Methods and pharmaceutical compositions for treating myopia

Abstract

This application relates to methods and pharmaceutical compositions for treating myopia. The pharmaceutical compositions or methods of this application can effectively control myopia, are safe with no significant side effects, and have good prospects for clinical application.

Description

[0001] This application is a divisional application of the invention patent application filed on April 29, 2022, with Chinese patent application number 202210472306.1 and title "Method and Pharmaceutical Composition for Treating Myopia".

[0002] Related applications

[0003] The disclosure of this invention claims priority to Chinese Patent Application No. 202110485864.7, filed on April 30, 2021, which is incorporated herein by reference in its entirety. Technical Field

[0004] This application relates to methods and pharmaceutical compositions for treating myopia, and belongs to the pharmaceutical field. Background Technology

[0005] In 350 BC, Aristotle first used the term "myopia" (Paulus TVM de Jong, Br JOphthalmol. 2018 Aug; 102(8):1021-102) to refer to a refractive error. Currently, myopia is one of the most serious public health problems in the world. Early literature indicated that in 2010, the number of people with myopia worldwide was close to 1.84 billion, accounting for 27% of the world's total population at that time, of which 170 million were highly myopic, accounting for 2.8%. It is estimated that by 2050, the global prevalence of myopia will reach more than 50% (Brien A Holden, Ophthalmology. 2016 May; 123(5):1036-42). The incidence of myopia among children and adolescents aged 6 to 18 in my country is particularly serious. In 2016, an epidemiological survey of 57,904 cases showed that the prevalence of myopia among primary and secondary school students in six provinces and cities sampled in North China, East China, South China, Southwest China, and Northwest my country was 55.7%. Among them, the prevalence of myopia in the 6-8 year old group, 10-12 year old group, 13-15 year old group, and 16-18 year old group was 35.8%, 58.9%, 73.4%, and 81.2%, respectively (Zhou Jia, Ma Yinghua, Ma Jun et al. Analysis of the prevalence of myopia among primary and secondary school students in six provinces and cities in China and its influencing factors. Chinese Journal of Epidemiology 2016; 37:29-34.). Epidemiological data show that the global prevalence of myopia and high myopia is constantly rising. Significant changes in social, lifestyle and environmental factors are one of the important reasons for the continuous rise in the prevalence of myopia, the younger age of onset of myopia and the severity of myopia (Susan Vitale, Arch Ophthalmol. 2009 Dec; 127(12):1632-9). This trend will not improve significantly in the short term.

[0006] Myopia has many harmful effects. In addition to causing blurred vision at a distance, myopia, especially high myopia, can also cause serious complications such as glaucoma, cataracts, retinal detachment, retinal tear, posterior staphyloma, macular hemorrhage or myopic macular degeneration, choroidal neovascularization, etc., which can damage vision-related quality of life, increase the difficulty of vision-related work, and even lead to 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 of the Invention

[0007] In view of the above-mentioned technical problems, this application provides a use of benzalkonium chloride or benzalkonium acid, or its optical isomer or its racemic mixture, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or its derivative, or its crystalline compound, or a combination of these substances, characterized in that the use is one of the following or at least two of the following:

[0008] (a) For the prevention and / or treatment of myopia and related symptoms;

[0009] (b) Used to delay, reduce or treat abnormal development of the eyeball associated with refractive errors;

[0010] (c) To enable individuals to obtain clearer distance vision without the aid of or replacement of lenses (such as myopic eyeglasses or orthokeratology lenses) or without relying on other vision correction methods (such as refractive surgery);

[0011] (d) Used to control, inhibit, delay or slow down the (speed) of the (continuous) negative refractive error process in myopic individuals or individuals with a tendency to develop myopia;

[0012] (e) Used in combination with surgery (such as refractive surgery, laser eye surgery, or phakic surgery) or other vision correction methods (such as contact lenses) to prevent and / or treat myopia and its related symptoms;

[0013] (f) Used in combination with one or more other medications to prevent and / or treat myopia and myopia-related symptoms;

[0014] (g) Used to reduce the distance between the retina and the lens, preferably in myopic individuals or individuals with a tendency to myopia;

[0015] (h) Used to reduce myopia, or treat myopia, or treat myopia, or control the progression of myopia, or correct myopia, or alleviate myopia, or prevent myopia in adolescents;

[0016] (i) Used to suppress or treat myopia caused by lens lesions;

[0017] (j) for preparing a pharmaceutical composition, formulation, or device to achieve at least one of the uses described in (a) to (i) above.

[0018] In some embodiments, benzalkonium chloride or benzalkonium acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound, or a combination of these substances, is used as the sole or principal active ingredient.

[0019] In some embodiments, the sole active ingredient or the main active ingredient is one whose content accounts for more than 50%, 60%, 70%, 80%, 90%, or 100% of all active ingredients, and the percentage is a mass ratio or molar ratio.

[0020] In some embodiments, these substances or combinations thereof are formulated or designed with one or more other drugs for continuous, simultaneous, sequential, alternating, spaced-out, or individual administration.

[0021] In some implementations, the abnormal development of the eyeball associated with refractive errors is during the early childhood stage (e.g., 2-28 years old in humans), primarily induced by environmental factors or mainly caused by human factors (e.g., prolonged close-range reading, frequent use of electronic screens, continuous near vision without opportunities for far vision, improper use of refractive corrective glasses, drug side effects, obesity, trauma, poor lighting in the learning environment, lack of outdoor activities), while genetic factors are secondary, accompanying, synergistic factors, or the refractive developmental abnormalities are completely unrelated to genetic factors. The main characteristic of such abnormalities 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.

[0022] In some implementations, the administration method is systemic (e.g., oral, intravenous infusion), or local (e.g., eye drops, intravitreal injection, skin ointment or cream application), or parenteral (e.g., transdermal, microneedle administration), or non-invasive (e.g., applying eye ointment to the cornea or squeezing it into the capsule formed by stretching the lower eyelid), or non-invasive (e.g., using an eye spray).

[0023] In some embodiments, the skin ointment or ointment is applied using a 3% skin ointment or eye ointment.

[0024] In some embodiments, the above-mentioned administration methods (such as eye drops, oral administration) are used simultaneously, in combination, alternately, at intervals, alone, or selected from one of them.

[0025] In some embodiments, the formulations used for topical administration include, but are not limited to, aqueous, oily, or suspension formulations. These formulations may contain pharmacologically and / or physiologically active ingredients, such as mydriatic components, decongestant components, extraocular muscle (e.g., ciliary muscle) modulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotective components (to avoid or reduce hepatotoxicity), blood-retinal barrier enhancing components (making it more difficult for compounds to penetrate the physiological barrier), vitamins, amino acids, antibacterial components, sugars, polymers or their derivatives, cellulose or its derivatives, local anesthetic components, glaucoma treatment components, cataract treatment components, etc.

[0026] In some embodiments, the concentration or percentage of these substances or combinations thereof in the pharmaceutical composition, formulation or device is at least 0.01%, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more preferably 0.1%; or the concentration or percentage 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.

[0027] In some embodiments, the pharmaceutical composition or formulation may be an injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, lozenge, granule, ointment, syrup, oral liquid, aerosol, nasal drops, topical preparation, oral preparation, etc.; preferably, it is an ophthalmic dosage form, including but not limited to eye drops, eye ointments, eye sprays, implants, ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections, or intraocular injections; it may also be a free solution, oil-water mixture, suspension, liniment, lotion, cream, drops, granules, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0028] In some implementations, the myopic individual or the individual with a tendency to develop myopia is a person, which may be a child, adolescent, middle-aged or elderly person, preferably a person aged 3 to 26, more preferably a person aged 6 to 18; or an adult or a minor, preferably a person whose eyes (eyeballs) are still in the growth and development stage; or a school-age person, preferably a student in the first to twelfth grades.

[0029] In some embodiments, myopia is defined as refractive myopia or axial myopia; congenital myopia (myopia at birth or before school age), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), and late-onset myopia (after adulthood); low myopia (mild myopia), moderate myopia, and high myopia (severe myopia); pseudomyopia, true myopia, and mixed myopia; myopia in children and / or adolescents (preferably aged 3-26 years, more preferably aged 6-18 years), myopia in minors, myopia in adolescents, myopia in adults, and myopia in the elderly; simple myopia and pathological myopia; axial simple myopia and simple axial myopia; axial myopia in children and / or adolescents (preferably aged 3-26 years, more preferably aged 6-18 years); axial myopia in school-aged and preschool children; primary myopia and secondary myopia; and primary myopia in children and / or adolescents. Myopia (preferred age group: 3-26 years old, preferred age group: 6-18 years old); progressive myopia in children and / or adolescents (preferred age group: 3-26 years old, preferred age group: 6-18 years old); curvature myopia, index myopia, positional myopia, bending myopia; myopia caused by prolonged close-range eye use, myopia and pseudomyopia caused by eye strain, negative refractive error caused by adverse drug reactions, myopia, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by mismatch of refractive media (composition), refractive myopia, myopia caused by refractive developmental abnormalities, myopia caused by excessive eye growth, myopia caused by poor eye hygiene, myopia caused by various reasons where the focal point of distant objects falls in front of the retina, myopia with poor or ineffective treatment with atropine, myopia caused by insufficient outdoor exercise, accommodative tension myopia, childhood myopia, and myopia dominated by environmental factors.

[0030] In some implementations, myopia-related symptoms include complications of myopia, such as complications of high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular disease, visual field defects, progressive or sudden decrease in vision (especially near vision), eye strain and / or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, needing to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye strain, difficulty seeing while driving, especially at night (night myopia), retinal atrophy and degeneration (hemorrhagic and tear), subretinal neovascularization, and phthisis bulbi.

[0031] 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), ampicillin, sine monoamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pipexidine, pirenzepine, pirenzepine, methylamine, chlorpromazine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as blockers, antagonists, or inhibitors targeting M3 receptors), bendanoic acid, or various salts thereof. The following are listed: lysine, benzyl lysine or its various salt forms, polyunsaturated fatty acids (such as DHA, EPA), rhodioloside, styracin, prazosin, homatropine, anisodamine (racemic), tropicamide, niacin, piracetam, tanshinone extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenosine nucleotide antagonists, vasodilators, mydriatics, smooth muscle relaxants, antivasospasm drugs, collagen metabolism regulators, anti-allergy drugs, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, local ophthalmic anesthetics, or ophthalmic preparations.

[0032] In some embodiments, 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, ampicillin, dopamine, timolol maleate, adrenaline, pyrazine, pipfenpine, pirenzepine, pirenzepine, methylamine, chlorpromazine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers, antagonists, or inhibitors), bendazac or its various salt forms, bendazac lysine or its various salt forms. Polyunsaturated fatty acids (such as DHA, EPA), rhodioloside, styracin, prazosin, homatropine, anisodamine (racemic), tropicamide, niacin, piracetam, tanshinone extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenosine nucleotide antagonists, vasodilators, smooth muscle relaxants, anti-vasospasm drugs, collagen metabolism regulators, anti-allergy drugs, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, local ophthalmic anesthetics, mydriatics, or ophthalmic preparations or drugs.

[0033] In some embodiments, the formulation may also be an oral product or cosmetic such as a health product, food, dietary supplement, nutritional product, or beverage; wherein the cosmetic may be one or a combination of several of the following: free solution, oil-water mixture, suspension, liniment, lotion, spray, cream, drops, granule, ointment, paste, pill, suppository, emulsion, patch.

[0034] In some embodiments, the device is an instrument, equipment, consumable, system, medical device, health care product, or product that can release drugs or has drug delivery function or potential drug delivery capability, such as contact lenses, eyeglasses, artificial lenses, sutures, orthokeratology lens cleaning (maintenance) systems, eye patches, vision-enhancing patches, colored contact lenses, microneedles, eye spray systems, eye massagers (myopia massagers), eye fumigation devices, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia treatment devices, or combinations of drugs and devices for myopia prevention and control. Attached Figure Description

[0035] Figure 1 : Benzalkonium chloride controls the progression of myopia.

[0036] Figure 2 Safety of benzalkonium chloride eye drops in treatment.

[0037] Figure 3 Different concentrations of benzyldamine lysine eye drops for myopia prevention and control.

[0038] Figure 4 Safety of treatment with different concentrations of benzalkonium chloride.

[0039] Figure 5 Benzalkonium chloride increases the thickness of the choroid in individuals with myopia.

[0040] Figure 6 The therapeutic effects of benzalkonium chloride eye drops and benzalkonium chloride ointment applied to the eyes.

[0041] Figure 7 Safety of benzalkonium chloride eye drops and benzalkonium chloride ointment for ocular application.

[0042] in, Figure 1-5 The statistical differences between the *benzyldamine lysine (benzyldamine acid) treatment group and the negative control group were statistically significant. The statistical differences between the # atropine treatment group and the negative control group were statistically significant. * represents p<0.05, ** represents p<0.01, *** represents p<0.001, # represents p<0.05, ## represents p<0.01, and ### represents p<0.001. Figure 6 and Figure 7In the study, *differences were observed between the benzalkonium chloride eye drops group and the saline group; #differences were observed between the atropine group and the saline group; and $differences were observed between the benzalkonium chloride ointment group and the saline group. * represents p<0.05, *** represents p<0.001, # represents p<0.05, ## represents p<0.01, and $ represents p<0.05.

[0043] Figure 8 Lysine alone cannot treat myopia. #Difference between BDL and saline solution group, # represents p<0.05, ## represents p<0.01, ### represents p<0.001.

[0044] Figure 9 Bendazac eye drops alone have the same myopia treatment effect as bendazac lysine eye drops. The differences between #BDL and the saline solution group, and between *bendazac and the vehicle solution group, are shown. * represents p<0.05, *** represents p<0.001, ## represents p<0.01, and ### represents p<0.001.

[0045] Figure 10 Safety of simple benzalkonium chloride treatment.

[0046] Figure 11 Safety of lysine-only treatment.

[0047] Figure 12 : Benadryl acid inhibited the reduction of choroidal thickness in myopic individuals, * indicates p<0.05.

[0048] Figure 13 Sorbinil and Zopolrestat cannot treat myopia.

[0049] Figure 14 Safety evaluation of aldose reductase inhibitor administration.

[0050] Figure 15 m-Hydroxymethylaniline cannot treat myopia. #Statistical difference between the atropine group and the negative control group, ## represents p<0.01. Detailed Implementation

[0051] The embodiments of the technical solution of this application will now be described in detail with reference to the accompanying drawings. These embodiments are only used to more clearly illustrate the technical solution of this application and are therefore merely examples, and should not be used to limit the scope of protection of this application.

[0052] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0053] Myopia is the most common type of refractive error, referring to a refractive state in which parallel light rays, after being refracted by the eye's refractive system in a relaxed state of accommodation, focus in front of the retina. There are four common classifications of myopia: (1) based on the magnitude of refractive error, it can be divided into mild (low) myopia, moderate myopia, and high (severe) myopia; (2) based on whether the refractive components are abnormal, it can be divided into refractive myopia and axial myopia; (3) based on whether pathological changes have occurred, it can be divided into pathological myopia and simple myopia; (4) based on the cause, it can be divided into primary myopia and secondary / compound myopia. Regardless of the type of myopia, the mismatch between the components of the refractive system (i.e., the refractive media, including the cornea, lens, and vitreous body) is the key to the formation of myopia and the determination of its severity. Taking refractive myopia as an example, assuming other refractive components are normal, if an individual's corneal curvature is abnormal, the focal point of parallel light rays after passing through the cornea will deviate from its original position on the retina, thus causing a change in refractive power. This is commonly seen in myopia caused by keratoconus. Another example is myopia caused by certain diseases altering the lens's refractive index, which directly affects the projection position of parallel light rays on the retina. In this case, if the focal point of the parallel light rays falls in front of the retina, it is called myopia caused by lens disease. Refractive component mismatch also includes situations where an enlarged vitreous cavity causes the retina to shift posteriorly, resulting in the focal point of distant objects falling in front of the retina, manifesting as a negative refractive power. Therefore, the above classification methods for myopia are further subdivided in clinical practice based on specific circumstances. However, refractive power is generally recognized as the sole indicator for determining all types of myopia, measuring their severity, and evaluating the effectiveness of myopia treatment. According to the "Technical Guidelines for Clinical Research of Drugs for Controlling the Progression of Myopia" and the consensus of the academic community, the most common type of myopia in children and adolescents (especially those aged 6-18) is axial simple myopia (Paul N Baird, Nat Rev Dis Primers. 2020 Dec 17; 6(1):99. and AJ 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.), with the main site of axial elongation being the posterior pole of the eyeball. Consistent with human myopia, long-term experimental myopia models in mammals (such as tree rats, marmosets, and guinea pigs) have also shown axial elongation, scleral thinning, and thinning of scleral collagen fibers (Neville A McBrien, Prog Retin Eye Res. 2003 May; 22(3):307-38.).In the actual preclinical development stage of drugs, researchers almost always use two classic myopia disease models, form-deprivation (FD) or lens-induced (LI), to evaluate the efficacy of myopia control drugs (DA Goss, Am J Optom Physiol Opt. 1981 Oct; 58(10): 859-69. and Hao Wu, Proc Natl Acad Sci US A. 2018 Jul 24; 115(30): E7091-E7100. and Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083.). Compounds that have both therapeutic and control effects on these two myopia models are considered to have the greatest potential for drug development.

[0054] The pathogenesis of myopia is not fully understood. Currently, environmental factors are considered the main contributing factor to the high incidence and severity of myopia, while genetically caused myopia is relatively rare. Environmental factors include excessive accommodation, peripheral retinal hyperopic defocus, abnormal lighting (lighting abnormalities), and form deprivation. The specific mechanism by which these factors induce myopia may be that after the retina recognizes near visual information that induces myopia, these signals are transmitted through the choroid to the sclera, leading to changes in the extracellular matrix composition of the sclera, ultimately causing a decrease in refractive power until it becomes negative, thus forming myopia. This can be simply summarized as optical defocus triggering a defocus-specific signal, 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 grows along with other parts of the body. Humans, like other mammals, exhibit farsightedness from birth to infancy. In subsequent growth stages, as the refractive components of the eyeball further develop and the axial length of the eye moderately elongates, the focal point of parallel light rays overlaps with the retina (i.e., the focal point falls on the retina), resulting in emmetropia. If prolonged and continuous near visual information occurs during this developmental process, a series of refractive component mismatches can occur, including excessive elongation of the eyeball. This causes the focal point of parallel light rays to fall in front of the retina, resulting in myopia. Therefore, ensuring the matching of various refractive components during eyeball development and preventing excessive eyeball growth is key to myopia prevention and control. Previous studies have found that refractive developmental abnormalities in myopic individuals are related to scleral remodeling, scleral tissue loss due to reduced connective tissue synthesis, and increased degradation of type I collagen (COL1). Dopamine, insulin, and nitric oxide may also be involved.

[0055] Currently, eyeglasses are the primary method for correcting myopia in children and adolescents, while adult patients can undergo laser surgery. Although myopia can be corrected in most cases with eyeglasses, contact lenses, or refractive surgery, its progression cannot be slowed. Any type of myopia, once it develops into high myopia, becomes a particularly dangerous vision problem due to the high risk of complications involving the retina, choroid, and sclera. Therefore, myopia correction should not be simply understood as myopia treatment. Clinically, myopia treatment mainly focuses on inhibiting or slowing the progression of myopia, involving both optical and pharmacological methods. Orthokeratology lenses can slow the progression of myopia in children and adolescents, but the effectiveness of this treatment varies greatly among individuals and requires close assistance from a professional optometrist (Jinhai Huang, Ophthalmology. 2016 Apr; 123(4):697-708.). Pharmacological options for myopia control are very limited (Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov; 40(11):833-852.). For example, although atropine eye drops have shown myopia treatment effects in many studies, clinical observations have shown a rebound in myopia after discontinuation of the drug, and serious side effects such as pupil dilation and photophobia during use (Prema Ganesan, Expert Rev Ophthalmol. 2010 Dec 1; 5(6):759-787.). Moreover, it has not been approved for use by the National Medical Products Administration in China. 7-Methylxanthine is another drug under investigation for myopia control, but its safety and efficacy require more data support (Klaus Trier, J Ocul Biol Dis Infor. 2008 Dec; 1(2-4): 85-93. and Tatiana VTkatchenko, Trends Pharmacol Sci. 2019 Nov; 40(11): 833-852.). Therefore, there is currently a lack of drugs with proven efficacy and safety for controlling the progression of myopia, and there is an unmet clinical need in this disease area.

[0056] Bendazac Lysine (BDL) or bendazac acid is known to have analgesic, antipruritic, anti-necrotic, choleretic, and lipid-lowering effects. Clinically, bendazac lysine is used to treat cataracts by preventing lens protein denaturation.

[0057] The inventors unexpectedly discovered through research that bendazac or bendazac lysine can treat, prevent or slow down myopia and its related symptoms. These compounds can effectively control, inhibit, delay or slow down the progression of myopia and are ultimately used to prepare preparations or drug compositions for the prevention and treatment of myopia. Furthermore, these compounds have advantages such as high drug safety and few adverse reactions.

[0058] In view of the above findings, this application provides the use of benzalkonium chloride or benzalkonium acid, or its optical isomer or racemic mixture, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound, or a combination of these substances, characterized in that the use is one of the following or at least two of the following:

[0059] (a) For the prevention and / or treatment of myopia and related symptoms;

[0060] (b) To inhibit or slow down the elongation of the axial length and / or the increase in the length (depth) of the vitreous cavity in individuals with myopia or those with a tendency to develop myopia;

[0061] (c) To increase the choroidal thickness of individuals with myopia or a tendency to develop myopia and / or to inhibit the reduction of their choroidal thickness;

[0062] (d) Used to delay, reduce or treat abnormal development of the eyeball associated with refractive errors;

[0063] (e) To enable an individual to obtain clearer distance vision without the aid of or replacement of lenses (such as myopic eyeglasses or orthokeratology lenses) or without relying on other vision correction methods (such as refractive surgery);

[0064] (f) Used to control, inhibit, delay or slow down the (speed) of the (continuous) negative refractive error process in myopic individuals or individuals with a tendency to develop myopia;

[0065] (g) Used in combination with surgery (such as refractive surgery, myopia laser surgery, lens surgery) or other vision correction methods (such as contact lenses) to prevent and / or treat myopia and its related symptoms;

[0066] (h) Used in combination with one or more other medications to prevent and / or treat myopia and myopia-related symptoms;

[0067] (i) For reducing the distance between the retina and the lens, preferably for reducing the distance between the retina and the lens in myopic individuals or individuals with a tendency to myopia;

[0068] (j) For the purpose of reducing myopia, or treating myopia, or myopia treatment, or controlling myopia progression, or myopia correction, or alleviating myopia, or myopia prevention in adolescents;

[0069] (k) Used to suppress or treat myopia caused by lens lesions;

[0070] (l) Used to maintain refractive stability in individuals whose eyes are in the developmental stage, particularly to control the rate of axial elongation of the eye to maintain its match with the refractive medium, preferably, the match can maintain emmetropia or maintain emmetropia as much as possible;

[0071] (m) is used to maintain refractive stability in individuals whose eyes are in the developmental stage, particularly to control the rate of axial elongation to maintain its match with the refractive medium, preferably, the match can prevent the occurrence of myopia or inhibit the increase of myopia degree;

[0072] (n) is used to prepare a pharmaceutical composition, formulation, or device for achieving at least one of the uses described in (a) to (m) above.

[0073] In some embodiments, benzalkonium chloride or benzalkonium acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound, or a combination of these substances, is used as the sole or principal active ingredient.

[0074] In some embodiments, the sole active ingredient or the main active ingredient is one whose content accounts for more than 50%, 60%, 70%, 80%, 90%, or 100% of all active ingredients, and the percentage is a mass ratio or molar ratio.

[0075] In some embodiments, these substances or combinations thereof are formulated or designed with one or more other drugs for continuous, simultaneous, sequential, alternating, spaced-out, or individual administration.

[0076] In some implementations, the refractive error-related abnormal development of the eyeball is during the early childhood stage (e.g., 2-28 years old in humans), mainly induced by environmental factors or primarily caused by human factors (e.g., prolonged close-range reading, frequent use of electronic screens, continuous near vision without opportunities for far vision, improper use of refractive corrective glasses, drug side effects, obesity, trauma, poor lighting in the learning environment, lack of outdoor activities), while genetic factors are secondary, accompanying, synergistic factors, or the refractive development abnormality is completely unrelated to genetic factors. Its main characteristic 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.

[0077] In some embodiments, benzalkonium chloride or its analogues or derivatives are one of the following compounds (a)-(c):

[0078] (a) Wherein, R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na;

[0079] (b) Wherein, R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na;

[0080] (c) R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na.

[0081] In some embodiments, administration is carried out via systemic methods (e.g., oral administration, intravenous infusion), or local methods (e.g., eye drops, intravitreal injection, application of skin ointment or ointment, preferably 3% skin ointment or ophthalmic ointment), or parenteral methods (e.g., administration via mucosa, transdermal administration, microneedle administration), or non-invasive methods (e.g., applying eye ointment to the cornea or squeezing it into the capsule formed by stretching the lower eyelid), or non-invasive methods (e.g., administration via ophthalmic spray).

[0082] In some implementations, the administration methods (such as eye drops, oral administration) are used simultaneously, in combination, alternately, at intervals, alone, or selected from one of them.

[0083] In some embodiments, the formulations used for topical administration include, but are not limited to, aqueous, oily, or suspension formulations. These formulations may contain pharmacologically and / or physiologically active ingredients, such as mydriatic components, decongestant components, extraocular muscle (e.g., ciliary muscle) modulating components, anti-inflammatory components, astringent components, antihistamine components, anti-allergic components, hepatoprotective components (to avoid or reduce hepatotoxicity), blood-retinal barrier enhancing components (making it more difficult for compounds to penetrate the physiological barrier), local anesthetic components, glaucoma treatment components, cataract treatment components, etc.

[0084] In some embodiments, the concentration or percentage of these substances or combinations thereof in the pharmaceutical composition, formulation or device is at least 0.01%, preferably from 0.01% to 0.8%, preferably from 0.05% to 0.5%, more preferably 0.1%; or the concentration or percentage of these substances or combinations thereof is less than 0.01%, the percentage being expressed as a mass / volume concentration (ratio) or mass ratio or molar (number) ratio, preferably the concentration being the usage concentration or storage concentration.

[0085] In some embodiments, the concentrations of these substances or combinations thereof are, for example, 0.01%-0.05%, 0.05%-0.1%, or 0.1%-0.5%, the percentages being expressed as mass / volume concentration (ratio), preferably the concentrations being the usage concentration or the storage concentration.

[0086] In some embodiments, the pharmaceutical composition or formulation may be an injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, lozenge, granule, ointment, syrup, oral liquid, aerosol, nasal drops, topical preparation, oral preparation, etc.; preferably, it is an ophthalmic dosage form, including but not limited to eye drops, eye ointments, eye sprays, implants, ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections, or intraocular injections; it may also be a free solution, oil-water mixture, suspension, liniment, lotion, cream, drops, granules, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0087] In some implementations, the myopic individual or the individual with a tendency to develop myopia is a person, which may be a child, adolescent, middle-aged or elderly person, preferably a person aged 3 to 26, more preferably a person aged 6 to 18; or an adult or a minor, preferably a person whose eyes (eyeballs) are still in the growth and development stage; or a school-age person, preferably a student in the first to twelfth grades.

[0088] In some embodiments, myopia is defined as refractive myopia or axial myopia; congenital myopia (myopia at birth or before school age), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), and late-onset myopia (after adulthood); low myopia (mild myopia), moderate myopia, and high myopia (severe myopia); pseudomyopia, true myopia, and mixed myopia; myopia in children and / or adolescents (preferably aged 3-26 years, more preferably aged 6-18 years), myopia in minors, myopia in adolescents, myopia in adults, and myopia in the elderly; simple myopia and pathological myopia; axial simple myopia and simple axial myopia; axial myopia in children and / or adolescents (preferably aged 3-26 years, more preferably aged 6-18 years); axial myopia in school-aged and preschool children; primary myopia and secondary myopia; and primary myopia in children and / or adolescents. Myopia (preferred age group: 3-26 years old, preferred age group: 6-18 years old); progressive myopia in children and / or adolescents (preferred age group: 3-26 years old, preferred age group: 6-18 years old); curvature myopia, index myopia, positional myopia, bending myopia; myopia caused by prolonged close-range eye use, myopia and pseudomyopia caused by eye strain, negative refractive error caused by adverse drug reactions, myopia, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by mismatch of refractive media (composition), refractive myopia, myopia caused by refractive developmental abnormalities, myopia caused by excessive eye growth, myopia caused by poor eye hygiene, myopia caused by various reasons where the focal point of distant objects falls in front of the retina, myopia with poor or ineffective treatment with atropine, myopia caused by insufficient outdoor exercise, accommodative tension myopia, childhood myopia, and myopia dominated by environmental factors.

[0089] In some implementations, the aforementioned myopia may or may not include myopia or myopia symptoms caused by lens lesions.

[0090] In some implementations, myopia-related symptoms or signs include complications of myopia, such as complications of high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular disease, visual field defects, progressive or sudden decrease in visual acuity (especially near vision), eye strain 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, needing to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye strain, difficulty seeing while driving, especially at night (night myopia), retinal atrophy and degeneration (hemorrhagic and tear), subretinal neovascularization, and phthisis bulbi.

[0091] 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), ampicillin, sine monoamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pipexidine, pirenzepine, pirenzepine, methylamine, chlorpromazine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), and M receptor blockers (such as blockers, antagonists, or inhibitors targeting M3 receptors). (Prescriptions), polyunsaturated fatty acids (such as DHA, EPA), rhodioloside, styracin, prazosin, homatropine, anisodamine (racemic), tropicamide, niacin, piracetam, tanshinone extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenosine nucleotide antagonists, vasodilators, mydriatics, smooth muscle relaxants, antivasospasm drugs, collagen metabolism regulators, anti-allergy drugs, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, local ophthalmic anesthetics, or ophthalmic preparations.

[0092] In some embodiments, the pharmaceutical composition, formulation, or device further comprises a medical preparation or drug, said medical preparation or drug including bendazac or various salt forms thereof, or bendazac lysine or various salt forms thereof. This means that in these pharmaceutical compositions, formulations, or devices, the final form is a combination of "benzandac or various salt forms thereof" with bendazac lysine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound; or that in these pharmaceutical compositions, formulations, or devices, the final form is a combination of "benzanda lysine or various salt forms thereof" with bendazac, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound.

[0093] In some embodiments, the medical preparation or drug may also be administered concurrently with the drug composition, preparation or device, such as during a specific single administration (treatment) process, simultaneously or sequentially, on the same day, in the same week, in the same month, or in the same year; or alternately, such as alternately administered every 4 hours, every 12 hours, every other day, every other week, every other month, or every other year.

[0094] In some embodiments, 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, ampicillin, dopamine, timolol maleate, adrenaline, pyrazine, pipexidine, pirenzepine, pirenzepine, methylamine, chlorpromazine, acetylcholinesterase inhibitors, dopamine agonists, γ-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (such as M3 receptor blockers, antagonists, or inhibitors), and polyunsaturated fatty acids (such as D...). HA, EPA), rhodioloside, styracin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, tanshinone extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenosine nucleotide antagonists, vasodilators, smooth muscle relaxants, anti-vasospasm drugs, collagen metabolism regulators, anti-allergy drugs, anti-inflammatory drugs, hepatoprotective drugs, therapeutic components for ophthalmic diseases, local ophthalmic anesthetics, mydriatics, or ophthalmic preparations or drugs.

[0095] In some embodiments, one or more other drugs may also include bendamalic acid or various salt forms thereof, or bendama lysine or various salt forms thereof. This means that when these substances of this application are used in combination with these drugs, they can ultimately be in the form of "bendamalic acid or various salt forms thereof" combined with bendama lysine, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound; or when these substances of this application are used in combination with these drugs, they can ultimately be in the form of "bendama lysine or various salt forms thereof" combined with bendamalic acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogue or derivative, or its crystalline compound.

[0096] In some embodiments, combined use means that one or more other drugs are administered concurrently, such as during a specific single medication (treatment) process, administered simultaneously or sequentially, on the same day, in the same week, in the same month, or in the same year; or administered alternately at intervals, such as alternately administered every 4 hours, every 12 hours, every other day, every other week, every other month, or every other year.

[0097] In some embodiments, the formulation may also be an oral product or cosmetic such as a health product, food, dietary supplement, nutritional product, or beverage; wherein the cosmetic may be one or a combination of several of the following: free solution, oil-water mixture, suspension, liniment, lotion, spray, cream, drops, granule, ointment, paste, pill, suppository, emulsion, patch.

[0098] In some embodiments, the device is an instrument, apparatus, consumable, system, medical device, health care product, or product that can release drugs or has drug delivery function or potential drug delivery capability, such as contact lenses, eyeglasses, artificial lenses, sutures, orthokeratology (Ortho-k) lens cleaning (maintenance) systems, eye patches, vision-enhancing patches, colored contact lenses, microneedles, eye spray systems, eye massagers (myopia massagers), eye fumigation devices, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, myopia treatment devices, or combinations of drugs and devices for myopia prevention and control. In some embodiments, the device may be referred to as an ophthalmic device.

[0099] Terms and Definitions

[0100] 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 pertains; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the application; the terms “comprising” and “having”, and any variations thereof, in the specification, claims, and foregoing description of the drawings are intended to cover non-exclusive inclusion.

[0101] In this document, “one or more” means that at least one of the elements is present; there may be multiple such elements unless otherwise explicitly specified.

[0102] In the description of this application, the term "and / or" is merely a description of the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. Additionally, the character " / " in this document generally indicates that the preceding and following related objects have an "or" relationship.

[0103] In this document, references to "embodiment" or "mode of embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment (or "mode of embodiment") may be included in at least one embodiment (or "mode of embodiment") of this application. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment (or "mode of embodiment"), nor is it a separate or alternative embodiment (or "mode of embodiment") mutually exclusive with other embodiments (or "mode of embodiment"). It will be explicitly and implicitly understood by those skilled in the art that the embodiments (or "mode of embodiment") described herein can be combined with other embodiments (or "mode of embodiment").

[0104] In this specification and the appended claims, unless the context clearly specifies otherwise, the singular forms, including the singular forms “a,” “an,” and “the,” specifically cover the plural indicators of the terms they refer to. Additionally, as used herein, unless otherwise specifically indicated, the word “or” means “inclusive” rather than “exclusive” in the sense of “and / or.”

[0105] As used herein, references to the numerical range of variables are intended to convey that this application can be implemented with variables equal to any value within that range. Thus, for intrinsically discontinuous variables, the variable may be equal to any integer value within the numerical range, including the endpoints of the range. Similarly, for intrinsically continuous variables, the variable may be equal to any real value within the numerical range, including the endpoints of the range. For example, a variable described as having a value between 0 and 2 may be 0, 1, or 2 for intrinsically discontinuous variables, and may be 0.0, 0.1, 0.01, 0.001, or any other real value for intrinsically continuous variables.

[0106] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If the use of this term is unclear to those skilled in the art, then in the context of its use, “about” will mean a value within the range of the listed value plus or minus 10%.

[0107] The terms "individual" and "subject" include humans and non-human animals, such as farm animals like sheep, pigs, cattle, and horses; pet animals like dogs and cats; laboratory animals like mice, rats, and non-human primates. In a preferred embodiment, the mammal is a human.

[0108] As used herein, “administering” a compound, formulation, test article, or drug to a subject includes any route by which a compound is introduced into or delivered to a subject to perform its intended function. “Administration” can be performed by any suitable route, including but not limited to oral, intraocular, intranasal, parenteral (via intravenous, intramuscular, intraperitoneal, or subcutaneous) or topical administration. “Administration” includes self-administration and administration by another person.

[0109] In this article, "use alone" means that only one method of administration is used at each stage of the entire medication process, while the method of administration can be changed at different stages of the medication process (but there is no alternation).

[0110] In this article, "choose one" means that the entire medication process is limited to only one route of administration and will not be changed.

[0111] As used herein, the term "amino acid" includes naturally occurring amino acids, synthetic amino acids, amino acid analogs, and amino acid mimics that function in a manner similar to that of naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that have been modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs refer to compounds having the same basic chemical structure as naturally occurring amino acids, for example, an α-carbon, carboxyl, amino, and R group bound to hydrogen. Examples of such amino acid analogs include homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics refer to chemical compounds having a structure different from the general chemical structure of amino acids, but functioning in a manner similar to that of naturally occurring amino acids. In this document, commonly known three-letter or one-letter symbols, as recommended by the IUPAC-IUB Biochemical Nomenclature Committee, may refer to amino acids.

[0112] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or preventive effect, such as causing prevention or relief of symptoms associated with an ophthalmic condition. The amount of composition administered to a subject will depend on the type and severity of the disease and the individual's characteristics, such as general health, age, sex, weight, ethnicity, degree of myopia, rate of myopia progression, and tolerance to the drug. The amount also depends on the extent, severity, and type of the disease, and the treatment regimen established by a professional (e.g., a physician). A skilled technician will be able to determine the appropriate dosage based on these and other factors. The pharmaceutical composition may also be administered in combination with one or more other therapeutic compounds, biologics, and therapeutic molecules (e.g., peptides). In the methods described herein, benzalkonium chloride, benzalkonium lysine compounds, or pharmaceutical compositions containing them may be administered to a subject with one or more symptoms or syndromes of an ophthalmic condition. For example, a "therapeutic effective amount" of benzalkonium lysine refers to an average level of physiological effect that minimizes the severity of the ophthalmic condition, preferably an average level of physiological effect that minimizes the progression of myopia.

[0113] As used herein, the terms “formulation,” “pharmaceutical composition,” and “composition” are used interchangeably and can refer to a mixture of two or more compounds, elements, or molecules. In some respects, 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. Compositions can take almost any physical form, including solid, liquid (e.g., solution), or gas.

[0114] The term "dosage form" can include one or more formulations or compositions provided in a form suitable for administration to a subject. For example, an injectable dosage form can be a formulation or composition prepared in a manner suitable for administration by injection.

[0115] As used in this article, the term "pharmaceutically acceptable" means approved for use in animals, preferably in humans, by regulatory authorities such as the CFDA (China), EMEA (Europe) and / or FDA (US) and / or any other national regulatory authorities.

[0116] As used herein, an "ophthalmologically acceptable carrier" is an ophthalmologically acceptable solvent, suspension, or medium for delivering a pharmaceutical composition to the eye of a subject. The carrier may be solid or liquid. The carrier is "ophthalmologically acceptable" in a sense that it is suitable for application to the eye without causing any significant adverse reactions.

[0117] As used herein, the term "simultaneously" means administering at least two active ingredients via the same or different routes (e.g., oral and ophthalmic) at the same or substantially the same time; or administering and performing surgery at the same or substantially the same time; or administering and applying a treatment device at the same or substantially the same time.

[0118] As used in this article, the term "alone" means that, when administering a treatment, the administration is limited to only one method or one substance at the same time or substantially the same time, such as administering only one active ingredient.

[0119] As used herein, the term "sequential administration" refers to the administration of at least two active ingredients at different times, via the same or different routes of administration. More specifically, "sequential administration" means the complete administration of one of the active ingredients before the administration of other active ingredients. Thus, an active ingredient may be administered several seconds, minutes, hours, or days before the administration of other active ingredients.

[0120] As used herein, the terms “treatment,” “control,” “inhibition,” “delay,” “reduction,” “control,” “prevention,” or “mitigation” refer to therapeutic measures and preventive or preventive measures aimed at preventing or mitigating (alleviating) a target condition or disorder, or even eliminating or reversing it. For example, if a subject exhibits observable and / or measurable avoidance, reduction, and disappearance of one or more symptoms and signs of an ophthalmic condition, or a slowing of disease progression, after receiving a therapeutic amount of a benzyldamine lysine compound or a pharmaceutical composition containing it according to the methods described herein, then the subject's ophthalmic condition is successfully treated. It should also be understood that the various modes of treatment or prevention of medical conditions described herein are intended to mean “significant,” which includes complete treatment or prevention as well as less than complete treatment or prevention, wherein some biologically or medically relevant result is achieved. For example, in some embodiments, “treatment” does not require 100% elimination or prevention of myopia or myopia symptoms. In some embodiments, the treatment of myopia or myopia-related symptoms according to the method of this application reduces, inhibits, prevents, and / or reverses, for example, by at least about 5%, at least about 10%, or at least about 20%, compared to levels observed in the absence of the composition or method of this application (e.g., in biologically matched control subjects, individuals, or specimens not exposed to the composition or compound of the method of this 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 the absence of the compound of the method of this application.

[0121] The term "myopia tendency (individual)" used in this article can refer to situations where the refractive error level has already decreased but has not yet become negative; it can also refer to individuals who are predicted or identified as having a myopia susceptibility or high-risk group by authoritative institutions or professional physicians; it can also refer to individuals with a family history of myopia; it can also refer to individuals who receive more near visual information but lack opportunities to see at a distance; it can also refer to situations where the incidence (prevalence) of myopia or the severity of myopia once it develops is not lower than the average level; it can also refer to situations where adverse reactions to medication or postoperative risks of surgery include a decrease in refractive error; it can also refer to situations where, without intervention using medication or other myopia treatment (control) methods, the individual will develop myopia or their refractive error will drop below 0.

[0122] "Ophthalmic composition" or "ophthalmic preparation" or "ophthalmic formulation" refers to an ophthalmic composition, or ophthalmic pharmaceutical composition, or ophthalmic pharmaceutical product; or the pharmaceutical part of a drug, preparation, cosmetic, health product, or combination or device of medicine or medical device used for the prevention and / or treatment of eye diseases, for the protection, maintenance, improvement, avoidance, mitigation or reversal of vision impairment.

[0123] "Fish oil" refers to lipids derived from higher animals, especially fish (such as cod, salmon), squid, and seals, particularly 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.

[0124] "Analogous compound" refers to a structural derivative of a parent compound (such as benzyl lysine or benzyl lysine mentioned in this application) that differs from the parent compound by only one element (including isotopes).

[0125] As used herein, the term "derivative" of a compound includes any molecule related to the function and / or structure of the compound, such as its acid, amide, ester, ether, acetylated variant, hydroxylated variant, or alkylated (C1-C6) variant, halogenated, deuterated, etc. The derivative should have a Tanimoto similarity index greater than 0.4, preferably greater than 0.5, more preferably greater than 0.6, and even more preferably greater than 0.7 with respect to the parent drug. The Tanimoto similarity index is widely used to measure the degree of structural similarity between two molecules. The Tanimoto similarity index can be calculated using online software such as Small MoleculeSubgraph Detector. Preferred derivatives should be structurally and functionally related to the parent compound, meaning they should retain at least some of the parent drug's activity, such as the bendazac lysine derivatives or analogues described in *Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents* (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010). More preferably, they should have a regulatory effect on refractive development. Furthermore, "derivatives" also include metabolites of the drug, for example, those produced by (biochemical) modification or processing of the drug via a specialized catalytic system after administration to the organism, and which exhibit or retain the drug's biological activity. Metabolites have been disclosed as responsible for a large portion of the therapeutic effects of the parent drug.

[0126] As used in this article, “metabolite” refers to a modified or processed drug that retains at least some of the activity of the parent drug, preferably has an inhibitory effect on aldose reductase (AR) activity, or has a therapeutic, preventive, or slowing effect on myopia and related symptoms.

[0127] As used herein, the term "therapeuticly acceptable salt" refers to a salt or zwitterionic form of a compound disclosed herein that is water-soluble or oil-soluble, or dispersible and therapeutically acceptable, as defined herein. Salts may be prepared during the final isolation and purification of the compound, or individually by reacting a compound in its appropriate free base form with a suitable acid. Representative acid addition salts include acetates, adipates, alginates, L-ascorbic acid salts, aspartates, benzoates, benzenesulfonates (besylate), hydrogen sulfates, butyrates, camphorates, camphorsulfonates, citrates, disglucose salts, formates, fumarates, gentianates, glutarate, glycerophosphates, glycolates, hemisulfates, heptanates, hexanoates, hippurates, hydrochlorides, hydrobromide salts, hydroiodates, 2-hydroxyethanesulfonate (hydroxyethanesulfonate), lactates, and maleate salts. Salts, malonates, DL-mandelates, mesitylenesulfonates, methanesulfonates, naphthalenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, primates, pectinates, persulfates, 3-phenylpropionates, phosphonates, picrates, neopentanoates, propionates, pyroglutamates, succinates, sulfonates, tartrates, L-tartrates, trichloroacetic acid salts, trifluoroacetic acid salts, phosphates, glutamates, bicarbonates, para-toluenesulfonate (p-tosylate), and undecanoates. Furthermore, the basic groups in the compounds disclosed herein can be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; decyl, lauryl, myristyl, and sterol chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (such as oxalic acid, maleic acid, succinic acid, and citric acid). Salts can be formed through coordination of the compounds with alkali metal or alkaline earth metal ions. Therefore, this application includes sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0128] The term "these substances" as used in this application refers to bendazac lysine or bendazac acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogues or derivatives, or their crystalline compounds.

[0129] Myopia (nearsightedness) refers to the condition where, in a relaxed state, parallel light rays converge in front of the retina after passing through the eye's refractive system. It is classified into refractive myopia and axial myopia based on the cause of refraction. Both present with blurred vision at a distance and good near vision. In the early stages of myopia, there are often fluctuations in distance vision. Because accommodation is used less or not at all when focusing on near objects, convergence function weakens accordingly, making exophoria or exotropia more likely. Symptoms related to myopia also include poor night vision, floaters, and flashes of light. Fundus changes of varying degrees may occur, such as myopic lamina, macular hemorrhage, or subretinal neovascularization. Irregularly shaped white atrophic spots may appear, or there may be pigmented, round black spots (Fuchs' spots). Peripheral retinal lattice degeneration and cystic degeneration may occur. Vitreous liquefaction, opacity, and posterior vitreous detachment may occur at a young age. The risk of retinal tears and detachment is higher than in normal individuals. Often, due to the elongated anteroposterior diameter of the eyeball, the eyeball protrudes, and the posterior portion of the eyeball is greatly expanded, leading to scleral staphyloma. Those exhibiting the above clinical symptoms are referred to as pathological myopia.

[0130] Myopia can be a serious condition that weakens the eyes. The underlying defect (risk) of myopia is that the eyeball is slightly elongated, causing the lens to focus light from distant objects slightly in front of the retina. Therefore, myopia is often referred to as shortened vision or nearsightedness. In severe cases, this elongation of the eyeball can stretch and thin certain internal parts of the eye, increasing the risk of retinal detachment, cataracts, glaucoma, blindness, and more. Therefore, myopia is far more serious than simply shortened vision.

[0131] Myopia involves axial elongation of the eye and affects most people. Myopia typically begins during elementary school years and progresses until eye growth is complete. Although corrective lenses can be used, the progression of myopia can still lead to increased visual impairment. This application discloses the importance of pharmaceutical compositions and therapies for treating, preventing, controlling, inhibiting, slowing, delaying, reducing, and / or mitigating the occurrence and development of myopia, particularly pharmaceutical compositions, devices containing or delivering said pharmaceutical compositions, and methods of using them, which facilitate administration or implementation, reduce potential side effects, and provide therapeutic benefits.

[0132] The academic community has discussed and studied various causes of myopia, such as genetic susceptibility, prolonged reading or screen time, and insufficient exposure to bright light. Regardless of the underlying cause of myopia in a given situation, it may be one or more of the factors listed above, and the elongated eyeball associated with myopia weakens in all those affected by this condition. Because the eyes develop during childhood and school age, myopia typically occurs in school-aged children and adolescents and can remain with these individuals throughout their lives. Therefore, proactive medical interventions, such as those for school-aged children and adolescents, can improve the quality of life of these individuals during their youth and for the remainder of their lives.

[0133] "Myopic individuals" or "individuals with a tendency to be myopic" are children, adolescents, middle-aged people or the elderly, preferably people aged 3 to 26, more preferably people aged 6 to 18; or minors, preferably people whose eyes (eyeballs) are still in the growth and development stage; or school-age people, preferably students in grades one to twelve.

[0134] In this document, the terms "myopia" and "nearsightedness" are used interchangeably and are not distinguished by their respective meanings. Researchers in this field should correctly understand the meaning of "myopia" or "nearsightedness" in this application based on its context.

[0135] Specific types of "myopia" include: refractive myopia or axial myopia; congenital myopia (myopia at birth or before school age), early-onset myopia (under 14 years old), late-onset myopia (16-18 years old), and late-onset myopia (after adulthood); low myopia (mild myopia), moderate myopia, and high myopia (severe myopia); pseudomyopia and true myopia; myopia in children and / or adolescents (preferred age group: 3-26 years old, more preferred age group: 6-18 years old), myopia in minors, myopia in adults, and myopia in the elderly; simple myopia and pathological myopia; axial simple myopia and simple axial myopia. Vision; axial myopia in children and / or adolescents (preferred age group: 3-26 years, more preferred age group: 6-18 years); axial myopia in school-aged and preschool children; primary myopia and secondary myopia; primary myopia in children and / or adolescents (preferred age group: 3-26 years, more preferred age group: 6-18 years); or progressive myopia in children and / or adolescents (preferred age group: 3-26 years, more preferred age group: 6-18 years); myopia caused by prolonged close-range eye use, myopia caused by eye strain and pseudomyopia, negative refractive error caused by adverse drug reactions, and myopia.

[0136] "Axial myopia" refers to myopia where the anteroposterior diameter of the eyeball is too long (the axial length of the eyeball exceeds the normal range, causing it to be mismatched with other refractive components), while the refractive power (the refractive properties of other refractive components of the eye such as the cornea and lens) is basically within the normal range.

[0137] "Refractive myopia" refers to myopia where the axial length is basically within the normal range, but the main cause is a change in the refractive properties of the refractive components.

[0138] Pathological myopia, also known as degenerative myopia, is a degenerative disease of the fundus. Patients typically have a high degree of myopia (generally greater than 600 degrees), significantly impaired visual function, and particularly poor distance vision. In addition, visual field, light perception, and contrast sensation are often abnormal, frequently accompanied by poor night vision (night blindness), floaters, and flashes of light. 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, which can lead to blindness in severe cases.

[0139] "Simple myopia" refers to myopia that usually develops during school age, gradually stabilizes as development stops, has a myopia degree of less than 600 degrees, and generally shows no obvious pathological changes in the fundus. It is also known as acquired myopia. This type of myopia progresses and can be corrected to normal vision with appropriate lenses. Other visual function indicators are mostly normal.

[0140] "Primary myopia" specifically refers to a type of myopia of unknown cause, the etiology of which cannot be determined using current diagnostic techniques. During its development, it exhibits non-temporary functional-structural changes specific to myopia, including congenital myopia and acquired simple myopia.

[0141] "Concurrent / secondary myopia" refers to temporary myopia caused by impaired eye accommodation or abnormal refractive index due to internal or external factors (such as toxic myopia, drug-induced myopia, traumatic myopia, diabetic myopia, and early-stage cataract myopia). This type of myopia is characterized by a clear triggering factor and fluctuating vision. It is commonly prevalent among the elderly.

[0142] "Axial simple myopia," sometimes also called simple axial myopia, is a type of simple myopia characterized by the image focal point being located in front of the retina due to the elongation of the axial length of the eye and / or the increase in the depth of the vitreous cavity. In this type of myopia, the refractive tissues of the eye (such as corneal curvature) are basically normal, and it is the most common type of myopia in children and adolescents, occurring most frequently in people aged 2 to 30.

[0143] "Progressive myopia" refers to a type of myopia in which the refractive power continues to decrease over time or with the increase of an individual's age. If this type of myopia is not intervened, it will generally eventually develop into high myopia.

[0144] "Moderate myopia" usually refers to myopia of 300 degrees or more but less than 600 degrees.

[0145] Curvature myopia is myopia caused solely by an increase in the curvature of the cornea or lens.

[0146] "Index myopia" is myopia caused by an increase in the refractive power of the aqueous humor and lens due to an increase in the refractive index. It belongs to refractive myopia.

[0147] "Accommodative tension myopia" is myopia caused by excessive near-vision load on the eyeball and over-accommodation of the ciliary muscle, resulting in accommodative tension or accommodative spasm.

[0148] "Myopia caused by lens lesions" refers to a type of myopia caused by changes in the structural parameters or internal structure of the lens due to denaturation of lens proteins, accompanied by changes in some physical properties such as thickness, hardness, and refractive index, which in turn causes parallel light rays to converge in front of the retina after passing through the diseased lens.

[0149] "Distance vision," also known as uncorrected distance vision, is medically defined as visual acuity measured when looking directly ahead at a horizontal distance of 5 meters from a visual acuity chart, without wearing glasses or any auxiliary devices that enhance vision (such as eyeglasses, contact lenses, colored contact lenses, pinhole lenses, etc.).

[0150] "Myopia-related symptoms" include complications caused by myopia, such as complications of high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal tear, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular disease, visual field defects, progressive or sudden decrease in vision (especially near vision), eye strain and / or pain, night blindness, astigmatism, anisometropia, blindness, vitreous liquefaction, vitreous opacity, strabismus, frequent blinking, frequent eye rubbing, anisometropia, blurred vision when looking at distant objects, needing to squint or partially close the eyelids to see distant objects clearly, headaches caused by eye fatigue, difficulty seeing while driving, especially at night (night myopia), retinal atrophy and degeneration (hemorrhagic and tear), subretinal neovascularization, and phthisis bulbi.

[0151] "Abnormal development of the eyeball" refers to abnormal development of the size of the eyeball during childhood and adolescence (e.g., 3-26 years old). Its main characteristic is an excessively long axial length, which causes parallel light rays to focus in front of the retina after passing through the normal refractive system of the eye. It may be a developmental abnormality mainly induced by environmental factors or mainly caused by human factors (such as prolonged close-range reading, frequent use of electronic screens, continuous near vision without opportunities for far vision, and improper use of refractive corrective glasses), while genetic factors are secondary, accompanying, or synergistic factors, or the abnormal development is completely unrelated to genetic factors.

[0152] "Benzydary lysine", chemical name L-lysine (1-benzyl-1H-indazole-3-oxy) acetate, molecular formula: C6H 14 N2O2·C 16 H 14 N2O3, molecular weight: 428.49, structural formula as follows:

[0153]

[0154] "Bendazic acid", structural formula as follows:

[0155]

[0156] "Bendazac or derivatives of benzyl lysine" includes optical isomers or their racemic mixtures or metabolites (such as 5-hydroxybendazac), and may also include, but is not limited to, those listed by Hong Shen et al. (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010). Commercially available eye drops containing benzyl lysine (such as National Drug Approval Number H20063847) can be used, or benzyl lysine and its derivatives can be prepared using processes well known to those skilled in the art. An exemplary preparation method includes the following steps: The first step involves the synthesis of α-benzylphenylhydrazine by reacting phenylhydrazine with benzyl chloride as a starting material via benzylation. The second step involves the cyclization of α-benzylphenylhydrazine with urea under high temperature conditions to obtain 3-hydroxy-1-benzylindazole. The third step of the synthesis involves carboxylation of 3-hydroxy-1-benzylindazole with chloroacetic acid to obtain bendanoic acid, namely α-[(1-benzyl-1H-indazole-3-yl)oxy]acetic acid. The fourth step involves salt formation of bendanoic acid with L-lysine in tetrahydrofuran, followed by recrystallization in ethanol to obtain the final product bendanolysine.

[0157] “analogues or derivatives of benzalkonium chloride or benzalkonium chloride,” such as (a)-(c):

[0158] (a) Wherein, R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na;

[0159] (b) Wherein, R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na;

[0160] (c) R1 is H, P (Protium), D (Deuterium), T (Tritium), p-CH3, mF, m-Cl, or p-Cl; R2 is H, P (Protium), D (Deuterium), T (Tritium), K, or Na.

[0161] "Preparation" refers to oral products such as health products, food, dietary supplements, nutritional products, and beverages, or cosmetics; wherein, the cosmetics may be one or a combination of several of the following: free solution, oil-water mixture, suspension, liniment, lotion, spray, cream, drops, granule, ointment, paste, pill, suppository, emulsion, and patch.

[0162] "Device" refers to instruments, equipment, consumables, systems, medical devices, health care products, or products that can release drugs or have drug delivery functions or potential drug delivery capabilities, such as contact lenses, eyeglasses, artificial lenses, sutures, orthokeratology lens cleaning (maintenance) systems, eye patches, vision-enhancing patches, colored contact lenses, microneedles, eye spray systems, eye massagers (myopia massagers), eye fumigation devices, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, or drug-device combinations for myopia prevention and control.

[0163] The term "sole active ingredient or main active ingredient" in this application refers to any other active substance for treating myopia that is not present or contains only a small amount of, except for bendazac lysine or bendazac acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogues or derivatives, or its crystalline compound, or a combination of these substances. For example, the content of benzalkonium chloride or benzalkonium acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogues or derivatives, or its crystalline compound, or a combination of these substances, accounts for more than 50%, 60%, 70%, 80%, 90%, or 100% of the total active ingredient, said percentage being a mass ratio or molar ratio; or the content of benzalkonium chloride or benzalkonium acid, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analogues or derivatives, or its crystalline compound, or a combination of these substances, contributes more than 50%, 60%, 70%, 80%, 90%, or 100% to the efficacy of myopia treatment during medication.

[0164] Drug combination therapy is a widely used and powerful strategy in medicine aimed at achieving synergistic therapeutic effects, reducing dosage and toxicity, and minimizing or delaying 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). This application discloses compounds, such as benzyldine, for the treatment, prevention, or mitigation of myopia and related symptoms, to enhance myopia (diopter) reduction or slowing of myopia (progress) while avoiding or minimizing adverse side effects, such as those observed with atropine therapy. The drug composition of this application demonstrates significantly superior technical efficacy compared to atropine in the treatment, prevention, or mitigation of myopia and related symptoms, and no adverse reactions such as photophobia or pupillary dilation were observed in experiments, except for improvements in refractive parameters. In the experiment, no discomfort or ocular abnormalities were observed in any of the animals that received the drug. Based on the existing clinical applications of benzalkonium chloride or benzalkonium chloride, it can be considered that it will have good drug safety in the clinical treatment of myopia and related symptoms.

[0165] Through experiments, we unexpectedly discovered that bendazac and bendazac lysine can significantly slow down the refractive error progression in form-deprived guinea pigs and negative lens-induced guinea pig myopia models, and can significantly inhibit axial elongation. Based on this, it can be confirmed that bendazac and its salt compounds have therapeutic, preventive or control effects on myopia progression in animals, especially humans, such as school-aged children, adolescents or young adults.

[0166] This application provides a method for treating or preventing myopia and related symptoms in a subject, comprising administering to the subject a therapeutically effective amount of bendazac, bendazac lysine, and / or their therapeutically acceptable salts and derivatives. Preferably, the bendazac or bendazac lysine is administered alone; preferably, the bendazac and / or bendazac lysine is administered simultaneously or sequentially with other drugs; preferably, the bendazac and / or bendazac lysine is administered in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is prepared as an ophthalmic preparation; preferably, the ophthalmic preparation further comprises a pharmaceutically acceptable carrier; preferably, the carrier is an ophthalmologically acceptable carrier.

[0167] This application also provides a technique and method for inhibiting the progression of axial myopia by suppressing the elongation of the axial length of the eye, comprising administering to a subject a therapeutically effective amount of bendanoic acid, bendanoic acid lysine, and / or their therapeutically acceptable salts and derivatives. Preferably, the bendanoic acid or bendanoic acid lysine is administered alone; preferably, the bendanoic acid and / or bendanoic acid lysine is administered simultaneously or sequentially with other drugs; preferably, the bendanoic acid and / or bendanoic acid lysine is administered in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is prepared as an ophthalmic formulation; preferably, the ophthalmic formulation further comprises a pharmaceutically acceptable carrier; preferably, the carrier is an ophthalmologically acceptable carrier.

[0168] This application also provides a technique and method for reducing myopia, comprising administering to a subject a therapeutically effective amount of bendazac, bendazac lysine, and / or their therapeutically acceptable salts and derivatives. Preferably, the bendazac or bendazac lysine is administered alone; preferably, the bendazac and / or bendazac lysine is administered simultaneously or sequentially with other drugs; preferably, the bendazac and / or bendazac lysine is administered in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is prepared as an ophthalmic formulation; preferably, the ophthalmic formulation further comprises a pharmaceutically acceptable carrier; preferably, the carrier is an ophthalmologically acceptable carrier.

[0169] This application also provides a hyperopia-improving agent for myopic individuals, which can improve distance vision by reducing the distance between the focal point of the eye's imaging of distant objects and the retina. The hyperopia-improving agent contains bendazac, bendazac lysine, and / or their therapeutically acceptable salts and derivatives. Preferably, the myopic individual has refractive myopia. Preferably, the myopic individual has axial myopia.

[0170] This application also relates to pharmaceutical compositions or methods for treating, preventing, or controlling myopia and related symptoms in individuals such as toddlers, school-aged children, adolescents, or young adults. In some embodiments, the treatment target of the technical solution of this application is adolescents aged 6-28 years, preferably 6-18 years, and most preferably 12-18 years. In some embodiments, the treatment target of the technical solution of this application is adults. In some instances, treating, preventing, or controlling myopia and related symptoms may include administering a therapeutically effective amount of a pharmaceutical composition or dosage form to a subject in need.

[0171] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a bendanoic acid compound or a salt thereof and its derivatives, such as protium, deuterium, or tritium-substituted compounds.

[0172] In other embodiments, for any one or more pharmaceutical compositions, devices, or methods of treatment, said pharmaceutical composition contains at least one of bendazac or a therapeutically acceptable salt (such as bendazac lysine) or a derivative thereof; or, said pharmaceutical composition contains bendazac lysine or a therapeutically acceptable salt thereof or a derivative thereof; preferably, it contains both bendazac and bendazac lysine; preferably, it contains both bendazac lysine and bendazac dicalcium phosphate; preferably, it contains bendazac dicalcium phosphate; preferably, it further contains a pharmaceutically acceptable carrier; preferably, said device delivers said pharmaceutical composition in a sustained-release manner.

[0173] In some embodiments of the pharmaceutical compositions, devices or treatment methods disclosed herein, the treatment subject (patient) is treated for a period of time ranging from about 0.5 months to 20 years, such as a period of 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.

[0174] In other embodiments, according to any one or more of the pharmaceutical compositions, devices, or treatment methods described in any of the above embodiments and other embodiments herein, wherein the pharmaceutical composition is an aqueous composition, preferably having an osmotic pressure similar to or the same as that of tears; or the pharmaceutical composition is an ophthalmic composition (such as a topical ophthalmic composition) or an ophthalmic preparation, preferably an aqueous ophthalmic preparation, an ophthalmic gel preparation, an ophthalmic emulsion, an ophthalmic liposome, an ophthalmic ointment (preferably an eye ointment, preferably containing petrolatum or liquid paraffin); or the pharmaceutical composition is an eye drop preparation, an eye spray preparation, a topical preparation, a nanoparticle suspension, or nano discs, a sustained-release preparation, or a subconjunctival reservoir, etc.

[0175] In some embodiments, the pharmaceutical compositions disclosed herein may be aqueous ophthalmic preparations, such as in the form of eye drops. For example, the aqueous ophthalmic preparations described herein may be packaged in an eye drop bottle and administered as drops. In some embodiments, the aqueous ophthalmic preparations may be administered as a single application (i.e., a single dose), which may include one, two, three, or more drops instilled into the patient's eye. In some embodiments, a dose of the aqueous ophthalmic preparation described herein is one drop of the aqueous composition from the eye drop bottle.

[0176] In some embodiments, the pharmaceutical composition disclosed herein may be an ophthalmic gel formulation. For example, the ophthalmic gel formulation may be packaged in an eye drop bottle and administered as drops. In some embodiments, the ophthalmic gel formulation may be administered as a single application (i.e., a single dose), which may include one, two, three, or more drops instilled into a patient's eye. In some embodiments, a dose of the ophthalmic gel described herein is one drop of gel composition from the eye drop bottle.

[0177] In some embodiments, the pharmaceutical compositions disclosed herein may be ophthalmic ointment formulations. For example, the ophthalmic ointment formulation may be packaged in a tube or other squeezeable container having a dispensing nozzle through which an ointment strip will be delivered. In some embodiments, the ophthalmic ointment formulation may be administered as a single application (i.e., a single dose), which may include one or more strips inserted into the patient's eye. In some embodiments, a dose of the ophthalmic ointment is a strip of ointment composition dispensed through a dispensing nozzle.

[0178] In other embodiments, the pharmaceutical composition is an ocular pharmaceutical composition contained within a contact lens blister pack.

[0179] In other embodiments, the pharmaceutical composition is administered via a non-invasive route of administration.

[0180] In other embodiments, according to any one or more of the pharmaceutical compositions, devices, or treatment methods described in any of the above embodiments and other embodiments herein, said device is preferably an ophthalmic device, for example, it can be understood as an object placed on or present in the eye. The device can provide optical correction. The device includes (but is not limited to) colored contact lenses, contact lenses, ocular inserts, corneal covers, corneal inlays, nanosheets, liposomes, nanoparticles, punctal plugs, or hydrogel matrices having microfluidic reservoirs.

[0181] In other embodiments, the pharmaceutical composition is a sustained-release formulation contained within the device.

[0182] In other embodiments, the pharmaceutical composition is contained within the device.

[0183] In other embodiments, the pharmaceutical composition is an ophthalmic composition and the ophthalmic composition is contained within the device.

[0184] In other embodiments, the device needs to contain a pharmaceutical composition or be able to deliver the pharmaceutical composition to the target tissue for myopia treatment.

[0185] In other embodiments, the device delivers the pharmaceutical composition in a sustained-release manner.

[0186] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of ophthalmic diseases or conditions.

[0187] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of premyopia, myopia (eye), or myopia progression.

[0188] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of high myopia, moderate myopia, or low myopia.

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

[0190] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of an individual (patient) diagnosed with premyopia (or at risk of developing myopia or with a tendency to develop myopia).

[0191] In other embodiments, the pharmaceutical composition is substantially uniformly distributed throughout the device.

[0192] In other embodiments, the device is contained within a contact lens blister pack.

[0193] In other embodiments, the pharmaceutical composition is immersed in the device within the contact lens blister pack.

[0194] Cells, organs, or tissues can be contacted with compounds such as bendazac or bendazac lysine using any method known to those skilled in the art. Suitable methods include in vitro, indirect in vivo, or in vivo methods. In vivo methods generally involve administering the bendazac or / and bendazac lysine compounds of this application, or pharmaceutical compositions containing them, to mammals, preferably to humans. When used in vivo for treatment, the bendazac or / and bendazac lysine compounds, or pharmaceutical compositions containing them, can be administered to the subject in an effective amount (i.e., an amount with the desired therapeutic effect). The dosage and administration regimen will depend on the severity of the ophthalmic condition in the subject, the subject, and the subject's medical history.

[0195] 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-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are modified forms of compounds that readily undergo chemical changes under physiological conditions to yield the compound. Furthermore, prodrugs can be converted into the compound in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, prodrugs can be gradually converted into the compound. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or the parent drug. For example, they may be bioavailable through oral administration, while the parent drug may not. Prodrugs may also have higher solubility in pharmaceutical compositions than the parent drug. Many prodrug derivatives are known in the art, such as prodrug derivatives that depend on the hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound that is administered as an ester (“prodrug”) but is then metabolized and hydrolyzed into a carboxylic acid (the active entity).

[0196] The compounds disclosed herein can exist as therapeutically acceptable salts, including acid addition salts. Suitable salts include those formed with organic and inorganic acids, which are generally pharmaceutically acceptable; base addition salts can also be formed and are pharmaceutically acceptable. For a more comprehensive discussion of the preparation and selection of salts, please refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0197] Base addition salts can be prepared during the final separation and purification of compounds by reacting the carboxyl group with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary, or tertiary amine. Therapeuticly acceptable cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium 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-diphenylhydroxymethylamine, and N,N'-dibenzylethylenediamine. Other representative organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0198] While the compounds of this application may be administered in the form of crude chemicals, they may also be provided as pharmaceutical formulations. Therefore, pharmaceutical formulations are provided herein comprising one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is harmless to the recipient. A suitable formulation depends on the chosen route of administration. Any suitable and well-known techniques, carriers, and excipients as understood in the art may be used; for example, see Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be produced in any manner known in the art, such as by means of conventional mixing, dissolving, granulation, sugar coating, fine grinding, emulsification, encapsulation, embedding, or compression treatments.

[0199] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, mucosal, transdermal, rectal, and topical (including skin, oral cavity, sublingual, ocular, intranasal, and intraocular) administration, the most suitable route depending on, for example, the recipient's condition and illness. Formulations can be conveniently provided in unit dosage forms and can be prepared by any method known in the pharmaceutical field. Typically, these methods involve the step of combining the compound of this application or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvation (“active ingredient”) with a carrier constituting one or more excipients. Generally, the active ingredient is uniformly and tightly combined with a liquid carrier or a finely fragmented solid carrier, or both, and then, if necessary, the product is shaped into the desired formulation, thereby preparing the formulation.

[0200] The formulations of the compounds disclosed herein suitable for oral administration may be provided in separate units, such as capsules, tablets, each containing a predetermined amount of the active ingredient; in powder or granule form; in solution or suspension in aqueous or non-aqueous liquids; or in oil-in-water or water-in-oil emulsions. The active ingredient may also be provided in pellets, syrups, pharmaceutical sugars, or pastes.

[0201] Orally applicable pharmaceutical formulations include tablets, push-in capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compression in a suitable machine of a free-flowing form of the active ingredient (such as powder or granules), optionally mixed with a binder, inert diluent or lubricant, surfactant, or dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of powdered compounds wetted with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of the active ingredient therein. The dosage of all formulations intended for oral administration should be appropriate for such administration. Push-in capsules may contain the active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate) and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, or liquid polyethylene glycol). In addition, stabilizers may be added. Sugar-coated pellet cores with suitable coatings are provided. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or sugar-coated pellet coating to identify or characterize different combinations of active compound dosages.

[0202] Examples of fillers or diluents used in oral pharmaceutical formulations (such as capsules and tablets) include, but are not limited to, lactose, mannitol, xylitol, dextran, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, glucose dextran, dextran, dextrin, dextran, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer (e.g., polyethylene oxide), and hydroxypropyl methylcellulose. Fillers may contain complexed solvent molecules, as in the case where the lactose used is lactose monohydrate.

[0203] Examples of disintegrants used in oral pharmaceutical preparations (such as capsules and tablets) include, but are not limited to, sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinyl polypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0204] In addition, flow aids and lubricants can be used in oral pharmaceutical formulations to ensure uniform blending of excipients during mixing. Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl stearate palmitate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, and zinc stearate. Examples of flow aids include, but are not limited to, silica (SiO2), talc corn starch, and poloxamer. Poloxamer (or available from BASF Corporation) is an ABA block copolymer in which the A block is a hydrophilic polyethylene glycol homopolymer and the B block is a hydrophobic polypropylene glycol homopolymer.

[0205] Examples of tablet binders include, but are not limited to, gum arabic, alginate, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copolyvidone, methyl cellulose, liquid glucose, maltodextrin, polymethyl methacrylate, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth gum, and corn gluten.

[0206] The compound can be formulated for parenteral administration by injection, such as via bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage forms, for example, in ampoules or multi-dose containers with added preservatives. The composition may be in the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The formulation may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a lyophilized (freeze-dried) state, requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile pyrogen-free water, just before use. Ready-to-use injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types previously described. In a preferred embodiment, the pharmaceutical composition of this application is in the form of an injection, particularly a syringe. Preferably, the pharmaceutical composition is administered via intraocular injection, more preferably via intravitreal injection.

[0207] Formulations intended for parenteral administration include: aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high-concentration solutions.

[0208] In addition to the aforementioned formulations, compounds can also be formulated into storage formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or formulated as slightly soluble derivatives, such as slightly soluble salts.

[0209] For oral or sublingual application, the composition may be in the form of tablets, lozenges, tablets, or gels formulated in a conventional manner. This composition may contain the active ingredient in a flavored matrix such as sucrose and gum arabic or tragacanth.

[0210] The compound can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter, polyethylene glycol or other glycerides.

[0211] Some of the compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes applying the compounds disclosed herein to the eyes, epidermis, external mouth, ears, and / or nose, such that the compounds do not significantly enter the bloodstream. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0212] The active ingredient for topical application may comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In some embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 2% w / w of the formulation, preferably 0.1%-0.5% w / w. In some embodiments, it may comprise 0.01% w / w, 0.05% w / w, 0.1% w / w, 0.25% w / w, or 0.5% w / w of the formulation.

[0213] In some embodiments, the active ingredient for topical application may comprise, for example, 0.001% w / v to 10% w / v (by weight / volume, g / 100 ml) of the formulation. In some embodiments, the active ingredient may comprise up to 10% w / v. In other embodiments, it may comprise less than 5% w / v. In some embodiments, the active ingredient may comprise 0.2% w / v to 0.5% w / v. In other embodiments, it may comprise 0.1% w / v to 2% w / v of the formulation, preferably 0.1%-0.5% w / v. In some embodiments, it may comprise 0.01% w / v, 0.05% w / v, 0.1% w / v, 0.25% w / v, or 0.5% w / v of the formulation.

[0214] In a preferred embodiment, formulations intended for topical application to the eyes or ears in aqueous solutions or suspensions are in the form of drops. Formulations intended for topical application to the nose in aqueous solutions or suspensions are in the form of drops, sprays, or aerosols. The term "aqueous" generally means an aqueous formulation in which the formulation contains >50%, more preferably >75%, and particularly >90% water by weight. These drops can be delivered by single-dose ampoules, which are preferably sterile, thus allowing for the elimination of the antibacterial component of the formulation. Alternatively, drops can be delivered by multi-dose vials, which preferably include a device for extracting any preservatives during formulation delivery, as is 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 hydrofluoroalkyl propellants. Alternatively, the active pharmaceutical ingredient can be delivered in the form of a dry powder.

[0215] In a specific embodiment, the formulation of this application is administered twice daily. However, the formulation may also be formulated for administration at any frequency, including once weekly, once every five days, once every three days, once every two days, once daily, three times daily, four times daily, five times daily, six times daily, eight times daily, hourly, or any higher frequency. Depending on the treatment regimen, this frequency of administration may also be maintained for varying durations. The duration of a particular treatment regimen may range from a single dose to regimens extending to several months or years.

[0216] Formulations intended for topical application in the mouth (e.g., oral cavity or sublingual region) include sugar tablets containing the active ingredient in a flavored matrix (such as sucrose and gum arabic or tragacanth) and lozenges containing the active ingredient in a matrix such as gelatin and glycerin or sucrose and gum arabic.

[0217] For inhalation administration, the compound can be conveniently delivered by a blower, nebulizer pressurization pack, or other convenient device for delivering aerosol sprays. The pressurization pack may contain a suitable propellant, such as hydrofluorocarbon, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for inhalation or blow-in administration, the compound according to this application may be in the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch). The powder composition may be provided in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, from which the powder may be administered by means of an inhaler or blower.

[0218] Preferred unit-dose formulations are those containing an effective dose or an appropriate proportion of the active ingredient as described below.

[0219] It should be understood that, in addition to the ingredients specifically mentioned above, the above formulations may also include other reagents that are conventional in the art for the type of formulation of interest, such as flavoring agents for formulations suitable for oral or intranasal administration.

[0220] The compound can be administered orally or by injection at doses ranging from 0.01 to 300 mg / kg per day. The adult dose range is generally from 0.1 mg to 50 mg / day. Tablets or other forms of presentation, provided in discrete units, conveniently contain an amount of one or more compounds that are effective at such doses or in combination, for example, containing 0.05 mg to 100 mg, typically about 1 mg to 50 mg, preferably 5 mg.

[0221] Compounds can be administered in various ways, such as orally, topically, or by injection. The precise amount of compound administered to a patient is the responsibility of the attending physician. The specific dosage level for any particular patient depends on a number of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, the exact condition being treated, and the severity of the indication or symptom being treated. Furthermore, the route of administration may vary depending on the condition and its severity.

[0222] In some cases, it may 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 a patient experiences after receiving one of the compounds described herein is liver damage, it may be appropriate to administer a hepatoprotective agent in combination with the initial therapeutic agent. Or, for example only, the efficacy of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the total therapeutic benefit to the patient is enhanced). Or, for example only, the benefit experienced by the patient may be enhanced by administering one of the compounds described herein with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. For example only, in myopia treatment involving the administration of one of the compounds described herein, the therapeutic benefit may be enhanced by also providing the patient with another myopia treatment agent (such as atropine). In any case, regardless of the disease, condition, or symptom being treated, the total benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0223] Pharmaceutical compositions in dry or liquid form can be provided as single-dose or multi-dose pharmaceutical compositions.

[0224] In one embodiment of this application, the liquid or dry pharmaceutical composition is provided as a single dose, meaning that the container providing it contains one dose of the drug. Alternatively, the liquid or dry pharmaceutical composition is a multi-dose pharmaceutical composition, meaning that the container providing it contains more than one therapeutic dose, i.e., the multi-dose composition contains at least two doses. Such multi-dose compositions can be used for different patients who require them, or can be used for a single patient, wherein the remaining dose is stored for later use after the first dose is administered.

[0225] In another aspect of this application, the pharmaceutical composition is in a container. Containers for liquid or dry pharmaceutical compositions include, 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 reconstituted solution is provided in the second chamber of the dual-chamber syringe.

[0226] Before applying the dried composition to a patient in need of it, the dried composition is reconstituted. Reconstitution can be performed in the container providing the dried composition, such as a vial, syringe, dual-chamber syringe, ampoule, or cartridge. Reconstitution is performed by adding a predetermined amount of reconstitution solution to the dried composition. The reconstitution solution is a sterile liquid such as water or a buffer solution, which may contain other additives such as preservatives and / or antimicrobial agents such as benzyl alcohol and cresol. Preferably, the reconstitution solution is sterile water. When the dried composition is reconstituted, it is referred to as a “reconstituted pharmaceutical composition” or simply “reconstituted composition.”

[0227] The pharmaceutical composition of this application can be administered in the form of an ophthalmic preparation, which contains an ophthalmologically acceptable carrier.

[0228] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific method of administration.

[0229] The active substance content of the pharmaceutical composition of this application. When the drugs are mixed, the concentration of the drugs can be selected to be an effective and suitable amount of each drug.

[0230] The formulations and methods of this application have been used in any subject who may benefit from the formulations and methods of this application. Subjects are typically mammals, and more typically humans. However, this application is not limited to treating humans and may be used for veterinary purposes.

[0231] In another aspect, this application provides an apparatus containing a pharmaceutical composition comprising bendazac or a therapeutically acceptable salt thereof (such as bendazac lysine) or a derivative thereof, preferably wherein the apparatus delivers the pharmaceutical composition in a sustained-release manner.

[0232] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the device delivers the pharmaceutical composition in a sustained-release manner, preferably with a circadian rhythm.

[0233] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions, for example, as ophthalmic compositions for the treatment of ophthalmic conditions or illnesses.

[0234] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of premyopia, myopia, or myopia progression.

[0235] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of high myopia, moderate myopia, or low myopia.

[0236] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of patients diagnosed with premyopia (or at risk of developing myopia or with a tendency to develop myopia).

[0237] In some embodiments of the pharmaceutical compositions, devices or treatments disclosed herein, the pharmaceutical composition is ophthalmologically applied to the patient's eye, preferably a myopic eye.

[0238] In some embodiments of the pharmaceutical compositions, devices, or treatment methods disclosed herein, the pharmaceutical composition is applied topically.

[0239] In some embodiments of the pharmaceutical compositions, devices, or treatments disclosed herein, the pharmaceutical composition is ophthalmologically applied to a patient's eye via the device.

[0240] In some embodiments of the pharmaceutical compositions, devices or treatments disclosed herein, the pharmaceutical composition is administered 1, 2, 3, 4 or 5 times daily.

[0241] The dosage, toxicity, and therapeutic efficacy of therapeutic drugs can be determined through standard pharmaceutical procedures in experimental animals, for example, to determine the LD50 (the lethal dose in the 50% of the total) and ED50 (the effective therapeutic dose in the 50% of the total). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds exhibiting a high therapeutic index are preferred. Although compounds with toxic side effects can be used, consideration should be given to designing delivery systems or suitable routes of administration that can target such compounds to the corresponding tissue or lesion site to minimize potential damage to unrelated cells or tissues and thereby reduce side effects.

[0242] Data obtained from animal studies can be used to formulate dosage ranges for human use. Depending on the type of formulation used and the route of administration, the dosage can vary within this range, and sometimes may even exceed it. A series of different dosages can be established in animal models to obtain parameters including minimum effective concentration, circulating blood concentration ranges after a single dose and multiple doses, and drug exposure. These results, converted to body surface area, can be used to more accurately help determine the useful dosage in humans.

[0243] Those skilled in the art will recognize that certain factors can influence the dosage and duration of effective treatment of a subject, including but not limited to the severity of the disease or disorder, whether the subject fully complies with treatment, prior treatment, health condition and / or the subject's age, and any other pre-existing conditions. Furthermore, treating a subject with the therapeutically effective amount of the composition described herein can include a single treatment or a series of treatments.

[0244] The methods of this application control, slow, reduce, delay, and / or decelerate the progression of myopia in treated patients within the following ranges relative to untreated patients: approximately 5-95%, approximately 5-90%, approximately 5-80%, approximately 5-70%, approximately 5-60%, approximately 5-50%, approximately 5-40%, approximately 5-30%, approximately 5-20%, approximately 10-100%, approximately 20-90%, approximately 30-90%, approximately 40-90%, approximately 50-90%, or approximately 75-90%.

[0245] The use of a pharmaceutical composition, device, or treatment method shall limit the negative refractive error of the target eye to approximately 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.

[0246] In some embodiments, the methods of this application have been used to halt or reverse myopia progression in treated patients. These patients have high myopia, moderate myopia, or low myopia; or the patients are premyopic (or at risk of developing myopia).

[0247] In some embodiments, the methods of this application are used to prevent, control, slow down, delay, postpone, and / or decelerate axial (or longitudinal) growth of the treated patient's eye.

[0248] In some embodiments, the methods of this application are applied to control, slow down, reduce, delay, and / or decelerate the development of myopia in patients diagnosed with myopia or at risk of developing myopia, increase the choroidal thickness (ChT) of the patient's eye (e.g., a myopic eye, a pre-myopic eye, or an eye at risk of developing myopia), and / or reduce the axial (or longitudinal) growth rate of the patient's eye (e.g., a myopic eye, a pre-myopic eye, or an eye at risk of developing myopia).

[0249] In some embodiments, the method of this application controls, slows, reduces, delays, and / or decelerates the axial (or longitudinal) growth of the treated patient's eye relative to untreated growth by approximately 5-95%, approximately 5-90%, approximately 5-80%, approximately 5-70%, approximately 5-60%, approximately 5-50%, approximately 5-40%, approximately 5-30%, approximately 5-20%, approximately 10-100%, approximately 20-90%, approximately 30-90%, approximately 40-90%, approximately 50-90%, or approximately 75-90%.

[0250] In some embodiments, the application of the method of this application resulted in a smaller increase in pupil size or no pupil dilation compared to atropine monotherapy.

[0251] In some embodiments, the oral formulation is a solid dosage form such as tablets, capsules, granules, and powders, and a liquid dosage form such as syrups and beverages; optionally (a): in the solid dosage form, excipients, lubricants, binders, disintegrants, etc. may be formulated, preferably, preservatives, antioxidants, colorants, and sweeteners may be formulated, more preferably, additives may be used; optionally (b): in the liquid dosage form, solvents, solubilizers, suspending agents, and isotonic agents may be included, preferably, reagents, buffers, analgesics, etc. may be mixed, more preferably, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used.

[0252] In some embodiments, the drug may be an injection, tablet, lyophilized powder for injection, capsule, effervescent tablet, chewable tablet, lozenge, granule, ointment, syrup, oral liquid, aerosol, nasal drops, topical preparation, oral preparation, etc.; preferably, it is an ophthalmic dosage form, including but not limited to eye drops, eye ointments, eye sprays, implants, ophthalmic gels, eye patches, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections, and intraocular injections; it may also be a free solution, oil-water mixture, suspension, liniment, lotion, cream, drops, granules, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0253] In some embodiments, the "ophthalmic preparation or drug" is administered concurrently with the pharmaceutical composition or preparation of this application, such as during a specific single administration (treatment) process, administered simultaneously or sequentially, on the same day, in the same week, in the same month, or in the same year; or administered alternately at intervals, such as alternately administered at 4-hour intervals, alternately administered at 12-hour intervals, alternately administered every other day, alternately administered every other week, alternately administered every other month, or alternately administered every other year.

[0254] Specific embodiments of this application will be described in detail below. Although this application has been described in conjunction with these specific embodiments, it should be understood that it is not intended to limit this application to such specific embodiments.

[0255] Example 1: Preparation method and source of main reagents or formulations (pharmaceutical compositions)

[0256] Benzydamine lysine preparations include two categories: commercially available finished drugs and pharmaceutical compositions formulated by the inventors using only benzyldamine lysine compounds as the active pharmaceutical ingredient. The finished benzyldamine lysine drug (BDL(S)), namely the 0.5% benzyldamine lysine eye drops (National Drug Approval Number H20063847) commercially available in China, is used directly for topical administration to the eyes of guinea pig myopia models. The benzyldamine lysine compound was purchased from MedChemExpress. Without adding other pharmaceutical excipients or other compounds, the benzyldamine lysine compound powder was directly and completely dissolved in 0.9% physiological saline to prepare a 5 mg / ml (11.669 mM) formulation (BDL). At room temperature, the formulation is clear, transparent, homogeneous, and free of visible turbidity. When administering to test subjects, it is applied directly to the eyes or diluted with 0.9% physiological saline according to the dosage requirements before application.

[0257] Benadryl acid preparations include two categories: those directly purchased from commercially available drugs and those prepared by the inventors using bendryl acid compounds themselves. The commercially available drug is a 3% bendryl acid ointment, purchased by the inventors from Iwaki Pharmaceutical Co., Ltd., Japan; the bendryl acid compound was purchased from MedChemExpress. A 330 mg / ml (1166.9 mM) stock solution was prepared by completely dissolving bendryl acid in DMSO and stored at -20°C. Before the experiment, a working solution was prepared using a ratio of stock solution:PEG300:Tween80:0.9% physiological saline = 1:45:5:49, resulting in a final concentration of 3.3 mg / ml (11.669 mM) for the bendryl acid preparation. All preparation operations were performed in a dark room.

[0258] Lysine was purchased from MedChemExpress and was completely soluble in 0.9% physiological saline to prepare a test formulation of 1.7 mg / ml (11.669 mM).

[0259] M-hydroxy-methylaniline was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd. Hydroxy-methylaniline was completely dissolved in 0.9% physiological saline to prepare a 250 mM stock solution, which was stored at -20°C. Before the experiment, it was diluted with 0.9% physiological saline; the final concentration of the hydroxy-methylaniline preparation used in the examples was 5 mM. All preparation operations were performed in a dark room.

[0260] Sorbinil, an aldose reductase inhibitor (ARI), was purchased from MedChemExpress. Sorbinil powder was dissolved in DMSO to prepare a 4.8 mg / ml (20 mM) stock solution, which was stored at -20°C. Before the experiment, it was diluted with 0.9% physiological saline. The final concentration of Sorbinil used in the examples was 24 μg / ml (100 μM). All operations were performed in the dark.

[0261] Zopolrestat, an aldose reductase inhibitor, was purchased from MedChemExpress. Zopolrestat powder was dissolved in DMSO to prepare a stock solution of 84 mg / ml (1M) and stored at -20°C. Before the experiment, it was diluted with physiological saline. The final concentration of Zopolrestat used in the examples was 420 μg / ml (1mM). All operations were performed in the dark.

[0262] Atropine powder was purchased from Stanford Chemicals and completely dissolved in 0.9% physiological saline to prepare a 1 mg / ml, or 0.1% formulation (positive control). All procedures were performed in a dark room.

[0263] All other formulations or pharmaceutical compositions not mentioned were prepared and stored in accordance with standard laboratory methods and standards. All formulations were prepared using conventional physical and chemical solubilizing methods such as heating, stirring, and pH adjustment, as appropriate. No compound precipitation occurred before administration of any formulation.

[0264] Example 2: Construction and Experimental Methods of Animal Models

[0265] Form deprivation and lens-induced myopia models in guinea pigs are classic and widely recognized animal models of myopia in this field, and can be used to evaluate the efficacy and safety of myopia treatment drugs. Their construction methods are well-known to those skilled in the art. The establishment, drug administration, and data analysis of the guinea pig form deprivation myopia model (FDM) and lens-induced myopia model (LIM) were all performed according to the procedures and procedures outlined in the inventors' laboratory's published literature. [1-4] The embodiments of this application use healthy guinea pigs (i.e., without underlying diseases such as hypertension, hyperglycemia, eye diseases or abnormalities), and both males and females are used. The animal experiments of this application have been reviewed and approved by the Experimental Animal Ethics Committee of Wenzhou Medical University. The method for constructing the form deprivation and lens-induced guinea pig myopia model used in the following Example 3 is as follows:

[0266] Three-week-old tricolor guinea pigs were housed in the experimental animal facility of Wenzhou Medical University under a 12-hour light (400-500 lux) / 12-hour darkness environment with free access to water and food. The myopia model was established using monocular form deprivation (FD) and lens induction (LI). For form deprivation, a specially designed, non-detachable eye patch was used to completely cover the animal's right eye, while the other eye (left eye) received normal vision. For lens induction, a -4D lens was fixed in front of the animal's right eye, while the left eye received normal vision. The lens was cleaned twice daily to prevent blurring. Drug administration was performed daily from 9:00 AM to 9:30 AM. During administration, the eye patch or lens was removed from the control and experimental groups under red light, and the animals were injected subconjunctivally with either 0.1 ml of solvent control or 5 mg / mL of the test drug or a positive control in the right eye. After injection, to ensure successful and non-invasive administration, the eye patch and lens were immediately restored. The administration process for each animal was controlled to be approximately 10 seconds. Drug administration began on the day of modeling. Animals deprived of visual perception were given the drug once a day for two consecutive weeks, while animals induced by lens were given the drug once a day for one consecutive week.

[0267] Animal grouping

[0268] 1. Visual deprivation group:

[0269] Visual deprivation plus solvent injection group: each eye wore an eye patch and was injected with physiological saline solution for 2 weeks, sample size = 11.

[0270] Visual deprivation plus drug injection group: a patch was worn in one eye and benzalkonium chloride (0.5 mg / day) was injected into the eye for 2 weeks. Sample size = 14.

[0271] Visual deprivation plus positive control group: One eye was blindfolded and the blindfolded eye was injected with 0.1% atropine for 2 weeks, sample size = 12.

[0272] 2. Lens induction group:

[0273] Lens induction and solvent injection group: each eye wore a -4D lens and was injected with physiological saline solution for 1 week. Sample size = 14.

[0274] Lens induction plus drug injection group: a single eye wore a -4D lens and was injected with benzalkonium chloride (0.5 mg / day) for 1 week. Sample size = 14.

[0275] Animal eyeball parameter measurement

[0276] All animals in the same model drug efficacy experiment were measured within the same time period, with the first measurement at 3 weeks of age. Refractive error and axial length parameters were measured in the animals before the experiment, at 1 week, and at 2 weeks (FD only). Refractive error was measured using an eccentric infrared photoretinoscope (EIR) built in our laboratory; three measurements were taken for each eye, and the average value was used as the final result. Axial length parameters of guinea pigs were measured using an A-mode ultrasound probe on a Cinescan A / B ultrasound diagnostic system (Quantel Medical, Aviso, France). The ultrasound frequency was 11 MHz, and the ultrasound propagation velocities for different refractive media of the eye were set as follows: anterior chamber 1557.5 m / s, lens 1723.3 m / s, and vitreous 1540 m / s. The measurements included anterior chamber depth (ACD), lens thickness (LT), vitreous cavity depth (VCD), and axial length (AL). About two minutes before the test, the guinea pig's test eye was anesthetized with 0.5% promecaine hydrochloride eye drops (Alcon, Belgium). Each eye was measured 6 times, and the average value was taken as the final result.

[0277] Example 3: In vivo therapeutic effect experiment of benzalkonium chloride

[0278] The experimental animals were 3-week-old tricolor guinea pigs, divided into two main groups: the form deprivation group (FD) and the lens induction group (LI). The form deprivation group was further divided into three subgroups: the negative control group received a daily periorbital injection of 100 μL of physiological saline, the experimental group received a daily periorbital injection of the same volume of benzyldamine lysine (0.5 mg), and the positive control group received a daily periorbital injection of 0.1% atropine (100 μL). The lens induction group was also divided into two subgroups: the negative control group received a daily periorbital injection of 100 μL of physiological saline, and the experimental group received a daily periorbital injection of the same volume of benzyldamine lysine (0.5 mg). Refractive, vitreous cavity, and axial length parameters were measured in both eyes of all subjects before the first administration, at 1 week of administration, and at 2 weeks of administration (FD only).

[0279] Experimental results:

[0280] One week after administration of the FD group, the saline injection group induced myopia of -3.75±1.76D, and two weeks later, it induced myopia of -6.17±1.52D. In contrast, the benzyldamine lysine injection group induced myopia of -2.15±1.09D after one week of administration, showing a 42.6% reduction in myopia compared to the saline group. At this time, the myopia induced by 0.1% atropine was -2.98±1.54D, representing a myopia suppression rate of 20.5%. Two weeks after administration of benzyldamine lysine, the induced myopia was -3.46D, showing a 43.9% reduction in myopia compared to the saline group. The myopia induced by 0.1% atropine was -3.93D, representing a myopia suppression rate of 36.4%. Correspondingly, the elongation of vitreous cavity depth and axial length was inhibited by benzyldamine lysine (see...). Figure 1 In summary, compared with the saline group, the benzalkonium chloride administration group significantly inhibited the negative refractive power, vitreous cavity depth elongation, and axial length elongation in guinea pigs with form deprivation myopia.

[0281] One week after administration of the LI group, the saline injection group induced myopia of -4.42±0.95D, while the benzyldamine lysine injection group induced myopia of -3.49±1.15D after one week of administration. The saline group, however, suppressed myopia by 21.0%. Figure 1 It can be seen that, compared with the saline group, the benzalkonium chloride administration group significantly inhibited the negative refractive error of guinea pigs with lens-induced myopia. At the same time, the elongation of vitreous cavity depth and axial length was also inhibited by benzalkonium chloride.

[0282] Furthermore, no ocular abnormalities or individual toxic reactions were observed in any of the animals treated with benzalkonium chloride throughout the experimental period, and corneal curvature (RCC), anterior chamber depth (ACD), and lens thickness (LT) were not affected by the test drug (see [link to study]). Figure 2 ).

[0283] The above experiments demonstrate that benzyldamine lysine can significantly slow down the negative refractive error progression in myopic individuals and significantly inhibit axial elongation. It can also significantly improve form deprivation and lens-induced myopia-related symptoms in guinea pigs, suggesting its potential application in myopia prevention and control, especially in the treatment, prevention, or improvement of refractive or axial myopia and related symptoms. The experimental results of this application prove that benzyldamine lysine has excellent preventive, slowing, and therapeutic effects on myopia in humans, especially children and adolescents.

[0284] Example 4: Commercial benzyl lysine eye drops (0.5%, BDL(S)) inhibit myopia progression

[0285] 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 3-8 diopters (D) and binocular anisometropia not exceeding 2D were selected and 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. [4] 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.

[0286] The results showed consistency with the conclusions of Example 3. The changes in refractive error and axial length parameters in the negative control group animals were consistent with the expected changes in the myopia model, and the positive control drug atropine demonstrated its expected efficacy in the experiment. These results demonstrate that both myopia models were successfully established in this experiment and can be used for efficacy evaluation of the test drug. Commercially available 0.5% benzalkonium chloride eye drops in China can significantly inhibit and slow the progression of myopia in both the form deprivation myopia model and the negative lens-induced myopia model. In other words, the process of negative refractive error in myopic individuals was successfully delayed and effectively controlled by benzalkonium chloride eye drops. Furthermore, in some animals in the benzalkonium chloride treatment group, the inventors found that their myopia progression was almost completely terminated by the test drug. Regarding refractive error in the FDM group, after one week of treatment, 0.5% benzyldamine lysine eye drops showed better therapeutic effects on myopia than 0.1% atropine eye drops, but there was no statistically significant difference between the two. After two weeks of treatment, the therapeutic effects of 0.5% benzyldamine lysine eye drops on myopia were similar to those of 0.1% atropine eye drops, and both showed highly significant differences in efficacy compared to the negative control group. In the LIM group, benzyldamine lysine also effectively prevented the progression of myopia. The rate at which the refractive error of the drug intervention group became negative was significantly slower than that of the control group, and there was a significant difference in refractive error between the two groups at the end of the experiment. Benzyldamine lysine also effectively treated myopia induced by negative lenses. Specifically, under the same myopic visual information input conditions (both -4D), at the same detection time point (one week of treatment), the refractive error of the drug intervention group was greater than that of the solvent group (both were negative values; the mean refractive error of the negative control group had already reached -4D, while that of the drug intervention group had not), indicating that benzyldamine lysine can effectively control the progression of myopia. Meanwhile, in the two classic myopia research models mentioned above, the increase in vitreous cavity depth (VCD) and the elongation of axial length (AL) were effectively inhibited after treatment with benzalkonium chloride (with statistically significant differences compared to the negative control group). Furthermore, in the form deprivation experiment, the corresponding indicators in the commercially available benzalkonium chloride group were superior to those in the atropine group at both detection time points. In addition, no ocular abnormalities or individual toxic reactions were observed in any of the animals in the benzalkonium chloride treatment group throughout the entire experimental period, and corneal curvature (RCC), anterior chamber depth (ACD), and lens thickness (LT) were not affected by the test drug. In the positive control group, animals showed pupillary dilation after atropine administration.

[0287] In summary, without significant adverse drug reactions, commercially available benzalkonium chloride eye drops can effectively prevent and treat myopia in mammals (including humans), especially slowing and controlling the progression of myopia. It can significantly improve symptoms in myopia disease models, demonstrating that benzalkonium chloride effectively reduces (inhibits) axial length elongation and vitreous cavity depth increase in individuals with myopia or a myopia predisposition. This suggests its applicability to myopia prevention and control, whether for the treatment, prevention, or improvement of refractive or axial myopia and related symptoms. Therefore, commercially available benzalkonium chloride eye drops can be used for myopia treatment, particularly to control the rate of disease progression and reduce the complications and blindness risk associated with high myopia, especially during childhood and adolescence.

[0288] Example 5: Dose-response relationship experiment of different concentrations of benzyldine for myopia treatment (0.01%, 0.05%, 0.1%, and 0.5%)

[0289] Healthy 3-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, underwent refractive power (infrared eccentric refractometer) and axial length (A-scan) measurements. Animals with refractive power between 3-8 diopters (D) and binocular anisometropia not exceeding 2D were randomly divided into the following 6 groups: FD + saline group (negative control), FD + 0.01% benzyldamine lysine, FD + 0.05% benzyldamine lysine, FD + 0.1% benzyldamine lysine, FD + 0.5% benzyldamine lysine (experimental group, referring to individuals with FDM model treated with 0.5% benzyldamine lysine), and FD + 0.1% atropine (positive control). For greater clarity, percentages were converted to milligrams for plotting. Form deprivation (FD) myopia modeling was initiated in the guinea pigs at 8:00 AM on the first day of the experiment. The form deprivation myopia model employed a mask method. The headgear was fabricated by the inventor using a 10-inch milky-white, non-toxic latex balloon. In guinea pigs, the right eye (experimental eye) was covered by the headgear, while the left eye (contralateral eye) remained uncovered. FD induction was performed continuously throughout the entire benzyldamine lysine efficacy study period, with the headgear only briefly removed for drug administration or ocular examinations (such as refractive error measurement). Headgear position was checked daily at 8:00 AM, 12:00 PM, and 7:00 PM, and before drug administration, and individuals whose headgear fell off more than three times were culled. Starting from the day of model induction, the corresponding solvent (negative control) or drug for the experimental eye of the FDM model 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 weeks. Refractive error and axial length parameters of the test animals were measured at the start of the efficacy study, and at weeks 1 and 2. All data collection and processing methods were identical to those used in previously published literature by the inventor's laboratory. [4]The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. All the above efficacy experiments were repeated at least three times. The benzalkonium chloride preparation was prepared by the inventor using physiological saline.

[0290] The experimental results showed that the changes in refractive error and axial length parameters in the negative control group animals were consistent with the expected changes in the myopia model, and the positive control drug atropine demonstrated its expected efficacy in the experiment. These results prove that the myopia model was successfully established in this experiment and can be used to evaluate the efficacy of benzalkonium chloride. Compared with the negative control group, benzalkonium chloride (containing no other pharmaceutical excipients except 0.9% saline as a solvent) dose-dependently slowed the progression of myopia in the subjects. With increasing benzalkonium chloride dosage, the myopia inhibition rate (calculated as: (drug group refractive error - solvent group refractive error) also increased accordingly, indicating that the higher the dosage of benzalkonium chloride, the better the myopia (eye) control effect. Regarding refractive power, the benzyldamine lysine preparation formulated by the inventors using only physiological saline showed the same efficacy as commercially available benzyldamine lysine. Specifically, after one week of use, 0.5% benzyldamine lysine was more effective than 0.1% atropine in treating myopia, but there was no statistically significant difference between atropine and benzyldamine lysine. After two weeks of use, the effect of 0.5% benzyldamine lysine on myopia was similar to that of 0.1% atropine eye drops, and both showed highly significant differences compared to the negative control group. This indicates that benzyldamine lysine, as the main or sole active ingredient, can play a therapeutic and preventative role in myopia. Statistically, both the 0.05% and 0.1% benzyldamine lysine preparations also showed significant therapeutic effects on myopia (effectively inhibiting the negative refractive power progression). The low-concentration group (0.01% benzyldamine lysine) showed similar refractive power to the negative control group after one week of testing, and slightly better than the negative control group after two weeks, but without statistical significance. Three concentrations of benzyldamine lysine (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 lowest concentration (0.01%), the higher concentrations of benzyldamine lysine, like atropine, effectively inhibited the elongation of the posterior segment (vitreous cavity depth and axial length) in the subjects and effectively controlled, inhibited, delayed, or slowed the (continuous) negative refractive error progression in myopic individuals or those with a tendency to develop myopia. Compared with the solvent group, the above inhibitory effects showed significant differences or extremely significant differences (see...). Figure 3 During the administration period, no ocular irritation or abnormalities were observed in any of the benzalkonium chloride groups. Anterior chamber depth, lens thickness, and pupil size were not affected by benzalkonium chloride administration. In the positive control atropine group, all animals showed pupil dilation after administration, with statistically significant differences compared to the solvent group (see...). Figure 4 This is consistent with the adverse reactions of the drug reported in clinical trials.

[0291] The results of this embodiment demonstrate that benzalkonium chloride alone can prevent and treat myopia, or benzalkonium chloride can be used to prepare formulations or pharmaceutical compositions for the prevention and treatment of myopia. Preferably, the concentration of benzalkonium chloride in the above-mentioned formulations or pharmaceutical compositions is not less than 0.01%, and can be 0.05%-1%. Considering the FDA's (Food and Drug Administration's) view that benzalkonium chloride may cause serious liver toxicity in humans, the need for long-term continuous use of myopia treatment drugs, and the specific requirements of regulatory authorities regarding the safety of pediatric drugs, the inventors believe that a concentration of 0.1%-0.25% benzalkonium chloride eye drops is a reasonable formulation for clinical myopia prevention and control, that is, the concentration of benzalkonium chloride in the formulation or pharmaceutical composition is preferably 0.1% to 0.25%. In addition to increasing the concentration of benzalkonium chloride during preparation, other methods to achieve or improve the myopia control effect of benzalkonium chloride in myopic or myopic-prone individuals include increasing the ocular bioavailability of benzalkonium chloride, increasing the frequency of drug administration, combining it with other myopia treatment drugs, and optimizing the formulation of benzalkonium chloride preparations. In summary, the benzalkonium chloride preparations or drug compositions described above can effectively reduce (inhibit) the elongation of axial length and the increase of vitreous cavity depth in myopic or myopic-prone individuals; these preparations or drug compositions can treat (control) myopia, especially in individuals aged 6 to 18 years.

[0292] Example 6: Benzyl lysine can significantly increase choroid thickness.

[0293] (a) Benzyl lysine effectively inhibits the decrease in choroidal thickness in FDM and LIM guinea pig models.

[0294] Three-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, underwent refractive power (infrared eccentric photorefractive optics) and axial length (A-scan) measurements. Animals with refractive power between 3-8 diopters (D) and binocular anisometropia not exceeding 2D were selected and randomly divided into the following four groups: form deprivation (FD) + solvent control (NS) group, FD + 0.5% benzyldamine lysine eye drops (BDL(S)) group, 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. In the guinea pig model, the right eye (experimental eye) was covered by the headgear, while the left eye (contralateral eye) was not covered. 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 benzalkonium chloride efficacy experiment, with the headgear or lens only briefly removed for drug administration or choroidal thickness measurement. The headgear position was checked or the lens wiped daily at 6:00 AM, 12:00 PM, and 6:00 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 experimental eye of the FDM model 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 weeks. For the lens-induced myopia model, starting from the day of modeling, individuals in the lens-induced group were given either a solvent (negative control) or a drug (benzyldenafil) daily between 9 and 10 AM. The administration method was a subconjunctival injection of 100 μl into the experimental eye, once daily for one week. For both myopia models, 30-60 minutes after the last administration, the choroidal thickness of all eyes was measured using Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). All data collection and processing methods were identical to those used in the inventors' published literature. [4] The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject, and the statistical method was an independent samples t-test. All the above efficacy experiments were repeated at least twice. The test drug (0.5% benzalkonium chloride eye drops) and the solvent control (negative control group) were produced and provided to the inventor by the same commercial benzalkonium chloride eye drops manufacturer.

[0295] The results showed that, regardless of whether it was the FDM or LIM model, benzyldine could effectively increase the choroidal thickness of guinea pigs in both the FDM and LIM models compared to the solvent control group, and there was a statistically significant difference between the two (the difference between the solvent control group and the drug group in the LIM model was extremely significant). Specifically, the pharmacological effects were that the experimental eyes of guinea pigs in both the FDM and LIM model solvent groups showed a decrease in choroidal thickness, while benzyldine could inhibit the decrease in choroidal thickness in myopic eyes. In the FDM model, the mean difference in choroidal thickness between the experimental and contralateral eyes was -17.51 ​​micrometers, while after benzalkonium chloride intervention, the mean difference in choroidal thickness between the experimental and contralateral eyes in myopic individuals was -9.20 micrometers, indicating that the choroidal thickness of the experimental eye approached the level of the normal eye in the same individual after drug intervention (the difference between the two decreased). In the LIM model, the mean difference in choroidal thickness between the experimental and contralateral eyes was -23.38 micrometers, while after benzalkonium chloride intervention, the mean difference in choroidal thickness between the experimental and contralateral eyes in myopic individuals was -6.31 micrometers. In some animals, the choroidal thickness of the experimental eye even completely recovered to the level of the normal eye after drug administration (see...). Figure 5 Corneal curvature (RCC), anterior chamber depth (ACD), and lens thickness (LT) were not affected by the test drug. In summary, benzyldane lysine can significantly inhibit choroidal thinning and slow down the thinning trend in myopic or myopic individuals.

[0296] In myopic individuals, parallel light rays, after being refracted by the relaxed refractive system of the eye, focus in front of the retina. When benzyldamine increases the choroidal thickness in a myopic individual, it causes the retina to shift towards the lens, ultimately shortening the distance between the focal point and the retina, or even bringing them into perfect harmony. The distance between the focal point and the retina is the degree of myopia. Benzyldamine can shorten this distance or inhibit its increase in myopic individuals, thus reducing the degree of myopia. Administering benzyldamine to myopic individuals results in better distance vision and an effective reduction in their myopic refractive state (myopia is treated, and the degree of myopia is reduced), including improved distance vision. Therefore, the myopia treatment (prevention) effect exhibited by benzalkonium chloride in this application is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia or true myopia, and is also unrelated to factors such as the age, gender, degree of myopia, rate of myopia progression, ethnicity and age of onset of myopia of the drug user. That is, benzalkonium chloride has a therapeutic and preventive effect on all types of myopia.

[0297] Example 7: The therapeutic effects of administering benzalkonium chloride eye drops and benzalkonium chloride ointment to the eyes (non-invasive or non-surgical administration methods).

[0298] Three-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, underwent refractive error (infrared eccentric refractometer) and axial length (A-scan) measurements. Animals with refractive power between 3-8 diopters (D) and binocular anisometropia not exceeding 2D were selected and randomly divided into three groups: FD + saline group, FD + 0.5% benzalkonium chloride eye drops (self-prepared), and FD + 0.1% atropine group. On the first day of the experiment, at 8:00 AM, the guinea pigs were subjected to visual deprivation using a mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). FD induction continued throughout the benzalkonium chloride efficacy experiment, with the head cap only briefly removed during drug administration or eye examinations (such as refractive error measurement). The head cap position was checked daily at 8:00 AM, 12:00 PM, and 7:00 PM, and before drug administration, and individuals whose head caps fell off more than three times were culled. Starting from the day of model establishment, the experimental eye was given the corresponding solvent or drug via direct eye drops between 9-10 AM daily, and a second eye drop was administered between 2:30-3:30 PM, i.e., twice-daily, with each dose being 25 μl, for two consecutive weeks. Refractive error and axial length parameters of the test animals were measured at the beginning of the pharmacodynamic experiment, and at weeks 1 and 2. All data collection and processing methods were identical to those used in the inventors' laboratory's published literature. [4] The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. All the above efficacy experiments were repeated at least twice.

[0299] Due to the modeling method, the guinea pig's eye structure (its eyeballs are relatively protruding compared to humans and it does not actively close its eyes), and the animals' normal blinking, the actual effective therapeutic dose of the drug received by each test eye was lower than the peribulbar injection dose for the same volume of eye. Furthermore, the total daily volume of eye drops administered to the test animals was also less than the injection volume in Example 5. Therefore, in this example, the efficacy of direct eye drops administration, whether using benzalkonium chloride eye drops or 0.1% atropine, was inferior to the therapeutic effect of peribulbar injection for myopia. The changes in refractive error and axial length parameters in the negative control group animals were consistent with the expected changes in the myopia model, and the positive control drug atropine exhibited its expected efficacy in the experiment. All of these factors demonstrate that the myopia model was successfully established in this experiment and can be used for evaluating the efficacy of benzalkonium chloride. Regarding axial length parameters, compared to the saline solution group, both benzyldamine lysine and 0.1% atropine significantly inhibited axial elongation in the form deprivation myopia model (statistically different). Both showed almost identical inhibitory effects on increased axial length and vitreous cavity depth in myopic individuals. The myopia inhibition rates of benzyldamine eye drops at 1 and 2 weeks were similar to those of the 0.1% atropine eye drops group (35.5% vs. 28.1% and 33.9% vs. 36.9%, respectively), and both showed statistically significant differences in efficacy compared to the negative control solution group (see...). Figure 6However, the atropine group experienced pupillary dilation as an adverse reaction during administration, while no significant ocular abnormalities were observed in the benzydamine lysine group. Neither atropine nor benzydamine lysine interventions affected corneal curvature, anterior chamber, or lens-related parameters in the subjects (see...). Figure 7 In the inventor's laboratory, using 0.01% atropine eye drops, a concentration commonly used in current clinical trials, under the same administration conditions (consistent myopia model, administration method, administration frequency, and administration volume) in this embodiment, this concentration of atropine showed no therapeutic effect on the guinea pig myopia model, neither in refractive power nor axial length parameters. This may be related to the short time the eye drops remain on the ocular surface after administration. Therefore, from the perspective of efficacy and safety, benzyldamine lysine has a better risk-benefit ratio than atropine for the treatment of individual myopia (e.g., daytime use of benzyldamine lysine does not cause photophobia similar to that caused by atropine pupil dilation during myopia treatment), and is particularly suitable for myopia treatment in children and adolescents and myopia prevention and control in school-aged individuals.

[0300] For the test drug ointment formulation, no control group was set up in this embodiment because the 3% bendadine ointment used is a commercially available product in Japan, and the inventors could not obtain a corresponding formulation without bendadine. Atropine ointment containing the same excipients was also excluded for the same reason. However, for the efficacy evaluation of this bendadine formulation in myopia treatment, the inventors can still refer to the indicators of the same batch and the same model control group in the non-invasive drug delivery experiment of this application. The specific experimental procedure was as follows: bendadine ointment was applied to the corneal surface and periocular skin of the test eye (experimental eye) of the guinea pig visual deprivation myopia model described in this application, and the eyelids were manually and quickly closed 10 times. However, due to the inability of the ointment to be absorbed quickly and the coverage of the eye patch and the normal blinking of the animal, the inventors found that there was a certain amount of bendadine ointment residue on the inside of the eye patch when the drug was administered for the next time. The dosage of bendadine ointment was 18mg±2mg each time. Starting from the day of modeling, the deprivation eye was administered the drug at 9-10 am every day, and the second drug was administered at 2:30-3:30 pm, that is, twice a day for 2 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. [4] The statistical basis is the difference between the experimental eye and the contralateral eye of the same subject.

[0301] The myopia inhibition rates of 3% bendazac ointment after 1 and 2 weeks of administration were 17.7% and 25.9%, respectively. The therapeutic effect was inferior to that of 0.5% bendazac lysine or 0.1% atropine from the same batch, but significantly better than the untreated group in the same batch of form deprivation myopia models. Possible reasons include: the modeling occlusion affecting ocular absorption of bendazac in the ointment; or the formulation being primarily for human skin administration, thus its bioavailability in guinea pig eyes is not optimal. However, bendazac (ointment) still showed effective control of myopia. Besides inhibiting the negative refractive error progression in myopic individuals, it also suppressed the increase in vitreous cavity depth and axial length elongation. Specifically, after 2 weeks of administration, the mean increase in vitreous cavity depth and axial length in the bendazac ointment myopia treatment group was 0.09 mm, while the corresponding values ​​in the untreated myopia group were 0.13 mm and 0.12 mm, respectively (see [link to relevant documentation]). Figure 6 It is evident that the elongation of the axial length in myopic individuals is primarily due to the increase in vitreous cavity depth, and bendazac can simultaneously reduce both the increase in vitreous cavity depth and the elongation of the axial length in myopic individuals. No significant ocular abnormalities were observed in animals after bendazac administration, and the pupillary, corneal curvature, anterior chamber, and lens-related parameters of the subjects were not affected by the drug (see...). Figure 7 ).

[0302] In summary, besides intraocular injection, bendazac and its salt forms (such as lysine salts) can also effectively treat and control myopia using other non-invasive (non-surgical) administration methods, slowing down the negative refractive error progression in myopic individuals or those with a myopia predisposition. Specifically, bendazac lysine eye drops can be administered directly to the eyes, or bendazac eye ointment can be applied to the eyes to treat myopia, inhibiting axial elongation and reducing vitreous cavity depth increase in myopic individuals or those with a myopia predisposition.

[0303] Example 8: Effects of Lysine and Benadryl Acid Eye Drops on Myopia

[0304] Three-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, were selected based on refractive power (infrared eccentric refractometer) 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 5 groups: FD + saline group (NS), FD + L-lysine, FD + 0.5% bendazac lysine (BDL), FD + DMSO (a solvent control group for bendazac), and FD + bendazac (experimental group, referring to individuals with FDM model treated with bendazac). On the first day of the experiment, at 8:00 AM, the guinea pigs underwent visual deprivation using a mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). FD induction continued throughout the entire efficacy experiment period, with the mask only briefly removed during drug administration or eye examinations (such as refractive power measurement). The headgear position was checked daily at 8:00 AM, 12:00 PM, and 7:00 PM, and before drug administration, starting from the beginning of the efficacy experiment. Individuals whose headgear fell off more than three times were discarded. Starting from the day of model establishment, the corresponding group of solvents or drugs were administered to the experimental eyes via subconjunctival injection, with an injection volume of 100 μl, once daily for two consecutive weeks, from 9:00 AM to 10:00 AM. Refractive error and axial length parameters were measured at the beginning of the efficacy experiment and at weeks 1 and 2. All data collection and processing methods were identical to those used in published literature by the inventor's laboratory. [4] The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. All the above efficacy experiments were repeated at least three times, and the drug formulations were all prepared by the inventors themselves.

[0305] The experimental results showed that the changes in refractive error and axial length parameters in the negative control animals, whether using saline or DMSO solvent, were consistent with the expected changes in the myopia model. Furthermore, the positive control drug, 0.5% benzalkonium chloride, demonstrated its expected efficacy in the experiment. These results confirm the successful establishment of the myopia model in this experiment, which can be used to evaluate the efficacy of benzalkonium chloride and lysine. Using the same molar amount of lysine as 0.5% benzalkonium chloride alone did not inhibit the progression of myopia, whether it was negative refractive error, vitreous cavity depth, or axial length elongation. At 1 and 2 weeks of administration, the myopia degree in the lysine intervention group was even higher than that in the saline group, while the same molar amount of benzalkonium chloride effectively inhibited the negative refractive error progression in both groups, showing a statistically significant difference compared to the saline group (see...). Figure 8 Therefore, lysine does not have any medicinal effect in treating or preventing myopia. The medicinal effect of benzyl lysine in treating myopia is not directly related to the lysine component in its molecule. Any pharmaceutically acceptable salt of benzyl lysine can be used for the treatment and prevention of myopia.

[0306] Compared with the DMSO solvent control group, the myopia inhibition rate of bendazac alone was 33.4% and 30.1% at 1 and 2 weeks, respectively. Its myopia treatment effect was consistent with the positive control group of the same batch of equimolar bendazac lysine, and both showed statistically significant differences compared with their respective negative controls. This demonstrates that bendazac is the key and only component of the bendazac lysine molecule that exerts its pharmacological effect in myopia treatment, effectively inhibiting and slowing the progression of negative refractive error in myopic individuals. Compared with the DMSO solvent group, bendazac administration also significantly inhibited axial elongation and slowed the increase in vitreous cavity depth in myopic individuals, showing statistically significant differences compared with the negative control group. Its effect was similar to that of the experimental group of the same batch of equimolar bendazac lysine (see...). Figure 9 ).

[0307] No obvious ocular abnormalities were observed in animals after administration of benzalkonium chloride, benzalkonium chloride, or lysine. The pupillary diameter, corneal curvature, anterior chamber depth, and lens thickness of the subjects were not affected by the drugs (see [link to relevant data]). Figure 10-11 ).

[0308] In the above experiment, choroidal thickness was measured 2 weeks after administration of bendamarine and its corresponding solvent as negative controls, according to the protocol described in this application. The results showed that bendamarine alone (in eye drop form) could inhibit the reduction of choroidal thickness in myopic eyes. The mean difference in choroidal thickness between the experimental eye and the contralateral eye in myopic individuals was -18.82 micrometers, while the mean difference in choroidal thickness between the experimental eye and the contralateral eye after bendamarine intervention was -8.47 micrometers. There was a statistically significant difference between the bendamarine drug group and the DMSO solvent group (see [link to relevant documentation]). Figure 12 Therefore, bendazac and bendazac lysine show consistent efficacy in inhibiting the reduction of choroidal thickness in myopic or myopic individuals. Bendazac can significantly inhibit the reduction of choroidal thickness and slow down the trend of choroidal thinning in myopic or myopic individuals.

[0309] The above results demonstrate that bendazac and its corresponding compounds in any salt form (such as bendazac lysine) can effectively treat myopia by inhibiting axial elongation and slowing the increase in vitreous depth, thereby delaying the negative refractive error progression in myopic individuals or those with a myopia tendency. Simultaneously, bendazac and its pharmaceutically acceptable salts (such as bendazac lysine) can effectively increase choroidal thickness and reduce myopia. The dosage forms of bendazac and its pharmaceutically acceptable salts (such as bendazac lysine) in the treatment and prevention of myopia can be eye drops, eye ointments, eye sprays, eye injections, and eye gels; devices, formulations, or pharmaceutical compositions containing these compounds (drugs) can be used to control the progression of myopia.

[0310] Example 9: The therapeutic effects of Sorbinil and Zopolrestat on a guinea pig form deprivation myopia model

[0311] Three-week-old tricolor guinea pigs, after excluding individuals with obvious eye diseases or abnormalities, underwent refractive power (infrared eccentric refractometer) 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 three groups: FD+DMSO, FD+Sorbinil, and FD+Zopolrestat. Based on compound database information, the IC50 of zopolrestat... 50 =3.1 nM, IC50 of sorbinil 50 =3.14±0.02μM. The final concentration of Zopolrestat used in the inventor's experiment was 1mM, and the final concentration of Sorbinil was 100μM. On the first day of the experiment, guinea pigs were subjected to form deprivation myopia modeling at 8:00 AM. The form deprivation myopia model used the mask method. The headgear was provided by the inventor using a 10-inch milky white non-toxic latex balloon. The right eye (experimental eye) of the guinea pig model was covered by the headgear, while the left eye (contralateral eye) was not covered. FD induction continued throughout the entire benzyldamine lysine efficacy experiment period, with the headgear only briefly removed during drug administration or ocular testing (such as refractive error measurement). The headgear position was checked daily at 8:00 AM, 12:00 PM, and 7:00 PM, and before drug administration. Individuals whose headgear fell off more than 3 times were discarded. Starting from the day of model establishment, the corresponding solvent or drug was administered to the experimental eyes of the FDM model once daily between 9 and 10 AM, via subconjunctival injection, with an injection volume of 100 μl, for two consecutive weeks. Refractive error and axial length parameters of the test animals were measured at the beginning of the pharmacodynamic experiment, and at one and two weeks. All data collection and processing methods were identical to those used in previously published literature by the inventors' laboratory. [4] The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject. All the above efficacy experiments were repeated at least 3 times. In this embodiment, the test drug and solvent control (negative control group) were prepared by the inventor.

[0312] The results showed that Sorbinil and Zopolrestat had no therapeutic effect on myopia and could not control myopia progression. These two aldose reductase inhibitors could not inhibit FD-induced negative refractive error or slow the progression of axial elongation in myopic individuals. Throughout the experimental period, at each time point, there were no significant differences in either refractive error or axial length parameters between the Sorbinil and Zopolrestat groups compared to the solvent group. Figure 13 Furthermore, Sorbinil and Zopolrestat had no effect on corneal curvature, anterior chamber depth, or lens thickness in the subjects (see [link to study]). Figure 14 In summary, aldose reductase is not a target for the development of drugs for myopia treatment, and not all aldose reductase inhibitors have the efficacy of myopia prevention and control.

[0313] Example 10: Therapeutic effect of m-hydroxy-methylaniline on a guinea pig form deprivation myopia model

[0314] The efficacy of the drug was evaluated using the guinea pig form deprivation myopia model described in this application. All individuals underwent refractive error and axial length measurements. After removing ineligible animals, they were randomly divided into three groups: FD + 0.9% saline (NS), FD + m-hydroxymethylaniline (compound A), and FD + 0.1% atropine (positive control). On the first day of the experiment, guinea pigs were subjected to form deprivation at 8:00 AM using a mask method, with the right eye covered (experimental eye) and the left eye uncovered (contralateral eye). Starting from the day of model establishment, the corresponding solvent or drug was administered to the experimental eye between 9:00 and 10:00 AM daily via subconjunctival injection, with an injection volume of 100 μl, once daily for one week. Refractive error and axial length parameters were measured at the beginning and end of the efficacy experiment. All data collection and processing methods were the same as in other embodiments of this application, and the statistical basis was the difference between the experimental eye and the contralateral eye of the same subject.

[0315] In this experiment, the changes in refractive error and axial length parameters in the negative control group animals were consistent with the expected changes in the myopia model, and the positive control drug atropine demonstrated its expected efficacy. These findings demonstrate that the myopia model was successfully established and can be used to evaluate the efficacy of the test drug. The experimental results are as follows: Figure 15 As shown, administration of m-hydroxymethylaniline did not inhibit the increase in refractive power, vitreous cavity depth, or axial length. This indicates that m-hydroxymethylaniline has no preventive or therapeutic effect on myopia. After administration of m-hydroxymethylaniline, the axial length and refractive power of the test individuals did not show statistically significant differences compared to the negative control group. The drug did not inhibit axial elongation in myopic individuals, nor did it slow the increase in vitreous cavity depth. In this example, atropine showed a normal myopia treatment effect, but all test animals in this group experienced pupillary dilation, and anterior chamber depth and lens thickness were not affected after drug intervention. Figure 15 In summary, the experimental results demonstrate that not all compounds (drugs) with cataract treatment effects can be used to treat myopia; and not all compounds with antioxidant activity or that can reduce BLOA (Biological Liquid Oxidant Activity) have myopia prevention and control efficacy.

[0316] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and not to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application, and they should all be covered within the scope of the claims and specification of this application. In particular, as long as there is no structural conflict, the various technical features mentioned in the embodiments can be combined in any way. This application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

[0317] References:

[0318] 1Lu F, Zhou X, Zhao H, et al. Axial myopia induced by a monocularly-deprived facemask in guinea pigs: A non-invasive and effective model. Exp EyeRes 2006;82:628-636.

[0319] 2Lu F, Zhou X, Jiang L, et al. Axial myopia induced by hyperopic defocusin guinea pigs: A detailed assessment on susceptibility and recovery. Exp EyeRes 2009;89:101-108.

[0320] 3Wu H, Chen W, Zhao F, et al. Scleral hypoxia is a target for myopiacontrol. Proc Natl Acad Sci USA 2018;115:E7091-E7100.

[0321] 4Pan M, Zhao F, Xie B, et al. Dietary omega-3 polyunsaturated fatty acids are protective for myopia. Proc Natl Acad Sci USA 2021; 118.

Claims

1. The use of benzyldane, or a pharmaceutically acceptable salt thereof, or a combination thereof, as the sole active ingredient in the preparation of a pharmaceutical composition or apparatus, characterized in that, The use of the pharmaceutical composition or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and its symptoms; the symptoms being selected from anisometropia, elongation of axial length, increase in vitreous cavity depth, decrease in choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat refractive error-related abnormal development of the eyeball in individuals with myopia or a predisposition to myopia, wherein the main characteristic of the refractive error-related abnormal development of the eyeball is that, in a relaxed state of accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina. (c) Controlling, inhibiting, delaying or slowing down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (d) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (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 drug composition or device can be administered via systemic administration, local administration, parenteral administration, or non-invasive administration. The dosage of the benzyldane, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective dose. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

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 or device, and the use of the pharmaceutical composition or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and its symptoms; the symptoms being selected from anisometropia, elongation of axial length, increase in vitreous cavity depth, decrease in choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat refractive error-related abnormal development of the eyeball in individuals with myopia or a predisposition to myopia, wherein the main characteristic of the refractive error-related abnormal development of the eyeball is that, in a relaxed state of accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina. (c) Controlling, inhibiting, delaying or slowing down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (d) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (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 are selected from atropine, dibazol, pirenzepine, 7-methylxanthine, ampicillin, dopamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pirfenpine, pirenzepine, methylamine, chlorpheniramine, γ-aminobutyric acid, naloxone, 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 drug composition or device can be administered via systemic administration, local administration, parenteral administration, or non-invasive administration. The dosage of the benzyldane, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective dose. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

3. The use of benzyldaza lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, as the main active ingredient in a composition formed with one or more other pharmaceutical products, characterized in that, The composition is intended for use in the preparation of a pharmaceutical composition or device, and the use of the pharmaceutical composition or device is selected from one of the following (a)-(f): (a) Prevention and / or treatment of myopia; (b) Prevention and / or treatment of myopia symptoms, wherein the myopia 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; (c) Delaying, reducing or treating abnormal development of the eyeball related to refractive error in individuals with myopia or a predisposition to myopia, the main characteristic of which is that, in a relaxed state of eye accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina, resulting in myopia; (d) To control, inhibit, delay or slow down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (e) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (f) For the prevention of: posterior staphyloma caused by high myopia, retinal detachment caused by high myopia, retinal tear caused by high myopia, subretinal neovascularization caused by high myopia, vitreous liquefaction caused by high myopia, progressive or sudden loss of near vision caused by high myopia, visual field defects caused by high myopia, blindness and phthisis bulbi caused by high myopia, choroidal neovascularization caused by high myopia, and choroidal atrophy caused by high myopia; The term "main active ingredient" refers to the fact that the content of benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 50% of all active ingredients, and the percentage is a mass ratio or molar ratio. The dosage of the benzyldane, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective dose. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

4. The use as described in claim 3, characterized in that, The other one or more drugs are selected from atropine, dibazol, pirenzepine, 7-methylxanthine, ampicillin, dopamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pirfenpine, pirenzepine, methylamine, chlorpheniramine, γ-aminobutyric acid, naloxone, 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.

5. The use as described in any one of claims 1-4, characterized in that, The individuals who develop the aforementioned myopia are children, adolescents, middle-aged or elderly people.

6. The use as described in any one of claims 3-4, characterized in that, The term "major active ingredient" refers to the fact that the content of benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 60% of all active ingredients, and the percentage is a mass ratio or molar ratio.

7. The use as described in any one of claims 3-4, characterized in that, The term "major active ingredient" refers to the content of benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, which accounts for more than 70% of all active ingredients, and the percentage is a mass ratio or molar ratio.

8. The use as described in any one of claims 3-4, characterized in that, The term "major active ingredient" refers to the fact that the content of benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 80% of all active ingredients, and the percentage is a mass ratio or molar ratio.

9. The use as described in any one of claims 3-4, characterized in that, The term "major active ingredient" refers to the fact that the content of benzyl lysine, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 90% of all active ingredients, and the percentage is a mass ratio or molar ratio.

10. The use as described in any one of claims 1-4, 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 or device is at least 0.01%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

11. The use as described in any one of claims 1-4, 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 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.

12. The use as described in any one of claims 1-4, 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 or device is 0.05% to 1%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

13. The use as described in any one of claims 1-4, 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 or device is 0.1% to 0.25%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

14. The use as described in claim 5, characterized in that, The pharmaceutical composition is an ophthalmic preparation or an oral preparation.

15. The use as described in claim 5, characterized in that, The pharmaceutical composition or device is further combined with surgery and / or other vision correction methods.

16. The use as described in claim 5, characterized in that, The pharmaceutical composition or device may also 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.

17. The use as described in claim 16, characterized in that, The pharmaceutical composition or device is used simultaneously or intermittently with one or more other active ingredients.

18. The use of bendanoic acid, or a pharmaceutically acceptable salt thereof, or a combination thereof, as the sole active ingredient in the preparation of a pharmaceutical composition or apparatus, characterized in that, The use of the pharmaceutical composition or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and its symptoms; the symptoms being selected from anisometropia, elongation of axial length, increase in vitreous cavity depth, decrease in choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat refractive error-related abnormal development of the eyeball in individuals with myopia or a predisposition to myopia, wherein the main characteristic of the refractive error-related abnormal development of the eyeball is that, in a relaxed state of accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina. (c) Controlling, inhibiting, delaying or slowing down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (d) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (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 or device is intended for individuals with myopia or individuals with a predisposition to myopia, wherein the individuals are mammals; The dosage of the benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective amount. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

19. The use of benzalkonium chloride, 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 or device, and the use of the pharmaceutical composition or device is selected from one of the following (a)-(e): (a) Prevention and / or treatment of myopia and related symptoms; the related symptoms are selected from anisometropia, elongation of axial length, increase in vitreous cavity depth, decrease in choroidal thickness, and blurred vision when looking at distant objects; (b) Delay, reduce or treat refractive error-related abnormal development of the eyeball in individuals with myopia or a predisposition to myopia, wherein the main characteristic of the refractive error-related abnormal development of the eyeball is that, in a relaxed state of accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina. (c) Controlling, inhibiting, delaying or slowing down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (d) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (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 are selected from atropine, dibazol, pirenzepine, 7-methylxanthine, ampicillin, dopamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pirfenpine, pirenzepine, methylamine, chlorpheniramine, γ-aminobutyric acid, naloxone, 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 or device is intended for individuals with myopia or individuals with a predisposition to myopia, wherein the individuals are mammals; The dosage of the benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective amount. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

20. Use of bendazac, or a pharmaceutically acceptable salt thereof, or a combination thereof, as the main active ingredient in a composition formed with one or more other pharmaceutical products, characterized in that, The composition is intended for use in the preparation of a pharmaceutical composition or device, and the use of the pharmaceutical composition or device is selected from one of the following (a)-(f): (a) Prevention and / or treatment of myopia; (b) Prevention and / or treatment of myopia symptoms, wherein the myopia 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; (c) Delaying, reducing or treating abnormal development of the eyeball related to refractive error in individuals with myopia or a predisposition to myopia, wherein the main characteristic of the abnormal development is that, in a relaxed state of eye accommodation, parallel light rays are refracted by the eye's refractive system and focus in front of the retina, resulting in myopia; the myopia does not include myopia caused by lens disease; (d) To control, inhibit, delay or slow down the process and / or speed of negative refractive error in myopic individuals or individuals with a tendency to develop myopia; (e) Used to reduce the distance between the retina and lens in individuals with myopia or a predisposition to myopia; (f) For the prevention of: posterior staphyloma caused by high myopia, retinal detachment caused by high myopia, retinal tear caused by high myopia, subretinal neovascularization caused by high myopia, vitreous liquefaction caused by high myopia, progressive or sudden loss of near vision caused by high myopia, visual field defects caused by high myopia, blindness and phthisis bulbi caused by high myopia, choroidal neovascularization caused by high myopia, and choroidal atrophy caused by high myopia; The term "main active ingredient" refers to the fact that the content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 50% of all active ingredients, and the percentage is a mass ratio or molar ratio. The pharmaceutical composition or device is intended for individuals with myopia or individuals with a predisposition to myopia, wherein the individuals are mammals; The dosage of the benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, is a therapeutically effective amount. The myopia mentioned does not include myopia caused by lens lesions, and the myopia mentioned refers to refractive myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true and semi-pseudomyopia, progressive myopia, simple myopia, pathological myopia, primary myopia, secondary myopia, curvature myopia, index myopia, positional myopia, bending myopia, myopia caused by prolonged close-range use of the eyes, myopia and pseudomyopia caused by eye strain, myopia caused by reading, myopia caused by using mobile phones and other electronic products, myopia caused by excessive eyeball growth, myopia caused by poor eye hygiene, myopia that is not effective or ineffective in atropine treatment, myopia caused by insufficient outdoor exercise, accommodative tension myopia, or myopia dominated by environmental factors.

21. The use as described in claim 20, characterized in that, The other one or more drugs are selected from atropine, dibazol, pirenzepine, 7-methylxanthine, ampicillin, dopamine, timolol maleate, adrenaline, pirenzepine, pyrazine, pirfenpine, pirenzepine, methylamine, chlorpheniramine, γ-aminobutyric acid, naloxone, 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.

22. The use as described in any one of claims 18-21, characterized in that, The individuals who develop the aforementioned myopia are children, adolescents, middle-aged or elderly people.

23. The use as described in any one of claims 20-21, characterized in that, The term "major active ingredient" refers to the fact that the content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 60% of the total active ingredients, and the percentage is a mass ratio or molar ratio.

24. The use as described in any one of claims 20-21, characterized in that, The term "major active ingredient" refers to the fact that the content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 70% of all active ingredients, and the percentage is a mass ratio or molar ratio.

25. The use as described in any one of claims 20-21, characterized in that, The term "major active ingredient" refers to the fact that the content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 80% of all active ingredients, and the percentage is a mass ratio or molar ratio.

26. The use as described in any one of claims 20-21, characterized in that, The term "major active ingredient" refers to the fact that the content of benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof, accounts for more than 90% of all active ingredients, and the percentage is a mass ratio or molar ratio.

27. The use as described in any one of claims 18-21, characterized in that, The concentration or percentage of the benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition or device is at least 0.01%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

28. The use as described in any one of claims 18-21, characterized in that, The concentration or percentage of the bendazac, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition or device is 0.01% to 0.8%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

29. The use as described in any one of claims 18-21, characterized in that, The concentration or percentage of the bendazac, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition or device is 0.05% to 0.5%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

30. The use as described in any one of claims 18-21, characterized in that, The concentration or percentage of the benzalkonium chloride, or a pharmaceutically acceptable salt thereof, or a combination thereof in the pharmaceutical composition or device is 0.1%, wherein the percentage is a mass / volume ratio, or a mass ratio, or a molar ratio.

31. The use as described in claim 22, characterized in that, The pharmaceutical composition or device may also 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.

32. The use as described in claim 31, characterized in that, The pharmaceutical composition or device is used simultaneously or intermittently with one or more other active ingredients.

33. The use as described in claim 22, characterized in that, The pharmaceutical composition is an ophthalmic preparation or an oral preparation.

34. The use as described in claim 22, characterized in that, The drug composition or device can be administered via systemic administration, local administration, parenteral administration, or non-invasive administration.

35. The use as described in any one of claims 31-34, characterized in that, The pharmaceutical composition or device is further combined with surgery and / or other vision correction methods.

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