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] The present disclosure relates to a composition comprising benzatropine or a pharmaceutically acceptable salt thereof, a method for preparing a benzatropine composition, and a method for preventing or treating myopia, reducing the progression of myopia, or preventing the progression of myopia by administering a benzatropine composition.

Background Art

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

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

[0004] The prevalence of myopia (nearsightedness) is expected 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 the use of corrective corneas, multifocal soft contact lenses, bifocal glasses for both near and far vision, or bifocal glasses, 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 the progression of myopia. Among these studies, natural atropine, isolated as a racemic mixture from Atropa belladonna, has been shown to be very promising in its ability to reduce the progression of myopia. Several large-scale randomized clinical trials conducted in Asian countries, namely, the ATOM1, ATOM2, and LAMP studies, tested the efficacy of natural atropine at various dose strengths 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 have demonstrated the efficacy of natural atropine in reducing the progression of myopia, but high doses of natural atropine are required. However, these higher doses are associated with debilitating side effects, including pupillary dilation and photosensitivity. Furthermore, natural atropine is essentially unstable in aqueous solutions having physiological pH values. For example, atropine decomposes into tropic acid and tropine in aqueous solutions having neutral pH values.Due to this decomposition, natural atropine cannot survive as a pharmacological agent for the treatment of myopia. Therefore, there has been a long-standing unsolved need for a pharmacological agent that is stable in an aqueous solution having a physiological pH value and that prevents, treats, reduces the progression of, or prevents the progression of myopia.

Summary of the Invention

Means for Solving the Problems

[0006] The present disclosure provides an aqueous pharmaceutical solution comprising benzatropine of formula I:

Chemical formula

[0007] The present disclosure also provides benzatropine of formula I:

Chemical formula

[0008] The present disclosure also relates to benzatropine of formula I:

Chemical formula

[0009] The present disclosure also provides a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia in a subject in need thereof, the method comprising administering to the eye of the subject a therapeutically effective amount of benzatropine of formula I: [Chemical formula] 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

Figure 1-2

Modes for Carrying Out the Invention

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which 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 do 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 term "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") is inclusive and open-ended, includes the recited options, and does not exclude additional unrecited elements or method steps.

[0021] As used herein, the term "contacting" means bringing two compounds, molecules, or entities together in an in vitro or in vivo system.

[0022] As used herein, the terms "individual", "subject", and "patient" are used interchangeably and mean any animal described herein.

[0023] As used herein, the phrase "in need thereof" means that an "individual", "subject", or "patient" has been identified as having a need for a particular method, prophylaxis, or treatment. In some embodiments, the identification can be by means of any diagnostic. In any of the methods, prophylaxis, and treatments described herein, an "individual", "subject", or "patient" may be in need thereof.

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

[0025] As used herein, the term "isolated" means that the compounds described herein or pharmaceutically acceptable salts thereof are separated from any of the following other components, e.g., by conventional techniques: a) natural sources, such as plants or cells, such as bacterial cultures, or b) synthetic organic chemical reaction mixtures.

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

[0027] As used herein, "ophthalmically compatible" refers to formulations, polymers, and other materials, and / or dosage forms that are recognized in the art and are suitable for use in contact with eye tissues of humans and animals without undue toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable benefit / risk ratio as determined by one of ordinary skill in the art.

[0028] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. A composition suitable for pharmaceutical use can be sterile, homogeneous and / or isotonic. In certain embodiments, the pharmaceutical composition can be prepared in an aqueous form, e.g., in a prefilled syringe or other single- or multi-dose container. In certain embodiments, the pharmaceutical composition of the present invention is ophthalmically compatible and is suitable for ocular administration to a human subject, e.g., 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 scope of sound medical judgment and is suitable for use in contact with the tissues of humans and other animals. In some embodiments, "pharmaceutically acceptable" means that, for use in animals, more specifically humans, it is approved by a regulatory authority of the federal or state government or is listed in the United States Pharmacopeia or other generally recognized pharmacopeias. In some embodiments, a pharmaceutically acceptable compound, substance, composition, and / or dosage form does not produce a persistent adverse effect on the subject or on the general health of the subject being treated. However, transient effects such as mild irritation or a "stinging" sensation are common to the administration of a drug, and the presence of such transient effects will be recognized as not inconsistent with the composition, formulation, or ingredient in question (e.g., excipient).

[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 are non-toxic acid addition salts, namely, sulfate, thiosulfate, citrate, maleate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophosphate, trifluoroacetate, and salts of pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)), including but not limited to salts containing pharmaceutically acceptable anions that form salts. Compounds containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids described above. Compounds that are essentially acidic can form base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, 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. The salts also include quaternary ammonium salts of the compounds described herein where the compound has one or more tertiary amine moieties.

[0031] As used herein, the term "prevent" or "preventing" means reducing the risk of acquiring myopia.

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

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

[0034] As used herein, the phrase "quaternary ammonium salt" means a derivative of a disclosed compound having one or more tertiary amine moieties, wherein at least one of the tertiary amine moieties in the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation, e.g., methylation or ethylation (and the cation is balanced by anions such as Cl - , CH3COO - , and CF3COO - ).

[0035] As used herein, the phrase "solubilizer" means an agent that results in the formation of a micellar 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 active agent is present in solution and a second portion of the active agent is present in suspension in a liquid matrix in particulate form.

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

[0038] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response that is sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder, and / or inhibition (partial or complete) of the progression of the disorder, or improved treatment, cure, prevention, or elimination of the disorder, or a side effect. The amount required to elicit a therapeutic response can be based, for example, on the age, health status, size, and gender of the subject. The optimal amount can also be determined based on monitoring the response of the subject to the treatment.

[0039] As used herein, the terms "treating," "being treated," or "treatment" mean both therapeutic treatment and prophylactic or preventative means, 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, alleviation of symptoms; reduction in the degree of myopia; stabilization of myopia (i.e., not getting worse); delay or slowing in the onset of myopia or progression of myopia; improvement of myopia, whether detectable or not; improvement of at least one measurable physical parameter, not necessarily distinguishable by the patient; or enhancement or improvement of myopia. Treatment includes inducing a clinically significant response, optionally without an excessive level of side effects.

[0040] It should be understood that certain features of the disclosure that are described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of the disclosure that are described in the context of a single embodiment for brevity's sake may also be provided separately or in any suitable sub-combination.

[0041] The resolution of a racemic mixture of compounds can be carried out by any of a number of methods known in the art, including, for example, fractional recrystallization using a chiral resolution acid, which is an optically active salt-forming organic acid. Resolution agents suitable for the fractional recrystallization method include, but are not limited to, optically active acids such as the D- and L-forms 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 resolution agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., the S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like, but are not limited thereto. The resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolution agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by one of ordinary skill in the art.

[0042] Suitable compounds described herein may also include tautomeric forms. Tautomeric forms result from the exchange of a single bond adjacent to a double bond along with the accompanying movement of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic 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, and the proton can occupy two or more positions in heterocyclic systems including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be stereochemically fixed in one form by appropriate substitution.

[0043] The compounds described herein also include hydrates and solvates, as well as anhydrous and nonsolvated forms.

[0044] The compounds described herein can also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms having 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 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% 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 in this specification can be prepared as prodrugs. Examples of prodrugs include those containing one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, which, when administered to a patient, are cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively, such as the compounds described in this specification. 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 in this specification. The preparation and use of prodrugs are discussed in T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both of which are incorporated herein by reference in their entirety).

[0047] Compounds containing an amine functional group can also form N-oxides. References herein to compounds containing an amine functional group include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Examples of N-oxides include N-oxides of the nitrogen atoms of tertiary amines or 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., peroxycarboxylic acid) (see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).

[0048] Unless otherwise expressly stated, it is never intended that any method or aspect described in this specification be construed as requiring that its steps be performed in a particular order. Thus, where a method claim does not specifically state in the claim or description that the steps should be limited to a particular order, in no way is it ever intended that an order be inferred, whether from the logical, grammatical organization or punctuation of the arrangement of steps or the flow of operations, or from any possible basis of implicit interpretation, including matters related to the number or type of aspects described in this specification.

[0049] The present disclosure provides an aqueous pharmaceutical solution comprising benzatropine of formula I:

Chemical formula

[0050] 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, 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 propionate buffer. In some embodiments, at least one buffer comprises at least one malate 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 malonate buffer. In some embodiments, at least one buffer comprises at least one malate buffer. In some embodiments, at least one buffer comprises at least one mandelate 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 tartrate 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 comprising 2-amino-2-methyl-1-propanol.

[0051] 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.

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

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

[0054] In some embodiments, the 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 from about 0.1 to about 50 mM. In some embodiments, the concentration of at least one additional buffer is from about 0.5 to about 15 mM. In some embodiments, the concentration of at least one additional buffer is from about 1 to about 10 mM. In some embodiments, the concentration of at least one additional buffer is from 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, at least one additional buffer comprises 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 from about 0.01 to about 5% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is from about 0.05 to about 2.5% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is from about 0.1 to about 1% (weight / weight) based on the total weight of the aqueous pharmaceutical 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 aqueous pharmaceutical 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 aqueous pharmaceutical solution. In some embodiments, at least one isotonic agent is sodium chloride. In some embodiments, the concentration of at least one isotonic agent is from about 0.1 to about 3% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is from about 0.5 to about 1.5% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is about 1% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is about 1% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, at least one isotonic agent comprises propylene glycol.In some embodiments, the concentration of at least one isotonic agent is about 1.5 to about 2.5% (w / w) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is about 2% (w / w) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, the concentration of at least one isotonic agent is about 2% (w / w) based on the total weight of the aqueous pharmaceutical solution. In some embodiments, at least one isotonic agent includes glycerol.

[0057] In some embodiments, the volume osmolarity 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 volume osmolarity 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 volume osmolarity 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 volume osmolarity 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, the volume osmolarity of the aqueous pharmaceutical solution is about 300 mOsm / kg based on the total weight of the aqueous pharmaceutical 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 aqueous pharmaceutical 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 aqueous pharmaceutical solution.

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

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

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

[0063] In some embodiments, at least one solubilizer comprises dimethyl sulfoxide, and the dimethyl sulfoxide concentration is about 20% (weight / weight) based on the total weight of the aqueous pharmaceutical solution.

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

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

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

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

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

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

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

[0072] In some embodiments, at least one additional solubilizer comprises dimethyl sulfoxide, and the concentration of dimethyl sulfoxide is about 20% (weight / weight) based on the total weight of the aqueous pharmaceutical solution.

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

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

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

[0076] 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, metacresol, chlorocresol, benzoic acid, sorbic acid, thimerosal, phenylmercuric 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 thimerosal. In some embodiments, at least one preservative comprises phenylmercuric 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 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, metacresol, chlorocresol, benzoic acid, sorbic acid, thimerosal, phenylmercuric nitrate, bronopol, propylene glycol, polyquaternium-1, or benzethonium chloride.

[0079] In some embodiments, the aqueous pharmaceutical solution does not contain benzalkonium chloride. In some embodiments, the aqueous pharmaceutical solution does not contain methylparaben. In some embodiments, the aqueous pharmaceutical solution does not contain ethylparaben. In some embodiments, the aqueous pharmaceutical solution does not contain propylparaben. In some embodiments, the aqueous pharmaceutical solution does not contain butylparaben. In some embodiments, the aqueous pharmaceutical solution does not contain benzyl alcohol. In some embodiments, the aqueous pharmaceutical solution does not contain chlorobutanol. In some embodiments, the aqueous pharmaceutical solution does not contain phenol. In some embodiments, the aqueous pharmaceutical solution does not contain metacresol. In some embodiments, the aqueous pharmaceutical solution does not contain chlorocresol. In some embodiments, the aqueous pharmaceutical solution does not contain benzoic acid. In some embodiments, the aqueous pharmaceutical solution does not contain sorbic acid. In some embodiments, the aqueous pharmaceutical solution does not contain thimerosal. In some embodiments, the aqueous pharmaceutical solution does not contain phenylmercuric nitrate. In some embodiments, the aqueous pharmaceutical solution does not contain bronopol. In some embodiments, 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.

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

[0081] In some embodiments, the aqueous pharmaceutical solution further comprises at least one additional buffer and at least one additional solubilizer. In some embodiments, the concentration of benzatropine is from about 0.05% to about 0.2% (w / w). 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 aqueous pharmaceutical solution has a pH value of from about 5 to about 6.

[0082] In some embodiments, the aqueous pharmaceutical solution further comprises at least one additional buffer and at least one additional solubilizer. In some embodiments, the concentration of benzatropine is from about 0.1% to about 0.15% (w / w). 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 aqueous pharmaceutical solution has a pH value of from about 6 to about 7.

[0083] In some embodiments, the concentration of benzatropine or a pharmaceutically acceptable salt or prodrug thereof is from 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 tonicity agent comprises mannitol or sodium chloride. In some embodiments, at least one solubilizer comprises hydroxypropyl-β-cyclodextrin. In some embodiments, the aqueous pharmaceutical solution has a pH value of from about 5.5 to about 6.5.

[0084] The present disclosure also provides a process for preparing an aqueous solution comprising benzatropine of formula I:

Chemical formula

[0085] The present disclosure also provides a process for preparing an aqueous solution comprising benzatropine of formula I:

Chemical formula

[0086] The present disclosure also provides a method for preventing myopia, treating myopia, reducing the progression of myopia, or preventing the progression of myopia in a subject in need thereof, the method comprising administering to the eye of the subject a therapeutically effective amount of benzatropine of formula I:

Chemical formula

[0087] The compounds described herein can 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. The pharmaceutical composition can 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 can be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or irrigants (e.g., Caphosol). The pharmaceutical carrier can be a liquid such as water and oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil. The pharmaceutical carrier can also be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Additionally, adjuvants, stabilizers, thickeners, lubricants, and coloring agents can be used.

[0088] The compounds described in this specification can be administered alone (as a single compound or as one or more of the 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 (e.g., a) amikacin, anisomycin, apramycin, azithromycin, blasticidin S, brefeldin A, butirosin, chloramphenicol, chlortetracycline, clindamycin, clotrimazole, cycloheximide, demeclocycline, dibekacin, dihydrostreptomycin, doxycycline, duramycin, emetine, erythromycin, fusidic acid, G-418, gentamicin, herbimycin A, hygromycin B, josamycin, kanamycin, kirromycin, lincomycin, meclocycline, mepartricin, midecamycin, minocycline, neomycin, netilmicin, nitrofurantoin, nourseothricin, oleandomycin, oxytetracycline, paromomycin, puromycin, rapamycin, ribostamycin, rifampicin, rifamycin, rosamicin, sisomicin, spectinomycin, spiramycin, streptomycin, tetracycline, domeclocycline, thiamphenicol, methacycline, thiostrepton, tobramycin, tunicaamycin, tylosin, viomycin, and virginiamycin, including but not limited to protein synthesis inhibitors;b) DNA synthesis inhibitors including, but not limited to, camptothecin, 10-deacetylbaccatin III, azacitidine, 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-diammineplatinum(II) dichloride, coumamycin A1, L(+)-lactic acid, cytochalasin B, cytochalasin D, dacarbazine, daunorubicin, distamycin A, doxorubicin, echinomycin, enrofloxacin, etoposide, flumequine, formycin, fumagillin, ganciclovir, gliotoxin, lomefloxacin, metronidazole, misramycin A, mitomycin C, nalidixic acid, netropsin, nitrofurantoin, nogalamycin, nonactin, novobiocin, ofloxacin, oxolinic acid, paclitaxel, phenazine, phleomycin, pipemidic acid, rebeccamycin, sinefungin, streptozocin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine-purum, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfachinoxaline, sulfasalazine, sulfacetamide, sulfathiazole, trimethoprim, tubercidin, 5-azacitidine, cordycepin, and formycin A;c) Cell wall synthesis inhibitors including, but not limited to, (+)-6-aminopenicillanic acid, 7-aminodesacetoxycephalosporanic acid, amoxicillin, ampicillin, azlocillin, bacitracin, carbenicillin, cefaclor, cefamandole, cefazolin, cefmetazole, cefixime, cefoperazone, cefotaxime, cefurosine, ceftriaxone, cephalexin, cephalosporin, cephalothin, cefradine, ceftazidime, cloxacillin, D-cycloserine, dicloxacillin, D-penicillamine, ceftizoxime, econazole, ethambutol, lysostaphin, moxalactam, nafcillin, nikkomycin Z, nitrofurantoin, oxacillin, penicillic acid, penicillin G, phenethicillin, phenoxymethylpenicillic acid, fosfomycin, pipemidic acid, piperacillin, ristomycin, and vancomycin; d) Cell membrane equivalence inhibitors including, but not limited to, amphotericin B, 2-mercaptopyridine, 4-bromocalcium ionophore A23187, colistin, alamethicin, calcium ionophore A23187, chlorhexidine, clotrimazole, econazole, hydrocortisone, filipin, gliotoxin, gramicidin A, gramicidin C, ionomycin, lasalocid A, lonomycin A, monensin, narasin, nigericin, nisin, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, sulfisoxazole, pyrimethamine, mafenide, nonactin, nystatin, phenazine, pimaricin, polymyxin, DL-penicillamine, praziquantel, salinomycin, surfactin, and valinomycin;e) Enzyme inhibitors including, but not limited to, (+)-usnic 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, -, antipyrine, ascomycin, azaserine, bafilomycin, cerulenin, chloroquine, cinoxacin, ciprofloxacin, mevastatin, concanamycin A, concanamycin C, coumamycin A1, L(+)-lactic acid, cyclosporin A, econazole, enrofloxacin, etoposide, flumecin, formycin A, furazolidone, furoic acid, geldanamycin, gliotoxin, gramicidin A, gramicidin C, herbimycin A, indomethacin, irgasan, lomefloxacin, mycophenolic acid, mithiotiazole, nalidixic acid, netropsin, niclosamide, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-methyl-1-deoxynojirimycin, nikkomycin, nogalamycin, nonactin, novobiocin, ofloxacin, oleandomycin, oligomycin, oxolinic acid, piericidin A, pipemidic acid, radicicol, rapamycin, rebeccamycin, sinefungin, staurosporine, stigmatellin, succinylsulfathiazole, succinylsulfathiazole, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide, sulfachinoxaline, sulfasalazine, sulfathiazole, triacsin C, trimethoprim, and viomycin A1; f) Membrane modifiers including, but not limited to, paracelsin); g) Aminoglycosides; and h) Fluoroquinolones.;

[0089] The amount of the compound administered can be a therapeutically effective amount. The dosage administered depends on the characteristics of the subject being treated, such as the particular animal being treated, age, weight, health, type of co-treatment if any, and frequency of treatment, as well as the nature and degree of myopia, and can be readily determined by one of ordinary skill in the art (e.g., by a clinician). The selection of a particular dosage regimen can be selected, adjusted, or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response. Additionally, in vitro or in vivo assays can optionally be used to assist in identifying the optimal dosage range. The exact dosage used in the composition can also depend on the route of administration and should be determined according to the judgment of the physician and the circumstances of each patient.

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

[0091] One or more ophthalmic lubricants can also optionally be included in the composition to promote lacrimation or as a "dry eye" agent. Such agents include, but are not limited to, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc. It will be understood that promoting lacrimation is beneficial in the present invention only when lacrimation is naturally lacking in order to restore the normal degree of lacrimal fluid secretion. When excessive lacrimation occurs, the residence time of the composition in the eye can be shortened.

[0092] The present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the 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 pharmaceuticals or biological products, the notice reflecting the agency's approval of the manufacture, use, or sale for administration to humans for treating myopia as described herein. In some embodiments, the kit comprises two or more of the compounds or compositions described herein.

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

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

[0095] In some embodiments, the pharmaceutical aqueous solution exhibits increased bioavailability. In some embodiments, the bioavailability comprises 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 an eye drop.

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

[0098] The present disclosure also provides for the use of any of the aqueous pharmaceutical solutions described herein for treating a subject having an eye disease or for preventing a subject from developing an eye disease. The present disclosure also provides for the use of any aqueous pharmaceutical solution lacking a preservative described herein for treating a subject having an eye disease or for preventing a subject from developing an eye disease. The present disclosure also provides for the use of any of the aqueous pharmaceutical solutions described herein in the manufacture of a medicament for treating a subject having an eye disease or for preventing a subject from developing an eye disease. The present disclosure also provides for the use of any aqueous pharmaceutical solution lacking a preservative described herein in the manufacture of a medicament for treating a subject having an eye disease or for preventing a subject from developing an eye disease. In some embodiments, the eye disease is myopia.

[0099] Examples are provided below so that the subject matter disclosed herein can be understood more efficiently. It is to be understood that 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 The high doses of atropine required to prevent myopia are associated with debilitating side effects including mydriasis and photosensitivity (ATOM1, ATOM2, and LAMP studies). Furthermore, atropine is well known to decompose in aqueous solution to tropine and tropic acid: [Chemical formula]

[0101] The problem of atropine instability is partly due to the lack of substitution at the α-position. In an attempt to avoid this problem, substitution at the α-position of atropine was considered and tested in the FDM chicken model. Briefly, monocular form deprivation myopia (FDM) was induced in the right eye of chickens using translucent diffuser goggles, while the contralateral left eye was left without goggles to serve as a control (normal) eye. After myopia induction (on days 2 and 4), the right eye with goggles was treated with intravitreal injection of vehicle with or without drug, while the left non-goggled eye was injected with saline. On day 5, the refractive error of the eyes was measured using retinoscopy. The animals were then euthanized, the eyes were removed, and the axial length was measured using digital calipers. Methylatropine, fluoroatropine, and benzylatropine were found to be effective in the FDM chicken model (see Figure 1, panel A). However, unexpectedly, benzylatropine was found to be about 10-fold less concentrated but as effective as atropine in the FDM chicken model (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 tests were performed via radioligand displacement assays using known radiolabeled receptor-selective ligands as references to determine the ability (dose-response) of the newly synthesized compounds to bind to different muscarinic receptors. The binding affinity (ki) of the synthesized compounds can be determined from the IC50 and KD values.

[0103] [Table 1]

[0104] Atropine and methylatropine were found to bind non-selectively to muscarinic receptors, while benzatropine 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 suggested, in particular, an opportunity to avoid side effects associated with natural atropine. Accordingly, benzatropine was identified as a lead candidate.

[0105] Example 2: Solubility of Atropine, Methylatropine, and Benzatropine As part of an initial formulation development approach, atropine, methylatropine, and benzatropine 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 benzatropine was good in both vehicles, and it was expected that the pH of both vehicles would change little after atropine, methylatropine, and benzatropine had dissolved. The theoretical and measured concentrations of atropine, methylatropine, and benzatropine in the resulting formulations are shown in Table 2.

[0106] [Table 2]

[0107] Natural atropine (i.e., atropine sulfate monohydrate) dissolved readily in both vehicles, while methylatropine and benzatropine unexpectedly did not dissolve completely 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, it was considered that lowering the initial pH value of the vehicle was necessary to: i) ensure higher solubility and ii) reach the ophthalmologically acceptable target pH (5 - 8). Also, the addition of an isotonic agent was necessary to reach the 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 yielded a final pH close to the acceptable ideal range (pH 5 - 8) for ophthalmic products.

[0113] Lowering the pH of the vehicle was expected to completely dissolve benzylatropine, similar to methylatropine. However, unexpectedly, benzylatropine did not completely dissolve upon pH adjustment (Tables 6 and 7).

[0114]

Table 6

[0115]

Table 7

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

[0117]

Table 8

[0118] The polyethylene glycol 400 (PEG-400) used as the "neat" solution provided the highest drug solubility of 8.01 mg / g (0.8%). However, the recommended concentration of PEG-400 as an inert ingredient 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 the concentration of benzyl atropine.

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

[0120] [Table 9]

[0121] As shown in Table 9, the solubility doubled with the change 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 benzyl atropine in the presence of citric acid or acetate buffer (Table 10).

[0123] [Table 10]

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

[0125] Considerable effort was 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 benzyl atropine without reprecipitation 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, the acetic acid / phosphate buffered vehicle was found to produce a formulation with the highest concentration of benzyl acetate and the most ophthalmologically acceptable pH. The effectiveness of this "double buffer" vehicle was unexpected.

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

[0129]

Table 12

[0130]

Table 13

[0131] In addition to what is described herein, various modifications of the described subject matter will be apparent to those skilled in the art from the foregoing description. Such modifications are also 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 publications, international patent application publications, gene bank accession numbers, etc.) is hereby incorporated by reference in its entirety into this specification.

Claims

Claim 1 Benzylatropine of formula I: 【Chemical 1】 Or a pharmaceutically acceptable salt or prodrug thereof, at least one buffer, at least one isotonic agent, and at least one solubilizer, wherein the concentration of the benzylatropine or a pharmaceutically acceptable salt or prodrug thereof is about 0.01 to about 0.2% (weight / weight), an aqueous pharmaceutical solution. Claim 2 The aqueous pharmaceutical solution according to 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 containing 2-amino-2-methyl-1-propanol. Claim 3 The aqueous pharmaceutical solution according to claim 1 or claim 2, further comprising at least one additional buffer. Claim 4 The aqueous pharmaceutical solution according to 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. Claim 5 The aqueous pharmaceutical solution according to 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. Claim 6 The aqueous pharmaceutical solution according to any one of claims 1 to 5, wherein the at least one isotonic agent comprises sorbitol, propylene glycol, dextrose, glycerin, mannitol, potassium chloride, or sodium chloride, or any combination thereof. Claim 7 The aqueous pharmaceutical solution according to any one of claims 1 to 6, wherein the at least one solubilizer comprises polyethylene glycol-400, polyethylene glycol-35 / hydrogenated castor oil, polypropylene glycol, polysorbate-80, polyethylene glycol-40 stearate, poloxamer-407, dimethyl sulfoxide, or hydroxypropyl-β-cyclodextrin, or any combination thereof. Claim 8 The at least one solubilizer includes hydroxypropyl-β-cyclodextrin, and the concentration of the hydroxypropyl-β-cyclodextrin is about 2.5, about 5, or about 10% (weight / weight) based on the total weight of the aqueous pharmaceutical solution. The aqueous pharmaceutical solution according to any one of claims 1 to 7.

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

10. The aqueous pharmaceutical solution according to any one of claims 1 to 9, wherein the aqueous pharmaceutical solution has a pH value 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 includes 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. Further including at least one additional buffer and at least one additional solubilizer: The concentration of the benzylatropine is about 0.05 to about 0.2% (weight / weight); The at least one buffer includes at least one acetate buffer; The at least one isotonic agent includes sodium chloride; The at least one solubilizer includes polyethylene glycol-400; The at least one additional buffer includes at least one phosphate buffer; The at least one additional solubilizer includes polyethylene glycol-35; The aqueous pharmaceutical solution has a pH value of about 5 to about 6, The aqueous pharmaceutical solution according to claim 1.

14. Further including at least one additional buffer and at least one additional solubilizer: The concentration of the benzylatropine is about 0.1 to about 0.15% (weight / weight); The at least one buffer includes at least one acetate buffer; The at least one isotonic agent includes sodium chloride; The at least one solubilizer includes polyethylene glycol-400; The at least one additional buffer includes at least one phosphate buffer; The at least one additional solubilizer includes polyethylene glycol-35; The aqueous pharmaceutical solution has a pH value of about 6 to about 7, The aqueous pharmaceutical solution according to claim 1.

15. The concentration of the benzylatropine is about 0.1 to about 0.15% (weight / weight); The at least one buffer includes at least one acetate buffer; The at least one isotonic agent includes mannitol or sodium chloride; The at least one solubilizing agent includes hydroxypropyl-β-cyclodextrin; The aqueous pharmaceutical solution has a pH value of about 5.5 to about 6.5, The aqueous pharmaceutical solution according to claim 1.

16. Benzylatropine of formula I: [Chemical 2] Or a process for preparing an aqueous solution containing a pharmaceutically acceptable salt or prodrug thereof, comprising: Providing an aqueous solution containing at least one acetate buffer, at least one solubilizing agent, and at least one additional solubilizing agent, the aqueous solution having a pH value of about 4 to about 5; and Adding the benzylatropine or a pharmaceutically acceptable salt or prodrug thereof to the aqueous solution, wherein the benzylatropine or a pharmaceutically acceptable salt or prodrug thereof dissolves in the aqueous solution, thereby providing an aqueous solution of benzylatropine or a pharmaceutically acceptable salt or prodrug thereof. comprising, The concentration of the benzylatropine or a pharmaceutically acceptable salt or prodrug thereof in the aqueous solution is about 0.01 to about 0.2% (weight / weight), and the aqueous solution has a pH value greater than about 5.

17. The product of the process according to claim 16, wherein the aqueous solution of benzylatropine is in the form of an aqueous pharmaceutical solution.

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

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

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