Compositions and methods for preventing or delaying onset of myopia comprising atropine

Abstract

Methods of preventing or delaying the onset of myopia in a pre-myopia patient and of reducing or preventing the progression of myopia in a low-myopia patient by using a composition comprising less than 0.025% atropine are disclosed.

Description

[0001] This application is a divisional application of an invention patent application with an application date of February 20, 2018, application number 201880025791.X, and invention name “Compositions and methods containing atropine for preventing or delaying the onset of myopia”.

[0002] Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 461,723, filed on February 21, 2017. The entire contents of the aforementioned provisional patent application are incorporated herein in their entirety for all purposes. Technical Field

[0004] The present application relates to methods of preventing or delaying the onset of myopia and methods of reducing or preventing the progression of myopia by administering a composition comprising very low concentrations of atropine. Background Art

[0005] Myopia, also known as nearsightedness or short sightedness, is a refractive error of the eye in which visual images are focused in front of the retina, often resulting in blurred vision of distant objects. Myopia is particularly prevalent among Asians, reportedly as high as 70-90% in Asian countries. Myopia can be corrected with medical lenses (e.g., glasses or contact lenses) or refractive surgery (e.g., LASIK or phakic intraocular lens implantation).

[0006] Patients with higher degrees of myopia are at higher risk of developing vision-threatening diseases such as degenerative retinal changes such as peripheral lattice changes, tears and detachments, myopic choroidal neovascularization, myopic macular holes and perforations, posterior staphylomas, myopic macular degeneration, early-onset cataracts (ages 30 to 40), open-angle glaucoma, peripapillary atrophy, and optic disc tilt and depression. If not properly treated, these diseases may lead to vision loss later in life. Children with early-onset myopia are more likely to eventually develop high myopia. Data from a recent Singapore paper on adults in Singapore, China, India, and Malaysia showed that the pathological symptoms of myopia, especially staphylomas and chorioretinal atrophy, worsen with age, myopic refraction, and axial length (Chang et al (2013)). As such, controlling the development and progression of myopia in patients during childhood so that the final myopia is lower than otherwise (e.g., -5.00D instead of -10.00D) will have a significant beneficial impact on the lives of patients. Summary of the invention

[0007] The present application relates to preventing or delaying the onset of myopia before its onset, or preventing or reducing the progression of myopia using a composition comprising very low concentrations of atropine.

[0008] In one aspect, the present disclosure provides a method for preventing or delaying the onset of myopia, comprising administering to the eye of a subject a composition comprising less than 0.025% atropine. In some embodiments, atropine is present in the form of atropine sulfate. In some embodiments, the composition comprises about 0.01% atropine. In some embodiments, wherein the composition comprises about 0.001% to 0.0249% atropine. In some embodiments, the composition comprises about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021%, 0.022%, 0.023%, 0.024%, 0.0245%, or 0.0249% atropine. In some embodiments, the subject is 4 to 21 years old. In some embodiments, the subject is 5 to 9 years old. In some embodiments, the subject suffers from pre-myopia.

[0009] In some embodiments, the composition is applied every other day, or at least once a day, or at least twice a day. In some embodiments, each application is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid. In some embodiments, the application continues for a period of at least six months, one year, two years, three years, four years, five years, six years, seven years, ten years, or longer.

[0010] In some embodiments, the composition further comprises at least one pharmaceutically acceptable excipient. In some embodiments, at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose. In some embodiments, benzalkonium chloride is present in the composition at a concentration of about 0.01%. In some embodiments, hydroxypropyl methylcellulose is present in the composition at a concentration of about 1%. In some embodiments, there is no preservative excipient in the composition.

[0011] In some embodiments, prior to administration of the composition, the spherical equivalent (SE) of the eye is in the range of +1.00 D to -0.49 D. In some embodiments, the SE is measured by an autorefractometer after administration of the ciliary muscle paralysis.

[0012] In some embodiments, the subject has no astigmatism or has no more than 1.50D of astigmatism as measured by cycloplegic or non-cycloplegic autorefraction prior to administration of the composition.

[0013] In some embodiments, during administration of the composition, the pupil of the eye does not dilate or dilates no more than 2 mm, e.g., no more than 1.9 mm, no more than 1.8 mm, no more than 1.7 mm, no more than 1.5 mm, no more than 1.49 mm. In some embodiments, the eye has no clinically significant loss of accommodation or experiences no more than 10D of loss of accommodation, e.g., no more than 9D, no more than 8.5D, no more than 8.8D, or no more than 8D. In some embodiments, the eye has no clinically significant loss of near visual acuity from loss of accommodation.

[0014] In some embodiments, the myopia onset is delayed by greater than 6 months, 12 months, 18 months, two years, three years, five years, six years, eight years, or longer.

[0015] In another aspect, the present disclosure provides a method for reducing or preventing myopia progression, comprising applying a composition comprising less than 0.025% atropine to the eye of a subject, wherein the composition is applied no more than once every two days, once every three days, or once every four days. In some embodiments, each application is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid. In some embodiments, before applying the composition, the SE of the eye is less than -1.50D. In some embodiments, before applying the composition, the SE of the eye is in the range of -0.50D to -1.50D. In some embodiments, the subject is between 4 and 21 years old. In some embodiments, the subject is between 5 and 9 years old. In some embodiments, atropine is present in the form of atropine sulfate. In some embodiments, the composition comprises about 0.001% to 0.0249% atropine, for example, about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245%, or about 0.0249% atropine. In some embodiments, the composition further comprises at least one pharmaceutically acceptable excipient. In some embodiments, at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose. In some embodiments, there is no preservative excipient in the composition.

[0016] In some embodiments, the average change in SE during the two years after the start of the composition is reduced by at least 20% compared to the control. In some embodiments, the treatment patient, such as a patient with anterior myopia, reduces the refractive change by at least 10%, at least 20%, at least 30%, or at least 40%, or at least 50%, for example, at least 53%, within 2 weeks, 1 month, 2 months, 6 months, one year, two years or more from the start of treatment. In some embodiments, the treatment patient, such as a patient with anterior myopia, reduces the increase in axial length by at least 10%, at least 15%, at least 20%, at least 30% within 1 week, 2 weeks, 1 month, 2 months, 6 months, one year, two years or more from the start of treatment. In some embodiments, the treatment patient, such as a patient with anterior myopia, can reduce the refractive change by at least 10%, at least 20%, at least 30%, or at least 40%, or at least 50%, for example, at least 53%.

[0017] In some embodiments, compared to the control, the administration of the atropine composition disclosed herein reduces the refractive change (i.e., myopic refractive error shift) by at least 10%, for example, at least 20%, at least 30%, or at least 40%, at least 50%, or at least 53%. In some embodiments, compared to the control, the patient treated with the composition disclosed herein, such as a patient with pre-myopia, reduces the rate of myopia progression or myopic shift rate after the onset of myopia by at least 10%, for example, at least 20%, at least 30%, or at least 40%, at least 50% or at least 53%. In some embodiments, compared to the control, the length of the time period from the start of treatment to the onset of myopia in the patient treated with the composition disclosed herein is increased by at least 10%, for example, at least 20%, at least 30%, or at least 40%, at least 50% or at least 53%.

[0018] In some embodiments, during administration of the composition, the pupil of the eye does not dilate or dilates no more than 1.9 mm, no more than 1.8 mm, no more than 1.7 mm, no more than 1.5 mm, no more than 1.49 mm. In some embodiments, the eye does not lose accommodation or loses accommodation no more than 10D, such as no more than 9D, no more than 8.5D, no more than 8.8D, or no more than 8D.

[0019] The present disclosure also provides use of atropine in preparing a composition for preventing or delaying the onset of myopia progression, and the composition comprises less than 0.025% atropine.

[0020] The present disclosure also provides use of atropine in the preparation of a composition for reducing or preventing myopia progression in a subject with SE less than -1.50D, wherein the composition comprises less than 0.025% atropine, wherein the composition is administered no more frequently than once every two days.

[0021] Also provided herein is the use of a composition in a method for preventing or delaying the onset of myopia progression, wherein the composition comprises less than 0.025% atropine. In some embodiments, the composition comprises 0.001% to 0.0249% atropine.

[0022] Also provided herein is a method for reducing or preventing progression of myopia in a subject, wherein the composition comprises less than 0.025% atropine, wherein the composition is administered no more than once every two days. In some embodiments, the subject's SE is less than -1.50 D. In some embodiments, the subject's SE is less than -0.50 D. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1A and Figure 1BThe effects of atropine treatment on axial elongation and refractive error are shown separately.

[0024] Figure 2 is a schematic diagram of a flow chart illustrating the study design of ATOM3.

[0025] FIG. 3A to FIG. 3B Shown are the effects of pretreatment with 0.01% atropine on ocular biometrics of lens-induced myopia in C57BL / 6J mice. DETAILED DESCRIPTION

[0026] Several studies on myopia control (preventing myopia progression) have included the use of agents in the form of contact lenses, glasses, and topical eye drops, primarily involving the use of atropine or antimuscarinics. All of these forms of myopia control therapy aim to slow the progression of myopia in children who have already become myopic.

[0027] Previously, the Atropine Management Myopia Study (ATOM) trials ATOM1 and ATOM2 involved young children aged 6 to 12 years who were already myopic, had an SE of at least -2.00D and were improving in myopia prior to study recruitment. Various concentrations of atropine have been shown to be effective in preventing or reducing progression of myopia in these children when administered at least once daily. See, e.g., WO2012 / 161655.

[0028] However, no clinical trials have been conducted to date to evaluate the feasibility of using very low concentrations of atropine to prevent the onset of myopia before it develops. No studies have been conducted to evaluate the effect of using a composition comprising very low concentrations of atropine no more frequently than every other day on the progression of myopia.

[0029] The present application relates to the use of a composition comprising a very low concentration of atropine to prevent or delay the onset of myopia before it occurs, and also to the use of the composition no more frequently than once every two days to reduce myopia progression after the patient has developed low myopia.

[0030] definition

[0031] Unless otherwise indicated, all concentration units refer to weight / volume. When a value of a parameter is stated to be within a range, the value of the parameter can be the lower or upper limit, or any value therebetween.

[0032] Unless otherwise specified, whenever the language indicates that the SE value is greater than or higher than a negative reference value, this means that the SE value is negative and its absolute value is greater than the absolute value of the negative reference value. For example, an SE value greater than -0.5D may be -1.0D.

[0033] Unless otherwise specified, whenever language indicates the expression "A+ / -B," A refers to the mean and B refers to the standard deviation ("SD"). For example, a dilation of 0.74+ / -0.75 mm means a mean dilation of 0.74 mm and a SD of 0.75.

[0034] When used in conjunction with a value, the term "about" refers to any value that is reasonably close to the value, that is, within ±10% of the value. In particular, it will include the value itself. For example, a value of 0.009% and a value of 0.011% are both considered to be "about 0.01%."

[0035] The term "myopia" refers to a condition in a patient wherein the patient has at least one eye with a SE value greater than -0.5 D, e.g. -1.0 D, -2.0 D. Depending on the context, "myopia" also refers to a condition in an eye with a SE value higher than -0.5 D.

[0036] The term "pre-myopia" refers to a condition in a patient where the patient has at least one eye with a SE value in the range of -0.49 D to 1.00 D. Depending on the context, myopia may also refer to a condition in an eye with a SE value in the range of -0.49 D to 1.00 D.

[0037] The term "low myopia" refers to a condition of a patient wherein the patient has at least one eye with a SE value in the range of -0.50 D to -1.50 D. Depending on the context, "low myopia" may also refer to a condition of an eye with a SE value in the range of -0.50 D to -1.50 D.

[0038] The term "high myopia" refers to a person having an SE value of at least one eye greater than -5.0 D. Depending on the context, "high myopia" may also refer to a condition in which the eye has an SE value greater than -5.0 D.

[0039] The term "drop" refers to a unit of measurement of volume that is equal to the amount dispensed in one drop from a dropper or dropper to the eye. Typically, one drop contains 20 to 100 microliters of liquid. In some cases, one drop contains 30 to 70 microliters of liquid, such as about 50 microliters of liquid.

[0040] The term "patient" or the term "subject" used interchangeably in this disclosure refers to any individual, regardless of the state of myopia. In some embodiments, the patient is a child between 5 and 12 years old, such as a child between 5 and 9 years old. In some embodiments, the patient is a child between 5 and 9 years old with pre-myopia.

[0041] The term "atropine composition" refers to a composition comprising atropine or an atropine salt (e.g., atropine sulfate or atropine acetate). Thus, where atropine is present in the form of a salt, such as atropine sulfate, the concentration of atropine refers to the weight / volume concentration of the atropine salt in the atropine composition.

[0042] As used herein, the term "unit dosage regimen" refers to physically discrete units suitable as unit doses for human subjects, each unit containing a predetermined amount of a compound (e.g., atropine as described herein) or a compound, calculated to be sufficient to produce the desired therapeutic effect. In some cases, a compound such as atropine is present in each unit together with a pharmaceutically acceptable diluent, carrier or vehicle. In some cases, each unit is free of preservatives.

[0043] Shortsighted

[0044] Refractive error refers to a condition in which the eye cannot bend light correctly, resulting in blurred images. The main types of refractive error include myopia (nearsightedness), hyperopia (hyperopia), presbyopia (loss of near vision with age), and astigmatism. Myopia is associated with axial elongation of the eye, which causes the eyeball to elongate and / or the cornea to become too curved. As axial elongation proceeds, the eyeball may become too long or the cornea (the transparent front cover of the eye) may be too curved, and as a result, the light entering the eye is not focused correctly, and distant objects appear blurry. Myopia also depends on the curvature of the cornea and the optical power of the lens. Although myopia can develop at any age, typically the onset of myopia occurs during elementary school age and progresses until the growth of the eye is complete.

[0045] Spherical equivalent (SE) is commonly used in ophthalmology clinics to assess myopia. Spherical equivalent is a single number in diopter, and can be defined as a spherical power whose focus coincides with the minimum confusion circle of a spherical cylindrical lens. SE is determined based on the values ​​of the sphere and cylinder of the eye, and is usually expressed as the sum of half of the sphere value and the cylinder value. Therefore, spherical equivalent is a convenient clinical method for representing data from several sources of refractive power. With the progression of myopia, the refractive power becomes negative - ametropia develops -, the axial length increases, and the absolute value of SE increases (SE becomes a more negative value). Myopia occurs due to the failure of the normal process of emmetropization, which is essentially endogenous to the eye. There is a mismatch between the focal length of the eye and the axial length, which is too long for the refractive power of the lens and cornea. Therefore, with the progression of myopia, the refractive power turns from hyperopia to myopia. In animal studies, myopia is usually assessed by measuring the refractive power (i.e., ametropia) in diopter and measuring the elongation of the axial length. Diopter is a unit of optical power equal to the reciprocal of the focal length of a given lens in meters. Refractive error varies in diopters for animal studies as well as in spherical equivalents in ophthalmology clinics.

[0046] Myopic patients have at least one eye with a spherical equivalent value ("SE") of -0.5D or higher, such as -2.0D or higher. The higher the absolute SE value, the higher the degree of myopia. Patients without myopia generally have a positive SE value or a negative SE value of less than -0.5D.

[0047] patient

[0048] In one aspect, the present disclosure provides a method for preventing or delaying the onset of myopia by administering a composition comprising a very low concentration of atropine to a subject. For this aspect of the invention, the subject is not myopic before atropine treatment, i.e., the SE of the eye is a positive value or a negative value less than -0.5 D. In some embodiments, the subject is in a pre-myopia stage before being treated with atropine, and they have a SE value in the range of +1.00 D to -0.49 D, e.g., 0.80 D to -0.49 D, or 0.50 D to -0.40 D.

[0049] In another aspect, the present disclosure provides a method for reducing or preventing myopia progression in a subject, comprising administering a composition comprising a very low concentration of atropine, the composition being administered to the patient at a frequency of no more than once every two days. In some cases, the subject has low myopia, i.e., has a negative SE value greater than -0.5D but less than -1.50D.

[0050] Patients who can benefit from atropine treatment disclosed herein can be of any age group. In some embodiments, the patient is at least 5 years old. In preferred embodiments, the patient is a child between the ages of 5 and 17, such as 5 to 12 years old, such as 5 to 9 years old. In some cases, the patient's age is between 5 and 6 years old or 7 to 9 years old. In some cases, the patient has no history of heart disease or severe respiratory disease. In some cases, the patient's distance vision is determined by the log Mar eye chart, and both eyes can be corrected to logMAR0.2 or better. In some cases, the normal intraocular pressure of the subject is determined to be no more than 21mmHg by tonometry. In some cases, the subject has at least one myopic parent. In some cases, except myopia or pre-myopia, the patient has normal eye health.

[0051] Methods that can be used to determine the eye health of a patient are well known. Non-limiting exemplary methods include slit lamp examination, fundus photography, intraocular lens (IOL) Mater biometry and / or ciliary muscle paralysis auto-optometry / auto-keratometry. In some cases, two, three, or all of the above methods are performed to assess the patient's eye health, including assessing the degree of myopia by determining the SE value.

[0052] atropine

[0053] Atropine is a non-selective muscarinic antagonist that degrades slowly, usually disappearing within 7 to 14 days. Currently, atropine is used as a ciliary muscle paralytic to temporarily paralyze the accommodation reflex to dilate the pupil. Atropine can also be used to treat many eye-related diseases, such as uveitis and early amblyopia, and was previously used to treat patients who already have moderate to high myopia, that is, patients with negative SE values ​​above -2.00D. In humans and mice, atropine can bind to five types of muscarinic receptors that are mainly present in scleral fibroblasts. These scleral fibroblasts are responsible for controlling scleral growth.

[0054] Throughout this disclosure, the term "accommodation amplitude" is used interchangeably with the term "accommodation" and refers to the eye's ability to focus on near objects. Atropine can cause systemic and local side effects, such as pupil dilation and decreased accommodation amplitude. The increase in pupil size causes an exponential increase in the amount of light entering the eye and may cause glare and photophobia. Excessive ultraviolet light entering the eye may increase the risk of cataracts or macular degeneration. The reduction in accommodation amplitude may reduce near vision, causing affected children to require bifocal or progressive glasses to read or see near objects.

[0055] The present disclosure provides a method for preventing or delaying the onset of myopia by administering a composition comprising a very low concentration of atropine to the eye. Also provided is a method for reducing or preventing the progression of myopia by administering a low concentration of atropine at a low frequency, i.e., no more than once every two days. The composition generally comprises less than 0.025% atropine, such as about 0.001% to about 0.0249% atropine, about 0.005% to about 0.002%, about 0.008% to about 0.015%, such as about 0.009% to about 0.012%. In a specific embodiment, the composition comprises about 0.01% atropine. In some embodiments, the composition comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245% or about 0.0249% atropine. In some embodiments, the atropine in the composition is present in the form of a salt such as atropine sulfate.

[0056] In some embodiments, treatment of a patient with a composition disclosed herein can delay the onset of myopia by greater than 1 month, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 12 months, greater than 18 months, greater than two years, greater than three years, greater than five years, greater than six years, or greater than eight years compared to a control. For the purposes of this disclosure, a control refers to an individual who has not been treated with an atropine composition disclosed herein. In a preferred embodiment, the individuals in the control group are from the same age group and the same pre-myopia or myopia stage as the individuals treated with a composition disclosed herein.

[0057] In some embodiments, treatment of a patient, such as a patient with anterior myopia, with a composition disclosed herein can reduce the increase in axial length (the length from the center of the cornea to the location on the retina where the image is clearest) by at least 10%, at least 15%, at least 20%, at least 30% within a period of one week to eight years (e.g., one month to five years, four months to four years, six months to three years, or one year to two years) from the start of treatment.

[0058] In some embodiments, compared with a control, a patient treated with a composition disclosed herein, such as a patient with pre-myopia, can reduce refractive change (i.e., myopic refractive error shift) by at least 10%, such as at least 20%, at least 30%, or at least 40%, at least 50%, or at least 53%. In some embodiments, compared with a control, a patient treated with a composition disclosed herein, such as a patient with pre-myopia, can reduce the rate of myopia progression or the rate of myopia shift after the onset of myopia by at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, or at least 53%. In some embodiments, compared with a control, a patient treated with a composition disclosed herein can increase the length of time from the start of treatment to the onset of myopia by at least 10%, such as at least 20%, at least 30%, or at least 40%, at least 50%, or at least 53%.

[0059] Pharmaceutical composition

[0060] In some embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and atropine, and a method of administering the composition to prevent or delay the onset of myopia or to reduce or prevent the progression of myopia.

[0061] Pharmaceutically acceptable excipients include carbohydrate or protein fillers, including but not limited to: sugars, including lactose, sucrose, mannitol or sorbitol; starch from corn, wheat, rice, potato or other plants; cellulose such as methylcellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth; and proteins such as gelatin and collagen. If necessary, disintegrants or solubilizers such as cross-linked polyvinyl pyrrolidone, agar, alginic acid or its salts, such as sodium alginate, can be added. In some embodiments, the pharmaceutically acceptable excipient comprises benzalkonium chloride in a concentration range of 0.005% to 0.02%, such as about 0.01%. In some embodiments, the pharmaceutically acceptable excipient comprises hydroxypropyl methylcellulose in a concentration range of 0.5% to 2%, such as about 1%. In some embodiments, the pharmaceutically acceptable excipient comprises both hydroxypropyl methylcellulose and benzalkonium chloride.

[0062] In some embodiments, the atropine composition is prepared in liquid form for ocular administration. Details of techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0063] Liquid form preparations include solutions, suspensions and emulsions, for example water or water / propylene glycol solutions. Solutions suitable for ocular administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, stabilizers, buffers, dispersants, solubilizers, preservatives and / or thickeners as desired. In some embodiments, the solution can be prepared by dispersing finely divided atropine in water with a viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth, and gum arabic, and a dispersant or wetting agent, such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, or benzalkonium chloride.

[0064] The pharmaceutical composition can be packaged in a unit dose regimen. This can reduce administration errors and contamination. In some embodiments, the pharmaceutical composition is a preservative-free composition in a unit dose regimen.

[0065] Also included are solid form preparations that are intended to be converted shortly before use to liquid form preparations for ocular administration. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also serve as a diluent, binder, preservative, tablet disintegrating agent, or encapsulating material.

[0066] The pharmaceutical preparations of the present disclosure can be provided as salts and can be formed with many acids, including but not limited to sulfuric acid, hydrochloric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble in aqueous or other protic solvents of the corresponding free base form. In other cases, the preparation can be a lyophilized powder in 1mM to 50mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, with a pH range of 4.5 to 5.5, and the lyophilized powder is combined with a buffer before use.

[0067] The pharmaceutical preparation is preferably in unit dosage form. In this dosage form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient atropine. The unit dosage form can be a packaged preparation that contains discrete quantities of the preparation, such as packaged tablets, capsules, and powders or solutions in droppers, vials or ampoules.

[0068] Application

[0069] Atropine compositions disclosed herein can be delivered to the eye via a topical route, formulated into solutions, suspensions, emulsions, gels, ointments, pastes, etc. In some cases, the atropine composition is formulated into a solution to be applied, one drop per eye at each application. Typically, one drop has a volume between 20 μL and 100 μL, such as 25 μL to 60 μL, such as 50 μL. The atropine composition can be applied at any time within 24 hours a day. In some cases, atropine solutions are applied to these patients once, twice or more a day to prevent or delay the onset of myopia in patients; especially those in the pre-myopia stage. In some cases, atropine solutions are applied every two days, every three days or every four days to reduce or prevent the progression of myopia in patients, especially those with lower myopia. In some cases, each application is performed by dripping at least one drop, at least two drops or at least three drops to the eye, wherein each drop contains about 20 to 100 microliters of liquid.

[0070] The duration of treating a patient (e.g., a child suffering from pre-myopia or low myopia) with atropine can vary according to the severity of the subject's condition and the subject's reaction to atropine. Typically, compositions disclosed herein include very low concentrations of, for example, about 0.01% atropine, which can be used for a very long period of time and will not cause clinically significant side effects. Therefore, treatment with atropine according to the present invention can last up to five years, six years, eight years, ten years or even longer. In some embodiments, the composition can be used for about 4 weeks to 10 years, more typically about 6 weeks to about 5 years, most typically about 1 year to 2 years. Suitable administration periods also include about 6 months to about 1 year, 18 months to 2 years, 9 to 16 months, 16 to 24 months, 16 to 32 months, 24 to 32 months, 24 to 48 months, 32 to 48 months, 32 to 52 months, 48 ​​to 52 months, 48 ​​to 64 months, 52 to 64 months, 52 to 72 months, 64 to 72 months, 64 to 80 months, 72 to 80 months, 72 to 88 months, 80 to 88 months, 80 to 96 months, 88 to 96 months, and 96 to 104 months. Suitable administration periods also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, and 50 months. Generally, administration of the atropine composition should be continued until a clinically significant improvement in the condition is observed.

[0071] In some embodiments, the administration of atropine compositions is not continuous and can stop one or more time periods, and then the administration is resumed for one or more time periods. Suitable time periods for administration cessation include 5 to 9 months, 5 to 16 months, 9 to 16 months, 16 to 24 months, 16 to 32 months, 24 to 32 months, 24 to 48 months, 32 to 48 months, 32 to 52 months, 48 ​​to 52 months, 48 ​​to 64 months, 52 to 64 months, 52 to 72 months, 64 to 72 months, 64 to 80 months, 72 to 80 months, 72 to 88 months, 80 to 88 months, 80 to 96 months, 88 to 96 months, 96 to 100 months. Suitable periods of time during which administration is discontinued also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 96, 96, and 100 months.

[0072] The atropine compositions disclosed herein may be used in combination with other active agents known to be useful in preventing the onset or progression of myopia, or with adjunct agents that may not be effective alone but may aid in the efficacy of atropine.

[0073] The atropine composition can be placed in a suitable container, such as a bottle or dropper, and labeled for use in treating a designated condition. For administration of the atropine composition, such labeling includes, for example, instructions regarding the amount, frequency, and method of administration.

[0074] Atropine compositions can also be prepared as unit doses containing an appropriate amount of the active ingredient atropine. The unit dosage regimen can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders, or a solution in a dropper, vial, or ampoule.

[0075] Determining the effects of atropine

[0076] The present disclosure provides a method for preventing or delaying the onset of myopia in a subject without myopia before treatment. The effect of atropine on preventing or delaying the onset of myopia can be evaluated by checking the eyes and determining the time when the patient first becomes myopic during regular, scheduled visits during treatment, i.e., when the patient's SE reaches about -0.5D or slightly above this time. The time is then compared with the time of onset of myopia in a control group that does not receive atropine treatment but receives vehicle placebo eye drops. The age and ethnic background of the control subjects are usually the same or very similar to those of the patients treated with atropine. Before the start of atropine treatment, the subjects in the control group may also have an eye health status comparable to that of the individuals in the treatment group. In a preferred embodiment, the individuals from the control group are pre-myopic and between 5 and 9 years old. The eye health of these individuals can be determined using the above method, and may include one or more of the following: measuring far and near logMar visual acuity, performing non-ciliary muscle paralysis automatic optometry / automatic keratometry, performing a coverage test, performing eyeglass measurements, measuring photopic pupil diameter, and measuring accommodative amplitude. In some embodiments, the data related to the time of myopia onset of the control is average historical patient data from an existing clinical database.

[0077] The eye health of patients selected for treatment is monitored at the beginning of treatment and during regular examinations during and / or after treatment. In some cases, patients are monitored during and / or after treatment, for example, every four months, every five months, every six months, every seven months, or every eight months. In some cases, patients are examined for eye health, including the degree of myopia at 6, 12, 18, 24, and 30 months after the start of treatment. Parameters that can be used to determine SE are also recorded at each visit, and SE values ​​are determined thereafter.

[0078] Pre-myopic subjects who have not received any treatment, such as children aged between 5 and 9 years old, usually develop myopia within 6 to 12 months. Treating patients with the composition disclosed herein can prevent or delay the onset of myopia. Typically, the composition comprises less than 0.025% atropine, such as about 0.001% to 0.0249% atropine. In a specific embodiment, the composition comprises about 0.01% atropine. In some embodiments, the composition comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245% or about 0.0249% atropine. In some embodiments, the atropine in the composition is present in salt form, such as atropine sulfate. In some cases, the patient does not develop myopia until two years, three years after being diagnosed with pre-myopia. In some cases, the onset of myopia is delayed by more than 6 months, 12 months, 18 months, 2 years, 3 years, 5 years, 6 years, 8 years or more compared to a control.

[0079] The present disclosure also provides a method for reducing or preventing myopia progression using the atropine composition disclosed above. In some cases, these patients have been diagnosed with low myopia. As with the effect of evaluating the composition on preventing or delaying the onset of myopia, the effect of preventing or delaying myopia progression can also be evaluated by regularly monitoring the patient before, during and / or after the atropine treatment period. During these examinations, ocular health parameters are obtained, and SE values ​​are determined, and compared with SE in the control over the same length of time period. In some cases, no SE changes are observed during and after treatment with a composition comprising a very low concentration of atropine, indicating that atropine treatment prevents the progression of myopia. In some cases, myopia still progresses and negative SE values ​​continue to increase, but compared with the increase in SE in the control, the increase is smaller, indicating that the progression of myopia is reduced. In some embodiments, atropine treatment over a period of time can reduce the average change in SE by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 80%, compared with the control of the same time period length. In some cases, the time period is six months, one year, two years, three years, five years, or six years, or longer.

[0080] The compositions disclosed herein contain very low concentrations of atropine, e.g., less than 0.025%, e.g., 0.01%, and they do not cause significant adverse effects, such as pupil dilation and / or loss of accommodation. The pupil dilation associated with treatment is generally no greater than 2 mm, e.g., no greater than 1.9 mm, no greater than 1.8 mm, no greater than 1.7 mm, no greater than 1.5 mm, or no greater than 1.49 mm. Typically, patients treated with the compositions disclosed above may experience a pupil dilation of 0.74+ / -0.75 mm. The loss of accommodation associated with treatment is also minimal, generally no greater than 10 D, e.g., no greater than 9 D, no greater than 8.5 D, no greater than 8.8 D, or no greater than 8 D. Typically, patients treated with the compositions disclosed above may experience a loss of accommodation of 4.6+ / -4.2 D.

[0081] Example

[0082] The following examples are for illustrative purposes only and should not be construed as limitations of the claimed invention. A variety of alternative techniques and procedures may be used by those skilled in the art that similarly allow the intended invention to be successfully performed.

[0083] Example 1. Inducing form deprivation myopia in mice

[0084] The mouse is a good preclinical model for evaluating pharmacological treatments for myopia because the mouse eye has a very similar structure and biochemistry to the human eye, and previous studies have validated the mouse model of myopia. The mouse eye also has similar pharmacological targets as those in the human eye. Results showed that topical administration of atropine before the eye undergoes a procedure to induce myopia can avoid some or all myopic changes. It has been shown that all muscarinic receptor types that are relevant in the fibroblasts of the tough outer connective tissue coating of the eye, the sclera, are similar for mouse and human eyes.

[0085] Typically, form deprivation myopia ("FDM") can be reliably produced in mice by attaching a -10D lens to the mouse eye for 6 weeks. This results in an increase in the axial length and refractive error of the mouse eye. In this procedure, the eye is treated with atropine once a day for 1 to 14 days before the -10D lens is placed on the eye. The initial experimental groups (n=8 / group) will include: a) atropine treatment is initiated on day 21, and no lens is placed and continued for 4 weeks; b) after two weeks of atropine treatment, a -10D lens is placed on day 35 and lens treatment is continued for 4 weeks; c) after one week of atropine treatment, a -10D lens is placed on day 35 and lens treatment is continued for 4 weeks; d) a -10D lens is placed on day 35 without prior atropine treatment and continued for 4 weeks; e) a control with no lens or atropine.

[0086] After the start of experimental treatment, mice will be monitored for changes in axial length and refractive error every two weeks using procedures as previously published. Refractive and biometric measurements will be performed every two weeks. Axial length will be measured using in vivo optical low-coherence interferometry (OLCI-AcMaster). Refraction will be measured by an automated decentered light reflector. Details of these methods have been described previously (Barathi VA & Beuerman RW, 2011; Barathi et al 2013).

[0087] Example 2. Effects of atropine eye drops before inducing form deprivation myopia in a mouse model

[0088] method:

[0089] Animals: Breeding pairs of B6J (Mice) mice were obtained from Jackson Lab and produced offspring. Newborn control animals were housed in groups of 6, while experimental animals were housed individually in standard mouse cages after 21 days of age at 25°C with a schedule of 12:12 hours of light-on and light-off, and mice had ad libitum access to pellets and water. Approval was obtained from the SingHealth Animal Care and Utilization Committee (IACUC), and all procedures performed in this study were in accordance with the Association for Research in Vision and Ophthalmology (ARVO) statement for the use of animals in ophthalmological and vision research.

[0090] Mouse myopia model: On day 21, a -10D contact lens (PMMA contact lens from Grey Tint, 8.5 mm diameter, 8 mm base curve, refractive index: 1.43, axial thickness: 0.5 mm) was placed on the right eye by sticking to a loop of Velcro and then to a matching piece of Velcro previously sutured to the periocular skin. The lens of the eyeglasses was cleaned daily in dim light, and the left eye was left uncovered and used as a control. All optical appliances were removed on day 63 after birth.

[0091] Treatment options:

[0092] Delayed FDM was induced in four groups of mice: Groups 1-4. Group 1 (n=6, 3 batches) received topical application of 10 μl of 1% atropine sulfate (ATG) daily on day 35 for 4 weeks, Group 2 (n=6, 3 batches) received topical application of 10 μl of 1% atropine sulfate (ATG) daily on day 21 for 2 weeks, and then induced myopia with -10D lenses (pATG+LIM) for 4 weeks, Group 3 (n=6, 3 batches) was treated with -10D lenses only to induce myopia (lenses were applied on day 21 and continued for 6 weeks), Group 4 (n=3 [both eyes were blank controls ( 3 groups) were used as non-immune controls. The right eye was used as the experimental eye in all groups, and the left eye was used as the contralateral control. It is noted that experimentally induced myopia in mice has been found to have a contralateral effect of induction and drug intervention.

[0093] Ocular biometric assessments: Refraction and biometric measurements were recorded weekly until the end of the study. Axial length was measured using in vivo optical low-coherence interferometry (OLCI-AcMaster). Refraction was measured by an automated decentered light reflector. Details of these methods have been described previously (Barathi VA et al., 2013; Barathi VA & Beuerman RW, 2011).

[0094] Statistical analysis: Statistical analysis was performed using SPSS software (Version 11.0, Chicago, 145 USA). The results are expressed as mean ± standard error (SEM). All values ​​of the lens-induced eyes were statistically compared with all values ​​of the contralateral eyes within the same group using paired sample t-test. The mean inter-eye difference was used for independent sample t-test between the experimental group and the normal group. Statistical analysis between groups was performed by one-way analysis of variance (ANOVA), and statistical significance was considered when P < 0.05.

[0095] result :

[0096] Atropine treatment that delays the induction of myopia is effective in reducing the effects on axial length and refraction that would otherwise occur. Eyes that received atropine sulfate for 2 weeks before inducing myopia (-10D lenses for 4 weeks) maintained hyperopia ( Figure 1B , p<0.01). However, this was significantly different compared to -10D lens treatment without prior atropine. Additionally, these results were associated with lower degrees of hyperopia compared to eyes treated with 1% atropine. This result suggests that atropine pretreatment reduced the progression of myopia.

[0097] Atropine treatment reduced axial elongation: spectacle lens induction over a 35-day period resulted in statistically significant axial elongation compared with contralateral control eyes ( Figure 1A , p<0.01, n=18).

[0098] Group 2, as a preventive measure against induced myopia, received daily application of 1% atropine to block most of the elongation of the axial length, with spectacle lens-induced myopia ( Figure 1A , p<0.01, n=18), but did not significantly affect the rate of axial elongation compared with eyes treated with 1% atropine daily (p=0.114). There were no significant differences in biometric measurements between blank and contralateral control eyes.

[0099] Changes in refractive error during atropine treatment: In the eye wearing only -10D lenses, refraction shifted from hyperopia to myopia 6 weeks after induction ( Figure 1B , p<0.01, compared with contralateral control, n=18). Before induction of myopia (wearing -10D lenses for 4 weeks), the eye that received atropine sulfate for 2 weeks was hyperopic ( Figure 1B , p<0.01) and was significantly different compared to the -10D lens treatment. However, this was less hyperopia compared to the 1% atropine treated eyes. This result suggests that atropine prevention treatment reduced the progression of myopia.

[0100] No significant differences were observed in the contralateral control eyes compared to the blank control eyes. Example 3 Effects of 0.01% atropine in a mouse model

[0101] method

[0102] Animals: Three-week-old C57BL / 6J mice were purchased from InVivos, Singapore, and housed in the Animal House Unit of the Singapore Health Laboratory Medicine Centre. The experimental animals were housed individually in standard mouse cages at 25°C with a schedule of 12:12 h light on (325 lx) and off (0 lx), and mice had ad libitum access to pellets and water. All procedures performed in this study were in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the SingHealth IACUC. Both eyes of each animal were screened for ocular abnormalities such as corneal opacities and anterior polar cataracts. Animals with any form of ocular abnormalities (approximately 10%) were removed from the study.

[0103] Mouse model of experimental myopia: On postnatal day 35, a spectacle lens-induced myopia model was established by placing a -15D hard lens on the right eye of the animal as the experimental eye. Briefly, a -15D lens (blue-tinted PMMA spectacle lens, outer radius of curvature 8.5, inner curvature 8mm, lens thickness 0.5mm, Flexilens, India) was bonded to a Velcro ring (with an 8mm base curve). The fitting was then attached to Velcro, which had previously been glued to the hair around the right experimental eye using cyanoacrylate (Super Glue gel, UHU, Germany). This setting ensures that there is an air gap of 1.5mm between the back of the lens and the anterior surface of the cornea, so that the contact lens optically acts as a spectacle lens. In the experimental study, the right eye of the blank group was attached with a flat lens and served as a negative control. Both eyes of each animal were checked daily for any infection, and the lenses were also cleaned regularly under dim red light. In this study, the left eye remained uncovered and was not used for any eye biometric measurements. During lens induction, an Elizabethan collar made of thin plastic was mounted around the neck of each mouse. This was done to prevent the mice from removing their lenses. Food pellets were placed on the floor of the cage to make eating easier. This strategy was previously followed by other groups in their lens-induced myopia mouse model (Schaeffel et al., 2004).

[0104] Treatment regimen: A total of 27 mice were divided into 4 different groups as described in Table 1 below. Group 1 and Group 2 were treated with vehicle and 0.01% atropine, respectively, starting on postnatal day 22 and continuing for 2 weeks until postnatal day 35. 7 μL of drug was topically applied to the right eye under dim red light at the same time each day. Lens (-15D or plano) induction was then performed on postnatal day 35, which remained attached until day 49.

[0105]

[0106] result

[0107] Ocular biometrics, such as axial length (AL) and refraction measurements, were measured as described in Example 2. Measurements were performed before and 2 weeks after lens induction, on days 35 and 49, respectively. See Table 2. Data were analyzed using GraphPad Prism software version 7.02. Changes in AL and refraction between any two groups were analyzed using independent unpaired t-tests. Differences with p values ​​< 0.05 were considered statistically significant. Data are reported as mean + / - SEM. Body weight was recorded on days 22, 35, and 49 after birth. Neither medication (atropine and vehicle) nor lens treatment adversely affected body weight at any given time. Changes in AL and refraction on day 49 relative to measurements on day 35 are shown in Table 2, Table 2. Figure 3A and Figure 3B The results, expressed as mean + / - SEM (n = 6 / 7 per group), showed that -15D lens induction for 2 weeks resulted in a change in myopic diopter (from 1.22D + / - 0.89 to -2.97D + / - 0.44; two-tailed p-value = 0.0083) relative to the blank group in mice, and an increase in AL of the experimental eyes by ∼22% (from 0.087mm + / - 0.005 to 0.106mm + / - 0.008; two-tailed p-value = 0.0606). Topical application of 0.01% atropine for 2 weeks prior to lens induction reduced the increase in AL in lens-induced myopic eyes by ∼15% compared to myopic eyes of vehicle-pretreated mice (the mean of AL change decreased from 0.108mm + / - 0.007 in Group 1 to 0.092mm + / - 0.008 in Group 2; two-tailed p-value = 0.1557). In addition, 0.01% atropine pretreatment can also induce a refractive shift from myopia to hyperopia 2 weeks after defocused eye compensation achieved by -15D lenses (changes in refractive measurements between postnatal days 35 and 49 were -2.89D+ / -0.59 and -1.33D+ / -0.82 in Group 1 and Group 2, respectively; two-tailed p-value = 0.1483). In addition, vehicle treatment did not have any effect on ocular biological changes in the lens-induced myopia model (two-tailed p-values ​​were 0.8712 and 0.6341 for changes in AL and refraction, respectively). In summary, these results indicate that pretreatment with 0.01% atropine in growing eyes can minimize the development of lens-induced experimental myopia in mice.

[0108]

[0109] Example 4. ATOM3 Research

[0110] 1. Study population

[0111] 1.1 List the number and nature of subjects to be enrolled

[0112] Eligible children, aged 5 to 9 years, 420 were pre-myopic (SE -0.49D to 1.00D) and 150 had low myopia (SE -0.50D to -1.50D). Pre-myopic children were randomized to receive daily 0.01% atropine eye drops or placebo, and low myopic children were randomized to receive daily 0.01% atropine, alternate-day 0.01% atropine, or daily placebo.

[0113] 1.2 Recruitment criteria and procedures

[0114] Recruitment: The goal is to recruit 570 eligible children during the study period. Previously, the Singapore Eye Research Institute was able to recruit 400 myopic children in 1 year, but recruiting younger and pre-myopic children may be more challenging. When communicating with the public about the study, all researchers will develop and use standardized materials (such as brochures and letters) describing the study.

[0115] Recruitment strategies included recruiting doctors at eye clinics (at the Singapore National Eye Centre), during eye forums, media releases, advertisements, letters to doctors, optometrists or opticians, and letters to parents of myopic patients (e.g., at high myopia clinics).

[0116] 1.3 Inclusion criteria

[0117] Written informed consent has been obtained from the parents and assent has been obtained from the child

[0118] 5 to 9 years old

[0119] One of the parents is myopic (at least one eye <-3D)

[0120] Refractive error of +1.00D to -0.49D (pre-myopic children) and -0.50D to -1.50D (low-myopic children) measured by ciliary muscle paralysis autorefraction

[0121] Astigmatism measured by cycloplegic or non-cycloplegic autorefraction does not exceed 1.50D

[0122] · Distance vision in both eyes can be corrected to logMAR 0.2 or higher

[0123] Normal intraocular pressure does not exceed 21 mmHg

[0124] · Eyes are healthy except for myopia

[0125] ·Be in good health, with no history of heart disease or severe respiratory disease

[0126] The researchers determined that no regular use of medications for asthma was required in the past year

[0127] No allergic reaction to atropine, cyclopentolate, proparacaine and benzalkonium chloride 1.4 Exclusion criteria

[0128] Children with ocular pathology or systemic disease that may affect vision or refractive error

[0129] Any ocular disease that contraindicates topical atropine

[0130] Previous use of atropine or pirenzepine

[0131] ·Defects in binocular function or stereoscopic vision

[0132] Amblyopia or pronounced strabismus, including intermittent strabismus

[0133] Any other condition that would prevent compliance with the protocol, including unwillingness or avoidance of wearing contact lenses during the study

[0134] 2. Study Design

[0135] Design: Randomized, controlled, double-blind study

[0136] Participants: Eligible children, aged 5 to 9 years, 420 with pre-myopia (SE +1.00 to -0.49D) and 150 with low myopia (SE -0.50 to -1.50D). Pre-myopic children will be randomized to receive daily atropine 0.01% eye drops or placebo, and low myopic children will be randomized to receive daily atropine 0.01%, alternate-day atropine 0.01%, or daily placebo. Figure 2 .

[0137] 2.1 Randomization and blinding

[0138] Randomization will be performed using an internet-based procedure hosted by the Singapore Clinical Research Institute (SCRI). To minimize observational bias, this study is designed as a double-blind trial in which neither the study participants, the investigators responsible for measuring study outcomes, nor the optometrists are aware of the treatment being given. To achieve this goal, the following steps will be followed:

[0139] · Once the consent form is signed and the child is deemed eligible, he / she will be assigned a study number that does not indicate treatment assignment.

[0140] The randomized treatment drops used from the initial visit to month 30 (for pre-myopia) and month 24 (for low myopia) will be pre-labeled so that no one can separate the treatment drops from the placebo eye drops.

[0141] In the low myopia group randomized to receive atropine every other day, the number of days (odd or even) on which atropine is instilled will also be randomized.

[0142] All investigators and study team (except unblinded pharmacists or unblinded coordinators) will be masked to the type of treatment drops, as all drops that will be randomized from the initial visit to month 30 (for pre-myopia) and month 24 (for low myopia) will be pre-sorted and packaged in the same bottle before arrival at the clinic.

[0143] Parents or guardians are asked to seek advice only from the Clinic Coordinator or Coordinating Optometrist on matters relating to their child's treatment, such as any unusual side effects.

[0144] The children will initially be observed by an investigation team who will carry out the assessments. They will receive a cycloplegic in both eyes before seeing the investigators or commissioned optometrists involved in measuring the study outcomes.

[0145] • These researchers or commissioning optometrists will not make any measurements that would provide clues to the treatment given.

[0146] There will be four stratified groups based on the age of the subjects. Each group will have a different range of trial numbers:

[0147] Front myopia -

[0148] Group 1 (subjects aged 5 to 6 years) - trial numbering will start from 1001.

[0149] Group 2 (subjects aged 7 to 9 years) - trial numbering will begin in 2001.

[0150] Low myopia -

[0151] Group 3 (subjects aged 5 to 6 years) - trial numbering will start from 3001.

[0152] Group 4 (subjects aged 7 to 9 years) - trial numbering will begin from 4001.

[0153] Eligible children will be registered by the coordinating optometrist and assigned a trial number from the registration list according to the stratification group to which the child belongs (e.g. the first eligible subject aged 5 to 6 years (pre-myopia) will belong to the first group and be assigned trial number 1001, the next 1002 etc.). The assigned trial number will be recorded on the registration form.

[0154] 2.2 Study visits and procedures

[0155]

[0156]

[0157] 2.2.1. Screening visits and procedures

[0158] At the first / recruitment visit, the purpose and design of the study will be explained to parents and children. Parents and children will be counseled on their rights and responsibilities, and written informed consent will be obtained. Medical history (excluding any known existing ocular or systemic disease), medication allergy history (excluding possible allergy to drops), and parental myopia history will be obtained. Children will be screened for ocular pathology by assessing their distance and near logMar visual acuity, non-ciliary autorefraction / autokeratometry, cover testing, measurement of optometric pupil size, accommodative amplitude, and intraocular pressure measurement. If visual acuity with current glasses is >0.2, non-ciliary subjective refraction to assess best corrected far logMar VA will be performed.

[0159] If the child is unlikely to meet the inclusion / exclusion criteria for the study, the parents will be informed and no further testing will be performed. Parents will be advised to take their children to an ophthalmologist if there are ocular conditions that may require further investigation.

[0160] Other baseline assessment tests will be performed, such as cycloplegic autorefraction / autokeratometry, subjective refraction, slit-lamp examination, fundus photography, and IOL Master. The children will then be given the trial medication.

[0161] At each return visit, parents and children will be asked about eye drop use and whether any adverse events have occurred in the past 6 months. Difficulties with accommodation when performing near work and other activities, photophobia or sensitivity to outdoor light, and problems with daily activities will be determined. A diary of eye drop use and eye drop bottles (used and unused) will be collected.

[0162] Medical history review

[0163] At the first / recruitment visit, medical history (to exclude any known existing ocular or systemic disease), medication allergy history (to exclude possible allergy to the drops), and parental myopia history will be obtained.

[0164] Risk Factor Questionnaire

[0165] In the first 18 or 36 months, parents completed a questionnaire assessing myopia risk factors, which included environmental exposures (near work and outdoor activities) and familial risk factors (refractive status of parents and siblings).

[0166] Eyeglass measuring instrument

[0167] The spectacles meter will be used to assess current eyeglass prescriptions (if applicable).

[0168] Display far and near logMARVA

[0169] Visual acuity will be tested by an optometrist using distance and near logMAR VA charts.

[0170] Coverage Tests

[0171] The presence or absence of ocular alignment will be assessed by an optometrist at the baseline and month 6 visits using the distance and near cover-no-cover tests.

[0172] Auto-refraction and auto-keratometry

[0173] Autorefraction and automated keratometry will be tested at each visit using a tabletop autorefractometer, Canon RK. Five refractive error measurements will be performed in each eye.

[0174] Subjective refraction (non-cycloplegic / cycloplegic)

[0175] Vision testing using a combination of lenses will provide the best corrected visual acuity (BCVA).

[0176] Optic pupil size

[0177] Pupil size will be measured under photopic conditions (80 lux) using a desktop autorefractometer Canon RK.

[0178] Adjustment range

[0179] The magnitude of the adjustment will be measured using the RAF rule.

[0180] Intraocular pressure measurement

[0181] Intraocular pressure will be measured using a non-contact tonometer or a contact tonometer such as the I-care device.

[0182] Ciliary muscle paralysis eye drops

[0183] At each scheduled study visit, 1 drop of 0.5% procaine will be used to achieve ciliary muscle paralysis, followed by 3 drops of 1% cyclopentolate 5 minutes later. Complete ciliary muscle paralysis is considered to occur 30 minutes after the last drop of medication is applied.

[0184] Ciliary autorefraction and best-corrected visual acuity

[0185] Refractive error will be measured at baseline and at subsequent follow-up visits by ciliary muscle paralysis autorefraction using a Canon RK autorefractometer. Ciliary muscle paralysis autorefraction was chosen as the measurement tool for refractive error because of its reliability, validity, and objectivity, thus allowing standardized measurements over time.

[0186] At each visit, 5 refractive error measurements will be taken for each eye. For each of these 5 measurements, the spherical equivalent value will be calculated using the method of Thibos et al., and the mean spherical equivalent value will then be calculated and used as a measure of progression for each eye.

[0187] Slit lamp examination

[0188] A slit lamp examination will be performed by an ophthalmologist or a trained and certified optometrist. The health of the eye, iris, and lens surface will be assessed.

[0189] Fundus photography

[0190] Fundus photographs of the posterior pole will be obtained at baseline and at each annual visit. The health of the optic nerve, macula, and retina will be assessed by a trained optometrist, and all photographs will be reviewed by an ophthalmologist on the study team.

[0191] IOL Master

[0192] Non-contact local interferometry will be used to measure axial length. This is performed using the Zeiss IOL Master, which measures the length between the corneal vertex and the retinal pigment epithelium along the visual axis using a red fixed beam with a resolution of 12um and an accuracy of 5um. Five measurements will be taken per eye at each visit. The axial length measurement will be based on the average of the 5 values ​​when the maximum deviation between the maximum and minimum values ​​is 0.05mm or less. Other measurements that will be recorded simultaneously include anterior chamber depth and corneal curvature.

[0193] 2.2.2. Study visits and procedures

[0194] Baseline visit

[0195] The selected children will be given the following First / Screening Exam (by coordinating or researching an optometrist):

[0196] Eyeglass tester (if applicable)

[0197] Presentation of far and near logMar VA (with glasses, if applicable)

[0198] Long-range and short-range coverage testing

[0199] Non-cycloplegic autorefraction and autokeratometry

[0200] Non-ciliary muscle paralysis subjective refraction (if presenting distance logMar VA>0.2) and recording the best corrected distance VA

[0201] Photopic pupil diameter

[0202] Adjustment range

[0203] Intraocular pressure measurement

[0204] If the child still appears to meet the study inclusion / exclusion criteria,

[0205] Use of anesthetic and ciliary muscle numbing eye drops

[0206] · Ciliary muscle paralysis autorefraction and autokeratometry

[0207] Subjective refraction with ciliary muscle palsy and best corrected far ciliary muscle palsy logMar VA

[0208] Slit lamp examination

[0209] Fundus photography

[0210] IOL Master

[0211] Randomization and distribution of eye drops

[0212] Once randomized, the study optometrist or coordinator will weigh and dispense the allocated eye drops to the child and provide verbal and written information about the use of the eye drops to the parent / guardian and child.

[0213] Children in the former myopia group will receive 1 box of 6-8 bottles (1 bottle is used for one month).

[0214] Children in the low myopia group will receive 2 boxes, each box contains 6-8 bottles (2 bottles are used for one month, every other day).

[0215] Diary Table

[0216] A six-month diary form will be provided to all subjects' parents / guardians. Parents and children will be asked to tick a box for the dates when eye drops were used.

[0217] 4.2.2.2 Follow-up visit (6, 12, 18, 24 and 30 month visits)

[0218] program

[0219] The clinic coordinator will

[0220] Update history, including review of any side effects or problems with eye drops

[0221] Reviewing compliance, including asking parents / guardians whether they knew the type of treatment their children were being given

[0222] Collect and weigh used eye drop bottles and diaries from past visits

[0223] Risk Factor Questionnaire. Page 14. The optometrist coordinating the study visits and procedures listed on page 13 will

[0224] Update history (if not completed by clinical coordinator)

[0225] Measure far and near logMar VA (with glasses if applicable)

[0226] Conduct lens measurements (if applicable)

[0227] Perform coverage test (at 6-month visit)

[0228] ·Measurement of the amplitude of accommodation (at the 6, 12, and 24 month visits)

[0229] Measurement of photopic pupil diameter (at the 6, 12, and 24 month visits)

[0230] Perform intraocular pressure measurement (at the 6th, 12th, and 24th month visits)

[0231] ·Administer local anesthetics and cycloplegics

[0232] Research optometrists will

[0233] · Perform ciliary muscle paralysis autorefraction and autokeratometry

[0234] ·Perform subjective refraction with ciliary muscle paralysis

[0235] ·Measure the best corrected ciliary muscle paralysis logMAR distance visual acuity

[0236] ·Slit lamp examination (at annual visit)

[0237] Obtain fundus photography (at annual visit)

[0238] · Obtain biometrics through IOL Master

[0239] After the study optometrist's examination, the coordinating optometrist will

[0240] Review all forms for completeness and accuracy

[0241] A letter to the school and eyeglass prescription for your child, if necessary

[0242] Refill your child's eye drops (except for former myopia at the 30-month visit and low myopia at the 24-month visit)

[0243] Arrange an appointment for the next scheduled visit

[0244] For pre-myopia, children will stop eye drops from month 30 and receive a 6-month washout. Washout is an observation period after atropine cessation, assuming the drug is no longer present.

[0245] For low myopia, children will stop eye drops from the 24th month and receive flushing for 12 months.

[0246] 4.2.2.5 Access Scope

[0247] All follow-up visits will be scheduled within ±21 calendar days of the target date. All visits should fall within the window of that specific visit.

[0248] access Target Window Range Baseline visit (timing start point) Timing start point NA 6 Months Visit 180 days from the start of the countdown 159-201 days First Year Visit 360 days from the start of the countdown 339-381 days 18 Months of Access 540 days from the start of the countdown 519-561 days Second Year Visit 720 days from the start of the countdown 699-741 days 30 months of access 900 days from the start of the countdown 879-921 days Third Year Visit 1080 days from the start of the countdown Days 1059-1101

[0249] 2.2.3. Final study visit

[0250] 36 Month Visit / Exit Visit

[0251] The clinic coordinator will

[0252] Update History

[0253] Risk Factor Questionnaire

[0254] The coordinating optometrist will

[0255] Update history (if not completed by clinical coordinator)

[0256] Measure far and near logMar VA (with glasses if applicable)

[0257] Conduct lens measurements (if applicable)

[0258] ·Measure photopic pupil diameter

[0259] Measure the adjustment range

[0260] ·Administer local anesthetics and cycloplegics

[0261] Research Optometrists will:

[0262] · Perform ciliary muscle paralysis autorefraction and autokeratometry

[0263] ·Perform subjective refraction with ciliary muscle paralysis

[0264] ·Measure the best corrected ciliary muscle paralysis logMAR distance visual acuity

[0265] Perform a slit lamp examination

[0266] Obtain fundus photography

[0267] · Obtain biometrics through IOL Master

[0268] After the study optometrist's examination, the coordinating optometrist will

[0269] Review all forms for completeness and accuracy

[0270] A letter to the school and eyeglass prescription for your child, if necessary

[0271] 2.3 Stopping / Withdrawal

[0272] 2.3.1. Stopping criteria

[0273] Early stopping rule

[0274] Former myopic children:

[0275] If the evidence of efficacy or the lack of efficacy or strong evidence of efficacy makes it unethical to continue the study, early stopping may be considered.

[0276] Children with low myopia:

[0277] If there is evidence of non-inferiority of the lower-dose regimen, consideration will be given to stopping treatment early.

[0278] It is expected that some subjects may experience adverse events or drug reactions due to the eye drops. In these cases, the subject may choose to stop treatment. The researchers may also decide to withdraw a subject from the trial at any time if they believe that the subject's continued participation would be detrimental to their health. However, these subjects will be followed up for the treatment analysis.

[0279] 3. Test materials

[0280] The trial medication from the Baseline visit to the 30-month visit will be formulated as: 0.01% atropine

[0281] Active: Atropine sulfate 0.01%

[0282] Vehicle: Hydroxypropyl methylcellulose 1%

[0283] Preservative: Benzalkonium chloride 1:10000

[0284] Placebo

[0285] Activity: None

[0286] Vehicle: Hydroxypropyl methylcellulose 1%

[0287] Preservative: Benzalkonium chloride 1:10000

[0288] All trial drugs will be produced by Xepa-Soul Pattinson (M) Sdn Bhd.

[0289] 3.1 Test products

[0290] The study drug is a clear, colorless, sterile solution. The solution is supplied in a 5 ml plastic dropper bottle. The study drug contains the active ingredient atropine sulfate 0.01% w / v and the preservative benzalkonium chloride 0.01% w / v. The placebo contains no active ingredient and contains the preservative benzalkonium chloride 0.01% w / v. Appendix 3 contains the product instructions for atropine 0.01%.

[0291] 3.2 Storage and Drug Accountability

[0292] The study drug contained the active ingredients: atropine sulfate 0.01% w / v and the preservative benzalkonium chloride 0.01% w / v. The placebo contained no active ingredients and contained the preservative benzalkonium chloride 0.01% w / v. The solution was provided in a 5 ml plastic dropper bottle. The storage temperature of the study drug was below 30°C.

[0293] As a double-blind study, study medication used from the baseline visit to Month 30 (for pre-myopia) and Month 24 (for low myopia) will be labeled only with the trial number. Labeling will be completed by an independent pharmacist. Each labeled bottle will contain either atropine 0.01% or placebo. The label on each bottle will include the brief study title, the name of the eye drop bottle, the manufacturer's name and country of origin, batch number, trial number, expiration date, dosing frequency, storage conditions, and the words "For Clinical Trial Use Only."

[0294] Labeled bottles were distributed at each scheduled visit, from the baseline visit to the 24-month visit (for pre-myopia) and the 18-month visit (for low myopia).

[0295] 4. Treatment

[0296] 4.1 Study drug formulation

[0297] Composition of the trial drug

[0298] The test drug will be prepared as: 0.01% atropine

[0299] Active: Atropine sulfate 0.01%

[0300] Vehicle: Hydroxypropyl methylcellulose 1%

[0301] Preservative: Benzalkonium chloride 1:10000

[0302] Placebo

[0303] Activity: None

[0304] Vehicle: Hydroxypropyl methylcellulose 1%

[0305] Preservative: Benzalkonium chloride 1:10000

[0306] 4.2 Administration of Study Drug

[0307] Former myopia group: Place one drop into both eyes every night.

[0308] Low myopia group: one drop was dropped into each eye on odd-numbered days of the calendar marked as "odd nights", and one drop was dropped into each eye on even-numbered days of the calendar marked as "even nights".

[0309] 4.3 Special restrictions / requirements

[0310] During the study period, subjects were advised to avoid wearing contact lenses and other myopia treatments.

[0311] If a subject develops an upper respiratory tract infection / fever, study drug may be withheld and resumed after resolution of the adverse event.

[0312] If any ocular inflammation, infection, or injury occurred, study medication was discontinued until the adverse event resolved.

[0313] 4.4 Blinding

[0314] A sealed emergency envelope containing the randomisation intervention for each subject will be provided to the PI and kept in a secure cabinet at the Singapore Eye Research Institute. Designated staff with access to the envelope must be given clear instructions that the sealed code must be opened only in the event of an emergency medical situation where the intervention is required. If the sealed code for a particular subject is broken, the PI must record the reason for the code breakage and scan the intact envelope to SCRI immediately. The original form must then be provided to the SCRI Project Coordinator.

[0315] 5. Security Measures

[0316] 5.1 Definitions

[0317] An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship to that treatment.

[0318] A serious adverse event (SAE) or reaction is any untoward medical occurrence at any dose that: results in death; is life-threatening; requires hospitalization or prolongs existing hospitalization; results in persistent or severe disability / incapacity; is a congenital anomaly / birth defect; or is potentially life-threatening to the patient and may require medical or surgical intervention to prevent one of the above outcomes. Report all serious SAEs.

[0319] 6. Data Analysis

[0320] Data will be collected by a team of trained and authorized ophthalmologists, optometrists, nurses and coordinators.

[0321] 7. Sample size and statistical methods

[0322] 7.1 Determination of sample size

[0323] For the former myopic group of study participants:

[0324] Prevalence estimates: Data from 2 schools in the SCORM showed a 43% prevalence of myopia within 3 years (Saw et al, IOVS 2005). Based on the roughly linear change in spherical equivalent values ​​in the SCORM (Wong et al., IOVS 2010), the prevalence within 2.5 years is estimated to be 2.5 / 3 of 43%, which is about 35%. This should be a conservative estimate (underestimate) of the prevalence in the absence of intervention, because the target age group (5-9 years) is younger than the SCORM (7-9 years), and the prevalence is higher in younger age groups.

[0325] Effect size estimate: Comparing placebo control with 0.01% atropine in ATOM1 and ATOM2 (Chia et al., Ophth 2011), the risk ratio for myopia progression greater than 0.5D decrease over 2 years was approximately 0.6.

[0326] Sample size: Assuming the effect size of the risk ratio = 0.6 and the control incidence = 35%, n = 175 is required for each group for 80% power and 5% two-sided type 1 error rate. Assuming a 15% loss to follow-up (11% loss to follow-up for ATOM2), a sample size of approximately 210 is required for each group. The total sample size (two groups combined) is 420.

[0327] For the low myopia group of study participants

[0328] Correlation due to both eyes of each child: ATOM2 data showed that the correlation between SEs of the same child's two eyes caused a high design effect (1.74) (Chia et al. Opht 2011). Therefore, the analysis of both eyes of each child is only slightly more informative than the analysis of one randomly selected eye of each child. For the purpose of sample size planning, we conservatively assumed that each child had only one eye's worth of information.

[0329] Estimates of mean and SD of SE change: SCORM data (Saw et al. IOVS 2005) show that in low myopia (-3D to -0.5D), the mean 2-year change in SE is approximately -1.6D. The SD is approximately 0.67.

[0330] Effect size estimate: In ATOM1 and ATOM2, the average 2-year decrease in SE was approximately -1.2 D in placebo and -0.5 D in 0.01% atropine daily (Chia et al. Opht 2011), a decrease of approximately 58%. Administration of 0.01% atropine every other day and 0.01% atropine daily can reduce the average change in SE by at least 30% (i.e. 30% of 1.6 D = 0.48 D).

[0331] Sample size: Based on the above parameters, for 90% power and a two-sided 5% test, a minimum of 41 participants per aim is required to demonstrate the primary aim of efficacy of 0.01% atropine administered daily and 0.01% atropine administered every other day compared with placebo control. We will recruit 50 children with low myopia for each of the three study arms, bringing the total sample size to 150. This allows for approximately 15% dropouts.

[0332] 7.2 Statistics and Analysis Plan

[0333] All statistical analyses were based on the intention-to-treat principle.

[0334] In the prevention trial, the proportion of participants with positive myopia before the primary endpoint (SE < -0.5D) and secondary endpoint (SE < -1.5D or wearing glasses) at 2.5 years will be estimated with 95% confidence intervals (CI) for each group. The difference in proportions and their 95% CI will be estimated by a generalized linear model with a binomial distribution and an identity link function.

[0335] In the low myopia trial, the robust standard error of clustered data will be used for inference, and the data of both eyes will be analyzed together. The mean change in SE from baseline to 2 years between the 3 groups of low myopia participants and between each atropine group and the placebo group will be compared using a generalized linear model with a Gaussian distribution, a discriminant link function, and a Wald test. The difference in the mean change in SE between the every-other-day and every-day atropine groups (daily minus every-other-day) and its 90% CI will be estimated.

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[0510] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in view of them will be recommended to those skilled in the art, and will be included within the spirit and scope of the present application and the scope of the appended claims. All publications, serial accession numbers, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0511] Preferred Embodiments

[0512] 1. A method for preventing or delaying the onset of myopia comprising administering to an eye of a subject a composition comprising less than 0.025% atropine.

[0513] 2. The method according to claim 1, wherein the atropine is in the form of an atropine salt.

[0514] 3. The method according to item 2, wherein the atropine salt is atropine sulfate or atropine acetate.

[0515] 4. The method of claim 1, wherein the composition comprises about 0.01% atropine.

[0516] 5. The method of claim 1, wherein the composition comprises about 0.001% to 0.0249% atropine.

[0517] 6. The method of claim 1, wherein the composition comprises about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021%, 0.022%, 0.023%, 0.024%, 0.0245% or 0.0249% atropine.

[0518] 7. The method according to item 1, wherein the composition is applied every other day, or at least once a day, or at least twice a day.

[0519] 8. The method according to item 1, wherein each application is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid.

[0520] 9. The method according to all the preceding items, wherein the administration continues for a period of at least six months, one year, two years, three years, four years, five years, six years, seven years, ten years or longer.

[0521] 10. The method according to claim 1, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

[0522] 11. The method according to item 1, wherein the at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose.

[0523] 12. The method of item 11, wherein the benzalkonium chloride is present in the composition at a concentration of about 0.01%.

[0524] 13. The method according to item 11, wherein the hydroxypropyl methylcellulose is present in the composition at a concentration of about 1%.

[0525] 14. The method according to item 1, wherein the composition does not contain a preservative.

[0526] 15. The method according to item 1, wherein the subject is at least 5 years old.

[0527] 16. The method according to item 1, wherein before applying the composition, the spherical equivalent value (SE) of the eye is in the range of +1.00D to -0.49D.

[0528] 17. The method according to item 16, wherein the SE is measured by an autorefractometer after applying ciliary muscle paralysis.

[0529] 18. The method according to item 1, wherein the subject has no astigmatism or has no more than 1.50D of astigmatism prior to administration of the composition as measured by ciliary muscle paralysis or non-ciliary muscle paralysis autorefraction.

[0530] 19. The method according to item 1, wherein during the application of the composition, the pupil of the eye is not dilated or is dilated no more than 2 mm.

[0531] 20. The method according to item 1, wherein the eye has no accommodative loss or an accommodative loss of no more than 9D.

[0532] 21. The method according to any preceding item, wherein the subject has at least one myopic parent.

[0533] 22. The method of claim 1, wherein the onset of myopia is delayed by more than six months, twelve months, eighteen months, two years, three years, five years, six years, eight years or longer.

[0534] 23. A method of reducing or preventing the progression of myopia comprising administering to an eye of a subject a composition comprising less than 0.025% atropine, wherein the composition is administered no more frequently than once every two days, once every three days, or once every four days.

[0535] 24. The method according to item 23, wherein each application is performed by instilling at least one drop, at least two drops or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid.

[0536] 25. The method according to item 23, wherein the SE of the eye is less than -1.50D before applying the composition.

[0537] 26. The method according to item 25, wherein before applying the composition, the SE of the eye is in the range of -0.50D to -1.50D.

[0538] 27. The method according to item 23, wherein the subject is at least 5 years old.

[0539] 28. The method according to item 23, wherein the subject is 5 to 9 years old.

[0540] 29. The method according to item 23, wherein the atropine is in the form of atropine sulfate.

[0541] 30. The method of claim 23, wherein the composition comprises about 0.001% to 0.0249% atropine.

[0542] 31. A method according to claim 23, wherein the composition comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245% or about 0.0249% atropine.

[0543] 32. The method according to claim 23, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

[0544] 33. The method according to claim 32, wherein the at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose.

[0545] 34. The method of item 33, wherein the benzalkonium chloride is present in the composition at a concentration of about 0.01%.

[0546] 35. The method of item 33, wherein the hydroxypropyl methylcellulose is present in the composition at a concentration of about 1%.

[0547] 36. The method according to item 23, wherein the mean change in SE is reduced by at least 20% compared to the control over a period of two years after the start of administration of the composition.

[0548] 37. The method according to item 23, wherein during the application of the composition, the pupil of the eye is not dilated or is dilated no more than 2 mm.

[0549] 38. The method of claim 23, wherein the eye has no accommodative loss or an accommodative loss of no more than 9D.

[0550] 39. Use of a composition in a method for preventing or delaying the onset of myopia progression, wherein the composition comprises less than 0.025% atropine.

[0551] 40. Use of a composition according to item 39, wherein the composition comprises about 0.01% atropine.

[0552] 41. Use of a composition according to item 39, wherein the composition comprises 0.001% to 0.0249% atropine.

[0553] 42. Use of a composition in a method for reducing or preventing myopia progression in a subject having a SE less than -1.50D, wherein the composition comprises less than 0.025% atropine, wherein the composition is administered no more frequently than once every two days.

[0554] 43. Use of a composition according to item 39 or 42, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

[0555] 44. Use of a composition according to item 39, wherein the composition does not contain a preservative.

Claims

1. Use of a composition comprising less than 0.025% atropine in the preparation of a medicament for preventing or delaying the onset of myopia, wherein the medicament is formulated for administration to the eye of a subject.

2. The method according to claim 1, wherein the atropine is in the form of an atropine salt.

3. The use according to claim 2, wherein the atropine salt is atropine sulfate or atropine acetate.

4. The use according to claim 1, wherein the composition comprises about 0.01% atropine.

5. The use according to claim 1, wherein the composition comprises about 0.001% to 0.0249% atropine.

6. The use according to claim 1, wherein the composition comprises about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021%, 0.022%, 0.023%, 0.024%, 0.0245% or 0.0249% atropine.

7. The use according to claim 1, wherein the medicament is for administration every other day, or at least once a day, or at least twice a day.

8. The use according to claim 1, wherein each application is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid.

9. The use according to all preceding claims, wherein the administration continues for a period of at least six months, one year, two years, three years, four years, five years, six years, seven years, ten years or longer.

10. The use according to claim 1, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

11. The use according to claim 1, wherein the at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose.

12. The use according to claim 11, wherein the benzalkonium chloride is present in the composition at a concentration of about 0.01%.

13. The use according to claim 11, wherein the hydroxypropyl methylcellulose is present in the composition at a concentration of about 1%.

14. The use according to claim 1, wherein the composition is free of preservatives.

15. The use according to claim 1, wherein the subject is at least 5 years old.

16. The use according to claim 1, wherein the spherical equivalent value (SE) of the eye is in the range of +1.00D to -0.49D before administration of the medicament.

17. The use according to claim 16, wherein the SE is measured by an autorefractometer after administration of ciliary muscle paralysis.

18. The use according to claim 1, wherein the subject has no astigmatism or has no more than 1.50D of astigmatism as measured by cycloplegic or non-cycloplegic autorefraction prior to administration of the medicament.

19. The use according to claim 1, wherein during the administration of the medicament, the pupil of the eye is not dilated or is dilated no more than 2 mm.

20. The use according to claim 1, wherein the eye has no accommodative loss or an accommodative loss of no more than 9D.

21. The use according to any preceding claim, wherein the subject has at least one myopic parent.

22. The use of claim 1, wherein the onset of myopia is delayed by more than six months, twelve months, eighteen months, two years, three years, five years, six years, eight years or longer.

23. Use of a composition comprising less than 0.025% atropine in the preparation of a medicament for reducing or preventing the progression of myopia, wherein the medicament is formulated for administration to the eye of a subject no more frequently than once every two days, once every three days, or once every four days.

24. The use according to claim 23, wherein each application is performed by instilling at least one drop, at least two drops or at least three drops into the eye, wherein each drop contains about 20 to 100 microliters of liquid.

25. The use according to claim 23, wherein the SE of the eye is less than -1.50D before administration of the medicament.

26. The use according to claim 25, wherein the SE of the eye is in the range of -0.50D to -1.50D before administration of the medicament.

27. The use according to claim 23, wherein the subject is at least 5 years old.

28. The use according to claim 23, wherein the subject is 5 to 9 years old.

29. The use according to claim 23, wherein the atropine is in the form of atropine sulfate.

30. The use of claim 23, wherein the composition comprises about 0.001% to 0.0249% atropine.

31. The use of claim 23, wherein the composition comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245%, or about 0.0249% atropine.

32. The use according to claim 23, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

33. Use according to claim 32, wherein the at least one pharmaceutically acceptable excipient is selected from benzalkonium chloride and hydroxypropyl methylcellulose.

34. The use according to claim 33, wherein the benzalkonium chloride is present in the composition at a concentration of about 0.01%.

35. The use according to claim 33, wherein the hydroxypropyl methylcellulose is present in the composition at a concentration of about 1%.

36. The use according to claim 23, wherein the mean change in SE is reduced by at least 20% compared to a control over a two year period after initiation of administration of the medicament.

37. The use according to claim 23, wherein during administration of the medicament, the pupil of the eye is not dilated or is dilated no more than 2 mm.

38. The use according to claim 23, wherein the eye has no accommodative loss or an accommodative loss of no more than 9D.

39. A composition for preventing or delaying the onset of myopia progression, wherein the composition comprises less than 0.025% atropine.

40. The composition of claim 39, wherein the composition comprises about 0.01% atropine.

41. The composition of claim 39, wherein the composition comprises 0.001% to 0.0249% atropine.

42. The composition of claim 39, which reduces or prevents myopia progression in a subject with a SE less than -1.50D, wherein the composition comprises less than 0.025% atropine, wherein the composition is administered no more frequently than once every two days.

43. The composition of claim 39, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

44. The composition of claim 39, wherein the composition is free of preservatives.

45. A method for inducing a form deprivation myopia mouse model, comprising attaching a -10D lens to the mouse eye for 6 weeks.

46. ​​The method of claim 45, which results in an increase in axial length and refractive error in the eye of a mouse.

47. The method of claim 45 or 46 comprising placing a -10D contact lens on one eye and the other eye is left uncovered and used as a control.

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