TW202317111A - Methods of treatment and inhibition - Google Patents

Abstract

Disclosed is the use of a nicotinic acetylcholine receptor agonist for treating or inhibiting the development or progression of a visual disorder, including a visual disorder of the posterior segment of the eye, such as myopia.

Description

Treatment and Inhibition Methods

The present invention relates generally to the use of nicotinic acetylcholine receptor agonists for treating or inhibiting the development or progression of visual disorders, including visual disorders of the posterior segment of the eye, such as myopia.

Reference in this specification to any prior publication (or information derived therefrom) or any known matter is not and should not be considered an acknowledgment or endorsement or in any way to imply that such prior publication (or information derived therefrom) information) or known matters form part of the general general knowledge in the field covered by this specification.

Myopia (commonly known as short-sightedness) refers to visual impairment caused by excessive elongation of the eyes (ocular axial length) during development. Myopia is the leading cause of poor vision and the most common eye disease worldwide. By some estimates, myopia could affect as many as one-third of the world's population by 2030. Prevalence is highest in East Asian cities, with approximately 80-90% of school leavers myopic in many areas.

Current treatment options to reduce the progression of myopia include increased time outdoors, optical methods (such as single vision lenses, bifocal lenses, multifocal lenses, peripheral lenses, and orthokeratology), and drugs (such as the acetylcholine receptor antagonists atropine and pirenzepine).

Traditionally, treatment with agents such as the non-specific muscarinic acetylcholine receptor antagonist atropine, with atropine treatment being the most widely used agent for the treatment of myopia, has been most effective in reducing the rate of myopia progression. In addition to atropine, several other acetylcholine receptor antagonists have been shown to inhibit myopia in animal models and, in some cases, humans (Siatkowski et al. (2004) Arch Ophthalmol , 122 (11): 1667-1674). These antagonists are known to be active on the retina, retinal pigment epithelium, choroid and/or sclera (McBrien et al. (2013) Ophthalmic Physiol Opt , 33: 373-378). However, widespread use of atropine has been inhibited by concerns about post-treatment rebound effects and short- and long-term side effects.

Delivery of drugs to the posterior segment of the eye presents significant challenges due to the large number of barriers present within the eye. This is especially important for topically administered treatments, where it is estimated that less than 5% of topically administered drugs reach intraocular tissues (Janoria et al. (2007) Expert Opin Drug Deliv , 4(4): 371-88; Mantelli et al. al. (2013) Curr Opin Allergy Clin Immunol , 13(5): 563-568). Problems with topical administration for drug delivery to the posterior segment of the eye include high tear turnover, ineffective absorption, nasolacrimal drainage, impermeability of the corneal epithelium, short anterior corneal residence time, and anterior segment enzymes. ) to drug metabolism leading to extensive anterior corneal drug loss (Janoria et al. (2007) Expert Opin Drug Deliv , 4(4): 371-88). One of the main barriers to drug penetration into the eye is the corneal epithelium. The structure of the corneal epithelium is similar to the blood-brain barrier, with tight junctions surrounding the cells below the apical surface (Mantelli et al. (2013) Curr Opin Allergy Clin Immunol , 13(5): 563-568). Similar to the blood-brain barrier, tight junctions in the corneal epithelium mainly constitute a barrier to the entry of pathogens and topically administered drugs (Mantelli et al. (2013) Curr Opin Allergy Clin Immunol , 13(5): 563-568). Drugs capable of overcoming these barriers would be advantageous as therapies for ocular diseases.

There is a need for new therapies for treating or inhibiting the development or progression of visual disorders, particularly posterior segment visual disorders such as myopia.

As mentioned above, antagonists of acetylcholine receptors, such as atropine and pirenzepine, are known in the art to be useful in the treatment and prevention of myopia. This indicates that hyperactivity of the retinal cholinergic system may be the basis for the development of myopia, and acetylcholine receptor agonists will increase the growth rate of the eye, resulting in elongation of the eye axis, thereby promoting the development of myopia. The present invention is based in part on the discovery that agonists of nicotinic acetylcholine receptors can reduce or inhibit axial elongation and refractive shift in animal models of myopia. The present inventors have discovered that nicotinic acetylcholine receptor agonists are active when applied topically to the eye of an individual, including by topical administration. Accordingly, the present inventors contemplate that nicotinic acetylcholine receptor agonists may be useful in the treatment of visual disorders, particularly in the posterior segment of the eye, such as those associated with ocular overgrowth (e.g., axial elongation), including myopia .

In one aspect, there is provided a method for treating or inhibiting the development or progression of visual impairment in a subject, the method comprising, consisting of, or consisting essentially of: administering ocular nicotine B to a subject Acylcholine receptor agonists. In particular embodiments, the visual impairment is an impairment of the posterior segment of the eye.

In some embodiments, the individual is not administered an acetylcholine receptor antagonist. In some embodiments, the individual is not administered a sympathetic antagonist. In some embodiments, the individual is not administered a sympathetic agonist. In specific embodiments, the sympathetic agonist is not dopamine or a pharmaceutically acceptable salt or prodrug thereof, and/or the sympathetic agonist is not levodopa or a pharmaceutically acceptable salt thereof . In some embodiments, the individual is not administered an alpha agonist and/or antagonist.

In some embodiments, the visual impairment is associated with abnormal eye growth, particularly axial elongation.

In certain embodiments, the visual impairment is myopia.

In some embodiments, the nicotinic acetylcholine receptor agonist is selected from the group consisting of nicotine, epibatidine, encenicline, varenicline ), succinylcholine, galantamine, carenicline, quinine derivatives, 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[ 3.2.1] Octane (DBO-83), Cytisine, Anatoxin-A, Dimethylphenylpiperazinium (DMPP), 4-{[2-(1-Methylpyrrolidine- 2-yl)ethyl]thio}phenol (SIB-1553A), rivanicline (RJR-2403), 3-methyl-5-[(2S)-1-methylpyrrolidine-2 -yl]-1,2-oxazole (ABT-418), 3-[(2S)-2-azetidinemethoxy]pyridine (A-85380), 3-[(2S)-2- Azetidinemethoxy]-5-iodopyridine (5-iodo-A-85380), and the aforementioned salts or prodrugs. In a specific embodiment, the nicotinic acetylcholine receptor agonist is nicotine.

The method may further involve administering more than one nicotinic acetylcholine receptor agonist, such as two or three agonists.

In some embodiments, the nicotinic acetylcholine receptor agonist is administered as a composition comprising the nicotinic acetylcholine receptor agonist and a pharmaceutically acceptable carrier or thinner.

In a specific embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, such as an aqueous carrier selected from the group consisting of saline, water, aqueous buffers, containing water and miscible solvents (miscible solvent) aqueous solution, and the aforementioned combination.

In some embodiments, the pH of the composition is in the range of about 4 to about 8, especially in the range of about 5 to about 7.

In a particular embodiment of the invention, the nicotinic acetylcholine receptor agonist is topically administered to the eye of the individual. In an alternative embodiment, the nicotinic acetylcholine receptor agonist is injected into the eye of the individual, eg, by intravitreal injection.

In another aspect of the present invention, there is provided a nicotinic acetylcholine receptor agonist for treating or inhibiting the development or progression of visual impairment in an individual, wherein the nicotinic acetylcholine receptor agonist Apply to the eye of the subject. In particular embodiments, the visual impairment is an impairment of the posterior segment of the eye.

In some embodiments, the individual is not administered an acetylcholine receptor antagonist. In a further embodiment, the individual is not administered a sympathetic antagonist and/or a sympathetic agonist. In specific embodiments, the sympathetic agonist is not dopamine or a pharmaceutically acceptable salt or prodrug thereof, and/or the sympathetic agonist is not levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the individual is not administered an alpha agonist and/or antagonist.

In some embodiments, the visual impairment is associated with abnormal eye growth, particularly axial elongation.

In certain embodiments, the visual impairment is myopia.

In some embodiments, the nicotinic acetylcholine receptor agonist is selected from the group consisting of nicotine, ebaculin, ennicline, varenicline, succinylcholine, galant Mineral, Karenicline, Quinine Derivatives, 3-(6-Chloro-3-pyridazinyl)-3,8-Diazabicyclo[3.2.1]octane (DBO-83), Broom Base, Anatoxin-A, Dimethylphenylpiperazinium (DMPP), 4-{[2-(1-Methylpyrrolidin-2-yl)ethyl]thio}phenol (SIB-1553A), Rivarenicline (RJR-2403), 3-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole (ABT-418), 3-[( 2S)-2-azetidinemethoxy]pyridine (A-85380), 3-[(2S)-2-azetidinemethoxy]-5-iodopyridine (5-iodo-A -85380), and salts or prodrugs of the aforementioned, especially nicotine.

The nicotinic acetylcholine receptor agonist may be in the form of a composition comprising the nicotinic acetylcholine receptor agonist and a pharmaceutically acceptable carrier or diluent. In a specific embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, for example: an aqueous carrier selected from the group consisting of saline, water, aqueous buffer, water-containing and miscible Aqueous solutions of solvents, and combinations of the foregoing. In such embodiments, the pH of the composition may range from about 4 to about 8 or from about 5 to about 7.

In some embodiments, the nicotinic acetylcholine receptor agonist is administered topically to the eye of the individual. In an alternative embodiment, the nicotinic acetylcholine receptor agonist is injected into the eye of the individual, eg, by intravitreal injection.

In another aspect, there is provided the use of a nicotinic acetylcholine receptor agonist in the manufacture of a medicament for treating or inhibiting the development or progression of visual impairment in an individual, wherein the medicament is formulated for use in the eye of the individual medication. In particular embodiments, the visual disorder is a disorder of the posterior segment of the eye.

In some embodiments, the medicament does not contain an acetylcholine receptor antagonist. The medicament may additionally or alternatively be free of sympathetic antagonists and/or sympathetic agonists. In some embodiments, the sympathetic agonist is not dopamine or a pharmaceutically acceptable salt or prodrug thereof and/or levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament is free of alpha agonists and/or antagonists.

In some embodiments, the visual impairment is associated with abnormal eye growth (eg, axial elongation).

In certain embodiments, the visual impairment is myopia.

In some embodiments, the nicotinic acetylcholine receptor agonist is selected from the group consisting of nicotine, ebaculin, ennicline, varenicline, succinylcholine, galant Mineral, Karenicline, Quinine Derivatives, 3-(6-Chloro-3-pyridazinyl)-3,8-Diazabicyclo[3.2.1]octane (DBO-83), Broom Base, Anatoxin-A, Dimethylphenylpiperazinium (DMPP), 4-{[2-(1-Methylpyrrolidin-2-yl)ethyl]thio}phenol (SIB-1553A), Rivarenicline (RJR-2403), 3-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole (ABT-418), 3-[( 2S)-2-azetidinemethoxy]pyridine (A-85380), 3-[(2S)-2-azetidinemethoxy]-5-iodopyridine (5-iodo-A -85380), and the aforementioned salts or prodrugs.

In some embodiments, the medicament further comprises a pharmaceutically acceptable carrier or diluent. In certain embodiments, the pharmaceutically acceptable carrier is an aqueous carrier, for example, an aqueous carrier selected from the group consisting of saline, water, aqueous buffers, aqueous solutions comprising water and miscible solvents. Aqueous solutions, and combinations of the foregoing. In some embodiments, the pH of the drug is in the range of about 4 to about 8 or about 5 to about 7.

In certain embodiments, the medicament is formulated for topical administration to the eye of a subject. In an alternative embodiment, the drug is formulated for injection into the eye of a subject, eg, by intravitreal injection.

1. definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

The articles "a" and "an" are used herein to refer to one or more (ie, at least one) of the objects of the article. By way of example, "an element" means one element or more than one element.

"About" means an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length relative to a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length Variations of up to 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1%.

The term "administration concurrently, administering concurrently or administered concurrently, etc." refers to the administration of a single composition containing two or more active substances, or each active substance as a separate composition and/or by a separate route Concurrent or simultaneous or sequential administration over a sufficiently short period of time such that effective results are equivalent to those obtained when all such active substances are administered as a single composition. "Simultaneously" means that the active agents are administered at substantially the same time, and ideally together in the same formulation. "Contemporaneously" means that the active agents are administered closely in time, eg, one agent is administered within about 1 minute to about 1 day before or after the other agent. Any contemporaneity is useful. Typically, however, when not administered simultaneously, the agents will be administered within about 1 minute to about 8 hours, preferably within less than about 1 to about 4 hours. When administered concurrently, these agents are suitably administered at the same site in the individual. The term "same site" includes the exact location, but can be within about 0.5 cm to about 15 cm, preferably within about 0.5 cm to about 5 cm. The term "separately" as used herein refers to administering the agents at intervals, for example at intervals of about one day to several weeks or months. The active agents can be administered in any order. The term "sequentially" as used herein means that the agents are administered sequentially, for example at intervals of minutes, hours, days or weeks. The active agent may be administered in regularly repeated cycles, as appropriate.

The term "agent" includes compounds that induce a desired pharmacological and/or physiological effect. The term further includes pharmaceutically acceptable and pharmacologically active ingredients of those compounds specifically mentioned herein, including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the above terms are used, it is understood to include the active agent itself as well as pharmaceutically acceptable and pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs and the like. The term "agent" should not be construed narrowly, but extends to small molecules, protein molecules (such as peptides, polypeptides and proteins) and compositions containing them and genetic molecules (such as RNA, DNA and their mimetics and chemical analogs substances) and cell reagents.

As used herein, the term "agonist" and its grammatical equivalents refer to a molecule that partially or fully activates the action of another molecule, such as a receptor or an intracellular mediator, by any mechanism. In the context of the present invention, the term "agonist" refers to a direct agonist molecule that activates nicotinic acetylcholine receptors. The term "direct agonist" refers to an agonist that acts by contacting (eg, binding to) a nicotinic acetylcholine receptor and stimulates or enhances activation of the receptor. "Agonism" or "activation" (and their equivalents) of a nicotinic acetylcholine receptor increases receptor activity and/or function, e.g., response to Na ⁺ , K ⁺ and/or The permeability of Ca ²⁺ ions and the regulation of the release of transmitters. In specific embodiments, the nicotinic acetylcholine receptor agonist is a selective agonist of nicotinic acetylcholine receptors over muscarinic acetylcholine receptors. In some embodiments, the agonist exhibits greater than about 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or greater than about 1000-fold selectivity for nicotinic acetylcholine receptors.

The term "and/or" as used herein refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when construed in an alternative (or).

The term "axial length" as used herein refers to the distance from the anterior portion of the cornea to the origin of the retina (ie, the distance between the anterior and posterior poles of the eyeball). The term "ocular axial elongation" refers to an increase in the axial length of the eye. Axial elongation may also be referred to herein as axial growth.

The term "carrier" as used herein refers to a solid or liquid diluent, especially a liquid diluent. "Pharmaceutically acceptable carrier" means a pharmaceutical vehicle that consists of a material that is not biologically or otherwise undesirable, i.e., a material that is compatible with the active agent of choice. administered together to an individual without causing any or substantial adverse reaction. A carrier can include excipients and other additives such as: diluents, detergents, colorants, wetting or emulsifying agents, pH buffering agents, preservatives, and the like. In certain embodiments, the carrier is an aqueous carrier. The term "aqueous carrier" as used herein refers to a liquid aqueous diluent, where aqueous carriers include, but are not limited to, water, saline, aqueous buffers, and diluents containing water-soluble or water-miscible additives such as dextrose or glycerol. aqueous solution. Aqueous vehicles can also be in the form of oil-in-water emulsions.

Throughout this specification and the appended claims, unless the context requires otherwise, the word "comprise (and variants such as comprises and comprising)" will be understood to mean including stated integers or steps, or A group of integers or steps without excluding any other integer or step, or a group of integers or steps. Thus, use of the term "comprising" and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. "Consisting of" shall include, without limitation, whatever follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory and that other elements may not be present. "Consisting essentially of" means including any element listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or action specified for the listed element in this disclosure . Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending on whether they affect the activity or effect.

The term "disorder" as used herein refers to an abnormality in the physical state and/or function of the body as a whole or a part thereof. Disorders may be caused by, for example, genetic factors, environmental factors, disease or trauma.

The phrase "inhibit the development of" as used herein refers to the prophylaxis of increasing an individual's resistance to developing a disease, disorder or condition (such as myopia) or in other words reducing the likelihood of an individual developing a disease, disorder or condition Treatment, and treatment after a disease, disorder, or condition has begun, aimed at alleviating or eliminating it altogether or preventing it from getting worse. The phrase also includes within its scope the prevention of the disease, disorder or condition in individuals who may be predisposed to the disease, disorder or condition but have not yet been diagnosed. The phrase "inhibit the progression of" refers to treatment that prevents the worsening or further development of a disease, disorder or condition.

The terms "patient" and "individual" are used interchangeably herein to refer to any individual, particularly a vertebrate individual, and even more especially a mammalian individual, for whom treatment or prevention is desired. Suitable vertebrates that fall within the scope of the present invention include, but are not limited to, any member of the subphylum Chordate, including primates such as humans, monkeys and apes, and include: Cynomolgus monkeys (cynomolgus monkeys) and/or rhesus monkeys (common macaques) of Macaca fascicularis) and baboons (Papio ursinus), as well as marmosets (from species of the genus Eumarmoset), squirrel monkeys (from species of the genus Squirrel Monkey) and marmosets (from species of the genus Tamarin); and, ape species such as chimpanzees (genus Chimpanzee)), rodents (such as mice, rats, guinea pigs), lagomorphs (such as rabbits , hares), bovines (e.g. domestic cattle), ovines (e.g. sheep), caprines (e.g. goats), porcines (e.g. pigs), equines (e.g. horses), canines (e.g. dogs), felines (e.g. cats), birds (e.g. chickens, turkeys, ducks, geese, companion birds (e.g. canaries, budgerigars, etc.)), marine mammals (e.g. dolphins, whales), reptiles (such as snakes, frogs, lizards, etc.) and fish. In particular embodiments, the individual is a primate (such as a human) in need of treatment or inhibition of the progression or development of a visual disorder (such as myopia). In certain embodiments wherein the individual is a human. In some embodiments, the individual is a human child or young adult, e.g., from about 2 years of age to 20 years old. However, it should be understood that the terms "patient" or "individual" do not imply the presence of symptoms .

The term "posterior segment" as used herein refers to the posterior segment of the eye, which includes the anterior vitreous membrane and all optical structures behind it, including the vitreous humor, retina, retinal pigment epithelium, choroid, optic nerve, and posterior sclera. Thus, when applied to visual disorders, the term refers to disorders of structures at the back of the eye, such as disorders of the retina, posterior sclera, choroid, or retinal pigment epithelium. In certain embodiments, the posterior segment disorder is a retinal disorder (ie, a disorder of the retina).

The terms "reduce", "inhibit", "prevent" and grammatical equivalents when used to refer to the level of a substance and/or phenomenon in a first sample relative to a second sample, mean Means that the amount of a substance and/or phenomenon in a first sample is lower than the amount of a substance and/or phenomenon in a second sample by an amount that is statistically significant using any art-accepted method of statistical analysis any amount. When these terms are used to refer to the effect of a compound, the first sample can be a sample in the presence of the compound and the second sample can be a control sample in the absence of the compound. In one aspect, the degree of reduction can be determined subjectively, such as when a patient refers to their subjective perception of disease symptoms (eg, blurred or impaired vision, etc.). In another aspect, the degree of reduction can be determined objectively, eg, when the tested visual acuity is improved compared to an earlier test of the patient, or when the axial length of the eye remains the same or decreases. In another embodiment, the amount of a substance and/or phenomenon in the first sample is at least 10% lower than the amount of the same substance and/or phenomenon in the second sample. In another embodiment, the amount of a substance and/or phenomenon in the first sample is at least 25% lower than the amount of the same substance and/or phenomenon in the second sample. In yet another embodiment, the amount of a substance and/or phenomenon in the first sample is at least 50% lower than the amount of the same substance and/or phenomenon in the second sample. In another embodiment, the amount of a substance and/or phenomenon in the first sample is at least 75% lower than the amount of the same substance and/or phenomenon in the second sample. In yet another embodiment, the amount of a substance and/or phenomenon in the first sample is at least 90% lower than the amount of the same substance and/or phenomenon in the second sample.

The terms "salts" and "prodrugs" as used herein include any pharmaceutically acceptable salts, esters, hydrates, etc. which, when administered to a recipient, provide (directly or indirectly) an agent or complex of the invention. substance or any other compound. The term "pharmaceutically acceptable salts" refers without limitation to derivatives of the components of the disclosed complexes or agents, wherein the parent compound is converted into its salt form by converting the existing acid or base moiety ( Modified, for example, by reacting a free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, base or organic salts of acidic residues such as carboxylic acids, and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, Camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate , glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, decamate Dialkyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate , pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate Salt, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate and valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylammonium Amine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. The pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both; Preferably prepared by reaction in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of suitable salts can be found, for example, in: Remington (1985) Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 17th edition; Stahl and Wermuth (2002) Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; And, Berge et al. (1977) Journal of Pharmaceutical Science , 66: 1-19, each of which is incorporated herein by reference in its entirety.

"Pharmacologically acceptable" salts of the compounds provided herein are salts that are not biologically or otherwise undesirable.

The phrase "visual disorder" as used herein refers to a condition that alters the vision of an individual. In particular embodiments, such conditions are associated with a reduction in "visual acuity," which is typically associated with a decrease or diminution in visual acuity or clarity. Thus, a decrease in "visual acuity" generally refers to any measurable decrease or decrease in the sharpness or clarity of form vision, which depends on the sharpness of the retinal focus within the eye and the sensitivity of the brain's interpretive capabilities. In certain embodiments, visual acuity refers to Snellen acuity (eg, 20/20). A visual impairment can be a disease, disorder or condition.

Unless otherwise specified, each implementation aspect described herein shall be applicable to each implementation aspect by reference. 2. Abbreviation

The following abbreviations are used throughout this application: nAChR = nicotinic acetylcholine receptor mAChR = muscarinic acetylcholine receptor FDM = form deprivation myopia mM = millimolar concentration 3. Nicotinic acetylcholine receptor agonist

The present inventors have determined that agonists of nicotinic acetylcholine receptors are useful for treating or inhibiting the development or progression of a visual disorder in an individual, particularly where the visual disorder is a disorder of the posterior segment of the eye, including myopia.

A nicotinic acetylcholine receptor agonist can be any nicotinic acetylcholine receptor or subtypes (for example: α7, α4β7, α3β4, α4β2, α1β1δε, and α1β1δγ nicotinic acetylcholine receptor (nAChR)). Suitable compounds include small molecules, protein molecules such as peptides, polypeptides, and proteins, and genetic molecules such as RNA, DNA, and their mimetics and chemical analogs, as well as cellular reagents. In certain embodiments, the nicotinic acetylcholine receptor agonist is a small molecule.

Exemplary nAChR agonists include, but are not limited to, nicotine, ebacillin, ennicline, varenicline, succinylcholine, galantamine, karenicline, quinine derivatives (such as described in Leonik et al . al. (2007) Bioorg Med Chem Lett , 17(6): 1520-1522), N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide ( PNU-282987), quinamide, quinuclidine carbamate, and quinine ether (eg, as described in Annadurai et al. (2016) Med Chem , 12(6): 574-584), 3 -(6-Chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (DBO-83), Cytisine, Anatoxin-A, Dimethylphenylpiperidine Azinium (DMPP), 4-{[2-(1-methylpyrrolidin-2-yl)ethyl]thio}phenol (SIB-1553A), rivarenicline (RJR-2403), 3-methyl Base-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole (ABT-418), 3-[(2S)-2-azetidinylmethoxy base]pyridine (A-85380), 3-[(2S)-2-azetidinylmethoxy]-5-iodopyridine (5-iodo-A-85380), 3-(2,4 - Dimethoxybenzylidene) neonicotinoid (GTS-21) and its salts or prodrugs. In a specific embodiment, the nAChR agonist is nicotine or a salt or prodrug thereof, especially nicotine.

While not wishing to be bound by theory, it has been suggested that, due to the lack of nAChRs in the anterior segment, the use of nAChR agonists avoids potential off-target effects that may be related to the use of mAChR agonists and nonselective acetylcholine receptors. agonist related. Unlike nAChR, mAChR is known to be present in the anterior segment of the eye (Nietgen et al. (1999) Eye (Lond) , 13: 285-300).

In some embodiments, the acetylcholine receptor agonist may be in the form of a derivative, such as a pharmaceutically acceptable salt and/or solvate thereof, or a prodrug thereof. In some embodiments, the acetylcholine receptor agonist is in the form of a hydrate. Suitable salts and prodrugs of nicotinic acetylcholine receptor agonists are well known to those skilled in the art. For example, suitable varenicline prodrugs include those described in US 10,954,250 B2, suitable galantamine prodrugs include [(1S,12S,14R)-9-methoxy-4-methyl-11 -Oxa-4-azatetracyclo[8.6.1.0 ^1,12 .0 ^6,17 ]heptadecane-6(17),7,9,15-tetraen-14-yl]benzoate ( Gln-1062 or Memogain®).

Those skilled in the art will be able to readily synthesize nicotinic acetylcholine receptor agonists using conventional techniques on the basis of general knowledge in the art, or will be able to obtain agonists from commercial sources, such as from Sigma Aldrich Co. LLC get. For example, nicotine in the form of nicotine or nicotine ditartrate is commercially available from a variety of sources (eg Sigma Aldrich Co. LLC) and synthetic routes are available eg in EP 2487172 A1, the entirety of which Incorporated herein by reference.

Suitable assays for determining agonism and/or activation of nicotinic acetylcholine receptors will be readily apparent to those skilled in the art. For example, binding can be assessed by contacting cells expressing a nicotinic acetylcholine receptor with a compound and screening for binding of a ligand (e.g., acetylcholine) that inhibits the nicotinic acetylcholine receptor (e.g., ligand body binding test). Agonist activity can be detected by screening for the activity, presence or expression of downstream cellular targets or products (e.g. calcium, potassium or sodium levels, rubidium ion efflux, or glutamate, GABA and dopamine levels, etc.) Evaluate. Available methods include but are not limited to surface plasmon resonance, bioluminescence resonance energy transfer, chemiluminescence, luminescent proximity assay, immunofluorescence, western blotting, immunoprecipitation, immunostaining, scintillation proximity assay assay) or electrophysiological techniques to detect such activity, presence or expression. Commercially available kits and/or products can also be used, such as: nAChR (α4/β2) Human Ion Channel Binding (Agonist Radioligand) Assay (Cat# 3029; Eurofins DiscoverRx Corporation, Fremont, CA, USA) or Fluo -4 NW Calcium Assay Kit (Cat. No. F36206, ThermoFisher Scientific Inc., Waltham, MA, USA). 4. Composition

According to the present invention, nicotinic acetylcholine receptor agonists are useful in compositions and methods for treating or inhibiting the development or progression of a visual disorder in a subject, particularly wherein the visual disorder is a disorder of the posterior segment of the eye. Accordingly, in some embodiments, a nicotinic acetylcholine receptor agonist may be administered to an individual in the form of a pharmaceutical composition comprising a nicotinic acetylcholine receptor agonist and a pharmaceutically acceptable Carrier or diluent, consisting of nicotinic acetylcholine receptor agonist and pharmaceutically acceptable carrier or diluent, or consisting essentially of nicotinic acetylcholine receptor agonist and pharmaceutically acceptable carrier or diluent composition.

In a specific embodiment, the composition is free of acetylcholine receptor antagonists. In some embodiments, the composition is free of sympathetic antagonists (as described in WO 2009077736 A2). In some embodiments, the composition is free of sympathetic agonists (as described in WO 2009077736 A2). In such embodiments, the sympathetic agonist may not be dopamine or a pharmaceutically acceptable salt or prodrug thereof, and/or the sympathetic agonist may not be levodopa or a pharmaceutically acceptable salt thereof.

In some embodiments, the composition is free of alpha-blockers (including dapiprazole or thymoxamine), beta-blockers, brimonidine And/or iopidine (apraclonidine). In some embodiments, the composition does not include a second agent that modulates eye growth, particularly eye axial length.

In a specific embodiment, the composition does not contain alpha agonists and/or antagonists (as described in WO 2020252057 A1).

The amount of nicotinic acetylcholine receptor agonist in the composition may depend on the visual disorder being treated, individual characteristics such as body weight and age, and the route of administration. In some embodiments, the amount of nicotinic acetylcholine receptor agonist in the composition is about 0.00001% to about 60% weight/volume (w/v), about 0.0001% to about 50% of the composition w/v, about 0.001% to about 40% w/v, about 0.01% to about 35% w/v, about 0.02% to about 30% w/v, about 0.03% w/v to about 25% w/v , about 0.04% to about 20% w/v, about 0.05% to about 15% w/v, about 0.06% to about 10% w/v, about 0.065% to about 9% w/v, about 0.07% to about 8% w/v, about 0.075% to about 7% w/v, about 0.08% to about 6% w/v, about 0.085% to about 5% w/v, about 0.09% to about 4% w/v, From about 0.095% to about 3% w/v, from about 0.1% to about 2% w/v, or from about 0.105% to about 1% w/v (and all integers therebetween); especially about 0.1%, 0.2% of the composition %, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% w/v.

As understood by those skilled in the art, the choice of a pharmaceutically acceptable carrier or diluent will depend on the route of administration and the nature of the condition and subject being treated. The particular carrier or delivery system and route of administration can be readily determined by those skilled in the art. The carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the agonist is not depleted during the preparation of the formulation and that the agonist can reach the site of action intact. The pharmaceutical compositions of the present invention may be administered to the eye of a subject by a variety of routes including, but not limited to, topically (e.g., in the form of eye drops or gels) or intravitreal, subconjunctival, intracameral, intrascleral, intracorneal or subretinal injections; especially topical or intravitreal, intrascleral or intracorneal injections. In some embodiments, the compositions of the invention are administered by suprachoroidal injection or by microneedle injection, eg, by intrascleral or intracorneal administration. Administration in the form of intraocular depots or implants is further contemplated.

Suitable pharmaceutically acceptable carriers include, but are not limited to, aqueous vehicles, oils, fatty acids, silicone liquid carriers such as perfluorocarbon or fluorinated liquid carriers (eg, as described in U.S. Patent 6,458,376 B1 ) and combinations thereof.

In some embodiments, the composition includes oil. Suitable oils include, but are not limited to, almond oil; castor oil; mineral oil; olive oil; peanut oil; coconut oil; soybean oil; corn oil; anise oil; clove oil; cassia oil; cassia oil (cinnamon oil); peanut oil (arachis oil); maize oil (maize oil); coriander oil; rosemary oil; peppermint oil; eucalyptus oil; oils such as canola, cottonseed, linseed, safflower, sesame, or sunflower and other seed oils; silicone oil; or a combination of the foregoing. In some embodiments, the oil may be included in the composition in the form of an oil-in-water emulsion, optionally together with a surfactant and an aqueous carrier. Oil may be present in an amount from about 0.1% to about 20% w/v of the composition.

In some embodiments, the carrier is an aqueous carrier. The aqueous carrier is preferably a pharmaceutically acceptable aqueous carrier. A variety of pharmaceutically acceptable aqueous carriers well known in the art can be used. For example, the aqueous carrier can be selected from, but not limited to, saline, water, aqueous buffers, aqueous solutions comprising water and miscible solvents, and combinations of the foregoing. In some embodiments, the aqueous carrier is saline. When saline is used, it is preferably isotonic to the point of administration (eg, the eye). For example, in some embodiments, the saline comprises about 0.15 to about 8% w/v sodium chloride; preferably about 0.18% to about 7% w/v, about 0.22% to about 5% w/v, or About 0.45% to about 3% w/v sodium chloride; more preferably about 0.5 to about 2% w/v or about 0.65% to about 1.5% w/v sodium chloride; most preferably about 0.9% w /v sodium chloride.

In some embodiments where the aqueous carrier is not isotonic (eg, water), the composition may contain a tonicity agent. Any pharmaceutically acceptable tonicity agent known in the art may be used. Suitable tonicity agents include, but are not limited to, boric acid, sodium phosphate buffer, sodium chloride, dextrose, trehalose, potassium chloride, calcium chloride, magnesium chloride, polypropylene glycol, glycerin, mannitol, or salts or combinations of the foregoing. Tonicity agents may be present in the composition in an amount providing isotonicity with the point of administration (eg, the eye), for example in the range of 0.02 to about 15% w/v.

In some embodiments, the carrier is a buffer, wherein the buffer maintains a pH of about 4 to about 8, about 5 to about 7, or about 5.0, 5.5, 6.0, 6.5, or 7.0. Suitable buffers include, but are not limited to, acetic acid, citric acid, sodium metabisulfite, histidine, sodium bicarbonate, sodium hydroxide, boric acid, borax, alkali metal phosphates, phosphate or citrate buffers, or combinations of the foregoing . Buffering agents can be present in the composition in an amount suitable to maintain the desired pH.

In some embodiments, the pH of the composition is in the range of about 4 to about 8 (and all integers therebetween), or about 5 to about 7; or about 5.0, 5.5, 6.0, 6.5, or 7.0.

In some embodiments, the composition further includes an antioxidant. An antioxidant can be any compound that slows, inhibits or prevents oxidation of any component of the composition, particularly the nicotinic acetylcholine receptor agonist. Suitable antioxidants may include, but are not limited to, ascorbic acid or vitamin C, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, acetylcysteine, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbyl palmitate, alpha-thioglycerol, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol or vitamin E, tocopheryl acetate , dibutylhydroxytoluene, soybean lecithin, sodium thioglycolate, butylated hydroxyanisole, propyl gallate, uric acid, melatonin, thiourea, or salts or combinations thereof. In some embodiments, the antioxidant is ascorbic acid or a salt thereof.

The antioxidant may be present in an amount suitable to substantially slow, inhibit or prevent oxidation of any component of the composition, particularly the nicotinic acetylcholine receptor agonist. For example, antioxidants can be present in the composition at about 0.01% to about 10% w/v, about 0.01% to about 5% w/v, about 0.03% to about 4% w/v, about 0.05% to about 3% present in an amount of w/v, from about 0.07% to about 2% w/v, from about 0.09% to about 1% w/v, or from about 0.1% to about 0.5% w/v; especially about 0.1% w/v of the composition The amount of /v.

The composition may further comprise a surfactant. A variety of pharmaceutically acceptable surfactants well known in the art can be used. Exemplary surfactants include, but are not limited to, the following classes of surfactants: alcohols; amine oxides; block polymers; carboxylated alcohol or alkylphenol ethoxylates; carboxylic acids/fatty acids; Phenol; Ethoxylated Fatty Esters, Oils, Fatty Amines, or Fatty Alcohols (such as Cetyl Alcohol); Fatty Esters; Fatty Acid Methyl Ester Ethoxylates; Glyceryl Esters (such as Glyceryl Monostearate); Ethylene Glycol Esters ; lanolin-based derivatives; lecithin or its derivatives; lignin or its derivatives; methyl esters; monoglycerides or their derivatives; polyethylene glycol; polypropylene glycol; alkylphenol polyethylene glycol; Mercaptan polyethylene glycols; polypropylene glycol ethoxylates; polyethylene glycol ethers (e.g. Cetomacrogol 1000); polymeric surfactants; propoxylated and/or ethoxylated fatty acids , alcohols or alkylphenols; protein-based surfactants; sarcosine derivatives; sorbitan derivatives (e.g. polysorbate); sorbitol esters; esters of sorbitol macrogol ethers; fatty acid alkyl alcohols Amides; N-alkyl polyhydroxy fatty acid amides; N -alkoxypolyhydroxy fatty acid amides; Alkyl polyglycosides; Quaternary ammonium compounds (such as benzalkonium chloride); cyclodextrins (such as alpha-, beta-, or gamma-cyclodextrins); sucrose or glucose esters or derivatives thereof; sulfosuccinates (such as dioctyl sodium sulfosuccinate); or combinations of the foregoing. Without wishing to be bound by theory, the presence of surfactants can be used to emulsify the aqueous carrier with oil (if the aqueous carrier and oil are included in the composition), and can enhance the activity of active ingredients (such as nicotinic acetylcholine receptors). agonist) penetration through the corneal epithelium. Surfactants may be present in amounts ranging from about 0.1% to about 30% w/v of the composition.

In some embodiments, the composition further includes a rheology modifier. Rheology modifiers can be used to modify the surface tension and fluidity of the composition, and can also aid in the residence time of the composition on the ocular surface when applied topically. Suitable rheology modifiers are well known in the art. For example, the rheology modifier can be selected from but not limited to hyaluronic acid, chitosan, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, dextran, methylcellulose, hydroxypropylmethylcellulose Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl guar gum, acrylates (e.g., Carbopol polymer), poloxamer, gum arabic, xanthan gum , guar gum, locust bean gum, carboxymethylcellulose, alginate, starch (from rice, corn, potato or wheat), carrageenan, konjac, aloe vera gel, agarose, pectin, tragacanth Gum, curdlan gum, gellan gum, scleroglucan, and derivatives and combinations thereof. The rheology modifier should be present in an amount sufficient to achieve the desired viscosity of the composition. The rheology modifier may be present in an amount of about 0.5% to about 5% w/v of the composition.

The composition may further contain preservatives. For example, if the composition is formulated for topical administration in multiple unit dosage form, a preservative is particularly useful to prevent microbial contamination of the composition from multiple uses from the same container. Suitable preservatives include any pharmaceutically acceptable preservatives conventionally used in the art to prevent microbial contamination of the compositions. Non-limiting examples include sodium perborate, stabilized oxychloro complex, polyquaternium-1, phenylmercuric acid, benzalkonium chloride, chlorobutanol, phenyl acetate Mercury, phenylmercuric nitrate, chlorhexidine, benzododecinium bromide, cetrimonium chloride, thimerosal, methylparaben, p- Propylparaben, polyquaternium ammonium chloride, polyaminopropylbiguanide, hydrogen peroxide, benzoic acid, phenolic acid, sorbic acid, benzyl alcohol, or salts or combinations thereof. The preservative is present in an amount to provide sufficient preservative activity. For example, preservatives may be present in an amount from about 0.001% to about 1% w/v of the composition.

It may be desirable to increase the penetration of the composition into the eye. Accordingly, in some embodiments, the compositions of the present invention may further comprise a penetration enhancer. Suitable penetration enhancers include, but are not limited to: dimethylsulfoxide (DMSO); cyclodextrins (eg, alpha-, beta-, or gamma-cyclodextrins); EDTA; decamethonium; A glycocholate; a cholate; a saponin; a fusidate; a taurocholate; a polyethylene glycol ether; a polysorbate; or a salt, derivative, or combination of the foregoing. In some embodiments, the penetration enhancer is dimethylsulfoxide. Other penetration enhancers include nanoparticles, microemulsions, liposomes, or micelles, which in some embodiments encapsulate one or more components of the composition, including a nicotinic acetylcholine receptor agonist. The penetration enhancer is present in an amount that facilitates the penetration of the nicotinic acetylcholine receptor agonist through the corneal epithelium. For example, penetration enhancers may be present in an amount ranging from about 0.1% to about 30% w/v of the composition.

In a specific embodiment, the penetration enhancer is a micelle. Suitable micelles include, but are not limited to, Triton X-100 micelles; surfactant nanomicelles, such as sodium lauryl sulfate, dodecyltrimethylammonium bromide, cetyltrimethylammonium Nanomicelles formed by ammonium bromide, n-dodecyltetra(ethylene oxide), vitamin E TGPS, octyloxyol-40 and/or dioctylphosphatidylcholine; polymeric micelles, for example, are composed of the following Micelles formed: poly(caprolactone), poly(D,L-lactide), polypropylene oxide, poly(β-benzyl-1-aspartate), methoxypoly(ethylene Diol)-hexyl-substituted poly(lactide), Pluronic F127 poly(oxyethylene)/poly(oxypropylene)/poly(oxyethylene), F 68, F127, poly(hydroxyethylasparagamide)- Polyethylene glycol-hexadecylamine, polyethylene glycol 40 stearate, N-isopropylacrylamide cross-linked with vinylpyrrolidone and acrylic acid, N,N'-methylenebisacrylamide, Pluronic F127 and chitosan, polylactic acid, polyglycolic acid, polyethylene glycol, polyethylene oxide, N-phthaloyl carboxymethyl chitosan, poly(2-ethylhexyl acrylate) -b-poly(acrylic acid), poly(tert-butyl acrylate)-b-poly(2-vinylpyridine), poly(ethylene oxide)-b-polycaprolactone, poly(ε-caprolactone )-b-poly(ethylene glycol)-b-poly(ε-caprolactone), poly(ε-caprolactone)-b-poly(methacrylic acid), poly(ethylene glycol)-b-poly (ε-caprolactone-co-trimethylene carbonate), poly(aspartic acid)-b-polylactide, poly(ethylene glycol)-block-poly(aspartic acid-hydrazide) , poly(N-isopropylacrylamide-co-methacrylic acid)-g-poly(D,L-lactide) and/or chitosan oligosaccharides grafted with stearic acid. In a specific embodiment, the micelles encapsulate the nicotinic acetylcholine receptor agonist in the composition. In some embodiments, the micelles comprise a nicotinic acetylcholine receptor agonist. Further exemplary micellar systems are described in: Mandal et al. (2017) J Control Release , 248: 96-116, which is incorporated herein by reference in its entirety.

In some embodiments, the penetration enhancer is a liposome. Suitable liposomes include, but are not limited to, liposomes prepared from dipalmitoylphosphatidylcholine, such as lecithinylcholine, and liposomes described in: Benita et al. (1984) J Microencapsul , 1(3 ): 203-216; Rathod and Deshpande (2010) indian J Pharm , 72(2): 155-160; Muneer et al. (2017) J Nanomed Nanotechnol , 8:3; and, Agarwal et al. (2016) Drug Delivery , 4: 1075-1091, which is hereby incorporated by reference in its entirety.

The composition may further comprise a chelating agent. Suitable chelating agents include, but are not limited to, aminocarboxylic acids or salts thereof, such as: EDTA, cyanotriacetic acid, cyanotripropionic acid, diethylenetriaminepentaacetic acid, 2-hydroxyethyl-ethylenediamine-triacetic acid , 1,6-diamino-hexamethylene-tetraacetic acid, 1,2-diamino-cyclohexanetetraacetic acid, O, O ′-bis(2-aminoethyl)-ethylene glycol- Tetraacetic acid, 1,3-diaminopropane-tetraacetic acid, N,N -bis(2-hydroxybenzyl)ethylenediamine- N,N -diacetic acid, Ethylenediamine- N,N' -diacetic acid, Ethylenediamine- N,N' -dipropionic acid, triethylenetetraminehexaacetic acid, 7,19,30-trioxa-1,4,10,13,16,22,27,33-octaaza Bicyclo[11,11,11]pentacane (O-bis-tren), ethylenediamine-N,N'-bis(methylenephosphonic acid), iminodiacetic acid, N,N-bis( 2-Hydroxyethyl)glycine (DHEG), 1,3-diamino-2-hydroxypropane-tetraacetic acid, 1,2-diaminopropane-tetraacetic acid, ethylenediamine-tetra(methylene phosphonic acid), N- (2-hydroxyethyl)iminodiacetic acid, or combinations or salts of the foregoing; especially pharmaceutically acceptable salts or mixed salts of EDTA (for example: disodium, trisodium, tetrasodium , dipotassium, tripotassium, lithium, dilithium, ammonium, diammonium, calcium or calcium disodium); most especially disodium EDTA. Chelating agents may be present in an amount from about 0.01% to about 1% w/v of the composition.

The compositions of the present invention may further comprise any other pharmaceutically acceptable excipients normally present in topical or injectable ophthalmic formulations. For example, the composition may further comprise alcohols (such as isopropanol, benzyl alcohol, cetyl alcohol or ethanol), lubricants (such as glucose, glycerin, polyethylene glycol, polypropylene glycol or derivatives thereof), polysaccharides ( For example, chitosan, chitin, dermatan, hyaluronate, heparin, chondroitin, cyclodextrin or its derivatives), or a combination of the foregoing.

The present invention further contemplates administration in the form of an intraocular depot or implant (for example: a depot as described in Kaiser et al. (2007) Surv Ophthalmol , 52 (Suppl 1): S62-69; or as described in Implants in: Kumari et al. (2010) J Adv Pharm Technol Res , 1(3): 291-296).

Although a nicotinic acetylcholine receptor agonist may be the only active ingredient administered to an individual, it is within the scope of the invention to administer other active ingredients concurrently with the agonist. For example, in some embodiments, a nicotinic acetylcholine receptor agonist can be combined with one or more dopamine receptor agonists (including dopamine and/or levodopa), gamma-aminobutyric acid (GABA) Antibody antagonists, serotonin receptor antagonists, retinoic acid, nitric oxide sources (such as L-arginine), or nitric oxide synthase inhibitors are administered concomitantly. A nicotinic acetylcholine receptor agonist may also be administered concomitantly with one or more muscarinic acetylcholine receptor agonists or non-selective acetylcholine receptor agonists.

Nicotinic acetylcholine receptor agonists may be used therapeutically after or in combination with other active ingredients. The nicotinic acetylcholine receptor agonist may be administered or applied separately, simultaneously or sequentially from other active ingredients.

Therefore, in another embodiment of the present invention, the composition of the present invention further comprises a dopamine receptor agonist. A dopamine receptor agonist may have agonist activity on any dopamine receptor subtype, including but not limited to any receptor from the D1 class (D1 and D5 receptors) and D2 class (D2, D3 and D4 receptors) receptor families. isoforms, and dopamine receptor heterodimers. Suitable dopamine receptor agonists include, but are not limited to, dopamine, quinpirole, apomorphine, ropinirole, pramipexole, dexpramipexole, Piribedil, rotigotine, bromocriptine, lisuride, cabergoline, 2-amino-6,7-dihydroxy -1,2,3,4-tetrahydronaphthalene (ADTN), pergolide, caledopa, dihydrexidine, doxathrine, polypropylene apo Propylnorapomorphine, quinagolide, roxindole, sumanirole, fenoldopam, ergocornine, 1-phenyl- 2,3,4,5-Tetrahydro-(1H)-3-benzoxazine-7,8-diol (also known as SKF-38393), 2-(N-phenethyl-N-propyl) Amino-5-hydroxytetralin (PPHT; also known as N-0434), dihydroergotamine, (1R,3S)-1-(aminomethyl)-3-phenyl-3,4- Dihydro-1H-isochromene-5,6-diol (also known as A-68930), carmoxirole, or a salt or combination of the foregoing. In some embodiments, the dopamine receptor agonist is dihydroergotamine tartrate, 2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride or (1R, 3S)-1-(Aminomethyl)-3-phenyl-3,4-dihydro-1H-isochromene-5,6-diol hydrochloride. In some embodiments, the composition of the present invention further comprises dopamine and/or levodopa or a pharmaceutically acceptable salt thereof.

The amount of dopamine receptor agonist in the composition may depend on the disease being treated and the route of administration. In some embodiments, the amount of dopamine receptor agonist in the composition is from about 0.01% to about 20% w/v of the composition (and all integers therebetween).

In some embodiments, the compositions of the present invention further comprise a GABA receptor antagonist. GABA receptor antagonists may have antagonistic activity against any GABA receptor subtype, including but not limited to GABA _A , GABA _B and/or GABA _A -rho (formerly GABA _C ) receptors. Suitable GABA receptor antagonists include, but are not limited to, bicuculline, flumazenil, gabazine, phenylenetetrazol, (1,2,5,6- Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (also known as CGP-46381), 4-imidazoleacetic acid, Indian Toxin (picrotoxin), piperidin-4-ylphosphinic acid (PPA), piperidin-4-ylselenic acid (SEPI), 3-aminopropyl yl-N-butylphosphinic acid (also known as CGP-36742), (hexahydropyridin-4-yl)methylphosphinic acid (P4MPA), or a salt or combination of the foregoing.

The amount of GABA receptor antagonist in the composition may depend on the disease being treated and the route of administration. In some embodiments, the amount of GABA receptor antagonist in the composition is from about 0.01% to about 20% w/v of the composition (and all integers therebetween).

In some embodiments, the composition further comprises a serotonin receptor antagonist, which may include but not limited to cyproheptadine, methysergide, quetiapine (quetiapine), ketanserin, risperidone, trazodone, dolasetron, granisetron, ondansetron, Palo Palonosetron, tropisetron, alosetron, cilansetron, mirtazapine, chlorpromazine, methylergoline ( metergoline), mianserin, mirtazapine, oxetorone, pizotifen, propranolol, ritanserin, spiperone ( spiperone), or a salt or combination of the foregoing.

In some embodiments, the composition further comprises a nitric oxide synthase inhibitor, representative examples of which include, but are not limited to, L- N ^G -nitroarginine methyl ester, N ^G -methyl-L-spermine acid (tilarginine), N ⁵ -(1-iminoethyl)-L-ornithine, L- N ^G -propyl-L-arginine, L- N ^G- Nitroarginine, N ^G -amino-L-arginine, N ^G , N ^G -dimethyl-L-arginine, L- N ⁶ -(1-iminoethyl)isoamine acid, L-thiocitrulline (L-thiocitrulline), S-methyl-L-thiocitrulline, spermine (agmatine), L-canavanine, L- N ⁵ -(1-imino Butyl)ornithine, N ⁵ -(1-imino-3-butenyl)-L-ornithine, N-(3-(aminomethyl)benzyl)acetamidine, 7-nitro Indazole, 7-bromonitroindazole, 1-(2-trifluoromethylphenyl) imidazole, 2-imino-4-methylpiperidine, aminoguanidine, S-(2-aminoethyl base) isothiourea, S,S'-(1,3-phenylene-bis(1,2-ethanediyl))bis-isothiourea, S,S'-(1,4-phenylene Base-bis(1,2-ethanediyl))bis-isothiourea, α-guanidinoglutamic acid, and salts and combinations of the foregoing.

In some embodiments, the composition further comprises a muscarinic acetylcholine receptor agonist (mAChR). Suitable mAChR agonists include, but are not limited to, muscarine, pilocarpine, methacholine, bethanechol, cevimeline, (2S)-2-ethyl-8-methyl- 1-Thia-4,8-diazaspiro[4,5]dec-3-one (NGX267), 4-[N-(3-chlorophenyl)aminoformyloxy]-2-butynyl -Trimethylammonium chloride (McN-A-343), 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate (L-689,660), xanox Merrill Lynch, 5-propargyloxycarbonyl-1,4,5,6-tetrahydropyrimidine (CDD-0097), 4-n-butyl-1-(4-(2-methylphenyl)-4-oxo Generation-1-butyl)-piperidine (AC-42), arecoline, 1-[3-(4-butylpiperidin-1-yl)propyl]-3,4-dihydroquinoline-2 (1H)-keto (77-LH-28-1), neracetam, milameline, levetiracetam, 4-[[2-[(2-methyl Ethylbenzoyl)amino]ethyl]amino]-1-piperidinecarboxylate (VU0357017), (2S,2′R,3′S,5′R)-1-methyl-2 -(2-Methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-thylidenemethyl iodide, phenylpropargyloxy-1,2,5-thiadiazole-quinine (NNC 11-1314), (3S)-1,4-bis-(3-[(3-azabicyclo[2.2.2]octyl)-1,2,5-thiadiazol-4-yl Oxy]-1-propyn-1-yl)benzene, 2-L-(+)-tartrate (NNC 11-1607), (3S)-1,3-bis-(3-[(3-nitro Heterobicyclo[2.2.2]octyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl)benzene, 2-L-(+) tartrate ( NNC 11-1585), 3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (pentylthio -TZTP), arecoline propargyl ester, 5-methylfuran, furan, iperoxo, aceclidine, tazomeline, sabcomeline, and the aforementioned salts or prodrugs. In some embodiments, the mAChR agonist is selected from muscarine, pilocarpine, methylcholine, urethanecholine, cevimeline, NGX267, McN-A-343, 1-azabicyclo[2.2.2 ] Octane, L-689,660, Xanomeline, CDD-0097, AC-42, Arecoline, 77-LH-28-1, Neriracetam, Miramerine, Levetiracetam, VU0357017, and The aforementioned salts or prodrugs. In some embodiments, the mAChR agonist is muscarine or pilocarpine, or a salt or prodrug of the foregoing, particularly muscarine or pilocarpine, most particularly muscarine.

In some embodiments, the composition further comprises a non-selective acetylcholine receptor agonist (ie, an agonist of both nAChR and mAChR). In some embodiments, the non-selective acetylcholine receptor agonist is selected from the group consisting of acetylcholine, carbachol, oxotremorine, and salts of the foregoing or prodrugs. In a specific embodiment, the non-selective acetylcholine receptor agonist is carbacholine, oxytremorine, or a salt or prodrug of the foregoing, especially carbacholine or oxytremorine. In some embodiments, the non-selective acetylcholine receptor agonist is oxotremorine.

In some embodiments, compositions of the invention are formulated for topical administration to the eye. In this regard, the compositions of the invention may be in the form of eye drops or gels; especially eye drops. Without wishing to be bound by theory, compositions formulated for topical administration to the eye are believed to increase user compliance, particularly when the compositions are used as a prophylactic or control measure. This may be particularly important if the composition is administered to a child individual. In addition, such formulations may reduce the incidence of off-target effects of nicotinic acetylcholine receptor agonists.

In some embodiments, compositions of the invention are formulated so that the nicotinic acetylcholine receptor agonist permeates the corneal epithelium. In preferred embodiments, greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the dose of the nicotinic acetylcholine receptor agonist penetrates the corneal epithelium .

When formulated as eye drops or gels, the compositions of the present invention may be in single unit dose or multiple unit dose form, preferably multiple unit dose form.

In an alternative embodiment, the composition is formulated for direct injection into the eye. In specific embodiments, the composition is formulated for intravitreal, subconjunctival, intracameral, intrascleral, intracorneal or subretinal injection ; especially intravitreal, intrascleral or intracorneal injections; most especially intravitreal injections. In some embodiments, the composition is formulated for suprachoroidal injection or for injection via microneedles, eg, intrascleral or intracorneal administration.

Other excipients and components of the compositions can be readily determined by those skilled in the art. Formulation and administration techniques can be found, for example, in: Remington (1980), Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences), Mark Publishing Company (Mack Publishing Co.), Easton, PA, latest edition; suitable excipients can be See, eg, Katdare and Chaubel (2006), Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

The composition can be prepared, for example, by mixing the components in a pharmaceutically acceptable carrier or diluent, and adjusting the pH of the composition to the desired pH, e.g., at about 4 to about 8, about 5 to a pH in the range of about 7, or about 5.0, 5.5, 6.0, 6.5 or 7.0 if desired. The pH of the composition can be adjusted using any pharmaceutically acceptable pH adjusting agent conventionally used in the art (eg, hydrochloric acid, sodium hydroxide, etc.). Suitable reagents will be apparent to those skilled in the art.

The composition may also be sterilized, eg, by filtration, autoclaving and/or gamma irradiation, before use. 5. How to use

As described herein, the present inventors have determined that nicotinic acetylcholine receptor agonists, when administered topically to the eye of an individual (including via topical administration), reduce axial elongation and refractive error in an animal model of myopia offset. Accordingly, nicotinic acetylcholine receptor agonists are useful in methods of treating or inhibiting the progression or development of visual disorders, particularly visual disorders in the posterior segment of the eye, such as those associated with ocular overgrowth including axial elongation (e.g. Shortsighted). Nicotinic acetylcholine receptor agonists may also be used in the manufacture of a medicament for the uses described herein.

In one aspect, there is provided a method for treating or inhibiting the development or progression of visual impairment in an individual, the method comprising, consisting of, or consisting essentially of: administering nicotine acetylcholine to the eye of the individual Alkaline receptor agonist. The present invention further provides a nicotinic acetylcholine receptor agonist for treating or inhibiting the development or progression of visual impairment in a subject, wherein the nicotinic acetylcholine receptor agonist is administered to the eyes of the subject; Use of a nicotinic acetylcholine receptor agonist for treating or inhibiting the development or progression of visual impairment in a subject, wherein the nicotinic acetylcholine receptor agonist is administered to the eye of the subject; and, a tobacco Use of an alkali acetylcholine receptor agonist for the manufacture of a medicament for treating or inhibiting the development or progression of a visual impairment in a subject, wherein the medicament is formulated for administration to the eye of the subject.

In particular embodiments, the visual impairment is an impairment of the posterior segment of the eye.

The methods and uses relate to the topical administration of nicotinic acetylcholine receptor agonists to the eye. Thus, a nicotinic acetylcholine receptor agonist is administered (eg, topically or via intraocular injection) or formulated for administration to the eye of the individual. Without wishing to be bound by theory, since systemic administration requires high doses, topical ocular administration is proposed to substantially avoid or minimize the side effects normally associated with systemic administration of therapeutic agents, particularly with respect to the ocular site of action side effects.

The present inventors have discovered that for the activity of a nicotinic acetylcholine receptor agonist no additional active agent needs to be administered. Accordingly, in certain embodiments, no acetylcholine receptor antagonist is administered to the individual. In some embodiments, the individual is not administered a sympathetic antagonist (as described in WO 2009077736 A2). Also contemplated are methods in which the individual is not administered a sympathetic agonist (as described in WO 2009077736 A2). In such embodiments, the sympathetic agonist may not be dopamine or a pharmaceutically acceptable salt or prodrug thereof, and/or the sympathetic agonist may not be levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the individual is not administered an alpha agonist and/or antagonist (as described in WO 2020252057 A1 ).

In some embodiments, the individual is not administered an alpha-blocker (including dapiprazole or moceseli), a beta-blocker, brimonidine, and/or alvin (alaclonidine). In some embodiments, the individual is not administered a second agent that modulates eye growth, particularly eye axial length. In a particular embodiment, the medicaments for use according to the invention are free of such medicaments.

Suitable nicotinic acetylcholine receptor agonists and aspects of their implementation are described in Section 3 above.

Nicotinic acetylcholine receptor agonists may be used to inhibit the progression of visual disturbances, particularly in the posterior segment of the eye, in individuals. In this regard, nicotinic acetylcholine receptor agonists are useful for treating visual impairment in individuals. In some embodiments, the nicotinic acetylcholine receptor agonist slows the progression of visual impairment in the individual.

Nicotinic acetylcholine receptor agonists may also be used to inhibit the development of visual impairment in individuals. Accordingly, nicotinic acetylcholine receptor agonists are useful for preventing visual impairment in individuals. In some embodiments, a nicotinic acetylcholine receptor agonist delays the onset of visual impairment in an individual, ie, increases the age at which the visual impairment occurs in the individual, and thus reduces the likely severity of the visual impairment.

In some embodiments, the visual disorder is a disorder involving decreased levels of dopamine in the eye, in particular decreased levels of dopamine in the retina. Thus, the visual disorder may be one in which an increase in dopamine levels in the eye (particularly the retina) is associated with effective treatment or inhibition of the progression or development of the visual disorder.

In some embodiments, the visual disorder is a disorder involving reduced levels of acetylcholine in the eye, particularly reduced levels of acetylcholine in the retina, choroid, retinal pigment epithelium, and/or posterior sclera, especially the retina. Thus, the visual disorder may be a visual disorder in which an increase in the level of acetylcholine in the eye is associated with effective treatment or inhibition of the progression or development of the visual disorder. In some embodiments, the visual disorder is a visual disorder wherein increased levels of acetylcholine in the posterior portion of the retina, choroid, retinal pigment epithelium, and/or sclera are associated with effective treatment or inhibition of progression or development of the visual disorder; Especially in the retina.

Suitable visual disorders include, but are not limited to, visual disorders associated with diabetic retinopathy or Parkinson's disease, retinitis pigmentosa, age-related macular degeneration, myopia (eg, caused by genetic and/or environmental factors such as congenital, juvenile-onset, school-onset and adult-onset myopia), Stargardt disease, rod-cone dystrophy, Leber Leber congenital amaurosis, retinoschisis, choroideremia, Best disease, congenital stationary night blindness and cone nutrition Bad (cone dystrophy).

Visual impairments associated with Parkinson's disease include, but are not limited to, decreased visual acuity, decreased contrast sensitivity, and/or impaired color perception caused by Parkinson's disease. In some embodiments, the visual impairment is not related to Parkinson's disease.

Visual impairment associated with diabetic retinopathy includes, but is not limited to, decreased visual acuity, decreased contrast sensitivity, and reduced peripheral visual field caused by diabetic retinopathy. In some embodiments, the visual impairment is not a visual impairment associated with diabetic retinopathy.

In some embodiments, the visual disorder is not glaucoma, diabetic retinopathy, and/or age-related macular degeneration.

In a specific embodiment, the visual impairment is associated with abnormal eye growth, particularly excessive or increased eye growth. In such embodiments, the visual impairment may be caused by abnormal eye growth, particularly eye growth or growth. In a preferred embodiment, the visual disturbance is associated with an abnormality in the axial length of the eye, in particular axial elongation (ie, an increase in the axial length of the eye). Therefore, abnormalities in axial length (especially axial elongation) may lead to visual impairment.

In some embodiments, the visual disorder is a disorder in which inhibition of eye growth, particularly axial elongation, is desired.

In certain embodiments, the visual impairment is myopia.

Further provided herein is a method of inhibiting eye growth in a subject comprising, consisting of, or consisting essentially of: administering a nicotinic acetylcholine receptor agonist to the eye of the subject. In another aspect, there is provided a nicotinic acetylcholine receptor agonist for inhibiting eye growth in an individual, wherein the nicotinic acetylcholine receptor agonist is administered to the eye of the individual; a nicotinic acetylcholine receptor Use of a nicotinic acetylcholine receptor agonist for inhibiting eye growth in an individual, wherein the nicotinic acetylcholine receptor agonist is administered to the eye of the individual; and, a nicotinic acetylcholine receptor agonist in the preparation of Use in a medicament for inhibiting eye growth in a subject, wherein the medicament is formulated for administration to the eye of the subject.

In particular embodiments, the growth of the eye is axial elongation (ie, axial growth).

In some embodiments, eye growth is associated with decreased levels of dopamine or acetylcholine in the individual's eye, particularly in the choroid, retina, retinal pigment epithelium, and/or the posterior portion of the sclera (especially in the retina). In certain embodiments, the growth of the eye is associated with myopia, thus, further contemplated are embodiments in which the individual has myopia, is at risk of developing myopia, or is susceptible to myopia.

Without wishing to be bound by theory, it is hypothesized that administration of a nicotinic acetylcholine receptor agonist contributes to choroidal dilatation, and reduces scleral growth and/or remodeling, thereby reducing ocular axial elongation. Thus, it is suggested that agonists may be active in the choroid, retina, retinal pigment epithelium and/or posterior sclera.

Section 3 describes suitable nicotinic acetylcholine receptor agonists and aspects of their implementation.

The methods and uses relate to the topical administration of nicotinic acetylcholine receptor agonists to the eye. Thus, a nicotinic acetylcholine receptor agonist is administered (eg, topically or via intraocular injection) or formulated for administration to the eye of the individual.

In certain embodiments, no additional active agent is administered to the subject as described above, eg, no acetylcholine receptor antagonist, sympathetic antagonist, and/or sympathetic agonist is administered to the subject as described above. The sympathetic agonist may not be dopamine or a pharmaceutically acceptable salt or prodrug thereof and/or levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, no alpha agonist and/or antagonist is administered to the subject. Alternatively, the individual is not administered alpha-blockers (including dapiprazole or moceseli), beta-blockers, brimonidine, and/or alvin (alaclonidine). In some embodiments, the individual is not administered a second agent that modulates eye growth (eg, eye axial elongation) as described above. The medicament may also be free of one or more of these agents.

Further contemplated is a method for treating or inhibiting the progression or development of an ocular disorder in which inhibition of eye growth is desired, the method comprising, consisting of, or consisting essentially of administering nicotine acetylcholine to the eye of an individual receptor agonist. The present invention also provides a nicotinic acetylcholine receptor agonist for use in treating or inhibiting the progression or development of an eye disorder in which inhibition of eye growth is desired (wherein the nicotinic acetylcholine receptor agonist is administered to a subject eyes), the use of the nicotinic acetylcholine receptor agonist for this purpose, and the use of the nicotinic acetylcholine receptor agonist for the manufacture of a medicament for this purpose. In a particular embodiment, the disorder is a disorder of the posterior segment of the eye.

In a specific embodiment, the eye growth is axial elongation. In a specific implementation aspect, the eye disorder is myopia.

Section 3 describes suitable nicotinic acetylcholine receptor agonists and aspects of their implementation.

In particular embodiments, the subject is not administered additional active agents, such as acetylcholine receptor antagonists, sympathetic antagonists, sympathoagonists, alpha-blockers (including dapiprazole or molar Cicely), beta-blockers, brimonidine, albindine (alaclonidine), alpha agonists and/or antagonists, and/or second agents that regulate eye growth (e.g. axial elongation), Aspects of its implementation are discussed above.

Nicotinic acetylcholine receptor agonists are also useful in treating or inhibiting the progression or development of ocular disorders in which increased acetylcholine activity is required. In some embodiments, increased acetylcholine activity may be desired in the posterior portion of the retina, choroid, retinal pigment epithelium, and/or sclera, particularly in the retina. In a particular embodiment, the disorder is a disorder of the posterior segment of the eye.

Suitable embodiments, including those for nicotinic acetylcholine receptor agonists and eye disorders, are as described above. In a specific implementation aspect, the eye disorder is myopia.

Although the nicotinic acetylcholine receptor agonist may be administered directly to the individual, the nicotinic acetylcholine receptor agonist may suitably be administered to the individual in the form of a pharmaceutical composition. Suitable compositions and aspects of their implementation are described in Section 4 above. In some embodiments, the methods and uses of any of the above aspects involve administering a composition comprising a nicotinic acetylcholine receptor agonist and one or more pharmaceutically acceptable carriers, diluents An agent or excipient consisting of a nicotinic acetylcholine receptor agonist and one or more pharmaceutically acceptable carriers, diluents or excipients, or consisting essentially of a nicotinic acetylcholine receptor agonist agent and one or more pharmaceutically acceptable carriers, diluents or excipients. Suitable embodiments of pharmaceutically acceptable carriers, diluents and excipients are described in Section 4.

The methods and uses of any of the above aspects of the invention comprise administering to the eye of a subject a nicotinic acetylcholine receptor agonist or a composition comprising the agonist. A nicotinic acetylcholine receptor agonist can be administered topically, by topical application to the surface of the eye of the individual, or by direct injection into the eye of the individual. Nicotinic acetylcholine receptor agonists may also be administered in the form of intraocular depots or implants.

In some embodiments, a nicotinic acetylcholine receptor agonist or a composition thereof is administered topically to the eye of an individual, eg, in the form of eye drops or a gel. In a preferred embodiment, the nicotinic acetylcholine receptor agonist or a composition thereof is administered as eye drops. A nicotinic acetylcholine receptor agonist or a composition thereof may be applied to any surface of the eye (preferably the cornea/sclera) thereby allowing the nicotinic acetylcholine receptor agonist to penetrate into the eye. In some embodiments, the composition is formulated such that the nicotinic acetylcholine receptor agonist penetrates the corneal epithelium.

In other embodiments, the nicotinic acetylcholine receptor agonist or composition thereof is administered by injection into the eye. For example, a nicotinic acetylcholine receptor agonist or a composition thereof may be injected directly into the sclera, anterior chamber, or vitreous, or may be injected into the subconjunctival, peribulbar, retrobulbar, or suprachoroidal space. In a specific embodiment, the nicotinic acetylcholine receptor agonist or a composition thereof is administered via intravitreal, subconjunctival, intracameral, intrascleral, intracorneal or subretinal injection; in particular intravitreal, scleral Intra or intracorneal injection; most particularly intravitreal injection. In some embodiments, the nicotinic acetylcholine receptor agonist or composition thereof is administered via suprachoroidal injection. In some embodiments, the nicotinic acetylcholine receptor agonist or composition thereof is administered by intravitreal injection. In other embodiments, a nicotinic acetylcholine receptor agonist or composition thereof is injected using microneedles, for example, via intrascleral or intracorneal administration. For administration via these routes, compositions comprising a nicotinic acetylcholine receptor agonist may be in the form of sterile injectable solutions.

The preferred portion of the eye for administration of a nicotinic acetylcholine receptor agonist or a composition thereof is the portion that allows penetration of the nicotinic acetylcholine receptor agonist into the posterior segment of the eye, preferably into the retina, choroid, retinal pigment epithelium and/or the posterior portion of the sclera, particularly with penetration into the retina. Application to the cornea/sclera and conjunctiva is preferred for topical administration, or the nicotinic acetylcholine receptor agonist or a composition thereof may be injected into the subconjunctival, peribulbar, retrobulbar or suprachoroidal space, Or injected into the sclera, cornea, anterior chamber or vitreous.

When applied topically, nicotinic acetylcholine receptor agonists or compositions thereof can be used with both hard and soft contact lenses.

Dosage regimens for different indications can be established according to methods well known to those skilled in the art. Dosage of the composition will depend on the condition to be treated, the age of the individual and the route of administration. Any of the methods or uses described herein may comprise administering an effective amount of a nicotinic acetylcholine receptor agonist.

The nicotinic acetylcholine receptor agonists or compositions thereof may be administered topically or by injection in suitable amounts to provide from about 0.00001 mg/kg/day to about 30 mg/kg/day, especially about 0.0001 mg/kg/day mg/kg/day to about 12 mg/kg/day, especially about 0.001 mg/kg/day to about 4 mg/kg/day, more especially about 0.001 mg/kg/day to about 2 mg/kg/day dose of nicotinic acetylcholine receptor agonist. In some embodiments, the nicotinic acetylcholine receptor agonist or composition thereof is administered in an appropriate amount to provide about 0.00001 mg/kg/day to about 30 mg/kg/day, especially about 0.0001 mg/kg/day mg/kg/day to about 12 mg/kg/day, more particularly about 0.001 mg/kg/day to about 4 mg/kg/day, most especially about 0.001 mg/kg/day to about 2 mg/kg/day daily dose of nicotinic acetylcholine receptor agonist.

When administered topically as eye drops, compositions comprising a nicotinic acetylcholine receptor agonist may be administered in an amount of 1 to 6 drops (and all integers therebetween) per eye, which may be equivalent to, for example, Amounts from about 0.01 milliliters to about 0.24 milliliters (and all integers therebetween). Drops may be applied to each eye 1 to 4 times daily. Equivalent dosages are provided when the composition comprising a nicotinic acetylcholine receptor agonist is formulated as a gel. Those skilled in the art will know suitable dispensers for topical administration of compositions comprising a nicotinic acetylcholine receptor agonist.

When administered by injection, the composition comprising a nicotinic acetylcholine receptor agonist may be administered in an amount of about 0.001 ml to about 0.5 ml (and all integers therebetween), especially about 0.01 ml. Compositions comprising a nicotinic acetylcholine receptor agonist may be administered on a monthly to daily basis.

In order to easily understand the present invention and put it into practice, specific preferred embodiments will now be described by means of the following non-limiting examples. EXAMPLES General Methods Animals and Feeding

White-Leghorn chicken ( Gallus gallus , 1 day old) was obtained from Barter & Sons Hatchery (Horsley Park, NSW, Australia). Animals were kept in a temperature-controlled room with free access to food and water. Place them under normal laboratory lighting (500 lux, fluorescent) with a 12:12 h light-dark cycle. Myopia induction and eye parameter measurement

As previously described (Thomson et al. (2019) Sci Rep , 9: 18345; incorporated herein by reference in its entirety), the eye was deprived of form perception and Induces myopia growth while inducing form deprivation myopia (FDM).

In order to evaluate the effect of the test agent on eye development, A-scan ultrasonography (A-scan ultrasonography) and automated infrared photoretinoscopy (automated infrared photoretinoscopy) were used before the experiment and the next day after the completion of the experiment (Day 4). ) were measured for axial length and refraction. This followed a previously described procedure (Thomson et al. (2019) Sci Rep , 9: 18345). One-way analysis of variance (ANOVA) was used to test, and then Student's T-test (Student's T-test) and Bonferroni correction were performed to statistically analyze the changes in axial length and refraction between groups. All data are presented as mean ± standard error of the mean (SEM). Example 1 - Effect of nicotinic acetylcholine receptor agonists on the development of FDM Materials and methods

To examine the effect of nicotinic acetylcholine receptor agonists on the development of FDM, chicks were randomly assigned to one of the treatment groups defined below (n = 5 per group) and treated for 4 days. – Install a translucent diffuser on the chick’s left eye to induce FDM; – Install a translucent diffuser above the left eye of the chick and treat it with daily intravitreal injection of 15 mM nicotine solution; – A translucent diffuser was installed above the left eye of the chicks and treated with daily topical eye drops of 15 mM nicotine solution; – Age-matched untreated control group.

For drug therapy, the composition is administered in the form of local eye drops or intravitreal injection (under mild isoflurane anesthesia). Compositions were prepared by dissolving nicotine in 1 x phosphate buffered saline. Adjust the pH to pH 6.0.

Intravitreal injections were performed as follows: 10 µl (0.01 ml) of the test composition was injected once daily into the vitreous cavity of the eye using a 30-gauge needle attached to a Hamilton syringe.

Topical administration was carried out by applying two drops (80 microliters) of the test composition to the corneal surface of the eye using an eye drop dispenser. Apply the drops to the chicks twice a day. result

Nicotine significantly inhibited the excessive axial elongation associated with the development of FDM (ANOVA F(11,43)=11.302, p<0.05) and myopic refractive shift (ANOVA F(11,43)=17.252, p<0.05) (See Figure 1 and Table 1). Compared with topical eye drops, intravitreal injection was significantly better in axial length (Wilks Λ (Wilks' Lambda)=0.403, F(1,47)=4.082, p<0.05) and refraction (Wilks Λ=0.437, F( 1,47)=4.185, p<0.05) had a stronger protective effect against FDM. However, as mentioned above, nicotine significantly inhibits the development of FDM when administered as topical eye drops. Table 1 Raw data and pairwise comparisons of the effect of nicotinic acetylcholine receptor agonists on FDM . Nicotine (15 mM) was administered to chicks undergoing FDM trials either as intravitreal injection or topical eye drops. Values are expressed as mean ± standard error of the mean. Significant values (p<0.05) are highlighted in bold. situation Refractive difference (after treatment minus contralateral control; diopters) Significance compared to FDM (refractive) Axial length difference (after treatment minus contralateral control; mm) Significance (Axial Length) Compared to FDM untreated 0.02±0.09 p<0.05 0.02±0.04 p<0.05 FDM only -3.84±0.16 - 0.38±0.04 - FDM + nicotine injection -1.94±0.60 p<0.05 0.10±0.07 p<0.05 FDM + nicotine eye drops -2.08±0.40 p<0.05 0.18±0.04 p<0.05 Example 2 - Effect of Topical Application of Nicotine on FDM Development Materials and Methods

To determine the effect of nicotine on FDM, chicks were fitted with a translucent diffuser to induce FDM and received one of the following treatments for four days: 1. A translucent diffuser was installed above the left eye of chicks to induce FDM, without drug treatment (FDM only) (n=6); 2. Chicks were fitted with a translucent diffuser above the left eye and treated with daily topical eye drops of 1.5 mM nicotine solution (n=6); 3. Chicks were fitted with a translucent diffuser over the left eye and treated with daily topical eye drops of 15 mM nicotine solution (n=6); and 4. Chicks were fitted with a translucent diffuser over the left eye and treated with daily topical eye drops of 50 mM nicotine solution (n=6).

For groups 2 to 4, apply two drops (80 microliters) once daily to the corneal surface of the eye at the onset of light exposure using an eye drop dispenser. For all treatment groups, at the end of the four-day course of treatment, the extent of FDM development was assessed by refraction measured using infrared photorefraction and axial length measured using A-scan ultrasonography.

Test compositions were prepared by dissolving nicotine in 1 x phosphate buffered saline. Adjust the pH to pH 6.0.

For all treatment groups, the left eye was used as the experimental eye, while the right eye remained untreated and served as the contralateral control eye. Accordingly, relative myopic shifts in refraction and axial length in FDM-treated eyes are reported relative to values in the fellow control eye. Refractive measurements were performed on the FDM-treated (left) eye and the contralateral control (right) eye using automated infrared light retinoscopy, and the refractive values represent the mean spherical equivalent of 10 measurements for each eye equivalent). Axial length measurements were taken using A-scan ultrasonography (Biometer AL-100; Tomey Corporation, Nagoya, Japan) in chicks anesthetized with 5% isoflurane and an oxygen supply of 1 L per minute, where each scan represented 10 The average of the measurements was taken and the average of three scans was used for each eye. Treatment effects were analyzed by one-way analysis of variance (ANOVA). After ANOVA, students' unpaired t-test (student's unpaired t-test) and Bonferroni correction were performed for multiple testing to analyze the specificity of the effect between groups. result

In terms of relative myopic excursion and axial elongation, nicotine treatment significantly inhibited the development of FDM in all treatment groups (see Figure 2). For refraction and axial length, ANOVA showed significant treatment effect (refraction F(3,21)=3.758, p=0.03; axial length F(3,21)=2.664, p=0.04). The refraction (p<0.05) and axial length (p<0.05) of each treatment group were significantly different from those of the pure FDM group.

The disclosure of each patent, patent application, and publication cited herein is hereby incorporated by reference in its entirety.

Citation of any reference herein shall not be construed as an admission that such reference is available as "prior art" to the present application.

Throughout the specification, the intention has been to describe preferred embodiments of the invention, not to limit the invention to any one embodiment or specific collection of features. Accordingly, those skilled in the art will appreciate that, based on the present description, various modifications and changes can be made to the specific embodiments illustrated without departing from the scope of the present invention. All these modifications and changes are included within the scope of the appended patent application scope. Related applications

This application claims priority to Australian Provisional Application No. 2021902069, filed 7 July 2021, entitled "Methods of treatment and inhibition", which application is hereby incorporated by reference in its entirety middle.

Figure 1 is a graphical representation of the effect of nicotinic acetylcholine receptor agonists on the development of form-deprivation myopia (FDM) in terms of (A) refraction and (B) axial length. Chicks were treated with nicotine (15 mM), administered as intravitreal injection or topical eye drops (n = 5 per group). The values shown represent the axial length and refractive differences between the treated and fellow control eyes at the end of the experimental period (4 days). All data are presented as mean ± standard error of the mean. Statistics represent differences relative to the FDM alone group (*p<0.05).

Figure 2 is a graphical representation of the effect of nicotine on the development of FDM in terms of (A) refraction and (B) axial length. Chicks were treated daily with topical eye drops containing 1.5 mM, 15 mM or 50 mM nicotine (n = 6 per group). The values shown represent the axial length and refractive differences between the treated and fellow control eyes at the end of the experimental period (4 days). All data are presented as mean ± standard error of the mean.

Claims (20)

Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament for treating or inhibiting the development or progression of visual impairment in an individual, wherein the medicament is formulated for administration to the eye of the individual. The use as described in claim 1, wherein the visual disorder is a hindrance of the eye. The use as described in Claim 1 or Claim 2, wherein the medicine does not contain an acetylcholine receptor antagonist. The use as described in Claim 1 or Claim 2, wherein the medicament does not contain a sympathetic antagonist. The use as described in Claim 1 or Claim 2, wherein the medicine does not contain a sympathetic nerve agonist. The use as described in claim 5, wherein the sympathetic nerve stimulant is not dopamine, or a pharmaceutically acceptable salt or prodrug thereof. The use as described in Claim 5, wherein the sympathetic agonist is not levodopa or a pharmaceutically acceptable salt thereof. The use as described in claim 1 or claim 2, wherein the visual impairment is related to abnormal eye growth. The use as described in claim 1 or claim 2, wherein the visual impairment is related to ocular axial elongation. The use as described in Claim 1 or Claim 2, wherein the visual impairment is myopia. The use as described in claim 1 or claim 2, wherein the nicotinic acetylcholine receptor agonist is selected from the group consisting of nicotine, epibatidine, ennicloline ( encenicline), varenicline, succinylcholine, galantamine, carenicline, quinine derivatives, 3-(6-chloro-3-pyridazinyl)-3 ,8-Diazabicyclo[3.2.1]octane (DBO-83), Cytisine, Anatoxin-A, Dimethylphenylpiperazinium (DMPP), 4-{[2- (1-methylpyrrolidin-2-yl)ethyl]thio}phenol (SIB-1553A), rivanicline (RJR-2403), 3-methyl-5-[(2 S )- 1-Methylpyrrolidin-2-yl]-1,2-oxazole (ABT-418), 3-[(2 S )-2-azetidinemethoxy]pyridine (A-85380), 3-[(2 S )-2-azetidinemethoxy]-5-iodopyridine (5-iodo-A-85380), and the aforementioned salts or prodrugs. The use as described in claim 11, wherein the nicotinic acetylcholine receptor agonist is nicotine. The use as described in Claim 1, wherein the medicine further comprises a pharmaceutically acceptable carrier or diluent. The use as described in claim 13, wherein the pharmaceutically acceptable carrier is an aqueous carrier. The use as claimed in claim 14, wherein the aqueous carrier is selected from the group consisting of saline, water, aqueous buffer, aqueous solution comprising water and miscible solvents, and combinations thereof. The use as claimed in any one of claims 13 to 15, wherein the pH of the drug is in the range of about 4 to about 8. The use as claimed in claim 16, wherein the pH of the drug is in the range of about 5 to about 7. The use as described in claim 1 or claim 2, wherein the medicament is formulated for topical administration to the individual's eyes. The use as described in claim 1 or claim 2, wherein the medicament is formulated for injection into the individual's eye. The use as described in claim 19, wherein the drug is formulated for administration by intravitreal injection.

Images