Aqueous pharmaceutical composition containing benzylatropine and its use

Abstract

The present disclosure relates, in part, to an aqueous pharmaceutical solution comprising benzatropine or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizing agent, a process for preparing an aqueous solution comprising benzatropine, a product of such a process, and a method of preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia in a subject in need thereof by administering a therapeutically effective amount of such an aqueous pharmaceutical solution to the eye of the subject.

Description

[Technical Field]

[0001] This disclosure relates to compositions comprising benzylatropine or a pharmaceutically acceptable salt thereof, methods for preparing a benzylatropine composition, and methods for preventing or treating myopia, reducing the progression of myopia, or preventing the progression of myopia by administering a benzylatropine composition. [Background technology]

[0002] Myopia is a condition of the eye, sometimes called nearsightedness. For example, myopia can describe an object that has good near vision but poor far 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 accommodative power is relaxed. This is usually due to the eyeball being too long from front to back, but myopia can also be caused by an excessively curved cornea and / or increased refractive power of the lens (World Wide Web, "aoa.org / documents / optometrists / CPG-15").

[0003] Myopia has four forms, each evaluated by determining the spherical equivalent refractive error (RE) of the eye when accommodation is relaxed. Pre-myopia is a state where the spherical equivalent RE is ≤ +0.75 diopters (D) and > -0.50 D. Myopia is a state where the spherical equivalent RE is ≤ -0.50 D. Low myopia is a state where the spherical equivalent RE is ≤ -0.50 D and > -6.00 D. High myopia is a state where the spherical equivalent RE is ≤ -6.00 D.

[0004] The prevalence of myopia (nearsightedness) is projected to increase rapidly and double by 2050. Furthermore, high myopia is often associated with an increased risk of blindness (Holden et al., Ophthalmology, 2016, 123, 1036-42). Current treatments include corrective corneas, the use of multifocal soft contact lenses, bifocal or progressive eyeglasses, but the effectiveness of such treatments is at best moderate.

[0005] Several animal and human studies have evaluated different classes of pharmacological agents for their ability to reduce myopia progression. Of these studies, natural atropine isolated as a racemic mixture from belladonna (Atropa belladonna) has shown great promise in its ability to reduce myopia progression. Several large-scale randomized clinical trials conducted in Asian countries, namely the ATOM1, ATOM2, and LAMP studies, have tested the efficacy of natural atropine at various dose intensities to reduce 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.2019.126(1):113-124]. These clinical studies demonstrate the effectiveness of natural atropine in reducing myopia progression, but require high doses. However, these higher doses are associated with debilitating side effects, including pupillary dilation and photosensitivity. Furthermore, natural atropine is inherently unstable in aqueous solutions with physiological pH values. For example, atropine decomposes into tropic acid and tropine in aqueous solutions with a neutral pH value.Due to this degradation, natural atropine cannot survive as a pharmacological agent for the treatment of myopia. Therefore, there has been a long-standing unmet need for a pharmacological agent that is stable in aqueous solutions with a physiological pH value and can prevent, treat, reduce, or halt the progression of myopia. [Overview of the Initiative] [Means for solving the problem]

[0006] This disclosure relates to benzylatropine of formula I: [ka] The present invention provides a pharmaceutical aqueous solution comprising a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizer. In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01 to about 0.2% (weight / weight), preferably about 0.05 to about 0.2% (weight / weight).

[0007] This disclosure also relates to benzylatropine of formula I: [ka] The present invention provides a process for preparing an aqueous solution containing benzylatropine or a pharmaceutically acceptable salt or prodrug thereof, the process comprising the steps of providing an aqueous solution containing at least one acetate buffer, at least one solubilizer, and at least one additional solubilizer, and adding benzylatropine 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 benzylatropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01 to about 0.2% (weight / weight), preferably about 0.05 to about 0.2% (weight / weight). In some embodiments, the aqueous solution of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0008] This disclosure also relates to benzylatropine of formula I: [ka] The present invention provides a product of a process for preparing an aqueous solution containing a pharmaceutically acceptable salt or prodrug thereof, the process comprising the steps of providing an aqueous solution containing at least one acetate buffer, at least one solubilizer, and at least one additional solubilizer, and adding benzylatropine 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 benzylatropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01 to about 0.2% (weight / weight), preferably about 0.05 to about 0.2% (weight / weight). In some embodiments, the aqueous solution of benzylatropine has a pH value greater than about 5.

[0009] This disclosure also provides a method for preventing, treating, reducing the progression of myopia, or preventing the progression of myopia in subjects requiring it, the method comprising: a therapeutically effective amount of benzylatropine of formula I to the eye of the subject: [Chemical] It includes administering an aqueous pharmaceutical solution containing benzatropine or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizing agent. In some embodiments, the concentration of benzatropine or a pharmaceutically acceptable salt or prodrug thereof is from about 0.01% to about 0.2% (weight / weight), preferably from about 0.05% to about 0.2% (weight / weight).

[0010] The accompanying drawings incorporated herein and constituting a part of this specification illustrate some aspects and, together with the description, serve to explain the principles of the present disclosure.

Brief Description of the Drawings

[0011] [Figure 1-1] It shows that in form deprivation-induced myopia (FDM) in the chicken model, the synthetic atropine derivatives showed superior efficacy over myopia control. Panel A shows that the change in refractive error (goggle eye value - non-goggle eye value) in diopters (abscissa) for methylatropine (α-Me), fluoroatropine (fluro-atropine) (α-F), and benzatropine (α-Bz) decreased significantly with respect to a 5% v / v ethanol solution (ordinate). [Figure 1-2] It shows that in form deprivation-induced myopia (FDM) in the chicken model, the synthetic atropine derivatives showed superior efficacy over myopia control. Panel B shows the change in refractive error (goggle eye value - non-goggle eye) values in diopters (abscissa) observed for 5% v / v ethanol, atropine (Atro_240 nmol; ordinate), and benzatropine (Bz.atro_3A_24_nmol and Bz.atro_3B_24_nmol, where 3A and 3B refer to individual isomers of benzatropine) (ordinate) (abscissa).

Modes for Carrying Out the Invention

[0012] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0013] As used herein, the term "a" or "an" means "at least one" or "one or more" unless the context clearly indicates otherwise.

[0014] As used herein, the term "about" means that the recited numerical value is approximate and that small variations will not significantly affect the implementation of the disclosed embodiments. When a numerical value is used, unless otherwise indicated by the context, "about" means that the numerical value can vary by ±10% and still remain within the scope of the disclosed embodiments.

[0015] As used herein, the term "animal" includes, but is not limited to, mammals, humans, and non-human vertebrates such as wild animals, domestic animals, and livestock.

[0016] As used herein, the terms "antagonize" and "antagonizing" mean to reduce or completely eliminate one or more effects.

[0017] As used herein, the term "benzatropine" means a compound of Formula I, including racemic mixtures and isolated enantiomers of the compound of Formula I.

[0018] As used herein, the term "carrier" means a diluent, adjuvant, or excipient with which a compound is administered in a composition.

[0019] As used herein, the term "compound" means all stereoisomers, tautomers, isotopes, and polymorphs of the compounds described herein.

[0020] 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 unrestricted, including the alternatives that follow these terms, and do not exclude any additional unlisted elements or processes.

[0021] As used herein, the term “to bring into contact” means to bring together two compounds, molecules, or entities in an in vitro or in vivo system.

[0022] As used herein, the terms “individual,” “subject,” and “patient” are interchangeable and mean any animal described herein.

[0023] As used herein, the phrase “needs it” means that an “individual,” “subject,” or “patient” has been identified as having a need for a particular method, prevention, or treatment. In some embodiments, the identification may be by diagnosis by any means. In any of the methods, preventions, and treatments described herein, an “individual,” “subject,” or “patient” may need it.

[0024] As used herein, the term “integer” means a numerical value that is an integer. For example, “integers from 1 to 5” means 1, 2, 3, 4, or 5.

[0025] As used herein, the term “isolated” means that a compound described herein or a pharmaceutically acceptable salt thereof has been isolated from any other component, for example, by prior art: a) a natural source, e.g., a plant or cell, e.g., a bacterial culture, or b) a mixture of synthetic organic chemical reactions.

[0026] As used herein, the term “mammal” means rodents (i.e., mice, rats, or guinea pigs), monkeys, sheep, cats, dogs, cattle, horses, pigs, or humans. In some embodiments, the mammal is a human.

[0027] As used herein, “ophthalmologically suitable” means formulations, polymers, and other materials and / or dosage forms that are recognized in the art and suitable for use in contact with the eye tissue of human and animal objects without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio determined by a person skilled in the art.

[0028] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. A composition suitable for pharmaceutical use may be sterile, homogeneous, and / or isotonic. In certain embodiments, a pharmaceutical composition may be prepared in aqueous form, for example, in a pre-filled syringe or other single or multi-dose container. In certain embodiments, the pharmaceutical composition of the present invention is ophthalmologically suitable, for example, for ocular administration to a human subject by topical or other known delivery methods. In some embodiments, the disclosed pharmaceutical composition is suitable for intravitreal administration. In some embodiments, the pharmaceutical composition of the present invention is suitable for administration by intravitreal injection. In yet another embodiment, the pharmaceutical composition is administered orally.

[0029] As used herein, the phrase “pharmaceutically acceptable” means that a compound, substance, composition, and / or dosage form is within the bounds of sound medical judgment and suitable for use in contact with human and other animal tissues. In some embodiments, “pharmaceutically acceptable” means that it is approved by a federal or state regulatory authority for use in animals, more specifically in humans, or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia. In some embodiments, a pharmaceutically acceptable compound, substance, composition, and / or dosage form does not cause a sustained adverse effect on the subject or the general health of the subject being treated. However, transient effects, such as mild irritation or a “stinging” sensation, are common with the administration of drugs, and it will be recognized that the presence of such transient effects is not inconsistent with the composition, formulation, or component (e.g., excipient) in question.

[0030] As used herein, the phrase “pharmaceutically acceptable salt” includes, but is not limited to, salts of acidic or basic groups. Compounds that are essentially basic can form a wide variety of salts with various inorganic and organic acids. Acids that can be used in the preparation of pharmaceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts, namely sulfates, thiosulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, bisulfites, phosphates, acidic phosphates, isonicotinates, borates, acetates, lactates, salicylates, citrates, acidic citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acidates, succinates, maleates, gentisinates, fumarates, glucons, and glucarates. These compounds form salts containing pharmaceutically acceptable anions, including but not limited to glucaronates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, bicarbonates, malons, mesylates, esylates, napsydisylates, tosylates, besylates, orthophosphates, trifluoroacetates, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Compounds containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds that are inherently acidic can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium salts, magnesium salts, ammonium salts, sodium salts, lithium salts, zinc salts, potassium salts, and iron salts, but are not limited to these. Salts also include quaternary ammonium salts of the compounds described herein, wherein the compound has one or more tertiary amine moieties.

[0031] As used herein, the terms “prevention” or “prevention” mean reducing the risk of acquiring myopia.

[0032] As used herein, the term “prodrug” means a derivative of a known direct-acting drug, which may have enhanced delivery properties and therapeutic value compared to the active drug, and which is converted to the active drug by an enzymatic or chemical process.

[0033] As used herein, the term “purified” means that, if isolated, the isolate contains at least 90%, at least 95%, at least 98%, at least 99%, or 100% of the compound described herein, based on the weight of the isolate.

[0034] As used herein, the term “quaternary ammonium salt” means that at least one of the tertiary amine moieties in the parent compound is alkylated, for example, via methylation or ethylation (and the cation is Cl - CH3COO - , and CF3COO - This means derivatives of the disclosed compound having one or more tertiary amine moieties, which are modified by converting the tertiary amine moiety to a quaternary ammonium cation (balanced by anions such as ).

[0035] As used herein, the term "solubilizer" means an agent that results in the formation of a micelle solution or a true solution of a drug.

[0036] As used herein, the term “solution / suspension” means a liquid composition in which a first portion of the activator is present in solution and a second portion of the activator is present in particulate form in a suspension in a liquid matrix.

[0037] As used herein, the phrase "substantially isolated" means a compound that has been at least partially or substantially isolated from the environment in which it was formed or detected.

[0038] As used herein, the term “therapeutic dose” means the amount of an active compound or pharmaceutical agent that elicits a desired biological or pharmacokinetic response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician. The therapeutic effect depends on the disorder being treated or the desired biological effect. Therefore, the therapeutic effect may be a reduction in the severity of symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or an improved treatment, cure, prevention or elimination of the disorder, or a side effect. The amount required to elicit a therapeutic response may be based, for example, on the age, health status, size, and sex of the subject. The optimal amount may also be determined based on monitoring the subject's response to the treatment.

[0039] As used herein, the terms “to treat,” “to be treated,” or “to treat” mean both therapeutic measures and prophylactic or preventative measures, the purpose of which is to prevent or slow (reduce) myopia or to obtain a beneficial or desired clinical outcome. For the purposes of this specification, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the degree of myopia; a state of myopia stabilization (i.e., non-worsening); delay or slowing of the onset of myopia or the progression of myopia; improvement of myopia, whether detectable or undetectable; improvement of at least one measurable physical parameter, which is not necessarily identifiable by the patient; or enhancement or improvement of myopia. Treatment includes inducing a clinically significant response without, in some cases, excessive levels of side effects.

[0040] For clarity, certain features of this disclosure described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable subcombination.

[0041] The separation of racemic mixtures of compounds can be carried out by any of the many methods known in the art, including fractional recrystallization using chiral splitting acids, which are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids, such as the D and L isomers of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R isomers, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. Separation of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0042] Suitable compounds described herein may also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, accompanied by the movement of a proton. Tautomers include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms, where the proton can occupy two or more positions in heterocyclic systems, 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. Tautomers may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0043] The compounds described herein include hydrates and solvates, as well as anhydrous and non-solvated forms.

[0044] The compounds described herein can also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Carbon ( 12 C) can be replaced at any position with 13 C or 14 C. Nitrogen ( 14 N) can be replaced with 15 N. Oxygen ( 16 O) can be replaced at any position with 17 O or 18 O. Sulfur ( 32 S) can be replaced with 33 S, 34 S or 36 S. Chlorine ( 35 Cl) can be replaced with 37 Cl. Bromine ( 79 Br) can be replaced with 81 Br.

[0045] In some embodiments, the compound or its salt is substantially isolated. Partial separation can include, for example, a composition enriched in any one or more of the compounds described herein. Substantial separation can include a composition comprising at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of any one or more of the compounds or their salts described herein. Methods for isolating compounds and their salts are routine in the art.

[0046] The compounds described herein can be prepared as prodrugs. Examples of prodrugs include the compounds described herein, which comprise one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and which, upon administration to a patient, 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 the alcohol and amine functional groups of the compounds described herein. The preparation and use of prodrugs are discussed in T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACSSymposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both incorporated herein by reference in their entirety).

[0047] Compounds containing amine functional groups can also form N-oxides. References herein to compounds containing amine functional groups also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Examples of N-oxides include those of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) (see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).

[0048] Unless otherwise explicitly stated, no method or embodiment described herein is ever intended to be construed as requiring its steps to be performed in a specific order. Therefore, unless a method claim explicitly states in the claim or description that the steps should be limited to a specific order, no order is ever intended to be inferred in any way. This applies to any possible implicit grounds of interpretation, including the logic of the arrangement of steps or operational flows, the plain meaning derived from grammatical organization or punctuation, or matters relating to the number or type of embodiments described herein.

[0049] This disclosure relates to benzylatropine of formula I: [ka] The present invention provides a pharmaceutical aqueous solution comprising benzylatropine or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizer. In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01 to about 0.2% (weight / weight). In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.05 to about 0.2% (weight / weight). In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.1 to about 0.15% (weight / weight). In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.11 to about 0.14% (weight / weight). In some embodiments, the concentration of benzylatropine or its pharmaceutically acceptable salt or prodrug is about 0.12 to about 0.13% (weight / weight).

[0050] In some embodiments, at least one buffer comprises at least one acetate buffer, at least one propionic acid buffer, at least one malic acid buffer, at least one fumarate buffer, at least one lactate buffer, at least one malonic acid buffer, at least one malic acid buffer, at least one mandelic acid buffer, at least one citrate buffer, at least one tartaric acid 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, at least one buffer comprises at least one phosphate buffer. In some embodiments, at least one buffer comprises at least one acetate buffer. In some embodiments, at least one buffer comprises at least one propionic acid buffer. In some embodiments, at least one buffer comprises at least one malic acid buffer. In some embodiments, at least one buffer comprises at least one fumarate buffer. In some embodiments, at least one buffer comprises at least one lactate buffer. In some embodiments, at least one buffer comprises at least one malonic acid buffer. In some embodiments, at least one buffer comprises at least one malic acid buffer. In some embodiments, at least one buffer comprises at least one mandelic acid buffer. In some embodiments, at least one buffer comprises at least one citrate buffer. In some embodiments, at least one buffer comprises at least one tartaric acid buffer. In some embodiments, at least one buffer comprises at least one succinate buffer. In some embodiments, at least one buffer comprises at least one phosphate buffer. In some embodiments, at least one buffer comprises at least one borate buffer. In some embodiments, at least one buffer comprises at least one bicarbonate buffer. In some embodiments, at least one buffer comprises at least one buffer containing 2-amino-2-methyl-1-propanol.

[0051] In some embodiments, the pharmaceutical aqueous 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.

[0052] In some embodiments, the concentration of at least one buffer is about 0.1 to about 50 mM. In some embodiments, the concentration of at least one buffer is about 5 to about 40 mM. In some embodiments, the concentration of at least one buffer is about 10 to about 30 mM. In some embodiments, the concentration of at least one buffer is about 15 to about 20 mM. In some embodiments, the concentration of at least one buffer is about 18 mM. In some embodiments, the concentration of at least one buffer is about 18 mM. In some embodiments, the concentration of at least one buffer is about 20 to about 40 mM. In some embodiments, the concentration of at least one buffer is about 25 to about 35 mM. In some embodiments, the concentration of at least one buffer is about 30 mM. In some embodiments, the concentration of at least one buffer is about 30 mM.

[0053] In some embodiments, at least one buffer comprises at least one acetate buffer or at least one phosphate buffer. In some embodiments, the concentration of at least one buffer is about 15 to about 25 mM. In some embodiments, the concentration of at least one buffer is about 20 mM. In some embodiments, the concentration of at least one buffer is about 20 mM.

[0054] In some embodiments, at least one buffer comprises at least one citrate buffer or at least one phosphate buffer.

[0055] In some embodiments, the concentration of at least one additional buffer is about 0.1 to about 50 mM. In some embodiments, the concentration of at least one additional buffer is about 0.5 to about 15 mM. In some embodiments, the concentration of at least one additional buffer is about 1 to about 10 mM. In some embodiments, the concentration of at least one additional buffer is about 2.5 to about 7.5 mM. In some embodiments, the concentration of at least one additional buffer is about 5 mM. In some embodiments, the concentration of at least one additional buffer is about 5 mM. In some embodiments, the at least one additional buffer includes at least one phosphate buffer.

[0056] In some embodiments, at least one isotonic agent comprises sorbitol, propylene glycol, dextrose, glycerin, mannitol, potassium chloride, or sodium chloride, or any combination thereof. In some embodiments, at least one isotonic agent comprises sorbitol. In some embodiments, at least one isotonic agent comprises propylene glycol. In some embodiments, at least one isotonic agent comprises dextrose. In some embodiments, at least one isotonic agent comprises glycerin. In some embodiments, at least one isotonic agent comprises mannitol. In some embodiments, at least one isotonic agent comprises potassium chloride. In some embodiments, at least one isotonic agent comprises sodium chloride. In some embodiments, the concentration of at least one isotonic agent is about 0.01 to about 5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 0.05 to about 2.5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 0.1 to about 1% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 0.3% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 0.3% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the at least one isotonic agent is sodium chloride. In some embodiments, the concentration of at least one isotonic agent is about 0.1 to about 3% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 0.5 to about 1.5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 1% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 1% (by weight / by weight) of the total weight of the pharmaceutical aqueous solution. In some embodiments, the at least one isotonic agent includes propylene glycol.In some embodiments, the concentration of at least one isotonic agent is about 1.5 to about 2.5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 2% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one isotonic agent is about 2% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the at least one isotonic agent includes glycerol.

[0057] In some embodiments, the volumetric osmolality of the pharmaceutical aqueous solution is approximately 260 to approximately 330 mOsm / kg based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the volumetric osmolality of the pharmaceutical aqueous solution is approximately 270 to approximately 320 mOsm / kg based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the volumetric osmolality of the pharmaceutical aqueous solution is approximately 280 to approximately 310 mOsm / kg based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the volumetric osmolality of the pharmaceutical aqueous solution is approximately 290 to approximately 300 mOsm / kg based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the volumetric osmolality of the pharmaceutical aqueous solution is approximately 300 mOsm / kg based on the total weight of the pharmaceutical aqueous solution.

[0058] In some embodiments, at least one solubilizer 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. In some embodiments, at least one solubilizer comprises polyethylene glycol-400. In some embodiments, at least one solubilizer comprises polyethylene glycol-35 / castor oil. In some embodiments, at least one solubilizer comprises polypropylene glycol. In some embodiments, at least one solubilizer comprises polysorbate-80. In some embodiments, at least one solubilizer comprises polyethylene glycol-40 stearate. In some embodiments, at least one solubilizer comprises poloxamer-407. In some embodiments, at least one solubilizer comprises dimethyl sulfoxide. In some embodiments, at least one solubilizer comprises hydroxypropyl-β-cyclodextrin.

[0059] In some embodiments, the concentration of at least one solubilizer is about 0.1 to about 30% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one solubilizer is about 1 to about 10% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0060] In some embodiments, at least one solubilizer comprises polyethylene glycol-400, the concentration of which polyethylene glycol-400 is about 1%, about 3.5%, or about 5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, at least one solubilizer comprises polyethylene glycol-35 / castor oil, the concentration of which polyethylene glycol-35 / castor oil is about 5% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0061] In some embodiments, at least one solubilizer comprises polysorbate-80, with a concentration of polysorbate-80 of about 1% or about 4% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, at least one solubilizer comprises polyethylene glycol-40 stearate, with a concentration of polyethylene glycol-40 stearate of about 7% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0062] In some embodiments, at least one solubilizer comprises poloxamer-407, and the concentration of poloxamer-407 is approximately 2% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0063] In some embodiments, at least one solubilizing agent comprises dimethyl sulfoxide, the concentration of which is approximately 20% (by weight / by weight) of the total weight of the pharmaceutical aqueous solution.

[0064] In some embodiments, at least one solubilizer comprises hydroxypropyl-β-cyclodextrin, the concentration of which is about 2.5%, about 5%, or about 10% (by weight) of the total weight of the aqueous pharmaceutical solution.

[0065] In some embodiments, the pharmaceutical aqueous solution comprises at least one additional solubilizer. In some embodiments, the at least one additional solubilizer 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.

[0066] In some embodiments, at least one additional solubilizer comprises polyethylene glycol-400. In some embodiments, at least one additional solubilizer comprises polyethylene glycol-35 / castor oil. In some embodiments, at least one additional solubilizer comprises polypropylene glycol. In some embodiments, at least one additional solubilizer comprises polysorbate-80. In some embodiments, at least one additional solubilizer comprises polyethylene glycol-40 stearate. In some embodiments, at least one additional solubilizer comprises poloxamer-407. In some embodiments, at least one additional solubilizer comprises dimethyl sulfoxide. In some embodiments, at least one additional solubilizer comprises hydroxypropyl-β-cyclodextrin. In some embodiments, the concentration of at least one additional solubilizer is about 0.1 to about 30% (weight / weight) based on the total weight of the pharmaceutical aqueous solution. In some embodiments, the concentration of at least one additional solubilizer is about 1 to about 10% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0067] In some embodiments, at least one additional solubilizer comprises polyethylene glycol-400, the concentration of which is about 1%, about 3.5%, or about 5% (by weight) of the total weight of the pharmaceutical aqueous solution.

[0068] In some embodiments, at least one additional solubilizer comprises polyethylene glycol-35 / castor oil, the concentration of which is about 5% (by weight / by weight) based on the total weight of the pharmaceutical aqueous solution.

[0069] In some embodiments, at least one additional solubilizer comprises polysorbate-80, the concentration of which is about 1% or about 4% (weight / weight) based on the total weight of the pharmaceutical aqueous solution.

[0070] In some embodiments, at least one additional solubilizer comprises polyethylene glycol-40 stearate, the concentration of which is approximately 7% (by weight / by weight) of the total weight of the pharmaceutical aqueous solution.

[0071] In some embodiments, at least one additional solubilizer comprises poloxamer-407, the concentration of which is approximately 2% (by weight / by weight) of the total weight of the pharmaceutical aqueous solution.

[0072] In some embodiments, at least one additional solubilizing agent comprises dimethyl sulfoxide, the concentration of which is about 20% (by weight / by weight) of the total weight of the pharmaceutical aqueous solution.

[0073] In some embodiments, at least one additional solubilizer comprises hydroxypropyl-β-cyclodextrin, the concentration of which is about 2.5%, about 5%, or about 10% (by weight) of the total weight of the pharmaceutical aqueous solution.

[0074] In some embodiments, the combined concentration of at least one solubilizer and at least one additional solubilizer exceeds 5.0% (by weight / by weight) based on the total weight of the pharmaceutical aqueous solution.

[0075] In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5 to about 8. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5 to about 7. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.0 to about 7.0. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5 to about 6. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.0 to about 6.0. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.5 to about 6.5. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.5. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 6. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.5. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 6.

[0076] In some embodiments, the pharmaceutical aqueous solution further comprises at least one preservative. In some embodiments, the at least one preservative includes benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, chlorobutanol, phenol, metacresol, chlorocresol, benzoic acid, sorbic acid, thiomersal, phenylmercury nitrate, bronopol, propylene glycol, polyquaternium-1, or benzethonium chloride, or any combination thereof.

[0077] In some embodiments, at least one preservative comprises benzalkonium chloride. In some embodiments, at least one preservative comprises methylparaben. In some embodiments, at least one preservative comprises ethylparaben. In some embodiments, at least one preservative comprises propylparaben. In some embodiments, at least one preservative comprises butylparaben. In some embodiments, at least one preservative comprises benzyl alcohol. In some embodiments, at least one preservative comprises chlorobutanol. In some embodiments, at least one preservative comprises phenol. In some embodiments, at least one preservative comprises metacresol. In some embodiments, at least one preservative comprises chlorocresol. In some embodiments, at least one preservative comprises benzoic acid. In some embodiments, at least one preservative comprises sorbic acid. In some embodiments, at least one preservative comprises thiomersal. In some embodiments, at least one preservative comprises phenylmercury nitrate. In some embodiments, at least one preservative comprises bronopol. In some embodiments, at least one preservative comprises propylene glycol. In some embodiments, at least one preservative comprises polyquaternium-1. In some embodiments, at least one preservative comprises benzethonium chloride.

[0078] In some embodiments, the pharmaceutical aqueous solution does not contain preservatives. In some embodiments, the pharmaceutical aqueous solution does not contain benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, chlorobutanol, phenol, metacresol, chlorocresol, benzoic acid, sorbic acid, thiomersal, phenylmercury nitrate, bronopol, propylene glycol, polyquaternium-1, or benzethonium chloride.

[0079] In some embodiments, the pharmaceutical aqueous solution does not contain benzalkonium chloride. In some embodiments, the pharmaceutical aqueous solution does not contain methylparaben. In some embodiments, the pharmaceutical aqueous solution does not contain ethylparaben. In some embodiments, the pharmaceutical aqueous solution does not contain propylparaben. In some embodiments, the pharmaceutical aqueous solution does not contain butylparaben. In some embodiments, the pharmaceutical aqueous solution does not contain benzyl alcohol. In some embodiments, the pharmaceutical aqueous solution does not contain chlorobutanol. In some embodiments, the pharmaceutical aqueous solution does not contain phenol. In some embodiments, the pharmaceutical aqueous solution does not contain metacresol. In some embodiments, the pharmaceutical aqueous solution does not contain chlorocresol. In some embodiments, the pharmaceutical aqueous solution does not contain benzoic acid. In some embodiments, the pharmaceutical aqueous solution does not contain sorbic acid. In some embodiments, the pharmaceutical aqueous solution does not contain thiomersal. In some embodiments, the pharmaceutical aqueous solution does not contain phenylmercury nitrate. In some embodiments, the pharmaceutical aqueous solution does not contain bronopol. In some embodiments, the pharmaceutical aqueous solution does not contain propylene glycol. In some embodiments, the pharmaceutical aqueous solution does not contain polyquaternium-1. In some embodiments, the pharmaceutical aqueous solution does not contain benzethonium chloride.

[0080] In some embodiments, the pharmaceutical aqueous solution is placed in a dropper bottle. In some embodiments, the dropper bottle is a multi-purpose dropper bottle.

[0081] In some embodiments, the pharmaceutical aqueous solution further comprises at least one additional buffer and at least one additional solubilizer. In some embodiments, the concentration of benzylatropine is about 0.05 to about 0.2% (weight / weight). In some embodiments, at least one buffer comprises at least one acetate buffer. In some embodiments, at least one isotonic agent comprises sodium chloride. In some embodiments, at least one solubilizer comprises polyethylene glycol-400. In some embodiments, at least one additional buffer comprises at least one phosphate buffer. In some embodiments, at least one additional solubilizer comprises polyethylene glycol-35. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5 to about 6.

[0082] In some embodiments, the pharmaceutical aqueous solution further comprises at least one additional buffer and at least one additional solubilizer. In some embodiments, the concentration of benzylatropine is about 0.1 to about 0.15% (weight / weight). In some embodiments, at least one buffer comprises at least one acetate buffer. In some embodiments, at least one isotonic agent comprises sodium chloride. In some embodiments, at least one solubilizer comprises polyethylene glycol-400. In some embodiments, at least one additional buffer comprises at least one phosphate buffer. In some embodiments, at least one additional solubilizer comprises polyethylene glycol-35. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 6 to about 7.

[0083] In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.1 to about 0.15% (weight / weight). In some embodiments, at least one buffer solution comprises at least one acetate buffer solution. In some embodiments, at least one isotonic agent comprises mannitol or sodium chloride. In some embodiments, at least one solubilizer comprises hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical aqueous solution has a pH value of about 5.5 to about 6.5.

[0084] This disclosure also relates to benzylatropine of formula I: [ka] The present invention provides a process for preparing an aqueous solution containing benzylatropine or a pharmaceutically acceptable salt or prodrug thereof, the process comprising the steps of providing an aqueous solution containing at least one acetate buffer, at least one solubilizer, and at least one additional solubilizer, and adding benzylatropine 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, benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is dissolved in the aqueous solution to provide the aqueous solution. In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.05 to about 0.2% (weight / weight). In some embodiments, the aqueous solution of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0085] This disclosure also relates to benzylatropine of formula I: [ka] The present invention provides a product of a process for preparing an aqueous solution containing a pharmaceutically acceptable salt or prodrug thereof, the process comprising the steps of providing an aqueous solution containing at least one acetate buffer, at least one solubilizer, and at least one additional solubilizer, and adding benzylatropine 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, benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is dissolved in the aqueous solution to provide the aqueous solution. In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.05 to about 0.2% (weight / weight). In some embodiments, the aqueous solution of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof has a pH value greater than about 5.

[0086] This disclosure also provides a method for preventing, treating, reducing the progression of myopia, or preventing the progression of myopia in subjects requiring it, the method comprising: a therapeutically effective amount of benzylatropine of formula I to the eye of the subject: [ka] or the administration of a pharmaceutical aqueous solution comprising a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizer. In some embodiments, the concentration of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.05 to about 0.2% (weight / weight). In some embodiments, a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia includes a method for preventing myopia. In some embodiments, a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia includes treating myopia. In some embodiments, a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia includes reducing myopia. In some embodiments, a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia includes preventing myopia. In some embodiments, the pharmaceutical aqueous solution is administered once daily. In some embodiments, the pharmaceutical aqueous solution is administered twice daily. In some embodiments, the pharmaceutical aqueous solution is administered every other day, and the concentration of benzylatropine in the pharmaceutical aqueous solution is higher than the concentration that would be necessary to treat myopia in the subject if the pharmaceutical aqueous solution were administered to the subject's eye once daily.

[0087] The compounds described herein may be included in formulations containing pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, wetting agents, solubilizers, preservatives, and the like. Pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, polymers such as calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polyethylene glycol. In some embodiments, the compounds described herein can be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or rinses (e.g., Caphosol). Pharmaceutical carriers may be liquids such as water and oil, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. The pharmaceutical carrier may be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Furthermore, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used.

[0088] The compounds described herein may be administered alone (as a single compound or as one or more compounds described herein) or in combination with other agents (simultaneously or sequentially). For example, the compounds may be administered in combination with any one or more of the following: antibiotics (e.g., a) amikacin, anisomycin, apramycin, azithromycin, blastosidine S, brefelzin A, butyrosine, chloramphenicol, chlortetracycline, clindamycin, clotrimazole, cycloheximide, demeclocycline, dibekacin, dihydrostreptomycin, doxycycline, duramycin, emetine, erythromycin, fusidic acid, G-418, gentamicin, herbolic acid, hygromycin B, josamycin, kanamycin, chilomycin, lincomycin, meclocycline, mepal Protein synthesis inhibitors including, but not limited to, trichine, midecamycin, minocycline, neomycin, netylmycin, nitrofurantoin, noseotrichine, oleandomycin, oxytetracycline, paromomycin, puromycin, rapamycin, ribostamycin, rifampicin, rifamycin, rosamicin, shisomycin, spectinomycin, spiramycin, streptomycin, tetracycline, domeclocycline, thianphenicol, metacycline, thiostrepton, tobramycin, tunicamycin, tyrosine, biomycin, and virginiamycin;b) Camptothecin, 10-deacetylbaccatin III, azacitidine, 7-aminoactinomycin D, 8-quinolinol, 9-dihydro-13-acetylbaccatin III, acralubicin, actinomycin D, actinomycin I, actinomycin V, bafilomycin A1, bleomycin, capreomycin, chromomycin, cinoxacin, ciprofloxacin, norfloxacin, cis-diamine platinum(II) dichloride, coumamycin A1, L(+)-lactic acid, cytochalasin B, cytochalasin D, dacarbazine, daunorubicin, distamycin A, doxorubicin, echinomycin, enrofloxacin, etoposide, flumequin, formycin, fumagiline, ganciclovir, gliotoxin, lomefloxacin, metronidazole, DNA synthesis inhibitors including, but not limited to, mithramycin A, mitomycin C, nalidixic acid, netropsin, nitrofurantoin, nogaramycin, nonactin, novobiocin, ofloxacin, oxolinic acid, paclitaxel, phenazine, phleomycin, pipemidic acid, rebeccamycin, synefungin, streptonigrin, streptozocin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine-purum, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfaquinoxaline, sulfasalazine, sulfacetamide, sulfathiazole, trimethoprim, tubercidine, 5-azacitidine, cordycepin, and formycin A;c)(+)-6-aminopenicillaneic acid, 7-aminodesacetoxycephalosporaneic acid, amoxicillin, ampicillin, azurocillin, bacitracin, carbenicillin, cefaclor, cephamandol, cefazolin, cefmetazole, cefixime, cefoperazone, cefotaxime, cefsulodine, ceftriaxone, cephalexin, cephalosporin, cephalothin, cefradiin, ceftazi Dicloxacillin, D-cycloserine, dicloxacillin, D-penicillamine, ceftizoxime, econazole, ethambutol, lysostafine, moxalactam, nafcillin, nikkomycin Z, nitrofurantoin, oxacillin, penicillin, penicillin G, pheneticillin, phenoxymethylpenicillin, fosfomycin, pipemidic acid, piperacillin, ristomycin, and vanco Cell wall synthesis inhibitors, including but not limited to mycin; d) Cell membrane equivalence inhibitors, including but not limited to amphotericin B, 2-mercaptopyridine, 4-bromocalsimycin A23187, colistin, aramethicin, calsimycin A23187, chlorhexidine, clotrimazole, econazole, hydrocortisone, philipin, gliotoxin, gramicidin A, gramicidin C, ionomycin, rasaloside A, ronomycin A, monensin, naracin, nigericin, nisin, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, sulfisoxazole, pyrimethamine, mafenide, nonactin, nistatin, phenazine, pimaricin, polymyxin, DL-penicillamine, praziquantel, sarinomycin, surfactin, and valinomycin;e)(+)-usnic acid, (±)-miconazole, (S)-(+)-camptothecin, 1-deoxymannojirimycin, 2-heptyl-4-hydroxyquinoline N-oxide, cordicepin, antimycin, 1,10-phenanthroline, 6-diazo-5-oxo-L-norleucine, 8-quinolinol, -, antipine, ascomycin, azacerin, bafilomycin, cerurenin, chloroquine, cinoxacin, ciprofloxacin, me Vastatin, Conkanamycin A, Conkanamycin C, Coomamycin A1, L(+)-Lactate, Cyclosporine A, Econazole, Enrofloxacin, Etoposide, Flumequin, Formycin A, Furazolidone, Fusaric Acid, Geldanamycin, Gliotoxin, Gramicidin A, Gramicidin C, Herbimycin A, Indomethacin, Yirgasan, Lomefloxacin, Mycophenolic Acid, Myxothiazole, Naridixic Acid, Netropsin, Niklosa Mido, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-methyl-1-deoxynojirimycin, Nikkomycin, Nogaramycin, Nonactin, Novobiocin, Ofloxacin, Oleandmycin, Oligomycin, Oxolinic acid, Piericidine A, Pipemidic acid, Radicicol, Rapamycin, Rebeccamycin, Synefungin, Staurosporine, Stigmatelin, Succinylsulfathiazole, Saku f) Enzyme inhibitors including but not limited to synylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfaquinoxaline, sulfasalazine, sulfathiazole, triaxin C, trimethoprim, and pieomycin A1; f) Membrane modifiers including but not limited to paracercin; g) Aminoglycosides; and h) Fluoroquinolones.

[0089] The amount of compound administered may be a therapeutically effective amount. The dose administered may depend on the characteristics of the target being treated, e.g., the specific animal being treated, age, weight, health, type of concurrent treatment if any, and frequency of treatment, as well as the nature and degree of myopia, and may be readily determined by those skilled in the art (e.g., by clinicians). The selection of a specific dose regimen may be selected, adjusted, or dose-set by a clinician according to methods known to clinicians in order to obtain the desired clinical response. Furthermore, in vitro or in vivo assays may be used to help identify the optimal dose range. The exact dose used in a composition may also depend on the route of administration and should be determined according to the physician's judgment and the circumstances of each patient.

[0090] The pharmaceutical composition may be in unit dosage forms. In such dosage forms, the composition can be divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged preparation, the packaging containing separate amounts of the preparation in vials or ampoules.

[0091] One or more ophthalmic lubricants may also be included in the composition to promote tearing or as a “dry eye” agent. Such agents include, but are not limited to, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. It will be understood that promoting tearing is beneficial in this invention only when tearing is naturally deficient in order to restore the normal level of tear secretion. In cases of excessive tearing, the residence time of the composition in the eye can be reduced.

[0092] This disclosure also provides pharmaceutical packs or kits comprising one or more containers filled with one or more compounds or compositions described herein. Such containers may optionally be accompanied by a notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting the agency's approval for the manufacture, use, or sale of the products described herein for human administration to treat myopia. In some embodiments, the kit comprises two or more compounds or compositions described herein.

[0093] This disclosure also provides a method for treating a subject having myopia or preventing a subject from developing myopia, the method comprising administering one of the pharmaceutical aqueous solutions containing benzylatropine described herein to the eye of the subject. This disclosure also provides a method for treating a subject having myopia or preventing a subject from developing myopia, the method comprising administering one of the pharmaceutical aqueous solutions described herein to the eye of the subject.

[0094] In some embodiments, the administration is directed to a single eye of the subject. In some embodiments, the administration is directed to both eyes of the subject.

[0095] In some embodiments, the pharmaceutical aqueous solution exhibits increased bioavailability. In some embodiments, the bioavailability includes corneal bioavailability, conjunctival bioavailability, or ocular bioavailability.

[0096] In some embodiments, the pharmaceutical aqueous solution can be administered to the eye in the form of eye drops.

[0097] In some embodiments, the pharmaceutical aqueous solution is administered topically to one or more tissues of the eye. The frequency of administration is typically such that the dosing interval, e.g., the period between one administration during waking hours and the next, is about 2 to 12 hours, about 3 to 8 hours, or about 4 to 6 hours. It will be understood by those skilled in the art that the appropriate dosing interval depends to some extent on the length of time that the selected composition can maintain the desired concentration of the pharmaceutical aqueous solution in the tear fluid and / or the target tissue (e.g., conjunctiva or cornea).

[0098] This disclosure also provides the use of any pharmaceutical aqueous solution described herein for treating subjects having an eye disease or for preventing subjects from developing an eye disease. This disclosure also provides the use of any pharmaceutical aqueous solution lacking preservatives described herein for treating subjects having an eye disease or for preventing subjects from developing an eye disease. This disclosure also provides the use of any pharmaceutical aqueous solution described herein in the manufacture of a drug for treating subjects having an eye disease or for preventing subjects from developing an eye disease. This disclosure also provides the use of any pharmaceutical aqueous solution lacking preservatives described herein in the manufacture of a drug for treating subjects having an eye disease or for preventing subjects from developing an eye disease. In some embodiments, the eye disease is myopia.

[0099] Examples are provided below to allow for a more efficient understanding of the subject matter disclosed herein. These examples are for illustrative purposes only and should not be construed as limiting the claimed subject matter in any way. [Examples]

[0100] Example 1: Identification of benzylatropine as a lead compound High doses of atropine required to prevent myopia are associated with debilitating side effects, including pupillary dilation and photosensitivity (ATOM1, ATOM2, and LAMP studies). Furthermore, atropine is well known to decompose into tropine and tropic acid in aqueous solution. [ka]

[0101] The instability of atropine is partly due to the lack of substitution at the α-position. In an attempt to circumvent this problem, substitution at the α-position of atropine was considered and tested in an FDM chicken model. Briefly, monocular morphological deprivation myopia (FDM) was induced in the right eye of chickens using a translucent diffuser goggle, while the converse left eye served as a control eye (normal) and was not goggled. After myopia induction (days 2 and 4), the right eye with the goggle was treated with intravitreal injection of a vehicle with or without the drug, while the left eye without the goggle was injected with saline. On day 5, the refractive error of the eye was measured using a retinoscope. The animals were then euthanized, the eye was removed, and its axial length was measured using a digital caliper. Methylatropine, fluoroatropine, and benzylatropine were found to be effective in the FDM chicken model (see Figure 1, Panel A). However, benzylatropine was unexpectedly found to be as effective as atropine in the FDM chicken model, but at approximately 10 times lower concentrations (see Figure 1, Panel B).

[0102] Next, the binding coefficients of atropine, methylatropine, and benzylatropine to M1, M2, M3, M4, and M5 muscarinic receptors were determined (Table 1). In vitro pharmacological studies were performed via radioligand substitution studies using known radiolabeled receptor-selective ligands as references to determine the ability of newly synthesized compounds to bind to different muscarinic receptors (dose-response). The binding affinity (ki) of the synthesized compounds could be determined from the IC50 and KD values.

[0103] [Table 1]

[0104] Atropine and methylatropine were found to bind non-selectively to muscarinic receptors, but benzylatropine unexpectedly bound weakly to M1 and M4 receptors but not at all to M2, M3, and M5 receptors. The lack of M3 receptor binding, in particular, suggested an opportunity to avoid the side effects associated with natural atropine. Therefore, benzylatropine was identified as a lead candidate.

[0105] Example 2: Solubility of atropine, methylatropine, and benzylatropine As part of an initial formulation development approach, atropine, methylatropine, and benzylatropine 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. A 5-minute vortex was used to provide the best possible conditions for solubilization. The solubility of atropine, methylatropine, and benzylatropine was good in both vehicles, and it was expected that the pH of both vehicles would remain largely unchanged after the dissolution of atropine, methylatropine, and benzylatropine. The theoretical and experimental concentrations of atropine, methylatropine, and benzylatropine in the resulting formulations are shown in Table 2.

[0106] [Table 2]

[0107] Natural atropine (i.e., atropine sulfate monohydrate) readily dissolved in both vehicles, but methylatropine and benzylatropine unexpectedly did not completely dissolve in either vehicle. Furthermore, methylatropine and atropine unexpectedly contributed to an overall increase in the pH of the formulation (Table 3).

[0108] [Table 3]

[0109] Therefore, lowering the initial pH value of the vehicle was considered necessary to: i) ensure higher solubility and ii) reach an ophthalmologically acceptable target pH (5-8). In addition, the addition of an isotonic agent was necessary to reach an acceptable target range of 280-320 mOsm / kg (Tables 4 and 5).

[0110] [Table 4]

[0111] [Table 5]

[0112] Therefore, for methylatropine, a 20 mM phosphate buffer with a starting pH of 2.7-2.8 produced a final pH close to the acceptable ideal range (pH 5-8) for ophthalmic products.

[0113] It was expected that lowering the vehicle's pH would cause benzylatropine to dissolve completely, similar to methylatropine. However, unexpectedly, benzylatropine did not dissolve completely with pH adjustment (Tables 6 and 7).

[0114] [Table 6]

[0115] [Table 7]

[0116] Therefore, additional formulation components were needed to increase the solubility of benzylatropine. First, a single excipient was evaluated (Table 8).

[0117] [Table 8]

[0118] Polyethylene glycol 400 (PEG-400), used as a "neat" solution, provided the highest drug solubility at 8.01 mg / g (0.8%). However, the recommended concentration of PEG-400 as an inactive component in the final formulation is 5%. Neat propylene glycol and polypropylene glycol showed similar problems. In fact, dilution of polypropylene glycol from 100% v / v to 50% v / v resulted in a significant decrease in benzylatropine concentration.

[0119] Next, individual excipients were evaluated for their ability to solubilize benzylatropine in different buffers (Table 9).

[0120] [Table 9]

[0121] As shown in Table 9, solubility doubled with changes in the 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).

[0122] These excipients were also tested for their ability to solubilize benzylatropine in the presence of citrate or acetate buffer (Table 10).

[0123] [Table 10]

[0124] However, even the changes to citrate buffer and acetate buffer did not immediately balance the need for a high benzylatropine concentration on the one hand and the need for a formulation with an ophthalmologically acceptable pH on the other. In citrate buffer, for example, the concentration of benzylatropine increased when the starting pH was lower. However, the pH of the resulting formulation was also low at 4.4, which is likely to be irritating to the eye when instilled (Table 10, row 1). In contrast, when the starting pH was higher, the concentration of benzylatropine was lower (column 2). At starting pH lower than in acetate buffer, the resulting solution often did not have an ophthalmologically acceptable pH above 5 (column 3; see column 1). However, when the starting pH was higher, the concentration of benzylatropine was found to be lower (columns 5, see column 2). After considerable effort far beyond mere routine optimization, it was found that for a 30 mM acetate buffer / surfactant mixture, the acceptable starting pH was 4.5–4.6 (column 4). Stability assessments identified that a 5 mg / g concentration of benzylatropine was close to the saturation solubility limit of the compound when it rapidly precipitated from the solution during storage.

[0125] Significant efforts were made to simplify the formulation in order to reduce the total amount of surfactant (Table 11).

[0126] [Table 11]

[0127] The highest initial concentration was achieved with 7% PEG-40 stearate (Table 11, Column 3). The highest achievable concentration of benzylatropine that did not reprecipitate was 3.9 mg / g in the presence of 3.5% PEG-400, 5% PEG-35 castor oil, and 0.37% NaCl (Column 5). The combination of two different surfactants was unexpected. After extensive testing, it was found that an acetate / phosphate buffered vehicle produced a formulation with the highest concentration of benzyl acetate and the most ophthalmically acceptable pH. The efficacy of this “double buffered” vehicle was unexpected.

[0128] The physical stability of benzylatropine in phosphate buffer was further evaluated using hydroxypropyl-β-cyclodextrin (HPβCD) as a solubilizer. Unexpectedly, 10% HPβCD was found to effectively solubilize benzylatropine at concentrations close to its solubility limit (Tables 12 and 13).

[0129] [Table 12]

[0130] [Table 13]

[0131] In addition to those described herein, various modifications to the subject matter described herein will be apparent to those skilled in the art from the foregoing description. Such modifications also fall within the scope of the appended claims. Each reference cited herein (including, but not limited to, journal articles, U.S. and non-U.S. patents, published patent applications, published international patent applications, gene bank accession numbers, etc.) is incorporated herein by reference in its entirety.

Claims

1. Benzylatropine in formula I: 【Chemistry 1】 A pharmaceutical aqueous solution comprising a pharmaceutically acceptable salt thereof, at least one buffer, at least one additional buffer, at least one isotonic agent, and at least one solubilizer, wherein the concentration of benzylatropine or a pharmaceutically acceptable salt thereof is 0.01 to 0.2% (weight / weight), The at least one buffer solution comprises at least one phosphate buffer solution, The at least one additional buffer comprises at least one acetate buffer, and The at least one solubilizer 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. A pharmaceutical solution.

2. The pharmaceutical aqueous solution according to claim 1, wherein the at least one isotonic agent comprises sorbitol, polypropylene glycol, dextrose, glycerin, mannitol, potassium chloride, or sodium chloride, or any combination thereof.

3. The pharmaceutical aqueous solution according to claim 1, wherein the at least one solubilizing agent comprises hydroxypropyl-β-cyclodextrin, and the concentration of the hydroxypropyl-β-cyclodextrin is 2.5, 5, or 10% (by weight) based on the total weight of the pharmaceutical aqueous solution.

4. The pharmaceutical aqueous solution according to claim 1, wherein the pharmaceutical aqueous solution comprises at least one additional solubilizing agent.

5. The pharmaceutical aqueous solution according to claim 1, wherein the pharmaceutical aqueous solution has a pH value of 5 to 8.

6. The pharmaceutical aqueous solution according to claim 1, wherein the pharmaceutical aqueous solution further comprises at least one preservative.

7. The pharmaceutical aqueous solution according to claim 1, wherein the pharmaceutical aqueous solution does not contain a preservative.

8. It further comprises at least one additional solubilizer, The concentration of benzylatropine is 0.05 to 0.2% (by weight); The at least one buffer solution comprises at least one phosphate buffer solution; The at least one isotonic agent comprises sodium chloride; The at least one solubilizing agent comprises polyethylene glycol-400; The at least one additional buffer comprises at least one acetate buffer; The at least one additional solubilizer comprises polyethylene glycol-35; The aforementioned pharmaceutical aqueous solution has a pH value of 5 to 6. The pharmaceutical aqueous solution according to claim 1.

9. It further comprises at least one additional solubilizer, The concentration of benzylatropine is 0.1 to 0.15% (by weight); The at least one buffer solution comprises at least one phosphate buffer solution; The at least one isotonic agent comprises sodium chloride; The at least one solubilizing agent comprises polyethylene glycol-400; The at least one additional buffer comprises at least one acetate buffer; The at least one additional solubilizer comprises polyethylene glycol-35; The aforementioned pharmaceutical aqueous solution has a pH value of 6 to 7. The pharmaceutical aqueous solution according to claim 1.

10. Benzylatropine in formula I: 【Chemistry 2】 Or a process for preparing an aqueous solution containing the pharmaceutically acceptable salt thereof: To provide an aqueous solution comprising at least one acetate buffer, at least one phosphate buffer, at least one solubilizer, and at least one additional solubilizer, wherein the aqueous solution has a pH value of 4 to 5; The method includes adding benzylatropine or a pharmaceutically acceptable salt thereof to the aqueous solution, wherein the benzylatropine or a pharmaceutically acceptable salt thereof dissolves in the aqueous solution, thereby providing an aqueous solution of benzylatropine or a pharmaceutically acceptable salt thereof. A process wherein the concentration of benzylatropine or a pharmaceutically acceptable salt thereof in the aqueous solution is 0.01 to 0.2% (weight / weight), and the aqueous solution has a pH value greater than 5.

11. A pharmaceutical aqueous solution according to claim 1, for use in treating myopia or reducing the progression of myopia in a subject.

12. The pharmaceutical aqueous solution according to claim 11, wherein the pharmaceutical aqueous solution is administered every other day, and the concentration of benzylatropine or a pharmaceutically acceptable salt thereof in the pharmaceutical aqueous solution is higher than the concentration that would be necessary to treat myopia in the subject if the pharmaceutical aqueous solution were administered to the subject's eye once a day.

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