Ophthalmic composition comprising levodopa, antioxidant and aqueous carrier

Abstract

The present application relates to ophthalmic compositions comprising levodopa, an antioxidant, and an aqueous carrier. Disclosed are compositions comprising levodopa and an antioxidant for inhibiting the development or progression of visual disorders, including visual disorders associated with diabetic retinopathy or Parkinson's disease, as well as myopia.

Description

[0001] This application is a divisional application of application number 201780034347.X, filed on April 10, 2017, having the title "Ophthalmic compositions comprising levodopa, an antioxidant and an aqueous carrier".

[0002] This application claims priority from Australian provisional application number 2016901339, filed on April 11, 2016, entitled "Compositions and Methods of Use", the entire contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present invention relates generally to compositions comprising levodopa and an antioxidant for use in inhibiting the development or progression of visual impairment, including visual impairment associated with diabetic retinopathy or Parkinson's disease, and myopia. BACKGROUND

[0004] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0005] Myopia, commonly known as short-sightedness, is a visual impairment caused by excessive elongation (axial length) of the eye during development. Myopia is the leading cause of low vision and is the most common eye disease in the world, with some estimates that by the end of 2020, myopia could affect up to one-third of the world's population. The prevalence is highest in East Asian cities, where in many places, approximately 80-90% of school leavers are myopic.

[0006] The prevalence of myopia appears to be closely related to the amount of time spent outdoors in bright light. In particular, epidemiological studies have reported that time spent outdoors is an effective protective factor against the development of myopia in children. Animal studies have shown that this protective effect appears to be related to an increase in light-induced levels of dopamine within the eye.

[0007] Efforts are being made to reduce the onset and progression of myopia, including increasing the amount of time children spend outdoors in bright light. However, in many parts of the world, geographical location and local climate restrictions can prevent the brightness level being strong enough or the exposure time being long enough to prevent myopia. Furthermore, social and cultural barriers can prevent increasing the time children spend outdoors as it is perceived to hinder educational and academic progress.

[0008] Current treatment options to reduce progression of myopia include optical methods, such as single vision lenses, multifocal lenses, peripheral lenses, and corneal reshaping, and pharmaceutical agents, such as atropine and pirenzepine. With respect to optical methods, findings from clinical trials have been mixed, with most optical methods showing limited to no long-term effect on the rate of myopia progression. Optical methods also do not target the onset of myopia, only the progression of myopia. Traditionally, treatment with pharmaceutical agents such as atropine has been most effective at reducing the rate of myopia progression. However, widespread use of atropine has been inhibited due to concerns of rebound effects after treatment and severe short-term and long-term side effects.

[0009] Thus, there is a need for new therapies for inhibiting the development or progression of visual disorders, such as myopia. SUMMARY

[0010] The present invention is based, in part, on the discovery that an aqueous formulation of levodopa in combination with an antioxidant can penetrate ocular tissue and significantly increase intraocular dopamine levels, thereby inhibiting the development or progression of a visual disorder in a subject, particularly a visual disorder involving reduced dopamine levels in the eye, such as a visual disorder associated with diabetic retinopathy or Parkinson’s disease, or myopia.

[0011] Levodopa is a naturally occurring precursor of the neurotransmitters dopamine, adrenaline, and noradrenaline. Currently, levodopa is administered orally to treat Parkinson’s disease and to increase dopamine levels within the central nervous system, and to a lesser extent, dopamine levels systemically. However, oral administration of levodopa is not suitable for treatment of visual disorders, as it is undesirable to significantly increase dopamine levels in the brain of a subject with a visual disorder, and due to systemic distribution, oral administration requires large doses of levodopa.

[0012]

[0013] Levodopa In one aspect, the present invention provides an ophthalmic pharmaceutical composition comprising, consisting of, or consisting essentially of levodopa, an antioxidant, and an aqueous carrier. The inventors have discovered that it is desirable to formulate levodopa in an aqueous carrier such that it penetrates ocular tissue and is useful for increasing intraocular dopamine levels.

[0014] In another aspect of the application, there is provided a composition for use in inhibiting the progression or development of a visual impairment in a subject, the composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier. The composition can also be used in the treatment or prevention of a visual impairment.

[0015] In yet another aspect of the application, there is provided a method for inhibiting the progression or development of a visual impairment in a subject, the method comprising administering to the subject a composition of the application. In some embodiments, a visual impairment is treated in a subject. In other embodiments, a visual impairment is prevented in a subject.

[0016] Another aspect of the application provides the use of a composition of the application for inhibiting the progression or development of a visual impairment in a subject.

[0017] In a further aspect, the application provides a composition of the application for use in inhibiting the progression or development of a visual impairment in a subject.

[0018] The application also provides the use of a composition of the application in the manufacture of a medicament for inhibiting the progression or development of a visual impairment in a subject.

[0019] In still further aspects of the application, there is provided a method of preparing a composition of the application, the method comprising dissolving levodopa in an aqueous carrier at a pH in the range of from 0.5 to 2, adding an antioxidant to the composition, and adjusting the pH of the composition to a pH in the range of from 5 to 8.

[0020] Another aspect of the application provides an ophthalmic pharmaceutical composition formulated for topical administration to the eye, the ophthalmic pharmaceutical composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

[0021] In yet another aspect, the application provides a topical composition for use in inhibiting the progression or development of a visual impairment, the topical composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

[0022] In a further aspect, the application provides a method for inhibiting the progression or development of a visual impairment in a subject, the method comprising administering to the subject a composition comprising levodopa, an antioxidant, and an aqueous carrier; a composition consisting of levodopa, an antioxidant, and an aqueous carrier; or a composition consisting essentially of levodopa, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from the group consisting of a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0023] In yet a further aspect, there is provided use of a composition for inhibiting progression or development of a visual impairment in a subject, the composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0024] In another aspect, the present application provides a composition for use in inhibiting progression or development of a visual impairment in a subject, the composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0025] In yet a further aspect, there is provided use of a composition for inhibiting progression or development of a visual impairment in a subject, the composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0026] In a further aspect, the present application provides a method for inhibiting progression or development of a visual impairment in a subject, the method comprising administering to the subject a composition comprising levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier; consisting of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0027] In yet a further aspect, there is provided use of a composition for inhibiting progression or development of a visual impairment in a subject, the composition comprising levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier; consisting of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, an antioxidant, and an aqueous carrier, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease, and myopia.

[0028] In another aspect, the present application provides a composition for use in inhibiting the progression or development of a visual disorder in a subject, the composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate thereof or a prodrug thereof, an antioxidant, and an aqueous carrier, wherein the visual disorder is selected from a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0029] In yet another aspect, there is provided use of a composition in the manufacture of a medicament for inhibiting the progression or development of a visual disorder in a subject, the composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate thereof or a prodrug thereof, an antioxidant, and an aqueous carrier, wherein the visual disorder is selected from a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0030] In particular embodiments, the visual disorder is myopia.

[0031] In yet another aspect, there is provided a method for inhibiting the progression or development of a visual disorder in a subject, the method comprising administering to the subject a composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate thereof or a prodrug thereof, and a pharmaceutically acceptable carrier, wherein the visual disorder is selected from a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0032] In yet another aspect, there is provided a method for inhibiting the progression or development of a visual disorder in a subject, the method comprising administering to the subject a composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate thereof or a prodrug thereof, and a pharmaceutically acceptable carrier, wherein the visual disorder is selected from a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0033] In another aspect, the application provides a composition for use in inhibiting the progression or development of a visual disorder in a subject, the composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, and a pharmaceutically acceptable carrier, wherein the visual disorder is selected from the group consisting of a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0034] In yet another aspect, there is provided use of a composition in the manufacture of a medicament for inhibiting the progression or development of a visual disorder in a subject, the composition comprising, consisting of, or consisting essentially of levodopa or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, and a pharmaceutically acceptable carrier, wherein the visual disorder is selected from the group consisting of a visual disorder associated with diabetic retinopathy, a visual disorder associated with Parkinson’s disease, and myopia.

[0035] In some embodiments, the composition comprises, consists of, or consists essentially of levodopa and a pharmaceutically acceptable carrier. In particular embodiments, the pharmaceutically acceptable carrier is an aqueous carrier.

[0036] In particular embodiments, the visual disorder is myopia. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 Refractive development of chick eyes in response to diffuser wear (form deprivation myopia induction) and treatment with levodopa / carbidopa composition is shown.

[0038] Figure 2 Change in axial length of chick eyes in response to diffuser wear and treatment with levodopa / carbidopa composition is shown.

[0039] Figure 3 Refractive development of chick eyes in response to diffuser wear and treatment with levodopa or levodopa / carbidopa composition is shown.

[0040] Figure 4 Changes in axial length of chick eyes in response to diffuser wear and treatment with levodopa or levodopa / carbidopa combination.

[0041] Figure 5 Refraction development of chick eyes in response to diffuser wear and intravitreal injection of levodopa or levodopa / carbidopa combination. * = p<0.05; ** = p<0.01; *** = p<0.001 vs. G2 (form-deprivation myopia only).

[0042] Figure 6 Changes in axial length of chick eyes in response to diffuser wear and intravitreal injection of levodopa or levodopa / carbidopa combination. * = p<0.05; ** = p<0.01; *** = p<0.001 vs. G2 (form-deprivation myopia only).

[0043] Figure 7 Refraction development of chick eyes in response to diffuser wear and topical application of levodopa, levodopa / carbidopa or levodopa / DMSO combination. * = p<0.05; ** = p<0.01; *** = p<0.001 vs. G13 (form-deprivation myopia only).

[0044] Figure 8 Changes in axial length of chick eyes in response to diffuser wear and topical application of levodopa, levodopa / carbidopa or levodopa / DMSO combination. * = p<0.05; ** = p<0.01; *** = p<0.001 vs. G13 (form-deprivation myopia only).

[0045] Figure 9 Refraction development of chick eyes in response to diffuser wear and topical application of levodopa over a four-week period [vs. otherwise untreated eyes (no experimental myopia), = age-matched untreated controls; = form-deprivation myopia; = form-deprivation myopia and 0.3% w / v (15 mM) levodopa topical treatment; = 0.3% w / v (15 mM) levodopa topical treatment].

[0046] Figure 10 Changes in axial length of chick eyes in response to diffuser wear and topical application of levodopa over a four-week period [vs. otherwise untreated eyes (no experimental myopia), = age-matched untreated controls; = form-deprivation myopia; = form-deprivation myopia and 0.3% w / v (15 mM) levodopa topical treatment; = 0.3% w / v (15 mM) levodopa topical treatment].

[0047] Figure 11 Refractive development of chick eyes in response to diffuser wear and topical application of levodopa with ADTN, atropine and pirenzepine is shown. * = p<0.05; ** = p<0.01, vs. G2 (form-deprivation myopia only).

[0048] Figure 12 Change in axial length of chick eyes in response to diffuser wear and topical application of levodopa with ADTN, atropine and pirenzepine is shown. * = p<0.05; ** = p<0.01; *** = p<0.001, vs. G2 (form-deprivation myopia only).

[0049] Figure 13 Histological analysis of retinas from chick eyes stained with 1% toluidine blue after diffuser wear and four weeks of topical levodopa treatment is shown. Figure 13 A in Figure 1 1 shows a stained retina from a chick contralateral control eye, wherein the other eye was fitted with a translucent diffuser to induce FDM; Figure 13 B in Figure 1 1 shows a stained retina from a chick eye fitted with a translucent diffuser to induce FDM; Figure 13 C in Figure 1 1 shows a stained retina from a chick contralateral control eye, wherein the other eye was fitted with a translucent diffuser to induce FDM and treated with daily topical application of a composition comprising 0.3% w / v levodopa; Figure 13 D in Figure 1 1 shows a stained retina from a chick eye fitted with a translucent diffuser to induce FDM and treated with daily topical application of a composition comprising 0.3% w / v levodopa; Figure 13 E in Figure 1 1 shows a stained retina from a chick contralateral control eye, wherein the other eye was treated with daily topical application of a composition comprising 0.3% w / v levodopa; Figure 13 F in Figure 1 1 shows a stained retina from a chick eye treated with daily topical application of a composition comprising 0.3% w / v levodopa; and Figure 13 G in Figure 1 1 shows a stained retina from an eye of an age-matched untreated control chick.

[0050] Figure 14 TUNEL assay analysis of retinas from chick eyes after diffuser wear and four weeks of topical levodopa treatment is shown.Figure 14 A in FIG. 1 indicates a negative control; Figure 14 B in FIG. 1 indicates a positive control; Figure 14 C in FIG. 1 indicates a retinal section from an eye of an age-matched, untreated control chick; Figure 14 D in FIG. 1 indicates a retinal section from a chick eye fitted with a translucent diffuser to induce FDM; Figure 14 E in FIG. 1 indicates a retinal section from a chick eye treated with daily topical administration of a composition comprising 0.3% w / v levodopa; and Figure 14 F in FIG. 1 indicates a retinal section from a chick eye fitted with a translucent diffuser to induce FDM and treated with daily topical administration of a composition comprising 0.3% w / v levodopa. DETAILED DESCRIPTION

[0051] 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, preferred methods and materials are described. For the purposes of the present application, the following terms are defined below.

[0052] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0053] By "about," it is intended that a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length be variable up to 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the referenced quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0054] As used herein, the term "and / or" means and includes any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted in the alternative (or).

[0055] The phrase "aqueous carrier" is used herein to refer to a liquid aqueous diluent, wherein the aqueous carrier includes, but is not limited to, water, saline, aqueous buffers, and aqueous solutions containing water-soluble or water-miscible additives such as dextrose or glycerol. The aqueous carrier can also be in the form of an oil-in-water emulsion.

[0056] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term "comprising" and similar terms is not intended to imply that any other integer or step is optional or non-essential. For "consisting of," it means including, and limited to, whatever follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are mandatory or required and no other elements can be present. For "consisting essentially of," it means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are mandatory or required, but other elements are optional and can or can not be present depending upon whether or not they affect the activity or action of the listed elements.

[0057] As used herein, the term "condition" refers to an abnormality in the physical state of the body as a whole or a part thereof.

[0058] As used herein, the terms "salt" and "prodrug" include any pharmaceutically acceptable salt, ester, hydrate, solvate, or any other compound which, upon administration to a recipient, is capable of providing (directly or indirectly) the desired compound or an active metabolite or residue thereof. Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium. In addition, basic nitrogenous bases can be quaternized with such agents as low alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl, diethyl, and dibutyl sulfates; and other agents. It will be understood, however, that non-pharmaceutically acceptable salts also fall within the scope of the application, as these can be useful in the preparation of pharmaceutically acceptable salts. The preparation of salt and prodrug derivatives can be carried out by methods known in the art. For example, metal salts can be prepared by reaction of the desired compound with a metal hydroxide. Acid salts can be prepared by reaction of the appropriate acid with the desired compound.

[0059] As used herein, the phrase "dissolved form" refers to a form in which a compound such as levodopa is dissolved in a liquid such that a solution comprising the compound uniformly distributed is obtained, the solution being substantially free of solid compound. In some embodiments, the liquid is an aqueous carrier as described herein.

[0060] As used herein, the term "subject" refers to a vertebrate subject, particularly a mammalian or avian subject, for whom therapy or prophylaxis is desired. Suitable subjects include, but are not limited to, primates; avians; livestock animals such as sheep, cattle, horses, deer, donkeys, and pigs; laboratory test animals such as rabbits, mice, rats, guinea pigs, and hamsters; companion animals such as cats and dogs; and captive wild animals such as foxes, deer, and wild canines. In particular embodiments, the subject is a human. In some embodiments, the subject is a human child or young adult, e.g., from about 2 years of age to 20 years of age. It will be understood, however, that the above terms do not imply the presence of a symptom.

[0061] As used herein, the phrase "visual disorder" refers to a condition that alters a subject's vision. In particular embodiments, such a condition is associated with a decrease in "visual acuity," which is generally associated with a decrease or reduction in visual sharpness or clarity. Thus, a decrease in "visual acuity" generally refers to any measurable decrease or reduction in the sharpness or clarity of form vision, depending on the sharpness of the retinal focus within the eye and the sensitivity of the brain's interpretive abilities. In certain embodiments, visual acuity refers to Snellen acuity (e.g., 20 / 20).

[0062] Unless otherwise specifically noted, each embodiment described herein will be applied mutatis mutandis to all embodiments.

[0063] 2. Compositions The present application is based, in part, on the recognition that aqueous compositions comprising levodopa and an antioxidant can significantly increase intraocular dopamine levels. Thus, the present inventors contemplate that aqueous compositions comprising levodopa and an antioxidant can be used to inhibit the development or progression of a visual disorder involving reduced dopamine levels in the eye.

[0064] The amount of levodopa in the composition can depend on the visual disorder being treated, the characteristics of the subject, such as weight and age, and the route of administration. In some embodiments, the amount of levodopa in the composition is in the range of from 0.01% w / v to 60% w / v, 0.02% w / v to 50% w / v, 0.03% w / v to 40% w / v, 0.04% w / v to 30% w / v, 0.05% w / v to 20% w / v, 0.06% w / v to 10% w / v, 0.065% w / v to 9% w / v, 0.07% w / v to 8% w / v, 0.075% w / v to 7% w / v, 0.08% w / v to 6% w / v, 0.085% w / v to 5% w / v, 0.09% w / v to 4% w / v, 0.095% w / v to 3% w / v, 0.1% w / v to 2% w / v, or 0.105% w / v to 1% w / v of the composition (and all integers therebetween); particularly about 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.9%, or 1% w / v of the composition.

[0065] In preferred embodiments, levodopa is in dissolved form in the composition. The skilled person will be well aware of procedures routinely used in the art to determine the solubility of a compound, for example those described in Goodwin (2006) J. Pharm. Pharmacol. 58(12): 1427-1438; Jouyban (2010) Handbook of Solubility Data for Pharmaceuticals (CRC Press); or Hefter and Tomkins (2003) The Experimental Determination of Solubilities (John Wiley & Sons, Ltd). For example, the solubility of a compound can be analysed using UV spectroscopy or high performance liquid chromatography. Drug Discovery Today: Technologies

[0066] In some embodiments, levodopa can be in the form of a derivative, for example a pharmaceutically acceptable salt and / or solvate thereof, or a prodrug thereof. In some embodiments, levodopa is in the form of a hydrate. In some embodiments, the pharmaceutically acceptable salt of levodopa is a hydrochloride salt, for example the hydrochloride salt described in US 2007 / 0027216 Al. In some embodiments, the prodrug of levodopa is (2 R )-2-phenylcarbonyloxypropyl (2 S )-2-amino-3-(3,4-dihydroxyphenyl)propionic acid ester methanesulfonate, as described in US 2009 / 0156679 Al; or a levodopa ester, for example levodopa methyl ester or levodopa ethyl ester, levodopa amide, levodopa carboxamide or levodopa sulfonamide, for example those described in US 2014 / 0088192 Al.

[0067] Without wishing to be bound by theory, the use of levodopa, which is naturally synthesised by and present in the human body, is believed to reduce side effects compared to therapies with non-naturally occurring agents, and as such, the compositions of the application will be suitable for long-term use. Furthermore, it is believed that the use of a naturally occurring compound will reduce the incidence of tolerance, which is often developed with existing agents for the treatment and / or prevention of visual disorders such as myopia.

[0068] ​The antioxidant can be any compound that slows, inhibits, or prevents oxidation of any component of the compositions of the present application, particularly levodopa. Suitable antioxidants can include, but are not limited to, ascorbic acid or vitamin C, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetylcysteine, sodium thiothiotate, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbyl palmitate, alpha-thioglycerol, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol or vitamin E, tocopherol acetate, butylated hydroxytoluene, soy lecithin, sodium thioethanolate, 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.

[0069] The antioxidant can be present in an amount suitable to substantially slow, inhibit, or prevent oxidation of any component of the compositions of the present application, particularly levodopa. For example, the antioxidant can be present in an amount ranging from 0.01% w / v to 10% w / v, 0.01% w / v to 5% w / v, 0.03% w / v to 4% w / v, 0.05% w / v to 3% w / v, 0.07% w / v to 2% w / v, 0.09% w / v to 1% w / v, or 0.1% w / v to 0.5% w / v of the composition; particularly in an amount of about 0.1% w / v of the composition.

[0070] The aqueous carrier is preferably a pharmaceutically acceptable aqueous carrier. A variety of pharmaceutically acceptable aqueous carriers known in the art can be used. For example, the aqueous carrier can be selected from, but is not limited to, saline, water, an aqueous buffer, an aqueous solution comprising water and a miscible solvent, and combinations thereof. In some embodiments, the aqueous carrier is saline. When saline is used, it is preferably isotonic for the point of administration, e.g., the eye. For example, in some embodiments, the saline comprises 0.15% w / v to 8% w / v sodium chloride; particularly 0.18% w / v to 7% w / v, 0.22% w / v to 5% w / v, or 0.45% w / v to 3% w / v sodium chloride; more particularly 0.5% w / v to 2% w / v or 0.65% w / v to 1.5% w / v sodium chloride; most particularly about 0.9% w / v sodium chloride.

[0071] In some embodiments where the aqueous carrier is not isotonic (e.g., water), the composition can include a tonicity agent. Any pharmaceutically acceptable tonicity agent known in the art can be used. Suitable tonicity agents include, but are not limited to, boric acid, acid sodium phosphate buffer, sodium chloride, dextrose, trehalose, potassium chloride, calcium chloride, magnesium chloride, polypropylene glycol, glycerol, mannitol, or salts or combinations thereof. The tonicity agent can be present in the composition in an amount that provides isotonicity to the site of administration, such as the eye, for example, in an amount ranging from 0.02% w / v to 15% w / v.

[0072] In some embodiments, the aqueous carrier is a buffer, where the buffer maintains the pH in a range from 5 to 8, 5.2 to 7.4, 5.5 to 7.4, or 5.5 to 6. In some embodiments, the buffer maintains the pH in a range from 5.5 to 6.5, in particular a range from 5.5 to 6 or 6 to 6.5. Suitable buffering agents include, but are not limited to, acetic acid, citric acid, sodium metabisulfite, histidine, sodium bicarbonate, sodium hydroxide, boric acid, borax, alkali metal phosphate, phosphate or citrate buffers, or combinations thereof. The buffering agent can be present in the composition in an amount suitable to maintain the desired pH.

[0073] In some embodiments, the pH of the composition is in a range from 5 to 8, 5.2 to 7.4, 5.5 to 7.4, or 5.5 to 6. In some embodiments, the pH of the composition is in a range from 5.5 to 6.5, in particular a range from 5.5 to 6 or 6 to 6.5. In some embodiments, the pH of the composition is in a range from 5.5 to 6. In some embodiments, the pH of the composition is in a range from 6 to 6.5.

[0074] In some embodiments, the compositions of the present application further comprise an inhibitor of aromatic L-amino acid decarboxylase. Suitable inhibitors of aromatic L-amino acid decarboxylase include, but are not limited to, carbidopa, benserazide, methyldopa, or salts or combinations thereof. In some embodiments, the inhibitor of aromatic L-amino acid decarboxylase is carbidopa. Without wishing to be bound by theory, it is believed that the inhibitor of aromatic L-amino acid decarboxylase reduces the conversion of levodopa to dopamine in non-neuronal tissue, and thus increases the bioavailability of levodopa in the compositions of the present application.

[0075] The amount of inhibitor of aromatic L-amino acid decarboxylase in the compositions of the present application will depend on the condition being treated, the route of administration of the composition, and the amount of levodopa in the composition. The inhibitor of aromatic L-amino acid decarboxylase should be present in an amount sufficient to significantly inhibit the decarboxylation of levodopa. In some embodiments, the ratio of levodopa to inhibitor of aromatic L-amino acid decarboxylase is from 20: 1 to 1 : 1, 15: 1 to 1 : 1, 10: 1 to 1 : 1, 9: 1 to 1 : 1, 8: 1 to 1 : 1, 7: 1 to 1 : 1, 6: 1 to 2: 1, or 5: 1 to 3: 1. In some embodiments, the ratio of levodopa to inhibitor of aromatic L-amino acid decarboxylase is about 4: 1.

[0076] In some embodiments, the amount of inhibitor of aromatic L-amino acid decarboxylase in the composition is in the range of from 0.0005% w / v to 30% w / v, 0.0025% w / v to 15% w / v, 0.005% w / v to 12.5% w / v, 0.0075% w / v to 10% w / v, 0.01% w / v to 7.5% w / v, 0.0125% w / v to 5% w / v, 0.015% w / v to 2.5% w / v, 0.0163% w / v to 2.25% w / v, 0.0175% w / v to 2% w / v, 0.0188% w / v to 1.75% w / v, 0.02% w / v to 1.5% w / v, 0.0213% w / v to 1.25% w / v, 0.0225% w / v to 1% w / v, 0.0238% w / v to 0.75% w / v, 0.025% w / v to 0.5% w / v, 0.0263% w / v to 0.25% w / v (and all integers therebetween) of the composition; particularly about 0.025% w / v, 0.03% w / v, 0.035% w / v, 0.04% w / v, 0.045% w / v, 0.05% w / v, 0.055% w / v, 0.06% w / v, 0.065% w / v, 0.07% w / v, 0.075% w / v, 0.08% w / v, 0.085% w / v, 0.09% w / v, 0.095% w / v, 0.1% w / v, 0.125% w / v, 0.15% w / v, 0.175% w / v, 0.2% w / v, 0.225% or 0.25% w / v of the composition.

[0077] The composition can also include or can be administered separately, simultaneously or sequentially with one or more ancillary pharmaceutically active agents. In some embodiments, the ancillary pharmaceutically active agent can increase activation of the dopaminergic system. Exemplary ancillary pharmaceutically active agents include, but are not limited to, dopamine receptor agonists, gamma-aminobutyric acid (GABA) receptor antagonists, and / or muscarinic acetylcholine receptor antagonists. In some embodiments, the pharmaceutically active agent is an agent for inhibiting the development or progression of a visual disorder, particularly a visual disorder involving reduced dopamine levels in the eye, such as myopia.

[0078] Without wishing to be bound by theory, it is believed that administration of more than one pharmaceutically active agent can reduce the development of tolerance to the therapy, particularly when the pharmaceutically active agents have different mechanisms of action and / or different molecular targets. For example, administration of the compositions of the present application with an existing pharmacological treatment for a visual disorder, such as atropine, can reduce the occurrence of receptor desensitization in response to the existing pharmacological treatment. It is also believed that administration of more than one pharmaceutically active agent can result in greater therapeutic effect than administration of each agent alone, such as increased efficacy, reduced side effects, and / or reduced tolerance.

[0079] In some embodiments, the compositions of the present application further comprise a dopamine receptor agonist. The dopamine receptor agonist can have agonist activity at any dopamine receptor subtype, including but not limited to any receptor subtype from the D1-like family (D1 and D5 receptors) and the D2-like family (D2, D3, and D4 receptors) of receptors, as well as dopamine receptor heterodimers. Suitable dopamine receptor agonists include, but are not limited to, quinpirole, apomorphine, ropinirole, pramipexole, dexpramipexole, piribedil, rotigotine, bromocriptine, lisuride, cabergoline, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), pergolide, calidopa, dihydrexidine, doxathrine, propyl-norapomorphine, quinagolide, droindole, sumanirole, fenoldopam, ergocornine, 1-phenyl-2,3,4,5-tetrahydro-(1 H )-3-benzazocin-7,8-diol (also known as SKF-38393), 2-( N -phenethyl- N -propyl)amino-5-hydroxytetrahydronaphthalene (PPHT; also known as N-0434), dihydroergotamine, (1 R ,3 S )-1-(aminomethyl)-3-phenyl-3,4-dihydro-1 H-Isochrome-5,6-diol (also known as A-68930), carmoxicillin, or a salt or combination thereof. In some embodiments, the dopamine receptor agonist is dihydroergotamine tartrate, 2-( N -Phenylacet- N -propyl)amino-5-hydroxytetrahydronaphthalene hydrochloride or (1 R ,3 S )-1-(aminomethyl)-3-phenyl-3,4-dihydro-1 H -Isochrome-5,6-diol hydrochloride. In some embodiments, the dopamine receptor agonist is selected from ADTN, quinpyrrole, apomorphine, and salts and combinations thereof; particularly ADTN and its salts.

[0080] The amount of dopamine receptor agonist in the composition can depend on the current treatment status and route of administration. In some embodiments, the amount of dopamine receptor agonist in the composition is within the following ranges: from 0.01% w / v to 20% w / v, 0.01% w / v to 10% w / v, 0.01% w / v to 5% w / v, 0.03% w / v to 3% w / v, 0.033% w / v to 2.7% w / v, 0.038% w / v to 2.4% w / v, 0.043% w / v to 2.1% w / v, 0.05% w / v to 1.8% w / v, 0.06% w / v to 1.5% w / v, 0.075% w / v to 1.2% w / v, 0.1% w / v to 0.9% w / v, or 0.15% w / v to 0.6% w / v (and all integers therebetween); particularly about 0.2% of the composition. w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, 0.33% w / v, 0.34% w / v, 0.35% w / v, 0.36% w / v, 0.37% w / v, 0.38% w / v, 0.39% w / v or 0.4% w / v.

[0081] In some embodiments, the compositions of the present invention further comprise a GABA receptor antagonist. The GABA receptor antagonist can have antagonistic activity in any GABA receptor subtype, including but not limited to GABA. A receptors, GABA B receptors and / or GABA A -rho (formerly GABA) CSuitable GABA receptor antagonists include, but are not limited to, paeonol, flumazenil, gabazine, phenyltetrazole, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphonic acid (TPMPA), (3-aminopropyl)(cyclohexylmethyl)phosphonic acid (also known as CGP-46381), 4-imidazolidineacetic acid, tetrandrine, piperidine-4-ylphosphonic acid (PPA), piperidine-4-ylselenoic acid (SEPI), and 3-aminopropyl- N -Butylphosphonic acid (also known as CGP-36742), (piperidin-4-yl)methylphosphonic acid (P4MPA), or salts or combinations thereof. In some embodiments, the GABA receptor antagonist is selected from TMPA, purslane, and salts and combinations thereof.

[0082] The amount of GABA receptor antagonist in the composition can depend on the current treatment status and route of administration. In some embodiments, the amount of GABA receptor antagonist in the composition is within the following ranges: 0.01% w / v to 20% w / v, 0.01% w / v to 10% w / v, 0.01% w / v to 5% w / v, 0.03% w / v to 3% w / v, 0.033% w / v to 2.7% w / v, 0.038% w / v to 2.4% w / v, 0.043% w / v to 2.1% w / v, 0.05% w / v to 1.8% w / v, 0.06% w / v to 1.5% w / v, 0.075% w / v to 1.2% w / v, 0.1% w / v to 0.9% w / v, or 0.15% w / v to 0.6% w / v (and all integers therebetween); particularly about 0.2% of the composition. w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, 0.33% w / v, 0.34% w / v, 0.35% w / v, 0.36% w / v, 0.37% w / v, 0.38% w / v, 0.39% w / v or 0.4% w / v.

[0083] In some embodiments, the compositions of the present application further comprise a muscarinic acetylcholine receptor antagonist. The muscarinic acetylcholine receptor antagonist can have antagonist activity at any muscarinic acetylcholine receptor subtype, including but not limited to the M1 receptor, the M2 receptor, the M3 receptor, the M4 receptor, and the M5 receptor. Suitable muscarinic receptor antagonists include, but are not limited to, atropine, pirenzepine, xibornil, scopolamine, cyclopentolate, ipratropium, oxitropium, tropicamide, oxybutynin, tolterodine, benztropine, dicycloverine, flavoxate, tiotropium, trihexphenidyl, solifenacin, darifenacin, benzatropine, mebeverine, procyclidine, aclidinium, muscarinic toxin 1 (MT1), muscarinic toxin 2 (MT2), muscarinic toxin 3 (MT3), muscarinic toxin 4 (MT4), muscarinic toxin 7 (MT7), or salts or combinations thereof. In some embodiments, the muscarinic acetylcholine receptor antagonist is selected from atropine, pirenzepine, xibornil, and salts and combinations thereof; particularly atropine and pirenzepine, and salts and combinations thereof.

[0084] The amount of muscarinic acetylcholine receptor antagonist in the composition can depend on the condition being treated and the route of administration. In some embodiments, the amount of muscarinic acetylcholine receptor antagonist in the composition is in the range of from 0.01% w / v to 30% w / v, 0.2% w / v to 20% w / v, 0.22% w / v to 18% w / v, 0.25% w / v to 16% w / v, 0.29% w / v to 14% w / v, 0.33% w / v to 12% w / v, 0.4% w / v to 10% w / v, 0.5% w / v to 8% w / v, 0.67% w / v to 6% w / v, or 1% w / v to 4% w / v (and all integers therebetween) of the composition; particularly about 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.9% w / v, 1% w / v, 1.1% w / v, 1.2% w / v, 1.3% w / v, 1.4% w / v, 1.5% w / v, 1.6% w / v, 1.7% w / v, 1.8% w / v, 1.9% w / v, 2% w / v, 2.1% w / v, 2.2% w / v, 2.3% w / v, 2.4% w / v, 2.5% w / v, 2.6% w / v, 2.7% w / v, 2.8% w / v, 2.9% w / v, 3% w / v, 3.1% w / v, 3.2% w / v, 3.3% w / v, 3.4% w / v, 3.5% w / v, 3.6% w / v, 3.7% w / v, 3.8% w / v, 3.9%, or 4% w / v of the composition.In particular embodiments, the amount of muscarinic acetylcholine receptor antagonist in the composition is in the range of from 0.0001% w / v to 30% w / v, 0.0003% w / v to 20% w / v, 0.0005% w / v to 10% w / v, 0.0007% w / v to 5% w / v, 0.0009% w / v to 2% w / v, 0.001% w / v to 1% w / v, 0.003% w / v to 0.5% w / v, 0.005% w / v to 0.2% w / v, 0.007% w / v to 0.15% w / v, or 0.009% w / v to 0.1% w / v of the composition (and all integers therebetween); particularly about 0.001% w / v, 0.002% w / v, 0.003% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, 0.01% w / v, 0.011% w / v, 0.012% w / v, 0.013% w / v, 0.014% w / v, 0.015% w / v, 0.016% w / v, 0.017% w / v, 0.018% w / v, 0.019% w / v, or 0.02% w / v of the composition; most particularly about 0.01% w / v of the composition.

[0085] The compositions of the present application can also comprise a surfactant. A variety of pharmaceutically acceptable surfactants known in the art can be used. Exemplary surfactants include, but are not limited to, surfactants of the following classes: alcohols; amine oxides; block polymers; carboxylated alcohols or alkylphenol ethoxylates; carboxylic acids / fatty acids; ethoxylated arylphenols; ethoxylated fatty esters, oils, amines, or alcohols such as cetyl alcohol; fatty esters; fatty acid methyl ester ethoxylates; glycerides such as glyceryl monostearate; glycol esters; lanolin-based derivatives; lecithin or derivatives thereof; lignin or derivatives thereof; methyl esters; monoglycerides or derivatives thereof; polyethylene glycol; polypropylene glycol; alkylphenol polyethylene glycol; alkylthiol polyethylene glycol; polypropylene glycol ethoxylates; polyethylene glycol ethers such as Cetomacrogol 1000; polymeric surfactants; propoxylated and / or ethoxylated fatty acids, alcohols, or alkylphenols; protein-based surfactants; sarcosine derivatives; sorbitan derivatives such as polysorbates; sorbitol esters; esters of sorbitol polyglycol ethers; fatty acid alkanolamides; N - alkyl polyhydroxy fatty acid amides; N- an alkoxypolyhydroxy fatty acid amide; an alkylpolysaccharide; a quaternary ammonium compound such as benzalkonium chloride; a cyclodextrin such as a- cyclodextrin, β-cyclodextrin, or γ-cyclodextrin; a sucrose ester or glucose ester or derivative thereof; a sulfosuccinate such as dioctyl sodium sulfosuccinate; or a combination thereof. Without wishing to be bound by theory, if an oil is included in the composition, the presence of a surfactant can serve to emulsify the aqueous carrier with the oil and can enhance the penetration of the active ingredient, e.g., levodopa, through the corneal epithelium. The surfactant can be present in an amount ranging from about 0.1% w / v to 30% w / v of the composition.

[0086] In some embodiments, the compositions of the present application further comprise a rheology modifier. Rheology modifiers can be used to alter the surface tension and flow of the composition and, when formulated for topical administration, can also aid in the residence time of the composition on the surface of the eye. 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, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl guar gum, acrylates such as Carbopol polymers, poloxamers, gum arabic, xanthan gum, guar gum, locust bean gum, carboxymethyl cellulose, 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 can be present in an amount ranging from about 0.5% w / v to 5% w / v of the composition.

[0087] The compositions of the present application can also include a preservative. The preservative can be particularly useful to prevent microbial contamination in the composition from the same container, which is subject to multiple uses, for example, if the compositions of the present application are formulated for topical administration in multiple unit dosage forms. Suitable preservatives include any pharmaceutically acceptable preservative conventionally used in the art to prevent microbial contamination in a composition. Non-limiting examples include sodium perborate, stabilized oxychloro complex, polyquaternium-1, phenylmercuric acid, benzalkonium chloride, chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate, chlorhexidine, benzododecinium bromide, cetrimonium chloride, thiomersal, methyl paraben, propyl paraben, polyquaternium ammonium chloride, polyaminopropyl biguanide, hydrogen peroxide, benzoic acid, phenolic acid, sorbic acid, benzyl alcohol, or salts or combinations thereof. The preservative should be present in an amount that provides sufficient preservative activity. For example, the preservative can be present in an amount ranging from about 0.001% w / v to 1% w / v of the composition.

[0088] It can be desirable to increase the penetration of the composition into the eye. This can be particularly useful when the composition is formulated for topical administration. Accordingly, the compositions of the present application can also include a penetration enhancer. In this regard, the compositions of the present application can include, but are not limited to, dimethyl sulfoxide (DMSO); a cyclodextrin such as a-cyclodextrin, b-cyclodextrin, or g-cyclodextrin; EDTA; decanoyl quaternary ammonium; glycocholate; cholate; saponin; fusidate; taurocholate; polyethylene glycol ether; polysorbate; or salts, derivatives, or combinations thereof. In some embodiments, the penetration enhancer is dimethyl sulfoxide. Other penetration enhancers include nanoparticles, liposomes, or micelles, which in some embodiments encapsulate levodopa. The penetration enhancer should be present in an amount that facilitates the penetration of levodopa across the corneal epithelium. For example, the penetration enhancer can be present in an amount ranging from about 0.1% w / v to 30% w / v of the composition.

[0089] In particular embodiments, the penetration enhancer is a micelle. Suitable micelles include, but are not limited to, Triton X-100 micelles, for example, as described in Jodko-Piorecka and Litwinienko (2015) Free Radical Biology and MedicineMicelles as described in 83:1-11; surfactant nanomicelles, such as those formed with sodium dodecyl sulfate, dodecyltrimethylammonium bromide, n-dodecyltetra(ethylene oxide), vitamin E TGPS, octylphenol polyether-40, and / or dioctylphosphatidylcholine; polymeric micelles, such as those formed with poly(caprolactone), poly(D,L-lactide), polypropylene oxide, poly(β-benzyl-1-aspartate), methoxy-poly(ethylene glycol)-hexyl-substituted poly(lactide), Pluronic F127 poly(ethylene oxide) / poly(propylene oxide) / poly(ethylene oxide), F68, F127, poly(hydroxyethyl aspartamide)-polyethylene glycol-hexadecylamine, and polyoxyl 40 stearate. N -Isopropylacrylamide and N , N '-Methylenebisacrylamide crosslinked vinylpyrrolidone and acrylic acid, Pluronic F127 and chitosan, polylactic acid, poly(glycolic acid), poly(ethylene glycol), poly(ethylene oxide)' N - Phthaloylcarboxymethyl chitosan ( N -phthaloylcarboxymethylchitosan), 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 Micelles formed of chitosan oligosaccharides grafted with isopropylacrylamide-co-methacrylic acid (g-poly(D,L-lactide)) and / or stearic acid; or micelles disclosed in US 2009 / 0092665 A1. In a particular embodiment, the micelles encapsulate levodopa in the composition.

[0090] The compositions of the present invention may further comprise a chelating agent. Suitable chelating agents include, but are not limited to, aminocarboxylic acids or their salts, such as EDTA, nitroglycerin, nitropropionic acid, diethylenetriaminepentaacetic acid, 2-hydroxyethyl-ethylenediaminetriacetic acid, 1,6-diamino-hexamethylenetetraacetic acid, 1,2-diamino-cyclohexanetetraacetic acid, etc. O , O '-Bis(2-aminoethyl)-ethylene glycol-tetraacetic acid, 1,3-diaminopropane-tetraacetic acid, N , Nbis(2-hydroxybenzyl)ethylenediamine N,N diacetic acid, ethylenediamine N , N diacetic acid, ethylenediamine N , N dipropionic acid, triethylenetetramine hexaacetic acid, 7,19,30-trioxa-1,4,10,13,16,22,27,33- octaazabicyclo[11,11,11]pentatriacontane O bis-tren), ethylenediamine N , N bis(methylene phosphonic acid), iminodiacetic acid, N,N bis(2-hydroxyethyl)glycine (DHEG), 1,3-diamino-2-hydroxypropane-tetraacetic acid, 1,2-diaminopropane-tetraacetic acid, ethylenediamine-tetrakis(methylene phosphonic acid), N (2-hydroxyethyl)iminodiacetic acid, or combinations or salts thereof; particularly a pharmaceutically acceptable salt or mixed salt of EDTA, such as disodium salt, trisodium salt, tetrasodium salt, dipotassium salt, tripotassium salt, lithium salt, dilithium salt, ammonium salt, diammonium salt, calcium salt, or calcium-disodium salt; most particularly disodium EDTA. The chelating agent can be present in an amount ranging from about 0.01% w / v to 1% w / v of the composition.

[0091] In some embodiments, the compositions of the present application can also include an 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; cinnamon oil; arachis oil; maize oil; caraway oil; rosemary oil; mint oil; eucalyptus oil; seed oils such as rapeseed oil, cottonseed oil, linseed oil, safflower oil, sesame oil, or sunflower oil; silicone oil; or combinations thereof. Such oils can be included in the composition in the form of an oil-in-water emulsion with an aqueous carrier, optionally together with a surfactant. The oil can be present in an amount ranging from about 0.1% w / v to 20% w / v of the composition.

[0092] The compositions of the present application can also include any other pharmaceutically acceptable excipient typically found in ophthalmic formulations. For example, the compositions can also include an alcohol such as isopropyl alcohol, benzyl alcohol, cetearyl alcohol, or ethanol; a lubricant such as dextrose, glycerin, polyethylene glycol, polypropylene glycol, or derivatives thereof; a polysaccharide such as chitosan, chitin, dermatan, hyaluronate, heparin, chondroitin, cyclodextrin, or derivatives thereof; or combinations thereof. Suitable pharmaceutically acceptable carriers include, but are not limited to, aqueous carriers as described herein, oils as described herein, fatty acids, silicone liquid carriers such as perfluorocarbons or fluorinated liquid carriers, e.g., as described in US 6458376 B1, and combinations thereof. In some embodiments, the compositions do not include an antioxidant.

[0093] In particular embodiments, the compositions of the present application can be formulated for topical administration to the eye. In this regard, the compositions of the present application can be in the form of an eye drop or a gel; especially an eye drop. Without wishing to be bound by theory, formulating the compositions for topical administration to the eye is believed to increase user compliance, particularly when the compositions are used as a prophylactic or control measure. This can be particularly important if the compositions are administered to pediatric subjects. Furthermore, such formulations can reduce the incidence of off-target effects of levodopa.

[0094] In some embodiments, the compositions of the present application are formulated for penetration of the corneal epithelium by levodopa. In preferred embodiments, greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the dose of levodopa penetrates the corneal epithelium.

[0095] When formulated as an eye drop or a gel, the compositions of the present application can be in a single unit dosage form or a multiple unit dosage form, preferably a multiple unit dosage form.

[0096] In alternative embodiments, the compositions of the present application are formulated for direct injection into the eye. In particular embodiments, the compositions of the present application are formulated for intravitreal injection, subconjunctival injection, intracameral injection, intrascleral injection, intracorneal injection, or subretinal injection; especially intravitreal injection, intrascleral injection, or intracorneal injection. In some embodiments, the compositions of the present application are formulated for suprachoroidal injection. In some embodiments, the compositions of the present application are formulated for injection via microneedles, e.g., via intrascleral administration or intracorneal administration.

[0097] Other excipients and components of the compositions can be readily determined by one of skill in the art. Techniques for formulation and administration can be found in, for example, Remington (1980) Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., latest edition; and suitable excipients can be found in, for example, Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

[0098] One of skill in the art will be familiar with the components of the compositions of the present application, and will therefore be able to readily synthesize or obtain these components, for example, from such as Sigma Aldrich Co. LLC. For example, levodopa is commercially available from many sources, for example, Sigma-Aldrich Co. LLC, and synthetic routes are available from, for example, Vandanyan and Hruby (2006) Synthesis of Essential Drugs (Elsevier) pp. 136-137; Vandanyan and Hruby (2016) Synthesis of Best-Seller Drugs (Academic Press) pp. 180-182; and US 4,962,223; all of which are incorporated by reference herein in their entirety.

[0099] 3. Process for the preparation of the compositions The inventors have found that the compositions of the present application can be prepared by dissolving levodopa in an aqueous carrier at a pH in the range of from 0.5 to 2.5, adding an antioxidant to the composition, and adjusting the pH of the composition to a pH in the range of from 5 to 8.

[0100] The pH at which the levodopa is dissolved in the aqueous carrier is in the range of from 0.5 to 2.5, preferably 1 to 2, most particularly 1.5 to 2. In some embodiments, the levodopa is dissolved in the aqueous carrier at a pH of about 2. Without wishing to be bound by theory, it is believed that maintaining the aqueous carrier at an acidic pH increases the solubility of the levodopa in the aqueous carrier.

[0101] The pH of the final composition is in the range from 5 to 8, preferably 5.5 to 7.5, in particular 5.5 to 7.4, most particularly 5.5 to 6. In some embodiments, the pH of the composition is in the range from 5.5 to 6.5, in particular in the range 5.5 to 6 or 6 to 6.5. In some embodiments, the pH of the composition is adjusted to a pH in the range from 5.5 to 6. In some embodiments, the pH of the composition is adjusted to a pH in the range from 6 to 6.5.

[0102] The pH of the composition can be adjusted using any pharmaceutically acceptable pH adjusting agent conventionally used in the art, for example hydrochloric acid, sodium hydroxide and the like. The skilled person will be well aware of suitable agents.

[0103] The inhibitor of aromatic L-amino acid decarboxylase, excipients and other components of the composition of the application can be added to the composition at any stage of the process. For example, the inhibitor of aromatic L-amino acid decarboxylase can be added to the solution of levodopa and aqueous carrier at a pH in the range from 0.5 to 2.5 before the pH of the composition is adjusted to a pH in the range from 5 to 8, or can be added to the composition after the pH of the composition is adjusted to a pH in the range from 5 to 8. In some embodiments, the inhibitor of aromatic L-amino acid decarboxylase and levodopa are simultaneously dissolved in the aqueous carrier at a pH in the range from 0.5 to 2.5.

[0104] The composition of the application can also be sterilised prior to use, for example by filtration, autoclaving and / or gamma irradiation.

[0105] Without wishing to be bound by theory, the use of this process to prepare the composition of the application increases the solubility of levodopa in the aqueous carrier, thereby eliminating the need for the presence of an organic carrier or organic agent to increase the solubility of levodopa in the composition.

[0106] 4. Methods of preventing and treating visual impairment The composition of the application can be used to inhibit the progression or development of a visual disorder in a subject, in particular a visual disorder involving reduced dopamine levels in the eye, for example a visual disorder associated with diabetic retinopathy or Parkinson’s disease, or myopia. Accordingly, the composition of the application can be used in a method of inhibiting the progression or development of a visual disorder in a subject. The composition of the application can also be used in the manufacture of a medicament for use as described herein.

[0107] The composition of the application can be used to inhibit the progression of a visual disorder in a subject. In this regard, the composition of the application can be used to treat a visual disorder. In some embodiments, the composition of the application can slow the progression of a visual disorder in a subject.

[0108] The compositions of the application can also be used to inhibit the development of a visual impairment in a subject. Thus, the compositions of the application can be used to prevent a visual impairment in a subject. In some embodiments, the compositions of the application can delay the onset of a visual impairment in a subject, i.e. can increase the age at which a subject is at when a visual impairment develops, and thus delay the likely severity of the visual impairment.

[0109] The visual impairment can be any visual impairment that involves reduced dopamine levels in the eye, in particular any visual impairment that involves reduced dopamine levels in the retina. Thus, the visual impairment can be any visual impairment in which increasing dopamine levels in the eye, in particular in the retina, is associated with effective inhibition of the progression or development of the visual impairment.

[0110] There are many visual impairments that involve reduced dopamine levels in the eye. For example, the visual impairment can be, but is not limited to, a visual impairment associated with diabetic retinopathy or Parkinson’s disease, myopia, increased ocular growth, reduced spatial and temporal contrast sensitivity, amblyopia, blurred or double vision, eye strain, problems with actively opening the eyes (apraxia), eyelid spasm (blepharospasm), excessive blinking, altered colour perception, reduced depth perception or visual hallucinations. In some embodiments, the visual impairment is selected from a visual impairment associated with diabetic retinopathy or Parkinson’s disease, and myopia. In particular embodiments, the visual impairment is myopia.

[0111] In some embodiments, the visual impairment is not associated with Parkinson’s disease.

[0112] The method comprises administering to the subject a composition of the application. The composition of the application can be administered topically by application to the surface of the eye or via direct injection into the eye.

[0113] In some embodiments, the composition is administered topically to the eye, for example in the form of an eye drop or a gel. In preferred embodiments, the composition is applied as an eye drop. The composition of the application can be applied to any surface of the eye, preferably the cornea / sclera, thereby allowing the components present in the composition, in particular levodopa, to penetrate into the eye. In some embodiments, the composition is formulated such that the levodopa penetrates the corneal epithelium.

[0114] In other embodiments, the composition is administered by injection into the eye. For example, the composition can be injected directly into the sclera, the anterior chamber or the vitreous, or can be injected into the subconjunctival space, the peribulbar space, the retrobulbar space or the suprachoroidal space. In particular embodiments, the composition of the application is administered via intravitreal injection, subconjunctival injection, intracameral injection, intrascleral injection, intracorneal injection or subretinal injection; in particular intravitreal injection, intrascleral injection or intracorneal injection. In some embodiments, the composition of the application is administered via suprachoroidal injection. In some embodiments, the composition of the application is administered by intravitreal injection. In other embodiments, the composition of the application is injected using microneedles, for example via intrascleral administration or intracorneal administration. For administration via these routes, the composition of the application can be in the form of a sterile injectable solution.

[0115] The part of the eye into or onto which the composition of the application is preferably administered is a part that allows penetration of the components, in particular levodopa, into the eye, preferably into the retina. Administration on the cornea / sclera and the conjunctiva is preferably for topical administration, or the composition can be injected into the subconjunctival space, the peribulbar space, the retrobulbar space or the suprachoroidal space, or into the sclera, the cornea, the anterior chamber or the vitreous.

[0116] When applied topically, the composition of the application can be used with both hard and soft contact lenses.

[0117] Dose regimens can be established for different indications according to methods well known to the person skilled in the art. The dose of the composition will depend on the condition to be treated, the age of the subject and the route of administration.

[0118] The composition of the application can be administered topically or by injection in a suitable amount so as to provide a dose of levodopa ranging from 0.001 mg / kg / day to 12 mg / kg / day, in particular from 0.001 mg / kg / day to 4 mg / kg / day, more particularly from 0.001 mg / kg / day to 2 mg / kg / day. In some embodiments, the composition is administered in a suitable amount so as to provide a dose of levodopa ranging from 0.001 mg / kg / day to 30 mg / kg / day, in particular from 0.001 mg / kg / day to 12 mg / kg / day, more particularly from 0.001 mg / kg / day to 4 mg / kg / day, most particularly from 0.001 mg / kg / day to 2 mg / kg / day.

[0119] When applied topically as eye drops, the compositions of the application can be applied in an amount ranging from 1 drop per eye to 6 drops per eye (and all integers therebetween), which can be equivalent to an amount ranging from about 0.04 mL per eye to 0.24 mL per eye (and all integers therebetween), for example. The drops can be applied from 1 to 4 times per day to each eye. When the compositions of the application are formulated as gels, equivalent dosages are provided. The skilled person will know suitable dispensers for topical application of the compositions of the application.

[0120] When administered by injection, the compositions of the application can be administered in an amount ranging from 0.001 mL to 0.5 mL (and all integers therebetween), in particular about 0.01 mL. The compositions of the application can be administered with a frequency ranging from once a week to once a day.

[0121] In order that the present application can be readily understood and put into practice, particular preferred embodiments will now be described by way of the following non-limiting examples.

[0122] Example Unless otherwise indicated, all materials used in the following examples are commercially available from, for example, Sigma-Aldrich Company.

[0123] Example 1 - Method of producing a 0.3% w / v levodopa composition Twelve mg of levodopa (commercially available from Sigma-Aldrich Co. LLC) was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid and lx phosphate buffered saline (PBS) (solution is about pH 2). After levodopa was dissolved, the solution was adjusted to pH 6 using sodium hydroxide to give a final volume of 4 mL.

[0124] Example 2 - Method of producing a 0.3% w / v levodopa, 0.08% w / v carbidopa composition Twelve mg of levodopa was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid and lx PBS (solution is about pH 2). After levodopa was dissolved, 3 mg of carbidopa (commercially available from Sigma-Aldrich Co. LLC) was added to the solution. The solution was adjusted to pH 6 using sodium hydroxide to give a final volume of 4 mL.

[0125] Example 3 - Method of producing a 0.03% w / v levodopa, 0.008% w / v carbidopa composition Twelve mg of levodopa was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid and lx PBS (solution is about pH 2). After levodopa was dissolved, 3 mg of carbidopa (commercially available from Sigma-Aldrich Co. LLC) was added to the solution. The solution was adjusted to pH 6 using sodium hydroxide to give a final volume of 4 mL.

[0126] Example 4 - Efficacy of levodopa compositions in preventing form deprivation myopia 44 male White Cockerel chickens were randomly assigned to one of 11 treatment groups as defined below (n=4 per group) and treated for a period of 5 days. G1-G11 represent Figure 1 and Figure 2 the labeling system used in

[0127] G1. Age-matched untreated control group G2. Chicks with a translucent diffuser on their left eye to induce form- deprivation myopia (FDM) G3. Chicks with a translucent diffuser on their left eye and daily intravitreal injection of the composition of Example 2 G4. Chicks with a translucent diffuser on their left eye and daily topical application of the composition of Example 2 G5. Chicks with a translucent diffuser on their left eye and daily oral administration of 10 mg / kg levodopa, 2.5 mg / kg carbidopa as a powder G6. Chicks with a translucent diffuser on their left eye and daily intravitreal injection of the composition of Example 3 G7. Chicks with a translucent diffuser on their left eye and daily topical application of the composition of Example 3 G8. Chicks with a translucent diffuser on their left eye and daily intravitreal injection of vehicle solution (0.1% ascorbic acid buffered in lx PBS) G9. Chicks with a translucent diffuser on their left eye and daily topical application of vehicle solution (0.1% ascorbic acid buffered in lx PBS) G10. Daily intravitreal injection of the composition of Example 2 G11. Daily topical application of the composition of Example 2 For drug treatment, either intravitreal injection or topical application was used, with the composition administered under light isoflurane anesthesia.

[0128] Intravitreal injection was performed as follows: using a 30 gauge needle attached to a Hamilton syringe, 10 pL (0.01 mL) of test composition was injected into the vitreous chamber of the eye once daily.

[0129] Topical application is performed as follows: Using an eye dropper, apply two drops (0.04 mL for two drops, or a total of 0.08 mL) of the test composition to the corneal surface of the eye. Apply the drops to chicks twice daily.

[0130] To determine changes in eye growth rate and myopia development, changes in axial length and refractive error were assessed. Myopia is associated with excessive elongation of the eye axially relative to normal growth rate. This excessive axial elongation leads to refractive changes associated with relative myopia. Axial length and refractive error were measured using A-scan ultrasonography (Biometer AL-100; Tomey Corporation, Nagoya, Japan) and automated infrared photo-retinoscopy, respectively. Statistical analysis of changes in both refractive error and axial length between groups involved one-way ANOVA followed by a student's t-test with Bonferroni correction. All data are expressed as mean ± standard deviation of mean (SEM).

[0131] Results The result is Figure 1 and Figure 2 Provided in [the text]. Compared to the contralateral control eye (G2, [the text is incomplete]. Figure 1 and Figure 2 Refractive error (p<0.001); Axial length (p<0.001) or age-matched untreated control eyes (G1, Figure 1 and Figure 2 As seen in (refractive error, p < 0.001; axial length p < 0.001), the attachment of a translucent diffuser to the left eye induced excessive axial elongation (G2, ) over a five-day period. Figure 2 Significant myopic shift in refraction (G2) associated with this condition. Figure 1 There were no differences in refractive development or axial length between contralateral control eyes in different treatment groups relative to each other (refractive p = 0.34; axial length p = 0.39) or age-matched untreated eyes (refractive p = 0.54; axial length p = 0.42).

[0132] The development of form deprivation myopia (G3, G4, G6, and G7) was eliminated within five days by intravitreal injection or topical application of the levodopa / carbidopa combination daily. Figure 1 and Figure 2). Specifically, the axial length of the eyes treated with the diffuser of the levodopa / carbidopa composition administered via intravitreal injection or topical application each day (G3, G4, G6, and G7, Figure 2 ) was not different from the axial length seen in the fellow control eyes (levodopa / carbidopa composition of Example 2 injected, p = 0.38; levodopa / carbidopa composition of Example 3 injected, p = 0.22; levodopa / carbidopa composition of Example 2 dropped, p = 0.33; levodopa / carbidopa composition of Example 3 dropped, p = 0.24) or age-matched untreated control eyes (levodopa / carbidopa composition of Example 2 injected, p = 0.27; levodopa / carbidopa composition of Example 3 injected, p = 0.18; levodopa / carbidopa composition of Example 2 dropped, p = 0.26; levodopa / carbidopa composition of Example 3 dropped, p = 0.19). Similarly, there was no significant difference in the refractive development between the eyes treated with the diffuser plus levodopa / carbidopa composition (G3, G4, G6, and G7, Figure 1 ) relative to the fellow controls (levodopa / carbidopa composition of Example 2 injected, p = 0.26; levodopa / carbidopa composition of Example 3 injected, p = 0.19; levodopa / carbidopa composition of Example 2 dropped, p = 0.23; levodopa / carbidopa composition of Example 3 dropped, p = 0.16) or age-matched untreated eyes (levodopa / carbidopa composition of Example 2 injected, p = 0.19; levodopa / carbidopa composition of Example 3 injected, p = 0.16; levodopa / carbidopa composition of Example 2 dropped, p = 0.16; levodopa / carbidopa composition of Example 3 dropped, p = 0.15). Thus, the eyes treated with the composition comprising levodopa and carbidopa showed neither increased axial elongation nor a change in refractive myopia in response to diffuser wear.

[0133] Levodopa and carbidopa were administered orally at an amount equivalent to that provided by topical application (10 mg / kg / day of levodopa and 2.5 mg / kg / day of carbidopa) each day for five days (G5, Figure 1 and Figure 2 ), there was approximately 50% less development of FDM (axial length, p < 0.05; refraction, p < 0.05) relative to that seen in the FDM group alone (G2). This protection was significantly less than that seen in response to intravitreal injection or topical administration of the levodopa / carbidopa composition, indicating that direct application to the eye is a more effective route of administration.

[0134] Vehicle solution was injected or topically applied to diffuser treated eyes for a five day period, did not alter FDM development (G8 and G9, Figure 1 and Figure 2 ). Furthermore, injection or topical application of levodopa / carbidopa composition to the other untreated eye (G10 and G11, Figure 1 and Figure 2 ) did not alter axial growth (injection, p = 0.63; drop, p = 0.57) or refractive development (injection, p = 0.71; drop, p = 0.62) relative to that seen in age-matched untreated control eyes.

[0135] Example 5 - Efficacy of levodopa compositions in preventing form deprivation myopia Thirty-two male white chicks were randomly assigned to one of eight treatment groups as defined below (n = 4 per group) and treated for a five day period. G1-G8 represent Figure 3 and Figure 4 the labeling system used in

[0136] G1. Age-matched untreated control group G2. Chicks with a translucent diffuser on their left eye to induce FDM G3. Chicks with a translucent diffuser on their left eye and daily intravitreal injection of the composition of Example 2 G4. Chicks with a translucent diffuser on their left eye and daily intravitreal injection of the composition of Example 1 G5. Chicks with a translucent diffuser on their left eye and daily topical application of the composition of Example 2 G6. Chicks with a translucent diffuser on their left eye and daily topical application of the composition of Example 1 G7. Chicks with a translucent diffuser on their left eye and daily oral administration of 10 mg / kg levodopa, 2.5 mg / kg carbidopa as a powder G8. Chicks with a translucent diffuser on their left eye and daily oral administration of 10 mg / kg levodopa Administration of the test composition and analysis of its activity were as described in Example 4.

[0137] Results Results are provided in Figure 3 and Figure 4 Again, relative to the contralateral control eye (G2, Figure 3 and Figure 4 ; refraction, p < 0.001; axial length, p < 0.001) or the age-matched untreated control eye (G1, Figure 3 andFigure 4 ; axial length, p < 0.001) seen in the left eye, attachment of the translucent diffuser induced a significant refractive myopic shift (G2, Figure 3 ) associated with excessive axial elongation (G2, Figure 4 ). There were no differences in refractive development or axial length between the fellow control eyes of the different treatment groups relative to each other (p = 0.27) or age-matched untreated eyes (p = 0.21).

[0138] Daily administration of the levodopa / carbidopa composition eliminated the development of FDM, such that there were no differences in axial elongation or refractive development in response to diffuser wear when compared to the fellow control eyes (refraction, p < 0.01; axial length, p < 0.01) or age-matched untreated eyes (refraction, p < 0.01; axial length, p < 0.01) (G3 and G5, Figure 4 and Figure 3 ). Daily administration of the levodopa composition reduced the development of FDM when compared to the positive control (G2, Figure 3 and Figure 4 ; refraction, p < 0.05; axial length, p < 0.05). However, this degree of inhibition was significantly lower than the composition containing the combination of levodopa and carbidopa.

[0139] Figure 3 Dissolve 0.12 mg of levodopa in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, and lx PBS (solution is approximately pH 2). After levodopa is dissolved, adjust the solution to pH 6 using sodium hydroxide to a final volume of 4 mL.

[0140] Figure 4 Dissolve 1.2 mg of levodopa in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, and lx PBS (solution is approximately pH 2). After levodopa is dissolved, adjust the solution to pH 6 using sodium hydroxide to a final volume of 4 mL.

[0141] Example 6 - Method of producing a 0.003% w / v levodopa composition Dissolve 1.2 mg of levodopa in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, 10% DMSO, and lx PBS. After levodopa is dissolved, adjust the solution to pH 6 using sodium hydroxide to a final volume of 4 mL.

[0142] Example 7 - Method of producing a 0.03% w / v levodopa composition Twelve mg levodopa was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, 10% DMSO, and lx PBS. After levodopa was dissolved, the solution was adjusted to pH 6 using sodium hydroxide to a final volume of 4 mL.

[0143] Example 8 - Method of producing a 0.03% w / v levodopa, 10% w / v DMSO composition Example 9 - Method of producing a 0.3% w / v levodopa, 10% w / v DMSO composition One.2 mg levodopa (1.5 mM) was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, and lx PBS. After levodopa was dissolved, the solution was adjusted to pH 6 using sodium hydroxide and 1.2 mg ADTN (1 mM; in the form of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide; commercially available from Sigma Aldrich Co. LLC) was dissolved in the solution to a final volume of 4 mL.

[0144] Example 10 - Method of producing a 0.03% w / v levodopa, 0.03% w / v 2-amino-6,7- dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) composition One.2 mg levodopa (1.5 mM) was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, and lx PBS. After levodopa was dissolved, the solution was adjusted to pH 6 using sodium hydroxide and 5.6 mg atropine (2 mM; in the form of atropine sulfate monohydrate; commercially available from Sigma Aldrich Co. LLC) was dissolved in the solution to a final volume of 4 mL.

[0145] Example 11 - Method of producing a 0.03% w / v levodopa, 0.14% w / v atropine composition One.2 mg levodopa (1.5 mM) was dissolved in a solution containing 0.15 M hydrochloric acid, 0.1% ascorbic acid, and lx PBS. After levodopa was dissolved, the solution was adjusted to pH 6 using sodium hydroxide and 28 mg pirenzepine (16 mM; in the form of pirenzepine dihydrochloride; commercially available from Sigma Aldrich Co. LLC) was dissolved in the solution to a final volume of 4 mL.

[0146] Example 12 - Method of producing a 0.03% w / v levodopa, 0.7% w / v pirenzepine composition One hundred twenty male white chicks were randomly assigned to one of the 24 treatment groups as defined below (n=5 per group) and treated for a period of 5 days. G1-G24 represent Example 13 - Effect of levodopa dose and presence of DMSO on prevention of form deprivation myopia The labeling system used in the following text.

[0147] G1. Age-matched untreated control group G2. Chicks with a translucent diffuser over their left eye to induce FDM G3. Chicks with a translucent diffuser over their left eye to induce FDM and daily oral administration of 20 mg / kg levodopa as a powder G4. Chicks with a translucent diffuser over their left eye to induce FDM and daily oral administration of 20 mg / kg levodopa and 5 mg / kg carbidopa as a powder G5. Chicks with a translucent diffuser over their left eye to induce FDM and daily intravitreal injection of the composition of Example 6 (0.003% w / v levodopa) G6. Chicks with a translucent diffuser over their left eye to induce FDM and daily intravitreal injection of the composition of Example 7 (0.03% w / v levodopa) G7. Chicks with a translucent diffuser over their left eye to induce FDM and daily intravitreal injection of the composition of Example 1 (0.3% w / v levodopa) G8. Daily intravitreal injection of the composition of Example 1 (0.3% w / v levodopa) G9. Chicks with a translucent diffuser over their left eye to induce FDM and daily intravitreal injection of the composition of Example 3 (0.03% w / v levodopa, 0.008% w / v carbidopa) G10. Chicks with a translucent diffuser over their left eye to induce FDM and daily intravitreal injection of the composition of Example 2 (0.3% w / v levodopa, 0.08% w / v carbidopa) G11. Daily intravitreal injection of the composition of Example 2 (0.3% w / v levodopa, 0.08% w / v carbidopa) G12. Age-matched untreated control group G13. Chicks with a translucent diffuser over their left eye to induce FDM G14. Chicks with a translucent diffuser over their left eye to induce FDM and daily oral administration of 20 mg / kg levodopa as a powder G15. Chicks with a translucent diffuser over their left eye to induce FDM and daily oral administration of 20 mg / kg levodopa and 5 mg / kg carbidopa as a powder G16. Chicks with a translucent diffuser over their left eye to induce FDM and daily topical administration of the composition of Example 6 (0.003% w / v levodopa) G17. Chicks with a translucent diffuser over their left eye to induce FDM and daily topical administration of the composition of Example 7 (0.03% w / v levodopa) G18. Chicks with a translucent diffuser attached to their left eye to induce FDM and topically administered with the composition of Example 1 (0.3% w / v levodopa) daily G19. Topically administered with the composition of Example 1 (0.3% w / v levodopa) daily G20. Chicks with a translucent diffuser attached to their left eye to induce FDM and topically administered with the composition of Example 3 (0.03% w / v levodopa, 0.008% w / v carbidopa) daily G21. Chicks with a translucent diffuser attached to their left eye to induce FDM and topically administered with the composition of Example 2 (0.3% w / v levodopa, 0.08% w / v carbidopa) daily G22. Topically administered with the composition of Example 2 (0.3% w / v levodopa, 0.08% w / v carbidopa) daily G23. Chicks with a translucent diffuser attached to their left eye to induce FDM and topically administered with the composition of Example 8 (0.03% w / v levodopa, 10% DMSO) daily G24. Chicks with a translucent diffuser attached to their left eye to induce FDM and topically administered with the composition of Example 9 (0.3% w / v levodopa, 10% DMSO) daily Administration of the test compositions and analysis of their activity were as described in Example 4.

[0148] Figures 5-8 Results are provided in Results . Relative to what was seen in age-matched, untreated control eyes (G1, Figures 5 to 8 and Figure 5 ; and G12, Figure 6 and Figure 7 , attachment of a translucent diffuser to the left eye induced significant myopic changes (G2, Figure 8 ; and G13, Figure 6 ; p < 0.001) associated with excessive axial elongation (G2, Figure 8 ; and G13, Figure 5 ; p < 0.001).

[0149] Intravitreal injection of levodopa compositions daily significantly inhibited the development of FDM, with the greatest effect with administration of 0.3% w / v levodopa composition (G5, p < 0.01; G6, p < 0.01; and G7, p < 0.001; Figure 7 ; and G5, p < 0.01; G6, p < 0.001; G7, p < 0.001; Figure 5). This effect was significantly greater than oral administration of levodopa (G3, Figure 6 and Figure 5 ) compared to compositions comprising levodopa alone, the addition of the aromatic L-amino acid decarboxylase inhibitor carbidopa increased the inhibitory effect of the composition (G9, p < 0.01; and G10, p < 0.01; Figure 6 ; and G9, p < 0.001; and G10, p < 0.001; Figure 5 ).

[0150] Topical administration of the levodopa composition every day significantly inhibited the development of FDM (G16, p < 0.05; G17, p < 0.01; and G18, p < 0.01; Figure 6 ; and G16, p < 0.01; G17, p < 0.01; and G18, p < 0.01; Figure 7 ) and showed a stronger effect than oral levodopa administration (G14, Figure 8 and Figure 7 ) compared to compositions comprising levodopa alone, the addition of carbidopa to the composition significantly increased the inhibitory effect (G20, p < 0.01; and G21, p < 0.01 Figure 8 ; and G20, p < 0.001; and G21, p < 0.001; Figure 7 ).

[0151] The addition of 10% DMSO to the topical levodopa composition significantly increased the inhibitory effect against the development of FDM (G23, p < 0.01; and G24, p < 0.01; Figure 8 ; and G23, p < 0.001; and G24, p < 0.001; Figure 7 ).

[0152] Figure 8 To evaluate the safety and efficacy of topical treatment with levodopa, 15 mM (0.3% w / v) levodopa composition (prepared according to Example 1) was tested for ocular administration twice daily over a four-week period. Male white chicks were kept under normal laboratory light (500 lux, fluorescent light) under a 12:12 hour light:dark cycle, with the lights turned on at 9:30 am and turned off at 9:30 pm. In all chicks, the left eye was experimentally treated, while the right eye remained untreated to serve as an ipsilateral control. Chicks were randomly assigned to one of four groups (n = 6 for each group) and treated over a four-week period under the following experimental conditions: 1. Age-matched untreated controls: Chicks remained untreated and did not receive ocular or levodopa treatment 2. Form-deprivation myopia (FDM): Chicks were fitted with a translucent diffuser over their left eye to induce FDM and did not receive further treatment 3. Form-deprivation myopia and topical 0.3% w / v (15 mM) levodopa treatment: Chicks were fitted with a translucent diffuser over their left eye to induce FDM and were topically administered the composition of Example 1 twice daily (9:30 am and 2 pm) 4. Topical 0.3% w / v (15 mM) levodopa treatment of the other untreated eye: The composition of Example 1 was topically administered to the chicks twice daily (9:30 am and 2 pm) Administration of the test composition was performed according to that described in Example 4.

[0153] To determine changes in eye growth rate and myopia development, axial length and refraction were measured using A-scan ultrasonography (Biometer AL-100; Tomey Corporation, Nagoya, Japan) and automated infrared fundus photography retinoscopy, respectively. Eye measurements (axial length and refraction) were performed on day one (before the start of the experiment) and every seven days for four weeks.

[0154] Example 14 - Safety and efficacy of topical levodopa administration over a four week period Results are provided in Results and Figure 9 Multivariate analysis of variance (MANOVA) with repeated measures design was used to compare the effects of different treatment regimens over time. Animals fitted with a translucent diffuser and treated with topical levodopa showed significantly smaller changes in refractive myopia compared to those fitted with a translucent diffuser and without levodopa treatment Figure 10 ; F(3,21) = 191.013; p < 0.001). Moreover, animals fitted with a translucent diffuser and treated with topical levodopa showed reduced axial elongation compared to those fitted with a translucent diffuser and without levodopa treatment Figure 9 ; F(3,21) = 34.129; p < 0.001).

[0155] Figure 10 Example 15 - Effect of co-treatment of levodopa with ADTN, atropine and pirenzepine on development of form deprivation myopia 70 male white Leghorn chicks were randomly assigned to one of 14 treatment groups as defined below (n=5 per group) and treated for a period of 5 days. G1-G14 represent Figure 11 andFigure 12 Marker system used in the middle.

[0156] G1. Age-matched untreated control group G2. Chicks fitted with a translucent diffuser over their left eye to induce FDM G3. Chicks fitted with a translucent diffuser over their left eye to induce FDM and injected intravitreally daily with a composition containing 1 mM ADTN (0.03% w / v) and 0.1% ascorbic acid in 1x PBS (pH 7) G4. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with a composition containing 1 mM ADTN (0.03% w / v) and 0.1% ascorbic acid in 1x PBS (pH 7) G5, G9 and G13. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with the composition of Example 7 (0.03% w / v levodopa) G6. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with the composition of Example 10 (0.03% w / v levodopa, 0.03% w / v ADTN) G7. Chicks fitted with a translucent diffuser over their left eye to induce FDM and injected intravitreally daily with a composition containing 2 mM atropine (0.14% w / v; in the form of atropine sulfate monohydrate) in distilled water (pH 7) G8. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with a composition containing 2 mM atropine (0.14% w / v; in the form of atropine sulfate monohydrate) in distilled water (pH 7) G10. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with the composition of Example 11 (0.03% w / v levodopa, 0.14% w / v atropine) G11. Chicks fitted with a translucent diffuser over their left eye to induce FDM and injected intravitreally daily with a composition containing 16 mM pirenzepine (0.7% w / v; in the form of pirenzepine dihydrochloride) in distilled water (pH 7) G12. Chicks fitted with a translucent diffuser over their left eye to induce FDM and topically applied daily with a composition containing 16 mM pirenzepine (0.7% w / v; in the form of pirenzepine dihydrochloride) in distilled water (pH 7) G14. Chicks fitted with a semi-transparent diffuser on their left eye to induce FDM and topically administered with the composition of Example 12 (0.03% w / v levodopa, 0.7% w / v pirenzepine) every day ADTN compositions were prepared by dissolving ADTN in a solution of 1 x PBS containing 0.1% ascorbic acid to a final concentration of 1 mM (0.03% w / v) and adjusting the pH to 7. Atropine and pirenzepine compositions were prepared by dissolving atropine (as atropine sulfate monohydrate) or pirenzepine (as pirenzepine dihydrochloride) in distilled water to a final concentration of 2 mM (0.14% w / v) and 16 mM (0.7% w / v), respectively, and adjusting the pH to 7.

[0157] Administration of the test compositions and measurement of ocular parameters were performed according to that described in Example 4.

[0158] Results Results are provided in Figure 11 and Figure 12 Compared to animals fitted with a semi-transparent diffuser only (G2), daily administration of the dopamine D2 receptor agonist ADTN (G3 and G4) significantly inhibited the refractive myopic changes and reduced the axial elongation, with intravitreal injection being more effective than topical administration (G3, p < 0.01; and G4, p < 0.05; Figure 11 ; G3, p < 0.001; and G4, p < 0.05; Figure 12 ). Notably, topical administration of a composition comprising both ADTN and levodopa (G6; Figure 11 and Figure 12 ) inhibited the refractive myopic changes (G6, p < 0.01; Figure 11 ) and reduced the axial elongation (G6, p < 0.01; Figure 12 ) to a greater extent than either compound alone (G4 and G5, respectively;

[0159] Compared to animals fitted with a semi-transparent diffuser only (G2), daily administration of the muscarinic acetylcholine receptor antagonist atropine (G7 and G8, Figure 11 and Figure 12 ) significantly inhibited the refractive myopic changes and reduced the axial elongation, with intravitreal injection being more effective than topical administration (G7, p < 0.01; and G8, p < 0.05; Figure 11 ; G7, p < 0.001; and G8, p < 0.05; Figure 12 ). Notably, topical administration of a composition comprising both atropine and levodopa (G10; Figure 11 andFigure 12 ) more strongly inhibited the refractive myopic changes (G10, p < 0.01; Figure 11 ) and reduced the axial elongation (G10, p < 0.01; Figure 12 ).

[0160] The M1 muscarinic acetylcholine receptor antagonist pirenzepine (G11 and G12, Figure 11 and Figure 12 ) significantly inhibited the refractive development of myopic changes and reduced the axial elongation (G11, p < 0.01; and G12, p < 0.05; Figure 11 ; G11, p < 0.001; and G12, p < 0.05; Figure 12 ) more strongly when administered intravitreally (G11, Figure 11 and Figure 12 ). The combination of pirenzepine and levodopa topically administered (G14, Figure 11 and Figure 12 ) had a greater inhibitory effect on the refractive development (G14, p < 0.01; Figure 11 ) and the axial length (G14, p < 0.01; Figure 12 Figure 11 Figure 12 ) than the topical administration of either compound alone.

[0161] Example 16 - Histological analysis of the effect of topical levodopa administration on the progression of form-deprivation myopia For base histological analysis using toluidine blue staining, the paraformaldehyde-fixed retinal sections were immersed in a 1% toluidine blue (Sigma Aldrich, Catalog No. 89640) aqueous solution for 1.5 minutes, then rinsed under running distilled water for 2 minutes. The sections were then mounted in glycerol before cover slipping. Sections were observed on a Motic BA410 optical microscope at 40x magnification and captured by a Moticam 10.0 megapixel camera in conjunction with MoticLive imaging module.

[0162] Retinal sections were from the eyes of male white Leghorn chicks: A. contralateral control eyes of chicks where the other eye was fitted with a translucent diffuser to induce FDM B. eyes of chicks fitted with a translucent diffuser to induce FDM C. The contralateral control eye of a chick, wherein the other eye was fitted with a translucent diffuser to induce FDM and treated with daily topical application of the composition of Example 1 (0.3% w / v levodopa). D. Eyes of chicks fitted with translucent diffusers to induce FDM and treated with daily topical application of the composition of Example 1 (0.3% w / v levodopa). E. The contralateral control eye of a chick, wherein the other eye was treated with daily topical application of the composition of Example 1 (0.3% w / v levodopa). F. Eyes of chicks treated with daily topical application of the composition of Example 1 (0.3% w / v levodopa). G. Eyes of age-matched untreated control chicks The levodopa composition was administered according to the description in Example 4.

[0163] Results The result is Figure 13 Provided in [the text]. For example, in [the text]. Figure 13 As can be seen, no changes in retinal structure or cell density were observed in the eyes of the following groups: age-matched untreated controls ( Figure 13 G in the middle), form deprivation ( Figure 13 B) The contralateral untreated control eye under all conditions ( Figure 13 A in Figure 13 C and Figure 13 E), form deprivation and daily topical application of a composition containing 0.3% w / v levodopa (in the context of E), Figure 13 (D) and daily topical application of a composition containing 0.3% w / v levodopa to other untreated animals ( Figure 13 (F in the text). Therefore, the levodopa composition does not exhibit retinal toxicity.

[0164] Example 17 - TUNEL staining analysis of the effect of topical levodopa administration on the progression of form-deprivation myopia TUNEL staining was performed using the Roche In Situ Cell Death Detection Kit (Roche). In Situ The Cell Death Detection Kit (AP) (Sigma Aldrich, catalog number 11684795910) was used. The protocol for staining retinal sections from male white roosters was based on that of Denton and Kumar (2015). Cold Spring Harb Protocdoi:10.1101 / pdb.prot086199. Briefly, retinal sections were prepared by washing in three changes of lx PBS in 0.1% Triton X-100 (lx PBST), permeabilised in 0.1% sodium citrate on ice for 5 minutes, then washed in three further changes of lx PBST. Sections were then incubated in TUNEL reaction mix according to the manufacturer’s instructions (negative controls were incubated in labelling mix only, while positive controls were incubated in DNAse 1 (100 U / mL) for 10 minutes prior to TUNEL labelling to induce DNA breaks, as observed in apoptosis). Following TUNEL labelling, sections were washed in three changes of lx PBS in the dark, prior to visualisation using a Leica DML fluorescent microscope at 20x magnification, with images captured by a Leica DFC 425 camera using Leica Application Suite version 4.8.

[0165] The samples analysed were as follows: A. Negative control (retinal sections treated with labelling solution only) B. Positive control (retinal sections treated with DNAse 1 to induce DNA strand breaks, indicative of apoptosis) C. Retinal sections from eyes of age-matched untreated control chicks D. Retinal sections from eyes of chicks fitted with a translucent diffuser to induce FDM E. Retinal sections from eyes of chicks treated by daily topical application of the composition of Example 1 (0.3% w / v levodopa) F. Retinal sections from eyes of chicks fitted with a translucent diffuser to induce FDM and treated by daily topical application of the composition of Example 1 (0.3% w / v levodopa) Administration of the levodopa composition was carried out in accordance with that described in Example 4.

[0166] Results As can be seen from Figure 14 , when compared to positive control retinal tissue treated with DNAse 1 to induce DNA nicks and genomic degradation (B in Figure 14 , retinal cells did not exhibit a response to form deprivation (D in Figure 14 or levodopa treatment (E and F in Figure 14 , respectively. Figure 14Figure 6 shows evidence of apoptosis in the RPE of the F) in Figure 5. Due to the absence of staining, visualization required over exposure of all retinal sections except the positive control retinal section, resulting in a brighter appearance being observed.

[0167] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated by reference in their entirety.

[0168] The citation of any reference in this document is not to be construed as an admission that it is prior art to the present application.

[0169] Throughout this specification, the purpose is to describe the preferred embodiments of the application, not to limit the application to any one embodiment or particular collection of features. Thus, those skilled in the art will recognize that various modifications and changes can be made to the preferred embodiments without departing from the scope of the application as set forth in the claims. All such modifications and changes are intended to be included within the scope of the claims.

[0170] The present application is also directed to the following items: 1. An ophthalmic pharmaceutical composition comprising, consisting of, or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

[0171] 2. A composition for inhibiting the progression or development of visual impairment comprising, consisting of, or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

[0172] 3. The composition of item 1 or item 2, wherein the antioxidant is selected from ascorbic acid, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetylcysteine, sodium thiosulfate, ethylenediaminetetraacetic acid, sodium nitrite, ascorbic acid stearate, ascorbic acid palmitate, alpha-thioglycerol, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol or vitamin E, tocopherol acetate, butylated hydroxytoluene, soy lecithin, sodium thioglycolate, butylated hydroxyanisole, propyl gallate, uric acid, melatonin, thiourea, and salts and combinations thereof.

[0173] 4. The composition of item 3, wherein the antioxidant is ascorbic acid.

[0174] 5. The composition of any one of items 1-4, further comprising an inhibitor of aromatic L-amino acid decarboxylase.

[0175] 6. The composition of item 5, wherein the inhibitor of aromatic L-amino acid decarboxylase is selected from carbidopa, benserazide, methyldopa, and combinations thereof.

[0176] 7. The composition of item 6, wherein the inhibitor of aromatic L-amino acid decarboxylase is carbidopa.

[0177] 8. The composition of any one of items 5-7, wherein the ratio of levodopa to the inhibitor of aromatic L-amino acid decarboxylase is in the range of from 20: 1 to 1 : 1.

[0178] 9. The composition of item 8, wherein the ratio of levodopa to the inhibitor of aromatic L-amino acid decarboxylase is 4: 1.

[0179] 10. The composition of any one of items 1-9, wherein the composition further comprises a dopamine receptor agonist.

[0180] 11. The composition of item 10, wherein the dopamine receptor agonist is selected from quinpirole, apomorphine, ropinirole, pramipexole, dexpramipexole, piribedil, rotigotine, bromocriptine, lisuride, cabergoline, 2-amino-6,7-dihydroxy-l,2,3,4-tetrahydronaphthalene, pergolide, calidopa, dihydrexidine, doxathrine, propylbenzylapomorphine, quinagolide, roxindole, sumanirole, fenoldopam, ergocornine, l-phenyl-2,3,4,5-tetrahydro-(l H )-3-benzazocin-7,8-diol, 2- N -phenylethyl- N -propyl)amino-5-hydroxytetrahydronaphthalene, dihydroergotamine, (l R ,3 S )-l-(aminomethyl)-3-phenyl-3,4-dihydro-l H -iso chromene-5,6-diol, carmoxirole, fenoldopam, and salts and combinations thereof.

[0181] 12. The composition of any one of items 1-11, wherein the composition further comprises a GABA receptor antagonist.

[0182] 13. The composition of item 12, wherein the GABA receptor antagonist is selected from bicucllline, flumazenil, gabazine, phenyltetrazole, (l,2,5,6-tetrahydropyridin-4-yl)methyl phosphinic acid, (3-aminopropyl)(cyclohexylmethyl)phosphinic acid, and salts and combinations thereof.

[0183] 14. The composition of any one of items 1-13, wherein the composition further comprises a muscarinic acetylcholine receptor antagonist.

[0184] 15. The composition of item 14, wherein the muscarinic acetylcholine receptor antagonist is selected from atropine, pirenzepine, scopolamine, hyoscine, cyclopentolate, ipratropium, oxitropium, tropicamide, oxybutynin, tolteridine, benztropine, dicycloverine, flavoxate, tiotropium, trihexphenidyl, solifenacin, darifenacin, benzalkonium, mebeverine, procyclidine, aclidinium, and salts and combinations thereof.

[0185] 16. The composition of any one of items 1-15, wherein the aqueous carrier is selected from saline, water, an aqueous buffer, an aqueous solution comprising water and a miscible solvent, and combinations thereof.

[0186] 17. The composition of any one of items 1-16, wherein levodopa is in a dissolved form.

[0187] 18. The composition of any one of items 1-17, wherein the pH of the composition is in the range from 5 to 8.

[0188] 19. The composition of item 18, wherein the pH of the composition is in the range from 5.2 to 7.4.

[0189] 20. The composition of item 19, wherein the pH of the composition is in the range from 5.5 to 6.

[0190] 21. The composition of any one of items 1-20, wherein the composition is formulated for topical administration to the eye.

[0191] 22. The composition of item 21, wherein the composition is in the form of an eye drop.

[0192] 23. The composition of item 21 or item 22, wherein the composition is formulated for penetration of levodopa through the corneal epithelium.

[0193] 24. The composition of any one of items 1-20, wherein the composition is formulated for direct injection into the eye.

[0194] 25. The composition of item 24, wherein the composition is formulated for intravitreal administration.

[0195] 26. A method of inhibiting the progression or development of a visual impairment in a subject, comprising administering to the subject the composition of any one of items 1-25.

[0196] 27. Use of a composition according to any one of items 1-25 for inhibiting the progression or development of a visual impairment in a subject.

[0197] 28. A composition according to any one of items 1-25 for use in inhibiting the progression or development of a visual impairment in a subject.

[0198] 29. The method, use or composition according to any one of items 26-28, wherein the visual impairment is selected from a visual impairment associated with diabetic retinopathy, a visual impairment associated with Parkinson’s disease and myopia.

[0199] 30. The method, use or composition according to item 29, wherein the visual impairment is myopia.

[0200] 31. A process for preparing a composition according to item 1 or item 2, comprising dissolving levodopa in the aqueous carrier at a pH in the range from 0.5 to 2.5, adding the antioxidant to the composition, and adjusting the pH of the composition to a pH in the range from 5 to 8.

[0201] 32. The process according to item 31, wherein the levodopa is dissolved in the aqueous carrier at pH 2.

[0202] 33. The process according to item 31 or item 32, wherein the pH of the composition is adjusted to a pH in the range from 5.5 to 6.

[0203] 34. An ophthalmic pharmaceutical composition, formulated for topical administration to the eye, comprising, consisting of, or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

[0204] 35. A topical composition for inhibiting the progression or development of a visual impairment, comprising, consisting of, or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

Claims

1. An ophthalmic pharmaceutical composition comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

2. A composition for inhibiting the progression or development of visual impairment comprising levodopa, an antioxidant, and an aqueous carrier; consisting of levodopa, an antioxidant, and an aqueous carrier; or consisting essentially of levodopa, an antioxidant, and an aqueous carrier.

3. The composition of claim 1 or claim 2, wherein the antioxidant is selected from ascorbic acid, phenolic acid, sorbic acid, sodium bisulfite, sodium metabisulfite, acetylcysteine, sodium thiothiosulfate, ethylenediaminetetraacetic acid, sodium nitrite, ascorbic acid stearate, ascorbic acid palmitate, alpha-thioglycerol, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol or vitamin E, tocopherol acetate, butylated hydroxytoluene, soy lecithin, sodium thioglycolate, butylated hydroxyanisole, propyl gallate, uric acid, melatonin, thiourea, and salts and combinations thereof.

4. The composition of claim 3, wherein the antioxidant is ascorbic acid.

5. The composition of any one of claims 1-4, further comprising an inhibitor of aromatic L-amino acid decarboxylase.

6. The composition of claim 5, wherein the inhibitor of aromatic L-amino acid decarboxylase is selected from carbidopa, benserazide, methyldopa, and combinations thereof.

7. The composition of claim 6, wherein the inhibitor of aromatic L-amino acid decarboxylase is carbidopa.

8. The composition of any one of claims 5-7, wherein the ratio of levodopa to the inhibitor of aromatic L-amino acid decarboxylase is in the range from 20: 1 to 1 :

1.

9. The composition of claim 8, wherein the ratio of levodopa to the inhibitor of aromatic L-amino acid decarboxylase is 4:

1.

10. The composition of any one of claims 1-9, wherein the composition further comprises a dopamine receptor agonist.

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