Methods and formulations for treating visual impairment

Abstract

The present invention provides ophthalmic formulations comprising long-acting beta-adrenergic receptor agonist (LABA) compounds, long-acting muscarinic antagonists (LAMA), and combinations thereof. Also provided are methods of treating visual impairment with LABA, LAMA, and combinations thereof.

Description

BACKGROUND

[0001] It is important to consider that myopia, amblyopia, and related vision disorders arise in childhood. It is at this early stage in life that effective corrective means should be introduced. Currently, the usual treatment is to wear glasses, but this is only a stopgap measure, as vision can continue to deteriorate, requiring ever-increasing lens powers. Physical changes can occur to the eyeball, which can lead to serious eye conditions. Thus, there is an ongoing search for more permanent forms of correction for these conditions, such as the use of the anticholinergic antagonist atropine, to treat myopia, amblyopia, and related conditions, especially in Asia. However, atropine can lose its effectiveness with long-term use, and has many undesirable side effects in the eye, and potentially life-threatening cardiac side effects in the body as a whole. In short, atropine can have undesirable side effects that should be avoided in pediatric ophthalmology, and current methods rely heavily on reducing dosing. SUMMARY

[0002] There is an urgent need for safe, effective, and more convenient alternatives to treat many vision disorders. Long-acting beta-adrenergic receptor agonists (LABAs) can safely and efficiently replace current treatment regimens for a wide variety of vision disorders. Long-acting muscarinic antagonists (LAMAs) are improved atropine-like compounds, and their clinical performance can be improved by the addition of LABAs or other beta-adrenergic receptor agonists.

[0003] Provided herein are methods of drug application and formulations for treating vision disorders by employing LABAs, LAMAs, and combinations of the two drug classes. These methods involve treating vision disorders such as pseudomyopia, preclinical myopia, cycloplegia, and myopia. In addition, other disorders characterized by abnormal ciliary muscle tone, such as anisometropia and amblyopia, can be treated using the compounds described herein. In addition to improving visual acuity, the methods described herein can attenuate axial elongation and abnormal development of the eyeball associated with vision disorders. Such corrective benefits are achieved by the administration of LABAs, LAMAs, or combinations thereof. In the case of myopia, LABAs maintain a stable and adjustable relaxation of the ciliary muscle, preventing the progression of myopia to presbyopia. By employing the compounds described herein, light can be more precisely focused on the retina and sharper vision can be achieved. Eye strain, a major exacerbating factor, can also be attenuated.

[0004] In the case of anisometropia, amblyopia, and certain related vision disorders, the pathophysiology is a persistent underuse of one eye. This underuse is progressive. The underused eye is often referred to as the “lazy” eye. The other eye can be referred to as the “normal” eye, the “unaffected” eye, the “dominant” eye, the “preferred” eye, or the “strong” eye. Ultimately, anisometropia, amblyopia, and related vision disorders result in the patient becoming completely dependent on the “dominant” eye and abandoning use of the “lazy” eye. The goal of treatment is to prevent abandonment of the “lazy” eye and to prevent the patient from developing monocular vision. This is currently achieved by applying a patch or atropine to the “dominant” or “strong” eye, resulting in a reduction in use of and over-reliance on the “dominant” or “preferred” eye, and an increase in the participation of the “weaker” eye, to restore binocular vision.

[0005] As provided in the methods described herein, LABAs can similarly be used to impair vision in the “normal” or “dominant” eye, described herein with the term “beta-adrenergic agonist penalty.”

[0006] Methods of treating impaired vision by modulating ciliary muscle tone using LABAs are also described. As non-limiting examples, such impaired vision conditions can include anisometropia, amblyopia, pseudomyopia, and myopia. LABA compounds are those compounds described as LABAs according to the American Academy of Allergy, Asthma, and Immunology (AAAAI Allergy and Asthma Medication Guide, 2016), and include formoterol, salmeterol, arformeterol, and olodaterol. The amount of LABA administered to a subject can range from about 0.001% to about 10% (weight / volume, e.g., mg / mL). Additional non-limiting methods of drug delivery to the ciliary muscle include, for example, anterior chamber implants, subconjunctival injections, subconjunctival / suprachoroidal implants, and topical application to the peri-orbital region (see, e.g., U.S. Patent No. 9820954).

[0007] Without being bound by theory, it is believed that LABAs as described herein can reduce the resting tone of the ciliary muscle, thereby reducing the onset of ciliary muscle contraction and spasm associated with pseudomyopia. In contrast, short-acting beta-adrenergic agonists, such as albuterol (Rekik, WO 2018 / 007864 Al, 2018) and isoproterenol can produce a relatively short-lived effect and a propensity for episodic ciliary spasm. The opposite effect of LABAs on ciliary muscle contraction as described herein can provide an effective treatment for myopia, thereby reducing or eliminating the need for eyeglasses or contact lenses, or slowing the rate of increasing prescription strength of corrective lenses. By employing the methods provided herein, the risk of retinal detachment, myopia-induced retinopathy, and glaucoma can be mitigated or prevented. Repeated episodes of retinal detachment can lead to blindness. However, the increase in ocular axial length that can occur in myopia and amblyopia can be attenuated or eliminated following treatment with LABAs using the methods described herein.

[0008] Antimuscarinic drugs, particularly atropine, have been used to treat myopia and amblyopia, but while effective, can cause side effects such as mydriasis, dry eye, and photophobia. The incidence of mydriasis can be reduced by using LABAs, optionally in combination with antimuscarinic drugs. Antimuscarinic drugs can also reduce lacrimal gland secretion, leading to “dry eye.” In fact, atropine has been used in animal models to produce dry eye (Burgalassi et al., Development of a simple dry eye model in the albino rabbit and evaluation of some tear substitutes. Ophthalmol Res. 31 :229-235, 1999). By using long-acting beta-adrenergic therapy in place of or in addition to antimuscarinic agents, the dry eye side effects can be avoided, reduced, or eliminated. Furthermore, antimuscarinic agents can produce serious cardiac side effects, which can be more pronounced in small children. Of particular concern is an increase in uncontrolled heart rate, which in some cases can be fatal. LABAs are known to be safe to the heart in children and have been widely used to treat asthma in adolescents. Thus, LABAs as described herein can be used in combination with antimuscarinic agents to reduce the required dose and thereby reduce unwanted side effects associated with antimuscarinic drugs. Formulations are provided having a concentration of LABA and / or LAMA of about 0.0001% to about 10% (weight / volume). The methods and formulations described herein can include one or more LABAs (or one or more LABAs and one or more antimuscarinic agents) and optionally an alpha-adrenergic compound, such as brimonodine.

[0009] As described herein, vision disorders as generally described can be effectively treated by using a LABA, LAMA, or a combination thereof. Depending on the vision disorder that can be corrected by changing, for example, ciliary muscle tone, the treatment can be to both eyes or to a single eye. Many drug delivery methods can be used, including, but not limited to, eye drops and implants.

[0010] A method for treating a vision disorder in a subject in need of vision correction is provided. The method includes administering a LABA, LAMA, or a combination thereof to one or both eyes of the subject.

[0011] The method can optionally include one or more of the following features. The administration can be ocular or periocular. The vision disorder can be a disorder that can be treated by ciliary muscle accommodation in the affected eye or the unaffected eye of the subject. The disorder can be selected from the group consisting of myopia, preclinical myopia, pseudomyopia, ciliary muscle paralysis, hyperopia, exophoria, amblyopia, anisometropia, esotropia, exotropia, Duane’s syndrome I, Duane’s syndrome II, Brown’s syndrome, surgical-induced ocular complications, ocular injury or orbital bone fracture, vision disorder caused by retinal detachment, vision disorder caused by cataract, vision disorder associated with diabetes, vision disorder associated with myasthenia gravis, and vision disorder associated with Grave’s disease. The LABA, LAMA, or a combination thereof can be administered to the affected eye, the unaffected eye, or both of the subject. The disorder can be selected from the group consisting of anisometropia, amblyopia, esotropia, exotropia, and complications thereof. The disorder can be selected from the group consisting of myopia, pseudomyopia, hyperopia, and exophoria. The LABA, LAMA, or a combination thereof can be administered to the eye as a topical ophthalmic formulation. The LABA, LAMA, or a combination thereof can be administered to the eye as eye drops. The LABA, LAMA, or a combination thereof can be administered to the eye by topical application to the peri-orbital skin. The LABA, LAMA, or a combination thereof can be administered to the eye as an implant. The implant can be an intracameral implant or a suprachoroidal implant. The LABA can be selected from the group consisting of albuterol, formoterol, salmeterol, arformoterol, olodaterol, and combinations thereof. The LAMA can be selected from the group consisting of tiotropium, aclidinium, glycopyrronium, and combinations thereof. The combination of LABA and LAMA can be in the form of a single hybrid molecule. Single hybrid molecules (MABAs) that exhibit both muscarinic antagonist and beta-adrenergic properties can be selected from batefenterol, AZD2115, and AZD8871.

[0012] The method, in addition to administering the LABA and / or LAMA, can optionally further comprise administering a muscarinic antagonist to the eye of the subject. The method can optionally include one or more of the following features. The muscarinic antagonist can be administered to the same eye of the subject to which the LABA is administered. The muscarinic antagonist can be selected from the group consisting of atropine, scopolamine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, cyclopentolate, atropine methonitrate, trihexyphenidyl, tolterodine, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, aclidinium bromide, and combinations thereof. The muscarinic antagonist can be atropine. Optionally, the subject can be a subject who was previously treated with atropine. Optionally, the dose of atropine used in combination with the LABA can be reduced relative to the dose of atropine administered to the subject prior to treatment with the LABA.

[0013] The method, in addition to administering the LABA and / or LAMA, can optionally further comprise administering an alpha-adrenergic agonist to the subject. The method can optionally include one or more of the following features. The alpha-adrenergic agonist can be selected from the group consisting of methoxamine, midodrine, oxymetazoline, metaraminol, phenylephrine, clonidine, guanfacine, guanabenz, guanoxybenz, guanethidine, xylazine, mizanidine, medetomidine, methyldopa, methylnorepinephrine, fadolmidine, dexmedetomidine, amidephrine, amitraz, anisodamine, apraclonidine, brimonidine, cirazoline, detomidine, epinephrine, ergotamine, etilefrine, indanidine, lofexidine, medetomidine, mephentermine, metaraminol, methoxamine, mivazerol, naphazoline, norepinephrine, norfenefrine, octopamine, oxymetazoline, phenylpropanolamine, propylhexedrine, rilmenidine, romifidine, synephrine, talipexole, salts thereof, and combinations thereof. The alpha-adrenergic agonist can be brimonidine.

[0014] The method can optionally further comprise administering a phosphodiesterase (PDE) inhibitor to the subject in addition to administering the LABA, LAMA, and / or alpha- adrenergic agonist. The method can optionally include one or more of the following features. The phosphodiesterase (PDE) inhibitor can be selected from the group consisting of: vinpocitine, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), 2-[(3,4-dimethoxyphenyl)methyl]-7-[(2R,3R)-2-hydroxy-6-phenylhexan-3-yl]-5-methyl-1H- imidazo[5,1-f][1,2,4]triazin-4-one, oxindole, 9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4- dimethoxybenzyl)-purin-6-one (PDP), inamrinone, milrinone, enoximone, anagrelide, cilostazol, and pimobendan, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, sildenafil, Tadalafil (tadalafil), vardenafil, udenafil, avanafil, dipyridamole, quinazoline, papaverine, and combinations thereof. The phosphodiesterase inhibitor can be theophylline.

[0015] Also provided are ophthalmic formulations comprising a LABA. The beta-adrenergic receptor agonist can be selected from the group consisting of: olodaterol, salbutamol, formoterol, salmeterol, bambuterol, clenbuterol, protokylol, and ulotropin, carmoterol, indacaterol, and combinations thereof. The LABA can be present at a concentration of about 0.0001% to about 10% w / v. The formulation can be a topical ophthalmic formulation. The topical ophthalmic formulation can be in the form of an eye drop. The topical ophthalmic formulation can be in the form of a peri-orbital formulation.

[0016] The ophthalmic formulation can optionally further comprise a muscarinic antagonist. The muscarinic antagonist can be selected from the group consisting of atropine, scopolamine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, cyclopentolate, atropine methonitrate, trihexyphenidyl, tolterodine, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, aclidinium bromide, and combinations thereof. The muscarinic antagonist can be atropine. The muscarinic antagonist can be present at a concentration of about 0.0001% to about 10% (w / v). Optionally, the ophthalmic formulation can comprise a muscarinic antagonist / β2-agonist hybrid molecule, which can be selected from bafituximab, AZD2115, and AZD8871.

[0017] Also provided is a method for improving visual acuity of an affected eye of a subject having myopia, comprising administering to the subject a LABA, a LAMA, or a combination thereof, or a β-adrenergic agonist / muscarinic antagonist in a single hybrid molecule to the subject.

[0018] The methods described herein provide several advantages. First, the methods can provide safe and effective, persistent (or, in some cases, long-term, semi-persistent) treatment of visual impairment by modulating ciliary tone. Thus, unlike corrective lenses, the methods described herein can prevent the development of more severe ocular conditions, such as retinal detachment, myopic retinopathy (such as neovascularization, lattice degeneration, and tears / holes), staphyloma, cataracts, and glaucoma, which can develop as a result of the progressive physical changes to the eyeball that occur with the visual impairment described herein if left untreated or if treated symptomatically by other means, such as corrective lenses.

[0019] Second, the methods described herein can reduce the dependence on corrective lenses in subjects with such visual impairment. For example, the methods described herein can result in visual improvement, including improvement in visual acuity. Abnormal axial elongation of the eye can be avoided, and thus complications, particularly severe, sight-threatening retinal disorders, can also be avoided.

[0020] Third, the methods described herein can reduce or even eliminate the use or dependence on treatments that can have more severe side effects. For example, the commonly used muscarinic agent, atropine, can produce ocular side effects such as dry eye, mydriasis, photophobia. Atropine can cause cardiac arrest when absorbed into the bloodstream, due to sympathetic nervous stimulation of the heart rate out of sync; this can arise due to the reduction or prevention of parasympathetic neuronal input that normally negatively regulates heart rate. Atropine is a derivative of Atropa Belladonna, one of the most toxic plants known (e.g., atropa belladonna poisoning). Unrestricted use of atropine in young children can be fatal. The methods described herein can provide a safe and effective alternative treatment for visual impairment using a reduced dose of atropine or other muscarinic antagonists. As described herein, the methods can provide a safe, effective, and optimized treatment for visual impairment without the use of atropine.

[0021] Fourth, the methods described herein can provide a sustained effect with a long duration of action in the eye of a subject, thereby allowing for increased safety. The methods described herein can provide long duration of accommodation of the ciliary muscle using a LABA, LAMA, or a combination thereof, which are administered together or separately, or as a hybrid molecule with both beta-adrenergic agonist properties and muscarinic antagonist properties. The methods and formulations described herein can optimally reduce and reset the tension of the ciliary muscle, thereby reducing the onset of ciliary muscle contraction and spasm. The methods and formulations described herein produce a greater effect on ciliary spasm than transient effects. The methods and formulations described herein do not cause sudden ciliary spasm nor do they convert myopic patients to presbyopic.

[0022] Fifth, by providing a long or extended duration of activity in the eye, the methods described herein can provide a safer and more practical treatment option for pediatric patients.

[0023] The details of one or more embodiments of the application are set forth in the accompanying drawings and the detailed description below. Other features, objects, and advantages of the application will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1A is a graph showing the effect of salmeterol on paired monkey longitudinal ciliary muscle preparations contracted by carbachol.

[0025] Figure 1B Figure 2 is a graph showing the effect of tiotropium on paired monkey longitudinal ciliary muscle preparations contracted by carbachol.

[0026] Figure 1C Figure 4 is a graph showing the effect of a combination of salmeterol and tiotropium on paired longitudinal ciliary muscle preparations contracted by carbachol. DETAILED DESCRIPTION

[0027] Provided herein are methods and formulations for treating visual impairment by employing long-acting beta-adrenergic receptor agonist (LABA) compounds, long-acting muscarinic antagonists (LAMA), and combinations thereof.

[0028] The present disclosure relates to the treatment of visual impairments (e.g., pseudomyopia, myopia, and other impairments such as aniseikonia and amblyopia) that can be altered (e.g., the symptoms or course of the disease can be altered) by ciliary muscle accommodation, including accommodation and adjustment of ciliary muscle tone. The methods provided include administering to a subject having a visual impairment a LABA, a LAMA, and combinations thereof, administered separately or together, or as a hybrid molecule having both beta-adrenergic agonist properties and muscarinic antagonist properties.

[0029] The tissue central to myopia is the ciliary muscle. The function of the ciliary muscle is to control the spherical shape of the lens, which controls the focus of light through the eye. The ability of the eye to focus on objects at different distances from the eye is known as accommodation, a key function of the eye.

[0030] Myopia often begins as pseudomyopia. Pseudomyopia describes a temporary shift in light refraction due to transient spasm of the ciliary muscle and the inability of the ciliary muscle to relax properly. Pseudomyopia can occur due to excessive parasympathetic neuronal activity or due to eye strain or fatigue. This persistent fatigue often leads to elongation of the eyeball over time. Persistent fatigue from children viewing objects up close is a contributing factor to the extension of the axial length of the eye.

[0031] Corrective lenses, such as eyeglasses and contact lenses, are commonly used to treat myopia, but these lenses often only shift the focal point so that light converges on the retina instead of in the vitreous humor. In short, eyeglasses and contact lenses often only improve vision by changing the focal point, not improving the control of the ciliary muscle over accommodation. The eye then tends to adjust to create a new focal point, and gradually, this leads to elongation of the eyeball. Thus, the prescription power of the lenses often deepens, the ciliary muscle function is further impaired, and a negative cycle can ensue. The ciliary muscle can remain tense, with lower ability to relax. Unwanted side effects can eventually occur, including retinal detachment, myopic retinopathy, and glaucoma.

[0032] Current drug therapies for myopia involve reducing the tension of parasympathetic neurons to relax the ciliary muscle. This is typically achieved using muscarinic receptor antagonists (almost always atropine). Atropine can cause dry eye, mydriasis, and photophobia, and can produce serious cardiac side effects when absorbed into the bloodstream. In some cases, the effects on heart rate can be fatal. Atropine can also become less effective over time. These characteristics make atropine particularly unpopular and potentially dangerous in pediatric patients (i.e., those who should receive corrective treatment).

[0033] While the parasympathetic nervous system primarily controls the tension of the ciliary muscle, the sympathetic nervous system provides the opposite regulatory input. Sympathetic neuronal input relaxes the ciliary muscle, counteracting the contractile activity of the parasympathetic nervous system. One of the several target receptors mediating ciliary muscle relaxation is the β-adrenergic receptor (β-adrenergic receptor). (See Hahnenberger, Exp Eye Res 46, 421-430, 1988). LABA can provide a method for stable control of ciliary muscle tone, and it can be used in combination with or as an alternative to atropine therapy.

[0034] Amblyopia (often called lazy eye) also manifests in childhood and, if left untreated, will result in monocular vision in adulthood. Anisometropia is often a precursor to amblyopia. In amblyopia and related visual impairments, one eye is preferentially used over the other (or lazy) eye. The "lazy" eye has weaker vision and is therefore neglected. There are many possible causes for the development of "lazy eye." These causes can include poor vision due to poor accommodation, suboptimal eye movements due to extraocular muscle dysfunction, or problems with the visual cortex. Regardless of the pathophysiological origin of "lazy eye," the treatment is the same.

[0035] A common treatment involves using separate prescription lenses for each eye. Glasses are not a long-term solution and only meaningfully improve vision in the dominant eye. Subjects often retain amblyopia.

[0036] Another common strategy that yields positive results involves weakening the dominant eye, or the unaffected eye, forcing the lazy or affected eye to take over. One method of weakening the dominant eye is to place a patch on it, for example, for six hours. However, pediatric patients may have poorer adherence to wearing the patch. Another approach, known as atropine punishment, involves impairing the focusing of the dominant eye by altering ciliary muscle tone and thus changing accommodation. LABA, LAMA, and combinations thereof, or hybrid molecules with β-adrenergic agonist and muscarinic antagonist properties, could be practical solutions for providing a more stable "punishment."

[0037] As described in the methods herein, LABA, LAMA, and combinations thereof, administered together or separately, or as hybrid molecules possessing β-adrenergic agonist and muscarinic antagonist properties, can modulate ciliary muscle tone to allow for the treatment of appropriate visual impairments. In the methods described herein, treatment with LABA, LAMA, or combinations thereof, or hybrid molecules possessing β-adrenergic agonist and muscarinic antagonist properties, can improve visual acuity, reduce axial elongation, and limit abnormal eye development associated with visual impairments. In treating subjects with myopia, LABA, LAMA, or combinations thereof, or hybrid molecules possessing β-adrenergic agonist and muscarinic antagonist properties, can maintain stable relaxation of the ciliary muscle and thereby improve accommodation, allowing light to focus precisely on the retina and resulting in clearer vision. Furthermore, the long-lasting effects provided by LABA, LAMA, and combinations thereof can lead to a faster recovery of use in "lazy" eyes and promote binocular vision. In treating subjects with anisometropia or amblyopia, application to the dominant eye can lead to a reduction in over-reliance on the "stronger" dominant preferred eye and an increase in the involvement of the "weaker" eye, thus restoring binocular vision. Eye fatigue, a major contributing factor to worsening, can also be alleviated.

[0038] A range of different intensities (doses) of LABA, LAMA, or both (when present in combination) have been considered. The dosage of LABA, LAMA, combinations thereof, or hybrid molecules possessing β-adrenergic agonist and muscarinic antagonist properties can be based on the individual needs of the individual subject. Individual visual acuity may vary in a single subject, and therefore dosage requirements may also differ. As used herein, dosage refers to the amount of active ingredient administered to an individual at each administration. Dosage will vary depending on many factors, including the normal dose range for a given therapy, frequency of administration, individual size and tolerability, severity of the condition being treated, risk of side effects, and route of administration. Those skilled in the art will recognize that dosage may be modified based on the factors mentioned above or based on treatment progress.

[0039] This article provides methods for treating visual impairment in subjects. Methods for treating visual impairment in subjects include administering LABA, LAMA, combinations thereof, or a single drug exhibiting both activities to the subject. The drugs may be formulated into suitable compositions for application to the subject, for example, the subject's eye. The composition may contain one or two drugs. If administered separately, the drugs are formulated into separate compositions. Methods for treating impaired vision by modulating ciliary muscle tone are also provided. For example, a method for treating impaired vision in subjects by modulating ciliary muscle tone using LABA, LAMA, combinations thereof, or a single drug exhibiting both activities is provided.

[0040] The methods described herein can be used to treat visual impairments in either the affected or unaffected eye that can be modified by ciliary muscle accommodation. Examples of visual impairments for which monocular therapy is preferred for the unaffected eye include anisometropia, amblyopia, hyperopia / myopia, esotropia, exotropia, Duenn syndrome I / II, Brown's syndrome, and monocular trauma (such as orbital fractures). Binocular therapy can preferably be used to treat pseudomyopia, myopia, exophoria, and visual complications caused by systemic diseases such as Graves' disease, myasthenia gravis, and diabetes. Depending on the apparent differences during visual examination, different drug “strengths” may be required. LABA, LAMA, combinations of β-adrenergic receptor agonists and LAMA, or single drugs exhibiting both activities can be administered to the affected eye of a subject with visual impairment. It is not intended to be theoretically constrained, but it is believed that LABA, LAMA, combinations of β-adrenergic receptor agonists and LAMA, or single drugs exhibiting both activities can modulate ciliary muscle tone in the affected eye, thereby alleviating at least one symptom of the visual impairment. Administering LABA, LAMA, a combination of a β-adrenergic receptor agonist and LAMA, or a single drug exhibiting both activities to the affected eye of a subject with visual impairment can improve the subject's vision. Optionally, LABA, LAMA, a combination of LABA and LAMA, or a single drug exhibiting both activities can be administered to the unaffected eye of a subject with visual impairment. Without being bound by theory, it is believed that LABA, LAMA, a combination of LABA and LAMA, or a single drug exhibiting both activities can modulate ciliary muscle tone in the unaffected eye, thereby alleviating at least one symptom of visual impairment. Administering LABA, LAMA, a combination of LABA and LAMA, or a single drug exhibiting both activities to the unaffected eye of a subject with visual impairment can improve vision in the subject's affected eye. As used herein, the affected eye is the eye of the subject that is considered to exhibit one or more symptoms associated with visual impairment. For example, non-restrictive symptoms may include irregular eye shape (e.g., elongation), decreased visual acuity (e.g., visual acuity less than 20 / 20, less than 20 / 25, less than 20 / 30, less than 20 / 40, less than 20 / 50, less than 20 / 70, less than 20 / 100, or less than 20 / 200). The unaffected eye is typically the eye that does not exhibit one or more symptoms associated with the visual impairment (e.g., impairment in the subject's other eye), limited or abnormal motility, or decreased visual acuity. However, due to the role of the unaffected eye in compensating for the visual impairment of the affected eye, the unaffected eye may exhibit some collateral symptoms, such as eye strain.The unaffected eye can be considered the dominant eye, such as in subjects with amblyopia (lazy eye).

[0041] LABAs suitable for use in the provided methods, formulations, and compositions may have long lipophilic side chains and typically exhibit a duration of 6 to 15 hours in lung smooth muscle. Non-limiting examples of LABAs include salbutamol, formoterol, salmeterol, and olodacaterol. Additionally, non-limiting ultra-long-acting β-adrenergic receptor agonists suitable for use in the methods, formulations, and compositions described herein include atorbutol, carmocaterol, and indacaterol. Combinations of β-adrenergic receptor agonists are also contemplated. Exemplary β-adrenergic receptor agonist compounds include those described in the American Academy of Allergy, Asthma, and Immunology (AAAAI Allergy and Asthma Medication Guide, 2016). LABAs can provide sustained, safe, and / or effective reduction in ciliary muscle resting tone, thereby providing treatment via administration to the affected or unaffected eye of a subject with visual impairment.

[0042] Previously, antimuscarinic agents (almost always atropine) were used to treat myopia and amblyopia. Recently, other muscarinic antagonists (including long-acting muscarinic blockers umeclidinium and tiotropium) have been considered for the treatment of myopia (WO Patent No. 2018 / 17445; WO Patent No. 2019 / 018749). While effective, these agents can cause side effects such as mydriasis and photophobia. The incidence of mydriasis and / or photophobia can be reduced by combining LABA with an antimuscarinic agent or by administering LABA instead of the antimuscarinic agent. Antimuscarinic agents may also reduce lacrimal secretion, leading to dry eye. Conversely, LABA therapy can minimize or even improve dry eye symptoms. Furthermore, antimuscarinic agents can cause serious cardiac side effects. Such side effects can be particularly pronounced and dangerous in children, who are the population commonly treated with drug-based therapies due to the visual impairment described in this article. Using a long-acting beta-agonist instead of an antimuscarinic can avoid these serious cardiac side effects. Therefore, LABA can be administered in combination with an antimuscarinic to reduce the required dose of the antimuscarinic, thereby reducing the risk of undesirable side effects associated with antimuscarinic agents such as atropine.

[0043] LABA is used in adequate doses to provide a prolonged residence time in the eye and / or altered by increasing bioavailability to increase the duration of its activity. The duration of action of LABA can be improved by forming ion-pair complexes or by utilizing excipients that increase the amount of drug penetrating into the eye and delivered to the ciliary muscle. LABA can improve therapeutic efficacy by extending the duration of action. At prescribed doses, sustained optimal effects on ciliary muscle tone can be achieved without rebound, spasm, or loss of activity due to low bioavailability of the drug's biological activity in the ciliary muscle tissue. For example, the long-acting effect of salmeterol has been determined to be based on its unique pharmacological properties (Coleman RA On the mechanism of the persistent action of salmeterol: what is the current position? Br J Pharmacol 2009; 158:180-182), rather than its bioavailability.

[0044] LABA, LAMA, combinations thereof, or a single drug exhibiting both activities can be administered as a topical ophthalmic preparation to the affected or unaffected eye of the subject. Optionally, the topical ophthalmic preparation can be administered as eye drops to the affected or unaffected eye of the subject.

[0045] Periorbital administration of LABA, LAMA, combinations thereof, or single drugs exhibiting both activities can be used (US Patent No. 9820954).

[0046] This topical ophthalmic preparation can be administered by applying it topically to the periorbital skin of either the affected or unaffected eye of a subject. During periorbital application, the preparation is applied to the superior and inferior periorbital skin of each eye, without applying it to the upper or lower eyelid or the eyelid margin. In some embodiments, the preparation is applied to the superior and inferior periorbital skin of each eye. Periorbital application of the ophthalmic preparation is further described in U.S. Patent No. 9,820,954.

[0047] Additional delivery methods may be used in the methods described herein to deliver LABA, LAMA, combinations thereof, or a single drug exhibiting both activities. These include implants, such as anterior chamber implants, subconjunctival implants, and suprachoroidal implants, when administered to the affected or unaffected eye of the subject; and injections, such as subconjunctival injections.

[0048] Non-limiting exemplary β-adrenergic receptor agonists that may be used in the methods described herein include LABAs such as artoterol, bamboolol, protokylol, clenbuterol, formoterol, salmeterol, or ultra-long-acting β-adrenergic receptor agonists such as abediterol, carmoterol, indacaterol, olodaterol, vilanterol, their salts, and combinations thereof. LABAs may be selected from the group consisting of formoterol, salmeterol, artoterol, olodaterol, their salts, and combinations thereof. Additional β-adrenergic receptor agonists include isoproterenol, denopamine, dobutamine, dopexamine, prenalterol, xamoterol, bupheninie, fenoterol, isoetarine, levalbuterol, metaproterenol, pirbuterol, procaterol, terbutaline, and ritodrine. Optionally, LABA is salmeterol. Optionally, LABA is formoterol. Optionally, LABA is a β2-adrenergic receptor agonist. Optionally, LABA is a β2 / β3-adrenergic receptor agonist. Optionally, LABA is a β2 / β1-adrenergic receptor agonist.

[0049] Optionally, some LABAs can be safely used in pediatric ophthalmology. According to the American Academy of Allergy, Asthma and Immunology (AAAAI Allergy and Asthma Medication Guide, 2016), salmeterol and formoterol are approved for use in children aged 4 and 5 years, respectively.

[0050] LABA can be present in the formulation at concentrations ranging from about 0.001% to about 10% (by weight / volume). For example, concentrations of about 0.001% to about 9%, about 0.001% to about 8%, about 0.001% to about 7%, about 0.001% to about 6%, about 0.001% to about 5%, about 0.001% to about 4%, about 0.001% to about 3%, about 0.001% to about 2%, about 0.001% to about 1%, about 0.001% to about 0.5%, about 0.001% to about 0.1%, 0.01% to about 9%, about 0.01% to about 8%, about 0.01% to about 7%, about 0.01% to about 6%, about 0.01% to about 5%, about 0.01% to about 0.5%, about 0.01% to about 4%, and about 0.01% of the composition. About 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 2%, about 0.05% to about 1%, about 0.05% to about 0.09%, about 0.01% to about 0.08%, about 0.01% to about 0.075%, about 1% to about 5%, about 2% to about 5%, about 3% to about 5% w / v, about 2% to about 8%, about 3% to about 7% w / w, about 4% to about 6%, about 5% to about 10%, about 5% to about 9%, or about 5% to about 8%, about 5% to about 7%, or about 5% to about 6%. In some embodiments, LABA is present in the composition at a concentration of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.2%, about 0.3%, about 0.4%, or about 0. It is present in amounts of 5%, about 0.6%, about 0.8%, about 0.9%, about 0.001% or about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.015%, about 0.025%, about 0.035%, about 0.045%, about 0.055%, about 0.065%, about 0.075%, about 0.085%, or about 0.095% w / v. Optionally, LABA is present in the composition in an amount of about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% w / v; wherein w / v is mg / mL.Further subdivisions within these ranges were also considered; for example, LABA at approximately 0.001% to approximately 0.1% (w / v), or approximately 0.0015%, 0.002%, 0.0025%, 0.003%, 0.0035%, 0.004%, 0.0045%, 0.005%, 0.0055%, 0.006%, 0.0065%, 0.007%, 0.0075%, 0.008%. It exists in equal amounts of %, 0.0085%, 0.009%, 0.0095%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, or 0.1%. Smaller incremental segmentation ranges were also considered; for example, LABA was present in amounts of about 0.2% to about 0.3% (w / v), or about 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, and 0.30% w / v.

[0051] LABA can exist as a salt or an ion-pair complex. Unbound by theory, it is believed that LABA ion-pair complexes can have an increased residence time in the eye compared to LABA not administered as an ion-pair complex.

[0052] The methods described herein may also include administering one or more muscarinic antagonists to the eye of a subject (e.g., the affected or unaffected eye, depending on the visual impairment). The formulations described herein may also contain one or more muscarinic antagonists. LAMA includes tiotropium bromide, buprofen bromide, and ganrofen bromide. Non-limiting examples of additional muscarinic antagonists include atropine, hyoscine, hydroxyzine, ipratropium, tropicamide, pirenzepine, diphenhydramine, doxylamine, dimenhydrinate, bicyclic amine, flavonoids, oxybutynin, tiotropium bromide, cyclopenton, metronidazole, benztropine, tolterodine, solifenacin, dafenapyr, bentropine, mebendazole, prazole, adesulfuron-methyl, and their bromide salts, their other counterion salts, and combinations thereof. Optionally, the muscarinic antagonist is atropine. Optionally, the muscarinic antagonist is tiotropium bromide. Optionally, the muscarinic antagonist is uridine bromide. Optionally, the muscarinic antagonist is aldidine bromide. Optionally, the muscarinic antagonist is ganro bromide. The muscarinic antagonist can be present in the formulation at a concentration of about 0.0001% to about 10%.

[0053] Subjects who can be treated with the provided methods and formulations for visual impairment include those previously treated with atropine. For example, a subject previously treated with atropine can be selected and treated with LABA. Administration of LABA can lead to a reduction in the need for atropine. For example, the dose of atropine used in combination with LABA in a subject can be reduced relative to the dose of atropine administered to the subject prior to LABA treatment. The need for or use of atropine can be reduced or eliminated entirely, so that subjects previously treated with atropine before initiating LABA treatment no longer require atropine when treated with LABA. Subjects may experience a reduction in side effects associated with atropine use, such as mydriasis, dry eye, and cardiac side effects.

[0054] The method may further include administering one or more alpha-adrenergic agonists to the eye of a subject. The alpha-adrenergic agonist may be combined with LABA, LAMA, a combination thereof, or a single drug exhibiting both activities. The formulations described herein may also contain one or more alpha-adrenergic agonists. The alpha-adrenergic agonist may be selected from alpha-1 agonists (e.g., methoxyamine, midodrine, oxymetazoline, metaraminol, phenoxybenzyl), alpha-2 agonists (e.g., clonidine, guanifacin, guanethidine, guanoxabine, guanethidine, toluidine, mezanidine, methyldopa, methylnorepinephrine, fadomidin, dexmedetomidine), or other alpha-adrenergic agonists, such as amifluan, dimethicone, etc. Scopolamine, aclonidine, brimonidine, cilazolin, detoxidine, adrenaline, ergotamine, etefolin, indanedin, lofexidine, medetomidine, mefenamic acid, metaraminol, methoxyamine, mirtazapine, naphazoline, norepinephrine, detoxolin, octopamine, oxymetazoline, phenylpropanolamine, cyclohexylpropylmethylamine, limeridin, romifedipine, synephrine, talicocel, their salts, and combinations thereof. Brimonidine is an alpha-adrenergic agonist. Alpha-adrenergic agonists can be present in formulations at concentrations from about 0.001% to about 10%.

[0055] The method may optionally further include applying one or more phosphodiesterase (PDE) inhibitors to the eye of a subject. The formulations described herein may also contain one or more phosphodiesterase (PDE) inhibitors. The phosphodiesterase inhibitor may be selected from non-selective inhibitors or subtype-selective inhibitors. Exemplary non-selective inhibitors may include, for example, theophylline, caffeine, aminophylline, IBMX (3-isobutyl-1-methylxanthine), paraxanthine, pentoxifylline, and theobromine. Exemplary non-selective inhibitors may include, for example, PDE1 selective inhibitors such as vinpocetine; PDE2 selective inhibitors such as EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), BAY... 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(2R,3R)-2-hydroxy-6-phenylhex-3-yl]-5-methyl-1H-imidazo[5,1-f][1,2,4]triazin-4-one), hydroxyindole, PDP (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purine-6-one), etc.; PDE3 selective inhibitors, such as amrinone, milrinone, enoxidone, etc. Nagrel, cilostazol, pimoxendan, etc.; PDE4 selective inhibitors, such as pine ketone, cyclophosphamide, isobutylasteride, piramysostide, luteolin, drotavirine, roflurane, apremilast, criborone, etc.; PDE5 selective inhibitors, such as sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, etc.; PDE7 selective inhibitors, such as quinazoline, etc.; PDE10 selective inhibitors, such as papaverine, etc.; and combinations thereof.

[0056] The method may also include administering one or more alpha-adrenergic antagonists to the eye of a subject. Alpha-adrenergic antagonists may be added to LABA, LAMA, combinations comprising a β-adrenergic receptor agonist and LAMA, or single drugs exhibiting both activities. The formulations described herein may also contain one or more alpha-adrenergic antagonists. Alpha-adrenergic agonists may be selected from the following non-limiting examples of α-1 antagonists: phenoxybenzamine, phentolamine, prazosin, doxazosin, bunazosin, alfuzosin, terazosin, tamsulosin, yohimbine, labetalol, carvedilol, tolazoline, trazodone, mirtazapine, indoramin, urapidil, and idazoxan.

[0057] The formulations described herein are administered via the periorbital skin surrounding the anterior portion of the eyeball. This provides a convenient and tolerable route of administration. Furthermore, the periorbital skin provides a large drug reservoir, which facilitates stable drug delivery to the active site. The active ingredient may be LABA, LAMA, a single drug exhibiting β-adrenergic receptor agonist and muscarinic activity, an α-adrenergic agonist, a phosphodiesterase inhibitor, or a combination thereof.

[0058] The formulation may be in the form of a topical ophthalmic preparation. Optionally, the topical ophthalmic preparation may be in the form of eye drops. Optionally, the topical ophthalmic preparation may be in the form of a topical cream, gel, hydrogel, organic gel, dry gel, lotion, nanocomposite hydrogel, foam, or solution dissolved in an organic solvent, for topical application to the periorbital skin. Optionally, the formulation may be in the form of an implant, such as an anterior chamber implant, subconjunctival implant, or suprachoroidal implant; or in the form of an injectable preparation, such as for subconjunctival injection.

[0059] Formulations containing the compounds described herein may contain physiologically compatible mediators used in formulations for the treatment of visual impairment. For example, the formulation may be an eye drop or an injection. The mediator may be selected from known ophthalmic mediators, including but not limited to: saline solutions, aqueous polyethers such as polyethylene glycol, ethylene polymers such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, acrylic polymers such as carboxylated polymethylene gel, vegetable fats such as peanut oil, polysaccharides such as dextran, glycosaminoglycans such as sodium hyaluronate, and salts such as sodium chloride and potassium chloride. The formulation may be in the form of a solution, suspension, ointment, gel, or foam.

[0060] When the methods provided herein are used, subjects may experience improvement or disappearance of one or more symptoms associated with visual impairment in the affected eye, or incidental symptoms (such as eye fatigue) in the unaffected eye. For example, non-limiting symptoms that may be improved include increased regularity in eye shape (e.g., less elongation) and improved visual acuity (e.g., achieving visual acuity better than 20 / 20, better than 20 / 25, better than 20 / 30, better than 20 / 40, better than 20 / 50, better than 20 / 70, better than 20 / 100, or better than 20 / 200). A method for improving visual acuity in the affected eye of a subject with myopia is provided, comprising administering LABA, LAMA, a combination of LABA and LAMA, or a single hybrid drug exhibiting both the properties of a β-adrenergic receptor agonist and a muscarinic antagonist to the subject's eye. LABA, LAMA, combinations of LABA and LAMA, or single drugs exhibiting both activities can provide sustained reduction in ciliary muscle resting tension, thereby reducing ciliary muscle contraction and spasm episodes in the affected eye of subjects in the preclinical stage of myopia or with pseudomyopia. Optionally, the opposing effects of LABA, LAMA, combinations of LABA and LAMA, or single drugs exhibiting both activities on ciliary muscle contraction will similarly treat myopia or ciliary muscle paralysis. Optionally, the need for the use of glasses or contact lenses may be reduced and / or eliminated. Optionally, the prescription power of corrective lenses may be reduced. Optionally, the use of LABA, LAMA, combinations of LABA and LAMA, or single drugs exhibiting both activities may slow the progression of the need for increased prescription power of corrective lenses over time. Optionally, the risk of retinal detachment, myopia-induced retinopathy, and glaucoma will be reduced or eliminated. Optionally, the use of LABA, LAMA, a combination of LABA and LAMA, or a single drug exhibiting both activities can slow, stop, or prevent the increase in axial length of the eyeball that may occur in subjects with myopia or amblyopia.

[0061] Several embodiments of the invention have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. For example, different amounts of LABA, LAMA, combinations comprising LABA and LAMA, or single drugs exhibiting both activities, as well as various forms thereof, can be used in the methods described herein. Therefore, other embodiments are also within the scope of the following claims.

[0062] Example

[0063] Example 1. Ciliary muscle isolated from non-human primates

[0064] A total of four longitudinal ciliary muscle strips were obtained from one monkey eye. Four tissue baths were used simultaneously for each experiment. The monkey ciliary muscle preparations were incubated in Krebs bicarbonate buffer, which was aerated with 95% O2 / 5% CO2 and contained 10... -6 M indomethacin. The preparation was conditioned under 200 mg tension and allowed to equilibrate for 30 minutes. The temperature was maintained at 37°C throughout the experiment. After equilibration, four tissue baths were subjected to (50 μL x 10) -3 M)10 -6 M-carbacholine (sufficient to produce moderate levels of 40% to 60% of the maximum response). If 10 -6 If carbacholine is insufficient to induce meaningful contraction, then use (50 μL x 3 x 10) -3 M)3X 10 -6 M or (50μL x 10) -2 M)10 -5 M. Allows the contractile response to stabilize. Tissue tension is recorded on a multichannel electrophysiological recorder.

[0065] The drugs of interest, salmeterol (JV-M1) and tiotropium bromide (JV-M5), were added cumulatively in 50 μL aliquots at an incremental concentration gradient: 10 -5 M(->10 -8 50 μL aliquots of sample (M); 10 -4 M(->10 -7 50 μL aliquots of sample (M); 10 -3 M(->10 -6 50 μL aliquots of sample (M); 10 -2 M(->10 -5 50 μL of sample (M) was aliquoted.

[0066] In one experiment, a combination of salmeterol and tiotropium bromide was added.

[0067] Once the cumulative addition of the drug solution is complete, the drug is washed out by rinsing three times with a selected volume of buffer solution.

[0068] 4 tissue baths were treated again with 10 -6 M (or a selected concentration) of carbacholine, and establish a stable contractile response.

[0069] The effects of salmeterol, tiotropium bromide, and their combinations on precontracted monkey ciliary muscle preparations are respectively... Figure 1A , Figure 1B and Figure 1C As shown in the image.

[0070] β 2- The adrenergic receptor agonist salmeterol and the muscarinic antagonist tiotropium produce similar dose-related decreases in ciliary muscle tone. Figure 1A and Figure 1B However, the relaxation range of tiotropium bromide was greater than that recorded for salmeterol. Upon washing, the contractile effect of further application of carbachol was reduced by both salmeterol and tiotropium bromide, consistent with their long-acting properties. Figure 1A and Figure 1B It was also shown that salmeterol administered first was more effective than administered later. The combination of salmeterol and tiotropium bromide was also highly effective in reducing ciliary smooth muscle tone. Figure 1C ).

[0071] Accommodating visual impairments caused by ciliary muscle dysfunction requires meticulous treatment. In myopia involving excessive ciliary smooth muscle tension, treatment should rely on moderate relaxation of the ciliary muscle, allowing the eye to still adapt to near vision. Significant relaxation of the ciliary smooth muscle will result in hyperopia and alternative, equally problematic visual impairments. Salmeterol (and other LABAs) and low-dose tiotropium bromide (and other LAMAs and muscarinic antagonists), and combinations thereof, will achieve the goal of optimal myopia treatment.

[0072] Example 2. Ocular bioavailability of salmeterol and tiotropium bromide after application to the periorbital skin of cynomolgus monkeys

[0073] Tiotropium bromide and salmeterol were prepared in phosphate-buffered saline, with salmeterol as a suspension. A total median amount of 208 μg tiotropium bromide and 155 μg salmeterol was obtained by applying the solution to the superior and inferior periorbital skin of one eye in multiple discontinuous applications using a microbrush. Animals were euthanized at predetermined time points after administration: 1 hour, 2 hours, 4 hours, and 24 hours. Blood and ocular tissue samples were then collected and prepared for LC / MS / MS analysis. The results for tiotropium bromide and salmeterol are shown in Tables 1 and 2, respectively.

[0074] Table 1. Quantification of tiotropium bromide levels (M concentration) in ciliary muscle and plasma at predetermined time after drug administration. (BLQ = below the limit of quantitation)

[0075] Time after dosing (h) 1 2 4 24 Plasma 4.5 x 10 -9 M]] BLQ BLQ BLQ Ciliary muscle 4.9 x 10 -8 M]] 7.7 x 10 -8 M]] 5.4 x 10 -9 M]] 0

[0076] Table 2. Quantification of salmeterol levels (M concentration) in ciliary muscle and plasma at predetermined time after administration. (BLQ = below the limit of quantitation)

[0077] Time after dosing (h) 1 2 4 5 Plasma BLQ BLQ BLQ BLQ Ciliary muscle 1.7 x 10 -8 M]] 8.4 x 10 -9 M]] 3.3 x 10 -8 M]] 5.8x10 -8 M]]

[0078] When tiotropium bromide (Table 1) and salmeterol (Table 2) are applied to the periorbital skin, the use of unoptimized aqueous formulations allows both drugs to enter the ciliary muscle at pharmacologically active concentrations. This allows for appropriate modulation of ciliary muscle tone to adequately correct visual impairment. It should be noted that sufficiently high drug levels were achieved in the ciliary muscle with only very low or no systemic exposure to tiotropium bromide and salmeterol, respectively.

Claims

1. Use of a hybrid molecule of a long-acting β-adrenergic receptor agonist / muscarinic antagonist in the preparation of a medicament for treating visual impairment in a subject, wherein said hybrid molecule is bafenertrol; The visual impairment described therein is an impairment that can be treated by the ciliary muscle accommodation in the subject's eye.

2. The use as claimed in claim 1, wherein the drug is administered to one or both eyes of the subject via ocular or periorbital application.

3. The use as claimed in claim 1, wherein the drug is applied to the unaffected eye of the subject.

4. The use as claimed in claim 3, wherein the obstacle is selected from the group consisting of: anisometropia, amblyopia, esotropia, and exotropia.

5. The use as claimed in claim 1, wherein the drug is applied to the affected eye of the subject.

6. The use as claimed in claim 5, wherein the obstacle is selected from the group consisting of: myopia, pseudomyopia, hypermyopia, and exophoria.

7. The use as claimed in claim 1, wherein the drug is applied to the eye as a topical ophthalmic preparation.

8. The use as claimed in claim 1, wherein the drug is applied to the eye as an eye drop.

9. The use as claimed in claim 1, wherein the drug is applied to the eye by local application to the periorbital skin.

10. The use as claimed in claim 1, wherein the drug is applied to the eye as an implant.

11. The use as claimed in claim 10, wherein the implant is an intraocular implant or a choroidal implant.

12. The use as claimed in claim 1, wherein the subject has previously been treated with atropine.

13. The use as claimed in claim 1, wherein the bafenertrol is used in combination with an alpha-adrenergic agonist.

14. The use as described in claim 13, wherein the α-adrenergic agonist is selected from the group consisting of: methoxyamine, midodrine, oxymetazoline, metaraminol, phenoxylin, clonidine, guanifaxine, guanazin, guanethidine, guanethidine, guanethidine, toluidine, mizanidine, medetomidine, methyldopa, methylnorepinephrine, fadomidin, dexmedetomidine, amiflunomide, dimethicone, anisodamine, Acloradine, bromidine, cilazolin, detoxidine, adrenaline, ergotamine, etefolin, indanedin, lofexidine, metodazole, mefenamic acid, metaraminol, methoxyamine, mirtazapine, naphazoline, norepinephrine, detoxolin, octopamine, oxymetazoline, phenylpropanolamine, cyclohexylmethylamine, limeridin, romifedipine, synephrine, talixoxol, their salts, and combinations thereof.

15. The use as described in claim 14, wherein the α-adrenergic agonist is brimonidine.

16. The use as described in claim 1, wherein the bafenertrol is used in combination with a phosphodiesterase (PDE) inhibitor.

17. The use as claimed in claim 16, wherein the phosphodiesterase (PDE) inhibitor is selected from the group consisting of: vinpocetine, erythropoietin-9-(2-hydroxy-3-nonyl)adenine (EHNA), 2-[(3,4-dimethoxyphenyl)methyl]-7-[(2... R ,3 R )-2-hydroxy-6-phenylhex-3-yl]-5-methyl-1 H -Imidazolo[5,1-f][1,2,4]triazine-4-one, hydroxyindole, 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purine-6-one (PDP), amrinone, milrinone, enoxidone, anagrelide, cilostazol and pimoxendan, pinemetrine, cyclophosphamide, isobutylasteride, piracetamide, luteolin, drotavirine, rofluster, apres, criborone, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, papaverine, and combinations thereof.

18. The use as described in claim 16, wherein the phosphodiesterase inhibitor is theophylline.

19. Use of a hybrid molecule of a long-acting β-adrenergic receptor agonist / muscarinic antagonist in the preparation of a medicament for improving visual acuity in the affected eye of a subject with myopia; The hybrid molecule mentioned is bafentro.

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