed state of accommodation, parallel light rays, after refraction by the eye's refractive system, focus in front of the retina; (c) Controlling, inhibiting, delaying or slowing the process and / or speed of negative refractive power in the eye, wherein myopia does not include myopia caused by lens disease; (d) Used to reduce the distance between the retina and the lens; (e) For the prevention of myopia-related symptoms; said related symptoms are selected from posterior staphyloma, retinal detachment, retinal tear, retinal atrophy and degeneration, subretinal neovascularization, macular hemorrhage, macular degeneration or macular disease, vitreous liquefaction, progressive or sudden loss of near vision, visual field defects, blindness and phthisis bulbi, choroidal neovascularization, and choroidal atrophy caused by high myopia; The other one or more drugs mentioned herein are selected from atropine, dibazol, pirenzepine, 7-methylxanthine, ampicillin, dopamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pipfenpine, pirenzepine, methylamine, chlorpheniramine, γ-aminobutyric acid, naloxone, bendazac, glucagon, retinoic acid, rhodioloside, styracin, prazosin, homatropine, anisodamine, tropicamide, nicotinic acid, piracetam, tanshinone extract, safflower extract, fish oil, bear bile extract, vitamins, and adenosine triphosphate. The pharmaceutical composition, formulation, or device is intended for use in individuals with myopia or those prone to developing myopia, wherein the individuals are mammals.

3. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition, formulation, or device may be further linked Combined with surgery and / or other vision correction methods.

4. The use as described in claim 3, characterized in that, The surgeries include refractive surgery, myopia laser surgery, or lens surgery; the other vision correction methods include contact lenses, myopia glasses, or orthokeratology lenses.

5. The use as described in claim 1 or 2, characterized in that, The abnormal development of the eyeball related to refractive errors refers to abnormal development of the size of the eyeball during childhood and adolescence, characterized by an excessively long axial length, causing parallel light rays to focus in front of the retina after passing through the eye's refractive system; or the abnormal development of the eyeball related to refractive errors is mainly induced by environmental factors; or the abnormal development of the eyeball related to refractive errors is mainly caused by human factors, while genetic factors are secondary, accompanying, or synergistic factors; or the abnormal development of the eyeball related to refractive errors is completely unrelated to genetic factors.

6. The use as described in claim 5, characterized in that, The human factors mentioned include prolonged close-range reading, frequent use of electronic screens, continuous near vision without opportunities for far vision, improper use of refractive glasses, drug side effects, obesity, trauma, poor lighting in the learning environment, and lack of outdoor activities.

7. The use as described in claim 1 or 2, characterized in that, The individuals with myopia or those prone to developing myopia are children, adolescents, middle-aged people, or the elderly.

8. The use as described in claim 1 or 2, characterized in that, The term "myopic individuals" or "individuals with a tendency to develop myopia" refers to people aged 3 to 26.

9. The use as described in claim 1 or 2, characterized in that, The term "myopic individuals" or "individuals with a tendency to develop myopia" refers to people aged 6 to 18.

10. The use as described in claim 1 or 2, characterized in that, The term "myopic individuals" or "individuals with a tendency to develop myopia" refers to people whose eyes are still in the growth and development stage.

11. The use as described in claim 1 or 2, characterized in that, The aforementioned myopia is axial myopia.

12. The use as described in claim 11, characterized in that, The axial myopia is defined as axial simple myopia.

13. The use as described in claim 1 or 2, characterized in that, The dosage of the benzyldane, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective dose.

14. The use as described in claim 1, characterized in that, The pharmaceutical composition, formulation, or device further comprises other active ingredients; the content of the benzyldamine lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, is more than 50% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

15. The use as described in claim 14, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 60% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

16. The use as described in claim 14, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 70% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

17. The use as described in claim 14, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 80% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

18. The use as described in claim 14, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 90% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

19. The use as described in any one of claims 14-18, characterized in that, The benzyl lysine, or its pharmaceutically acceptable salt, or a combination of these substances, contributes more than 50% to the efficacy of myopia treatment during medication.

20. The use as described in any one of claims 14-18, characterized in that, The benzyldane, or its pharmaceutically acceptable salt, or a combination of these substances, contributes more than 60% to the efficacy of myopia treatment during medication.

21. The use as described in any one of claims 14-18, characterized in that, The benzyl lysine, or its pharmaceutically acceptable salt, or a combination of these substances, contributes more than 70% to the efficacy of myopia treatment during medication.

22. The use as described in any one of claims 14-18, characterized in that, The benzyl lysine, or its pharmaceutically acceptable salt, or a combination of these substances, contributes more than 80% to the efficacy of myopia treatment during medication.

23. The use as described in any one of claims 14-18, characterized in that, The benzyl lysine, or its pharmaceutically acceptable salt, or a combination of these substances, contributes more than 90% to the efficacy of myopia treatment during medication.

24. The use as described in claim 2, characterized in that, The pharmaceutical composition, formulation, or device further comprises other active ingredients.

25. The use as described in claim 24, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 50% of the total active ingredients, wherein the percentage is a mass ratio or a molar ratio.

26. The use as described in claim 24, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 60% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

27. The use as described in claim 24, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 70% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

28. The use as described in claim 24, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 80% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

29. The use as described in claim 24, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 90% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

30. The use as described in claim 1 or 2, characterized in that, The concentration or proportion of the benzyldane lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, in the pharmaceutical composition, formulation, or device is at least 0.01%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

31. The use as described in claim 30, characterized in that, The concentration or percentage of the benzyldane lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition, formulation, or device is from 0.01% to 0.8%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

32. The use as described in claim 30, characterized in that, The concentration or percentage of the benzyldane lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition, formulation, or device is 0.05% to 0.5%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

33. The use as described in claim 30, characterized in that, The concentration or percentage of the benzyldane lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, in the pharmaceutical composition, formulation, or device is 0.1%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

34. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition or formulation is a free solution, an oil-water mixture, or a suspension.

35. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition or preparation is an injection, a lyophilized powder for injection, an aerosol, a cream, drops, an ointment, or a paste.

36. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition or preparation is a topical or oral preparation.

37. The use as described in claim 36, characterized in that, The topical preparation is an ophthalmic formulation.

38. The use as described in claim 37, characterized in that, The ophthalmic dosage forms include eye drops, eye ointments, eye sprays, implants, ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periorbital injections, or intraocular injections.

39. The use as described in claim 1 or 2, characterized in that, The device is capable of releasing drugs, or has drug delivery function, or has potential drug delivery capability.

40. The use as described in claim 39, characterized in that, The device includes instruments, equipment, consumables, and systems.

41. The use as described in claim 39, characterized in that, The device is an item used to alter the appearance of the eyes.

42. The use as described in claim 39, characterized in that, The device is a combination of medicine and medical device for myopia prevention and control.

43. The use as described in claim 39, characterized in that, The device includes an ocular surface drug delivery device, an intraocular drug delivery device, or a fundus drug delivery device.

44. The use as described in claim 39, characterized in that, The device includes a corneal contact lens, eyeglasses, an artificial lens, sutures, an orthokeratology (Ortho-k) lens cleaning and maintenance system, eye patches, microneedles, an eye spray system, an eye massager, an eye fumigation device, and an implantation pump.

45. The use as described in claim 39, characterized in that, The device includes an acupressure massager and colored contact lenses.

46. ​​The use as described in claim 39, characterized in that, The device includes wearable devices, eye relaxation devices, and myopia treatment devices.

47. The use as described in claim 1 or 2, characterized in that, The administration methods of the drug composition, formulation or device include systemic administration, local administration, parenteral administration, non-invasive administration and non-invasive administration.

48. The use as described in claim 47, characterized in that, The administration methods may be used in combination or individually.

49. The use as described in claim 47, characterized in that, The parenteral administration methods include administration via mucosa, transdermal administration, and microneedle administration.

50. The use as described in claim 47, characterized in that, The non-invasive administration method includes applying eye ointment to the cornea or squeezing it into the sac formed by stretching the lower eyelid.

51. The use as described in claim 47, characterized in that, The non-invasive drug delivery method includes administering medication using an eye spray.

52. The use as described in claim 47, characterized in that, The local administration methods include eye drops, intravitreal injection, and application of ointment or cream to the skin.

53. The use as described in claim 52, characterized in that, The skin ointment or ointment is a 3% skin ointment or eye ointment, wherein the percentage represents a mass / volume ratio, or a mass ratio, or a molar ratio.

54. The use as described in claim 47, characterized in that, The formulations used in the local administration method include aqueous, oil-based, or suspension formulations.

55. The use as described in any one of claims 14-18 or 24, characterized in that, The benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, is formulated or designed with one or more of the other active ingredients for continuous, simultaneous, sequential, alternating, spaced, or single administration.

56. The use as described in claim 1, characterized in that, The pharmaceutical composition, formulation, or device may be used in combination with one or more other active ingredients selected from acetylcholinesterase inhibitors, dopamine agonists, M receptor blockers, polyunsaturated fatty acids, non-selective adenosine antagonists, vasodilators, mydriatics, smooth muscle relaxants, antivasospasm drugs, collagen metabolism regulators, anti-allergic drugs, anti-inflammatory drugs, hepatoprotective drugs, or local ophthalmic anesthetics. The content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination of these substances, accounts for more than 50% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

57. The use as described in claim 56, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 60% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

58. The use as described in claim 56, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 70% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

59. The use as described in claim 56, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 80% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

60. The use as described in claim 56, characterized in that, The content of the benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 90% of the total active ingredients, wherein the percentage is a mass ratio or molar ratio.

61. The use as described in claim 2, characterized in that, The pharmaceutical composition, formulation, or device may be used in combination with one or more other active ingredients selected from acetylcholinesterase inhibitors, dopamine agonists, M receptor blockers, polyunsaturated fatty acids, non-selective adenosine monophosphate antagonists, vasodilators, mydriatics, smooth muscle relaxants, antivasospasm drugs, collagen metabolism regulators, anti-allergy drugs, anti-inflammatory drugs, hepatoprotective drugs, or local ophthalmic anesthetics.

62. The use as described in any one of claims 56-61, characterized in that, The M receptor blocker is an M3 receptor blocker, antagonist, or inhibitor, and the polyunsaturated fatty acid is DHA and / or EPA.

63. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition or preparation is a liniment, lotion, granule, spray, or patch.

64. The use as described in claim 1 or 2, characterized in that, The pharmaceutical composition or formulation is an emulsion.

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