Aqueous pharmaceutical composition comprising benzyl atropine and use thereof

Abstract

The present disclosure relates, in part, to an aqueous pharmaceutical solution comprising benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof, at least one buffering agent, at least one tension agent, and at least one solubilizing agent, methods of preparing an aqueous solution comprising benzyl atropine, products of such methods, and methods of preparing the aqueous solution comprising benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof. And methods of preventing myopia, treating myopia, reducing myopia progression, or preventing myopia progression in a subject by administering to the eye of the subject in need thereof a therapeutically effective amount of such an aqueous pharmaceutical solution.

Description

Technical Field

[0001] The present disclosure relates to compositions comprising benzyl atropine or a pharmaceutically acceptable salt thereof, methods of preparing the benzyl atropine compositions, and methods of preventing or treating myopia, reducing myopia progression, or preventing myopia progression by administering the benzyl atropine compositions. Background Art

[0002] Myopia is an eye condition sometimes referred to as nearsightedness. For example, myopia may describe a subject with good near vision but poor distance vision. Technically, myopia is a refractive error in which light rays entering the eye parallel to the optical axis focus in front of the retina when the eye's accommodation is relaxed. This is usually caused by the eyeball being too long from front to back, but myopia can also be caused by an overly curved cornea and / or increased optical power of the lens (World Wide Web "aoa.org / documents / optometrists / CPG-15").

[0003] There are four forms of myopia, each assessed by determining the spherical equivalent refractive error (RE) of the eye when the eye is relaxed. Premyopia is a condition in which the spherical equivalent RE is ≤+0.75 diopters (D) and >-0.50D. Myopia is a condition in which the spherical equivalent RE is ≤-0.50D. Low myopia is a condition in which the spherical equivalent RE is ≤-0.50D and >-6.00D. High myopia is a condition in which the spherical equivalent RE is ≤-6.00D.

[0004] The prevalence of myopia (nearsightedness) is increasing rapidly and is expected to double by 2050. In addition, high myopia is often associated with an increased risk of blindness (Holden et al., Ophthalmology, 2016, 123, 1036-42). Current treatments include orthokeratology, the use of multifocal soft contact lenses, the use of progressive spectacles, or the use of bifocal spectacles, but the effectiveness of such treatments is modest at best.

[0005] Several animal and human studies have evaluated the ability of different classes of pharmacological agents to reduce myopia progression. In these studies, natural atropine isolated as a racemic mixture from Atropa belladonna showed great promise in its ability to reduce myopia progression. Several large randomized clinical trials conducted in Asian countries (i.e., the ATOM1, ATOM2, and LAMP studies) investigated the effectiveness of various dose strengths of natural atropine in reducing myopia progression in children. [ATOM 1: Chua WH et al. Ophthalmology. Atropine for the Treatment of Childhood Myopia. 2006. 113: 2285-2291.; ATOM 2: Chia, A et al. Ophthalmology. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). 2012. 119(2): 347-354.; LAMP: Yam JC et al. Ophthalmology. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized Double-Blinded Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control [Low Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blind, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control]. 2019.126(1):113-124.] Although these clinical studies have demonstrated the effectiveness of natural atropine in reducing myopia progression, high doses of natural atropine are required. However, these higher doses are associated with debilitating side effects including pupil dilation and light sensitivity. In addition, natural atropine is inherently unstable in aqueous solutions with physiological pH. For example, atropine decomposes into tropic acid and tropine in aqueous solutions with neutral pH. This decomposition makes natural atropine unfeasible as a pharmacological agent for the treatment of myopia.Thus, there is a long-felt but unmet need for pharmacological agents that prevent myopia, treat myopia, reduce myopia progression, or prevent myopia progression, wherein such agents are stable in aqueous solutions having physiological pH. Summary of the invention

[0006] The present disclosure provides an aqueous pharmaceutical solution comprising benzyl atropine having Formula I:

[0007]

[0008] Or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one tonicity agent, and at least one solubilizing agent. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01% to about 0.2% (wt / wt), and preferably about 0.05% to about 0.2% (wt / wt).

[0009] The present disclosure also provides a method for preparing an aqueous solution comprising benzyl atropine having Formula I:

[0010]

[0011] or a pharmaceutically acceptable salt or prodrug thereof, the method comprising: providing an aqueous solution comprising at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent; and adding benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution. In some embodiments, the aqueous solution has a pH value of about 4 to about 5. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01% to about 0.2% (wt / wt), and preferably about 0.05% to about 0.2% (wt / wt). In some embodiments, the aqueous solution of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0012] The present disclosure also provides products of the methods of preparing an aqueous solution comprising benzyl atropine having Formula I:

[0013]

[0014] or a pharmaceutically acceptable salt or prodrug thereof, the method comprising: providing an aqueous solution comprising at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent; and adding benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution. In some embodiments, the aqueous solution has a pH value of about 4 to about 5. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01% to about 0.2% (wt / wt), and preferably about 0.05% to about 0.2% (wt / wt). In some embodiments, the aqueous solution of benzyl atropine has a pH value greater than about 5.

[0015] The present disclosure also provides methods of preventing myopia, treating myopia, reducing myopia progression, or preventing myopia progression in a subject in need thereof, the methods comprising administering to an eye of the subject a therapeutically effective amount of an aqueous pharmaceutical solution comprising benzyl atropine having Formula I:

[0016]

[0017] Or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one tonicity agent, and at least one solubilizing agent. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01% to about 0.2% (wt / wt), and preferably about 0.05% to about 0.2% (wt / wt). BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description, serve to explain the principles of the present disclosure.

[0019] Figure 1 It is shown that in the chicken model of form deprivation-induced myopia (FDM), synthetic atropine derivatives exhibit superior efficacy to myopic controls. Panel A shows that methyl atropine (α-Me), fluoro-atropine (α-F) and benzyl atropine (α-Bz) significantly reduce the change in refractive error measured in diopters (goggled eye value minus ungoggled eye value) (abscissa) relative to 5% v / v ethanol solution (ordinate). Panel B shows the change in refractive error measured in diopters (goggled eye value minus ungoggled eye value) (abscissa) observed for 5% v / v ethanol, atropine (Atro_240nmol; ordinate) and benzyl atropine (Bz.atro_3A_24_nmol and Bz.atro_3B_24_nmol, wherein 3A and 3B refer to the individual isomers of benzyl atropine) (ordinate). DETAILED DESCRIPTION

[0020] Unless defined otherwise, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0021] As used herein, the terms "a" or "an" mean "at least one" or "one or more" unless the context clearly indicates otherwise.

[0022] As used herein, the term "about" means that the listed values ​​are approximate and that small variations will not significantly affect the practice of the disclosed embodiments. Where numerical values ​​are used, unless the context indicates otherwise, "about" means that the numerical value may vary by ±10% and remain within the scope of the disclosed embodiments.

[0023] As used herein, the term "animal" includes, but is not limited to, mammals, humans, and non-human vertebrates, such as wild animals, livestock, and farm animals.

[0024] As used herein, the terms "antagonize" and "antagonizing" mean to reduce or completely eliminate one or more effects.

[0025] As used herein, the term "benzyl atropine" means a compound having Formula I, and includes racemic mixtures and separated enantiomers of compounds having Formula I.

[0026] As used herein, the term "carrier" means a diluent, adjuvant, or excipient with which the compound is administered in a composition.

[0027] As used herein, the term "compound" refers to all stereoisomers, tautomers, isotopes and polymorphs of the compounds described herein.

[0028] As used herein, the terms "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive and open-ended, and include the options following the term and do not exclude additional, unrecited elements or method steps.

[0029] As used herein, the term "contacting" means bringing two compounds, molecules or entities together in an in vitro system or an in vivo system.

[0030] As used herein, the terms "individual," "subject," and "patient," which are used interchangeably, refer to any animal described herein.

[0031] As used herein, the phrase "in need thereof" means that an "individual," "subject," or "patient" has been determined to be in need of a particular method, prevention, or treatment. In some embodiments, the determination can be made by any diagnostic means. In any of the methods, preventions, and treatments described herein, an "individual," "subject," or "patient" may be in need thereof.

[0032] As used herein, the term "integer" means a numerical value of an integer. For example, "an integer from 1 to 5" means 1, 2, 3, 4 or 5.

[0033] As used herein, the term "isolated" means that the compound described herein, or a pharmaceutically acceptable salt thereof, is separated from other components of either a) a natural source, such as a plant or a cell, such as a bacterial culture, or b) a synthetic organic chemical reaction mixture, such as by conventional techniques.

[0034] As used herein, the term "mammal" means a rodent (ie, a mouse, rat, or guinea pig), monkey, sheep, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0035] As used herein, "ophthalmologically compatible" is art-recognized and refers to formulations, polymers and other materials and / or dosage forms that are suitable for use in contact with ocular tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio as determined by one of ordinary skill in the art.

[0036] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. Compositions suitable for pharmaceutical use can be sterile, homogeneous and / or isotonic. In certain embodiments, the pharmaceutical composition can be prepared in an aqueous form, such as in a prefilled syringe or other single-dose or multi-dose container. In certain embodiments, the pharmaceutical composition of the present invention is ophthalmologically compatible and suitable for ophthalmic administration to human subjects by, for example, topical or other known delivery methods. In certain embodiments, the disclosed pharmaceutical composition is suitable for intravitreal administration. In certain embodiments, the pharmaceutical composition of the present invention is suitable for administration by intravitreal infusion. In yet another embodiment, the pharmaceutical composition is administered orally.

[0037] As used herein, the phrase "pharmaceutically acceptable" means that the compound, material, composition and / or dosage form is within the scope of reasonable medical judgment and is suitable for contact with the tissues of humans and other animals. In some embodiments, "pharmaceutically acceptable" means approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeias for use in animals and more particularly for humans. In some embodiments, pharmaceutically acceptable compounds, materials, compositions and / or dosage forms will not have a lasting adverse effect on the overall health of the subject or the subject being treated. However, it should be recognized that transient effects, such as slight irritation or "tingling" sensation, are common when administering drugs, and the presence of such transient effects is not inconsistent with the composition, formulation or ingredients (e.g., excipients) described.

[0038] As used herein, the phrase "pharmaceutically acceptable salt" includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including, but not limited to, sulfates, thiosulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, bisulfites, phosphates, acid phosphates, isonicotinates, borates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, oleates, tannates, pantothenates, The compounds comprising the amino moiety can form pharmaceutically acceptable salts with various amino acids other than the above acids. Compounds that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal salts or alkaline earth metal salts, particularly calcium salts, magnesium salts, ammonium salts, sodium salts, lithium salts, zinc salts, potassium salts, and iron salts. Salts also include quaternary ammonium salts of the compounds described herein, wherein these compounds have one or more tertiary amine moieties.

[0039] As used herein, the term "prevention" or "preventing" means reducing the risk of acquiring myopia.

[0040] As used herein, the term "prodrug" means a derivative of a known direct-acting drug that may have enhanced delivery characteristics and therapeutic value compared to the active drug and is converted to the active drug by enzymatic or chemical methods.

[0041] As used herein, the term "purified" means that when isolated, the isolate contains at least 90%, at least 95%, at least 98%, at least 99% or 100% of a compound described herein by weight of the isolate.

[0042] As used herein, the phrase "quaternary ammonium salt" means a derivative of the disclosed compounds having one or more tertiary amine moieties, wherein at least one tertiary amine moiety in the parent compound is converted to a quaternary ammonium cation by alkylation, such as methylation or ethylation (and the cation is replaced by an anion such as Cl - 、CH3COO - and CF3COO - balance) and is modified.

[0043] As used herein, the phrase "solubilizer" means an agent that causes the formation of a micellar solution or a true solution of the drug.

[0044] As used herein, the term "solution / suspension" means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in the form of microparticles suspended in a liquid matrix.

[0045] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it was formed or detected.

[0046] As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or agent that causes a biological or pharmaceutical response that a researcher, veterinarian, doctor or other clinician seeks in a tissue, system, animal, individual or human. The therapeutic effect depends on the condition being treated or the desired biological effect. Therefore, the therapeutic effect can be to reduce the severity of symptoms associated with the condition and / or inhibit (partially or completely) the development of the condition, or to improve treatment, cure, prevent or eliminate the condition or side effects. The amount required to elicit a therapeutic response can be based on, for example, the age, health, size and sex of the subject. The optimal amount can also be determined based on monitoring of the subject's response to treatment.

[0047] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the goal is to prevent or slow (mitigate) myopia, or to obtain a beneficial or desired clinical outcome. For purposes herein, beneficial or desired clinical outcomes include, but are not limited to, relieving symptoms; reducing the degree of myopia; stabilizing (i.e., not worsening) the myopic state; delaying the onset of myopia or myopia progression or slowing myopia or myopia progression; improving myopia, whether detectable or undetectable; improving at least one measurable physical parameter that is not necessarily discernible by the patient; or enhancing or improving myopia. Treatment includes optionally causing a clinically significant response without excessive side effects.

[0048] It will be appreciated that certain features of the disclosure described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination.

[0049] The resolution of the racemic mixture of a compound can be carried out by any of many methods known in the art, including, for example, fractional recrystallization using a chiral resolution acid (which is an optically active salified organic acid). Suitable resolution agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid in the form of D and L; and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolution agents suitable for fractional recrystallization methods include, but are not limited to, α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of a racemic mixture can also be carried out by eluting on a column filled with an optically active resolution agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0050] Suitable compounds described herein may also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, including but not limited to 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms may be in equilibrium or spatially locked into a form by appropriate substitution.

[0051] The compounds described herein also include hydrates and solvates, as well as anhydrous and non-solvated forms.

[0052] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. 12 C) Can be used in any position 13 C or 14 C instead. Nitrogen ( 14 N) can be used 15 N replaces. Oxygen ( 16 O) Can be used in any position 17 O or 18 O instead. Sulfur ( 32 S) can be used 33 S. 34 S or 36 S replaces. Chloro ( 35 Cl) can be used 37 Cl replaces. Bromine ( 79 Br) can be used 81 Br instead.

[0053] In some embodiments, the compounds or their salts are substantially isolated. Partial isolation can include, for example, a composition enriched with any one or more of the compounds described herein. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of any one or more of the compounds described herein or their salts. Methods for separating compounds and their salts are conventional in the art.

[0054] Compounds described herein can be prepared as prodrugs. Examples of prodrugs include compounds as described herein, which contain one or more molecular moieties of hydroxyl, amino, sulfhydryl or carboxyl groups attached to the compound, and when administered to a patient, they are cleaved in vivo to form free hydroxyl, amino, sulfhydryl or carboxyl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in compounds described herein. The preparation and use of prodrugs are discussed in the following documents: T. Higuchi et al., "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0055] Compounds containing amine functional groups can also form N-oxides. Compounds containing amine functional groups mentioned herein also include N-oxides. In the case where the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxides. Examples of N-oxides include N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Jerry March's Advanced Organic Chemistry, 4th edition, Wiley Interscience).

[0056] Unless otherwise expressly stated, it is by no means intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a particular order. Thus, in the absence of a method claim specifically stating in the claim or specification that the steps are restricted to a particular order, no order is intended to be inferred in any way. This applies to any possible non-explicit basis for interpretation, including logical issues regarding the arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0057] The present disclosure provides an aqueous pharmaceutical solution comprising benzyl atropine having Formula I:

[0058]

[0059] Or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one tonicity agent, and at least one solubilizing agent. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01% to about 0.2% (wt / wt). In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.05% to about 0.2% (wt / wt). In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.1% to about 0.15% (wt / wt). In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.11% to about 0.14% (wt / wt). In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.12% to about 0.13% (wt / wt).

[0060] In some embodiments, at least one buffer comprises at least one acetate buffer, at least one propionate buffer, at least one malate buffer, at least one fumarate buffer, at least one lactate buffer, at least one malonate buffer, at least one malate buffer, at least one mandelate buffer, at least one citrate buffer, at least one tartrate buffer, at least one succinate buffer, at least one phosphate buffer, at least one borate buffer, at least one bicarbonate buffer, or at least one buffer comprising 2-amino-2-methyl-1-propanol. In some embodiments, the at least one buffer comprises at least one phosphate buffer. In some embodiments, the at least one buffer comprises at least one acetate buffer. In some embodiments, the at least one buffer comprises at least one propionate buffer. In some embodiments, the at least one buffer comprises at least one malate buffer. In some embodiments, the at least one buffer comprises at least one fumarate buffer. In some embodiments, the at least one buffer comprises at least one lactate buffer. In some embodiments, the at least one buffer comprises at least one malonate buffer. In some embodiments, the at least one buffer comprises at least one malate buffer. In some embodiments, the at least one buffer comprises at least one mandelate buffer. In some embodiments, the at least one buffer comprises at least one citrate buffer. In some embodiments, the at least one buffer comprises at least one tartrate buffer. In some embodiments, the at least one buffer comprises at least one succinate buffer. In some embodiments, the at least one buffer comprises at least one phosphate buffer. In some embodiments, the at least one buffer comprises at least one boric acid buffer. In some embodiments, the at least one buffer comprises at least one bicarbonate buffer. In some embodiments, the at least one buffer comprises at least one buffer comprising 2-amino-2-methyl-1-propanol.

[0061] In some embodiments, the aqueous pharmaceutical solution further comprises at least one additional buffer. In some embodiments, the at least one additional buffer comprises at least one acetate buffer. In some embodiments, the at least one buffer comprises at least one phosphate buffer, and the at least one additional buffer comprises at least one acetate buffer.

[0062] In some embodiments, the concentration of the at least one buffer is about 0.1 to about 50mM. In some embodiments, the concentration of the at least one buffer is about 5 to about 40mM. In some embodiments, the concentration of the at least one buffer is about 10 to about 30mM. In some embodiments, the concentration of the at least one buffer is about 15 to about 20mM. In some embodiments, the concentration of the at least one buffer is about 18mM. In some embodiments, the concentration of the at least one buffer is about 18mM. In some embodiments, the concentration of the at least one buffer is about 20 to about 40mM. In some embodiments, the concentration of the at least one buffer is about 25 to about 35mM. In some embodiments, the concentration of the at least one buffer is about 30mM. In some embodiments, the concentration of the at least one buffer is about 30mM.

[0063] In some embodiments, the at least one buffer comprises at least one acetate buffer or at least one phosphate buffer. In some embodiments, the at least one buffer has a concentration of about 15 to about 25 mM. In some embodiments, the at least one buffer has a concentration of about 20 mM. In some embodiments, the at least one buffer has a concentration of about 20 mM.

[0064] In some embodiments, the at least one buffer comprises at least one citrate buffer or at least one phosphate buffer.

[0065] In some embodiments, the at least one additional buffer has a concentration of about 0.1 to about 50 mM. In some embodiments, the at least one additional buffer has a concentration of about 0.5 to about 15 mM. In some embodiments, the at least one additional buffer has a concentration of about 1 to about 10 mM. In some embodiments, the at least one additional buffer has a concentration of about 2.5 to about 7.5 mM. In some embodiments, the at least one additional buffer has a concentration of about 5 mM. In some embodiments, wherein the at least one additional buffer has a concentration of about 5 mM. In some embodiments, the at least one additional buffer comprises at least one phosphate buffer.

[0066] In some embodiments, the at least one tonicity agent comprises sorbitol, propylene glycol, dextrose, glycerol, mannitol, potassium chloride, or sodium chloride, or any combination thereof. In some embodiments, the at least one tonicity agent comprises sorbitol. In some embodiments, the at least one tonicity agent comprises propylene glycol.

[0067] In some embodiments, the at least one tonicity agent comprises dextrose. In some embodiments, the at least one tonicity agent comprises glycerol. In some embodiments, the at least one tonicity agent comprises mannitol. In some embodiments, the at least one tonicity agent comprises potassium chloride. In some embodiments, the at least one tonicity agent comprises sodium chloride. In some embodiments, the concentration of the at least one tonicity agent is about 0.01% to about 5% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 0.05% to about 2.5% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 0.1% to about 1% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 0.3% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution. In some embodiments, the at least one tonicity agent is sodium chloride. In some embodiments, the concentration of the at least one tonicity agent is about 0.1% to about 3% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 0.5% to about 1.5% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 1% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 1% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the at least one tonicity agent comprises propylene glycol. In some embodiments, the concentration of the at least one tonicity agent is about 1.5% to about 2.5% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one tonicity agent is about 2% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the at least one tonicity agent comprises glycerol.

[0068] In some embodiments, the molar osmotic pressure concentration of the aqueous pharmaceutical solution is about 260 to about 330 mOsm / kg based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the molar osmotic pressure concentration of the aqueous pharmaceutical solution is about 270 to about 320 mOsm / kg based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the molar osmotic pressure concentration of the aqueous pharmaceutical solution is about 280 to about 310 mOsm / kg based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the molar osmotic pressure concentration of the aqueous pharmaceutical solution is about 290 to about 300 mOsm / kg based on the total weight of the aqueous pharmaceutical solution. In some embodiments, wherein the molar osmotic pressure concentration of the aqueous pharmaceutical solution is about 300 mOsm / kg based on the total weight of the aqueous pharmaceutical solution.

[0069] In some embodiments, at least one solubilizing agent includes polyethylene glycol-400, polyethylene glycol-35 / castor oil, polypropylene glycol, polysorbate-80, polyethylene glycol-40 stearate, poloxamer-407, dimethyl sulfoxide, or hydroxypropyl-β-cyclodextrin, or any combination thereof. In some embodiments, the at least one solubilizing agent includes polyethylene glycol-400. In some embodiments, the at least one solubilizing agent includes polyethylene glycol-35 / castor oil. In some embodiments, the at least one solubilizing agent includes polypropylene glycol. In some embodiments, the at least one solubilizing agent includes polysorbate-80. In some embodiments, the at least one solubilizing agent includes polyethylene glycol-40 stearate. In some embodiments, the at least one solubilizing agent includes poloxamer-407. In some embodiments, the at least one solubilizing agent includes dimethyl sulfoxide.

[0070] In some embodiments, the at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin.

[0071] In some embodiments, the concentration of the at least one solubilizing agent is about 0.1% to about 30% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one solubilizing agent is about 1% to about 10% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0072] In some embodiments, the at least one solubilizing agent comprises polyethylene glycol-400, and wherein the concentration of polyethylene glycol-400 is about 1%, about 3.5%, or about 5% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the at least one solubilizing agent comprises polyethylene glycol-35 / castor oil, and wherein the concentration of polyethylene glycol-35 / castor oil is about 5% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0073] In some embodiments, the at least one solubilizing agent comprises polysorbate-80, and wherein the concentration of polysorbate-80 is about 1% or about 4% (wt / wt) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the at least one solubilizing agent comprises polyethylene glycol-40 stearate, and wherein the concentration of polyethylene glycol-40 stearate is about 7% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0074] In some embodiments, the at least one solubilizing agent comprises poloxamer-407, and wherein the concentration of poloxamer-407 is about 2% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0075] In some embodiments, the at least one solubilizing agent comprises dimethyl sulfoxide, and wherein the concentration of dimethyl sulfoxide is about 20% (wt / wt) based on the total weight of the aqueous drug solution.

[0076] In some embodiments, the at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin, and wherein the concentration of hydroxypropyl-β-cyclodextrin is about 2.5%, about 5%, or about 10% (wt / wt) based on the total weight of the aqueous drug solution.

[0077] In some embodiments, the aqueous pharmaceutical solution comprises at least one additional solubilizing agent. In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-400, polyethylene glycol-35 / castor oil, polypropylene glycol, polysorbate-80, polyethylene glycol-40 stearate, poloxamer-407, dimethyl sulfoxide, or hydroxypropyl-β-cyclodextrin, or any combination thereof.

[0078] In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-400. In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-35 / castor oil. In some embodiments, the at least one additional solubilizing agent comprises polypropylene glycol. In some embodiments, the at least one additional solubilizing agent comprises polysorbate-80. In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-40 stearate. In some embodiments, the at least one additional solubilizing agent comprises poloxamer-407. In some embodiments, the at least one additional solubilizing agent comprises dimethyl sulfoxide. In some embodiments, the at least one additional solubilizing agent comprises hydroxypropyl-β-cyclodextrin. In some embodiments, the concentration of the at least one additional solubilizing agent is about 0.1% to about 30% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of the at least one additional solubilizing agent is about 1% to about 10% (wt / wt) based on the gross weight of the aqueous pharmaceutical solution.

[0079] In some embodiments, the at least one additional solubilizer comprises polyethylene glycol-400, and wherein the concentration of polyethylene glycol-400 is about 1%, about 3.5%, or about 5% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0080] In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-35 / castor oil, and wherein the concentration of polyethylene glycol-35 / castor oil is about 5% (wt / wt) based on the total weight of the aqueous drug solution.

[0081] In some embodiments, the at least one additional solubilizer comprises polysorbate-80, and wherein the concentration of polysorbate-80 is about 1% or about 4% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0082] In some embodiments, the at least one additional solubilizer comprises polyethylene glycol-40 stearate, and wherein the concentration of polyethylene glycol-40 stearate is about 7% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0083] In some embodiments, the at least one additional solubilizing agent comprises poloxamer-407, and wherein the concentration of poloxamer-407 is about 2% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0084] In some embodiments, the at least one additional solubilizing agent comprises dimethyl sulfoxide, and wherein the concentration of dimethyl sulfoxide is about 20% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0085] In some embodiments, the at least one additional solubilizer comprises hydroxypropyl-β-cyclodextrin, and wherein the concentration of hydroxypropyl-β-cyclodextrin is about 2.5%, about 5%, or about 10% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0086] In some embodiments, the combined concentration of the at least one solubilizing agent and the at least one additional solubilizing agent is greater than 5.0% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

[0087] In some embodiments, the aqueous pharmaceutical solution has a pH of about 5 to about 8. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5 to about 7. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.0 to about 7.0. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5 to about 6. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.0 to about 6.0. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.5 to about 6.5. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.5. In some embodiments, the aqueous pharmaceutical solution has a pH of about 6. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.5. In some embodiments, the aqueous pharmaceutical solution has a pH of about 6.

[0088] In some embodiments, the aqueous pharmaceutical solution further comprises at least one preservative. In some embodiments, the at least one preservative comprises benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, chlorobutanol, phenol, m-cresol, chlorocresol, benzoic acid, sorbic acid, thimerosal, phenylmercuric nitrate, bronopol, propylene glycol, polyquaternium-1 or benzethonium chloride, or any combination thereof.

[0089] In some embodiments, the at least one preservative includes benzalkonium chloride. In some embodiments, the at least one preservative includes methyl paraben. In some embodiments, the at least one preservative includes ethyl paraben. In some embodiments, the at least one preservative includes propyl paraben. In some embodiments, the at least one preservative includes butyl paraben. In some embodiments, the at least one preservative includes benzyl alcohol. In some embodiments, the at least one preservative includes chlorobutanol. In some embodiments, the at least one preservative includes phenol. In some embodiments, the at least one preservative includes metacresol. In some embodiments, the at least one preservative includes chlorocresol. In some embodiments, the at least one preservative includes benzoic acid. In some embodiments, the at least one preservative includes sorbic acid. In some embodiments, the at least one preservative includes thimerosal. In some embodiments, the at least one preservative includes phenylmercuric nitrate. In some embodiments, the at least one preservative includes Bropol. In some embodiments, the at least one preservative includes propylene glycol. In some embodiments, the at least one preservative includes polyquaternium-1. In some embodiments, the at least one preservative includes benzethonium chloride.

[0090] In some embodiments, the aqueous pharmaceutical solution does not contain a preservative. In some embodiments, the aqueous pharmaceutical solution does not contain benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, chlorobutanol, phenol, m-cresol, chlorocresol, benzoic acid, sorbic acid, thimerosal, phenylmercuric nitrate, bromopol, propylene glycol, polyquaternium-1 or benzethonium chloride.

[0091] In some embodiments, wherein the aqueous pharmaceutical solution does not contain benzalkonium chloride. In some embodiments, wherein the aqueous pharmaceutical solution does not contain methylparaben. In some embodiments, wherein the aqueous pharmaceutical solution does not contain ethylparaben. In some embodiments, wherein the aqueous pharmaceutical solution does not contain propylparaben. In some embodiments, wherein the aqueous pharmaceutical solution does not contain butylparaben. In some embodiments, wherein the aqueous pharmaceutical solution does not contain benzyl alcohol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain chlorobutanol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain phenol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain metacresol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain chlorocresol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain benzoic acid. In some embodiments, wherein the aqueous pharmaceutical solution does not contain sorbic acid. In some embodiments, wherein the aqueous pharmaceutical solution does not contain thimerosal. In some embodiments, wherein the aqueous pharmaceutical solution does not contain phenylmercuric nitrate. In some embodiments, wherein the aqueous pharmaceutical solution does not contain Bropol. In some embodiments, wherein the aqueous pharmaceutical solution does not contain propylene glycol. In some embodiments, the aqueous pharmaceutical solution does not contain polyquaternium- 1. In some embodiments, the aqueous pharmaceutical solution does not contain benzethonium chloride.

[0092] In some embodiments, the aqueous pharmaceutical solution is placed in a dropper bottle. In some embodiments, the dropper bottle is a multiple use dropper bottle.

[0093] In some embodiments, the aqueous pharmaceutical solution further comprises at least one additional buffer and at least one additional solubilizing agent. In some embodiments, the concentration of benzyl atropine is about 0.05% to about 0.2% (wt / wt). In some embodiments, the at least one buffer comprises at least one acetate buffer. In some embodiments, the at least one tonicity agent comprises sodium chloride. In some embodiments, the at least one solubilizing agent comprises polyethylene glycol-400. In some embodiments, the at least one additional buffer comprises at least one phosphate buffer. In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-35. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5 to about 6.

[0094] In some embodiments, the aqueous pharmaceutical solution further comprises at least one additional buffer and at least one additional solubilizing agent. In some embodiments, the concentration of benzyl atropine is about 0.1% to about 0.15% (wt / wt). In some embodiments, the at least one buffer comprises at least one acetate buffer. In some embodiments, the at least one tonicity agent comprises sodium chloride. In some embodiments, the at least one solubilizing agent comprises polyethylene glycol-400. In some embodiments, the at least one additional buffer comprises at least one phosphate buffer. In some embodiments, the at least one additional solubilizing agent comprises polyethylene glycol-35. In some embodiments, the aqueous pharmaceutical solution has a pH of about 6 to about 7.

[0095] In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.1% to about 0.15% (wt / wt). In some embodiments, the at least one buffer comprises at least one acetate buffer. In some embodiments, the at least one tonicity agent comprises mannitol or sodium chloride. In some embodiments, the at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin. In some embodiments, the aqueous pharmaceutical solution has a pH of about 5.5 to about 6.5.

[0096] The present disclosure also provides a method for preparing an aqueous solution comprising benzyl atropine having Formula I:

[0097]

[0098] or a pharmaceutically acceptable salt or prodrug thereof, the method comprising: providing an aqueous solution comprising at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent; and adding benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution. In some embodiments, the aqueous solution has a pH value of about 4 to about 5. In some embodiments, benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is dissolved in the aqueous solution, thereby providing an aqueous solution. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution of benzyl atropine is about 0.05% to about 0.2% (wt / wt). In some embodiments, the aqueous solution of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0099] The present disclosure also provides products of the methods of preparing an aqueous solution comprising benzyl atropine having Formula I:

[0100]

[0101] or a pharmaceutically acceptable salt or prodrug thereof, the method comprising: providing an aqueous solution comprising at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent; and adding benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution. In some embodiments, the aqueous solution has a pH value of about 4 to about 5. In some embodiments, benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is dissolved in the aqueous solution, thereby providing an aqueous solution. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.05% to about 0.2% (wt / wt). In some embodiments, the aqueous solution of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0102] The present disclosure also provides methods of preventing myopia, treating myopia, reducing myopia progression, or preventing myopia progression in a subject in need thereof, the methods comprising administering to an eye of the subject a therapeutically effective amount of an aqueous pharmaceutical solution comprising benzyl atropine having Formula I:

[0103]

[0104] Or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one tonicity agent and at least one solubilizing agent. In some embodiments, the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.05% to about 0.2% (wt / wt). In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes a method for preventing myopia. In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes treating myopia. In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes reducing myopia. In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes preventing myopia. In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes preventing myopia. In some embodiments, the method for preventing myopia, treating myopia, reducing myopia progression or preventing myopia includes preventing myopia. In some embodiments, the aqueous pharmaceutical solution is applied once a day. In some embodiments, the aqueous pharmaceutical solution is applied twice a day. In some embodiments, the aqueous pharmaceutical solution is applied every other day, and wherein the concentration of benzyl atropine in the aqueous pharmaceutical solution is higher than the concentration necessary for treating myopia of the subject when the aqueous pharmaceutical solution is applied once a day to the subject's eye.

[0105] The compounds described herein may be included in formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, moisturizers, solubilizers, preservatives, etc. The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein may be used with medicaments, which include, but are not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or irrigants (e.g., Caphosol). The drug carrier may be a liquid, such as water and oil, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. The drug carrier may also be saline, gum arabic, gelatin, starch paste, talcum powder, keratin, colloidal silicon dioxide, urea, etc. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used.

[0106] The compounds described herein can be administered alone (as a single compound or one or more compounds described herein) or in combination with other agents (simultaneously or sequentially). For example, the compounds can be administered in combination with any one or more of the following: antibiotics, such as: a) protein synthesis inhibitors, including but not limited to amikacin, anisomycin, apramycin, azithromycin, blasticidin S, brefeldin A, butyrin, chloramphenicol, chlortetracycline, clindamycin, clotrimazole, cycloheximide, demeclocycline, dibekacin, dihydrostreptomycin, doxycycline, duramycin, emetine, erythromycin, fusidic acid, G 418, gentamicin, fumagillic acid, hygromycin B, josamycin, kanamycin, lincomycin, meclocycline, mepartricin, midecamycin, minocycline, neomycin, netilmicin, nitrofurantoin, nourseothricin, oleandomycin, oxytetracycline, paromomycin, puromycin, rapamycin, ribostamycin, rifampicin, rifamycin, rosterin, sithromycin, spectinomycin, spiramycin, streptomycin, tetracycline, domecycline, chloramphenicol, oxytetracycline, Thiostrepton, tobramycin, tunicamycin, tylosin, puromycin and virginiamycin; b) DNA synthesis interfering agents, including but not limited to camptothecin, 10-deacetylbaccatin III, azacytidine, 7-aminoactinomycin D, 8-quinolinol, 9-dihydro-13-acetylbaccatin III, aclarubicin, actinomycin D, actinomycin I, actinomycin V, bafilomycin A1, bleomycin, capreomycin, chromomycin, cinoxacin, ciprofloxacin, Norfloxacin, cis-diamminedichloroplatinum (II), coumermycin A1, L(+)-lactic acid, cytochalasin B, cytochalasin D, dacarbazine, daunorubicin, distamycin A, doxorubicin, echinocin, enrofloxacin, etoposide, flumequine, metopromycin, fumagillin, ganciclovir, gliotoxin, lomefloxacin, metronidazole, mithramycin A, mitomycin C, nalidixic acid, fumarin, nitrofurantoin, nogamycin, novobiocin, ofloxacin , oxolinic acid, paclitaxel, phenazine, phleomycin, pipemidic acid, phaeomycin, sinefungin, streptozocin, streptozotocin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidinepurum, sulfamethoxazole, sulfamethoxazole, sulfaquinoxaline, sulfasalazine, sulfacetamide, sulfathiazole, trimethoprim, tuberculin, 5-azacytidine, cordycepin, and metoprolol A;c) Cell wall synthesis disruptors, including but not limited to (+)-6-aminopenicillanic acid, 7-aminodesacetoxycephalosporinic acid, amoxicillin, ampicillin, oxacillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cephalosporin, cefmetazole, cefixime, cefoperazone, cefotaxime, cefsulodin, ceftriaxone, cefalexin, cephalosporin C, cephalosporin, cephradine, ceftazidime, cloxacillin, D-cycloserine, dicloxacillin, D-penicillamine, ceftizoxime, econazole, ethambutol, lysostaphin, ramoxef, nafcillin, hemicycline Z, nitrofurantoin, oxacillin, penicillic acid, penicillin G, phenoxyethyl penicillin, phenoxymethyl penicillin acid, fosfomycin, pipemidic acid, piperacillin, lestatin d) cell membrane permeability disruptors (ionophores), including but not limited to amphotericin B, 2-thiopyridine, 4-bromocalcimycin A23187, colistin, alamethicin, calcimycin A23187, chlorhexidine, clotrimazole, econazole, hydrocortisone, filipin, gliotoxin, gramicidin A, gramicidin C, ionomycin, lasalocidin A, ronomycin A, monensin, narasin, nigericin, nisin, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, sulfisoxazole, pyrimethamine, mafenide, inactivein, nystatin, phenazine, pimaricin, polymyxin B, DL-penicillamine, praziquantel, salinomycin, surfactin and valinomycin;e) enzyme inhibitors, including but not limited to (+)-lichenic acid, (±)-miconazole, (S)-(+)-camptothecin, 1-deoxymannojirimycin, 2-heptyl-4-hydroxyquinoline N-oxide, cordycepin, antimycin, 1,10-phenanthroline, 6-diazo-5-oxo-L-norleucine, 8-quinolinol, antinociceptives, ascomycin, azaserine, bafilomycin, cyanobacterium , chloroquine, cinoxacin, ciprofloxacin, mevastatin, concanavalin A, concanavalin C, coumermycin A1, L(+)-lactic acid, cyclosporin A, econazole, enrofloxacin, etoposide, flumequine, metopromycin A, furazolidone, fusaric acid, geldanamycin, gliotoxin, gramicidin A, gramicidin C, herbimycin A, indomethacin, triclosan, lomefloxacin, mycophenolic acid, myxothiazole, Nalidixic acid, spindlemycin, niclosamide, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-methyl-1-deoxynojirimycin, hemimycin, nogamycin, inactive, neomycin, ofloxacin, oleandomycin, oligomycin, oxolinic acid, penicillin A, pipemidic acid, radicicol, rapamycin, butterfly mycin, sinefungin, staurosporine, pilinomycin, succinylsulfathiazole, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamethoxine, sulfamethoxine, sulfaquinoxaline, sulfasalazine, sulfathiazole, triazine C, trimethoprim and vinomycin A1; f) membrane modifiers, including but not limited to paracelsin; g) aminoglycosides; and h) fluoroquinolones. ;

[0107] The amount of the compound to be administered can be a therapeutically effective amount. The dosage to be administered can depend on the characteristics of the subject being treated, such as the specific animal being treated, age, body weight, health status, type of simultaneous treatment (if any) and frequency of treatment, as well as the nature and degree of myopia, and can be easily determined by those skilled in the art (e.g., by a clinician). The selection of a specific dosage regimen can be selected or adjusted or titrated by a clinician according to methods known to clinicians to obtain a desired clinical response. In addition, in vitro or in vivo assays can be optionally used to help determine the optimal dosage range. The precise dosage to be used in these compositions can also depend on the route of administration, and should be determined according to the judgment of the practitioner and the circumstances of each patient.

[0108] The pharmaceutical composition can be in unit dosage form. In this form, the composition can be divided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a packaged preparation that contains discrete amounts of the preparation in a vial or ampoule.

[0109] One or more ophthalmic lubricants may also be optionally included in the composition to promote lacrimation or as a "dry eye" medicament. Such agents include, but are not limited to, polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and the like. It should be understood that promoting lacrimation is only beneficial in the present invention in the case of a natural lack of lacrimation, with the goal of restoring a normal level of tear secretion. In the event of excessive lacrimation, the residence time of the composition in the eye may be reduced.

[0110] The present disclosure also provides a drug package or a test kit, which contains one or more containers filled with one or more compounds or compositions described herein. Optionally, associated with such one or more containers may be a notice in a form prescribed by a government agency that manages the manufacture, use or sale of drugs or biological products, which reflects the agency's permission to manufacture, use or sell for human administration in order to treat myopia described herein. In some embodiments, the test kit contains more than one compound or composition described herein.

[0111] The present disclosure also provides methods for treating a subject with myopia or preventing a subject from developing myopia, which methods include administering to the subject's eye any aqueous pharmaceutical solution containing benzyl atropine as described herein. The present disclosure also provides methods for treating a subject with myopia or preventing a subject from developing myopia, which methods include administering to the subject's eye any aqueous pharmaceutical solution as described herein.

[0112] In some embodiments, the administration is to one eye of the subject. In some embodiments, the administration is to both eyes of the subject.

[0113] In some embodiments, the aqueous pharmaceutical solution exhibits increased bioavailability. In some embodiments, the bioavailability comprises corneal bioavailability, conjunctival bioavailability, or ocular bioavailability.

[0114] In some embodiments, the aqueous pharmaceutical solution can be administered to the eye in the form of eye drops.

[0115] In some embodiments, the aqueous drug solution is topically applied to one or more tissues of the eye. The frequency of application is typically such that the dosing interval (e.g., the time period between one dose and the next dose) during waking hours is about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. One skilled in the art will appreciate that the appropriate dosing interval depends, to some extent, on the length of time that the selected composition is able to maintain the desired concentration of the aqueous drug solution in the tears and / or target tissue (e.g., conjunctiva or cornea).

[0116] The disclosure also provides the use of any aqueous pharmaceutical solution described herein for treating a subject with an ocular condition or preventing a subject from developing an ocular condition. The disclosure also provides the use of any aqueous pharmaceutical solution described herein that does not contain a preservative for treating a subject with an ocular condition or preventing a subject from developing an ocular condition. The disclosure also provides the use of any aqueous pharmaceutical solution described herein in the manufacture of a medicament for treating a subject with an ocular condition or preventing a subject from developing an ocular condition. The disclosure also provides the use of any aqueous pharmaceutical solution described herein that does not contain a preservative in the manufacture of a medicament for treating a subject with an ocular condition or preventing a subject from developing an ocular condition. In some embodiments, the ocular condition is myopia.

[0117] In order to more effectively understand the subject matter disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be interpreted as limiting the claimed subject matter in any way.

[0118] Examples

[0119] Example 1: Identification of benzyl atropine as a lead compound

[0120] The higher doses of atropine required to prevent myopia are associated with debilitating side effects including pupil dilation and light sensitivity (ATOM1, ATOM2 and LAMP studies). Furthermore, it is known that atropine decomposes into tropicol and tropic acid in aqueous solution:

[0121] Degradation pathway A: Intermolecular aqueous hydrolysis

[0122]

[0123] Degradation pathway B: intermolecular cyclization followed by aqueous hydrolysis

[0124]

[0125] Part of the reason for the instability problem of atropine is the lack of substitution at the α position. To avoid this problem, substitutions at the α position of atropine were considered and tested in the FDM chicken model. Briefly, monocular form deprivation myopia (FDM) was induced in the right eye of a chicken using translucent diffusion goggles, while the contralateral left eye remained goggled to serve as a control eye (normal). After induction of myopia (days 2 and 4), the right eye with goggles was treated with intravitreal injections of vehicle with or without drug, while the left eye without goggles was injected with saline. On day 5, the refractive error of the eye was measured using a retinoscope. The animals were then euthanized, the eyes removed, and the axial length measured using a digital caliper. Methylatropine, fluoro-atropine, and benzyl atropine were found to be effective in the FDM chicken model (see Figure 1, panel A). However, unexpectedly, benzyl atropine was found to be as effective as atropine in the FDM chicken model, but at a concentration approximately one-tenth that of atropine (see Figure 1 , sub-figure B).

[0126] The binding coefficients of atropine, methylatropine and benzylatropine to M1, M2, M3, M4 and M5 muscarinic receptors were then determined (Table 1). In vitro pharmacology studies were performed to determine the ability of the newly synthesized compounds to bind to different muscarinic receptors (dose response) by radioligand displacement studies using known radiolabeled receptor selective ligands as references. The binding affinity (ki) of the synthesized compounds can be determined from IC50 and KD values.

[0127] Table 1

[0128]

[0129] Although atropine and methylatropine were found to have non-selective binding to muscarinic receptors, benzyl atropine was unexpectedly found to bind weakly to M1 and M4 receptors, but not at all to M2, M3, and M5 receptors. The lack of M3 receptor binding specifically suggested an opportunity to avoid the side effects associated with natural atropine. Thus, benzyl atropine was identified as a lead candidate.

[0130] Example 2: Solubility of Atropine, Methylatropine, and Benzylatropine

[0131] As part of the initial formulation development process, atropine, methyl atropine and benzyl atropine were screened in two simple vehicles: 30 mM phosphate buffer (pH 7.4) and phosphate buffered saline (pH 7.4) to evaluate their solubility profiles. Vortexing was used for five minutes to provide the best possible conditions for dissolution. It was expected that the solubility of atropine, methyl atropine and benzyl atropine was good in both vehicles, and after atropine, methyl atropine and benzyl atropine were dissolved, the pH of the two vehicles would remain essentially unchanged. The theoretical and actual concentrations of atropine, methyl atropine and benzyl atropine in the resulting formulations are listed in Table 2.

[0132] Table 2

[0133]

[0134] While native atropine (i.e., atropine sulfate monohydrate) was readily soluble in both vehicles, methylatropine and benzylatropine unexpectedly did not completely dissolve in either vehicle. In addition, methylatropine and atropine unexpectedly contributed to an overall increase in the pH of the formulations (Table 3).

[0135] Table 3

[0136]

[0137] Therefore, it was considered necessary to lower the initial pH of the vehicle in order to: i) ensure higher solubility; and ii) reach an ophthalmically acceptable target pH (5-8). In addition, tonicity agents needed to be added to reach an acceptable target range of 280-320 mOsm / kg (Tables 4 and 5).

[0138] Table 4: Concentrations of methylatropine

[0139]

[0140]

[0141] Table 5: Methylatropine, pH and osmolarity

[0142]

[0143] Thus, for methylatropine, a 20 mM phosphate buffer with a starting pH of 2.7-2.8 yields a final pH close to the ideal range (pH 5 to 8) tolerable for an ophthalmic product.

[0144] It was expected that lowering the pH of the vehicle would result in complete dissolution of benzyl atropine as well as methyl atropine. However, unexpectedly, benzyl atropine did not completely dissolve after pH adjustment (Tables 6 and 7).

[0145] Table 6: pH Adjustment of Methylatropine and Benzylatropine Solutions

[0146]

[0147] Table 7: HPLC analysis of methylatropine and benzylatropine solutions

[0148]

[0149] Therefore, additional formulation components are needed to increase the solubility of benzyl atropine.Initially, individual excipients were evaluated (Table 8).

[0150] Table 8: Solubility of benzyl atropine in surfactants

[0151]

[0152] Polyethylene glycol 400 (PEG-400), used as a "pure" solution, provides the highest drug solubility of 8.01 mg / g (0.8%). However, the recommended concentration of PEG-400 as an inactive ingredient in the final drug product is 5%. Pure propylene glycol and polypropylene glycol present similar problems. In fact, diluting polypropylene glycol from 100% v / v to 50% v / v results in a significant decrease in benzyl atropine concentration.

[0153] Additional individual excipients were then evaluated for their ability to dissolve benzyl atropine in different buffers (Table 9).

[0154] Table 9: Concentration of benzyl atropine in surfactant mixture

[0155]

[0156]

[0157] As shown in Table 9, there was a two-fold increase in solubility with the change in buffer vehicle (5% PEG-35 castor oil in phosphate buffer (pH 2.8) vs. 5% PEG-35 castor oil in acetate buffer (pH 2.8)).

[0158] These excipients were also tested for their ability to dissolve benzyl atropine in the presence of citrate or acetate buffer (Table 10).

[0159] Table 10: Dissolution mixtures with citrate and acetate buffers

[0160]

[0161]

[0162] *Formulation: 7.0% PEG-40 Stearate, 5.0% PEG-35 Castor Oil, 5.0% PEG-400

[0163] **Formulation: 7.0% PEG-40 Stearate, 5.0% PEG-35 Castor Oil, 3.5% PEG-400

[0164] However, even the change of citrate and acetate buffers cannot immediately balance the need for high benzyl atropine concentration on the one hand and the need for a drug product with an ophthalmologically acceptable pH on the other hand. For example, in citrate buffer, when the starting pH is low, the concentration of benzyl atropine increases. However, the pH of the resulting drug product is also low, at 4.4, which may irritate the eye when instilled (Table 10, row 1). In contrast, when the starting pH is high, the concentration of benzyl atropine is low (row 2). In acetate buffer and at a lower starting pH, the resulting solution often does not have an ophthalmologically acceptable pH greater than 5 (row 3; see row 1). However, when the starting pH is high, it is found that the concentration of benzyl atropine is low (row 5, see row 2). After considerable efforts far beyond conventional optimization, it was found that for 30mM acetate buffer / surfactant mixtures, an acceptable starting pH is between 4.5-4.6 (row 4). Through stability assessment, a concentration of 5 mg / g benzyl atropine was determined to be close to the saturation solubility limit of the compound as the compound precipitated out of solution during storage.

[0165] Considerable effort was made to simplify the formulation to reduce the total amount of surfactant (Table 11).

[0166] Table 11: Concentrations of Benzyl Atropine in Freshly Prepared Formulations

[0167]

[0168]

[0169] The highest initial concentration was achieved with 7% PEG-40 stearate (Table 11, row 3). The highest achievable concentration of benzyl atropine without reprecipitation was 3.9 mg / g (row 5) in the presence of 3.5% PEG-400, 5% PEG-35 castor oil, and 0.37% NaCl. The combination of two different types of surfactants was unexpected. After extensive research, it was found that the acetate / phosphate buffered vehicle produced the highest concentration of benzyl acetate and a drug product with the most ophthalmologically acceptable pH. The efficacy of this "double buffered" vehicle was unexpected.

[0170] The physical stability of benzyl atropine in phosphate buffer was further evaluated using hydroxypropyl-β-cyclodextrin (HPβCD) as a solubilizing agent. Unexpectedly, it was found that 10% HPβCD was able to effectively dissolve benzyl atropine at concentrations close to the solubility limit (Tables 12 and 13).

[0171] Table 12: Initial evaluation of HPβCD as a solubilizer for benzyl atropine

[0172]

[0173] Table 13: Initial evaluation of HPβCD as a solubilizer for benzyl atropine

[0174]

[0175] In addition to those described herein, various modifications of the subject matter will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including but not limited to journal articles, U.S. and non-U.S. patents, patent application disclosures, international patent application disclosures, gene bank accession numbers, etc.) is incorporated herein by reference in its entirety.

Claims

1. An aqueous pharmaceutical solution comprising benzyl atropine having formula I: or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one tonicity agent, and at least one solubilizing agent, wherein the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01% to about 0.2% (wt / wt).

2. The aqueous pharmaceutical solution of claim 1, wherein the at least one buffer comprises at least one acetate buffer, at least one propionate buffer, at least one malate buffer, at least one fumarate buffer, at least one lactate buffer, at least one malonate buffer, at least one malate buffer, at least one mandelate buffer, at least one citrate buffer, at least one tartrate buffer, at least one succinate buffer, at least one phosphate buffer, at least one borate buffer, at least one bicarbonate buffer, or at least one buffer comprising 2-amino-2-methyl-1-propanol.

3. An aqueous pharmaceutical solution according to claim 1 or claim 2, further comprising at least one additional buffer.

4. The aqueous pharmaceutical solution of claim 3, wherein the at least one buffer comprises at least one phosphate buffer and the at least one additional buffer comprises at least one acetate buffer.

5. The aqueous pharmaceutical solution of any one of claims 1 to 4, wherein the at least one buffer comprises at least one acetate buffer or at least one phosphate buffer.

6. The aqueous pharmaceutical solution of any one of claims 1 to 5, wherein the at least one tonicity agent comprises sorbitol, propylene glycol, dextrose, glycerin, mannitol, potassium chloride, or sodium chloride, or any combination thereof.

7. The aqueous pharmaceutical solution of any one of claims 1 to 6, wherein the at least one solubilizing agent comprises polyethylene glycol-400, polyethylene glycol-35 / castor oil, polypropylene glycol, polysorbate-80, polyethylene glycol-40 stearate, poloxamer-407, dimethyl sulfoxide, or hydroxypropyl-β-cyclodextrin, or any combination thereof.

8. The aqueous pharmaceutical solution of any one of claims 1 to 7, wherein the at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin, and wherein the concentration of hydroxypropyl-β-cyclodextrin is about 2.5%, about 5%, or about 10% (wt / wt) based on the total weight of the aqueous pharmaceutical solution.

9. The aqueous pharmaceutical solution according to any one of claims 1 to 8, wherein the aqueous pharmaceutical solution comprises at least one additional solubilizer.

10. The aqueous pharmaceutical solution of any one of claims 1 to 9, wherein the aqueous pharmaceutical solution has a pH of about 5 to about 8.

11. The aqueous pharmaceutical solution according to any one of claims 1 to 10, wherein the aqueous pharmaceutical solution further comprises at least one preservative.

12. The aqueous pharmaceutical solution according to any one of claims 1 to 10, wherein the aqueous pharmaceutical solution does not contain a preservative.

13. The aqueous pharmaceutical solution of claim 1, further comprising at least one additional buffer and at least one additional solubilizer, wherein: The concentration of benzyl atropine is about 0.05% to about 0.2% (wt / wt); The at least one buffer comprises at least one acetate buffer; The at least one tonicity agent comprises sodium chloride; The at least one solubilizing agent comprises polyethylene glycol-400; The at least one additional buffer comprises at least one phosphate buffer; The at least one additional solubilizing agent comprises polyethylene glycol-35; and The aqueous pharmaceutical solution has a pH of about 5 to about 6.

14. The aqueous pharmaceutical solution of claim 1, further comprising at least one additional buffer and at least one additional solubilizer, wherein: The concentration of benzyl atropine is about 0.1% to about 0.15% (wt / wt); The at least one buffer comprises at least one acetate buffer; The at least one tonicity agent comprises sodium chloride; The at least one solubilizing agent comprises polyethylene glycol-400; The at least one additional buffer comprises at least one phosphate buffer; The at least one additional solubilizing agent comprises polyethylene glycol-35; and The aqueous pharmaceutical solution has a pH of about 6 to about 7.

15. The aqueous pharmaceutical solution of claim 1, wherein: The concentration of benzyl atropine is about 0.1% to about 0.15% (wt / wt); The at least one buffer comprises at least one acetate buffer; The at least one tonicity agent comprises mannitol or sodium chloride; The at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin; and The aqueous pharmaceutical solution has a pH of about 5.5 to about 6.

5.

16. A method for preparing an aqueous solution comprising benzyl atropine having the formula I: or a pharmaceutically acceptable salt or prodrug thereof, the method comprising: providing an aqueous solution comprising at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent, wherein the aqueous solution has a pH of about 4 to about 5; as well as adding the benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution, wherein the benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof is dissolved in the aqueous solution, thereby providing an aqueous solution of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof, and wherein the concentration of benzyl atropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01% to about 0.2% (wt / wt), and wherein the aqueous solution has a pH value greater than about 5.

17. A product of the process according to claim 16, wherein the aqueous solution of benzyl atropine is in the form of an aqueous pharmaceutical solution.

18. A method of preventing myopia, treating myopia, reducing myopia progression, or preventing myopia progression in a subject in need thereof, the method comprising administering to an eye of the subject a therapeutically effective amount of the aqueous pharmaceutical solution of claim 1.

19. The method of claim 18, wherein the aqueous pharmaceutical solution is administered every other day, and wherein the concentration of benzyl atropine, or a pharmaceutically acceptable salt or prodrug thereof, in the aqueous pharmaceutical solution is greater than the concentration necessary to treat myopia in the subject when the aqueous pharmaceutical solution is administered to the eye of the subject once daily.

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