Oral extended-release dosage form of 7- methylxanthine (7-MX) for the treatment of myopia

Abstract

The present invention relates to an oral extended-release dosage form of 7-methylxanthine (7-MX) or a pharmaceutically acceptable salt thereof. The dosage form is designed for twice-daily administration and provides controlled release of the active agent, achieving pharmacokinetic characteristics including sustained plasma concentrations and reduced fluctuation compared to immediate-release formulations. The invention further relates to the use of such dosage forms in the treatment of myopia, wherein the extended-release characteristics enhance therapeutic effectiveness in myopia.

Description

[0001] “ORAL EXTENDED-RELEASE DOSAGE FORM OF 7- METHYLXANTHINE (7-MX) FOR THE TREATMENT OF MYOPIA”

[0002] FIELD OF THE INVENTION

[0003] The disclosure generally relates to oral Extended-release dosage forms of ND 10 chemically known as 7 -methylxanthine (7-MX) useful in myopia. The oral Extended-release dosage form have desired pharmacokinetic characteristics.

[0004] BACKGROUND OF THE INVENTION

[0005] The ‘7-Methylxanthine’ or ‘7-MX’ also known or ND10 has the chemical formula C6H6N4O2 (IUPAC name 7-Methyl-3,7-dihydro-lH-purine-2, 6-dione).

[0006] The term ‘7-Methylxanthine’ or ‘7-MX’ should be understood, unless otherwise indicated herein, to include any pharmaceutically acceptable form and salts of the compound. The 7-MX may be present in a crystalline, amorphous form or mixtures thereof. The 7-MX, salts of 7-MX, methods for synthesizing 7-MX, are disclosed in various literature.

[0007] Refractive error is a highly prevalent ocular condition characterized by the inability of light to focus precisely on the retina due to abnormal ocular shape or axial length, resulting in blurred vision. The principal categories of refractive error include myopia, hyperopia, astigmatism, and presbyopia.

[0008] Myopia, commonly referred to as short-sightedness or near-sightedness, is defined by impaired clarity of distant vision. It is estimated that more than 223 million individuals worldwide experience vision impairment, of which 48.3% are attributed to uncorrected refractive errors. Epidemiological data reveal that myopia affects approximately 1.89 billion people globally.

[0009] According to the World Health Organization report published in August 2024, the global burden of myopia is projected to rise to 3.36 billion cases by 2030. This escalation is expected to be predominantly influenced by modifiable lifestyle- related risk factors. Uncorrected myopia is currently the leading cause of distance vision impairment, while myopic macular degeneration associated with high myopia has been identified as a major cause of new incidences of blindness in regions such as Tajimi, Japan, and Shanghai, China.

[0010] Furthermore, myopia contributes to vision impairment not only through direct retinal degeneration but also by substantially increasing the risk for secondary ocular pathologies, including cataract formation and the early onset of glaucoma.

[0011] In 2010, myopia and high myopia were estimated to affect 27% (1,893 million) and 2.8% (170 million) of the global population, respectively. The prevalence of myopia is highest in East Asia, with countries such as South Korea, Singapore, Taiwan, and Japan reporting rates of 50% or higher. In contrast, the prevalence is comparatively lower in Europe, Australia, and North and South America. Preliminary projections, based on current prevalence data combined with agespecific and temporal population trends, indicate that by 2050, myopia and high myopia will affect an estimated 52% (4,949 million) and 10.0% (925 million) of the global population, respectively.

[0012] Myopia typically has its onset between 6 and 7 years of age and progresses until approximately 16 to 20 years of age. Currently available pharmacological and optical interventions are unable to fully arrest the progression of myopia. The caffeine metabolite 7 -methylxanthine (7-MX) has been shown to inhibit excessive axial elongation in two widely used experimental models of myopia — form deprivation myopia and lens-induced myopia — in guinea pigs, rabbits, and rhesus monkeys. However, the inhibitory effects of 7-MX were not replicated in form deprivation experiments in chickens, a species with a scleral structure that differs from mammals due to the partial presence of cartilage.

[0013] In 2009, the Danish Medicines Agency authorized the use of 7-MX for the treatment of myopia. The approved formulation is available as an immediate- release tablet containing 400 mg of 7-MX, administered three times daily, resulting in a total oral dose of 1,200 mg per day.

[0014] According to an article published in the British Journal of Ophthalmology (2023;107(10): 1538-1544. doi: 10.1136 / bjo-2021-320920, Epub 2022 Aug 22), an extended-release formulation of 7-MX, administered once or twice daily, is theoretically a more effective method of treatment. However, the desirable pharmacokinetic characteristics of such a formulation have not yet been disclosed.

[0015] The journal Investigative Ophthalmology & Visual Science (April 2019, Vol. 60, 1768. doi: 10.1167 / iovs.18-25958) notes that further research into 7-MX and related compounds is warranted. Efficacy may be enhanced through improved formulations, such as sustained-release preparations instead of standard tablet forms, since even twice-daily dosing may be insufficient to maintain an effective serum concentration of 7-MX, a compound with a relatively short half-life. Investigations into the feasibility of topical ophthalmic formulations of 7 -MX or related agents could also help reduce concerns about systemic side effects, particularly given the potential for long-term use in children.

[0016] Although the immediate-release tablet form achieves efficacious blood levels of 7-MX, as determined by the average plasma concentration over a 24 -hour period, the development of a sustained-release formulation could make it possible to reduce dosing frequency to twice daily while maintaining a consistent therapeutic effect. Such an approach would enhance treatment convenience and potentially improve patient compliance.

[0017] Due to the rapid elimination of 7-MX from the bloodstream, the oral immediate- release tablet is unable to maintain a stable plasma concentration, even when administered two or three times daily.

[0018] Alternatively, US20160338947A, assigned to Amorphex Therapeutics LLC, discloses a pilot placebo -controlled clinical trial in which an oral dose of 400 mg of 7 -methylxanthine was administered to 68 myopic children. The study demonstrated that 7-MX can reduce axial elongation and slow the progression of childhood myopia, with no reported adverse effects. These findings indicate that systemic treatment with 7-MX may help retard axial elongation and myopia progression in children, although they also suggest that larger doses may need to be explored. However, future large-scale clinical trials — necessary for regulatory approval — must consider the potential risks, as systemic administration of an adenosine agonist in children could produce serious side effects. This is particularly significant because adenosine receptors are involved in critical physiological processes, including cardiac regulation, coronary blood flow, and neural function.

[0019] The inventors of the present invention have unexpectedly discovered that the bio availability of 7-MX is sustained when its release is prolonged. Consequently, administering 7-MX in an extended-release dosage form can achieve efficacious blood levels while potentially minimizing risks associated with fluctuating plasma concentrations.

[0020] Summary of the invention

[0021] In one embodiment, the invention provides an Extended-release dosage form comprising 7-MX for use in a method for treating myopia in a subject in need thereof.

[0022] In another embodiment, the invention provides an extended-release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: administering the composition to the subject twice daily, wherein, upon oral administration to the subject, the composition provides a ratio of mean Cmax to Cmin of 7-MX in the range of about 2-fold to about 3.3-fold.

[0023] In another embodiment, the invention provides an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: administering the composition to the subject twice daily, wherein, upon oral administration to the subject, the composition provides a ratio of mean Cmax to Cmin of 7-MX in the range of about 4-fold to about 5-fold, and preferably about 4.9-fold. In another embodiment, the invention provides an extended -release dosage form comprising from about 450 mg to about 550 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: administering the dosage form to the subject twice daily under fed conditions, wherein, upon oral administration to the subject, the composition provides a steady-state minimum plasma concentration (Cmin,ss) of 7-MX after five consecutive days of administration in the range of about 1661.4 ng / mL to about 2658.24 ng / mL for a duration of approximately 12 to 18 hours.

[0024] In another embodiment, the invention provides a method of treating myopia in a human subject, the method comprising orally administering to the subject, on a twice-daily basis under fed conditions, an extended-release dosage form comprising 500 mg of 7 -methylxanthine (7-MX) or a pharmaceutically acceptable salt thereof, wherein upon administration the dosage form provides:

[0025] • a time to maximum plasma concentration (Tmax) of 7-MX between about 3 hours and about 16 hours;

[0026] • an area under the plasma concentration-time curve (AUC 0-24) within the range of about 80% to about 125% of approximately 45,000 ng-hr / mL;

[0027] • a maximum plasma concentration (Cmax) within the range of about 80% to about 125% of approximately 3,800 ng / mL of 7-MX, such that the ratio of Cmax to Cmin ranges from about 3 to about 5; wherein the dosage form provides effective treatment of myopia following administration to the subject.

[0028] In another embodiment, the invention provides a method of treating myopia in a human subject, the method comprising orally administering to the subject, on a twice-daily basis under fed conditions, an extended-release dosage form comprising 500 mg of 7 -methylxanthine (7-MX) or a pharmaceutically acceptable salt thereof, wherein upon administration the dosage form provides:

[0029] • a steady-state time to maximum plasma concentration (Tmax,ss) of 7-MX between about 3 hours and about 16 hours;

[0030] • a steady-state area under the plasma concentration-time curve (AUC0- 24, ss) within the range of about 80% to about 125% of approximately 45,000 ng-hr / mL;

[0031] • a steady-state maximum plasma concentration (Cmax,ss) within the range of about 80% to about 125% of approximately 3,800 ng / mL of 7 -MX, such that the ratio of Cmax,ss to Cmin,ss ranges from about 3 to about 5; wherein the dosage form provides effective treatment of myopia following administration to the subject.

[0032] In another embodiment, the invention provides the use of 7 -methylxanthine (7- MX) in the manufacture of an extended-release dosage form for the treatment of myopia, the dosage form comprising a matrix having dispersed therein 7-MX or a pharmaceutically acceptable salt thereof, and optionally having an extended- release coating over the matrix, wherein the dosage form, when tested in a dissolution medium comprising 900 mL of 0.1 N HC1 or 0.05 M acetate buffer at pH 4.5 at 37°C using a standard USP rotating paddle apparatus operated at 100 rpm, exhibits the following dissolution profile:

[0033] • not more than about 18% of 7-MX is released at 1 hour;

[0034] • between about 16% and about 30% of 7-MX is released at 2 hours;

[0035] • between about 31% and about 43% of 7-MX is released at 4 hours;

[0036] • between about 44% and about 65% of 7-MX is released at 6 hours; and

[0037] • not more than about 90% of 7-MX is released at 8 hours.

[0038] In another embodiment, the invention provides a method for treating myopia, the method comprising administering to a subject in need thereof an extended-release dosage form comprising 7 -methylxanthine (7-MX) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, wherein the dosage form, when tested in a dissolution medium comprising 900 mL of 0.1 N HC1 or 0.05 M acetate buffer at pH 4.5 at 37°C using a standard USP rotating paddle apparatus operated at 100 rpm, exhibits the following dissolution profile: not more than about 18% of 7-MX released at 1 hour; between about 16% and about 30% of 7-MX released at 2 hours; between about 31% and about 43% of 7-MX released at 4 hours; between about 44% and about 65% of 7-MX released at 6 hours; and not more than about 90% of 7-MX released at 8 hours.

[0039] In another embodiment, the invention provides an extended -release dosage form of 7-MX prepared by a dry granulation process or a wet granulation process.

[0040] In a further embodiment, the invention provides an extended-release dosage form comprising granules compressed to form a tablet or mini-tablet, granules filled into a capsule, or granules filled into a sachet.

[0041] In yet another embodiment, the invention provides a dosage form configured for administration as a single dose, divided doses, or multiple doses, thereby offering versatility in administration. In one example, a single administration comprises a 500 mg dosage form administered at once. In another example, a divided dose comprises the same 500 mg dosage form separated into two 250 mg units prior to administration. In yet another example, multiple doses comprise two separate 250 mg dosage forms administered either concurrently or sequentially, thereby providing flexibility and adaptability in the therapeutic regimen.

[0042] Brief description of the drawings

[0043] Figure- 1: Steady state plasma concentration profile of 7-MX 400 mg Immediate release and 500 mg Extended-release dosage form, under fed condition, after 72 hours administration in BA / BE study conducted in healthy human volunteers (A is a 7-MX 500 mg Extended-release formulation administered in twice a day regimen and B is a 7-MX 400 mg Immediate release formulation administered in thrice a day regimen).

[0044] Figure-2: Steady state plasma concentration profile (in log scale) of 7-MX 400 mg Immediate release and 500 mg Extended-release dosage form, under fed condition, after 72 hours administration in BA / BE study conducted in healthy human volunteers (A is a 7-MX 500 mg Extended-release formulation administered in twice a day regimen and B is a 7-MX 400 mg Immediate release formulation administered in thrice a day regimen). DETAILED DESCRIPTION

[0045] The terms ‘7-Methylxanthine’ or ‘7-MX’ relate to same chemical compound, and are used throughout the specification interchangeably, the formula of which is C6H6N4O2 (IUPAC name 7-Methyl-3,7-dihydro-lH-purine-2, 6-dione; Chemical name 7-methyl-3H-purine-2, 6-dione) as represented by structure below.

[0046] 7-MX covers the compound 7 methyl xanthene or one or more pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, racemates or stereoisomers thereof. It is non-selective adenosine antagonist.

[0047] The term “extended-release,” also referred to as sustained-release, prolonged- release, modified-release, or controlled-release, as used herein, refers to a pharmaceutical formulation or composition that is configured to release an active ingredient in a controlled manner over an extended period of time following administration, rather than delivering the entire dose immediately. Such extended- release of the active ingredient is effective to maintain therapeutically relevant plasma concentrations over a prolonged duration, typically ranging from about 12 hours to about 24 hours, thereby reducing the required frequency of dosing and enhancing patient compliance as well as therapeutic outcomes.

[0048] As used herein, the term “Cmin” or “Cmin(eff)” refers to the minimum concentration of a drug in blood plasma, typically measured immediately prior to administration of the subsequent dose. In a therapeutic context, “Cmin” or “Cmin(eff)” is utilized to characterize the lowest plasma concentration of the drug that ensures the drug level remains within the therapeutic window, such that the concentration is sufficient to elicit the desired therapeutic effect without reaching levels associated with toxicity. Monitoring and maintaining appropriate Cmin values is critical for optimizing dosing regimens, thereby maximizing clinical efficacy while minimizing adverse effects.

[0049] As used herein, the term “Cmax,ss” refers to the maximum plasma concentration of a drug at steady state, and the term “Cmin,ss” refers to the minimum plasma concentration of a drug at steady state.

[0050] The term “Tmax” refers to the time at which a drug attains its maximum plasma concentration (Cmax) following administration. When a drug reaches its maximum plasma concentration under steady-state conditions, the term is referred to simply as “Tmax,” rather than “Tmax,ss,” as a person skilled in the art understands that such a measurement is representative of steady- state conditions.

[0051] As used herein, the terms “subject,” “patient,” and “individual” are used interchangeably to refer to a vertebrate organism, preferably a mammal, and more preferably a human.

[0052] It is further recognized that in pediatric subjects, administration of a thrice-daily dosing regimen is challenging and is frequently associated with poor patient compliance.

[0053] As used herein, the term "effective treatment of myopia" refers to a pharmaceutical composition which, when administered to a subject in need thereof, is capable of maintaining constant plasma concentration of 7MX for a duration between 14 and 16 hours due to the sustained release and extended biological half-life of developed extended release formulation.

[0054] The term “fasted” as used herein is defined as follows: the dosing state which is defined following an overnight fast (wherein 0 caloric intake has occurred) of at least 10 hours. Subjects may administer the dosage form with 240 mL of water. No food should be allowed for at least 4 hours post-dose. Water may be allowed as desired except for one hour before and after drug administration.

[0055] The term “fed” or “under fed condition” as used herein is defined as follows: the dosing state which is defined following an overnight fast (wherein 0 caloric intake has occurred) of at least 10 hours, subjects then begin the recommended high fat meal breakfast 30 minutes prior to administration of the drug product. Subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after the start of the meal. The drug product may be administered with 240 mL of water. No food should be allowed for at least 4 hours post-dose. Water may be allowed as desired except for one hour before and after drug administration. A high fat (approximately 50 percent of the total caloric content of the meal is derived from fat) and high calorie (approximately 800 to 1000 calories) meal should be used as the test meal under the fed condition.

[0056] The term “about” as used herein is defined as follows: a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

[0057] The calculation of the mean area under the serum concentration versus time curve (AUC) is a well-known procedure in the pharmaceutical arts and is described, for example, in Welling, “Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986). AUC as used herein includes area under the concentration-time curve from time zero extrapolated to infinite time following single dose or the area under the concentration-time curve from time zero to time of the end of dosing interval following steady state / multiple dose. In addition, the calculations for Cmax, Cmin,ss Tmax, and elimination half-life (t* ), are also known to this of ordinary skill in the art and is described, for example, in Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005).

[0058] As used herein, the inventors have surprisingly discovered that an extended- release (ER) dosage form of 7-MX, when administered orally twice daily to a subject, confers the advantage of maintaining drug plasma concentrations above Cmin,ss for a duration exceeding 14 to 18 hours. This pharmacokinetic profile results in an increase in therapeutic efficacy from approximately 55% to about 80%, attributable to the prolonged maintenance of drug plasma concentrations due to prolonged biological half-life of 7.7 hr observed with extended release formulation. In comparison 7-MX biological half-life of 3.0 hr observed with immediate release formulation. Furthermore, administration of the ER dosage form reduces the dosing frequency required from three times daily, as necessary with immediate-release formulations, to twice daily, thereby improving patient compliance.

[0059] In one embodiment, the invention provides an extended-release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, wherein the extended-release dosage form most preferably comprises about 500 mg of 7-MX.

[0060] In another embodiment, the invention provides an extended -release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising orally administering the dosage form to the subject twice daily.

[0061] In another embodiment, the invention provides an extended-release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a ratio of steady- state maximum plasma concentration (Cmax,ss) to steady-state minimum plasma concentration (Cmin,ss) of 7-MX in the range of about 3-fold to about 5-fold, preferably in the range of about 4-fold to about 5-fold, and more preferably about 4.9-fold, and further provides a steady-state time to maximum plasma concentration (Tmax,ss) from about 3 hours to about 16 hours, preferably from about 4 hours to about 8 hours, and more preferably about 6 hours.

[0062] In another embodiment, the invention provides an extended -release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a ratio of steady- state maximum plasma concentration (Cmax,ss) to steady-state minimum plasma concentration (Cmin,ss) of 7-MX in the range of about 3-fold to about 5-fold, preferably in the range of about 4-fold to about 5-fold, and more preferably about 4.9-fold, and further provides a steady-state time to maximum plasma concentration (Tmax,ss) from about 4 hours to about 8 hours, and more preferably about 6 hours.

[0063] In another embodiment, the invention provides an extended -release dosage form comprising from about 450 mg to about 650 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state minimum plasma concentration (Cmin,ss) of 7-MX after 72 hours of administration in the range of about 1661.4 ng / mL to about 2658.24 ng / mL for a duration of approximately 12 to 18 hours, and preferably in the range of about 2159.82 ng / mL to about 2492.1 ng / mL for a duration of about 14 to 16 hours.

[0064] In another embodiment, the invention provides an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state maximum plasma concentration (Cmax,ss) of 7-MX in the range of about 3000 ng / mL to about 4000 ng / mL, and preferably about 3750 ng / mL. In another embodiment, the invention provides an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state minimum plasma concentration (Cmin,ss) of 7-MX in the range of about 500 ng / mL to about 1000 ng / mL, and preferably about 790 ng / mL.

[0065] In another embodiment, the invention provides an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state minimum plasma concentration (Cmin,ss) of 7-MX greater than about 1661 ng / mL for a duration of about 14 to 16 hours after 72 hours of administration.

[0066] In another embodiment, the invention provides an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state area under the plasma concentration-time curve over 24 hours (AUC0-24,ss) within 80% to 125% of a reference value, corresponding to between about 40,000 hr- ng / mL and about 50,000 hr- ng / mL, preferably between about 43,000 hr- ng / mL and about 46,000 hr- ng / mL, and more preferably about 45,000 hr- ng / mL.

[0067] In another embodiment, the invention provides an extended -release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides a steady-state area under the plasma concentration-time curve (AUCss, 0-T) within 80% to 125% of a reference value, corresponding to between about 20,000 hr-ng / mL and about 24,000 hr-ng / mL, preferably between about 22,000 hr-ng / mL and about 23,000 hr-ng / mL, and more preferably about 22,800 hr-ng / mL.

[0068] In another embodiment, the invention provides an extended -release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides:

[0069] • a steady-state time to maximum plasma concentration (Tmax,ss) of 7-MX between about 3 hours and about 16 hours;

[0070] • a steady- state area under the plasma concentration-time curve over 24 hours (AUC0-24,ss) within the range of 80% to 125% of about 45,000 hr-ng / mL;

[0071] • a steady-state maximum plasma concentration (Cmax,ss) within the range of 80% to 125% of about 3,800 ng / mL of 7-MX, such that the ratio of Cmax,ss to Cmin,ss is in the range of about 2 to 3.3, preferably about 2.5, and in certain embodiments about 4; wherein the dosage form provides effective treatment of myopia following administration to the subject.

[0072] In another embodiment, the invention provides an extended -release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides:

[0073] • a steady-state time to maximum plasma concentration (Tmax,ss) of 7-MX in the range of about 3 hours to about 16 hours; • a steady-state area under the plasma concentration-time curve (AUCO- 24, ss) within the range of about 80% to about 125% of approximately 45,000 hr-ng / mL;

[0074] • a steady-state maximum plasma concentration (Cmax,ss) within the range of about 80% to about 125% of approximately 3,800 ng / mL of 7 -MX, such that the ratio of Cmax,ss to Cmin,ss is in the range of about 2 to about 5, preferably in the range of about 4 to about 5, and more preferably about 4.8;

[0075] In another embodiment, the invention provides a method for treating myopia in a human subject, the method comprising: orally administering to the subject, on a twice-daily basis under fed conditions, an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7- MX) or a pharmaceutically acceptable salt thereof, wherein, upon administration, the dosage form provides:

[0076] • a time to maximum plasma concentration (Tmax) of 7 -MX in the range of about 3 hours to about 16 hours;

[0077] • a steady- state area under the plasma concentration-time curve over 24 hours (AUCO-24) within the range of about 80% to about 125% of approximately 45,000 hr-ng / mL;

[0078] • a steady- state maximum plasma concentration (Cmax) within the range of about 80% to about 125% of approximately 3,800 ng / mL of 7 -MX, such that the ratio of Cmax to Cmin is in the range of about 2 to about 3.3, preferably in the range of about 2.0 to about 2.5, and more preferably about 2.5; wherein the dosage form provides effective treatment of myopia following administration to the subject.

[0079] In another embodiment, the invention provides a method for treating myopia in a human subject, the method comprising: orally administering to the subject, on a twice-daily basis under fed conditions, an extended-release dosage form comprising about 500 mg of 7 -methylxanthine (7- MX) or a pharmaceutically acceptable salt thereof, wherein, upon administration, the dosage form provides:

[0080] • a steady-state time to maximum plasma concentration (Tmax,ss) of 7-MX in the range of about 3 hours to about 16 hours;

[0081] • a steady- state area under the plasma concentration-time curve over 24 hours (AUC0-24,ss) within the range of about 80% to about 125% of approximately 45,000 hr- ng / mL;

[0082] • a steady-state maximum plasma concentration (Cmax,ss) within the range of about 80% to about 125% of approximately 3,800 ng / mL of 7-MX; and

[0083] • a steady-state minimum plasma concentration (Cmin,ss) of approximately 1661 ng / mL; wherein the dosage form provides effective treatment of myopia following administration to the subject.

[0084] In another embodiment, the invention provides an extended -release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides the following pharmacokinetic parameters for 7-MX:

[0085] • a time to maximum plasma concentration (Tmax) in the range of about 3 hours to about 16 hours, preferably from about 4 hours to about 8 hours, and more preferably about 6 hours;

[0086] • a steady-state maximum plasma concentration (Cmax,ss) in the range of about 3000 ng / mL to about 4000 ng / mL, and preferably about 3750 ng / mL;

[0087] • a steady-state minimum plasma concentration (Cmin,ss) in the range of about 500 ng / mL to about 1000 ng / mL, and preferably about 790 ng / mL;

[0088] • a ratio of mean steady-state Cmax,ss to Cmin,ss in the range of about 2- fold to about 5-fold, and preferably about 5-fold;

[0089] • a steady- state area under the plasma concentration-time curve over 24 hours (AUC0-24,ss) within 80% to 125% of a reference value, corresponding to between about 40,000 hr-ng / mL and about 50,000 hr-ng / mL, preferably about 45,000 hr-ng / mL; and

[0090] • a steady- state area under the plasma concentration-time curve over the dosing interval (AUC0-r,ss) within 80% to 125% of a reference value, corresponding to between about 20,000 hr-ng / mL and about 24,000 hr-ng / mL, and preferably about 22,800 hr-ng / mL.

[0091] In another embodiment, the invention provides an extended -release dosage form comprising about 500 mg of 7 -methylxanthine (7-MX) for use in a method of treating myopia in a subject in need thereof, the method comprising: orally administering the dosage form to the subject twice daily under fed conditions, wherein, upon administration, the dosage form provides the following pharmacokinetic parameters for 7-MX:

[0092] • a steady- state time to maximum plasma concentration (Tmax,ss) of about 6 hours;

[0093] • a steady-state maximum plasma concentration (Cmax,ss) of about 3750 ng / mL;

[0094] • a steady- state minimum plasma concentration (Cmin,ss) of about 790 ng / mL;

[0095] • a mean ratio of Cmax,ss to Cmin,ss of about 5-fold;

[0096] • a steady- state area under the plasma concentration-time curve over 24 hours (AUC0-24,ss) within 80% to 125% of about 45,000 hr-ng / mL; and

[0097] • a steady- state area under the plasma concentration-time curve over the dosing interval (AUC0-r,ss) within 80% to 125% of about 22,800 hr- ng / mL.

[0098] In another embodiment, the invention provides an Extended-release dosage form comprising 7-MX, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the dosage form when added to a test medium comprising 900 mL of pH 0.1 N HC1 or 0.05M pH 4.5 acetate buffer at 37° C. in a standard USP rotating paddle apparatus and the paddles are rotated at 100 rpm, dissolves not more than 18% of the drug in 1 hour, between 16% to 30% of the drug in 2 hours and between 31 % to 43% in 4 hours, and between 44 to 65 % at 6 hours and not more than 90 % of 7-MX at 8 hours.

[0099] In another embodiment, the invention provides a method for treating myopia, comprising; administering to a subject an Extended-release dosage form comprising 7-MX, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the dosage form when added to a test medium comprising 900 mL of pH 0.1 N HC1 or 0.05M pH 4.5 acetate buffer at 37° C. in a standard USP rotating paddle apparatus and the paddles are rotated at 100 rpm, dissolves not more than 18% of the drug in 1 hour, between 16% to 30% of the drug in 2 hours and between 31 % to 43% in 4 hours, and between 44 to 65 % at 6 hours and not more than 90 % of 7-MX at 8 hours.

[0100] The Extended-release pharmaceutical compositions as disclosed herein may be formulated in various dosage forms like granules compressed for form tablet, filled into capsule or sachet; suspension; mini tablets, tablets or capsules. The technology used to prepare these compositions may be selected from Extended- release Matrix Systems; Matrix Systems (Multiarticulate); Osmotic Systems; Reservoir Systems; Bursting Osmotic Beads and Cores (Pulsatile Delivery); Bilayer Tablet etc.

[0101] The Extended-release compositions may comprise 7-MX, an Extended-release polymer and at least one pharmaceutically acceptable excipient. The wet, dry or solvent granulation process may be used to prepare Extended-release dosage form as disclosed in various embodiments.

[0102] The Extended-release polymer may be selected from hydroxypropyl methylcellulose (HPMC) selected from HPMC K100 LVCR, HPMC K4M, HPMC E 200, HPMC K100M, Polyethylene oxide or mixtures thereof.

[0103] The pharmaceutically acceptable excipient may be selected from diluent, binder, lubricant, glidant, disintegrant, flavouring agent, colouring agent or combinations thereof. Diluent includes, but is not limited to, lactose, mannitol, sorbitol, sucrose, dicalcium phosphate dihydrate, microcrystalline cellulose, starch, pregelatinized starch, magnesium aluminium silicate and mixtures thereof.

[0104] Binder includes, but is not limited to, polyvinylpyrrolidone (Povidone K-30) starch, pregelatinized starch, gelatin, polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and Veegum, and synthetic polymers such as acrylic acidand methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers and mixtures thereof.

[0105] Lubricant includes, but is not limited to, magnesium stearate, stearic acid calcium stearate, glycerol behenate, polyethylene glycol, talc, mineral oil and mixtures thereof.

[0106] Glidant, includes, but is not limited to, colloidal anhydrous silica, talc, colloidal silicon dioxide, magnesium stearate, silica, glycerol monostearates and mixtures thereof.

[0107] Disintegrant includes, but is not limited to, starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, clays, cellulose, alginate, gums, cross linked polymers, such as cross-linked PVP and mixtures thereof.

[0108] EXAMPLES: The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below

[0109] Example 1: Extended-release tablet composition of 7-MX

[0110] Example 2: Extended-release tablet composition of 7-MX Example 3: Extended-release tablet composition of 7-MX

[0111] Example 4: Extended-release tablet compositions of 7-MX

[0112] General process of preparation Extended-release compositions of 7-MX of Examples 1 to 4:

[0113] The Extended-release tablets of 7-MX were prepared by wet granulation method.

[0114] Drug and other excipients were weighed accurately. Drug was mixed with different polymers HPMC K4 MCR, and HPMC LVCR K100 individually. All the mixtures were individually blended with diluent in the polybag. Blends were shaken for few minutes. The mixtures of powders were individually sieved through sieve#36. Mixtures of powders were again shaken in polybag and weighed after proper blending. Binder solution of PVP K30 in iso-propyl alcohol was used to granulate the blend. The binder solution was added slowly, mixed thoroughly and air dried. Air dried material was passed through the sieve #16 to form the granules and dried in hot air oven at 50°C for 30 minutes. Magnesium stearate was sieved through sieve #60 and blended with the granules to increase the flow-ability of granules. All the granule blends were compressed into tablets using tablet punching machine.

[0115] Examples 5-7: Extended-release tablet compositions of 7-MX tablet 500 mg

[0116] *Evaporates during processing

[0117] Table-1: Dissolution profile of Prototype formulation Examples 6 in Acetate 0.1

[0118] N HCL, buffer 4.5 at 100 RPM in USP II dissolution

[0119] Table-2: Dissolution profile of Prototype formulation Examples 7 in Acetate 0.1

[0120] N HCL, buffer 4.5at 100 RPM in USP II dissolution

[0121] Examples 8-9: Extended-release tablet compositions of 7-MX tablet 500 mg

[0122] Process of preparation of compositions of Examples 5-9:

[0123] The formulations of Examples 5 to 9 can be prepared according to the process disclosed in Example 10 by adjusting weight of the ingredients as per each example.

[0124] Table-3: Dissolution profile of Prototype formulation Examples 8 in 0.1 N HCL, acetate buffer 4.5at 100 RPM in USP II dissolution t of Drug Released Acetate bu

[0125] 10 95 f 84

[0126] 12. 101. 89

[0127] Table-4: Dissolution profile of Prototype formulation Example 9 in 0.1 N HCL, acetate buffer 4.5at 100 RPM in USP II dissolution

[0128] Example 10: Extended-release 7-MX matrix tablet composition

[0129]

[0130] *Evaporates during processing

[0131] Process of preparation:

[0132] 7-MX was sifted through #20mesh. Lactose Monohydrate (Granulac), Hydroxypropyl Methylcellulose K4M premium CR was sifted through #40 mesh. The above sifted materials were loaded in the Rapid Mixer Granulator and mixed for 10 minutes at impeller slow speed and chopper off.

[0133] Binder solution was prepared by dissolving Povidone (PVPK-30) in Isopropyl alcohol and stirring continued until a clear solution is obtained. The prepared binder was added to the dry mix blend over a time period of 1 -2 minutes into the Rapid Mixer Granulator and granulated with impeller at slow speed and chopper off. Then the granules were kneaded for 2 minutes with impeller fast speed and chopper fast speed, to get desired granules. The wet mass was air dried for 15 minutes till the solvent evaporates and the drying continued at an inlet temperature of 50°C, till the LOD of the dried granules reaches between 1.0% and 2.5% w / w at 105°C for 3 minutes. The Dried granules were sifted through #20 mesh and retains was milled with Co Mill using 1.5mm screen and then the milled granules sifted through #20 mesh. The sized granules transferred into octagonal blender.

[0134] Lactose monohydrate (Flowlac 100), Hydroxypropyl Methylcellulose K100 LVCR, Hydroxypropyl Methylcellulose K4M premium CR, Colloidal anhydrous Silica were sifted through #40mesh and loaded in to the octagonal blender along with the sized granules and mixed for 15minutes. Magnesium stearate sifted through #60mesh and loaded in to the octagonal blender along with the prelubricated blend and mixed for 5minutes.

[0135] The Lubricated blend was compressed with average weight of 750 mg / tablet ± 3.0% (Between 727.50mg and 772.50mg) using 18.0 x 8.0mm, caplet shaped punches with target thickness of 4.80mm ± 0.30mm (Between 4.50mm and 5.10mm) and target hardness of Not less than 100 Newton with friability limit of NMT l%w / w.

[0136] Table-5: Dissolution profile of formulation in Examples 10 in 0.1 N HCL, acetate buffer 4.5at 100 RPM in USP II dissolution Example 11: Extended-release 7-MX matrix tablet composition

[0137] *Evaporates during processing

[0138] Table-6: Dissolution profile of formulation in Examples 11 in 0.1 N HCL, acetate buffer 4.5at 100 RPM in USP II dissolution

[0139] Time ( Amount of Drug

[0140] Example 12: Extended-release microspheres of 7-MX

[0141] Example 13 : Extended-release 7-MX matrix tablet composition in dose strength of 250 mg

[0142]

[0143] *Evaporates during processing

[0144] Example 14 : Extended-release 7-MX matrix tablet composition in dose strength of 450 mg

[0145] *Evaporates during processing

[0146] Example 15 : Extended-release 7-MX matrix tablet composition in dose strength of 600 mg

[0147] *Evaporates during processing

[0148] Example 16 : Extended-release 7-MX matrix tablet composition in dose strength of 65 mg

[0149]

[0150] *Evaporates during processing

[0151] 7-MX extended release tablets in different dose strength of 250 mg, 450 mg, 600 mg and 650 mg prepared using the similar process as specified in process of preparation Extended-release compositions of 7-MX for Example 1 to 4.

[0152] Preparation of 7-MX Microsphere formulation

[0153] 7-MX micro sphere formulation was prepared by spray drying method. The polymer was dispersed in the water and stirred for 30 minutes to make the polymer solution. Then maltodextrin was added in the prepared polymer solution and stirred for 15 minutes. After stirring solid drug (7-MX) was dispersed in the prepared polymer solution to make a slurry and was kept under vigorous stirring (1000 rpm) for at least 1 h for proper mixing of drug with the polymer. Spray drying of freshly prepared slurry was performed using a spray dryer at inlet and outlet temperature of 165°C and 65°C, respectively and feed pump speed of 15 rpm. The aspirator speed and atomization pressure were maintained at 1400 rpm and 3 kg / cm2, respectively. After preparation, 7MX powder was collected in the powder collecting chamber, weighed and immediately stored in glass vials under inert conditions. Table-7: Dissolution profile of 7-MX microsphere formulation of Example 12

[0154] Time (h) % Amount of Drug Rele Acetate buffer pH 4 PB

[0155] 0 i 0 ; 0 ; 0

[0156] Method for In vitro drug release:

[0157] USP Apparatus II (paddle type) was used for in vitro drug release of tablets. The dissolution media was equilibrated at 37°C for 30 minutes before the dissolution test. Tablets were placed in dissolution vessels. The dissolution media was maintained at 37°C and stirred at 100 rpm. At specific time intervals of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10 and 12h samples were withdrawn and drug concentration was determined using HPLC. The volume of media was replenished with equal volume of fresh dissolution media maintained at 37°C.

[0158] Dissolution studies was performed in following conditions:

[0159] Dissolution Studies in 0.1 N HCI at 100 rpm, using 900 ml of the media; and, Dissolution Studies in pH 4.5 Acetate buffer and 100 rpm, using 900 ml of the media.

[0160] Table-8: Dissolution profile of 7 MX 400 mg SR Tablets in release media

[0161]

[0162] Bioequivalence study of Extended- release tablet 500 mg BID vs Immediate release tablet 400 mg TID:

[0163] The studies are conducted in normal, healthy, adult, human male subjects under fed conditions. An open label, balanced, randomized, two -treatment, two-period, two-sequence, multiple-dose, steady state, crossover, comparative bioavailability study in healthy, adult, human subjects under fed conditions in 14 subjects.

[0164] Subjects were fasted overnight for at least 10 hours prior to high fat, high calories breakfast (approximately 800 to 1000 Kcal). Morning dosing was done exactly 30 minutes after the start of high fat, high calories breakfast. According to the randomization schedule, in one arm of the study, a single unit of Immediate release Tablet 400 mg was administered along with 240 ± 2 mL of water at ambient temperature in sitting posture at thrice a day for every 08 hours for 5 consecutive days from Dosing Day 01 to dosing day 05. In another arm of the study, a single unit of Extended-release Tablet 500 mg was administered along with 240 ± 2 mL of water at ambient temperature in sitting posture at twice a day for every 12 hours for 5 consecutive days from Dosing Day 01 to dosing day 05.

[0165] Dosage Forms Administered: 7-MX 500 mg Extended-release tablet and 7-MX 400 mg Immediate-release tablet prepared in Example 11. During study periods, blood samples to provide plasma for pharmacokinetic analysis was collected at periodic time points. PK samples were analyzed using standard validated LC-MS / MS analytical methods. Dose normalized natural log transformed AUCO-r, ss , Cmax, ss , AUCo-24hr , AUCo -12hr, CT;SS, Cmin.ss, Cav, tmax.ss, swing and Fluctuation% are analyzed for 7-MX using a PROC GLM effect ANOVA model with the main effect of treatment, period, sequence and subject nested within sequence as fixed effects.

[0166] Table 9: Bioequivalence data of 7 MX IR (Treatment A 400 mg) and ER formulation of Example 11 (Treatment B 500 mg)

[0167] Table 10: PK Parameters of extended-release tablet 500 mg (Dosed BID)

[0168] Based on a comparative dissolution data (table 12) of 500 mg Extended-release formulation of Examples 11 and 400 mg Immediate-release formulation it appears that the pattern of dissolution is important for achieving bioequivalence of 500 mg Extended-release formulation administered BID with a 400 mg Immediate-release formulation administered TID. Compression force also found to effect dissolution rate as per examples ...and found to be important process variable for development 250 and 500 mg Extended release 7-MX tablet formulation.

[0169] Table-11: Dissolution profile of 500 mg Extended-release (ER) formulation of Examples 11 and 400 mg Immediate-release (IR) formulation in 0.1 N HCL at 100 RPM in USP II dissolution.

[0170] Table-12: Dissolution profile of 500 mg Extended-release (ER) formulation of Examples 11 in acetate buffer pH 4.5 and pH 6.8 Phosphate buffer at 100 RPM in USP II dissolution.

[0171] Table 13: Effect of compression force on dissolution profile of 500 mg Extended release tablet

[0172] Table-14: Dissolution profile of 250 mg Extended-release (ER) formulation of Examples in 0.1 N HCL, acetate buffer pH 4.5 and pH 6.8 Phosphate buffer at 100 RPM in USP II dissolution. pH 6.8 Phosphate bu

[0173] 0 0 0 0

[0174] Table 15: Effect of compression force of hardness and dissolution profile of 250 mg Extended release tablet.

[0175] Table 16: PK Parameters of extended-release tablet 500 mg (Dosed BID) Table 17 : Other Parameters of extended-release tablet 500 mg (Dosed BID) and immediate release formulation 400 mg (Dosed TID)

Claims

CLAIM:1.An Extended-release dosage form comprising 7 -MX or a pharmaceutically acceptable salt thereof for use in a method for treating myopia in a subject in need thereof.

2. The Extended-release dosage form according to claim 1, wherein the dosage form is configured for single administration, divided dosages, or multiple dosages.

3. The Extended-release dosage form according to claim 1, comprising 450 to650 mg of 7-MX for oral administration to the subject on a twice daily basis.

4. The Extended-release dosage form according to claim 3, comprising 500 mg of 7 -MX.

5. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: a Tmax,ss from about 4 hours to about 8 hours, preferably about 6 hours.

6. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: a Cmax,ss of 7-MX in the range of about 3000 ng / mL to about 4000 ng / mL, and preferably about 3750 ng / mL.

7. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: a Cmin,ss of 7 -MX in the range of about 500 ng / mL to about 1000 ng / mL, and preferably about 790 ng / mL.

8. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: a Cmax,ss / Cmin,ss ratio in the range of about 2 to 5, preferably about 5.

9. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: an AUC0-24,ss within 80% to 125% of a reference value, corresponding to between about 40,000 hr-ng / mL and about 50,000 hr-ng / mL, preferably about 45,000 hr- ng / mL.

10. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides: an AUCss, 0-r within 80% to 125% of a reference value, corresponding to between about 20,000 hr-ng / mL and about 24,000 hr-ng / mL, preferably about 22,800 hr- ng / mL.

11. The Extended-release dosage form according to claim 4, wherein oral administration under fed condition provides:• a Tmax of about 6 hours;• a Cmax,ss of about 3750 ng / mL;• a Cmin,ss of about 790 ng / mL;• a Cmax,ss / Cmin,ss ratio of about 5;• an AUC0-24,ss within 80% to 125% of about 45,000 hr-ng / mL; and• an AUC0-T,SS within 80% to 125% of about 22,800 hr ng / mL.

12. The Extended-release dosage form according to claim 7, wherein oral administration under fed condition provides a Cmin,ss concentration after 5 days of about 10 micromoles for 12-18 hours.

13. The Extended-release dosage form according to claim 12, wherein the Cmin,ss concentration is maintained for 14-16 hours.

14. The Extended-release dosage form according to claim 7, comprising 500 mg of 7 -MX, wherein administration under fed condition provides a Cmin,ss of about 13 micromoles after 72 hours, maintained for about 14 hours.

15. The Extended-release dosage form according to claim 1, wherein the elimination half-life is 6-8 hours.

16. The Extended-release dosage form according to claim 3, wherein the dosage form is administered to pediatric, adolescent, or adult patients with progressive myopia.

17. The Extended-release dosage form according to claim 1, wherein the dosage form provides effective treatment of myopia with twice-daily oral administration under fed conditions.

18. The Extended-release dosage form according to claim 1 , wherein the dosage form when tested in USP Apparatus II (100 rpm, 900 mL, 0.1N HC1 or pH 4.5 buffer, 37 °C), exhibits the following dissolution profile:• not more than 18% of 7 MX is released at 1 hour;• 16-30% of 7 MX is released at 2 hours;• 31-43% of 7 MX is released at 4 hours;• 44-65% of 7 MX is released at 6 hours; and• not more than 90% i of 7 MX is released at 8 hours.

19. A method of treating myopia in humans, comprising orally administering to a patient on a twice-daily basis an Extended-release dosage form comprising 500 mg of 7 -MX or a pharmaceutically acceptable salt thereof.

20. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• a Tmax,ss from about 4 hours to about 8 hours, preferably about 6 hours.

21. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• a Cmax,ss of 7-MX in the range of about 3000 ng / mL to about 4000 ng / mL, and preferably about 3750 ng / mL.

22. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• a Cmin,ss of 7-MX in the range of about 500 ng / mL to about 1000 ng / mL, and preferably about 790 ng / mL.

23. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• a Cmax,ss / Cmin,ss ratio in the range of about 2 to 5, preferably about 5.

24. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• an AUC0-24,ss within 80% to 125% of a reference value, corresponding to between about 40,000 hr- ng / mL and about 50,000 hr- ng / mL, preferably about 45,000 hr- ng / mL.

25. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• an AUCss, 0-r within 80% to 125% of a reference value, corresponding to between about 20,000 hr- ng / mL and about 24,000 hr- ng / mL, preferably about 22,800 hr- ng / mL.

26. The method of treating myopia in humans according to claim 19, which upon administration under fed condition provides:• a Tmax of 6 hours;• a Cmax,ss of about 3750 ng / mL;• a Cmin,ss of about 790 ng / mL;• a Cmax,ss / Cmin,ss ratio of about 5;• an AUC0-24,ss within 80%-125% of about 45,000 hr- ng / mL;• an AUC0-T,SS within 80% to 125% of about 22,800 hr ng / mL.

27. The method of treating myopia in humans according to claim 19, wherein the dosage form is administered under long-term repeated dosing for stabilization of ocular growth.

28. Use of 7-MX in the manufacture of an Extended-release dosage form for the treatment of myopia, comprising a matrix with 7-MX or apharmaceutically acceptable salt thereof, and optionally an extended -release coating.

29. The use according to claim 28, wherein the dosage form when tested in USP Apparatus II (100 rpm, 900 m , 0.1N HC1 or pH 4.5 buffer, 37 °C), exhibits the following dissolution profile:• not more than 18% of 7 MX is released at 1 hour;• 16-30% of 7 MX is released at 2 hours;• 31-43% of 7 MX is released at 4 hours;• 44-65% of 7 MX is released at 6 hours; and• not more than 90% of 7 MX is released at 8 hours.

30. The use according to claim 28, wherein the dosage form comprises 450-650 mg of 7 -MX, preferably 500 mg.

31. The use according to claim 28, wherein the dosage form is configured for single, divided, or multiple administrations.

32. The use according to claim 28, wherein the dosage form comprises granules compressed into tablets or mini-tablets, granules filled into capsules, or granules filled into sachets.

33. The use according to claim 28, wherein the dosage form is prepared by dry granulation.

34. The use according to claim 28, wherein the dosage form is prepared by wet granulation.

35. The use according to claim 28, wherein the dosage form further comprises pharmaceutically acceptable excipients selected from diluents, binders or lubricants.

36. A method for treating myopia, comprising administering to a subject an Extended-release dosage form comprising 7 -MX and a pharmaceutically acceptable carrier, wherein when tested in USP Apparatus II (100 rpm,900 mL, 0.1N HC1 or pH 4.5 buffer, 37 °C), exhibits the following dissolution profile:• not more than 18% of 7 MX is released at 1 hour;• 16-30% of 7 MX is released at 2 hours;• 31-43% of 7 MX is released at 4 hours;• 44-65% of 7 MX is released at 6 hours; and• not more than 90% of 7 MX is released at 8 hours.

37. The method according to claim 36, wherein the dosage form comprises 450- 650 mg of 7 -MX, preferably 500 mg.

38. The method according to claim 36, wherein the dosage form is configured for single administration, divided dosages, or multiple dosages.

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