Methods and pharmaceutical compositions for treating myopia

Abstract

The present application relates to a method and pharmaceutical composition for treating, preventing or controlling myopia and its related symptoms. The pharmaceutical composition or method of the present application can effectively prevent and control myopia, is safe, has no obvious side effects, and has good clinical application prospects.

Description

[Technical Field]

[0001] This application relates to methods and medicaments for treating, preventing or controlling myopia and its associated conditions. [Background technology]

[0002] In 350 BC, Aristotle first used the term "myopia" (Paulus TVM de Jong, BRJ Ophthalmol. 2018 Aug; 102 (8):1021-102) to refer to refractive error. Myopia has now become one of the most serious public health problems worldwide. Early literature indicates that as of 2010, nearly 1.84 billion people worldwide suffered from myopia, accounting for 27% of the world's population. Of these, 170 million people (2.8%) suffered from severe myopia. In particular, in East Asian countries such as China, Japan, Korea, and Singapore, the myopia prevalence rate was nearly 50%, far exceeding that of Australia, Europe, and the United States. It is predicted that the global myopia prevalence rate will exceed 50% by 2050 (Brien A Holden, Ophthalmology. 2016 May; 123 (5): 1036-42). In China, the prevalence of myopia is particularly high among children and adolescents aged 6 to 18. A 2016 epidemiological survey of 57,904 samples found that the prevalence of myopia among primary and secondary school students in six provinces and cities in North China, East China, South China, Southwest China, and Northwest China was 55.7%, with the prevalence rates in the 6-8, 10-12, 13-15, and 16-18 age groups being 35.8%, 58.9%, 73.4%, and 81.2%, respectively (Zhou Jia, Ma Yinghua, Ma Jun et al., "Current Status of Myopia Prevalence and Analysis of Influencing Factors Among Primary and Secondary School Students in Six Provinces and Cities in China," Chinese Journal of Epidemiology 2016; 37: 29-34). Epidemiological data indicate that the prevalence of myopia and high myopia is increasing worldwide. Significant changes in social, lifestyle, and environmental factors are one of the important factors influencing the constant increase in myopia prevalence, the younger age at onset of myopia, and the increasing severity of myopia (Susan Vitale, Arch Ophthalmol. 2009 Dec; 127(12): 1632-9), and this trend does not seem to be improving significantly in the short term.

[0003] The harms of myopia are numerous. In addition to poor distance vision, myopia, especially severe myopia, can lead to serious complications such as glaucoma, cataracts, retinal detachment, retinal tears, posterior staphyloma, submacular hemorrhage or myopic macular degeneration, and choroidal neovascularization, which can impair vision-related quality of life, increase the difficulty of vision-related tasks, impair vision, 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). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Chen-Wei Pan,OphthalmiCPysiol Opt.2012 Jan; 32(1): 3-16 [Non-patent document 2] Seang-Mei Saw, Ophthalmic Physiol Opt.2005 Sep; 25(5): 381-91 [Non-patent document 3] 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 Eye Res 2006;82:628-636. [Non-patent document 4] 2Lu F, Zhou X, Jiang L, et al.Axial myopia induced by hyperopic defocus in guinea pigs:A detailed assessment on susceptibility and recovery.Exp Eye Res 2009;89:101-108. [Non-Patent Document 5] 3Wu H,Chen W,Zhao F,et al.Scleral hypoxia is a target for myopia control.Proc Natl Acad Sci USA 2018;115:E7091-E7100. [Non-patent document 6] 4Pan M,Zhao F,Xie B,et al.Dietary omega-3polyunsaturated fatty acids are protective for myopia.Proc Natl Acad Sci USA 2021;118. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above technical problems, the present application provides a use of bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analogue thereof, or a derivative thereof, or a crystalline compound thereof, or a combination of these substances, characterized in that said use satisfies one of the following or at least two of the following simultaneously: [Means for solving the problem]

[0006] (a) Used to prevent and / or treat myopia and its related conditions.

[0007] (b) Used to delay, reduce, or treat abnormal eye development associated with refractive errors.

[0008] (c) Used to obtain sharper distance vision under conditions in which an individual does not rely on or replace lenses (e.g., framed myopia glasses or orthokeratology lenses) or other vision correction procedures (e.g., refractive surgery).

[0009] (d) Used to control, inhibit, delay or slow down the process (rate) of (continuous) negative refractive power in myopic individuals or individuals prone to developing myopia.

[0010] (e) Used in combination with surgery (e.g., refractive surgery, myopic corneal laser surgery, lens surgery) or other vision correction procedures (e.g., corneal contact lenses) to prevent and / or treat myopia and its associated conditions.

[0011] (f) Used in combination with one or more other drugs to prevent and / or treat myopia and myopia-related conditions.

[0012] (g) Reducing the distance between the retina and the lens, preferably for use in reducing the distance between the retina and the lens in myopic or myopically prone individuals.

[0013] (h) Used to reduce myopia or to treat myopia or to control the progression of myopia or to correct myopia or to mitigate myopia or to prevent myopia in young people.

[0014] (i) Used to prevent or treat myopia caused by lens pathology.

[0015] (j) Used to manufacture a pharmaceutical composition, formulation, or device that realizes at least one of the uses (a) to (i) above.

[0016] In some embodiments, bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analog thereof, or a derivative thereof, or a crystalline compound thereof, or a combination of these substances is used as the sole or primary active ingredient.

[0017] In some embodiments, the sole or primary active ingredient is one that accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% of all active ingredients, where the percentages are by weight or mole ratios.

[0018] In some embodiments, these substances or combinations thereof and the one or more other drugs are prepared or designed for sequential administration, simultaneous administration, sequential administration, alternating administration, spaced administration, or separate administration.

[0019] In some embodiments, the abnormal ocular development associated with refractive errors is primarily environmentally induced or primarily man-made (e.g., prolonged close reading, frequent use of electronic screens, lack of distance vision due to continuous close vision, improper use of corrective glasses, side effects from medications, obesity, trauma, insufficient lighting in the learning environment, lack of outdoor exercise) during an individual's early childhood (e.g., 2-28 years of age in humans), and genetic factors are secondary, concomitant, or cooperating factors; or the abnormal development is a refractive developmental anomaly completely independent of genetic factors, characterized primarily by the fact that, under a relaxed and accommodative state, parallel light rays pass through the refractive system of the eye and are refracted to a focal point in front of the retina.

[0020] In some embodiments, the administration is systemic (e.g., oral, intravenous), or topical (e.g., eye drops, intravitreal injection, skin rub or ointment application), or parenteral (e.g., mucosal, transdermal, microneedle), or non-invasive (e.g., eye ointment applied to the cornea or in the pouch formed by pressing the lower eyelid back), or non-invasive (e.g., eye spray).

[0021] In some embodiments, the application of the skin rub or ointment is carried out using a 3% skin rub or eye ointment.

[0022] In some embodiments, the above administration methods (e.g., eye drops, oral) are used simultaneously, in combination, alternating, spaced apart, or singly, or any combination thereof.

[0023] In some embodiments, formulations used for topical administration include, but are not limited to, aqueous solutions, oily solutions, or suspensions. The formulations may contain pharmacologically and / or physiologically active ingredients, such as mydriatic ingredients, decongestant ingredients, ocular muscle (e.g., ciliary muscle) regulating ingredients, anti-inflammatory ingredients, astringents, antihistamine ingredients, antiallergic ingredients, hepatoprotective ingredients (to avoid or reduce liver toxicity), ingredients that enhance the blood-retinal barrier (making it difficult for compounds to penetrate the physiological barrier), vitamins, amino acids, antibacterial ingredients, sugars, polymers or derivatives thereof, cellulose or derivatives thereof, local anesthetic ingredients, glaucoma treatment ingredients, and cataract treatment ingredients.

[0024] In some embodiments, the concentration or ratio of these substances or combinations thereof in the drug composition, formulation, or device is at least 0.01% or more, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more preferably 0.1%, or the concentration or ratio of these substances or combinations thereof is less than 0.01%, and the percentages are expressed as mass / volume concentrations (ratios), mass ratios, or molar (number) ratios.

[0025] In some embodiments, the drug composition or formulation may be in the form of an injection, tablet, freeze-dried injection, capsule, effervescent tablet, chewable tablet, troche, granule, ointment, syrup, oral liquid, spray, nasal drops, topical preparation, oral preparation, etc., and is preferably in the form of an ophthalmic dosage form, including, but not limited to, eye drops (eye drops), eye ointment, eye spray, implant sheet, eye gel, eye pack, ophthalmic microsphere, ophthalmic sustained-release preparation, periocular injection, or intraocular injection, and may further be in the form of a free solution, oil-water mixture, suspension, rub, lotion, cream, drops, granular preparation, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0026] In some embodiments, the myopic individual or the individual prone to developing myopia is a human being, and may be a child, adolescent, middle-aged or elderly person, preferably between 3 and 26 years of age, more preferably between 6 and 18 years of age, or an adult or adolescent, preferably a person whose eyes are in the growth and development stage, or a school-age person, preferably a person in grades 1 to 12.

[0027] In some embodiments, the myopia is refractive or axial myopia; congenital myopia (myopia acquired at birth or before school age), early-onset myopia (before age 14), late-onset myopia (ages 16-18), late-onset myopia (ages 16-18), late-onset myopia (ages 16+), low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia, semi-true semi-pseudo (mixed) myopia; child and / or adolescent myopia (preferably ages 3-26). axial myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); axial myopia in school-age and pre-school populations; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); axial myopia in school-age and pre-school populations; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); more preferably, those aged 3-26 years, more preferably, those aged 6-18 years); progressive myopia in children and / or adolescents (preferably, those aged 3-26 years, more preferably, those aged 6-18 years); refractive myopia, exponential myopia, myopia due to forward displacement of refractive mediation, flexional myopia; myopia caused by prolonged eye use in close work, myopia and pseudomyopia caused by eye fatigue, negative refractive index caused by side effects of medication, myopia caused by reading, myopia caused by use of electronic products such as mobile phones, myopia caused by mismatch of refractive media (components), refractive myopia, myopia caused by abnormal refractive development, myopia caused by excessive growth of the eyeball, myopia caused by poor eye hygiene, myopia in which the focus of distant objects is in front of the retina due to various factors, and in which atropine treatment is ineffective or ineffective, myopia caused by lack of outdoor exercise, accommodative myopia, childhood myopia, and myopia caused by environmental factors.

[0028] In some embodiments, myopia-related symptoms include myopia complications such as, for example, high myopia complications, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal breaks, amblyopia, submacular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field defects, gradual or sudden decrease in vision (especially near vision), eye swelling and / or pain, night blindness, astigmatism, refractive index variation, blindness, vitreous liquefaction, vitreous opacification, strabismus, frequent blinking, frequent eye rubbing, refractive index variation, blurred vision when viewing distant objects and needing to squint or partially close the upper eyelid to see distant objects clearly, headache due to eye strain, difficulty seeing while driving, especially at night (dusk myopia), retinal atrophic degeneration (bleeds and breaks), subretinal neovascularization, and ocular atrophy.

[0029] In some embodiments, the pharmaceutical composition, formulation, or device further comprises a pharmaceutical formulation or drug, and the pharmaceutical formulation or drug is selected from the group consisting of a myopia treatment drug (e.g., atropine, bendazole, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), aminobenzylamine, timolol maleate, adrenaline, pirenzepine, perazine, perlapine, methylamine, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (e.g., blockers, antagonists, or inhibitors directed at the M3 receptor), bendazac or various salt forms thereof, bendazac lysine or various salt forms thereof, polyunsaturated fatty acids (e.g., DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenylate antagonists, vasodilators, mydriatics, smooth muscle dilators, vasospasm inhibitors, collagen metabolism regulators, anti-allergic drugs, anti-inflammatory drugs, liver protectors, ophthalmic disease treatment ingredients, ophthalmic local anesthetics, or ophthalmic agents.

[0030] In some embodiments, the one or more other drugs are a myopia treatment (e.g., atropine, bendazol, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, aminobenzylamine, timolol maleate, adrenaline, perazine, perlapine, methylamine, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (e.g., blockers or antagonists or inhibitors directed against the M3 receptor), bendazac or its various salts. forms, bendazacricin or its various salt forms, polyunsaturated fatty acids (e.g., DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenylate antagonists, vasodilators, smooth muscle dilators, vasospasmodics, collagen metabolism regulators, anti-allergic agents, anti-inflammatory agents, liver protectors, ophthalmic disease treatment ingredients, ophthalmic local anesthetics, mydriatics, or ophthalmic agents or drugs.

[0031] In some embodiments, the formulation may further be an oral product such as a health product, food, supplement, nutritional product, beverage, or cosmetic product, wherein the cosmetic product may be one or more of a free solution, an oil-water mixture, a suspension, a rub, a lotion, a spray, a cream, drops, a granular formulation, an ointment, a paste, a pill, a suppository, an emulsion, and a patch.

[0032] In some embodiments, the device is an instrument, device, consumer product, system, medical instrument, health-related product, or ocular appearance-altering product that can release a drug or has a drug delivery function or potential drug delivery capability, such as a corneal contact lens, eyeglasses, intraocular lens, suture, orthokeratology lens cleaning (maintenance) system, eye pack, eye brightening pack, colored contact lens, microneedle, ocular spray system, eye massager (myopic massager), ocular fumigation device, ocular surface drug delivery device, intraocular drug delivery device, ocular fundus drug delivery device, implant pump, wearable device, acupressure massager, eye relaxation device, myopia treatment device, or drug-device combination product for myopia prevention and control. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 shows the control of myopia progression by bendazacrysine. [Figure 2] FIG. 1 shows the therapeutic safety of bendazacricin ophthalmic solution. [Figure 3] FIG. 1 shows the preventive control of myopia by bendazacricin ophthalmic solution at different concentrations. [Figure 4] FIG. 1 shows the therapeutic safety of different concentrations of bendazacricin. [Figure 5] FIG. 1 shows an increase in choroidal thickness in myopic individuals by bendazacrysine. [Figure 6] FIG. 1 shows the therapeutic effects of instillation of bendazac lysine ophthalmic solution and application of bendazac ointment to the eye. [Figure 7]These figures show the safety of instillation of bendazac lysine ophthalmic solution and application of bendazac ointment to the eye. In Figures 1-5, * indicates a statistical difference between the bendazac lysine (Bendazac) administration group and the negative control group. # indicates a statistical difference between the atropine administration group and the negative control group. * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001, # indicates p<0.05, ## indicates p<0.01, and ### indicates p<0.001. In Figures 6 and 7, * indicates a difference between bendazac lysine ophthalmic solution and the saline group, # indicates a statistical difference between the atropine administration group and the saline group, and $ indicates a difference between the bendazac ointment 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. [Figure 8] This figure shows that single lysine cannot treat myopia. # indicates a difference between BDL and saline vehicle groups, # indicates p<0.05, ## indicates p<0.01, and ### indicates p<0.001. [Figure 9] This figure shows that single bendazac eye drops have a myopia treatment effect consistent with bendazac lysine eye drops. Here, # indicates a difference between BDL and the saline vehicle group, * indicates a difference between bendazac and the vehicle vehicle group. * indicates p<0.05, *** indicates p<0.001, ## indicates p<0.01, and ### indicates p<0.001. [Figure 10] FIG. 1 shows the therapeutic safety of single bendazac. [Figure 11] FIG. 1 shows the therapeutic safety of a single lysine. [Figure 12] This is a graph showing that bendazac inhibits the decrease in choroidal thickness in myopic individuals, where * indicates p<0.05. [Figure 13] Figure 1 shows that Sorbinil and Zopolrestat cannot treat myopia. [Figure 14] FIG. 1 shows a diagram illustrating the safety evaluation of administration of an aldose reductase inhibitor. [Figure 15]This figure shows that meta-hydroxymethylaniline cannot treat myopia. # indicates a statistical difference between the atropine-treated group and the negative control group, and ## indicates p<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following describes in detail the embodiments of the technical solution of the present application with reference to the drawings. The following embodiments are only used as examples to more clearly explain the technical solution of the present application, and do not limit the protection scope of the present application.

[0035] The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.

[0036] Myopia, the most common refractive error, refers to a refractive condition in which parallel light rays are refracted by the eye's refractive system and focused in front of the retina during accommodative relaxation. Myopia can be classified into four categories: (1) mild, moderate, and severe myopia based on the magnitude of the refractive index; (2) refractive myopia and axial myopia based on whether the refractive components are abnormal; (3) pathological myopia and simple myopia based on whether pathological changes have occurred; and (4) primary myopia and concurrent / secondary myopia based on the etiology. Regardless of the type of myopia that develops and progresses, the mismatch between the components of the refractive system (i.e., the refractive media, including the cornea, lens, and vitreous) is the key factor in determining the formation and severity of myopia. Taking refractive myopia as an example, assuming that 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, thereby causing a change in refractive power. In this case, myopia caused by keratoconus is common. Furthermore, changes in the refractive index of the lens due to certain pathologies also directly affect the projection position of parallel light rays on the retina. In this case, if parallel light rays are focused in front of the retina, it is called myopia caused by lens pathology. Other situations in which refractive components are misaligned include when the vitreous cavity is too large, causing the retina to shift backward, resulting in the intraocular imaging focus of distant objects being in front of the retina, resulting in a negative refractive power. Therefore, it is understood that the above myopia classification method will be further refined according to specific circumstances in actual clinical practice. However, refractive power is officially recognized as the only indicator for identifying all types of myopia, determining their severity, and evaluating the effectiveness of myopia treatment.According to the Technical Guidance Principles for Clinical Research on Drugs for Controlling Myopia Progression and academic consensus, the most common type of myopia in children and adolescents (especially those aged 6-18) is simple axial 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.), and it is recognized that the main area where axial elongation occurs is the posterior pole of the eye. It has now been discovered that long-term experimental myopia models in mammals (e.g., squirrels, aye-ayes, and guinea pigs) also exhibit axial elongation, scleral thinning, and thinning of scleral collagen fibers, which are consistent with the manifestations of myopia in humans (Neville A. McBrien, Prog Retin Eye Res. 2003 May; 22(3): 307-38.). During the preclinical development phase, researchers have primarily used two representative myopia models, form-deprivation (FD) and lens-induced (LI), to evaluate the efficacy of drugs for preventing and controlling myopia (DA Goss, Am J Optom Physiol Opt. 1981 Oct; 58(10): 859-69; Hao Wu, Proc Natl Acad Sci U S A. 2018 Jul 24; 115(30): E7091-E7100; and Sen Zhang, Invest Ophthalmol Vis Sci. 2019 Jul 1; 60(8): 3074-3083). Compounds that simultaneously demonstrate therapeutic and preventive effects in these two myopia models are considered to have the greatest potential for development as drugs.

[0037] The pathogenesis of myopia has yet to be fully elucidated. Currently, environmental factors are believed to be the primary contributors to the prevalence and severity of myopia, although genetic myopia is relatively rare. Environmental factors include overaccommodation, hyperopic defocusing of the peripheral retina, excessive lighting (abnormal light exposure), and morphological deprivation. The specific mechanism by which myopia is induced involves the retina perceiving near visual information that induces myopia, then transmitting these signals to the sclera via the choroid, causing changes in the components of the scleral extracellular matrix. This ultimately leads to a decrease in refractive power until the refractive power becomes negative, resulting in myopia. This can be summarized simply as: optical defocus triggers defocus-specific signals to regulate and control refractive development in the eye (Wen-Yi Wang, Biomed Pharmacother. 2021 Jan; 133: 111092; 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, eye size grows along with the rest of the body. Humans, from birth to infancy, are consistent with other mammals, and both express hyperopia. During subsequent developmental stages, as the refractive components of the eye 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 is formed on the retina), resulting in emmetropia. During this developmental process, if near visual information is continuously received for a long period of time, symptoms including misalignment of a series of refractive components, such as excessive elongation of the eye axis, occur, causing the focal point of parallel light rays to be in front of the retina, resulting in myopia. Therefore, how to ensure the alignment of each refractive component during the developmental process of the eye and prevent excessive eye growth are key points in preventing and controlling myopia. Previous research has found that refractive development abnormalities in myopic individuals are related to scleral regeneration, loss of scleral tissue due to decreased synthesis of connective tissue, and increased degradation of type 1 collagen (COL1), and that dopamine, insulin, and nitric oxide may also be involved.

[0038] Currently, framed eyeglasses are the primary method of correcting myopia in children and adolescents, while laser surgery may be used to correct myopia in adults. Myopia is often corrected with eyeglasses, contact lenses, or refractive surgery, but its progression cannot be slowed. Once myopia progresses to high myopia, it poses a high risk of retinal, choroidal, and scleral complications, making it a potentially dangerous vision problem. Therefore, myopia correction should not be simply understood as myopia treatment. Clinical myopia treatment primarily focuses on preventing or slowing myopia progression, and related approaches include optical and pharmacological approaches. Corneal orthopedic lenses can slow the progression of myopia in children and adolescents, but the effectiveness of these treatments varies greatly from person to person and requires the careful assistance of a professional optometrist (Jinhai Huang, Ophthalmology. 2016 Apr; 123(4): 697-708.). Pharmacological options for controlling myopia are quite limited (Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov; 40(11): 833-852.). For example, although atropine eye drops have been shown to be effective in treating myopia in numerous studies, clinical studies have shown that discontinuing administration of atropine can lead to a rebound in myopia and can cause serious side effects such as mydriasis and photophobia during use (Prema Ganesan, Expert Rev Ophthalmol. 2010 Dec1; 5(6): 759-787.). Therefore, its use is not permitted by the National Medical Products Administration in China. 7-Methylxanthine is another investigational myopia control drug, and more data are needed to support its safety and efficacy (Klaus Trier, J Ocul Biol Dis Infor. 2008 Dec; 1(2-4): 85-93. and Tatiana V Tkatchenko, Trends Pharmacol Sci. 2019 Nov; 40(11): 833-852.). Therefore, there is currently a lack of drugs with defined therapeutic efficacy and safety to control myopia progression, and there is an unmet clinical need in this field.

[0039] Bendazac lysine (BDL), or bendazac, is known to relieve pain, relieve itching, inhibit necrosis, improve gallbladder function, and treat blood lipid abnormalities. Clinically, bendazac lysine is used to treat cataracts by preventing lens protein degeneration.

[0040] Through research by the inventors, it was unexpectedly discovered that bendazac or bendazac-lysine has the role of treating, preventing or alleviating myopia and its related symptoms, and it has been stated that this type of compound can effectively control, inhibit, delay or slow the progression of myopia. Finally, when used in the preparation of pharmaceutical preparations or pharmaceutical compositions for preventing and treating myopia, this type of compound has the advantages of high safety in administration and few side effects.

[0041] In view of the above findings, the present application provides a use of bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analogue thereof, or a derivative thereof, or a crystalline compound thereof, or a combination of these substances, characterized in that said use is one of the following or simultaneously satisfies at least two of the following:

[0042] (a) Used to prevent and / or treat myopia and its related conditions. (b) Used to inhibit or reduce axial elongation and / or increase in the length (depth) of the vitreous cavity in an individual who is myopic or prone to developing myopia. (c) for increasing choroidal thickness and / or inhibiting the loss of choroidal thickness in myopic individuals or individuals prone to developing myopia. (d) Used to delay, reduce or treat abnormal eye development associated with refractive errors. (e) Used to provide sharper distance vision in an individual without relying on lenses (e.g., framed myopia glasses or orthokeratology lenses) or lens replacement, or other vision correction procedures (e.g., refractive surgery). (f) Used to control, inhibit, delay or slow down the process (rate) of (continuous) negative refractive power in myopic individuals or individuals prone to developing myopia. (g) Used in combination with surgery (e.g., refractive surgery, myopic corneal laser surgery, lens surgery) or other vision correction procedures (e.g., corneal contact lenses) to prevent and / or treat myopia and its associated conditions. (h) Used in combination with one or more other drugs to prevent and / or treat myopia and myopia-related conditions. (i) To reduce the distance between the retina and the lens, preferably for use in reducing the distance between the retina and the lens in myopic or myopically prone individuals. (j) Used to reduce myopia, or to treat myopia, or to control the progression of myopia, or to correct myopia, or to alleviate myopia, or to prevent myopia in young people. (k) Used to prevent or treat myopia caused by lens pathology. (l) It is used to maintain a stable refractive power in the developing eye of an individual, and in particular to control the rate of axial elongation so as to maintain consistency with the refractive medium, preferably such consistency as to maintain emmetropia or to maintain as much emmetropia as possible. (m) Used to maintain a stable refractive power in the developing eye of an individual, and in particular to control the rate of axial elongation to maintain consistency with the refractive medium, preferably such consistency being able to avoid the onset of myopia or inhibit the increase in myopic power. (n) Used to produce a pharmaceutical composition, formulation, or device that realizes at least one of the uses (a) to (m) above.

[0043] In some embodiments, bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analog thereof, or a derivative thereof, or a crystalline compound thereof, or a combination of these substances is used as the sole or primary active ingredient.

[0044] In some embodiments, the sole or primary active ingredient is one that accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% of all active ingredients, where the percentages are by weight or mole ratios.

[0045] In some embodiments, these substances or combinations thereof and the one or more other drugs are prepared or designed for sequential administration, simultaneous administration, sequential administration, alternating administration, spaced administration, or separate administration.

[0046] In some embodiments, the abnormal ocular development associated with refractive errors is primarily environmentally induced or primarily man-made (e.g., prolonged close reading, frequent use of electronic screens, lack of distance vision due to constant close focus, improper use of corrective glasses, side effects from medications, obesity, trauma, insufficient lighting in the learning environment, lack of outdoor exercise) during the individual's early childhood (e.g., 2-28 years of age in humans), and genetic factors are secondary, concomitant, or cooperating factors; or the abnormal development is a refractive malformation completely unrelated to genetic factors, characterized primarily by the fact that parallel light rays pass through the refractive system of the eye and are refracted to a focus in front of the retina under relaxed accommodation.

[0047] In some embodiments, the bendazac lysine or bendazac analogues or derivatives thereof is one of the following compounds (a)-(c):

[0048] (a) [ka] R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0049] (b) [ka] Here, R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0050] (c) [ka] Here, R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0051] In some embodiments, the compound is administered systemically (e.g., orally, by intravenous infusion), or topically (e.g., by eye drop, intravitreal injection, or application of a skin rub or ointment, preferably a 3% skin rub or eye ointment), or parenterally (e.g., mucosally, transdermally, or by microneedle administration), or non-invasively (e.g., by applying an eye ointment to the cornea or by placing the compound in a pouch formed by pressing the lower eyelid back), or by a non-invasive method (e.g., by eye spray).

[0052] In some embodiments, the administration methods (e.g., eye drops, oral) are used simultaneously, in combination, alternating, spaced apart, or singly, or any combination thereof.

[0053] In some embodiments, formulations used for topical administration include, but are not limited to, aqueous solutions, oily solutions, or suspensions. The formulations may contain pharmacologically and / or physiologically active ingredients, such as mydriatic ingredients, decongestant ingredients, ocular muscle (e.g., ciliary muscle) regulating ingredients, anti-inflammatory ingredients, astringents, antihistamine ingredients, anti-allergic ingredients, hepatoprotective ingredients (to avoid or reduce liver toxicity), ingredients that enhance the blood-retinal barrier (making it difficult for compounds to penetrate the physiological barrier), local anesthetic ingredients, glaucoma treatment ingredients, and cataract treatment ingredients.

[0054] In some embodiments, the concentration or ratio of these substances or combinations thereof in the drug composition, formulation, or device is at least 0.01% or more, preferably 0.01% to 0.8%, preferably 0.05% to 0.5%, more preferably 0.1%, or the concentration or ratio of these substances or combinations thereof is less than 0.01%, wherein the percentage is expressed as a mass / volume concentration (ratio) or a mass ratio or a molar ratio, and preferably the concentration is a working concentration or a storage concentration.

[0055] In some embodiments, the concentrations of these substances or combinations thereof are, for example, 0.01%-0.05%, 0.05%-0.1%, 0.1%-0.5%, where the percentages are expressed as mass / volume concentrations (ratios), and preferably the concentrations are working or storage concentrations.

[0056] In some embodiments, the drug composition or formulation may be in the form of an injection, tablet, freeze-dried injection, capsule, effervescent tablet, chewable tablet, troche, granule, ointment, syrup, oral liquid, spray, nasal drops, topical preparation, oral preparation, etc., and is preferably in the form of an ophthalmic dosage form, including, but not limited to, eye drops (eye drops), eye ointment, eye spray, implant sheet, eye gel, eye pack, ophthalmic microsphere, ophthalmic sustained-release preparation, periocular injection, or intraocular injection, and may further be in the form of a free solution, oil-water mixture, suspension, rub, lotion, cream, drops, granular preparation, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0057] In some embodiments, the myopic individual or the individual prone to developing myopia is a human being, and may be a child, adolescent, middle-aged or elderly person, preferably between 3 and 26 years of age, more preferably between 6 and 18 years of age, or an adult or adolescent, preferably a person whose eyes are in the growth and development stage, or a school-age person, preferably a person in grades 1 to 12.

[0058] In some embodiments, the myopia is refractive or axial myopia; congenital myopia (myopia acquired at birth or before school age), early-onset myopia (before age 14), late-onset myopia (ages 16-18), late-onset myopia (ages 16-18), late-onset myopia (ages 16+), low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia, semi-true semi-pseudo (mixed) myopia; child and / or adolescent myopia (preferably ages 3-26). axial myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); axial myopia in school-age and pre-school populations; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); axial myopia in school-age and pre-school populations; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); more preferably, those aged 3-26 years, more preferably, those aged 6-18 years); progressive myopia in children and / or adolescents (preferably, those aged 3-26 years, more preferably, those aged 6-18 years); refractive myopia, exponential myopia, myopia due to forward displacement of refractive mediation, flexional myopia; myopia caused by prolonged eye use in close work, myopia and pseudomyopia caused by eye fatigue, negative refractive index caused by side effects of medication, myopia caused by reading, myopia caused by use of electronic products such as mobile phones, myopia caused by mismatch of refractive media (components), refractive myopia, myopia caused by abnormal refractive development, myopia caused by excessive growth of the eyeball, myopia caused by poor eye hygiene, myopia in which the focus of distant objects is in front of the retina due to various factors, and in which atropine treatment is ineffective or ineffective, myopia caused by lack of outdoor exercise, accommodative myopia, childhood myopia, and myopia caused by environmental factors.

[0059] In some embodiments, the myopia may or may not include myopia due to lens pathology or myopic symptoms.

[0060] In some embodiments, myopia-related symptoms or physical signs include myopia complications such as, for example, high myopia complications, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal breaks, amblyopia, submacular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field defects, gradual or sudden decrease in vision (especially near vision), eye swelling and / or pain, night blindness, astigmatism, refractive index variation, blindness, vitreous liquefaction, vitreous opacification, strabismus, frequent blinking, frequent eye rubbing, refractive index variation, blurred vision when looking at distant objects and needing to squint or partially close the upper eyelid to see distant objects clearly, headache due to eye strain, difficulty seeing while driving, especially at night (dusk myopia), retinal atrophic degeneration (bleeds and breaks), subretinal neovascularization, and ocular atrophy.

[0061] In some embodiments, the pharmaceutical composition, formulation, or device further comprises a medical formulation or drug, and the medical formulation or drug is a myopia treatment (e.g., atropine, bendazole, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), aminobenzylamine, timolol maleate, adrenaline, pirenzepine, perazine, perlapine, methylamine, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (e.g., M receptor blockers, These include, but are not limited to, steroid hormone receptor antagonists (blockers, antagonists, or inhibitors targeting these receptors), polyunsaturated fatty acids (e.g., DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenylate antagonists, vasodilators, mydriatics, smooth muscle dilators, vasospasm inhibitors, collagen metabolism regulators, antiallergic drugs, anti-inflammatory drugs, liver protectors, ophthalmic disease treatment ingredients, local anesthetics for the eye, or ophthalmic agents.

[0062] In some embodiments, the drug composition, formulation, or device further comprises a medical preparation or drug, and the medical preparation or drug comprises bendazac or various salt forms thereof, or bendazac-ricin or various salt forms thereof. This means that these drug compositions, formulations, or devices ultimately form a combination form of "bendazac or various salt forms thereof" and bendazac-ricin, or its optical isomer, or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog, or its derivative, or its crystalline compound, or that these drug compositions, formulations, or devices ultimately form a combination form of "bendazac-ricin or various salt forms thereof" and bendazac, or its optical isomer, or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog, or its derivative, or its crystalline compound.

[0063] In some embodiments, the medical preparation or drug may be administered synchronously with the drug composition, formulation, or device, for example, specifically, administered simultaneously or before or after, on the same day, on the same week, in the same month, or in the same year, or alternately at intervals, for example, every 4 hours, every 12 hours, every other day, every other week, every other month, or every other year, for example.

[0064] In some embodiments, the one or more other drugs are a myopia treatment (e.g., atropine, bendazole, pirenzepine, muscarinic antagonists, 7-methylxanthine (7MX), pirenzepine, aminobenzylamine, timolol maleate, adrenaline, perazine, perlapine, pirenzepine, methylamine, chlorisondamine, acetylcholinesterase inhibitors, dopamine agonists, gamma-aminobutyric acid, naloxone, glucagon, retinoic acid, etc.), M receptor blockers (e.g., blockers or antagonists directed at M3 receptors, or inhibitors), polyunsaturated fatty acids (e.g., DHA, EPA), salidroside, formononetin, prazosin, homatropine, anisodamine (racemic), tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenylate antagonists, vasodilators, smooth muscle dilators, vasospasm inhibitors, collagen metabolism regulators, anti-allergic agents, anti-inflammatory agents, liver protectors, ophthalmic disease treatment ingredients, ophthalmic local anesthetics, mydriatics, or ophthalmic agents or drugs.

[0065] In some embodiments, the one or more other drugs may include bendazac or various salt forms thereof, or bendazac-ricin or various salt forms thereof. This means that when these substances according to the present application are used in combination with these drugs, the final combination of "bendazac or various salt forms thereof" and bendazac-ricin, or its optical isomer, or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog, or its derivative, or its crystalline compound, can be adopted; or when these substances according to the present application are used in combination with these drugs, the final combination of "bendazac-ricin or various salt forms thereof" and bendazac, or its optical isomer, or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its analog, or its derivative, or its crystalline compound, can be adopted.

[0066] In some embodiments, the conjoint use refers to the synchronous administration of the one or more other drugs, specifically, administration at the same time or before or after, on the same day, on the same week, on the same month, or on the same year during a single administration (treatment) course, or administration alternating at intervals, for example, alternating every 4 hours, alternating every 12 hours, alternating every other day, alternating every week, alternating every month, or alternating every other year.

[0067] In some embodiments, the formulation may further be an oral product such as a health product, food, supplement, nutritional product, beverage, or cosmetic product, wherein the cosmetic product may be one or more of a free solution, an oil-water mixture, a suspension, a rub, a lotion, a spray, a cream, drops, a granular formulation, an ointment, a paste, a pill, a suppository, an emulsion, and a patch.

[0068] In some embodiments, the device is a device, consumable, system, medical instrument, health-related product, or ocular appearance-altering device capable of releasing a drug or having a drug delivery function or potential drug delivery capability, such as a corneal contact lens, eyeglasses, intraocular lens, suture, orthokeratology lens cleaning (maintenance) system, eye pack, eye pack, colored contact lens, microneedle, ocular spray system, eye massager (for myopia), ocular fumigation device, ocular surface drug delivery device, intraocular drug delivery device, ocular fundus drug delivery device, implant pump, wearable device, acupressure massager, eye relaxation device, myopia treatment device, or drug-device combination product for myopia prevention and control. In some embodiments, the device may be referred to as an ophthalmic device.

[0069] Terms and Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. The terms used herein are merely for the purpose of describing specific examples and are not intended to limit this application. The terms "comprise" and "have" and any variations thereof in the specification and claims of this application and the description of the drawings above are intended to be non-exclusive inclusive. As used herein, "one or more" means that at least one of the element is present; unless otherwise expressly specified, more than one of such element may be present.

[0070] In the description of this application, the term "and / or" is merely used to explain the relationship between related objects, and means that there may be three types of relationship. For example, A and / or B may include the cases where A exists alone, where A and B exist simultaneously, and where B exists alone. In addition, the symbol " / " in this specification generally means that the related objects before and after it are in an "or" relationship.

[0071] An "example" or "embodiment" referred to in this specification means that a particular feature, structure, or characteristic described in the example (or "embodiment") can be included in at least one example (or "embodiment") of the present application. The appearance of the term in each place in the specification does not necessarily refer to the same example (or "embodiment"), nor is it an example (or "embodiment") that is exclusively independent of or an alternative to other examples (or "embodiments"). It is explicitly or implicitly understood by those skilled in the art that the examples (or "embodiments") described herein may be combined with other examples (or "embodiments").

[0072] As used in this specification and the appended claims, the singular forms "a," "an," and "the" are intended to specifically include plural referents of the terms they refer to, unless the context clearly indicates otherwise. Also, as used herein, the term "or" means "and / or" in its inclusive and not "exclusive" sense, unless otherwise specified.

[0073] As used herein, reference to a range of values ​​for a variable is intended to convey that the application may be practiced with the variable equal to any value within that range. Thus, for an inherently discrete variable, the variable may be equal to any integer value within that value range, including the end-points of the range. Similarly, for an inherently continuous variable, the variable may be equal to any real value within that value range, including the end-points of the range. As an example, a variable described as having a value between 0 and 2 may be 0, 1, or 2 for an inherently discrete variable, or 0.0, 0.1, 0.01, 0.001, or any other real value for an inherently continuous variable.

[0074] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is unclear to one of ordinary skill in the art, in the context in which the term is used, "about" refers to a value within a range of 10% plus or minus the recited value.

[0075] The terms "individual" and "subject" include human and non-human animals, including, for example, farm animals such as sheep, pigs, cows, and horses, pet animals such as dogs and cats, and laboratory animals such as mice, rats, and non-human primates. In a preferred embodiment, the mammal is a human.

[0076] As used herein, "administering" a compound, formulation, test article, or drug to a subject includes any route by which a compound can be introduced or delivered to a subject to perform its intended function. "Administration" can be accomplished by any suitable route, including, but not limited to, oral, intraocular, intranasal, parenteral (intravenous, intramuscular, intraperitoneal, or subcutaneous), or topical administration. "Administration" includes self-administration and administration by another person.

[0077] In the context of the administration methods herein, "single use" means that only one administration method is used at each step throughout the administration process, but the administration methods may be switched (but not alternated) at different steps in the administration process.

[0078] In the administration methods herein, "selectively use any one of them" means that only one administration route is used throughout the entire administration process and is not changed.

[0079] As used herein, the term "amino acid" includes naturally occurring amino acids, synthetic amino acids, amino acid analogs, and amino acid mimetics that act in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code and those that have been subsequently modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids, e.g., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group. Examples of amino acid analogs include homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics are chemical compounds that have a structure different from the common chemical structure of amino acids but function in a manner similar to naturally occurring amino acids. Amino acids may be referred to herein according to either their commonly known three letter symbols or the one-letter symbols proposed by the IUPAC-IUB Biochemical Nomenclature Commission.

[0080] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, e.g., an amount that prevents or alleviates symptoms associated with an ophthalmic disease. The amount of the composition administered to a subject depends 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 degree, severity, and type of disease and the treatment method determined by a specialist (e.g., a physician). A skilled artisan can determine the appropriate dose based on these and other factors. The pharmaceutical composition may also be administered in combination with one or more other therapeutic compounds, biological agents, and therapeutic molecules (e.g., polypeptides). In the methods described herein, bendazac, bendazac lysine compounds, or pharmaceutical compositions containing the same can be administered to a subject with one or more symptoms or syndromes of an ophthalmic disease. For example, a "therapeutically effective amount" of bendazacrylamide is an average level to minimize the physiological effects of an ophthalmic disease, preferably an average level to minimize and control the physiological effects of myopia progression.

[0081] As used herein, the terms "formulation," "drug composition," and "composition" can be used interchangeably and can refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation," "drug composition," and "composition" can be used to refer to a mixture of one or more active agents (active ingredients) with a carrier or other excipient. A composition can take any physical form, including most solids, liquids (e.g., solutions), or gases.

[0082] The term "dosage form" may include one or more formulations or compositions provided in a form suitable for administration to a subject. For example, an injectable dosage form may be a formulation or composition manufactured in a manner suitable for administration by injection.

[0083] As used herein, the term "pharmaceutically acceptable" means approved for use in animals, preferably humans, by a regulatory authority, e.g., CFDA (China), EMEA (Europe) and / or FDA (US) and / or any other country regulatory authority.

[0084] As used herein, an "ophthalmologically acceptable carrier" is an ophthalmologically acceptable solvent, suspending agent, or vehicle for application of a drug composition to the eye of a subject. The carrier may be solid or liquid. The carrier is "ophthalmologically acceptable" in some sense, i.e., the carrier is suitable for administration to the eye without causing any significant adverse effects.

[0085] As used herein, the term "simultaneous" refers to the administration of at least two active ingredients at the same time or substantially the same time when administered for treatment, via the same or different routes (e.g., oral or ophthalmic), or at the same time or substantially the same time and surgery, or at the same time or substantially the same time and the use of a therapeutic device.

[0086] As used herein, the term "single" refers to administration of one substance, such as one active ingredient, at the same time or substantially the same time when administered for treatment.

[0087] As used herein, the term "sequential administration" refers to the administration of at least two active ingredients at different times during treatment, and the administration routes may be the same or different. More specifically, "sequential administration" refers to the complete administration of one of the active ingredients before the administration of the other active ingredient. Thus, one active ingredient may be administered a few seconds, minutes, hours, or days before the administration of the other active ingredient.

[0088] As used herein, the terms "treat," "control," "inhibit," "delay," "reduce," "prophylactic control," "prevent," or "slow" refer to therapeutic treatments, prophylactic, or preventative measures aimed at preventing or alleviating (alleviating) a target disease or disorder, and even eliminating or reversing it. For example, a subject's ophthalmic disorder is successfully treated if, after receiving a therapeutic amount of a bendazacricin compound or a pharmaceutical composition containing the same according to the methods described herein, the subject exhibits observable and / or measurable avoidance, reduction, or elimination of one or more symptoms and syndromes of the ophthalmic disorder, or a slowing of the progression of the condition. It should be further understood that the various patterns of treating or preventing medical conditions described herein are intended to refer to "significant," including complete treatment or prevention, as well as non-complete treatment or prevention in which a specific biologically or medically relevant result is achieved. For example, in some embodiments, "treatment" does not require 100% elimination or prevention of myopia or myopic symptoms. In some embodiments, "treatment" of myopia or myopia-related symptoms with the methods of the present application includes, for example, reducing, inhibiting, blocking, preventing, and / or reversing myopia or myopia-related symptoms by at least about 5%, at least about 10%, or at least about 20%, compared to levels observed in the absence of a composition or method of the present application (e.g., a biologically compatible control subject, individual, or specimen not exposed to a composition or compound of a method of the present application). In some embodiments, myopia or myopia-related symptoms are treated by at least about 30%, at least about 40%, at least about 50%, or at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more (about 100%), compared to the myopia or myopia-related symptoms in the absence of a compound of a method of the present application.

[0089] The term "(individual) prone to myopia" as used in the specification may refer to a situation in which a decrease in the level of refractive power has already occurred but has not yet reached a negative value, or may refer to a constitution or high-risk group that is predicted or considered by an authoritative organization or a professional physician to be prone to myopia, or may further refer to an individual with a family history of myopia, or may further include a situation in which an individual has ample access to near visual information but lacks opportunities to see far away, or may refer to a situation in which the incidence (prevalence) of myopia, or once myopia has developed, the severity does not fall below the average level, or may refer to a situation in which a decrease in refractive power is included in side effects after administration or risks after surgery, or may refer to a situation in which the individual will become myopic or their refractive power will decrease to 0 or below unless intervention is made with a drug or other myopia treatment (preventive control) means.

[0090] "Ophthalmic composition" or "ophthalmic preparation" or "ophthalmic agent" means an ophthalmic composition, or ophthalmic drug composition, or ophthalmic drug product, or a drug, formulation, cosmetic, health product, drug-device combination product, or pharmaceutical portion of a device for the prevention and / or treatment of ophthalmic disease, the protection, maintenance, or improvement of vision, or the avoidance, reduction, or reversal of vision impairment.

[0091] "Fish oil" refers to an oily substance derived from higher animals, particularly fish (e.g., cod, salmon), squid, and seal, and particularly refers to the polyunsaturated fatty acids therein, including, but not limited to, omega-3 unsaturated fatty acids, DHA, EPA, DPA, ALA, nisinic acid, stearidonic acid, eicosatetraenoic acid, or combinations thereof.

[0092] "Analog" refers to a structural derivative of a parent compound (eg, bendazac or bendazac lysine as referred to in this application) that differs in only one element (including isotope) compared to the parent compound.

[0093] As used herein, the term "derivative" of a compound includes any molecule related to the function and / or structure of said compound, such as acids, amides, esters, ethers, acetylated, hydroxylated, or alkylated (C1-C6) variants of said compound, halides, deuterated derivatives, etc. Derivatives should have a Tanimoto coefficient with the parent drug of greater than 0.4, preferably greater than 0.5, more preferably greater than 0.6, and more preferably greater than 0.7. The Tanimoto coefficient is widely used to measure the degree of structural similarity between two molecules. The Tanimoto coefficient can be calculated using software such as Small Molecule Subgraph Detector, available online (http: / / www.ebi.ac.uk / thornton-srv / software / SMSD / ). Preferred derivatives should be structurally and functionally related to the parent compound, i.e., they should retain at least part of the activity of the parent drug, e.g., bendazac lysine derivatives or analogs described in the reference "Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents" (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010). More preferably, they should have a modulating effect on refractive development. The term "derivative" also includes drug metabolites, which are produced, for example, by (biochemical) modification or processing of the drug after administration of the molecule to an organism, usually by specialized catalytic systems, and which exhibit or retain the biological activity of the drug. It has already been disclosed that metabolites are responsible for most of the therapeutic effects of the parent drug.

[0094] As used herein, a "metabolite" is a modified or processed drug that retains at least some of the activity of the parent drug, preferably having an inhibitory effect on the activity of aldose reductase (AR) or an effect to treat, prevent, or slow the progression of myopia and related conditions.

[0095] As used herein, the term "therapeutically acceptable salts" refers to salts or zwitterionic forms of the compounds disclosed herein, which are water- or oil-soluble or dispersible and therapeutically acceptable, as defined herein. Salts can be prepared during the final isolation and purification of the compounds, or can be prepared separately by reacting the appropriate free base form of the compound with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, glucarate, formate, fumarate, gentisate, glutarate, glycerol phosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, and methyl. Mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate salts. Additionally, basic groups in the compounds disclosed herein can be quaternized using methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl ester, dibutyl, and diamyl; decyl, lauryl, myristyl, and sterol chlorides, bromides, and iodides; and benzyl and phenylethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (e.g., oxalic acid, maleic acid, succinic acid, and citric acid).Salts can be formed by coordination of the compounds with alkali metal or alkaline earth metal ions. Thus, the present application includes sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0096] "These substances" as used in this application refer to bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analogue or derivative thereof, or a crystalline compound thereof.

[0097] Myopia is the condition in which parallel light rays, after passing through the refractive system of the eyeball under a relaxed state of accommodation, are focused in front of the retina. Depending on the refractive factor, it can be divided into refractive myopia and axial myopia. Clinical manifestations of both conditions are poor and blurred vision at distances and good vision at near distances. Myopia often exhibits fluctuations in distance vision in the early stages, with little or no accommodation required for near vision, resulting in a corresponding weakening of the focusing function and a tendency to develop exotropia or exotropia. Myopia-related symptoms also include decreased night vision, floaters, and scintillating scotoma. Various degrees of fundus changes may occur, including the formation of a conus, macular hemorrhage, or subretinal neovascularization; irregularly shaped white atrophic spots; or round, dark spots due to pigmentation (Fuchs spots); lattice and cystic degeneration of the retina at the periphery. At a young age, vitreous liquefaction, opacification, and posterior vitreous detachment may occur, putting patients at a higher risk of retinal tears and detachments than normal individuals. The anterior-posterior diameter of the eyeball is long, the eyeball protrudes, and the posterior pole of the eyeball expands, forming scleral staphyloma, and the condition with the above clinical symptoms is called pathological myopia.

[0098] Myopia may be a severely weakening eye condition. The underlying defect (risk) of myopia is that the eyeball is slightly elongated, causing the lens to focus light rays from distant objects slightly in front of the retina. Therefore, myopia is usually referred to as foreshortening or near-sightedness. In severe cases, this elongation of the eyeball can stretch and thin certain parts of the interior of the eye, increasing the risk of retinal detachment, cataracts, glaucoma, and blindness. Therefore, myopia is much more serious than pure foreshortening.

[0099] Myopia involves axial elongation of the eye and affects the majority of people. The onset of myopia usually occurs during elementary school age and progresses until the eye's growth is complete. Even with the availability of corrective lenses, the progression of myopia can still increase visual defects. The present application recognizes the importance of pharmaceutical compositions and therapies for treating, preventing, prophylactically controlling, suppressing, inhibiting, decelerating, delaying, retarding, reducing, slowing down, and / or mitigating the onset and progression of myopia, and in particular, provides pharmaceutical compositions, devices containing or delivering the pharmaceutical compositions, and methods of use thereof that simplify administration or implementation, reduce potential side effects, and provide therapeutic efficacy or a combination thereof.

[0100] Academics have investigated various factors that contribute to myopia, such as genetic susceptibility, extended paperwork or screen time, and exposure to insufficiently bright light. Regardless of the underlying cause of myopia in a given situation, which may be any or multiple of the factors listed above, all individuals affected by this condition will experience weakened eyeballs associated with myopia. During childhood and school age, the eyes grow, and myopia typically develops in school-age children and adolescents and accompanies these individuals throughout their lives. Therefore, proactive interventional treatment for individuals, such as school-age children and adolescents, can improve the quality of life of these individuals during their youth and throughout their remaining lives.

[0101] A "myopic individual" or "individual prone to myopia" is a child, adolescent, middle-aged or elderly person, preferably a person aged 3 to 26, more preferably a person aged 6 to 18, or a minor, preferably a person whose eyes are in the growth and development stage, or a school-age person, preferably a person in grades 1 to 12.

[0102] In this specification, there is no distinction between the concepts represented by the terms "myopia" and "nearsightedness", and they are interchangeable. Researchers in the field should accurately understand the meaning of "myopia" or "nearsightedness" in this application based on the context in which it exists.

[0103] Specific types of "myopia" include refractive or axial myopia, congenital myopia (myopia acquired from birth or before school age), early-onset myopia (under age 14), late-onset myopia (ages 16-18), late-onset myopia (ages adult and older); low myopia (mild myopia), moderate myopia, high myopia (severe myopia); pseudomyopia, true myopia; child and / or adolescent myopia (preferably in people aged 3-26, more preferably in people aged 6-18), juvenile myopia, adult myopia, geriatric myopia; simple myopia, pathological myopia; simple axial myopia, simple axial myopia; child and / or adolescent myopia axial myopia in school-age and pre-school children; primary myopia, secondary myopia; primary myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); or progressive myopia in children and / or adolescents (preferably in people aged 3-26, more preferably in people aged 6-18); myopia caused by prolonged eye use in close work, myopia and pseudomyopia caused by eye fatigue, negative refractive power caused by drug side effects, and myopia.

[0104] "Axial myopia" is a type of myopia in which the anterior-posterior diameter of the eyeball is too long (the axial length exceeds the normal range, causing misalignment with other refractive components), but the refractive power (the refractive performance of other refractive components of the eye, such as the cornea and lens) is basically within the normal range.

[0105] "Refractive myopia" is myopia in which the axial length is basically within the normal range, but is caused mainly by a change in the refractive performance of the refractive component.

[0106] "Pathological myopia," also known as degenerative myopia, is a degenerative disorder of the fundus of the eye. Patients typically have a high myopic refractive power (generally greater than 600 degrees), significant visual impairment, and worse hyperopia. Abnormalities in visual field, light perception, and contrast perception are also common, and symptoms such as night vision loss (night blindness), floaters, and scintillating scotoma are often present. This type of myopia is characterized by obvious pathological changes in the fundus of the patient's eye, including thinning and atrophy of the retinal pigment epithelium, choroidal neovascularization and retinal detachment, and macular degeneration. In severe cases, this condition can lead to blindness.

[0107] "Simple myopia" is a condition that often develops during school age and gradually stabilizes once development stops. The myopia is 600 degrees or less, and there are generally no obvious pathological changes in the fundus. It is also called acquired myopia. This type of progressively developing myopia can be successfully corrected with appropriate lenses, and most other visual function indicators are normal.

[0108] "Primary myopia" is myopia of unknown cause, where the etiology and mechanism of onset cannot be identified using existing diagnostic techniques. It is described as a non-transient functional-structural change that exhibits myopia specificity during the onset and progression of the condition. It includes congenital myopia and acquired simple myopia.

[0109] "Concurrent / secondary myopia" refers to transient myopia caused by impaired eye accommodation due to the effects of internal and external factors, or abnormal refractive index (e.g., toxic myopia, drug-induced myopia, traumatic myopia, diabetic myopia, and myopia due to early cataracts). Most of these myopias have clear triggering factors and are characterized by repeated changes in vision. This type of myopia is common among the elderly.

[0110] "Simple axial myopia" is also called simple axial myopia. It is a type of simple myopia characterized by an image focus in front of the retina due to elongation of the eye axis and / or an increase in the depth of the vitreous cavity. This type of myopia is most common in children and adolescents, and is most common in people aged 2 to 30.

[0111] "Progressive myopia" is a type of myopia in which refractive power continually decreases with time or with increasing individual age, and such myopia, if not intervened, generally eventually progresses to high myopia.

[0112] "Moderate myopia" is usually between 300 and 600 degrees.

[0113] "Refractive myopia" is myopia that is simply due to an increased curvature of the cornea or lens.

[0114] "Index myopia" is myopia caused by an increase in refractive power due to an increase in the refractive index of the aqueous humor and crystalline lens, and belongs to refractive myopia.

[0115] "Accommodative tonic myopia" is myopia caused by the strain on the eyeball when looking at a nearby object, or by accommodation tonicity or accommodation spasm due to excessive adjustment of the ciliary muscles.

[0116] "Myopia due to lens lesions" is a type of myopia in which the structural parameters or internal structure of the lens change due to the denaturation of lens proteins, which in turn changes some physical properties such as thickness, hardness, and refractive index, and further causes parallel light rays to be focused in front of the retina after passing through the diseased lens.

[0117] "Distance vision," also known as unaided distance vision, is medically measured at a distance of 5 m horizontally from an eye chart, with the eyes open normally and looking straight ahead, without wearing glasses or any assistive devices that enhance vision (e.g., framed glasses, contact lenses, colored contact lenses, slit glasses, etc.).

[0118] "Myopia-related symptoms" include, for example, complications of myopia such as high myopia, floaters, glaucoma, posterior staphyloma, retinal detachment, retinal breaks, amblyopia, submacular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, visual field defects, gradual or sudden decrease in vision (especially near vision), eye swelling and / or pain, night blindness, astigmatism, refractive index variation, blindness, vitreous liquefaction, vitreous opacification, strabismus, frequent blinking, frequent eye rubbing, refractive index variation, blurred vision when looking at distant objects and the need to squint or partially close the upper eyelid to see distant objects clearly, headache due to eye strain, difficulty seeing while driving, especially at night (dusk myopia), retinal atrophy and degeneration (bleeds and breaks), subretinal neovascularization, and ocular atrophy.

[0119] "Abnormal eye development" refers to abnormal eye size development in children and adolescents (e.g., 3-26 years of age), characterized by excessively long axial lengths that result in the image being focused in front of the retina after parallel rays of light pass through the normal refractive system of the eye, or by developmental abnormalities primarily induced by environmental factors or primarily caused by human factors (e.g., prolonged reading or close work, frequent use of electronic screens, lack of opportunity to see distances due to continuous near vision, improper use of corrective glasses), with a secondary, concomitant, or cooperating genetic factor, or by the abnormal development being completely unrelated to genetic factors.

[0120] Regarding "bendazac lysine," its chemical name is L-lysine (1-benzyl-1H-indazol-3-oxy) acetate, and its molecular formula is CH 14 N2O2·C 16 H 14 It is N2O3, has a molecular weight of 428.49, and has the following structural formula:

[0121] [ka]

[0122] "Bendazac" has the following structural formula:

[0123] [ka]

[0124] "Bendazac or bendazacricin derivatives" includes optical isomers, racemates thereof, and metabolic products thereof (e.g., 5-hydroxybendazac), and may further include, but are not limited to, those listed by Hong Shen et al. (Bioorganic & Medicinal Chemistry Letters, 20, 2115-2118, 2010). Commercially available bendazacricin-containing ophthalmic solutions (e.g., National Pharmaceutical Standards H20063847) may be used, or bendazacricin and its derivatives may be prepared using processes well known to those skilled in the art. One exemplary preparation method includes the following three steps: The synthesis process includes the following steps: a first synthesis step in which phenylhydrazine is used as a starting material and is subjected to a benzyl group reaction with benzyl chloride to obtain α-benzylphenylhydrazine; a second synthesis step in which α-benzylphenylhydrazine is reacted with urea at high temperature to form a ring to obtain 3-hydroxy-1-benzelindazole; a third synthesis step in which 3-hydroxy-1-benzelindazole is subjected to a carboxymethylation reaction with chloroacetic acid to obtain bendazac, i.e., α-[(1-benzyl-1H-indazol-3-yl)oxo]acetic acid; and a fourth synthesis step in which bendazac and L-lysine are subjected to a salification reaction in tetrahydrofuran, followed by recrystallization from ethanol to obtain the final product, bendazac lysine.

[0125] "Bendazac lysine or bendazac analogues or derivatives thereof" refers to, for example, the following (a)-(c):

[0126] (a) [ka] , where R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0127] (b) [ka] Here, R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0128] (c) [ka] Here, R1 is H, P (protium), D (deuterium), T (tritium), p-CH3, mF, m-Cl, or p-Cl, and R2 is H, P (protium), D (deuterium), T (tritium), K, or Na.

[0129] "Preparation" refers to oral products such as health products, foods, supplements, nutrients, drinks, etc., or cosmetics, and the cosmetics may be one or a combination of free solutions, oil-water mixtures, suspensions, rubs, lotions, sprays, creams, drops, granules, ointments, pastes, pills, suppositories, emulsions, and patches.

[0130] "Device" means an instrument, device, consumable product, system, medical instrument, health-related product or ocular appearance-altering product that is capable of releasing a drug or has a drug delivery function or potential drug delivery capability, such as a corneal contact lens, eyeglasses, intraocular lens, suture, orthokeratology lens cleaning (maintenance) system, eye pack, eye brightening pack, colored contact lens, microneedle, ocular spray system, eye massager (myopic massager), ocular fumigation device, ocular surface drug delivery device, intraocular drug delivery device, ocular fundus drug delivery device, implant pump, wearable device or drug-device combination product for the prevention and control of myopia.

[0131] The "sole or main active ingredient" referred to in this application means that other than bendazacricin or bendazac, or its optical isomers or racemates or solvates or pharmaceutically acceptable salts or prodrugs or metabolites or analogs or derivatives or crystalline compounds thereof, or a combination of these substances, it does not contain or contains only a small amount of other active substances for treating myopia. For example, the content of bendazacricin or bendazac, or its optical isomers or racemates or solvates or pharmaceutically acceptable salts or prodrugs or metabolites or analogs or derivatives or crystalline compounds thereof, or a combination of these substances, accounts for 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% of all active ingredients, and the percentages are expressed as mass ratios or molar ratios. or bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or an analogue thereof, or a derivative thereof, or a crystalline compound thereof, or a combination of these substances, contributes 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% of the efficacy of the drug for treating myopia during administration.

[0132] Drug combination therapy is a powerful strategy widely used in medicine, aiming to achieve synergistic therapeutic effects, reduce dosage and toxicity, and minimize or delay the induction of drug resistance (Chou TC., "Drug combination studies and their synergy quantification using the Chou-Talalay method," Cancer Research (2010) 70: 440-6). The present disclosure identifies compounds such as bendazacrylamide for the treatment, prevention, or alleviation of myopia and its related symptoms, enhancing the effect of reducing myopia (power) or slowing the progression of myopia (process), while avoiding or minimizing side effects such as those observed with atropine therapy. The drug composition of the present application has a technical effect superior to atropine in the treatment, prevention, or alleviation of myopia and its related symptoms, and, apart from improving refractive index, no side effects such as photophobia or pupil dilation were observed during experiments. During the experiment, no discomfort or abnormal ocular phenomena were observed in any of the administered animals, and furthermore, based on the existing clinical applications of bendazacricin or bendazac, it is believed to have good drug safety for use in clinical treatment processes for the treatment, prevention or improvement of myopia and its related symptoms.

[0133] Through experiments, it has been unexpectedly discovered that bendazac and bendazac-lysine can significantly delay the process of negative refractive power in morphological deprivation guinea pig and concave lens-induced guinea pig myopia model, and significantly inhibit the elongation of the eye axis.Based on this, it has been proven that bendazac and its salt compounds have the effect of treating, preventing or controlling the progression of myopia in animals, especially humans, such as school-age children, adolescents or young adults.

[0134] The present application provides a method for treating or preventing myopia and its associated symptoms in a subject, comprising administering to the subject a therapeutically effective amount of bendazac, bendazac lysine, and / or therapeutically acceptable salts and derivatives thereof. Preferably, the bendazac or bendazac lysine is administered alone, preferably, the bendazac and / or bendazac lysine is administered simultaneously with 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 into an ophthalmic formulation, preferably, the ophthalmic formulation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmologically acceptable carrier.

[0135] The present application simultaneously provides a technique and a method for inhibiting the progression of axial myopia by inhibiting axial elongation, the technique and the method comprising administering to a subject a therapeutically effective amount of bendazac, bendazac lysine, and / or therapeutically acceptable salts and derivatives thereof. Preferably, the bendazac or bendazac lysine is administered alone, preferably, the bendazac and / or bendazac lysine is administered simultaneously with 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 into an ophthalmic formulation, preferably, the ophthalmic formulation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmologically acceptable carrier.

[0136] The present application simultaneously provides a technique and a method for reducing myopia, comprising administering to a subject a therapeutically effective amount of bendazac, bendazac lysine, and / or therapeutically acceptable salts and derivatives thereof. Preferably, the bendazac or bendazac lysine is administered alone, preferably, the bendazac and / or bendazac lysine is administered simultaneously with 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 into an ophthalmic formulation, preferably, the ophthalmic formulation further comprises a pharmaceutically acceptable carrier, preferably, the carrier is an ophthalmologically acceptable carrier.

[0137] The present application also provides a far-sightedness improver for a myopic individual, which can improve the far-sightedness of a myopic individual by reducing the distance between the retina and the focal point of distant objects in the eye. The far-sightedness improver includes bendazac, bendazac lysine, and / or therapeutically acceptable salts and derivatives thereof. Preferably, the myopic individual has refractive myopia. Preferably, the myopic individual has axial myopia.

[0138] The present application also relates to pharmaceutical compositions or methods for treating, preventing, or controlling myopia and its associated symptoms in individuals, such as infants, school-age children, adolescents, or young adults. In some embodiments, the subject of treatment with the technical solution of the present application is an adolescent, aged 6-28 years, preferably 6-18 years, and most preferably 12-18 years. In some embodiments, the subject of treatment with the technical solution of the present application is an adult. In some instances, treating, preventing, or controlling myopia and its associated symptoms may include administering a therapeutically effective amount of the pharmaceutical composition or dosage form to a subject in need thereof.

[0139] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a bendazac compound or its salts and derivatives thereof, such as protium, deuterium, and tritium substitutions.

[0140] In other embodiments, in any one or more drug compositions, devices, or treatment methods, the drug composition comprises at least one substance selected from the group consisting of bendazac or a therapeutically acceptable salt thereof (e.g., bendazac ricin) or a derivative thereof, or the drug composition comprises bendazac ricin or a therapeutically acceptable salt thereof or a derivative thereof, preferably comprising bendazac and bendazac ricin simultaneously, preferably comprising bendazac ricin and bendazocone calcium hydrogen phosphate simultaneously, preferably comprising bendazocone calcium hydrogen phosphate, preferably further comprising a pharmaceutically acceptable carrier, and preferably the device delivers the drug composition in a sustained release manner.

[0141] In some embodiments of the drug compositions, devices, or methods of treatment disclosed herein, the subject (patient) is treated for a period of time ranging from about 0.5 months to 20 years, e.g., 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.

[0142] In another embodiment, according to any one of the above embodiments and any one or more of the pharmaceutical compositions, devices, or methods of treatment in other embodiments herein, the pharmaceutical composition is an aqueous composition, preferably the aqueous composition has an osmolality similar to or matching that of tears, or the pharmaceutical composition is an ophthalmic composition (e.g., a topical ophthalmic composition) or ophthalmic formulation, preferably the ophthalmic formulation is an aqueous ophthalmic formulation, an ophthalmic gel formulation, an ophthalmic emulsion, an ophthalmic liposome, an ophthalmic ointment (preferably the ophthalmic ointment is an eye drop ointment, preferably the ophthalmic ointment comprises petrolatum or liquid paraffin), or the pharmaceutical composition is an eye drop formulation, an ophthalmic spray formulation, a topical formulation, a nanogranular suspension, or a nanowafer, a sustained-release formulation, or a subconjunctival reservoir, etc.

[0143] In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an aqueous ophthalmic formulation, such as eye drops. For example, the aqueous ophthalmic formulations described herein may be administered as drops in an eye dropper bottle. In some embodiments, the aqueous ophthalmic formulations may be administered as a single dosage (i.e., a single dose) and may include one, two, three, or more drops that are instilled into a patient's eye. In some embodiments, one dose of the aqueous ophthalmic formulations described herein is one drop of the aqueous composition from the eye dropper bottle.

[0144] In some embodiments, the pharmaceutical composition disclosed herein may be an ophthalmic gel formulation. For example, the ophthalmic gel formulation may be administered as drops in an eye dropper bottle. In some embodiments, the ophthalmic gel formulation may be administered as a single dosage (i.e., a single dose) and may include one, two, three, or more drops to be instilled into a patient's eye. In some embodiments, one dose of the ophthalmic gel described herein is one drop of the gel composition from the eye dropper bottle.

[0145] In some embodiments, the drug composition disclosed herein may be an ophthalmic ointment formulation. For example, the ophthalmic ointment formulation may be contained in a tube or other crushable container having a dispensing nozzle for delivering a strip of ointment therethrough. In some embodiments, the ophthalmic ointment formulation may be administered as a single dosage (i.e., a single dose) and may include one or more tubes that are placed in the patient's eye. In some embodiments, a dose of ophthalmic ointment is a single tube of ointment composition dispensed by a dispensing nozzle.

[0146] In other embodiments, the drug composition is an ophthalmic drug composition contained within a contact lens blister pack.

[0147] In other embodiments, the pharmaceutical composition is administered by a non-invasive route of administration.

[0148] According to any one of the above embodiments and any one or more of the pharmaceutical compositions, devices, or methods of treatment in other embodiments herein, in other embodiments, the device is preferably an ophthalmic device, e.g., one that is placed on or within the eye. The device can provide optical correction. Devices include, but are not limited to, colored contact lenses, contact lenses, ocular inserts, corneal onlays, corneal inlays, nanowafers, liposomes, nanogranules, punctal onlays, or hydrogel matrices with microfluid reservoirs.

[0149] In other embodiments, the drug composition is a sustained release formulation contained within a device.

[0150] In other embodiments, the drug composition is contained within a device.

[0151] In other embodiments, the drug composition is an ophthalmic composition, and said ophthalmic composition is contained within a device.

[0152] In other embodiments, the device must contain or can deliver a drug composition to the corresponding target tissue for the treatment of myopia.

[0153] In other embodiments, the device delivers the drug composition in a sustained release manner.

[0154] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of an ophthalmic disease or condition.

[0155] In another embodiment, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of pre-myopia, myopia (ocular) or myopia progression.

[0156] In another embodiment, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of high myopia, moderate myopia, or low myopia.

[0157] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of axial myopia or refractive myopia.

[0158] In other embodiments, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of an individual (patient) diagnosed with pre-myopia (or at risk of developing myopia or prone to developing myopia).

[0159] In other embodiments, the drug composition is distributed essentially uniformly throughout the device.

[0160] In other embodiments, the device is contained within a contact lens blister pack.

[0161] In other embodiments, the drug composition is impregnated within a device within a contact lens blister pack.

[0162] Any method known to those skilled in the art can be used to contact cells, organs, or tissues with a compound such as bendazac or bendazac-lysine. Suitable methods include in vitro methods, indirect in vivo methods, or in vivo methods. In vivo methods typically involve administering the bendazac and / or bendazac-lysine compounds of the present application or a pharmaceutical composition containing the same to a mammal, preferably a human. When used internally for treatment, the bendazac and / or bendazac-lysine compounds or a pharmaceutical composition containing the same can be administered to a subject in an effective amount (i.e., a desired therapeutically effective amount). The dosage and administration form will depend on the severity of the subject's ophthalmic disease, the subject, and the subject's medical history.

[0163] The compounds disclosed herein may 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). A prodrug of a compound described herein is a modified form that readily undergoes chemical change under physiological conditions to yield the compound. Alternatively, a prodrug can be converted to the compound in an ex vivo environment using chemical or biochemical methods. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are typically useful because, in some cases, they may be easier to administer than the compound or parent drug. For example, they may be orally bioavailable, thereby making them bioavailable, whereas the parent drug may not. A prodrug may also have higher solubility in a drug composition than the parent drug. Many prodrug derivatives are known in the art, such as those that rely on hydrolysis or oxidative activation of the prodrug. One non-limiting example of a prodrug is a compound that is administered as an ester (the "prodrug") but is subsequently metabolized and hydrolyzed to the carboxylic acid (the active entity).

[0164] The compounds disclosed herein can exist as therapeutically acceptable salts, including acid addition salts. Suitable salts include salts formed with organic and inorganic acids, and such acid addition salts are generally pharmaceutically acceptable. They may also be formed as alkali addition salts, which are also pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich, Wiley-VCHA, Zurich, Switzerland, 2002).

[0165] During the final isolation and purification of the compounds, alkali addition salts can be prepared by reacting the carboxyl group with a suitable alkali (e.g., hydroxide, carbonate, or bicarbonate of a metal cation), or ammonia or an organic primary, secondary, or tertiary amine. Cations of therapeutically acceptable salts 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-dibenzylphenylethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines suitable for the formation of alkali addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0166] While the compounds of the present application can be administered as crude chemicals, they can also be provided as pharmaceutical formulations. Accordingly, the present specification provides pharmaceutical formulations comprising one or more specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. By "acceptable," a carrier is meant to be compatible with the other ingredients of the formulation and not deleterious to the recipient. Appropriate formulations are determined by the chosen route of administration. Any known techniques, carriers, and excipients suitable and understood in the art can be used; see, for example, Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be produced by any method known in the art, including conventional mixing, dissolving, granulating, sugar-coating, comminuted, emulsifying, encapsulating, embedding, or pressing processes.

[0167] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, ophthalmic, intranasal, and intraocular) administration, with the optimum route depending, for example, on the condition and symptom of the recipient. The formulations may be conveniently provided in unit dosage form and may be prepared by any method known in the art of pharmacy. In general, these methods include the step of bringing into association a compound of the present application or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0168] Formulations of the compounds disclosed herein suitable for oral administration can be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. The active ingredient can also be presented as a bolus, syrup, electuary or paste.

[0169] Orally usable pharmaceutical preparations include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made by compressing in a suitable machine the optional active ingredient (e.g., powder or granules) in a free-flowing form mixed with an adhesive, inert diluent or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Tablets can optionally be coated or engraved to provide slow or controlled release of the active ingredient therein. The dosage of all formulations intended for oral administration should be compatible with such administration. Push-fit capsules can contain the active ingredient mixed with a filler (e.g., lactose), adhesive (e.g., starch), and / or lubricant (e.g., talc or magnesium stearate), and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol). Stabilizers may also be added. A suitable coating is provided for the dragee core. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, coating solvents, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to identify or characterize various combinations of active compound doses.

[0170] Examples of fillers or diluents used in oral drug formulations (e.g., capsules and tablets) include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, glucose binder (dextrate), dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer (e.g., polyethylene oxide), and hydroxypropyl methylcellulose. The filler may have complexed solvent molecules, for example, when the lactose used is lactose monohydrate.

[0171] Examples of disintegrants used in oral drug formulations (e.g., capsules and tablets) include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, crospovidone (polyvinylpolypyrrolidone), methylcellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0172] Oral drug formulations may also use glidants and lubricants to ensure uniform blending of excipients during mixing. Examples of lubricants include, but are not limited to, calcium stearate, glycerin stearate, glyceryl palmitate stearate, 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 glidants include, but are not limited to, silicon dioxide (SiO), talc, corn starch, and poloxamer. Poloxamer (also 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.

[0173] Examples of tablet adhesives include, but are not limited to, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copolyvidone, methylcellulose, liquid glucose, maltodextrin, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, starch, sucrose, gum tragacanth, and corn protein.

[0174] The compounds can be prepared for parenteral administration via injection, e.g., bullet injection or continuous infusion. Formulations for injection can be provided in unit dosage form, e.g., in ampoules or multi-dose containers with added preservatives. The compositions can be used in the form of suspensions, solutions, or emulsions, such as in oily or aqueous media, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. The formulations can be provided in unit-dose or multi-dose containers, such as sealed ampoules or vials, and can be stored in powder form or lyophilized (freeze-dried) with the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately before use. Injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types. In a preferred embodiment, the pharmaceutical composition of the present application is in the form of an injection, particularly a syringe. The pharmaceutical composition is preferably administered via intraocular injection, more preferably via intravitreal injection into the vitreous body.

[0175] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may also contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may further contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions.

[0176] In addition to the above-mentioned formulations, the compounds can also be prepared as preserved preparations. Such sustained release preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be prepared using suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or can be prepared as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0177] For buccal or sublingual administration, the compositions may take the form of tablets, dragees, tablets or gels prepared in the usual manner. Such compositions may contain the active ingredient in a flavorful matrix (for example, sucrose and gum arabic or gum tragacanth).

[0178] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository matrices such as cocoa butter, polyethylene glycol, or other glycerol esters.

[0179] Some compounds disclosed herein can be administered locally, i.e., non-systemically. This includes administering the compounds disclosed herein to the eye, epidermis, the outside of the mouth, ear, and / or nose, apparently without entering the bloodstream. Conversely, systemic administration includes oral, intravenous, intraperitoneal, and intramuscular administration.

[0180] The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In some embodiments, the active ingredient may comprise 2% to 5% w / w. In other embodiments, it may comprise 0.1% to 2% w / w, preferably 0.1% to 0.5% w / w, of the formulation. In some embodiments, it may comprise 0.01%, 0.05%, 0.1%, 0.25%, or 0.5% w / w of the formulation.

[0181] In some embodiments, the active ingredient for topical administration may comprise, for example, 0.001% w / v to 10% w / v (weight / volume, g / 100 ml) of the formulation. In some embodiments, the active ingredient may comprise as much as 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, preferably 0.1% to 0.5% w / v, of the formulation. In some embodiments, it may comprise 0.01%, 0.05%, 0.1%, 0.25%, or 0.5% w / v of the formulation.

[0182] In a preferred embodiment, formulations for topical administration to the eye or ear in aqueous solution or suspension are in the form of drops. Formulations for topical administration to the nose in aqueous solution or suspension are in the form of drops, sprays, or aerosols. The term "aqueous" generally refers to aqueous formulations in which the formulation contains >50%, more preferably >75%, and especially >90% water by weight. These drops can be delivered in single-dose ampoules, which may preferably be sterile and therefore may be free of antibacterial components. Alternatively, drops can be delivered in multi-dose bottles, which preferably contain a device that extracts any preservatives from the formulation as it is delivered; such devices are known in the art. Solution and suspension formulations can be administered nasally using an atomizer. Nasal delivery of solutions, suspensions, or powders can also be facilitated by propellant-based aerosol systems, including, but not limited to, hydrofluoroalkane-based propellants. Alternatively, the active drug ingredient can be delivered in powder form.

[0183] In certain embodiments, the formulations of the present application are administered twice daily. However, the formulations may be prepared for administration at any dosing frequency, including once weekly, once every 5 days, once every 3 days, once every 2 days, once daily, three times daily, four times daily, five times daily, six times daily, eight times daily, hourly, or more. Depending on the treatment, such dosing frequencies are maintained for different durations. The duration of a particular treatment can extend from a single administration to several months or years.

[0184] Formulations for topical administration in the mouth (e.g., buccal or sublingual) include dragees which comprise the active ingredient in a flavorful matrix (e.g., sucrose and gum arabic or gum tragacanth) and tablets which comprise the active ingredient in a matrix such as gelatin and glycerol or sucrose and gum arabic.

[0185] For administration by inhalation, the compounds can be easily delivered using an insufflator, a nebulizer, a pressurized bag, or other convenient device for delivering an aerosol propellant. The pressurized bag may contain a suitable propellant, such as a hydrofluoroalkane, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. If the aerosol is pressurized, a valve can be provided to deliver a metered amount to determine the dosage unit. Alternatively, for inhalation or insufflation administration, the compounds of the present application can be in the form of a powder composition, for example, a powder mix of the compound and a suitable powder matrix (e.g., lactose or starch). The powder composition can be presented in unit dosage form in, for example, capsules, cartridges, gelatin, or blister packs from which the powder can be administered using an inhaler or insufflator.

[0186] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0187] It should be understood that, apart from the ingredients specifically mentioned above, the formulations may further include other agents conventional to formulation types of note in the art; for example, formulations suitable for oral or nasal administration may include flavoring agents.

[0188] The compound can be administered orally or by injection at a dose of 0.01 to 300 mg / kg per day. The dose range for adults is generally 0.1 mg to 50 mg / day. Tablets or other presentation forms provided in discrete units may easily contain a fixed amount of one or more compounds, which is effective for such a dose or multiples thereof, for example, 0.05 mg to 100 mg, usually about 1 mg to 50 mg, preferably 5 mg.

[0189] The compound can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is determined by the attending physician. The specific dose for any particular patient will depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disease to be treated, and the severity of the indication or condition being treated. Additionally, the route of administration may vary and will depend on the disease condition and its severity.

[0190] In some cases, it may be preferable to administer at least one compound described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if a patient receives one of the compounds described herein and experiences liver damage, one of the side effects, it may be preferable to administer a liver protectant in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but when combined with another therapeutic agent, the therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit to the patient may be enhanced by administering one of the compounds described herein with another therapeutic agent (which may further comprise a therapy) that also has a therapeutic benefit. By way of example only, for the treatment of myopia by administering one of the compounds described herein, the therapeutic benefit may be enhanced by providing the patient with an additional myopia treatment agent (e.g., atropine). In either case, regardless of the disease, illness, or condition being treated, the benefit to the patient may be simply the addition of the two therapeutic agents, or it may be a synergistic benefit to the patient.

[0191] The drug composition in dry or liquid form can be supplied in the form of a single dose or multi-dose drug composition.

[0192] In one embodiment of the present application, a liquid or dry drug composition is provided in a single dose, meaning that the container in which it is provided contains one drug dose. Alternatively, a liquid or dry drug composition is a multi-dose drug composition, meaning that the container in which it is provided contains more than one therapeutic dose, i.e., the multi-dose composition contains at least two doses. Such a multi-dose composition can be used for different patients in need thereof, or it may be used for a single patient, in which case the first dose is applied and the remaining doses are stored until needed for use.

[0193] In another aspect of the present application, the drug composition is in a container. Containers for liquid or dry drug compositions include, for example, syringes, vials, vials with stoppers or seals, ampoules, and cartridges. In particular, the liquid or dry drug composition is provided in a syringe. When the drug composition is a dry drug composition, the container is preferably a dual-chamber syringe. In this embodiment, the dry drug composition is provided in a first chamber of the dual-chamber syringe, and the reconstitution solution is provided in a second chamber of the dual-chamber syringe.

[0194] Before administering the dry composition to a patient in need thereof, the dry composition is reconstituted. Reconstitution can be performed in the container in which the dry composition is provided, such as a vial, syringe, double-chamber syringe, ampoule, or cartridge. Reconstitution is performed by adding a predetermined amount of reconstitution solution to the dry composition. The reconstitution solution is a sterile liquid such as water or a buffer solution, and may contain other additives such as preservatives and / or antimicrobial agents, e.g., benzal alcohol and cresol. Preferably, the reconstitution solution is sterile water. When the dry composition is reconstituted, it is referred to as a "reconstituted drug composition" or a "reconstituted composition."

[0195] The pharmaceutical compositions of the present application may be administered in the form of an ophthalmic formulation, which comprises an ophthalmologically acceptable carrier.

[0196] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary and will depend upon the host treated and the particular mode of administration.

[0197] Content of active material in the drug composition of the present application: When mixing drugs, the drug concentration can be selected to be an effective amount of each drug.

[0198] The formulations and methods of the present application have been used in any subject that can benefit from the formulations and methods of the present application. The subject is typically a mammal, and more commonly a human. However, the present application is not limited to human treatment and is applicable to veterinary use as well.

[0199] In another aspect, the present application provides a device comprising a drug composition, the drug composition comprising bendazac or a therapeutically acceptable salt thereof (e.g., bendazac lysine) or a derivative thereof, and preferably, the device delivers the drug composition in a sustained release manner.

[0200] In some embodiments of the drug composition, device or method of treatment disclosed herein, the device delivers the drug composition in a sustained release manner, preferably, the sustained release has a day-night rhythm.

[0201] In some embodiments of the drug compositions, devices, or methods of treatment disclosed herein, the drug composition is formulated as an ophthalmic composition, e.g., formulated as an ophthalmic composition for the treatment of an ophthalmic disease or condition.

[0202] In some embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the pharmaceutical composition is formulated as an ophthalmic composition for the treatment of pre-myopia, myopia, or myopia progression.

[0203] In some embodiments of the drug composition, device, or method of treatment disclosed herein, the drug composition is formulated as an ophthalmic composition for the treatment of high myopia, moderate myopia, or low myopia.

[0204] In some embodiments of the drug compositions, devices, or methods of treatment disclosed herein, the drug compositions are formulated as ophthalmic compositions for the treatment of patients diagnosed with pre-myopia (or at risk of developing myopia or prone to developing myopia).

[0205] In some embodiments of the pharmaceutical compositions, devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered ophthalmically to the patient's eye, and preferably, the eye is myopic.

[0206] In some embodiments of the drug compositions, devices or methods of treatment disclosed herein, the drug compositions are administered topically.

[0207] In some embodiments of the drug compositions, devices or methods of treatment disclosed herein, the drug composition is ophthalmically administered to the patient's eye by a device.

[0208] In some embodiments of the drug compositions, devices, or methods of treatment disclosed herein, the drug compositions are administered 1, 2, 3, 4, or 5 times daily.

[0209] Standard pharmaceutical procedures for determining the dosage, toxicity, and therapeutic efficacy of therapeutic drugs involve animal testing, which is used, for example, to determine the LD50 (lethal dose in 50% of cases) and ED50 (effective therapeutic dose in 50% of cases). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit a high therapeutic index are preferred. Compounds with toxic side effects can be used, but consideration must be given to designing a delivery system or appropriate administration regimen that targets such compounds to the corresponding tissue or lesion site and reduces side effects by minimizing possible damage to unrelated cells or tissues.

[0210] Data obtained from animal studies can be used to formulate a range of dosages for use in humans. Depending on the type of formulation used and the route of administration utilized, the dosage can vary within this range and may even exceed this range. By establishing a range of different dosages in animal models, indicators can be obtained, including the lowest effective concentration, the range of circulating drug concentrations after single and multiple doses, and drug exposure. Such results can help more accurately determine useful doses in humans based on body surface area.

[0211] Those skilled in the art will recognize that there are several factors that can affect the dosage and time required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, whether the subject fully cooperates with treatment, previous treatments, the health status and / or age of the subject, and other diseases that may be present. Additionally, treating a subject with a therapeutically effective amount of a therapeutic composition described herein may include a single treatment or a series of treatments.

[0212] The control, slowing, reduction, delay and / or amelioration of myopia progression in treated patients using the methods of the present application is in the range of about 5-95%, about 5-90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, between about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about 40-90%, about 50-90%, or about 75-90% relative to untreated.

[0213] By using the drug composition, device or treatment method, the degree of negative refraction of the subject's eye is limited to about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D and less than 1.0D.

[0214] In some examples, the use of the methods of the present application has halted or reversed myopia progression in treated patients, who have high, moderate, or low myopia, or who are pre-myopic (or at risk of progressing to myopia).

[0215] In some embodiments, use of the methods of the present application prevents, controls, slows, mitigates, retards, and / or reduces axial (or longitudinal) growth of the eye of a treated patient.

[0216] In some examples, use of the methods of the present application controls, slows, reduces, delays, and / or mitigates myopia progression in a patient diagnosed with myopia or at risk of developing myopia, increases choroidal thickness (ChT) in the patient's eye (e.g., an eye that is myopic, pre-myopic, or at risk of developing myopia), and / or reduces the axial (or longitudinal) growth rate in the patient's eye (e.g., an eye that is myopic, pre-myopic, or at risk of developing myopia).

[0217] In some embodiments, use of the methods of the present application controls, slows, reduces, retards, and / or reduces the axial (or longitudinal) growth of a treated patient's eye by about 5-95%, about 5-90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about 40-90%, about 50-90%, or about 75-90% relative to untreated eye.

[0218] In some examples, use of the methods of the present application did not result in an increase in small pupil size or mydriasis compared to atropine monotherapy.

[0219] In some embodiments, oral formulations include solid formulations such as tablets, capsules, granules, and powder formulations, and liquid formulations such as syrups and beverage formulations. Optionally, (a) solid formulations may contain excipients, lubricants, adhesives, disintegrants, etc., preferably preservatives, antioxidants, colorants, and sweeteners, and more preferably additives. Optionally, (b) liquid formulations may contain solvents, solubilizers, suspending agents, and isotonic agents, and may preferably be mixed with reagents, buffers, analgesics, etc., and more preferably additives such as preservatives, antioxidants, colorants, sweeteners, etc.

[0220] In some embodiments, the drug may be in the form of an injection, tablet, freeze-dried injection, capsule, effervescent tablet, chewable tablet, troche, granule, ointment, syrup, oral liquid, spray, nasal drops, topical preparation, oral preparation, etc., and is preferably in the form of an ophthalmic dosage form, including, but not limited to, eye drops (eye drops), eye ointment, eye spray, implant sheet, eye gel, eye pack, ophthalmic microsphere, ophthalmic sustained-release preparation, periocular injection, and intraocular injection, and may further be in the form of a free solution, oil-water mixture, suspension, rub, lotion, cream, drops, granular preparation, spray, ointment, patch, paste, pill, suppository, or emulsion.

[0221] In some embodiments, the "ophthalmic agent or drug" is administered synchronously with the drug composition or formulation of the present application, for example, specifically, in a single administration (treatment) course, administered simultaneously or before or after, on the same day, on the same week, in the same month, or in the same year, or alternately at intervals, for example, alternately every 4 hours, alternately every 12 hours, alternately every other day, alternately every week, alternately every month, or alternately every year.

[0222] Specific examples of the present application are described in detail below, and although the present application has been described in conjunction with these specific embodiments, it will be understood that it is not intended to be limited to such specific embodiments.

[0223] Example 1 Preparation methods and sources of main reagents or preparations (drug compositions)

[0224] Bendazacricin formulations include both commercialized over-the-counter drugs and pharmaceutical compositions prepared by the inventors themselves using only bendazacricin compound as the active pharmaceutical ingredient. Bendazacricin over-the-counter drug (BDL(S)) is a 0.5% bendazacricin ophthalmic solution (National Pharmaceutical Standards Code H20063847) commercially available in China, and this formulation was used for direct topical administration to the eyes of a guinea pig myopia model. Bendazacricin compound was purchased from MedChemExpress. Bendazacricin compound powder was completely dissolved directly in 0.9% saline without the addition of other pharmaceutical auxiliary materials or other compounds to prepare a 5 mg / ml (11.669 mM) formulation (BDL). At room temperature, the formulation had a clear, transparent and homogeneous appearance overall, with no suspended matter visible to the naked eye, and when administered to test subjects, it was administered either by direct topical administration to the eye or by corresponding dilution with 0.9% saline according to the required dosage before use.

[0225] The bendazac formulations included both a commercially available over-the-counter drug purchased directly and one prepared by the inventors using pure bendazac compound. The commercially available over-the-counter drug was a 3% bendazac ointment purchased by the inventors from Nippon Iwaki Pharmaceutical Co., Ltd., and the bendazac compound was purchased from MedChemExpress. A mother solution of 330 mg / ml (1166.9 mM) was prepared by completely dissolving bendazac in DMSO and stored at -20°C. Before the start of the experiment, a working solution was prepared in the ratio of mother solution: PEG300: Tween80: 0.9% saline = 1:45:5:49, resulting in a final bendazac formulation concentration of 3.3 mg / ml (11.669 mM). All preparation procedures were performed in a dark room.

[0226] Lysine was purchased from MedChemExpress and was completely soluble in 0.9% saline, prepared as a test formulation at 1.7 mg / ml (11.669 mM).

[0227] M-hydroxy-methylaniline was purchased from Shanghai Bitumin Pharmaceutical Co., Ltd. Hydroxy-methylaniline was completely dissolved in 0.9% saline to prepare a 250 mM stock solution, which was then stored at -20°C. Before the start of the experiment, it was diluted with 0.9% saline to a final concentration of 5 mM for the hydroxy-methylaniline formulation used in the examples. All preparation procedures were performed in a dark room.

[0228] The aldose reductase inhibitor (ARI) Sorbinil was purchased from MedChemExpress. Sorbinil powder was dissolved in DMSO to prepare a 4.8 mg / ml (20 mM) stock solution and stored at -20°C. Before the start of the experiment, it was diluted with 0.9% saline to give a final concentration of 24 μg / ml (100 μM) for the Sorbinil formulation used in the examples. All manipulations were performed in a dark room.

[0229] The aldose reductase inhibitor zopolrestat 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 start of the experiment, it was diluted with saline to a final concentration of 420 μg / ml (1 mM) for the zopolrestat formulation used in the examples. All manipulations were performed in a dark room.

[0230] Atropine powder was purchased from Stanford Chemicals and completely dissolved in 0.9% saline to prepare a 1 mg / ml, i.e., 0.1% formulation (positive control). All procedures were performed in a dark room.

[0231] All other formulations or drug compositions not mentioned were prepared and stored according to the usual methods and standards of the laboratory. All formulation preparation processes may use usual physicochemical dissolution aids such as heating, stirring, pH adjustment, etc., and all formulations showed no compound precipitation before administration.

[0232] Example 2: Construction of animal model and experimental method

[0233] The form deprivation and lens-induced guinea pig myopia model is a representative and recognized animal model of myopia in the field, and can be used to evaluate the therapeutic efficacy and safety of myopia treatments. Its construction method is well known to those skilled in the art. The molding, 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 inventor's laboratory publications [1-4]. Healthy guinea pigs (i.e., without underlying diseases such as hypertension, hyperglycemia, or ocular diseases or abnormalities) were used in the examples of this application, and both males and females were used. The animal experiments in this application have been approved by the Wenzhou Medical University Experimental Animal Ethics Committee. The construction method of the form deprivation and lens-induced guinea pig myopia model used in Example 3 below is as follows.

[0234] Three-week-old tricolor guinea pigs were reared in the Wenzhou Medical University Laboratory Animal Laboratory and maintained under a 12-hour light (400-500 lux) / 12-hour dark environment with free access to water and food. The myopia model was performed using monocular morphological deprivation (FD) and lens induction (LI) molding methods. For morphological deprivation, a specially designed eye mask with 1% light transmittance and a self-adjusting mechanism was used to completely cover the animal's right eye, while the other eye (left eye) had normal vision. For lens induction, a -4D lens was fixed in front of the animal's right eye, while the left eye had normal vision. The lens was washed twice daily to prevent lens blurring. Medication was administered daily between 9:00 and 9:30 AM. During administration, the eye masks or lenses were removed from the control and experimental animals under red light, and 0.1 ml of the vehicle control, 5 mg / mL of the test drug, or the positive control was injected under the periconjunctiva of the right eye. Once the injection was confirmed to be successful and without injury, the eye masks and lenses were immediately replaced. The administration process for each animal was controlled to approximately 10 seconds. Administration began on the day of molding. The form-deprived animals were administered once daily for two consecutive weeks, and the lens-induced animals were administered once daily for one consecutive week.

[0235] Animal Grouping

[0236] 1. Form deprivation group:

[0237] Vehicle-deprived group: One eye was masked and saline was injected into the masked eye for 2 weeks. Sample size: 11.

[0238] Drug-injected deprivation group: One eye was covered with an eye mask, and bendazacricin (0.5 mg / day) was injected into the masked eye for 2 weeks. Sample size: 14.

[0239] Positive control group for morphological deprivation: one eye was masked and 0.1% atropine was injected into the masked eye for 2 weeks. Sample size = 12.

[0240] 2. Lens guidance group:

[0241] Vehicle-injected lens induction group: one eye was fitted with a -4D lens, and the other eye with the lens was injected with saline as a vehicle for one week. Sample size = 14.

[0242] Lens-induced drug injection group: one eye was fitted with a -4D lens, and the lens-fitted eye was injected with bendazacricin (0.5 mg / day) for one week. Sample size = 14.

[0243] Measurement of animal eye parameters

[0244] In a single drug efficacy experiment, all animals were measured within the same time period. The first measurement was at 3 weeks of age. Refractive index and axial parameters were measured for each animal before the experiment, 1 week after the experiment, and 2 weeks after the experiment (FD only). Refractive index was measured using an eccentric infrared photoretinoscope (EIR) built in our laboratory. Three measurements were taken per eye, and the average was used as the final result. Guinea pig axial parameters were measured using the A ultrasound probe of a Cinescan A / B ultrasound diagnostic system (Quantel Medical, Aviso, France). The ultrasound frequency was 11 MHz. The ultrasound propagation velocities in the different refractive media of the eye were set to 1557.5 m / s in the anterior chamber, 1723.3 m / s in the lens, and 1540 m / s in the vitreous, respectively. Measurements included anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL). Approximately 2 minutes before measurement, the guinea pigs were anesthetized with 0.5% proxymetacaine hydrochloride eye drops (Alcon, Belgium). Six measurements were taken for each eye, and the average was used as the final result.

[0245] Example 3: Experimental study of the in vivo therapeutic effect of bendazacricin

[0246] The experimental animals were 3-week-old tricolor guinea pigs, divided into two groups: a morphological deprivation group (FD) and a lens induction group (LI). The morphological deprivation group was divided into three subgroups: a negative control group receiving 100 μL of saline injections near the molding eye every day; an experimental group receiving the same volume of bendazac-lysine 0.5 mg injections near the molding eye every day; and a positive control group receiving 100 μL of 0.1% atropine injections near the molding eye every day. The lens induction group was divided into two subgroups: a negative control group receiving 100 μL of saline injections near the molding eye every day; and an experimental group receiving the same volume of bendazac-lysine 0.5 mg injections near the molding eye every day. Refraction, vitreous cavity, and axial parameters were measured in both eyes for all animals before the first injection, and after 1 and 2 weeks of treatment (FD only).

[0247] Test Results:

[0248] In the FD group, after one week of administration, the induced myopia in the saline injection group was -3.75 ± 1.76 D, and after two weeks, it was -6.17 ± 1.52 D. In the bendazac-lysine injection group, after one week of administration, the induced myopia was -2.15 ± 1.09 D, representing a 42.6% reduction in myopia compared to the saline group. Myopia induced by 0.1% atropine was -2.98 ± 1.54 D, representing a 20.5% reduction in myopia. After two weeks of administration of bendazac-lysine, the induced myopia was -3.46 D, representing a 43.9% reduction in myopia compared to the saline group. Myopia induced by 0.1% atropine was -3.93 D, representing a 36.4% reduction in myopia. Correspondingly, both the vitreous cavity depth and axial length elongation were suppressed by bendazacricin (see Figure 1). In other words, compared with the saline group, the bendazacricin-treated group significantly suppressed the negative refractive power, vitreous cavity depth elongation, and axial length elongation in guinea pigs with form deprivation myopia.

[0249] In the LI group, after one week of administration, the induced myopia in the saline-injected group was -4.42 ± 0.95 D. In the bendazac-lysine-injected group, after one week of administration, the induced myopia was -3.49 ± 1.15 D, a 21.0% reduction in myopia compared to the saline-injected group (Figure 1). As can be seen from the above, compared to the saline-injected group, the bendazac-lysine-injected group significantly reduced the negative refractive power of guinea pigs with lens-induced myopia, and bendazac-lysine also reduced the depth of the vitreous cavity and the elongation of the axial length.

[0250] In addition, all animals in the bendazacricin-treated groups showed no abnormal ocular conditions or individual toxic reactions throughout the experimental period, and the related indices of corneal curvature (RCC), anterior chamber depth (ACD), and crystalline thickness (LT) were not affected by the test drug (see Figure 2).

[0251] As can be seen from the above experiments, bendazac-lysine can significantly slow down the process of negative refractive power in myopic individuals, significantly inhibit axial elongation, and significantly improve myopia-related symptoms in morphological deprivation and lens-induced guinea pigs, indicating that bendazac-lysine can be used to prevent and control myopia, especially in the treatment, prevention, or improvement of refractive myopia or axial myopia and its related symptoms. The above experimental results of this application prove that bendazac-lysine has very high preventive, mitigating, and therapeutic effects on myopia in humans, especially in children and adolescents.

[0252] Example 4: Inhibition of myopia progression by bendazacrylamide ophthalmic solution (0.5%, BDL(S))

[0253] After excluding animals with obvious ocular disease or abnormalities, healthy 3-week-old tricolor guinea pigs were randomly assigned to five groups: form deprivation (FD) + vehicle control (NS), FD + 0.5% bendazac lysine ophthalmic solution (BDL(S)), FD + 0.1% atropine, lens-induced (LI) + vehicle control (NS), and LI + 0.5% bendazac lysine (BDL(S)). Starting at 8:00 AM on the first day of the experiment, the guinea pigs underwent molding for form deprivation (FD) or lens-induced (LI) myopia. The form deprivation myopia model employed the mask method. A mask made by the inventors using a 10-inch milky white, non-toxic latex balloon was placed on the right eye (control eye) of a guinea pig model, while the left eye (contralateral eye) was left unmasked. The lens-induced myopia model used a -4D lens purchased from Wenzhou Xin Vision Technology Co., Ltd., with specific parameters of -4D central power, 16mm base curve, and 11.8mm diameter. The lens was fixed in front of the guinea pig's right eye (control eye), while the left eye (contralateral eye) was left untreated. FD and LI induction were performed continuously throughout the entire bendazacrine efficacy experiment, with the mask or lens temporarily removed only during administration or ocular measurements (e.g., refraction measurement). After the start of the efficacy experiment, the headgear position was checked or the lens wiped at 8:00 AM, 12:00 PM, 7:00 PM, and before administration each day. Animals that removed the headgear or lens three or more times were culled. Starting on the day of molding, the corresponding vehicle or drug was administered to the experimental eye of the FDM model between 9:00 AM and 10:00 AM each day. The administration method was juxta-conjunctival injection in a volume of 100 μL, once daily for two consecutive weeks. The refraction and axial parameters of the test animals were measured at the start of the efficacy experiment, after one week, and after two weeks. All data collection and processing methods were the same as those published in the inventor's laboratory [4]. The statistical basis was the difference between the experimental eye and the contralateral eye of the same test animal.For the lens-induced myopia model, starting from the day of molding, animals in the lens-induced group were administered either vehicle (negative control) or drug (bendazac-lysine) via juxtaconjunctival injection in a volume of 100 μL once daily for one week at 9:00 AM. Refractive index and axial parameters of all test animals were measured at the beginning and end of the experiment, and all data collection and processing methods were based on the deprivation group. All efficacy experiments were repeated at least twice. The test drug (0.5% bendazac-lysine ophthalmic solution, National Pharmaceutical Standards Code H20063847) and the vehicle control (negative control group) in this example were manufactured by the same commercialized bendazac-lysine ophthalmic solution manufacturer and supplied to the inventors.

[0254] The results were consistent with those in Example 3. The changes in refraction and axial parameters of the animals in the negative control group were as expected in the myopia model, and the positive control drug atropine showed the expected efficacy during the experiment, demonstrating that the two myopia models in this experiment were successfully molded and can be used to evaluate the efficacy of the test drugs. The inventors discovered that 0.5% bendazac-lysine ophthalmic solution, commercially available in China, can significantly inhibit and slow the progression of myopia in the morphological deprivation myopia model and the concave lens-induced myopia model. That is, the process of negative refraction in myopic individuals can be successfully delayed and effectively controlled by bendazac-lysine ophthalmic solution. Furthermore, the inventors discovered that in individual animals in the bendazac-lysine treatment group, the myopia process was almost completely terminated by the test drug. In terms of refractive index in the FDM group, after one week of administration, 0.5% bendazac-lysine ophthalmic solution was more effective in treating myopia than 0.1% atropine ophthalmic solution, but there was no statistical difference between the two. After two weeks of administration, 0.5% bendazac-lysine ophthalmic solution was similar to 0.1% atropine ophthalmic solution in treating myopia, with a significant difference compared to the negative control group. In the LIM group, bendazac-lysine also effectively prevented the progression of myopia. The rate of negative refractive index in the drug intervention group was significantly slower than in the control group, and there was a significant difference between the refractive indexes of the two groups at the end of the experiment, indicating that bendazac-lysine effectively treated myopia induced by concave lenses. Specific results showed that under the same myopia visual information input conditions (all -4D), the refractive index of the drug intervention group was greater than that of the vehicle group at the same measurement time point (1 week of administration) (both negative values, with the mean refractive index of the negative control group reaching -4D, but not that of the drug intervention group), demonstrating that bendazac-lysine can effectively control myopia progression. At the same time, in the representative disease models mentioned above, after bendazac-lysine treatment, the increase in vitreous cavity depth (VCD) and the elongation of axial length (AL) of the animals were correspondingly effectively inhibited (statistically different from the negative control group). In morphological deprivation experiments, the commercially available bendazac-lysine group outperformed the atropine group in the above-mentioned corresponding indicators at both measurement time points.In addition, no abnormal ocular conditions or individual toxic reactions were observed in any of the bendazacricin-treated groups throughout the entire animal experiment, and the related indices of corneal curvature (RCC), anterior chamber depth (ACD), and corneal thickness (LT) were not affected by the test drug. In the positive control group, the animals' pupils dilated after atropine administration.

[0255] Based on the above, provided that no obvious side effects from the drug are observed, bendazac lysin ophthalmic solution products can effectively prevent, control, and treat myopia in mammals (including humans), particularly by reducing and controlling the severity of myopia and significantly improving related symptoms in myopia disease models. It was stated that bendazac lysin effectively reduced (inhibited) the elongation of the axial length of the eye in myopic or myopic-prone individuals and that bendazac lysin effectively reduced (inhibited) the increase in vitreous cavity depth. Therefore, it was demonstrated that bendazac lysin ophthalmic solution products can be used for the prevention and control of myopia, including the treatment, prevention, or amelioration of refractive or axial myopia and related symptoms. Therefore, commercialized bendazac lysin ophthalmic solution can be used to treat myopia (eye), particularly by reducing the risk of complications and blindness caused by high myopia, and by controlling the rate of progression of the disease, particularly in children and adolescents, through intervention.

[0256] Example 5 Dose-effect relationship study in the treatment of myopia with different concentrations of bendazacrylamide (0.01%, 0.05%, 0.1% and 0.5%)

[0257] After removing animals with obvious ocular disease or abnormalities, healthy 3-week-old tricolor guinea pigs underwent refraction (infrared eccentric ophthalmoscope) and axial measurement (A-ultrasound). Animals with refractive powers between 3 and 8 diopters (D) and binocular refractive index variance of less than 2D were selected and randomly divided into six groups: FD + saline (negative control), FD + 0.01% bendazac-lysine, FD + 0.05% bendazac-lysine, FD + 0.1% bendazac-lysine, FD + 0.5% bendazac-lysine (the experimental group, in which 0.5% bendazac-lysine was administered to FDM model animals), and FD + 0.1% atropine (positive control). For ease of understanding, percentages were converted to milligrams when plotting figures. Starting at 8:00 AM on the first day of the experiment, guinea pigs underwent form deprivation (FD) myopia molding. The morphological deprivation myopia model employed a mask technique. The inventors created a mask using a 10-inch, non-toxic, milky-white latex balloon. The right eye (control eye) of each molded guinea pig was fitted with a mask, while the left eye (contralateral eye) was left unmasked. FD induction was continuously performed throughout the entire bendazacricin efficacy experiment, with the mask temporarily removed only for administration or ocular measurements (e.g., refraction measurement). The mask position was monitored daily at 8:00 AM, 12:00 PM, 7:00 PM, and before administration. Animals that removed the mask three or more times were culled. Starting on the day of molding, the corresponding vehicle (negative control) or drug was administered to the target eye of the FDM model between 9:00 AM and 10:00 AM. The administration route was juxta-conjunctival injection in a volume of 100 μL. The administration was performed once daily for two consecutive weeks. The refraction and axial parameters of the test animals were measured at the start of the model efficacy experiment, one week after the experiment, and two weeks after the experiment. All data collection and processing methods were the same as those published by the inventor's laboratory [4], and the statistical basis was the difference between the experimental eye and the contralateral eye of the same test subject. All of the above efficacy experiments were repeated at least three times. The bendazacrine formulation was prepared by the inventor himself using normal saline.

[0258] The experimental results showed that the changes in refraction and ocular axis parameters of the animals in the negative control group were as expected for the myopia model, and the positive control drug atropine showed the expected efficacy during the experiment. Both of these demonstrated that the myopia model for this experiment was successfully molded and can be used to evaluate the efficacy of bendazac-lysine. Compared to the negative control group, bendazac-lysine (containing no other pharmaceutical additives other than 0.9% saline as a solvent) dose-dependently reduced the severity of myopia in the test subjects. With increasing bendazac-lysine dosage, the myopia suppression rate (calculated as (refraction of drug group - refraction of solvent group) / refraction of solvent group) also increased correspondingly, indicating that the higher the dose of bendazac-lysine, the greater the effect on preventing and controlling myopia (eye). In terms of refractive index, the bendazac lysine preparation prepared by the inventor using only saline showed efficacy consistent with that of commercially available bendazac lysine. That is, after one week of administration, 0.5% bendazac lysine had a higher myopia treatment effect than 0.1% atropine, but there was no statistical difference between atropine and bendazac lysine. After two weeks of administration, 0.5% bendazac lysine had a myopia treatment effect similar to that of 0.1% atropine ophthalmic solution, and the difference in efficacy between the two was very significant compared to the negative control group. This indicates that bendazac lysine, when used as the main or only active ingredient, can play a role in the treatment and prevention of myopia. Statistically, the 0.05% and 0.1% bendazac-lysine formulations also showed significant myopia treatment effects (effectively inhibiting the process of negative refractive index), and the low-concentration 0.01% bendazac-lysine group showed similar refractive index results to the negative control group after one week of measurement and slightly better results than the negative control group after two weeks of measurement, but there was no statistical difference. The three concentrations of bendazac-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.Here, except for the lowest concentration 0.01% bendazac-lysine experimental group, other higher concentrations of bendazac-lysine were similar to atropine. All of them effectively inhibited the elongation of the posterior segment of the eye (vitreous cavity depth and axial length) of the test subjects, and effectively controlled, inhibited, delayed, or slowed the (continuous) decrease in refractive index in myopic individuals or individuals prone to myopia. Compared to the vehicle group, the inhibitory effects were significantly different or the difference between the two groups was very significant (see Figure 3). During the administration period, none of the bendazac-lysine experimental groups showed any ocular irritation or abnormalities, and related indicators such as anterior chamber depth, ocular thickness, and pupil size were affected by bendazac-lysine administration. All animals in the positive control atropine group showed pupil dilation after administration, which was statistically different from the vehicle group (see Figure 4), which is consistent with the side effects of this drug reported in clinical trials.

[0259] The results of this example demonstrate that the mere use of bendazac lysine can prevent, control, and treat myopia (ocular). It also demonstrates that bendazac lysine can be used to prepare formulations or pharmaceutical compositions, and that the formulations or pharmaceutical compositions can be used to prevent, control, and treat myopia (ocular). Preferably, the concentration of bendazac lysine in the formulations or pharmaceutical compositions is 0.01% or higher, and may be 0.05%-1%. Considering three professional requirements: the Food and Drug Administration's (FDA) belief that bendazac may cause serious hepatotoxicity in humans, the need for long-term, sustained administration of myopia treatment drugs, and the regulatory authorities' requirement for safe administration in pediatrics, the inventors believe that a 0.1%-0.25% concentration of bendazac lysine ophthalmic solution is a reasonable compounding ingredient for clinical use in the prevention and control of myopia. That is, the concentration of bendazac lysine in formulations or pharmaceutical compositions is preferably 0.1%-0.25%. In addition to increasing the concentration of bendazac lysine when preparing a bendazac lysine preparation, other ways of using bendazac lysine to achieve or enhance its myopia prevention and control effect in myopic individuals or those prone to myopia include increasing the bioavailability of bendazac lysine in the eye, increasing the frequency of drug administration, co-administration with other myopia treatment drugs, and optimizing the formulation ingredients of bendazac lysine preparations, etc. In other words, the above-mentioned bendazac lysine preparations or pharmaceutical compositions can effectively reduce (inhibit) the elongation of the axial length of the eye in individuals who are myopic or prone to myopia, and can effectively reduce (inhibit) the increase in vitreous cavity depth in individuals who are myopic or prone to myopia, and the bendazac lysine preparations or pharmaceutical compositions can treat (prevent and control) myopia, especially for treating myopia in individuals aged 6 to 18.

[0260] Example 6 Bendazacricin can significantly increase choroidal thickness

[0261] (1) Bendazacrylamide effectively inhibits choroidal thinning in FDM and LIM guinea pig models

[0262] After removing animals with obvious ocular disease or abnormalities, 3-week-old tricolor guinea pigs were subjected to refraction (infrared eccentric ophthalmoscope) and axial measurement (A ultrasound). Animals with refractive power between 3 and 8 diopters (D) and binocular refractive index variation of 2D or less were selected and randomly divided into four groups: form deprivation (FD) + vehicle control (NS), FD + 0.5% bendazac lysine ophthalmic solution (BDL(S)), lens induction (LI) + vehicle control (NS), and LI + 0.5% bendazac lysine (BDL(S)). Starting at 8:00 a.m. on the first day of the experiment, the guinea pigs underwent form deprivation (FD) or lens induction (LI) myopic molding. The form deprivation myopia model used the mask method. A mask made by the inventors using a 10-inch milky white, non-toxic latex balloon was attached to the right eye (control eye) of the guinea pig molding, and no mask was attached to the left eye (contralateral eye). The lens-induced myopia model used a -4D lens, purchased from Wenzhou Xin Vision Technology Co., Ltd., with specific parameters of -4D central power, 16mm base curve, and 11.8mm diameter. The lens was fixed in front of the guinea pig's right eye (control eye), and the left eye (contralateral eye) was not treated. FD and LI induction were performed continuously throughout the entire bendazacrylamide efficacy experiment, with the mask or lens temporarily removed only during administration or choroidal thickness measurement. After the start of the drug efficacy experiment, the position of the headgear was checked or the lens wiped at 6:00 AM, 12:00 PM, 6:00 PM, and before administration every day. Animals that removed the headgear or lens three or more times were culled. Starting on the day of molding, the corresponding vehicle or drug was administered to the experimental eye of the FDM model between 9:00 AM and 10:00 AM every day via juxtabulbar subconjunctival injection in a volume of 100 μL. The administration was performed once daily for two consecutive weeks. For the lens-induced myopia model, the lens-induced group animals were administered vehicle (negative control) or drug (bendazacrylamide) between 9:00 AM and 10:00 AM every day from the day of molding. The administration was performed via juxtabulbar subconjunctival injection in a volume of 100 μL. The administration was performed once daily for one consecutive week.The choroidal thickness of the two myopia models was measured in all eyes using a Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany) 30-60 minutes after the final injection. All data collection and processing methods were the same as those 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, using an independent samples t-test. All efficacy experiments were repeated at least twice. The test drug (0.5% bendazac ricin ophthalmic solution) and the vehicle control (negative control group) were produced by the same commercial bendazac ricin ophthalmic solution manufacturer and supplied to the inventor.

[0263] The results showed that bendazac-lysine effectively increased choroidal thickness in guinea pigs in both the FDM and LIM models compared with the vehicle control group, with statistically significant differences between the two (the difference between the vehicle control group and the drug group in the LIM model was very significant). Specifically, the experimental eyes of guinea pigs in the vehicle group of the FDM and LIM models showed decreased choroidal thickness, but bendazac-lysine was able to 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. After bendazac-lysine treatment, the mean difference in choroidal thickness between the experimental and contralateral eyes of myopic individuals was -9.20 micrometers. Therefore, after drug treatment, the choroidal thickness of the experimental eyes approached that of normal eyes of the same individuals (the difference between the two narrowed). In the LIM model, the mean difference in choroidal thickness between the experimental and contralateral eyes was -23.38 micrometers. However, after bendazac-lysine treatment, the mean difference in choroidal thickness between the experimental and contralateral eyes of myopic individuals was -6.31 micrometers. In individual animals, the choroidal thickness of the experimental eye completely recovered to the level of normal eyes after treatment (see Figure 5). Corneal curvature (RCC), anterior chamber depth (ACD), and thoracic thickness (LT) indices were also unaffected by the test drug. These results suggest that bendazac-lysine significantly inhibits choroidal thinning in myopic individuals or individuals prone to myopia, thereby reducing the tendency for choroidal thinning.

[0264] In myopic individuals, parallel light rays are refracted by the refractive system of the accommodated relaxed eye and then focused in front of the retina. When bendazac-lysine increases the thickness of the choroid in the myopic individual, the retina moves toward the lens, ultimately shortening the distance between the myopic image focus and the retina and bringing them into favorable alignment. The distance between the image focus and the retina is the myopic power, and bendazac-lysine can shorten this distance or inhibit the increase in this distance in myopic individuals, thereby reducing the myopic power. When bendazac-lysine is administered to a myopic individual, the treated eye will have sharper distance vision, effectively reducing the myopic refractive condition (treating myopia and reducing myopic power), including improving the distance vision. Therefore, in this application, the myopia treatment (preventive control) effect embodied by bendazacrylamide is not limited to axial myopia, refractive myopia, pathological myopia, simple myopia, pseudomyopia, or true myopia, and is independent of factors such as the age, sex, degree of myopia, myopia progression rate, ethnicity, and age at onset of myopia of the subject, i.e., bendazacrylamide has therapeutic and preventive control effects on all types of myopia.

[0265] Example 7 Therapeutic Effects of Instillation of Bendazac Lysine Ophthalmic Solution and Application of Bendazac Plaster to the Eye (Non-invasive Administration Method or Non-invasive Administration Method)

[0266] After removing animals with obvious ocular disease or abnormalities, 3-week-old tricolor guinea pigs underwent refraction (infrared eccentric ophthalmoscope) and axial measurement (A-ultrasound). Animals with refractive power between 3 and 8 diopters (D) and binocular refractive index variation of 2D or less were selected and randomly divided into three groups: FD + saline, FD + 0.5% bendazacricin ophthalmic solution (prepared in-house), and FD + 0.1% atropine. At 8:00 AM on the first day of the experiment, the guinea pigs underwent morphological deprivation. A mask was applied to the right eye (experimental eye) and not to the left eye (contralateral eye). FD induction was continuously performed throughout the bendazacricin drug efficacy experiment, with the mask temporarily removed only during administration or ocular measurements (e.g., refraction measurement). After the start of the efficacy experiment, the headgear position was monitored at 8:00 AM, 12:00 PM, 7:00 PM, and before administration each day. Animals that removed the headgear three or more times were eliminated. Starting on the day of molding, the corresponding vehicle or drug was administered to the target eye daily between 9:00 AM and 10:00 PM. A second administration was administered between 2:30 PM and 3:30 PM. The administration was twice daily, with each administration volume at 25 μL. This was continued for two weeks. The refraction and axial parameters of the test animals were measured at the start of the efficacy experiment, and after one and two weeks. All data collection and processing methods were the same as in the inventor's laboratory publication [4]. The statistical basis was the difference between the target eye and the contralateral eye of the same test animal. All efficacy experiments were repeated at least twice.

[0267] Due to the molding method, the structure of the guinea pig's eye (their eyeballs are protruding relative to humans and cannot spontaneously close their eyes), and the animals' normal blinking, the effective therapeutic dose of drug actually obtained in each test eye was lower than the periocular injection dose of the same volume, and the total daily administration volume of eye drops to the test animals was also lower than the injection volume in Example 5. Therefore, in this example, the efficacy of direct administration of bendazacrine ophthalmic solution and 0.1% atropine was lower than the myopia treatment effect of periocular injection. The changes in refraction and axial parameters of the animals in the negative control group were as expected in the myopia model, and the positive control drug atropine showed the expected efficacy during the experiment. All of these prove that the molding of the myopia model for this experiment was successful and can be used to evaluate the efficacy of bendazacrine. In terms of axial parameters, bendazac-lysine and 0.1% atropine significantly inhibited axial elongation (statistically significant) in the morphological deprivation myopia model compared with the saline vehicle group. Both drugs showed similar inhibitory effects on increases in axial length and vitreous cavity depth in myopic individuals. After 1 and 2 weeks of bendazac-lysine administration, the myopia suppression rate was similar to that of the 0.1% atropine group (35.5% vs. 28.1% and 33.9% vs. 36.9%, respectively; both efficacy rates were statistically significant compared with the negative control vehicle group) (Figure 6). However, the atropine group experienced a side effect of pupil dilation during administration. No significant ocular abnormalities were observed in the bendazac-lysine group. Neither atropine nor bendazac-lysine significantly affected the corneal curvature, anterior chamber, or crystal-related indices of the test subjects when used for myopia treatment (Figure 7). In the inventor's laboratory, atropine ophthalmic solution with a concentration of 0.01% is currently widely used in clinical trials, and under the same administration conditions as in this example (maintaining the same myopia model, administration method, administration frequency, administration volume, etc.), atropine at this concentration did not show any therapeutic effect in the guinea pig myopia model in terms of refractive index or axial parameter index. This may be related to the short retention time of the ophthalmic solution formulation on the ocular surface after administration to animals.Therefore, after evaluation from the perspectives of efficacy and safety, bendazacrylamide has a better risk-benefit ratio than atropine in treating myopia (for example, when bendazacrylamide is used during the day, it does not cause the same phenomenon as photophobia caused by atropine's dilation while treating myopia), and is particularly suitable for the treatment of myopia in children and adolescents and for the prevention and control of myopia in school-age populations.

[0268] The 3% bendazac ointment used is a commercially available product in Japan, and the inventors were unable to obtain a corresponding bendazac-free formulation. Therefore, in this example, a control group was not established for the ointment-type test drug, and atropine ointment containing the same auxiliary materials was also excluded for the same reason. However, when evaluating the efficacy of this formulation of bendazac in treating myopia, the inventors can still refer to the control group indicators of the same batch and the same model in the non-invasive administration experiment in this application. The specific experimental procedure is as follows: bendazac ointment was applied to the corneal surface and periocular skin of the test eye (experimental eye) of the guinea pig morphological deprivation myopia model described in this application, and the eyelids were manually and quickly closed 10 times. However, the inventors discovered that the ointment was not absorbed quickly, and due to the eye mask and the animal's normal blinking, some bendazac ointment was also attached to the inside of the eye mask at the time of the next administration. Bendazac ointment was administered at a single dose of 18mg±2mg to the deprived eye every morning from 9:00-10:00am, with a second dose at 2:30-3:30pm, twice daily for two weeks. The refraction and axial parameters of the test animals were measured at the start of the efficacy experiment, and after one and two weeks. All data collection and processing methods were the same as in the inventor's laboratory publication [4], and the statistical basis was the difference between the test eye and the contralateral eye of the same test subject.

[0269] After 1 week and 2 weeks of administration of 3% bendazac ointment, the myopia suppression rates were 17.7% and 25.9%, respectively, which was slightly lower than that of the same batch of 0.5% bendazac lysine or 0.1% atropine, but much higher than that of the untreated group of the same batch of form-deprived myopia model.Possible reasons include that the mask on the molding affects the absorption of bendazac in the ocular ointment, or that the formulation is mainly intended for the skin administration route, so the formulation ingredients are not reasonable for the bioavailability of bendazac drug in the guinea pig eye. However, Bendazac (ointment) still demonstrated effective prevention and control of myopia. In addition to inhibiting the process of negative refractive power in myopic individuals, administration also inhibited the increase in vitreous chamber depth and the elongation of axial length in myopic individuals. Specifically, after two weeks of administration, the myopia treatment group treated with Bendazac ointment had an average increase in vitreous chamber depth of 0.09 mm and an average elongation of axial length of 0.09 mm, while the corresponding indicators in the non-intervention group were 0.13 mm and 0.12 mm (see Figure 6). Thus, axial elongation in myopic individuals is primarily due to an increase in vitreous chamber depth, and Bendazac can simultaneously reduce the increase in vitreous chamber depth and the elongation of axial length in myopic individuals. After administration of Bendazac, no obvious abnormalities were observed in the animals' eyes. The pupil, corneal curvature, anterior chamber, and crystal-related indicators of the test individuals were not affected by the drug (see Figure 7).

[0270] As described above, when administered via other non-invasive (non-invasive) routes other than intraocular injection, bendazac and its salt forms (e.g., lysine salt) can effectively treat and prevent myopia, and can delay the process of negative refractive power in myopic individuals or individuals prone to myopia. Specifically, myopia can be treated by direct administration of bendazac lysine ophthalmic solution or intraocular administration of bendazac ophthalmic ointment, thereby inhibiting axial elongation and reducing the increase in vitreous cavity depth in myopic individuals or individuals prone to myopia.

[0271] Example 8 Effect of single lysine and single bendazac eye drops on myopia

[0272] After removing animals with obvious ocular disease or abnormalities, 3-week-old tricolor guinea pigs underwent refraction (infrared eccentric ophthalmoscope) and axial measurement (A-ultrasound). Animals with refractive power between 3 and 8 diopters (D) and binocular refractive index variation of 2D or less were selected and randomly divided into five groups: FD + saline (NS), FD + lysine (L-lysine), FD + 0.5% bendazac lysine (BDL), FD + DMSO (vehicle control for bendazac), and FD + bendazac (experimental group, in which bendazac was administered to FDM model animals). At 8:00 AM on the first day of the experiment, the guinea pigs underwent morphological deprivation. A mask was placed on the right eye (experimental eye) and the left eye (contralateral eye) without a mask. FD induction was performed continuously throughout the entire efficacy experiment, with the mask temporarily removed only during administration or ocular measurements (e.g., refraction measurement). The mask position was monitored at 8:00 AM, 12:00 PM, 7:00 PM, and before administration every day after the start of the efficacy experiment. Animals that removed the mask three or more times were culled. Starting on the day of molding, vehicle or drug was administered to the corresponding experimental eye via juxtabuloconjunctival injection at 9:00 AM–10:00 AM every day. The injection volume was 100 μL, administered once daily for two consecutive weeks. Refraction and axial parameters were measured at the start of the efficacy experiment and at the end of the first and second weeks of the experiment. All data collection and processing methods were the same as those published in the inventor's laboratory [4]. Differences between the experimental and contralateral eyes of the same subject were used as the statistical basis. All efficacy experiments were repeated at least three times, and all drug formulations were prepared by the inventors themselves.

[0273] The experimental results showed that the changes in refraction and axial parameters of animals in the negative control group, whether treated with saline or DMSO solvent, were as expected for the myopia model, and the positive control drug, 0.5% bendazac-lysine, demonstrated the expected efficacy during the experiment. These findings demonstrate the successful construction of a myopia model for this experiment and its use in evaluating the efficacy of bendazac and lysine. The single administration of lysine at the same molar concentration as 0.5% bendazac-lysine had no inhibitory effect on myopia progression, including negative refraction, vitreous cavity depth, or axial length elongation. While the refraction index in the lysine treatment group was higher than that in the saline treatment group at 1 and 2 weeks, the same molar bendazac-lysine effectively inhibited the negative refraction progression in treated individuals, with statistically significant differences from the saline treatment group (see Figure 8). Therefore, lysine does not have any therapeutic effect on the treatment or prevention of myopia, and the myopia treatment effect of bendazac lysine is not directly related to the lysine component in the molecule, and any pharmaceutically acceptable salt of bendazac can be used for the treatment and prevention of myopia.

[0274] Compared with the DMSO vehicle control group, single-administered bendazac achieved myopia suppression rates of 33.4% and 30.1% at 1 and 2 weeks, respectively. This myopia treatment effect was consistent with that of the equimolar bendazac-lysine positive control group from the same batch, and there was a statistical difference between the two groups and their corresponding negative controls. This demonstrates that bendazac is the key and only part of the bendazac-lysine molecule that exerts its therapeutic effect in myopia treatment, and can effectively inhibit and slow the progression of refractive error in myopic individuals. Compared with the DMSO vehicle group, bendazac administration significantly inhibited axial elongation and reduced the increase in vitreous cavity depth in myopic individuals, with a statistical difference between the negative control group and the experimental group, which was similar to that of the equimolar bendazac-lysine experimental group from the same batch (see Figure 9).

[0275] After administration of bendazac-lysine, bendazac, or lysine, no obvious abnormalities were observed in the eyes of the animals, and the pupils, corneal curvature, anterior chamber depth, and related indices of corneal thickness of the test subjects were not affected by the drugs (see Figures 10-11).

[0276] In the above experiment, choroidal thickness was measured after two weeks of administration of bendazac and its corresponding vehicle negative control according to the solution described in this application. The results showed that a single administration of bendazac (in the form of eye drops) inhibited the decrease in choroidal thickness in myopic eyes, with the average difference in choroidal thickness between the experimental eye and the contralateral eye of myopic individuals being -18.82 micrometers. After bendazac administration, the average difference in choroidal thickness between the experimental eye and the contralateral eye of myopic individuals was -8.47 micrometers, showing a statistical difference between the bendazac drug group and the DMSO vehicle group (see Figure 12). Therefore, in inhibiting the decrease in choroidal thickness in myopic individuals or individuals prone to myopia, bendazac and bendazac lysine showed consistent efficacy, and bendazac significantly inhibited the decrease in choroidal thickness in myopic individuals or individuals prone to myopia, reducing the tendency for choroidal thickness to decrease.

[0277] The above results demonstrate that bendazac and any one of its salt forms (e.g., bendazac lysine) can effectively treat myopia, slowing the process of refractive error in myopic individuals or individuals prone to myopia by inhibiting axial elongation and reducing the increase in vitreous chamber depth. Furthermore, bendazac and its pharmaceutically acceptable salts (e.g., bendazac lysine) can effectively increase choroidal thickness and reduce myopia. The dosage form of bendazac and its pharmaceutically acceptable salts (e.g., bendazac lysine) for the treatment and prevention of myopia may be eye drops, eye ointments, eye sprays, ophthalmic injections, and eye gels, and devices, formulations, or pharmaceutical compositions containing such compounds (drugs) can be used to control the progression of myopia.

[0278] Example 9 Therapeutic Effects of Sorbinil and Zopolrestat on a Guinea Pig Model of Form Deprivation Myopia

[0279] After removing animals with obvious ocular disease or abnormalities, 3-week-old tricolor guinea pigs were subjected to refraction (infrared eccentric ophthalmoscope) and axial measurement (A-ultrasound). Animals with refractive power between 3 and 8 diopters (D) and binocular refractive index variation of 2D or less were selected and randomly divided into three groups: FD + DMSO, FD + Sorbinil, and FD + Zopolrestat. Based on compound database information, the IC50 of zopolrestat was 3.1 nM and the IC50 of sorbinil was 3.14 ± 0.02 μM. The final concentrations of the Zopolrestat formulation and the Sorbinil formulation used by the inventors during the experiment were 1 mM and 100 μM, respectively. At 8:00 AM on the first day of the experiment, the guinea pigs underwent form-deprivation myopic molding. The morphological deprivation myopia model employed a masking technique. The inventors placed a 10-inch, nontoxic, milky-white latex balloon mask on the right eye (experimental eye) of each guinea pig molding, and no mask on the left eye (contralateral eye). FD induction was continuously performed throughout the bendazacricin efficacy experiment, with the mask temporarily removed only for administration or ocular measurements (e.g., refraction measurement). The mask position was monitored daily at 8:00 AM, 12:00 PM, 7:00 PM, and before administration. Animals that removed the mask three or more times were culled. Starting on the day of molding, the vehicle or drug corresponding to the experimental eye of the FDM model was administered once daily between 9:00 AM and 10:00 AM. The administration frequency was 100 μL per day via juxtaconjunctival injection. The administration was continuous for two weeks. The refraction and axial parameters of the test animals were measured at the start of the model efficacy experiment and after one and two weeks. All data collection and processing methods were the same as in the literature published by the inventor's laboratory [4], and the statistical basis was the difference between the experimental eye and the contralateral eye of the same test subject. All of the above efficacy experiments were repeated at least three times. In this example, the test drugs and solvent controls (negative control groups) were all prepared by the inventor.

[0280] The results showed that administration of sorbinil and zopolrestat had no therapeutic effect on myopia and failed to control myopia progression. These two aldose reductase inhibitors inhibited the FD-induced refractive error process and failed to slow the progression of axial elongation in myopic individuals. Throughout the experimental period, sorbinil and zopolrestat showed no significant differences in refractive index or axial parameter indexes compared to the vehicle group at each measurement point (Figure 13). Furthermore, administration of sorbinil and zopolrestat did not affect the corneal curvature, anterior chamber depth, or corneal thickness-related indexes of the test individuals (see Figure 14). Therefore, aldose reductase is not a target for the development of myopia treatments, and not all aldose reductase inhibitors are effective in preventing and controlling myopia.

[0281] Example 10 Therapeutic effect of m-hydroxymethylaniline on a guinea pig model of morphological deprivation myopia

[0282] The efficacy of the drug was evaluated using the guinea pig model of myopia described in this application. Refractive index and ocular axis were measured for all animals. After excluding unsuitable animals, the animals were randomly divided into three groups: FD + 0.9% saline (NS), FD + metahydroxymethylaniline (Compound A), and FD + 0.1% atropine (positive control). At 8:00 AM on the first day of the experiment, guinea pigs underwent morphological deprivation. A mask was applied to the right eye (experimental eye) and the left eye (contralateral eye) without a mask. Starting on the day of molding, vehicle or drug was administered to the corresponding experimental eye group between 9:00 AM and 10:00 AM daily via juxtaconjunctival injection in a volume of 100 μL. The administration was performed once daily for one week. Refractive index and ocular axis parameters were measured at the beginning and end of the efficacy experiment. All data collection and processing methods were the same as in other examples of this application. The statistical basis was the difference between the experimental eye and the contralateral eye of the same subject.

[0283] In this experiment, the changes in refraction and axial parameters of the animals in the negative control group were as expected for the myopia model, and the positive control drug atropine demonstrated the expected efficacy during the experiment, demonstrating that the myopia model for this experiment was successfully molded and can be used to evaluate the efficacy of test drugs. As shown in Figure 15, the experimental results showed that administration of meta-hydroxymethylaniline did not result in a decrease in refraction or an increase in vitreous chamber depth or axial length, indicating that meta-hydroxymethylaniline has no effect on the prevention or treatment of myopia. After administration of meta-hydroxymethylaniline, neither the axial parameters nor the refraction of the test animals were statistically different from those of the negative control group, indicating that the drug had no inhibitory effect on axial elongation or slowing the increase in vitreous chamber depth in myopic individuals. In this experiment, atropine demonstrated a normal myopia treatment effect. None of the test animals in this group exhibited pupil dilation, and anterior chamber depth and lens thickness were unaffected after administration (Figure 15). From the above, the experimental results prove that not all compounds (drugs) with cataract treatment effects can be used to treat myopia, and not all compounds with antioxidant activity or that can reduce BLOA (Biological Liquid Oxidant Activity) have the medicinal effect of preventing and controlling myopia.

[0284] Finally, it should be noted that the above embodiments are merely for illustrating the technical solutions of the present application, and are not intended to limit the same. Although the present application has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may still be modified, or some or all of the technical features may be replaced with equivalents. Such modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application, and should all be included within the scope of the claims and description of the present application. In particular, as long as there is no structural conflict, the technical features described in the embodiments may be combined in any manner. The present application is not limited to the specific embodiments disclosed in the description, but includes all technical solutions within the scope of the claims.

[0285] References:

[0286] 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 Eye Res 2006;82:628-636.

[0287] 2Lu F, Zhou X, Jiang L, et al.Axial myopia induced by hyperopic defocus in guinea pigs:A detailed assessment on susceptibility and recovery.Exp Eye Res 2009;89:101-108.

[0288] 3Wu H,Chen W,Zhao F,et al.Scleral hypoxia is a target for myopia control.Proc Natl Acad Sci USA 2018;115:E7091-E7100.

[0289] 4Pan M,Zhao F,Xie B,et al.Dietary omega-3polyunsaturated fatty acids are protective for myopia.Proc Natl Acad Sci U S A 2021;118.

Claims

1. 1. A composition for treating, preventing, or delaying myopia or its related symptoms in an individual, comprising bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a crystalline compound thereof, or a combination of these substances, wherein said bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a crystalline compound thereof, or a combination of these substances, is the sole or major active ingredient in said composition; The symptoms related to myopia include severe myopia complications, floaters, glaucoma, posterior staphyloma, and retinal detachment. , retinal tears, amblyopia, submacular hemorrhage, choroidal neovascularization, choroidal atrophy, visual field defects, gradual or sudden decrease in vision, swelling or pain in the eye, night blindness, astigmatism, refractive index variation, blindness, vitreous liquefaction, vitreous opacification, strabismus, frequent blinking, frequent eye rubbing, blurred vision when looking at distant objects and needing to squint or partially close the upper eyelid to see distant objects clearly, headache due to eye fatigue, difficulty seeing while driving, retinal atrophy and degeneration, subretinal neovascularization, and ocular atrophy. A composition characterized by:

2. (a) used in combination with surgery, including at least one selected from the group consisting of refractive surgery, myopic corneal laser surgery, and lens surgery, to prevent and / or treat myopia and its associated conditions; (b) Used in combination with a vision correction device including at least one selected from the group consisting of corneal contact lenses, frame-type anti-myopia glasses, and orthokeratology lenses to prevent and / or treat myopia and its related symptoms; (c) used in combination with one or more other drugs to prevent and / or treat myopia and myopia-related conditions; The composition according to claim 1, characterized in that it contains at least one of (a) to (c).

3. 3. The composition according to claim 1, wherein the individual is a myopic individual or an individual prone to myopia.

4. 4. The method according to claim 3, wherein the myopic or myopically prone individual is a human being. The composition described above.

5. 4. The composition of claim 3, wherein the myopic or myopically prone individual is a child, adolescent, middle-aged or elderly person.

6. The myopia may be refractive myopia or axial myopia, congenital myopia, early-onset myopia, late-onset myopia, late-onset myopia, low myopia, moderate myopia, high myopia, pseudomyopia, true myopia, semi-true semi-pseudomyopia, childhood and / or adult myopia. or juvenile myopia, juvenile myopia, adult myopia, geriatric myopia, simple myopia, pathological myopia, simple axial myopia, axial myopia of children and / or adolescents, axial myopia in school-age and pre-school populations, primary myopia, secondary myopia, primary myopia of children and / or adolescents, progressive myopia of children and / or adolescents, refractive myopia, exponential myopia, myopia due to forward displacement of refractive media, flexional myopia, myopia due to prolonged eye use in close work, myopia and pseudomyopia due to eye strain, negative refraction or myopia due to side effects of medication, myopia due to reading, myopia due to use of electronic products, myopia due to mismatch of refractive media, refractive myopia, myopia due to abnormal refractive development, myopia due to excessive ocular growth, myopia due to poor eye hygiene, myopia with poor or ineffective treatment with atropine, myopia due to lack of outdoor exercise, and tension myopia or myopia due to environmental factors, 3. The composition according to claim 1 or 2.

7. The composition is for use in a systemic, topical, parenteral, non-invasive, or non-invasive manner. The composition according to claim 1 or claim 2.

8. the one or more other drugs and the bendazacricin or bendazac, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a crystalline compound thereof, or a combination of these substances, are administered sequentially, simultaneously, alternately, at intervals, or separately; The composition of claim 2.

9. the one or more other drugs comprise at least one selected from the group consisting of a myopia treatment drug, an M receptor blocker, bendazac or its various salt forms, bendazac lysine or its various salt forms, polyunsaturated fatty acids, salidroside, formononetin, prazosin, homatropine, anisodamine, tropicamide, nicotinic acid, piracetam, Danshen extract, safflower extract, fish oil, bear bile extract, vitamins, adenosine triphosphate (ATP), non-selective adenylate antagonists, vasodilators, smooth muscle dilators, vasospasmodics, collagen metabolism regulators, anti-allergic drugs, anti-inflammatory drugs, liver protectors, ophthalmic disease treatment ingredients, ophthalmic local anesthetics, mydriatics, and ophthalmic agents or drugs; The composition of claim 2.

10. The myopia treatment drugs include atropine, bendazole, pirenzepine, muscarinic antagonists, 7-methylxanthine, aminobenzylamine, timolol maleate, adrenaline, perazine, and perlapine.

10. The composition of claim 9, comprising at least one selected from the group consisting of Perlapine, perlapine, methylamine, chlorisondamine, an acetylcholinesterase inhibitor, a dopamine agonist, gamma-aminobutyric acid, naloxone, glucagon, and retinoic acid.

11. The composition according to claim 9, wherein the M receptor blocker is a blocker, antagonist, or inhibitor targeting the M3 receptor.

12. The concentration or ratio of the bendazacricin or bendazac, or an optical isomer or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a crystalline compound thereof, or a combination of these substances in the composition is at least 0.01% or more in terms of percentage, and the percentage is expressed as a ratio of mass / volume concentration, a mass ratio, or a ratio of moles.

3. The composition according to claim 1 or 2.

13. The composition is in the form of an injection, a tablet, a freeze-dried injection, a capsule, an effervescent tablet, a chewable tablet, a troche, a granule, an ointment, a syrup, an oral solution, a spray, a nasal drop, an external preparation, a suspension, a rub, a lotion, a cream, a drop, a granular preparation, a spray, an ointment, a patch, a paste, a pill, and a suppository or an emulsion.

3. The composition according to claim 1 or 2.

14. The composition is an ophthalmic dosage form.

14. The composition of claim 13.

15. The composition is in the form of eye drops, eye ointment, eye spray, implant sheet, eye gel, eye pack, ophthalmic microsphere, ophthalmic sustained release preparation, periocular injection or intraocular injection.

15. The composition of claim 14.

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