Treatment of myopic progression

Abstract

To provide compositions and methods of treating and / or preventing progression of myopia in an individual, such as a school-age child, adolescent, or young adult.SOLUTION: An ophthalmic composition comprises from about 0.03 wt.% to about 0.09 wt.% of copper perchlorate as the sole copper-containing agent, and a pharmaceutically acceptable carrier.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 614,230, filed on Jan. 5, 2018, which is hereby incorporated by reference herein in its entirety.

Background Art

[0002] Myopia is well known as a cause of vision loss. The fundamental defect of myopia is that the eyeball is slightly elongated, and the lens of the eyeball focuses the light from distant objects slightly in front of the retina. Uncorrected myopia is one of the major causes of distance vision impairment in the world. In severe cases, the elongation of the eyeball causes a part of the inside of the eyeball to stretch and become thin, increasing the risk of retinal detachment, cataract, glaucoma, blindness, etc. In addition, the prevalence of myopia is increasing and is predicted to affect half of the world's population by 2050.

Brief Description of the Drawings

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[0004] These drawings are provided to illustrate various aspects of the invention and are not intended to limit the scope with respect to dimensions, materials, construction, arrangement, or ratio, unless otherwise limited by the claims. **DETAILED DESCRIPTION OF THE INVENTION**

[0005] The following detailed description includes many details for illustrative purposes, but those skilled in the art will understand that many variations and modifications can be made to the following details and that they will be considered to be included herein. Accordingly, the following embodiments are described without losing generality with respect to the claims described and without imposing limitations. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. 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 disclosure belongs.

[0006] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells.

[0007] In this disclosure, terms such as "comprises", "comprising", "includes", and "having" can have the meanings ascribed to them in U.S. patent law, can mean "includes", "including", etc., and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed terms and include only those components, structures, steps, or the like specifically recited in connection with these terms and those in accordance with U.S. patent law. "Consisting essentially of" or "consists essentially of" has the meaning generally given by U.S. patent law. In particular, such terms are generally closed terms and, with the exception of allowing for additional items, materials, components, steps, or elements that do not substantially affect the basic and novel features or functions of the items used in connection therewith, are generally closed terms. For example, trace elements present in a composition but not affecting the nature or properties of the composition would be allowed under "consisting essentially of" language even if not explicitly recited in the list of items following such terms. When open-ended terms such as "comprising" or "including" are used in the specification, direct support should be given to, and it is understood that the reverse is also true for, "consisting essentially of" language and "consisting of" language as if explicitly stated.

[0008] The terms "first", "second", "third", "fourth", etc. in this specification and the claims, when present, are used to distinguish similar elements and are not necessarily used to describe a particular order or time sequence. It will be understood that any such terms used in this way are interchangeable in appropriate circumstances so that the embodiments described in this specification can operate in an order other than, for example, that illustrated or otherwise described herein. Similarly, when a method is described herein as having a series of steps, the order of such steps shown herein is not necessarily the only order in which such steps can be performed, some of the described steps may be omitted, and / or other specific steps not described herein may be added to the method.

[0009] As used herein, the term "coupled" is defined as being directly or indirectly connected by biological, chemical, mechanical, electrical or non-electrical means. "Directly coupled" structures or elements are attached in contact with each other. Objects described herein as being "adjacent" to each other may, depending on the context in which the term is used, be in physical contact with each other, very close to each other, or in the same general range or region. The appearance of the phrases "in one embodiment" or "in one aspect" in this specification does not necessarily refer to all the same embodiments or aspects.

[0010] As used herein, terms such as "therapeutic agent", "active agent" can be used interchangeably and refer to an agent that can produce a beneficial or positive effect on a subject when administered to the subject in a suitable or effective amount. In one aspect, the therapeutic agent or active agent can be a copper-containing material or compound.

[0011] As used herein, an "effective amount" of an agent is an amount sufficient to achieve a particular desired task or function of the agent. A "therapeutically effective amount" of a composition, drug, or agent means a non-toxic but sufficient amount of the composition, drug, or agent to achieve a therapeutic result when treating or preventing a condition in which the composition, drug, or agent is known to be effective. It is understood that various biological factors can affect the ability of a substance to perform its intended task. Thus, an "effective amount" or "therapeutically effective amount" may in some instances depend on such biological factors. Further, while the achievement of a therapeutic effect can be measured by a physician, veterinarian, or other qualified medical professional using evaluations known in the art, it is recognized that individual variability and response to treatment can make the determination of the achievement of a therapeutic effect somewhat subjective. The determination of an effective amount or therapeutically effective amount is within the scope of ordinary skill in the fields of pharmaceutical science and medicine.

[0012] As used herein, a "dosing regimen" or "regimen," such as a "treatment dosing regimen" or "preventive dosing regimen," refers to how, when, how much, and for what period of time an active agent or composition can or should be administered to a subject to achieve an intended treatment or effect.

[0013] As used herein, the terms "treat," "treatment," or "treating" refer to the administration of a therapeutic agent to a subject, whether asymptomatic or symptomatic. In other words, "treat," "treatment," or "treating" may be to reduce, improve, or eliminate symptoms associated with a condition present in the subject, or may be prophylactic (i.e., to prevent or reduce the occurrence of symptoms in the subject).

[0014] As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation" and "composition" may be used to refer to a mixture of one or more active agents and a carrier or other excipient. Compositions can take on almost any physical state, such as solids, liquids (e.g., solutions), gases, etc. Additionally, the term "dosage form" can include one or more formulations or compositions provided in a form for administration to a subject. For example, an injectable dosage form would be a formulation or composition prepared in a manner suitable for administration by injection.

[0015] As used herein, "subject" refers to an animal. In one embodiment, the animal may be a mammal. In another embodiment, the mammal may be a human.

[0016] As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is either completely enclosed or nearly completely enclosed. The exact tolerance from completeness may depend on the particular situation. However, generally, the proximity to completion is such that the overall result is the same as if absolute complete completion had been obtained. The use of "substantially" is equally applicable when used in a negative sense to refer to the complete or nearly complete absence of an action, characteristic, property, nature, state, structure, item, or result. For example, a composition that is "substantially free of" particles means that the composition is either completely lacking in particles or nearly completely lacking in particles, such that the same effect is obtained as if the particles were completely absent. In other words, a composition that is "substantially free of" a component or element can actually contain such an item as long as there is no measurable effect.

[0017] As used herein, comparative terms such as "increasing", "increased", "decreasing", "decreased", "better", "worse", "higher", "lower", "enhancing", "enhanced", "maximizing", "maximized", "minimizing", "minimized" refer to properties, results, or effects of an apparatus, composition, formulation, component, treatment, regimen, method, or activity that are measurably different from those of other apparatuses, compositions, formulations, components, treatments, regimens, methods, or activities. Additionally, comparative terms may refer to biological states, presences, absences, activity levels, or manipulations that are measurably different from endogenous biological states, presences, absences, activity levels, or manipulations. Comparative terms can be used to indicate differences in surrounding or adjacent regions, such as regions of tissue. Comparative terms can also be used to indicate differences in chemical or biological structures or activities (e.g., therapeutic activity or efficacy). Further, comparative terms can be used to indicate differences in biological or physiological results, activities, or states as compared to previous or other biological or physiological results, activities, or states. For example, an increase or decrease in lysyl oxidase activity can be determined by comparing the amount of lysyl oxidase at a first time point to the amount at a second time point. Such an increase or decrease may be attributable to such a composition or treatment when the composition or treatment is applied. More specifically, an increase in lysyl oxidase due to an applied composition or treatment can be determined or otherwise quantified by measuring the amount of lysyl oxidase before application of the composition or treatment and then measuring again after application of the composition or treatment. In some cases, the comparison may simply be made between points in time (e.g., endogenous state and treated state). In other cases, a comparison can be made between results achieved by two different applied formulations or treatments (e.g., formulations with different amounts of an active agent, etc.).

[0018] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range when a given value is "slightly above" or "slightly below" the endpoint. Unless otherwise specified, the use of the term "about" with a particular number or numerical range should be understood to provide support for such numerical terms or ranges without the term "about". For example, for convenience and brevity, the numerical range of "about 50 micrograms to about 80 micrograms" should also be understood to provide support for the range of "50 micrograms to 80 micrograms". Further, in this specification, it should be understood that even when the term "about" is used together, support for the actual numerical value is provided. For example, the recitation of "about" 30 is to be interpreted as providing support not only for values slightly above and slightly below 30, but also for the actual numerical value 30.

[0019] As used herein, a plurality of items, structural elements, components, and / or materials may be presented together in a common list for convenience. However, these lists should be interpreted as if each member of the list is individually identified as a separate and unique member. Thus, the individual members of such a list should not be construed as virtual equivalents of other members of the same list based solely on their presentation in a common group without suggesting otherwise.

[0020] In this specification, concentrations, amounts, and other numerical data can be expressed or presented in range format. Such range format is used merely for convenience and brevity, and thus, it should be understood that it is to be interpreted flexibly to include not only the numerical values explicitly listed as limitations of the range, but also all individual numerical values or sub-ranges subsumed within that range as if each numerical value and sub-range were explicitly recited. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also the individual values and sub-ranges within the indicated range. Thus, this numerical range includes individual values such as 2, 3, 4, etc., and sub-ranges such as 1 - 3, 2 - 4, 3 - 5, etc., just as if they were individually recited as 1, 2, 3, 4, 5.

[0021] This same principle applies to ranges that list only one numerical value as the minimum or maximum value. Further, such interpretation applies regardless of the breadth of the ranges or characteristics being described.

[0022] References to "an example" throughout this specification mean that a particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Thus, the appearances of the phrase "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0023] Exemplary embodiments An initial overview of embodiments of the invention is provided below, followed by a more detailed description of specific embodiments. This initial summary is intended to assist the reader in more quickly understanding the technical concepts, but is not intended to identify its key or essential features, nor is it intended to limit the scope of the claimed subject matter.

[0024] Myopia can be a severe debilitating eye disorder. The fundamental defect in myopia is that the eyeball is slightly elongated, causing the eye's lens to focus light from distant objects just in front of the retina. Thus, myopia is often called short-sightedness or near-sightedness. In severe cases, this elongation of the eyeball causes parts inside the eye to stretch or thin, increasing the risk of retinal detachment, cataracts, glaucoma, and blindness. As such, myopia can be much more severe than just being nearsighted.

[0025] Various causes of myopia have been suggested and studied, including, for example, genetic predisposition, prolonged reading and writing of books and screen time, and inappropriate exposure to bright light. Regardless of whether the fundamental cause of myopia is one or more of those listed above, the elongation of the eyeball associated with myopia can debilitate all those who fall into this condition. Since the eye grows through childhood, myopia generally develops in school-age children and adolescents and can stay with these individuals throughout their lives. Therefore, by improving the treatment of individuals such as school-age children and adolescents, the quality of life in both their adolescence and throughout their lives can be improved.

[0026] Accordingly, the present disclosure is directed to compositions and methods for treating and / or preventing the progression of myopia in individuals such as school-age children, adolescents, or young adults. In some examples, treating and / or preventing the progression of myopia can include administering a therapeutically effective amount of an ophthalmic composition or dosage form to a subject in need thereof.

[0027] In one example, an ophthalmic composition or dosage form is described herein. The ophthalmic composition or dosage form can include a copper-containing agent or other cross-linking agent in an amount sufficient to increase lysyl oxidase activity in the eye of a subject, or otherwise increase cross-linking in the subject's cornea to an extent that slows or halts myopia progression. The composition or dosage form can further include a pharmaceutically acceptable carrier. In some examples, the dosage form can be a ophthalmic composition formulated as a topical eye drop and contained in a container adapted to dispense the composition in a dropwise manner with a drop volume of about 5 μl to about 100 μl. In some examples, the ophthalmic composition can be a sustained release composition formulated to release a copper-containing agent over a prolonged period of time. In another embodiment, a method for using such a composition or dosage form is described. The method can include administering a therapeutically effective amount of the composition or dosage form described herein during a treatment period.

[0028] In some cases, myopia may be characterized by a decrease in corneal stiffness. However, as will be more apparent from the various embodiments and examples provided herein, the compositions, dosage forms, and methods described in this disclosure can increase corneal lysyl oxidase activity in the eye of a subject, increase collagen cross-linking in the cornea (such as LNL, HLNL, DHLNL, etc.), increase the strength of the corneal tissue of the subject's eye, and increase the rigidity of the cornea, flatten the myopic cornea, and provide many other advantages described herein that are useful for treating or preventing myopia progression in an individual.

[0029] More specifically, copper is a cofactor for lysyl oxidase (LOX), an enzyme that forms various types of collagen crosslinks. Thus, copper supplementation can be used to increase collagen binding through copper-containing salts, compounds, chelates, etc., or combinations thereof. Such supplementation can improve the biomechanical properties of the myopic cornea by increasing lysyl oxidase activity. Low corneal rigidity and corneal elongation may be associated with myopia, and copper supplementation improves the biomechanical properties of the cornea and induces corneal flattening, so topical or other appropriate copper therapies can provide a non-invasive and relatively cost-effective tool for treating and / or preventing the progression of myopia.

[0030] Accordingly, the ophthalmic compositions or dosage forms described herein can contain a copper-containing agent in an amount sufficient to increase lysyl oxidase activity in the eye of a subject, or a copper-containing agent in an amount sufficient to increase corneal crosslinking in a subject to treat or prevent myopia progression. Various copper-containing agents can be used, such as copper-containing salts, compounds, chelates, etc. Non-limiting examples of copper salts include copper sulfate, copper carbonate, copper acetate, copper chloride, copper bromide, copper fluoride, copper nitrate, copper hydroxide, copper iodide, copper perchlorate, copper molybdate, copper thiocyanate, copper tartrate, copper tetrafluoroborate, copper selenide, copper pyrophosphate, their hydrates, analogs, or combinations thereof. Other suitable copper carriers can include GHK-copper, tetraamine copper sulfate, copper-histidine, copper-glycinate, copper-gluconate, their hydrates, analogs, or combinations thereof. In some specific examples, the copper-containing agent can be a copper-containing salt. In some examples, the copper salt can be copper(II) sulfate or copper(II) sulfate pentahydrate.

[0031] Accordingly, the copper-containing agent can be any suitable copper-containing agent that can provide a therapeutically effective amount of copper to the eye of interest. The therapeutically effective amount can be sufficient, for example, to increase the corneal lysyl oxidase activity of the eye to an extent that delays or prevents the progression of myopia by increasing collagen crosslinking as compared to the collagen crosslinking prior to treatment. This can also increase the biomechanical strength of the cornea as compared to the biomechanical strength prior to treatment. Further, this can decrease the diopter of the cornea of the treated eye as compared to the diopter prior to treatment.

[0032] The therapeutically effective amount of the copper-containing agent can be based on the amount of copper carried by the copper-containing agent. In some examples, the copper-containing agent can provide a composition having a copper level of less than about 0.1 mg / ml, about 0.05 mg / ml, about 0.02 mg / ml, about 0.005 mg / ml, or about 0.002 mg / ml, but is still effective to increase lysyl oxidase activity and slow or stop the progression of myopia. It can be important to keep the copper level low enough to avoid copper-induced toxicity while maintaining an amount of biologically available copper sufficient to increase lysyl oxidase activity.

[0033] Accordingly, the therapeutically effective amount of the copper-containing agent can be determined based on the type of delivery vehicle, the type of copper-containing agent, the desired delivery period, etc. For example, depending on the method of formulating the composition, the composition can contain copper in an amount of about 0.00001 mg / ml or about 0.00005 mg / ml to about 5 mg / ml or about 50 mg / ml. In other examples, the composition can contain copper in an amount of about 0.00006 mg / ml to about 0.07 mg / ml, about 0.0006 mg / ml to about 0.007 mg / ml, about 0.0005 mg / ml to about 0.03 mg / ml, about 0.01 mg / ml to about 5 mg / ml, or about 0.001 mg / ml to about 0.005 mg / ml. In some additional examples, the composition can contain copper in an amount of about 0.0001 mg / ml to about 0.05 mg / ml, about 0.00025 mg / ml to about 0.015, about 0.0005 mg / ml to about 0.00075 mg / ml, or about 0.0008 mg / ml to about 0.0011 mg / ml. Accordingly, in some examples, the therapeutically effective amount can be defined as the amount of copper contained in the composition. For example, an amount of 0.0025 mg / ml of copper(II) sulfate pentahydrate gives a copper content of about 0.000636 mg / ml of copper in the composition. This is because the atomic weight of copper(II) sulfate pentahydrate is about 249.677 g / mol, but only about 63.5 g / mol or about 25% of the agent is copper itself. As an alternative example, an amount of 0.0018 mg / ml of copper(II) acetate anhydrous provides a composition having a copper content of about 0.00063 mg / ml. Accordingly, the therapeutically effective amount can be determined based on the copper content provided by the copper-containing agent rather than the amount of the copper-containing agent itself.

[0034] Alternatively, the therapeutically effective amount can be defined as the weight percentage of the copper-containing agent in the composition. Also in this case, depending on the method of formulating the composition, the therapeutically effective amount of the copper-containing agent can be in an amount of about 0.00001 wt% or about 0.0001 wt% to about 5 wt%, 10 wt%, or 15 wt%. In some examples, the therapeutically effective amount of the copper-containing agent can be from about 0.05 wt% to about 15 wt%, from about 0.01 wt% to about 10 wt%, or from about 0.005 wt% to about 5 wt%. In other examples, the therapeutically effective amount of the copper-containing agent can be in an amount of about 0.00001 wt% to about 0.0001 wt%, about 0.0001 wt% to about 0.0005 wt%, about 0.0001 wt% to about 0.0002 wt%, about 0.0002 wt% to about 0.0003 wt%, or about 0.0003 wt% to about 0.0004 wt%. In yet other examples, the therapeutically effective amount of the copper-containing agent can be in an amount of about 0.001 wt% to about 0.01 wt% or about 0.003 wt% to about 0.008 wt%. In yet other examples, the therapeutically effective amount of the copper-containing agent can be in an amount of about 0.01 wt% to about 0.1 wt%, or about 0.03 wt% to about 0.08 wt%. It should be noted that these weight percentages are calculated based on cupric sulfate (II) anhydrous. Thus, when alternative copper-containing agents are used, the weight percentages can be converted accordingly.

[0035] However, a particular amount of a copper-containing agent in a composition does not necessarily mean that all of the copper content becomes biologically available at the time of administration or becomes biologically available at the same rate. The bioavailability of copper can vary somewhat from one copper-containing component to another. Additionally, the bioavailability of copper can be affected by pH, viscosity, solubility, and other components. Thus, the therapeutically effective amount of a copper-containing agent can also be adjusted based on the bioavailability of copper with respect to a particular copper carrier, pH, formulation, etc. Further, the rate of release of the copper content from a particular dosage form can be adjusted based on the particular copper-containing agent used in the dosage form. For example, in some cases, a less soluble copper-containing agent (e.g., copper fluoride, copper hydroxide, copper carbonate) can be used to extend the release of the copper-containing agent from the composition. In some further examples, the rate of release can be controlled, additionally or alternatively, via a particular pharmaceutical carrier or formulation type.

[0036] In some cases, the copper-containing agent can also be administered with a therapeutically effective amount of a second active agent or therapeutic. In some examples, the second active agent can be an additional cross-linking agent. In some examples, the second active agent can provide an additional mechanism of action that works in concert with the cross-linking induced by the copper-containing agent and / or other cross-linking agents. For example, the second active agent can reduce axial elongation and accommodation (i.e., the process by which the eye changes its refractive power to maintain a clear focus on an image as its distance changes), or combinations thereof. Such additional agents can include riboflavin, rose bengal, hydroxylysine, calcium-containing agents, magnesium-containing agents, silver-containing agents, aluminum-containing agents, zinc-containing agents, iron-containing agents, asiatic extract, decorin, biglycan, keratocan, lumican, mimecan, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthine, and the like, or combinations thereof. In some examples, the additional or second active agent can include atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthine, and the like, or combinations thereof. In some specific examples, the second active agent can include atropine. In some additional examples, the second active agent can include homatropine. In further additional examples, the second active agent can include cyclopentolate. In further examples, the second active agent can include pirenzepine. In yet another example, the second active agent can include 7-methylxanthine. The second active agent can generally be present in an amount of about 0.001 wt% to about 0.1 wt%. In other examples, the second active agent can be present in an amount of about 0.005 wt% to about 0.05 wt%, or about 0.007 wt% to about 0.02 wt%.

[0037] Furthermore, in some examples, a plurality of different copper-containing agents can be administered simultaneously, with or without a second active agent or therapeutic agent. It should also be noted that in some examples, one or more alternative crosslinking agents can be administered in place of the copper-containing agent. For example, in some cases, the alternative crosslinking agent can be or can include any divalent or polyvalent ion or compound suitable for inducing or promoting crosslinking in the cornea. In some examples, the crosslinking agent can be or can include metal ions such as, for example, alkaline earth metals, transition metals, post-transition metals, or combinations thereof. In some examples, the crosslinking agent is or can include a cation. In some specific examples, the crosslinking agent is or can include divalent metal ions such as magnesium, iron, zinc, etc.

[0038] The copper-containing agent can be provided with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be formulated in various ways for delivering the copper-containing agent. Non-limiting examples can include solutions, suspensions, emulsions, gels, hydrogels, thermoresponsive gels, formulations for subconjunctival injection, formulations for sub-Tenon's injection, depot, films, sustained delivery matrices, contact lenses, cotton swabs, punctal plugs, gelling suspensions, etc., or combinations thereof. In some examples, the composition can be formulated for passive delivery to the eye. In other examples, the composition can be formulated for active delivery to the eye, such as iontophoresis, electroporation, sonoporation, etc. In a specific example, the formulation can be an eye drop. In some examples, the composition can be formulated as a copper-eluting contact lens, such as a soft lens, toric lens, hard lens, scleral lens, etc., or combinations thereof. The contact lens can be a daily disposable lens or a long-term use lens (e.g., a lens used from 2 days to over 2 weeks). In some examples, the composition can be formulated as a sustained release matrix for placement in contact with the surface of the eye, such as the cul-de-sac, conjunctiva, Tenon's capsule or the space under the Tenon's capsule. In some examples, the composition can be formulated as a biodegradable device, such as a lens, film, capsule, punctal plug, etc., or combinations thereof. The biodegradable device can be configured to biodegrade at a rate of about 1 week to about 6 months, or about 2 weeks to about 4 months, or about 1 month to about 2 months.

[0039] Depending on how the composition is formulated, the pharmaceutically acceptable carrier can include various excipients. For example, the pharmaceutically acceptable carrier can include one or more of solubilizing agents, tonicity agents, pH adjusters, thickening or gelling agents, polymers or polymer matrices, preservatives, water, etc., and combinations thereof.

[0040] Non-limiting examples of solubilizing agents can include phosphate buffered saline (PBS), Dulbecco's PBS, Alsever's solution, Tris buffered saline (TBS), water, Hank's BSS, Earle's BSS, Grey's BSS, Puck's BSS, Simm's BSS, Tyrode's BSS, BSS Plus, Ringer's lactate solution, normal saline (i.e., 0.9% saline), 1 / 2 normal saline, and other balanced salt solutions (BSS), or combinations thereof. The solubilizing agent can be present in various amounts in a pharmaceutically acceptable carrier depending on the particular formulation, method of treatment, etc.

[0041] Non-limiting examples of tonicity agents can include the solubilizing agents enumerated previously, as well as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, sorbitol, dextrose, glycerin, propylene glycol, ethanol, trehalose, etc., or combinations thereof. A tonicity agent can be used to provide appropriate tonicity of the formulation. In one aspect, the tonicity of the formulation is from about 200 to about 600 milliosmoles per liter (mOsm / L). In another aspect, the tonicity of the formulation can be from about 250 mOsm / L to about 350 mOsm / L. In another aspect, the tonicity of the formulation can be from about 350 mOsm / L to about 450 mOsm / L. In another aspect, the tonicity of the formulation can be from about 450 mOsm / L to about 550 mOsm / L. In yet another aspect, the tonicity of the formulation can be from about 400 mOsm / L to about 600 mOsm / L, from about 400 mOsm / L to about 500 mOsm / L, or from about 500 mOsm / L to about 600 mOsm / L. The tonicity agent can be present in various amounts in a pharmaceutically acceptable carrier depending on the particular formulation, method of treatment, etc.

[0042] Non-limiting examples of pH adjusters can include many acids, bases, and combinations thereof such as hydrochloric acid, phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. A pH adjuster can be used to provide an appropriate pH for the formulation. Where applicable, in one aspect, the pH can be from about 5.5 to about 8.5. In one aspect, the pH can be from about 5.8 to about 7.8. In another aspect, the pH can be from about 6.5 to about 7.8. In still other examples, the pH can be from about 7.0 to about 7.6. The pH adjuster can be present in various amounts in a pharmaceutically acceptable carrier depending on the particular formulation, treatment method, etc.

[0043] Non-limiting examples of thickening or gelling agents can include glycerol, propylene glycol, polyethylene glycol, polyvinyl alcohol, cellulose derivatives (such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, etc.), ethylvinyl alcohol, hyaluronic acid, etc., or combinations thereof. The thickening or gelling agent can be present in various amounts in a pharmaceutically acceptable carrier depending on the particular formulation, treatment method, etc.

[0044] Non-limiting examples of polymers that can be used to prepare polymer matrices for films, contact lenses, etc. can include biodegradable or non-biodegradable polymers. Non-limiting examples of polymers or combinations of polymers include poly(methyl methacrylate), polyorthoesters, hydroxyethyl methacrylate, polysiloxanes, poly(lactic-co-glycolic acid) (different ratios of lactic acid and glycolide content, and end groups such as acid or ester ends), polyvinyl alcohol, polyvinyl acetate, ethylene vinyl acetate, polyethylene glycol, polylactic acid, polyglycolic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, crosscarmellose, polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymers, their salts, etc., or combinations thereof. Certain copolymers such as poly(lactic acid)-poly(glycolic acid) block copolymers (PLGA), poly(glycolic acid)-polyvinyl alcohol block copolymers (PGA / PVA), hydroxypropyl methylcellulose (HPMC), polycaprolactone-polyethylene glycol block copolymers, crosscarmellose, etc. can be particularly effective in biodegradable matrices if desired.

[0045] In some examples, the composition can include a thermoresponsive polymer. Non-limiting examples of thermoresponsive polymers include poly(N-isopropylacrylamide), poly[2-(dimethylamino)ethyl methacrylate], hydroxypropyl cellulose, poly(vinyl caprolactam), polyvinyl methyl ether, polyethylene oxide, polyhydroxyethyl methacrylate, ABCBA type pentablock polymers, chitosan, etc., or combinations thereof. Such thermoresponsive polymers can bind or functionalize certain copper-containing agents within a certain temperature range and release the copper-containing agents when the temperature of the surrounding environment is changed, such as by contacting the composition with the eye or applying a heat source to the eye after administration of the composition.

[0046] Non-limiting examples of preservatives can include benzalkonium chloride (BAK), cetrimonium, sodium perborate, ethylenediaminetetraacetic acid (EDTA) and its various salt forms, chlorobutanol, and the like. The preservative can be present in various amounts in a pharmaceutically acceptable carrier depending on the particular formulation, method of treatment, and the like.

[0047] In one particular example, the pharmaceutically acceptable carrier can be formulated as an eye drop and can include PBS, BSS, or other suitable solubility or isotonicity agents. In another particular example, the pharmaceutically acceptable carrier can be formulated as an eye drop and can include artificial tears (e.g., RefreshTears®, Genteal®, OasisTears®, etc.). In some additional examples, the pharmaceutically acceptable carrier can be formulated as a thin film, ointment, gelling suspension, punctal plug, or contact lens.

[0048] Regardless of how the ophthalmic composition is formulated, the ophthalmic composition can be used as an ophthalmic dosage form for administering a therapeutically effective amount of the copper-containing agent. In some examples, the ophthalmic dosage form can provide from about 0.0005 μg to about 0.5 μg of copper per administration event. In still other examples, the ophthalmic dosage form can provide from about 0.006 μg to about 0.06 μg, from about 0.01 μg to about 0.03 μg, or from about 0.016 μg to about 0.044 μg of copper per administration event. In other examples, the ophthalmic dosage form can provide on average from about 0.0005 μg to about 5 μg of copper per day. In still other examples, the ophthalmic dosage form can provide on average from about 0.001 μg to about 2 μg, from about 0.006 μg to about 0.24 μg, from about 0.01 μg to about 0.12 μg, or from about 0.016 μg to about 0.18 μg of copper per day. It should be noted that not all of the copper provided by the dosage form will necessarily be bioavailable, although in some examples it is.

[0049] In some examples, the ophthalmic dosage form can be used in an effective dosing regimen to provide a therapeutically effective amount of the copper-containing agent. In some examples, the ophthalmic dosage form can be formulated for daily administration of the copper-containing agent. In this case, an effective dosing regimen can include administration of the eye drop dosage form once, twice, three times, four times, or more per day.

[0050] In still other examples, the eye drop dosage form can be formulated to biodegradably provide controlled or sustained release of the copper-containing agent over a predetermined period of time in another way. In still other examples, the eye drop dosage form can be formulated to release the copper-containing agent from a non-biodegradable matrix in a controlled or sustained manner. In such examples, the dosage form can be formulated to release the copper-containing agent over hours, days, or weeks as needed. In some specific examples, the dosage form can be formulated to deliver from about 0.005 mcg to about 250 mcg of copper per week. In still other examples, the dosage form can be formulated to deliver about 0.008 mcg to about 200 mcg / week, about 0.01 mcg to about 150 mcg / week, or about 0.1 mcg to about 100 mcg / week. Further, the dosage form can typically be formulated to have zero-order drug release kinetics, but this is not essential.

[0051] In some examples, the dosage form can be held or stored in a container as a pre-mixed composition that is ready for administration without further dilution or preparation. In some embodiments, a single container can hold a volume or amount of the composition that is appropriate for a single administration but less than an amount appropriate for multiple administrations. In still other examples, a single container can hold a volume or amount of the composition suitable for multiple administrations.

[0052] A number of suitable containers can be used. In one aspect, the container can be an amber-colored container. In some examples, the container can be made of glass, polypropylene, polyethylene, polycarbonate, polyvinyl chloride, etc., or combinations thereof. In some examples, the container can have a volume of from about 0.5 ml to about 50 ml. In another aspect, the container can have a volume of from about 1 ml to about 30 ml, from about 5 ml to about 20 ml, or from about 3 ml to about 15 ml. In one aspect, the container can hold a single dose of the therapeutic composition or dosage form. In another aspect, the container can hold multiple doses of the therapeutic composition or dosage form. In some examples, the container can be a vial, bottle, blister pack, sachet, etc.

[0053] In some examples, a copper-containing agent of from about 0.005 mg to about 1 mg can be included in the container. In still other examples, a copper-containing agent of from about 0.01 mg to about 0.5 mg can be included in the container. In some examples, from about 0.001 mg to about 0.5 mg of copper can be included in the container. In some examples, from about 0.005 mg to about 0.2 mg of copper can be included in the container.

[0054] In some specific examples, the dosage form can be a topical ophthalmic dosage form formulated as an eye drop and placed in a container adapted to dispense the composition in a dropwise manner with a drop volume of about 5 μl to about 100 μl. When the composition is formulated as an eye drop, in some examples, the container can include a suitable nozzle or tip capable of dispensing the composition. Thus, the container can usually be foldable for dispensing the composition. However, in some cases, after the composition is dispensed, air can be drawn back into the container, thereby potentially contaminating the composition. In some examples, the nozzle or tip can include a valve mechanism, a filter, or the like, or a combination thereof, to prevent or minimize the introduction of bacteria and other contaminants into the container. Further, as described above, the container can be adapted to administer the ophthalmic composition in a dropwise manner. For example, the container can be adapted to dispense the ophthalmic composition in a drop volume of about 5 μl to about 50 μl, such as about 15 μl, about 20 μl, about 25 μl, about 30 μl, about 35 μl, about 40 μl, about 45 μl, or about 50 μl. In some specific examples, the drop volume can be about 15 μl to about 40 μl, about 5 μl to about 30 μl, about 20 μl to about 30 μl, about 25 μl to about 35 μl, or about 30 μl to about 40 μl.

[0055] Also further included with the dosage form can be an administration mechanism, such as a syringe, a drip device, or other mechanism. In additional embodiments, a suitable package can be used to provide the composition, the container, and instructions for their use, and optionally an administration mechanism in a single integrated system.

[0056] The compositions or dosage forms described herein can also be used in methods for treating and / or preventing the progression of myopia. Such methods can include administering a therapeutically effective amount of the composition or dosage form to the subject's eye during a treatment period.

[0057] In one example, the composition or dosage form can be administered at 1 to 4 time points per day for each eye in need thereof. In some examples, such as when the composition is an eye drop, the dosage of the composition at each time point can be about 5 μl to about 100 μl, about 5 μl to about 50 μl, about 5 μl to about 30 μl, about 20 μl to about 30 μl, about 25 μl to about 35 μl, or about 30 μl to about 40 μl. The dosage form can generally provide about 0.0005 μg to about 500 μg of copper per drop of the ophthalmic composition. In some additional examples, the dosage form can provide about 0.0001 μg to about 5 μg, about 0.001 μg to about 50 μg, or about 0.005 μg to about 1 μg of copper per drop of the ophthalmic composition.

[0058] In some further examples, the composition or dosage form can be administered multiple times a day, once a day, once every 2 to 5 days, once a week, once every 2 weeks, etc. Optionally, the composition can be formulated to have a sustained release profile, such as for about 2 to 5 days, about 1 week, about 2 weeks, etc.

[0059] The treatment period may depend on several factors, such as the severity of the condition, the age of the subject at diagnosis, etc. For example, in some cases where the subject is a school-aged child, adolescent, or young adult (e.g., about 3 years old to about 25 years old, or about 5 years old to about 18 years old), the subject can receive treatment for about 6 months to chronic treatment, or about 1 year to about 5 years, or about 2 years to about 3 years, or other appropriate periods until the desired result is achieved.

[0060] In some examples, the ophthalmic composition can be administered as an eye drop. In some further examples, the ophthalmic composition can be administered as a subconjunctival injection. In other examples, the ophthalmic composition can be administered as a sub-Tenon's injection. In some further examples, the ophthalmic composition can be administered in the form of a topical film, topical gel, contact lens, punctal plug, etc. In some examples, the topical film, topical gel, contact lens, punctal plug, etc. can be configured to biodegrade over time to provide a controlled sustained release of the copper-containing agent.

[0061] In some examples, the copper-containing agent can be administered in connection with an eye shaping device, such as an orthokeratology type lens. In this way, the eye shaping device can reform to a desired or intended shape (e.g., a non-elongated shape), or otherwise hold the eye while improving the biomechanical strength of the eye during the desired shape, and correct myopic elongation. In some embodiments, the use of the shaping device can further improve the results or improvement rate of the treatment method.

[0062] Generally, the methods described herein can increase collagen crosslinking in the cornea compared to an untreated eye. More specifically, this method can increase the lysinonorleucine (LNL) crosslink density, the histidinyl-hydroxylysino-norleucine (HLNL) crosslink density, or both, as well as other collagen crosslinks associated with the cornea, compared to an untreated eye. Further, the methods described herein can reduce the radial strain of the cornea by at least about 10%, 25%, or 50% compared to an untreated cornea. Further, the methods described herein can reduce the corneal diopter of a myopic cornea compared to an untreated myopic cornea.

[0063] Examples Example 1 Copper-containing active agent can increase corneal lysyl oxidase activity Corneal stromal cells cultured from normal corneas and corneas with low corneal rigidity (n = 3 each) in 10% FBS DMEM were exposed to 0.0016 mg / mL CuSO4 in BSS control or balanced salt solution (BSS) and then filtered through a 0.25 μm filter. The conditioned medium was subjected to a peroxidase-conjugated fluorescence activity assay for lysyl oxidase (LOX).

[0064] The tissue was collected under aseptic technique in the surgical environment. The tissue sample was stored in a 10 cm tissue culture dish in Optisol solution. The corneal tissue was suspended in 15% fetal bovine serum (FBS) DMEM / F12 containing penicillin / streptomycin. The epithelium and Descemet's membrane were mechanically removed under a stereomicroscope. The sample was further cut into smaller pieces with surgical scissors and added to 1 mg / mL of collagenase. 10 mL per cornea was used. The sample pieces were plated in a 10 cm tissue culture dish and placed in a tissue culture incubator at 37 °C and 5% CO2. After 5 days, the cells were harvested and plated in 10% FBS DMEM without phenol red.

[0065] The LOX enzyme activity in the medium was measured using a peroxidase-conjugated fluorescence assay using Amplex red. Briefly, corneal stromal cells were plated in a 6-well plate at 0.2×10^6 cells in 2 mL of culture medium. After 3 days, the cultures were harvested for the LOX enzyme activity assay. 50 μL of each medium was placed in a black 96-well plate. Then, 50 μL of 2x assay buffer (2.4 M urea, 100 mM sodium borate (pH 8.2), 20 mM 1,5-diaminopentane, 20 μM Amplex red, 2 unit / mL horseradish peroxidase) was added. As a parallel assay, 500 μM aminopropionitrile (BAPN), which can completely reduce LOX activity, was added. The fluorescence of oxidized Amplex red was recorded every 10 minutes using a fluorescence plate reader. After subtracting the background fluorescence, the fluorescence intensity was plotted against the incubation time (Figures 1A and 1B).

[0066] Based on the peroxidase-conjugated fluorescence measurement lox activity assay, as shown in Figures 1A-1B, it can be seen that copper dramatically increased the LOX enzyme activity in fibroblasts from normal corneas and corneas with low corneal rigidity. This indicates that copper may increase collagen cross-linking by enhancing the LOX activity in myopic corneas.

[0067] Example 2 Treatment with a copper-containing agent increases corneal strength Measurements of corneal radial strain were performed on human cadaveric corneas and rabbit corneas. Human cadaveric corneas (n = 2 pairs) were cultured as described above in Example 1. The treatment group was immersed in 0.0016 mg / ml of CuSO4 for 2 weeks. Small portions of the sclera were also included at both ends of the samples. To minimize tissue dehydration, mineral oil was applied to the surface of the sclera-cornea-sclera strips. Rabbit corneas were divided into four groups. Two groups were treatment groups that received 0.0025 mg / ml of CuSO4 pentahydrate three times a day or 0.0025 mg / ml of CuSO4 pentahydrate once a day. Two groups functioned as controls receiving only BSS.

[0068] The sample was connected between the motor and the transducer, and a controlled pressure of 5 - 30 mmHg was applied to measure the resulting radial strain. The length of the sample between the two gripping jaws was approximately 10 mm. Geometric information of the sample such as width and thickness was entered into the Rheometrics System Analyzer (RSA) control panel. The thickness of the sample was measured with an ultrasonic thickness gauge (DGH 550 Pa-chette2; DGH Technology, Exton, PA).

[0069] The results showed a significant increase in stiffness and a decrease in radial strain after copper sulfate treatment (Figure 2). The average peak radial strain induced by the ocular pulse at 20 mmHg in the treated corneas was approximately 1.5 times lower than that in the untreated corneas. This represents an approximately 50% increase in corneal strength, indicating that crosslinking results in a stiffer corneal response. Also, as shown in Figure 3, treatment with CuSO4 pentahydrate provided corneal biomechanics comparable to those seen with laser crosslinking.

[0070] Example 3 Rabbit corneal topography The corneal curvature of a specific area was monitored by corneal topography that displays the refractive value results. Copper sulfate pentahydrate (CuSO4) at a dose of 0.0025 mg / ml was administered to New Zealand white rabbits once a day and three times a day. Additionally, a high-concentration sample of 0.025 mg / ml CuSO4 pentahydrate was administered to New Zealand white rabbits once a day during the treatment period. Three different controls were administered either without drops, with BSS, or with artificial tears. Each of the six groups included six controls respectively. Topography images were taken before treatment and for five weeks weekly. The measured values of visual acuity are the mean K value and the value at 3 mm. These values were compared with the visual acuity measurements of the laser-crosslinked cornea after one month and one year.

[0071] As shown in Figure 4, there was a greater decrease in diopter measurements in the treatment group compared to the control group. Additionally, treatment with CuSO4 for one month resulted in visual acuity similar to that observed in the laser-crosslinked cornea after one year.

[0072] Example 4 In Vivo Safety of Copper Eye Drops A copper sulfate (CuSO4) pentahydrate solution was prepared at a concentration of 0.0025 mg / ml and administered to rabbits three times a day (TID) or once a day (QD). Anterior segment evaluations were performed using a slit lamp biomicroscope and a Heidelberg Spectralis anterior segment optical coherence tomography (AS-OCT). Two rabbits (n = 4 eyes) were sacrificed on each of the 1st, 1st week, 4th week, and 6th week to measure the copper concentration in the eye tissues and compare with control (no drops) rabbits. Aqueous humor, vitreous, retina, cornea, lens, and blood samples were analyzed for copper ions using inductively coupled plasma mass spectrometry (ICP-MS).

[0073] Rabbits (n = 2) were sacrificed after 42 days by intravenous injection of 0.3 ml / kg of euthanasia solution, and the eyes were enucleated to read histological evaluation and signs of inflammation, tissue damage, scarring and fibrosis. The anterior part of the eye was fixed in 10% formaldehyde-glutaraldehyde solution, dehydrated with graded alcohols, embedded in paraffin, and sectioned with a microtome. Sections were stained with appropriate stains (hematoxylin and eosin and Masson trichrome).

[0074] There was no effect on electroretinogram (ERG) measurement by treatment with Cu. Furthermore, no toxicity was observed in any of the dissected eye tissues. Furthermore, corneal clouding was not observed, although it may occur up to approximately 1 year by laser crosslinking. These results are further shown in FIGS. 5A-5B. FIG. 5A shows an image of a hematoxylin and eosin stained cornea after 6 weeks of Cu treatment. FIG. 5B shows an image of a hematoxylin and eosin stained retina / choroid after 6 weeks of Cu treatment.

[0075] Example 5 Copper treatment induces central corneal flattening of the cornea of healthy rabbits in vivo The right eyes (n = 3) of New Zealand white rabbits were treated with 0.0016 mg / ml of CuSO4 three times a day for 24 days. The left eyes were treated with BSS (TID) for 24 days and used as controls. Corneal OCT images were taken at baseline and on day 24.

[0076] As shown in FIGS. 6A-6F, representative OCT images showed reproducible results, and the central part of the cornea of the right eye (treated with CuSO4) showed corneal flattening in all three treated eyes shown in FIGS. 6D, 6E, and 6F (see arrows), compared to the control eyes shown in FIGS. 6A, 6B, and 6C. This is due to an increase in crosslinking activity. Furthermore, as shown by OCT, the corneal epithelial layer was intact, suggesting no significant toxicity to the cornea. No inflammation or opacification was observed by slit lamp examination.

[0077] Example 6 Copper treatment slows the progression of myopia in albino guinea pigs Progressive myopia occurs more frequently in albino guinea pigs than in wild-type guinea pigs, even without the imposition of diffusers or lenses. Guinea pigs were exposed to a 12-hour light / 12-hour dark cycle. An eye drop containing 0.0025 mg / ml of CuSO4 pentahydrate in phosphate-buffered eye drops was administered to the right eye (OD) of albino guinea pigs at approximately 2 weeks of age (n = 4). The left eye (OS) received control drops (ophthalmic vehicle only). The eye drops (approximately 30 μL) were administered three times a day for approximately 6 weeks. Refractive abnormalities were measured by a pediatric ophthalmologist before treatment on day 1 and at subsequent time points according to the schedule shown in FIGS. 7A-7B. More specifically, refractive abnormalities were measured by streak retinoscopy of awake animals held by hand in which cycloplegia had been induced previously with approximately 2 drops of 1% cyclopentolate. FIGS. 7A-7B present the mean refractive error measurements of the subjects of each eye, using error bars and linear fits, respectively. As is apparent from FIGS. 7A-7B, copper treatment was effective in reducing the progression of myopia in the treated eye. Furthermore, histopathological analysis has shown that no toxicity was observed in the dissected eyes and that IOP measurements were within the normal range of 15-25 mmHg for all eyes during the study (data not shown).

[0078] Example 7 Increased lysinonorleucine (LNL) crosslinking in treated eyes The right eyes of New Zealand white rabbits were divided into a treatment group (0.0025 mg / ml of CuSO4 pentahydrate in phosphate buffered eye drops), a vehicle group (phosphate buffered eye drops), and a control group (no drops) (n = 6 / group). The eye drops were administered to the treated eyes three times a day for 6 weeks. The animals were followed weekly for IOP measurement, topography, and ocular response analysis. At the end of 6 weeks, the rabbits were sacrificed and the eyes were immediately dissected within 30 minutes after sacrifice. The recovered corneal weight was recorded. The samples were reduced with NaBH4 at room temperature, then washed twice with water, dried, and hydrolyzed with 6N HCl in vacuo at 110 °C for 18 hours. After hydrolysis, cross-linking enrichment was performed using the cellulose mini-column method. LNL was measured by mass spectrometry. As seen in Figure 8, LNL cross-linking was increased in the treated corneas compared to the vehicle and control groups. This indicates that the corneas of the treatment group were stiffer compared to the vehicle and control groups.

[0079] It should be understood that the above method is merely an illustration of some embodiments of the present invention. Those skilled in the art can devise numerous modifications and alternative arrangements without departing from the spirit and scope of the present invention, and the appended claims are intended to cover such modifications and arrangements. Accordingly, although the present invention has been described above with specificity and detail in connection with what is presently considered to be the most practical and preferred embodiments of the invention, it will be apparent to those skilled in the art that variations may be made without departing from the principles and concepts described herein.

Claims

**Claim 1** A method for treating or preventing the progression of myopia, the method comprising: administering to the eye of a subject a therapeutically effective amount of an ophthalmic composition during a treatment period, wherein the ophthalmic composition comprises: an amount of a copper-containing agent sufficient to increase corneal lysyloxidase activity in the eye of the subject and in an amount sufficient to treat the progression of myopia, and a pharmaceutically acceptable carrier A method. **Claim 2** The method according to claim 1, wherein the ophthalmic composition is formulated as one of a solution, a suspension, an emulsion, a gel, a hydrogel, a thermoresponsive gel, a depot, a film, a gelling suspension, a contact lens, or a punctal plug. **Claim 3** The method according to claim 1, wherein the ophthalmic composition is formulated as a sustained-release composition configured to release the copper-containing agent over a period of from about 2 days to about 6 months. **Claim 4** The method according to claim 3, wherein the administration is effected via one or more of placement of the composition in the cul-de-sac of the eye, placement of the composition in the conjunctival fornix of the eye, and placement of the composition in the sub-Tenon's space of the eye. **Claim 5** The method according to claim 3, wherein the ophthalmic composition is configured to deliver to the eye of the subject an average of from about 0.0001 μg to about 5500 μg of copper per day. **Claim 6** The method according to claim 1, wherein the copper-containing agent is present in the composition in an amount of from about 0.000001 wt% to about 15 wt%. **Claim 7** The method according to claim 1, wherein the amount of copper present in the composition is in the range of from about 0.00001 mg / ml to about 1 mg / ml. **Claim 8** The method according to claim 1, wherein the copper-containing agent is selected from the group consisting of copper sulfate, copper carbonate, copper acetate, copper chloride, copper hydroxide, copper gluconate, copper bromide, copper fluoride, copper nitrate, copper iodide, copper perchlorate, copper molybdate, copper thiocyanate, copper tartrate, copper tetrafluoroborate, copper selenide, copper pyrophosphate, GHK-copper, tetraammine copper sulfate, histidine copper, copper glycinate, and combinations thereof. **Claim 9** The method according to claim 1, wherein the pharmaceutically acceptable carrier comprises at least one of an isotonicity agent, a solubilizing agent, a thickening agent, a polymer, a buffering agent, a preservative, a pH adjuster, and water. **Claim 10** The method according to claim 1, wherein the composition has an osmolality of from about 200 mOsm / kg to about 600 mOsm / kg.

11. The method according to claim 1, wherein the composition has a pH of from about 5.5 to about 8.

5.

12. The method according to claim 1, wherein the composition further comprises an additional active ingredient.

13. The method according to claim 12, wherein the additional active ingredient is selected from the group consisting of riboflavin, rose bengal, hydroxylysine, calcium-containing agents, magnesium-containing agents, silver-containing agents, aluminum-containing agents, zinc-containing agents, iron-containing agents, acai extract, decorin, biglycan, keratocan, lumican, mimecan, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthine, and combinations thereof.

14. The method according to claim 12, wherein the additional active ingredient is included in the composition in an amount of from about 0.001 wt% to about 0.1 wt%.

15. The method according to claim 1, wherein the ophthalmic composition is formulated as an eye drop and is carried in a container adapted to dispense the composition in a dropwise manner with a drop volume of from about 5 μl to about 100 μl.

16. The method according to claim 15, wherein the dosage form provides from about 0.0001 μg to about 500 μg of copper per drop of the ophthalmic composition.

17. The method according to claim 1, wherein the composition is administered 1 to 4 times per day for each eye in need thereof.

18. The method according to claim 17, wherein from about 5 μl to about 100 μl of the composition is administered at each time point.

19. The method according to claim 1, wherein the composition is administered in association with an eye shaping device configured to reshape an elongated myopic eye.

20. The method according to claim 1, wherein the subject is a human subject from about 3 years to about 25 years of age.

21. The method according to claim 1, wherein the treatment period is from about 6 months to about 5 years.

22. An ophthalmic composition for treating the progression of myopia, comprising a copper-containing agent in an amount sufficient to regulate lysyl oxidase for treating the progression of myopia, and a pharmaceutically acceptable carrier and having.

23. In the composition according to claim 22, the ophthalmic composition is formulated as one of a solution, a suspension, an emulsion, a gel, a hydrogel, a thermoresponsive gel, a depot, a film, a gelled suspension, a contact lens, or a punctal plug.

24. In the composition according to claim 22, the ophthalmic composition is formulated as a sustained-release composition configured to release the copper-containing agent over a period of about 2 days to about 6 months.

25. In the composition according to claim 24, the ophthalmic composition is configured to deliver an average of about 0.0001 μg to about 500 μg of copper per day to the eye of the subject.

26. In the composition according to claim 22, the copper-containing agent is present in an amount of about 0.000001 wt% to about 15 wt%.

27. In the composition according to claim 22, the amount of copper present in the composition is in the amount of about 0.00001 mg / ml to about 1 mg / ml.

28. In the composition according to claim 22, the copper-containing agent is selected from the group consisting of copper sulfate, copper carbonate, copper acetate, copper chloride, copper hydroxide, copper gluconate, copper bromide, copper fluoride, copper nitrate, copper iodide, copper perchlorate, copper molybdate, copper thiocyanate, copper tartrate, copper tetrafluoroborate, copper selenide, copper pyrophosphate, GHK-copper, tetraammine copper sulfate, histidine copper, copper glycinate, and combinations thereof.

29. In the composition according to claim 22, the pharmaceutically acceptable carrier includes at least one of an isotonic agent, a solubilizing agent, a thickening agent, a polymer, a buffering agent, a preservative, a pH adjuster, and water.

30. In the composition according to claim 22, the composition has an osmolarity of about 200 mOsm / kg to about 600 mOsm / kg.

31. In the composition according to claim 22, the composition has a pH of about 5.5 to about 7.

8.

32. In the composition according to claim 22, the composition further has an additional active ingredient.

33. The composition according to claim 32, wherein the additional active ingredient is selected from the group consisting of riboflavin, rose bengal, hydroxylysine, calcium-containing agent, magnesium-containing agent, silver-containing agent, aluminum-containing agent, zinc-containing agent, iron-containing agent, acai extract, decorin, biglycan, keratocan, lumican, mimecan, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthine, and combinations thereof.

34. The composition according to claim 32, wherein the additional active ingredient is included in the ophthalmic composition in an amount of about 0.001 wt% to about 0.1 wt%.

35. A topical ophthalmic dosage form, wherein the dosage form is formulated as an eye drop and is carried in a container adapted to dispense the composition in a dropwise manner with a drop volume of about 5 μl to about 100 μl, and has the ophthalmic composition according to any one of claims 22 to 34.

36. The dosage form according to claim 35, wherein the dosage form provides about 0.0001 μg to about 500 μg of copper per drop of the ophthalmic composition.

37. The dosage form according to claim 35, wherein the container is adapted to dispense the composition with a drop volume of about 5 μl to about 100 μl.

38. Use of a copper-containing agent in the preparation of an ophthalmic pharmaceutical for treating the progression of myopia by increasing at least corneal lysyloxidase activity when administered to the eye of a subject in a therapeutically effective amount during a treatment period.

39. The use according to claim 38, wherein the ophthalmic pharmaceutical is formulated as one of a solution, suspension, emulsion, gel, hydrogel, thermoresponsive gel, depot, film, gelling suspension, contact lens, or punctal plug.

40. The use according to claim 38, wherein the ophthalmic pharmaceutical is formulated as a sustained-release composition configured to release the copper-containing agent over a period of about 2 days to about 6 months.

41. The use according to claim 40, wherein the administration is effected via one or more of placement of the composition into the cul-de-sac of the eye, placement of the composition onto the conjunctival dome of the eye, and placement of the composition into the space under the Tenon's capsule of the eye.

42. In the use according to claim 40, the ophthalmic composition is configured to deliver to the eye of the subject from about 0.0001 μg to about 5500 μg of copper per day on average.

43. In the use according to claim 38, the copper-containing agent is present in an amount of from about 0.000001 wt% to about 15 wt%.

44. In the use according to claim 38, the amount of copper present in the composition is in the amount of from about 0.00001 mg / ml to about 1 mg / ml.

45. In the use according to claim 38, the copper-containing agent is selected from the group consisting of copper sulfate, copper carbonate, copper acetate, copper chloride, copper hydroxide, copper gluconate, copper bromide, copper fluoride, copper nitrate, copper iodide, copper perchlorate, copper molybdate, copper thiocyanate, copper tartrate, copper tetrafluoroborate, copper selenide, copper pyrophosphate, GHK-copper, copper tetraamine sulfate, copper histidine, copper glycinate, and combinations thereof.

46. In the use according to claim 38, the pharmaceutically acceptable carrier comprises at least one of an isotonic agent, a solubilizing agent, a thickening agent, a polymer, a buffering agent, a preservative, a pH adjuster, and water.

47. In the use according to claim 38, the pharmaceutical has an osmolarity of from about 200 mOsm / kg to about 600 mOsm / kg.

48. In the use according to claim 38, the pharmaceutical has a pH of from about 5.5 to about 8.

5.

49. In the use according to claim 38, the pharmaceutical further has an additional active ingredient.

50. In the use according to claim 49, the additional active ingredient is selected from the group consisting of riboflavin, rose bengal, hydroxylysine, calcium-containing agent, magnesium-containing agent, silver-containing agent, aluminum-containing agent, zinc-containing agent, iron-containing agent, asai extract, decorin, biglycan, keratocan, lumican, mimecan, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthine, and combinations thereof.

51. In the use according to claim 50, the additional active ingredient is included in the ophthalmic composition in an amount of from about 0.001 wt% to about 0.1 wt%.

52. In the use according to claim 38, the ophthalmic pharmaceutical is formulated as an eye drop and is carried in a container adapted to dispense the composition in a dropwise manner with a drop volume of about 5 μl to about 100 μl.

53. In the use according to claim 52, providing about 0.0001 μg to about 500 μg of copper per drop of the ophthalmic composition.

54. In the use according to claim 38, the ophthalmic pharmaceutical is administered at 1 to 4 time points per day for each eye in need thereof.

55. In the use according to claim 54, about 5 μl to about 100 μl of the composition is administered at each time point.

56. In the use according to claim 38, the ophthalmic pharmaceutical is administered in association with an eye shaping device configured to reshape an elongated myopic eye.

57. In the use according to claim 38, the subject is a human subject from about 3 years to about 25 years of age.

58. In the use according to claim 38, the treatment period is about 6 months to about 5 years.

Images