Treatment of myopia progression

Abstract

To provide an ophthalmic composition for treating or preventing myopic progression.SOLUTION: An ophthalmic composition for use in a method of treating or preventing myopic progression is administered in a therapeutically effective amount to an eye of a subject during a treatment period. The ophthalmic composition comprises: copper perchlorate as an amount of a sole copper-containing agent that is sufficient to increase corneal lysyl oxidase activity in an eye of a subject in an amount sufficient to treat myopic progression; 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 January 5, 2018, and is incorporated herein by reference. [Background technology]

[0002] Myopia is a well-known cause of vision loss. The underlying defect in myopia is a slight elongation of the eyeball, which causes the eye's lens to focus light from distant objects slightly in front of the retina. Uncorrected myopia is one of the leading causes of distance vision impairment worldwide. In severe cases, the elongation of the eyeball causes parts of the inside of the eye to stretch and thin, increasing the risk of retinal detachment, cataracts, glaucoma, and blindness. The prevalence of myopia is also increasing, and is predicted to affect half of the world's population by 2050. The prior art documents relevant to the invention of this application are as follows (including documents cited during the international phase after the international filing date and documents cited when the application entered the national phase in other countries). (Prior art document) (Patent Documents) (Patent Document 1) International Publication No. 2017 / 155580 (Patent Document 2) U.S. Patent No. 3,416,530 (Patent Document 3) European Patent Application Publication No. 3103446 (Patent Document 4) U.S. Patent Application Publication No. 2006 / 0276777 (Non-Patent Literature) (Non-patent document 1) Wikipedia (Orthokeratology) Version: 18 September 2017 (18.09.2017). Retrieved: 1 April 2019 (01.04.2019) (https: / / en.wikipedia.org / w / index.php?title=Orthokeratology&oldid=801266165) pg 1, para 1 [Brief description of the drawings]

[0003] [Figure 1A] FIG. 1A is a graph showing increased lysyl oxidase activity in corneal fibroblasts in response to Cu treatment. [Figure 1B] FIG. 1B is another graph showing increased lysyl oxidase activity in corneal fibroblasts in response to Cu treatment. [Diagram 2] FIG. 2 is a graph showing the increase in corneal strength in response to Cu treatment. [Diagram 3]FIG. 3 is a chart showing improved corneal biomechanics in response to Cu treatment. [Figure 4] FIG. 4 is a chart showing the reduction in corneal diopter measurements in response to Cu treatment. [Figure 5A] FIG. 5A shows images of stained corneas after 6 weeks of Cu treatment. [Figure 5B] FIG. 5B shows images of stained retina / choroid after 6 weeks of Cu treatment. [Figure 6A-6F] 6A-6F show OCT images before and after BSS and CuSO4 treatment. 6A, 6B, and 6C of the control eye received BSS treatment. 6D, 6E, and 6F of the treated eye received CuSO4 treatment. [Figure 7A] FIG. 7A is a graph (with error bars) of the mean refractive error of treated eyes (OD) and untreated eyes (OS) in albino guinea pigs during a 6-week treatment regimen with CuSO4 pentahydrate. [Figure 7B] FIG. 7B is a graph (linear fit) of the mean refractive error of the treated eye (OD) and untreated eye (OS) in albino guinea pigs during a 6-week treatment regimen with CuSO4 pentahydrate. [Figure 8] FIG. 8 is a graph of LNL concentrations in treated (CuSO4 pentahydrate), vehicle, and control eyes of rabbits after a 6-week treatment regimen.

[0004] These drawings are provided to illustrate various aspects of the present invention and are not intended to be limiting in scope with respect to dimensions, materials, configurations, arrangements or proportions unless otherwise limited by the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Although the following detailed description contains many details for the purpose of illustration, those skilled in the art will understand that many variations and modifications to the following details can be made and are considered to be included herein. Thus, the following embodiments are described without loss of generality and without imposing limitations on the claims described. 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 dictates otherwise. Thus, for example, a reference to a "cell" includes a plurality of such cells.

[0007] In this disclosure, "comprises," "comprising," "including," "having," and the like, may have the meanings ascribed to them in U.S. patent law, and may mean "includes," "including," and the like, and are generally interpreted as open-ended terms. The terms "consisting of" or "consists of" are closed terms, including only those components, structures, steps, or the like that are specifically recited in association with these terms, and as such 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, except for exceptions that permit the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or functions of the item used in association therewith. For example, trace elements that are present in a composition but do not affect the properties or characteristics of the composition would be permitted if present under the "consisting essentially of" language even if they are not explicitly mentioned in the list of items following such a term. It is understood that when the specification uses open-ended terms such as "comprising" and "including," direct support should also be given to the "consists essentially of" and "consisting of" language as if expressly stated, and vice versa.

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

[0009] The term "coupled" as used herein is defined as directly or indirectly connected in a biological, chemical, mechanical, electrical or non-electrical manner. Structures or elements that are "directly coupled" are attached in contact with one another. Objects described herein as "adjacent" to one another may be in physical contact with one another, in close proximity to one another, or in the same general area or region of one another, depending on the context in which the phrase is used. Appearances of the phrases "in one embodiment" or "in one aspect" herein do not necessarily all refer to the same embodiment or aspect.

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

[0011] An "effective amount" of an agent as used herein is an amount sufficient to achieve a desired specific 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 in treating or preventing a condition for which the composition, drug, or agent is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Thus, an "effective amount" or a "therapeutically effective amount" may depend on such biological factors in some instances. Furthermore, while the achievement of a therapeutic effect may be measured by a physician, veterinarian, or other qualified medical personnel using assessments known in the art, it is recognized that individual variations and responses to treatment may make the achievement of a therapeutic effect a somewhat subjective determination. The determination of an effective amount or a therapeutically effective amount is within the ordinary skill in the art of pharmaceutical science and medicine.

[0012] As used herein, a "dosage regimen" or "regimen," such as a "therapeutic regimen" or a "prophylactic regimen," means how, when, how much, and for how long a dosage of 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 who is either asymptomatic or symptomatic. In other words, "treat," "treatment," or "treating" may be to reduce, ameliorate, or eliminate symptoms associated with a condition present in a subject, or may be prophylactic (i.e., to prevent or reduce the occurrence of symptoms in a 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" can be used to refer to a mixture of one or more active agents with a carrier or other excipients. A composition can be in almost any physical state, such as a solid, liquid (e.g., solution), gas, etc. Furthermore, the term "dosage form" can include one or more formulations or compositions provided in a format 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, a "subject" refers to an animal. In one aspect, the animal may be a mammal. In another aspect, the mammal may be a human.

[0016] The term "substantially" as used herein refers to the complete or nearly complete extent or degree of an action, characteristic, property, condition, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is completely enclosed or nearly completely enclosed. The exact allowable deviation from completeness may depend on the particular situation. In general, however, the closeness of completion is such that the same overall result would be obtained as if absolute perfect completion were obtained. The use of "substantially" also applies when used in a negative sense to refer to the complete or near complete absence of an action, characteristic, property, condition, structure, item, or result. For example, a composition that is "substantially free" of particles is completely devoid of particles or nearly completely devoid of particles, so that the same effect would be 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 "increase," "increased," "decreased," "better," "worse," "higher," "lower," "enhance," "enhanced," "maximize," "maximized," "minimize," "minimized," and the like, refer to a property, result, or effect of a device, composition, formulation, ingredient, treatment, regimen, method, or activity that is measurably different from the property, result, or effect of another device, composition, formulation, ingredient, treatment, regimen, method, or activity. Additionally, comparative terms may refer to a biological state, presence, absence, activity level, or manipulation that is measurably different from an endogenous biological state, presence, absence, activity level, or manipulation. Comparative terms can be used to indicate differences in surrounding or adjacent regions, e.g., regions of tissue. Comparative terms can also be used to indicate differences in chemical or biological structure or activity (e.g., therapeutic activity or efficacy). Additionally, comparative terms can be used to indicate differences in a biological or physiological result, activity, or condition compared to a previous or other biological or physiological result, activity, or condition. For example, an increase or decrease in lysyl oxidase activity can be identified by comparing the amount of lysyl oxidase at a first time point with the amount at a second time point. If a composition or treatment is applied, such an increase or decrease can be attributed to such composition or treatment. 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, a comparison may simply be made between a time point (e.g., an endogenous state and a treatment state). In other cases, a comparison can be made between the results achieved by two different applied formulations or treatments (e.g., formulations with different amounts of active agent, etc.).

[0018] The term "about" as used herein is used to provide flexibility to the endpoints of a numerical range when a given value is "a little above" or "a little 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 term or range without the term "about". For example, for convenience and brevity, the numerical range "about 50 micrograms to about 80 micrograms" should also be understood to provide support for the range "50 micrograms to 80 micrograms". Furthermore, it should be understood that support for the actual numerical value is provided even when the term "about" is used in conjunction with the term "about" herein. For example, the recitation of "about" 30 is interpreted to provide support for the actual numerical value 30 as well as values ​​a little above and a little below 30.

[0019] As used herein, a plurality of items, structural elements, components, and / or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list were individually identified as a separate and unique member. Thus, the individual members of such lists should not be construed as de facto equivalents of other members of the same list solely based on their presentation in a common group, without any suggestion to the contrary.

[0020] Concentrations, amounts, and other numerical data may be expressed or presented in a range format herein. It should be understood that such range formats are used merely for convenience and brevity, and should therefore be interpreted flexibly to include not only the numerical values ​​explicitly recited as range limitations, but also all individual numerical values ​​or subranges encompassed within the range, as if each numerical value and subrange were explicitly recited. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the values ​​of about 1 to about 5 explicitly recited, but also the individual values ​​and subranges within the indicated range. Thus, this numerical range includes individual values ​​such as 2, 3, 4, and the like, and subranges such as 1 to 3, 2 to 4, and 3 to 5, as well as the individual 1, 2, 3, 4, and 5.

[0021] This same principle applies to ranges that recite only one numerical value as a minimum or maximum value, and such interpretation applies regardless of the breadth of the range or characteristic being described.

[0022] References throughout this specification to an "example" 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 summary 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 understanding technical concepts more quickly, but is not intended to identify key or essential features thereof, nor is it intended to limit the scope of the claimed subject matter.

[0024] Myopia can be a severe and debilitating eye disease. The fundamental defect in myopia is a slight elongation of the eyeball, which causes the eye's lens to focus light from distant objects slightly in front of the retina. Hence, myopia is often referred to as short-sightedness or near-sightedness. In severe cases, this elongation causes parts of the inside of the eyeball to stretch and thin, increasing the risk of retinal detachment, cataracts, glaucoma, and blindness. Thus, myopia can be much more severe than simple nearsightedness.

[0025] Various causes of myopia have been suggested and studied, including genetic predisposition, long periods of reading and screen time, and inadequate exposure to bright light. Whether the underlying cause of myopia is one or more of those listed above, the elongation of the eyeball that accompanies myopia can be debilitating for anyone affected by the condition. Because the eye grows throughout childhood, myopia typically develops during school-age children and adolescents and can remain with these individuals throughout their lives. Therefore, improving the treatment of individuals such as school-age children and adolescents can improve the quality of life for these individuals both during adolescence and throughout their lives.

[0026] Thus, 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 may 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 crosslinking agent in an amount sufficient to increase lysyl oxidase activity in the subject's eye or otherwise increase crosslinking in the subject's cornea to an extent that slows or stops myopia progression. The composition or dosage form can further include a pharma- ceutically acceptable carrier. In some examples, the dosage form can be an ophthalmic composition formulated as a topical eye drop and contained in a container adapted to dispense the composition dropwise in 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 the copper-containing agent over an extended 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 a 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 more clearly shown by the various embodiments and examples provided herein, the compositions, dosage forms, and methods described in the present disclosure can increase corneal lysyl oxidase activity in the eye of a subject, can increase corneal collagen crosslinking (such as LNL, HLNL, DHLNL), can increase the strength of the corneal tissue of the eye of a subject, and can provide many other advantages described herein, such as increasing corneal stiffness and flattening the myopic cornea to help treat or prevent the progression of myopia in individuals.

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

[0030] Thus, the ophthalmic compositions or dosage forms described herein can include a sufficient amount of copper-containing agent to increase lysyl oxidase activity in the eye of a subject, or a sufficient amount of copper-containing agent to increase corneal cross-linking to treat or prevent myopia progression in a subject.Various copper-containing agents can be used, such as copper-containing salts, compounds, chelates, etc.Non-limiting examples of copper salts can 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, hydrates thereof, analogs, or combinations thereof.Other suitable copper carriers can include GHK-copper, tetraamine copper sulfate, copper-histidine, copper-glycinate, copper-gluconate, hydrates thereof, 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] Therefore, the copper-containing agent can be any suitable copper-containing agent that can provide a therapeutically effective amount of copper to the eye of the subject.The therapeutically effective amount can be sufficient to increase the corneal lysyl oxidase activity of the eye to a degree that retards or prevents the progression of myopia, for example, by increasing collagen cross-linking compared to collagen cross-linking before treatment.This can also increase the biomechanical strength of the cornea compared to the biomechanical strength before treatment.In addition, this can reduce the diopter of the cornea of ​​the treated eye compared to the diopter before 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 with 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 still be effective in increasing lysyl oxidase activity and slowing or stopping the progression of myopia. It can be important to keep copper levels low enough to avoid copper-induced toxicity while maintaining a sufficient amount of bioavailable copper to increase lysyl oxidase activity.

[0033] Thus, 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 how the composition is formulated, 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 may 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. Thus, in some examples, a therapeutically effective amount may 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 provides the composition with a copper content of about 0.000636 mg / ml copper. This is because while the atomic weight of copper(II) sulfate pentahydrate is about 249.677 g / mol, 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 anhydrous copper(II) acetate provides a composition with a copper content of about 0.00063 mg / ml. Thus, a 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 percent of the copper-containing agent in the composition. Again, depending on how the composition is formulated, the therapeutically effective amount of the copper-containing agent can be about 0.00001% by weight or about 0.0001% by weight to about 5% by weight, 10% by weight, or 15% by weight. In some examples, the therapeutically effective amount of the copper-containing agent can be about 0.05% by weight to about 15% by weight, about 0.01% by weight to about 10% by weight, or about 0.005% by weight to about 5% by weight. In other examples, the therapeutically effective amount of the copper-containing agent can be about 0.00001% by weight to about 0.0001% by weight, about 0.0001% by weight to about 0.0005% by weight, about 0.0001% by weight to about 0.0001% by weight to about 0.0002% by weight, about 0.0002% by weight to about 0.0003% by weight, or about 0.0003% by weight to about 0.0004% by weight. In yet other examples, the therapeutically effective amount of the copper-containing agent may be an amount of about 0.001% to about 0.01% by weight, or about 0.003% to about 0.008% by weight. In yet other examples, the therapeutically effective amount of the copper-containing agent may be an amount of about 0.01% to about 0.1% by weight, or about 0.03% to about 0.08% by weight. Note that these weight percentages are calculated based on anhydrous copper(II) sulfate. Thus, if an alternative copper-containing agent is used, the weight percentages can be converted accordingly.

[0035] However, a particular amount of copper-containing agent in a composition does not necessarily mean that all of the copper content will be bioavailable upon administration or will be bioavailable at the same rate. Copper bioavailability may vary to some extent from one copper-containing component to another. In addition, copper bioavailability may be affected by pH, viscosity, solubility, and other components. Thus, the therapeutically effective amount of copper-containing agent may also be adjusted based on the copper bioavailability for a particular copper carrier, pH, formulation, etc. Furthermore, the release rate of the copper content from a particular dosage form may 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) may be used to extend the release of the copper-containing agent from the composition. In some further examples, the release rate may additionally or alternatively be controlled via a particular pharmaceutical carrier or formulation type.

[0036] In some cases, the copper-containing agent may also be administered with a therapeutically effective amount of a second active or therapeutic agent. In some examples, the second active agent may be an additional crosslinking agent. In some examples, the second active agent may provide an additional mechanism of action that works in concert with the crosslinking induced by the copper-containing agent and / or other crosslinking agents. For example, the second active agent may reduce axial elongation, reduce 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), and the like, or combinations thereof. Such additional agents may include 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, mimican, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatopine, cyclopentolate, pirenzepine, 7-methylxanthanine, and the like, or combinations thereof. In some examples, the additional or second active agent can include atropine, homatropine, cyclopentolate, pirenzepine, 7-methylxanthanine, and the like, or combinations thereof. In some particular examples, the second active agent can include atropine. In some additional examples, the second active agent can include homatropine. In yet additional examples, the second active agent can include cyclopentolate. In a further example, the second active agent can include pirenzepine. In yet another example, the second active agent can include 7-methylxanthanine. The second active agent can generally be present in an amount of about 0.001% to about 0.1% by weight. In other examples, the second active agent can be present in an amount of about 0.005% to about 0.05% by weight, or about 0.007% to about 0.02% by weight.

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

[0038] The copper-containing agent can be provided in a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier can be formulated in various ways to deliver 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, depots, films, sustained delivery matrices, contact lenses, pledgets, punctal plugs, gelling suspensions, and the like, 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, and the like. In certain examples, 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, a toric lens, a hard lens, a scleral lens, and the like, or a combination thereof. The contact lens can be a daily disposable lens or an extended wear lens (e.g., a lens for use for 2 days to 2 weeks or more). In some examples, the composition can be formulated as a sustained release matrix for placement in contact with an ocular surface, such as the cul-de-sac, conjunctiva, Tenon's capsule, or sub-Tenon's space. In some examples, the composition can be formulated as a biodegradable device, such as a lens, film, capsule, punctal plug, or the like, or a combination 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 pharma- ceutically acceptable carrier can contain various excipients.For example, the pharma-ceutically acceptable carrier can contain one or more of solubilizing agents, isotonicity agents, pH adjusting agents, thickening or gelling agents, polymers or polymer matrices, preservatives, water, etc., and combinations thereof.

[0040] Non-limiting examples of solubilizing agents may include phosphate buffered saline (PBS), Dulbecco's PBS, Alsever's solution, Tris-buffered saline (TBS), water, balanced salt solutions (BSS) such as Hank's BSS, Earle's BSS, Gray's BSS, Puck's BSS, Simm's BSS, Tyrode's BSS, BSS Plus, Ringer's lactate solution, normal saline (i.e., 0.9% saline), ½ normal saline, or combinations thereof. Solubilizing agents can be present in the pharma- ceutically acceptable carrier in varying amounts depending on the particular formulation, method of treatment, and the like.

[0041] Non-limiting examples of tonicity agents may include the solubilizers listed above, as well as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, sorbitol, dextrose, glycerin, propylene glycol, ethanol, trehalose, and the like, or combinations thereof. Tonicity agents may be used to provide the appropriate isotonicity of the formulation. In one embodiment, the tonicity of the formulation is about 200 to about 600 milliosmoles per liter (mOsm / L). In another embodiment, the tonicity of the formulation may be about 250 mOsm / L to about 350 mOsm / L. In another embodiment, the tonicity of the formulation may be about 350 mOsm / L to about 450 mOsm / L. In another embodiment, the tonicity of the formulation may be about 450 mOsm / L to about 550 mOsm / L. In yet another embodiment, 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 the pharma- ceutically acceptable carrier in various amounts, 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. The pH adjuster can be used to provide an appropriate pH to the formulation. If applicable, in one embodiment, the pH can be about 5.5 to about 8.5. In one embodiment, the pH can be about 5.8 to about 7.8. In another embodiment, the pH can be about 6.5 to about 7.8. In yet another example, the pH can be about 7.0 to about 7.6. The pH adjuster can be present in a pharma- ceutically acceptable carrier in various amounts, depending on the particular formulation, method of treatment, etc.

[0043] Non-limiting examples of thickening or gelling agents may 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 may be present in a pharma- ceutically acceptable carrier in varying amounts, depending on the particular formulation, method of treatment, etc.

[0044] Non-limiting examples of polymers that can be used to prepare polymeric matrices for films, contact lenses, and the like can include biodegradable or non-biodegradable polymers. Non-limiting examples of polymers or combinations of polymers can include poly(methyl methacrylate), polyorthoesters, hydroxyethyl methacrylate, polysiloxanes, poly(lactic-co-glycolic acid) (with 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, croscamellose, polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymers, salts thereof, and the like, or combinations thereof. Certain copolymers, such as polylactic acid-polyglycolic acid block copolymer (PLGA), polyglycolic acid-polyvinyl alcohol block copolymer (PGA / PVA), hydroxypropyl methylcellulose (HPMC), polycaprolactone-polyethylene glycol block copolymer, and croscarmellose, can be particularly effective for biodegradable matrices, if desired.

[0045] In some examples, the composition can include a thermoresponsive polymer. Non-limiting examples of thermoresponsive polymers can include poly(N-isopropylacrylamide), poly[2-(dimethylamino)ethyl methacrylate], hydroxypropyl cellulose, poly(vinylcaprolactam), polyvinyl methyl ether, polyethylene oxide, polyhydroxyethyl methacrylate, ABCBA type pentablock polymer, chitosan, etc., or combinations thereof. Such thermoresponsive polymers can bind or function with a specific copper-containing agent within a certain temperature range, and release the copper-containing agent 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 may include benzalkonium chloride (BAK), cetrimonium, sodium perborate, ethylenediaminetetraacetic acid (EDTA) and its various salt forms, chlorobutanol, etc. Preservatives can be present in a pharma- ceutically acceptable carrier in varying amounts depending on the particular formulation, method of treatment, etc.

[0047] In one particular example, the pharma- ceutically acceptable carrier can be formulated as an eye drop and can include PBS, BSS, or other suitable solubility or tonicity agent. In another particular example, the pharma-ceutically 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 pharma-ceutically acceptable carrier can be formulated as a thin film, an ointment, a gelling suspension, a punctal plug, or a 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 a copper-containing agent. In some examples, the ophthalmic dosage form can provide about 0.0005 μg to about 0.5 μg of copper per administration event. In still other examples, the ophthalmic dosage form can provide about 0.006 μg to about 0.06 μg, about 0.01 μg to about 0.03 μg, or 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, about 0.0005 μg to about 5 μg of copper per day. In still other examples, the ophthalmic dosage form may provide, on average, about 0.001 μg to about 2 μg, about 0.006 μg to about 0.24 μg, about 0.01 μg to about 0.12 μg, or about 0.016 μg to about 0.18 μg of copper per day. It is noted that not all of the copper provided by the dosage form will necessarily be bioavailable, although in some instances it may be.

[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 ophthalmic dosage form once a day, twice a day, three times a day, four times a day, or more.

[0050] In still other examples, the eye drop dosage form can be formulated to biodegrade and provide a controlled or sustained release of the copper-containing agent over an otherwise predetermined period of time. 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 examples such as these, the dosage form can be formulated to release the copper-containing agent over a period of hours, days, or weeks, as needed. In some specific examples, the dosage form can be formulated to deliver about 0.005mcg to about 250mcg of copper per week. In still other examples, the dosage form can be formulated to deliver about 0.008mcg to about 200mcg per week, about 0.01mcg to about 150mcg per week, or about 0.1mcg to about 100mcg per week. Additionally, the dosage form can typically be formulated to have zero-order drug release kinetics, although this is not required.

[0051] In some instances, the dosage form can be held or stored in a container as a premixed composition ready to be administered without further dilution or preparation. In some embodiments, a single container can hold a volume or amount of a composition suitable for a single administration, but less than the amount suitable for multiple administrations. In yet other instances, a single container can hold a volume or amount of a composition suitable for multiple administrations.

[0052] Many suitable containers can be used. In one embodiment, the container can be an amber container. In some examples, the container can be made of glass, polypropylene, polyethylene, polycarbonate, polyvinyl chloride, or the like, or combinations thereof. In some examples, the container can have a volume of about 0.5 ml to about 50 ml. In another embodiment, the container can have a volume of about 1 ml to about 30 ml, about 5 ml to about 20 ml, or about 3 ml to about 15 ml. In one embodiment, the container can hold a single dose of the therapeutic composition or dosage form. In another embodiment, 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, or the like.

[0053] In some examples, the container can contain about 0.005 mg to about 1 mg of the copper-containing agent. In yet other examples, the container can contain about 0.01 mg to about 0.5 mg of the copper-containing agent. In some examples, the container can contain about 0.001 mg to about 0.5 mg of copper. In some examples, the container can contain about 0.005 mg to about 0.2 mg of copper.

[0054] In some particular examples, the dosage form may be a topical ophthalmic dosage form formulated as eye drops and placed in a container adapted to dispense the composition in a dropwise manner in drops of about 5 μl to about 100 μl. When the composition is formulated as eye drops, in some examples, the container may include a nozzle or tip adapted to dispense the composition. Thus, the container may usually be collapsible to dispense the composition. However, in some cases, after the composition is dispensed, air may be sucked back into the container, thereby contaminating the composition. In some examples, the nozzle or tip may 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. Additionally, as previously described, the container may 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] Further included with the dosage form may be an administration mechanism, such as a syringe, dropper, or other mechanism. In additional embodiments, suitable packaging may be used to provide the composition, container, and instructions for their use, and optionally the administration mechanism in a single, integrated system.

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

[0057] In one example, the composition or dosage form can be administered 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 amount of the composition administered 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. In yet other examples, the ophthalmic composition is configured to deliver, on average, from about 0.0001 μg to about 5500 μg of copper per day to the subject's eye.

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

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

[0060] In some examples, the ophthalmic composition can be administered as eye drops. In yet other examples, the ophthalmic composition can be administered as a subconjunctival injection. In other examples, the ophthalmic composition can be administered as a sub-Tenon injection. In still other examples, the ophthalmic composition can be administered in the form of a topical film, a topical gel, a contact lens, a punctal plug, and the like. In some examples, the topical film, the topical gel, the contact lens, the punctal plug, and the like 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 conjunction with an ocular shaping device, such as an orthokeratology-type lens. In this manner, the ocular shaping device can correct the elongation of the myopic eye while reforming or otherwise holding the eye in a desired or intended shape (e.g., a non-elongated shape) to improve the biomechanical strength of the eye while in the desired shape. In some examples, the use of the shaping device can further improve the outcome or rate of improvement of the treatment method.

[0062] In general, the methods described herein can increase collagen crosslinks in the cornea compared to untreated eyes. More specifically, the methods can increase lysino-norleucine (LNL) crosslink density, histidinyl-hydroxylysino-norleucine (HLNL) crosslink density, or both, as well as other collagen crosslinks associated with the cornea compared to untreated eyes. Furthermore, the methods described herein can reduce the radial distortion of the cornea by at least about 10%, 25%, or 50% compared to a cornea without treatment. Furthermore, the methods described herein can reduce the corneal diopter of a myopic cornea compared to an untreated myopic cornea.

[0063] Working Example Example 1 Copper-Containing Active Agents Can Increase Corneal Lysyl Oxidase Activity Corneal stromal cells cultured from normal and low cornea stiffness corneas (n=3 each) in 10% FBS DMEM were exposed to BSS control or 0.0016mg / mL CuSO4 in balanced salt solution (BSS) and then filtered through a 0.25μm filter. Conditioned media was subjected to a peroxidase-linked fluorescent activity assay of lysyl oxidase (LOX).

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

[0065] LOX enzyme activity in the medium was measured using a peroxidase-linked fluorescence assay using Amplex red. Briefly, corneal stromal cells were plated in 6-well plates at 0.2×10^6 cells in 2 mL of culture medium. After 3 days, the cultures were harvested for 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 min using a fluorescence plate reader. After subtracting background fluorescence, the fluorescence intensity was plotted against the incubation time (Figure 1A and 1B).

[0066] Based on the peroxidase-linked fluorometric lox activity assay, copper dramatically increased LOX enzyme activity in fibroblasts from normal and low-stiffness corneas, as shown in Figures 1A-1B, indicating that copper may increase collagen cross-linking by enhancing LOX activity in myopic corneas.

[0067] Example 2 Treatment with copper-containing agents increases corneal strength Corneal radial strain measurements were performed on human cadaver corneas and rabbit corneas. Human cadaver corneas (n=2 pairs) were cultured as previously described in Example 1. Treatment groups were immersed in 0.0016 mg / ml CuSO4 for 2 weeks. Small pieces of sclera were also included at both ends of the samples. Mineral oil was applied to the surface of the sclera-cornea-sclera strips to minimize tissue dehydration. Rabbit corneas were divided into four groups. Two groups were treatment groups that received either CuSO4 pentahydrate 0.0025 mg / ml three times a day or CuSO4 pentahydrate 0.0025 mg / ml once a day. Two groups served 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. Sample geometric information, such as width and thickness, was entered into a Rheometrics System Analyzer (RSA) control panel. Sample thickness was measured with an ultrasonic pachymeter (DGH 550 Pa-chette2; DGH Technology, Exton, PA).

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

[0070] Example 3 Rabbit Corneal Topography Corneal curvature in specific areas was monitored by corneal topography, which displays the results of refractive values. Copper sulfate pentahydrate (CuSO4) at 0.0025 mg / ml was administered to New Zealand white rabbits in doses of once daily and three times daily. In addition, a high concentration sample of CuSO4 pentahydrate at 0.025 mg / ml was administered to New Zealand white rabbits once daily during the treatment period. Three different controls were administered either without drops, BSS, or artificial tears. Each of the six groups contained six controls, respectively. Topographic images were taken before treatment and weekly for five weeks. Diopter measurements are the mean K value and the value at 3 mm. These values ​​were compared to diopter measurements of the laser crosslinked corneas after one month and one year.

[0071] As shown in Figure 4, there was a greater reduction in diopter measurements in the treatment group compared to the control group. Furthermore, one month of treatment with CuSO4 resulted in diopter measurements similar to those observed in laser crosslinked corneas after one year.

[0072] Example 4 In vivo safety of copper eye drops 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 evaluation was performed using slit-lamp biomicroscopy and Heidelberg Spectralis anterior segment optical coherence tomography (AS-OCT). Two rabbits (n=4 eyes) were sacrificed at each of day 1, week 1, week 4, and week 6 to measure copper concentrations in ocular tissues and compare them to control (no instillation) 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 euthanasia solution and eyes were enucleated for histological evaluation and signs of inflammation, tissue damage, scarring and fibrosis. The anterior segments of the eyes were fixed in 10% formaldehyde-glutaraldehyde solution, dehydrated in graded alcohols, embedded in paraffin and sectioned on a microtome. Sections were stained with appropriate stains (hematoxylin and eosin and Masson's trichrome).

[0074] There was no effect on electroretinogram (ERG) measurements from treatment with Cu. Furthermore, no toxicity was observed in any of the dissected ocular tissues. Furthermore, no corneal opacification was observed, whereas laser crosslinking can cause corneal opacification for up to approximately one year. These results are further illustrated in Figures 5A-5B. Figure 5A shows images of hematoxylin and eosin stained corneas after 6 weeks of Cu treatment. Figure 5B shows images of hematoxylin and eosin stained retina / choroids after 6 weeks of Cu treatment.

[0075] Example 5 Copper treatment induces central corneal flattening in healthy rabbit corneas in vivo Right eyes (n=3) of New Zealand White rabbits were treated with 0.0016 mg / ml CuSO4 three times daily for 24 days. Left eyes were treated with BSS (TID) for 24 days and served as controls. Corneal OCT photographs were taken at baseline and on day 24.

[0076] As shown in Figures 6A-6F, representative OCT images demonstrated reproducible results, with the central cornea of ​​the right eye (treated with CuSO4) exhibiting corneal flattening in all three treated eyes shown in Figures 6D, 6E, and 6F (see arrows) compared to the control eye shown in Figures 6A, 6B, and 6C. This is due to increased cross-linking activity. Furthermore, the corneal epithelial layer was intact as shown by OCT, suggesting that there was no significant toxicity to the cornea. Slit lamp examination revealed no inflammation or opacification.

[0077] Example 6 Copper treatment slows the progression of spontaneous 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-h light / 12-h dark cycle. Eye drops containing 0.0025 mg / ml CuSO4 pentahydrate in phosphate-buffered ophthalmic solution were administered to the right eyes (OD) of albino guinea pigs at approximately 2 weeks of age (n=4). The left eyes (OS) received control drops (ophthalmic vehicle only). Eye drops (approximately 30 μL) were administered three times daily for approximately 6 weeks. Refractive errors were measured by a pediatric ophthalmologist before treatment on day 1 and at subsequent time points, according to the schedule shown in Figures 7A-7B. In more detail, refractive errors were measured by streak retinoscopy in handheld awake animals in which cycloplegia had previously been induced with approximately 2 drops of 1% cyclopentolate. Figures 7A-7B present the subjects' mean refractive error measurements for each eye with error bars and linear fits, respectively. As is evident from Figures 7A-7B, copper treatment was effective in reducing myopia progression in the treated eyes. Furthermore, histopathological analysis indicates that no toxicity was observed in the dissected eyes and IOP measurements were within the normal range of 15-25 mmHg for all eyes in the study (data not shown).

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

[0079] It should be understood that the above methods are merely illustrative 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. Thus, while the present invention has been described above with specificity and detail in connection with what are currently considered to be the most practical and preferred embodiments of the present invention, it will be apparent to those skilled in the art that modifications, including those that are not departing from the principles and concepts described herein, may be made.

Claims

1. 1. An ophthalmic composition for use in a method for treating or preventing the progression of myopia, said ophthalmic composition being administered in a therapeutically effective amount to an eye of a subject for a treatment period; The ophthalmic composition comprises: copper perchlorate as the sole copper-containing agent in an amount sufficient to increase corneal lysyl oxidase activity in the subject's eye in an amount sufficient to treat the progression of myopia; A pharma- ceutically acceptable carrier; The composition of matter according to the present invention has the following structure:

2. 10. The composition of claim 1, wherein the ophthalmic composition is configured to deliver, on average, from about 0.0001 μg to about 5500 μg of copper per day to the eye of the subject.

3. 10. The composition of claim 1, wherein the copper-containing agent is present in the composition in an amount of about 0.000001% to about 15% by weight.

4. 10. The composition of claim 1, wherein the amount of copper present in the composition is from about 0.00001 mg / ml to about 1 mg / ml.

5. 10. The composition of claim 1, further comprising an additional active ingredient.

6. 6. The composition of claim 5, 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, mandarin orange, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatopine, cyclopentolate, pirenzepine, 7-methylxanthanine, and combinations thereof.

7. 7. The composition of claim 6, wherein the additional active ingredient is present in an amount of about 0.001% to about 0.1% by weight of the composition.

8. 10. The composition of claim 1, wherein the pharma- ceutically acceptable carrier comprises at least one of a tonicity agent, a solubilizer, a viscosity agent, a polymer, a buffer, a preservative, a pH adjuster, and water.

9. 10. The composition of claim 1, wherein the composition has a tonicity of about 200 mOsm / kg to about 600 mOsm / kg.

10. The composition of claim 1, wherein the composition has a pH of about 5.5 to about 8.

5.

11. 11. The composition of any one of claims 1 to 10, 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.

12. 12. The composition of claim 11, wherein the ophthalmic composition is formulated as a solution.

13. 13. The composition of claim 12, wherein the solution is formulated as an eye drop and is delivered in a container adapted to dispense the composition dropwise in a drop volume of about 5 μl to about 100 μl.

14. 14. The composition of claim 13, wherein the eye drop provides from about 0.0001 μg to about 500 μg of copper per drop of the ophthalmic composition.

15. 15. The composition of claim 14, wherein the composition is administered 1 to 4 times per day to each eye in need thereof.

16. 16. The composition of claim 15, wherein about 5 μl to about 100 μl of the composition is administered at each time point.

17. 12. The composition of claim 11, wherein the composition is administered in association with an eye plastic device configured to reshape an elongated myopic eye.

18. 12. The composition of claim 11, wherein the subject is a human subject between about 3 and about 25 years of age.

19. 12. The composition of claim 11, wherein the treatment period is from about 6 months to about 5 years.

20. 1. An ophthalmic composition for treating the progression of myopia, comprising: Copper perchlorate as the only copper-containing agent in a lysyl oxidase modulating amount sufficient to treat the progression of myopia; A pharma- ceutically acceptable carrier; A composition comprising:

21. 21. The composition of claim 20, wherein the ophthalmic composition is configured to deliver, on average, from about 0.0001 μg to about 5500 μg of copper per day to the eye of a subject.

22. 21. The composition of claim 20, wherein the copper-containing agent is present in the composition in an amount of about 0.000001% to about 15% by weight.

23. 21. The composition of claim 20, wherein the amount of copper present in the composition is an amount from about 0.00001 mg / ml to about 1 mg / ml.

24. 21. The composition of claim 20, further comprising an additional active ingredient.

25. 25. The composition of claim 24, 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, mandarin orange, fibromodulin, type VI collagen, type X collagen, type XII collagen, type XIV collagen, atropine, homatopine, cyclopentolate, pirenzepine, 7-methylxanthanine, and combinations thereof.

26. 26. The composition of claim 25, wherein the additional active ingredient is present in an amount of about 0.001% to about 0.1% by weight of the composition.

27. 21. The composition of claim 20, wherein the pharma- ceutically acceptable carrier comprises at least one of a tonicity agent, a solubilizer, a viscosity agent, a polymer, a buffer, a preservative, a pH adjuster, and water.

28. 21. The composition of claim 20, wherein the composition has a tonicity of about 200 mOsm / kg to about 600 mOsm / kg.

29. 21. The composition of claim 20, wherein the composition has a pH of about 5.5 to about 8.

5.

30. 30. The composition of any one of claims 20 to 29, 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.

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