Semi-fluorinated alkane compositions comprising hyoscyamine

Abstract

The present disclosure relates to pharmaceutical compositions comprising hyoscyamine, or a pharmaceutically acceptable salt thereof, dissolved or suspended in a vehicle comprising a semifluorinated alkane.

Description

[0001] describe Background Art

[0002] The stability of active pharmaceutical compounds during storage under various conditions is often a concern during the development of compound formulations. This aspect is particularly relevant for liquid formulations of pharmaceutically active compounds that can isomerize, because the isomerization process will result in structural changes in the compound, which can have a significant impact on the properties of the compound, including the pharmacological properties and pharmacokinetic characteristics of the compound.

[0003] For example, for enantiomeric compounds, it may often be the case that only one enantiomer of a pair of enantiomers may be active or provide the desired pharmacological effect, while the other enantiomer may be less active or even harmful. However, for some active pharmaceutical compounds, there may also be significant differences in the physiological activity between the two enantiomers; for example, one enantiomer may be pharmacologically active, while the other enantiomer may exhibit significant drug toxicity characteristics, such that the active pharmaceutical compound may be unsafe for clinical use.

[0004] Thus, for formulations of drug products containing only one or predominantly only one isomer (e.g., a single enantiomer of an active compound), it is important not only to maintain compound integrity and avoid or minimize compound degradation during storage, but also that there is no loss or change in the stereochemical purity of the compound in the composition.

[0005] Atropine is a racemic mixture of the enantiomers (S)-hyoscine and (R)-hyoscine, with (S)-hyoscine being the active enantiomer species. Aqueous formulations of atropine are commercially available at concentrations of 1.0% and 0.5% (w / v). These formulations have been tested and shown to be effective in treating the progression of myopia, however these high doses also have a very high incidence of adverse events, which typically lead to treatment discontinuation. Gradually decreasing doses of atropine have been tested to optimize safety and efficacy, and it has been found that once daily administration of 0.01% (w / v) atropine retains almost the same efficacy as the highest dose, but with almost no side effects. Since no formulation of 0.01% (w / v) atropine has been approved anywhere in the world, doctors must prescribe it off-label to compounding pharmacies to supply their patients. However, compounded (0.01% w / v) atropine is often pharmacologically unstable, resulting in products with a short shelf life (e.g., about 30 days). It has been observed that the closer the formulation is to physiological pH (about 7.4) and the lower the atropine concentration, the higher the degradation rate. As described above, unstable drug products are of concern not only from the perspective of therapeutic efficacy (loss or reduction in dosing accuracy) but also from the perspective of patient safety. Formulations have been developed to counteract or slow the degradation of atropine, including adjustment to a lower pH, however, this does not match the physiological pH of the eye or tears and is therefore less compatible with the eye or potentially irritating to the eye.

[0006] Alternative formulations of atropine have been prepared. For example, WO 20200160493 describes 8-methyl-9-azabicyclo[3.2.1]octan-3-yl and pyridine-r-ylmethanyl ester and amide compounds, as well as compositions comprising such compounds or atropine and semifluorinated alkanes such as perfluorohexyl octane or perfluorohexyl nonane.

[0007] US11191751 describes a topical ophthalmic composition for use in treating myopia, comprising atropine (free base) and a semifluorinated alkane as a liquid vehicle. However, the composition in the present disclosure comprises only atropine, a racemic mixture of two scopolamine enantiomers.

[0008] It is therefore an object of the present invention to provide a composition comprising an isomerizable compound (e.g. an enantiomer of a compound such as (S)-hyoscyamine) which improves the stability of the active compound (in particular during storage) but which can also be directly applied for therapeutic use (e.g. for topical ophthalmic administration).

[0009] Other objects of the present invention will become clear based on the following description of the invention, examples and claims. Summary of the Invention

[0010] In one aspect, the present invention provides a pharmaceutical composition comprising (S)-hyoscine or a pharmaceutically acceptable salt thereof, wherein the (S)-hyoscine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients; wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, structural isomers of these semifluorinated alkanes, and any combination thereof. The present disclosure also relates to a method for stabilizing (S)-hyoscine in a composition, the method comprising the step of dissolving (S)-hyoscine in a semifluorinated alkane.

[0011] In yet another aspect, the present disclosure also provides uses of these pharmaceutical compositions, for example as medicaments, such as for treating ophthalmic conditions or disorders.

[0012] In another aspect, the present disclosure relates to a liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is dissolved or suspended in a semifluorinated alkane, or dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients. The enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98%, or 99%. The present disclosure also relates to a method for stabilizing the enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, or preventing or reducing the loss of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition (e.g., loss of enantiomeric excess or enantiomeric purity). BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 depicts an HPLC chromatogram obtained for a composition comprising 0.1 mg / mL (S)-hyoscine in F4H5, the composition comprising 81.6% enantiomeric excess of (S)-hyoscine (enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is 9.87). DETAILED DESCRIPTION

[0014] In a first aspect, the present disclosure relates to a pharmaceutical composition comprising (S)-hyoscyamine or a pharmaceutically acceptable salt thereof, wherein the (S)-hyoscyamine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients. In one embodiment, the semifluorinated alkane is F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, structural isomers of these semifluorinated alkanes, or any combination or mixture of these compounds. Preferably, the composition is a liquid composition.

[0015] In another aspect, the present disclosure relates to a pharmaceutical composition comprising an isomerizable pharmaceutically active compound or a pharmaceutically acceptable salt thereof dissolved or suspended in a vehicle comprising a semifluorinated alkane.

[0016] The isomerizable pharmaceutically active compound is preferably a compound comprising at least one chiral stereocenter. In one embodiment, the compound comprises one chiral stereocenter. The compound may be one stereoisomer of a pair of stereoisomers (e.g., enantiomers). In other embodiments, the isomerizable compound according to the present disclosure may comprise more than one chiral stereocenter. In other embodiments, the compound may be a diastereomer.

[0017] In particular, the chiral stereocenter may be unstable or susceptible to racemization or inversion, or, in the case of a diastereomeric compound, susceptible to epimerization at one of the chiral stereocenters of the compound. In one embodiment, the chiral stereocenter is at an acidic or basic carbon.

[0018] In a related aspect, the present disclosure relates to a liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%, and wherein the enantiomer is dissolved or suspended in a semifluorinated alkane, or in a vehicle comprising a semifluorinated alkane and one or more excipients.

[0019] Enantiomeric excess (ee) is a measure of purity for chiral substances. It reflects the extent to which a sample contains an amount of one enantiomer (i.e., (S)-hyoscyamine, see 1a in the enantiomeric compound list in Table 1 below) that is greater than the amount of its mirror image stereoisomer (i.e., (R)-hyoscyamine, see 1b in the enantiomeric compound list in Table 1 below). A racemic mixture has an ee of 0%, while a completely pure single enantiomer (e.g., an enantiomerically pure compound) has an ee of 100%. A sample with 70% (S)-hyoscyamine (1a) and 30% (R)-hyoscyamine (1b) has an ee of 40% (70% - 30%).

[0020] In another aspect, the present disclosure relates to a liquid pharmaceutical composition comprising enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer to the second enantiomer is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1, wherein the one or more enantiomers are dissolved or suspended in a semifluorinated alkane; or dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients.

[0021] As understood herein, the liquid pharmaceutical composition comprising the enantiomer of a pharmaceutically active compound or its pharmaceutically acceptable salt refers to a composition comprising a pair of enantiomers of the same compound, wherein the enantiomer is a mirror image stereoisomer. The enantiomeric purity or stereochemical purity of a compound reflecting the degree or amount of an enantiomer or stereoisomer, for example, in a sample of the compound or in a composition, can be defined or represented, for example, by a ratio (i.e., enantiomeric ratio) or enantiomeric excess (ee) as defined herein. In some embodiments, the compound according to the present disclosure comprises a chiral stereocenter. In some embodiments, the compound comprises a chiral stereocenter on a carbon atom, wherein at least one substituent of the chiral stereocenter is i) a hydrogen moiety that is easily deprotonated under alkaline conditions and / or ii) an alcohol moiety that is easily dehydrated under acidic conditions.

[0022] Concerning the enantiomers of the pharmaceutically active compounds comprised in the composition according to the present disclosure, these may be chosen from the list consisting of compounds 1a to 49a comprised in column A or compounds 1b to 49b comprised in column B in Table 1 below.

[0023] Table 1

[0024]

[0025]

[0026] For a pair of enantiomers (first enantiomer or second enantiomer), column A refers to the first enantiomer of the enantiomer pair, and column B refers to the second enantiomer of the enantiomer pair. In some embodiments, the liquid pharmaceutical composition comprises an enantiomer of a pharmaceutically active compound selected from any row of Table 1, or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer (column A) to the second enantiomer (column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1, wherein the enantiomers are dissolved or suspended in a semifluorinated alkane; or dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients. In some embodiments, the liquid pharmaceutical composition comprises a mixture of two enantiomers of a pharmaceutically active compound selected from any row of Table 1, or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer (contained in column A) to the second enantiomer (contained in column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1, wherein the enantiomers are dissolved or suspended in a semifluorinated alkane; or dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients. Herein, a mixture of two enantiomers consists of the first enantiomer (contained in column A) and the corresponding second enantiomer (contained in column B) in the same row of Table 1 (e.g., a mixture of two enantiomers consists of the first enantiomer 3a [(R)-azelastine] and the second enantiomer 3b [(S)-azelastine]).

[0027] In some embodiments, the (first) enantiomer is selected from the list consisting of: (S)-hyoscyamine (1a), (S)-(-)-alprenolol (2a), (R)-azelastine (3a), (S)-azelastine (4a), (S)-bisoprolol (5a), (R)-(-)-bufuralol (6a), (S)-carprofen (7a), (S)-carvedilol (8a), (R)-carvedilol (9a), (S)-(-)-celiprolol (10a), (S)-chloroquine (11a), (S)-(+)-dimethylindene (12a), (R)-(-)-dimethylindine (13a), (S)-ecamprol (14a), (2S,3R)-epiconazole (15a), (S)-esmolol (16a), (S)-(-)-esmolol (17a), (R)-etodolac (18a), (S)-fenoprofen (19a), (R)-fexofenadine (20a), (S)-fexofenadine (21a), (S)-(+)-flurbiprofen (22a), (R)-(-)-flurbiprofen (23a), (S)-gatifloxacin (24a ), (S)-gemifloxacin (25a), (R,R)-(+)-jinaconazole (26a), (S)-hydroxychloroquine (27a), (S)-(+)-ibuprofen (28a), (S)-indoprofen (29a), (R)-ketamine (30a), (S)-ketoprofen (31a), (S)-ketorolac (32a), (S)-lomefloxacin (33a), (R)-lomefloxacin (34a), (S)-(-)-metoprolol (35a), (R)-(+)-metoprolol (36a), (R)-(-)-miconazole (37a), azole (37a), (S)-(-)-moprolol (38a), S-(-)-nadifloxacin (39a), (D)-nebivolol (40a), (L)-nebivolol (41a), (S)-(-)-oxprenolol (42a), (+)-pemetrexate (43a), (S)-(-)-propranolol (44a), (R)-(+)-propranolol (45a), (R)-sertaconazole (46a), (R)-(-)-sotalol (47a), (-)-terconazole (48a) and (+)-terconazole (49a).

[0028] In some embodiments, the (second) enantiomer is selected from the list consisting of: (R)-hyoscyamine (1b), (R)-(+)-alprenolol (2b), (S)-azelastine (3b), (R)-azelastine (4b), (R)-bisoprolol (5b), (S)-(+)-bufuralol (6b), (R)-carprofen (7b), (R)-carvedilol (8b), (S)-carvedilol (9b), (R)-(+)-celiprolol (10b), (R)-chloroquine (11b), (R)-(-)-dimethylindene (12b), (S)-(+)-dimethylindine (13b), (R)-ecamprol (14b), (2R,3S)-epiconazole (15b), (R)-esmolol (16b), (R)-(+)-esmolol (17b), (S)-etodolac (18b), (R)-fenoprofen (19b), (S)-fexofenadine (20b), (R)-fexofenadine (21b), (R)-(-)-flurbiprofen (22b), (S)-(+)-flurbiprofen (23b), (R)-gatifloxacin (24b), b), (R)-gemifloxacin (25b), (SS)-(-)-jinaconazole (26b), (R)-hydroxychloroquine (27b), (R)-(-)-ibuprofen (28b), (R)-indoprofen (29b), (S)-ketamine (30b), (R)-ketoprofen (31b), (R)-ketorolac (32b), (R)-lomefloxacin (33b), (S)-lomefloxacin (34b), (R)-(+)-metoprolol (35b), (S)-(-)-metoprolol (36b), (S)-(+)-miconazole (37b). azole (37b), (R)-(+)-moprolol (38b), R-(+)-nadifloxacin (39b), (L)-nebivolol (40b), (D)-nebivolol (41b), (R)-(+)-oxprenolol (42b), (-)-pemetrexate (43b), (R)-(+)-propranolol (44b), (S)-(-)-propranolol (45b), (S)-sertaconazole (46b), (S)-(+)-sotalol (47b), (+)-terconazole (48b), and (-)-terconazole (49b).

[0029] Preferably, the first enantiomer and the second enantiomer pair are compounds 1a:1b, 2a:2b, 3a:3b, 4a:4b, 5a:5b, 6a:6b, 7a:7b, 8a:8b, 9a:9b, 10a:10b, 11a:11b, 12a:12b, 13a:13b, 14a:14b, 15a:15b, 16a:16b, 17a:17b, 18a:18b, 19a:19b, 20a:20b, 21a:21b, 22a:22b, 23a:23b, 24a:24b, b, 25a:25b, 26a:26b, 27a:27b, 28a:28b, 29a:29b, 30a:30b, 31a:31b, 32a:32b, 33a:33b, 34a:34b, 35a:35b, 36a:36b, 37a :37b, 38a:38b, 39a:39b, 40a:40b, 41a:41b, 42a:42b, 43a:43b, 44a:44b, 45a:45b, 46a:46b, 47a:47b, 48a:48b, 49a:49b.

[0030] As mentioned above, the compositions of the present disclosure are compositions comprising semifluorinated alkanes. Semifluorinated alkanes are straight-chain or branched alkanes in which some hydrogen atoms are replaced by fluorine atoms. In one embodiment, the semifluorinated alkanes described and used in accordance with the present disclosure (which may be abbreviated as SFA) are composed of a straight-chain non-fluorinated hydrocarbon segment and a straight-chain perfluorinated hydrocarbon segment, wherein the perfluorinated hydrocarbon segment is attached to the non-fluorinated hydrocarbon segment. In a preferred embodiment, the semifluorinated alkanes used in the context of the present disclosure are preferably liquid semifluorinated alkanes.

[0031] In one embodiment, the semifluorinated alkane has the formula F(CF2) n (CH2) m H, wherein n and m are integers defining the number of carbons in the perfluorinated hydrocarbon segment and the non-fluorinated hydrocarbon segment, respectively. In another embodiment, the one or more semifluorinated alkanes included in the composition according to the present disclosure are of the formula F(CF2) n (CH2) m H, wherein n is an integer selected from 4 to 6, and m is an integer selected from 2 to 10. In another embodiment, the one or more semifluorinated alkanes are of the formula F(CF2) n (CH2) m H, wherein n is an integer selected from 4 to 6, and m is an integer selected from 4 to 8.

[0032] The nomenclature also commonly used for linear semifluorinated alkanes designates the perfluorinated hydrocarbon segment as RF and the non-fluorinated segment as RH, i.e., RFRH. Alternatively, the compound can be referred to as FnHm, where F refers to the perfluorinated hydrocarbon segment, H refers to the non-fluorinated segment, and n and m define the number of carbon atoms in the respective segments. For example, F3H3 is used for perfluoropropylpropane, F(CF2)3(CH2)3H. Furthermore, this type of nomenclature is commonly used for compounds with linear, i.e., unbranched, segments. Therefore, unless otherwise indicated, F3H3 should be assumed to refer to 1-perfluoropropylpropane, rather than its structural isomers, such as branched isomers such as 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

[0033] In one embodiment of the present disclosure, the composition or the vehicle of the composition may be composed of one or more semifluorinated alkanes selected from the following: F4H4, F4H5, F4H6, F4H8, F6H2, F6H4, F6H6, F6H8, F6H10 or structural isomers thereof and mixtures thereof. The chemical formulas of these semifluorinated alkanes can be expressed as F(CF2)4(CH2)4H, F(CF2)4(CH2)5H, F(CF2)4(CH2)6H, F(CF2)4(CH2)8H, F(CF2)6(CH2)2H, F(CF2)6(CH2)4H, F(CF2)6(CH2)6H, F(CF2)6(CH2)8H and F(CF2)6(CH2) 10 H. In another embodiment, the vehicle comprises a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, or structural isomers thereof, or any mixture or combination of these semifluorinated alkanes. In yet another embodiment, the composition or vehicle comprises a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, structural isomers thereof, and any mixture thereof.

[0034] In yet another embodiment, the semifluorinated alkane is F4H5 (1-perfluorobutyl-pentane), F6H8 (1-perfluorohexyl-octane), their structural isomers, or any mixture of these semifluorinated alkanes. 1-Perfluorobutyl-pentane, having the chemical formula F(CF2)4(CH2)5H, is an inert, water-insoluble liquid with a density of 1.284 g / cm3 at 25°C. 3 , and a refractive index of 1.3204 at 20°C. Alternative nomenclature for this compound includes F4H5, wherein F represents a linear perfluorinated alkane segment containing 4 carbon atoms, and wherein H represents a linear and non-fluorinated alkane segment containing 5 carbon atoms. Preferably, 1-perfluorobutyl-pentane is substantially free of water.

[0035] Optionally, the formulation may contain more than one semifluorinated alkane. As understood herein, the term "one" semifluorinated alkane does not exclude a plurality, unless the context provides otherwise. In other words, in some embodiments, the compositions or methods according to the present disclosure may involve the use or characteristics of one or more semifluorinated alkanes. For example, in order to achieve a specific target property, such as a specific density or viscosity, it may be useful to combine semifluorinated alkanes. If a mixture of semifluorinated alkanes is used, it is preferred that the mixture contains at least one of the following: F4H5, F4H6, F6H4, F6H6, F6H10. In one embodiment, the composition or vehicle contains at least two members selected from the following: F4H5, F4H6, F6H4, F6H6, F6H10. In one embodiment, the composition or vehicle comprises a mixture of 1-perfluorobutyl-pentane and 2-perfluorobutyl-pentane, optionally wherein 2-perfluorobutyl-pentane is present in the vehicle in an amount of up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w), or up to 0.2% (w / w); or present in the vehicle in an amount of 0.1% to 2% (w / w), or 0.01% to 1% (w / w), or 0.5% to 5% (w / w), relative to the total weight of the mixture of semifluorinated alkanes. In yet another embodiment, the vehicle of the composition according to the present disclosure comprises a mixture of 1-perfluorohexyl-octane and 2-perfluorohexyl-octane, optionally wherein 2-perfluorohexyl-octane is present in an amount of up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w), or in an amount of 0.1% to 2% (w / w), or 0.01% to 1% (w / w), or 0.5% to 5% (w / w), relative to the total weight of the mixture of semifluorinated alkanes.

[0036] In another embodiment, the vehicle of the composition according to the present disclosure consists essentially only of one or more semifluorinated alkanes as described herein, without additional excipients such as cosolvents (e.g., ethanol). For example, in one embodiment, the vehicle consists only of a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, or structural isomers thereof, and any combination or mixture of these semifluorinated alkanes. Or in other words, the vehicle consists essentially of 100% (w / w) of a semifluorinated alkane or a mixture of semifluorinated alkanes as defined above.

[0037] As used herein, the term "consists of" and the related terms "consisting or consist" should be understood to mean that, apart from those features preceded by the term, no other features are present. In the context of a composition, if any other ingredients or components besides those preceded by the term are present in the composition, they are present only in trace or residual amounts to such an extent that they do not confer technical advantage or relevance for the purposes of the present invention, as may be further understood, for example, by the terms "substantially" or "essentially" used in conjunction with these terms (e.g., "consists essentially of"). In contrast, in the context of a composition, the term "comprising" or the related terms "comprises or comprise" should be understood to mean that other features besides those preceded by the term may be present in the composition.

[0038] As understood herein, the vehicle of the composition according to the present disclosure comprises at least one semifluorinated alkane. The vehicle may optionally further comprise one or more excipients, as further described below. In one embodiment, the vehicle comprises more than one semifluorinated alkane. In another embodiment, the vehicle consists of one or more semifluorinated alkanes and optionally one or more pharmaceutically acceptable excipients, preferably excipients that are miscible or soluble in the semifluorinated alkane or semifluorinated alkane mixture. In one embodiment, the amount of the semifluorinated alkane or semifluorinated alkane mixture in the composition is at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.8% (w / w) relative to the gross weight of the composition.

[0039] In other embodiments according to the present disclosure, the pharmaceutical composition comprises from about 95% to about 99% (w / w), more preferably from about 98% to about 99% (w / w), even more preferably from about 98% to about 99.9% (w / w) of a semifluorinated alkane, based on the total weight of the composition. In one embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, 99% or at least 99.5% (w / w) of 1-perfluorobutyl-pentane (F4H5), and optionally also 2-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w / w) 1-perfluorobutyl-pentane (F4H5) and at most about 0.2%, 0.3%, 0.4%, 0.5%, or at most about 1% (w / w) 2-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition.

[0040] In another embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, 99% or at least 99.5% (w / w) of 1-perfluorohexyl-octane (F6H8), and optionally 2-perfluorohexyl-octane, based on the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98% or at least 99% (w / w) of 1-perfluorohexyl-octane (F6H8) and at most about 0.2%, 0.3%, 0.4%, 0.5% (w / w) or at most about 1% (w / w) of 2-perfluorohexyl-octane, based on the total weight of the pharmaceutical composition.

[0041] In one embodiment, the pharmaceutical composition of the present disclosure is a solution. As understood herein, the term "clear" solution refers to a liquid solution in which all solutes are completely soluble or have been completely dissolved under room temperature conditions (i.e., between 15° C. and 25° C.). A clear solution is not composed of any particulate or solid phase components and preferably has a refractive index close to that of water (i.e., 1.333) at room temperature.

[0042] In one embodiment, the composition according to the present disclosure is in the form of a solution, or alternatively in the form of a suspension. Therefore, as understood herein, the term "solution" or "clear solution" refers to a liquid solution in which all solutes are completely soluble or have been completely dissolved under room temperature conditions (i.e., between 15°C and 25°C). The resulting solution is not composed of any particulate or solid phase components. In one embodiment, the pharmaceutical composition according to the present disclosure comprises (S)-hyoscyamine dissolved in a vehicle comprising any one or combination of one or more semifluorinated alkanes as defined herein and optionally one or more excipients as defined herein, and the pharmaceutical composition is in the form of a clear solution. In another embodiment, the pharmaceutical composition according to the present disclosure comprises an enantiomer of a compound, for example, selected from Table 1, dissolved in a vehicle comprising any one or combination of one or more semifluorinated alkanes as defined herein and optionally one or more excipients as defined herein, wherein the composition is in the form of a clear solution.

[0043] On the other hand, a "suspension" can be defined as a dispersion, i.e., a dispersion as a system having at least one continuous phase (or coherent phase) and at least one discontinuous phase (or internal phase) dispersed in the continuous phase. In a suspension, the dispersed phase is in a solid state. For example, and in the context of the present disclosure, particles (i.e., in a solid state) comprising or consisting of an isomerizable pharmaceutically active compound or a pharmaceutically acceptable salt thereof, such as provided in Table 1, can be suspended in a liquid vehicle of the composition. The suspension used to implement the present invention is preferably a liquid suspension (wherein the continuous phase is a liquid) and is formulated to be suitable for administration as a medicament.

[0044] In another embodiment, the pharmaceutical composition according to the present disclosure consists of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%, and wherein the enantiomer is suspended in any one or combination of one or more semifluorinated alkanes as defined herein. In another embodiment, the pharmaceutical composition according to the present disclosure consists of an enantiomer (mixture of two enantiomers) of a compound selected from any row of Table 1, or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer (contained in column A) to the second enantiomer (contained in column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, wherein the enantiomer (mixture of two enantiomers) is suspended in any one or combination of one or more semifluorinated alkanes as defined herein.

[0045] Optionally, the composition according to the present disclosure may be composed of a vehicle comprising one or more excipients in addition to at least one semifluorinated alkane. In one embodiment, the vehicle of the composition consists of at least one semifluorinated alkane and one or more excipients. As used herein, the term "excipient" refers to any pharmaceutically acceptable, natural, synthetic or semisynthetic substance, compound or component that can be included in the vehicle and therefore included in the composition as described herein, for example to enhance or otherwise change the physical or chemical composition or stability of the composition. Pharmaceutically acceptable means that the excipient is safe, non-toxic, biocompatible and physiologically tolerable, for example for human pharmaceutical use; preferably, the excipient is suitable and safe for topical application to the human eye or its associated eye tissue.

[0046] The example of the excipient that can be included in the composition according to the present disclosure includes but is not limited to cosolvent, antioxidant, preservative, lipid, oily excipient, surfactant, lubricant or its combination.In one embodiment, excipient is a liquid miscible with semifluorinated alkanes, and when more than one excipient is included in the vehicle, it can also be miscible with any other excipient included in the vehicle of the composition.In one embodiment, excipient can be used as cosolvent, i.e., a compound that is suitable for enhancing solubility or solubilizing active compound and / or another excipient included in the composition. Cosolvent is preferably a liquid that is completely miscible with semifluorinated alkanes, i.e., it is mixed with semifluorinated alkanes to form a coherent phase and a single phase. In another embodiment, excipient can be dissolved in semifluorinated alkanes.

[0047] In some embodiments, the excipient is a cosolvent. The cosolvent can be an alcohol, such as an alkyl alcohol. In one embodiment, the alcohol is selected from ethanol, 1-propanol, isopropanol, and phenylethanol; or more preferably selected from ethanol and phenylethanol. Alternatively, in addition to the semifluorinated alkane (or mixture of semifluorinated alkanes) as defined herein, the vehicle of the composition may comprise or consist of at least one excipient, provided that the excipient is not an alcohol and / or is not a medium chain triglyceride (MCT) and / or is not light liquid paraffin.

[0048] In some embodiments, the excipient included in the vehicle is an oily excipient. Examples of oily excipients are triglycerides, mineral oil, and liquid paraffin. In one embodiment, in addition to semifluorinated alkanes, the vehicle also comprises an oily excipient selected from medium chain triglycerides (MCT) and light liquid paraffin.

[0049] In some embodiments, the vehicle of the composition comprises or consists of at least one semifluorinated alkane and any one or combination of a cosolvent or an oily excipient as described above.

[0050] In some embodiments, based on the gross weight of the composition, the one or more excipients are optionally independently present in the composition in an amount of at most 0.1wt%, 0.5wt%, 0.75wt%, 1.0wt%, 1.25wt%, 1.4wt%, 1.5wt%, 1.8wt%, 2.0wt%, 3.0wt%, 4.0wt% or at most 5.0wt% (w / w) or preferably at most 1wt% or at most 1.4wt%. In other embodiments, the composition includes one or more excipients, the amount of the one or more excipients optionally independently based on the gross weight of the composition between 0.1wt% to 5.0wt% or between 0.1wt% to 2.0wt% or between 0.01wt% to 1.4wt%. In other embodiments, based on the cumulative volume of composition, the one or more excipients are optionally independently present in the composition in an amount of at most 0.1% (v / v), 0.5% (v / v), 0.75% (v / v), 1.0% (v / v), 1.25% (v / v), 1.4% (v / v), 1.5% (v / v), 1.8% (v / v), 2.0% (v / v), 3.0% (v / v), 4.0% (v / v) or at most 5.0% (v / v) (w / w) or preferably at most 1% (v / v) or at most 1.4% (v / v). In other embodiments, composition comprises one or more excipients, the amount of the one or more excipients optionally independently based on the cumulative volume of composition between 0.1% to 5.0% (v / v) or between 0.1% to 2.0% (v / v) or between 0.01% to 1.4% (v / v).

[0051] In some embodiments, where the pharmaceutically active compound is hyoscyamine, the composition is substantially free of a) water; or b) a preservative; or c) one or more hyoscyamine degradation products selected from tropic acid, tropine, and anhydroatropine; or d) any combination of a), b), and c).

[0052] In other embodiments, the composition is substantially free of a) water; or b) preservatives.

[0053] As used herein, the term "at most about" or "at most" used in the context of a parameter such as related to the concentration or amount of (S)-hyoscyamine or an isomerizable active compound (e.g., any one of the enantiomeric compounds disclosed herein, e.g., as selected from Table 1) or presently related to the amount of one or more excipients in a composition, refers to any value greater than zero and up to and including the defined parameter, taking into account any degree of variability normally observed in measuring or determining that parameter using standard techniques and equipment known in the relevant art.

[0054] As understood herein, unless otherwise indicated, the term "% (w / v)" refers to expressing the amount of a component in a composition as a weight percentage relative to the total volume of the composition (where "w" means weight and "v" means volume). For example, 0.1% (w / v) would correspond to 1.0 mg of a component in 1 mL of a composition. As used herein and unless otherwise indicated, the term "% (w / w)" or alternatively "wt%" refers to expressing the amount of a component in a composition as a weight percentage relative to the total weight of the composition, where "w" means weight. As used herein and unless otherwise indicated, the term % (v / v) or volume percentage refers to the volume of a component in a composition relative to the total volume of the composition.

[0055] As understood herein, the term "substantially free" or alternatively "essentially free" or "free of a component" with respect to a composition ingredient or component means that the component is not present in more than trace amounts and, if present in trace amounts, does not provide any technical contribution or material advantage to the composition. In one embodiment, the compositions described herein are substantially free of water. In another embodiment, the compositions described herein may be substantially free of preservatives (such as antimicrobial preservatives).

[0056] As used herein, the term "about" and referring to or in connection with a parameter, such as, for example, the amount or concentration of a compound dissolved or suspended in a composition, includes the exact value specified as well as any value that falls within the degree of variability normally observed in measuring or determining these parameters using standard techniques and equipment known in the art.

[0057] As also understood herein, a pharmaceutically acceptable salt is a salt of a compound as provided herein that retains the biological properties of the compound and is non-toxic and compatible with pharmaceutical use. For example, a salt can be produced by adding an acid such as an organic acid or an inorganic acid such as sulfuric acid or hydrochloric acid.

[0058] The compositions of the present disclosure are compositions containing a higher enantiomeric ratio or a predominantly active pharmaceutically active compound (compound as defined above). These are formulated in semifluorinated alkanes and can also remain stable under long-term storage conditions, with minimal or reduced degradation or loss of the enantiomeric purity or stereochemical purity of the compound in the composition. Pharmaceutically active compounds can be provided in racemic form, wherein only one of the compounds can have the desired pharmacological or therapeutic effect, because due to stability issues and / or the tendency of the compound to gradually racemize under storage conditions, maintaining, for example, the stereochemical purity of the desired enantiomer may be difficult. From the perspective of therapeutic efficacy, loss or reduction of dosing accuracy is undesirable. In addition, the absence or much lower amount of non-therapeutic related enantiomers in the medicament may be advantageous because this reduces or avoids unnecessary exposure of the subject to the compound, although the compound has non-therapeutic effects (or adverse effects not yet known), the subject may still (unfavorably) have a physiological reaction to the compound.

[0059] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising (S)-hyoscyamine (or a pharmaceutically acceptable salt thereof), wherein the (S)-hyoscyamine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients as defined above.

[0060] Atropine (CAS 51-55-8) (also known as (±)-hyoscyamine, or phenylacetic acid, α-(hydroxymethyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl ester, endo (±)) is a racemate of two isomers, (S)-hyoscyamine and (R)-hyoscyamine (enantiomeric ratio 50:50). Atropine is a tropane alkaloid compound that is used as an antimuscarinic and anticholinergic agent. However, (S)-hyoscyamine (also known as (-)-hyoscyamine or (L)-hyoscyamine) is considered to be the active enantiomeric species of atropine, which is responsible for the physiological effects of atropine. The chemical structure of (S)-hyoscyamine is

[0061]

[0062] Aqueous formulations of racemic atropine are based on atropine sulfate (CAS 5908-99-6). As mentioned above, aqueous formulations of atropine are commercially available at concentrations of 1.0% and 0.5% (w / v). Lower-dose formulations of 0.01% (w / v) atropine have been found to be effective, but currently physicians must prescribe them off-label to compounding pharmacies to supply their patients. However, these compounded formulations of atropine, particularly lower-dose formulations (e.g., 0.01% (w / v)), are often pharmacologically unstable, resulting in products with short shelf lives. As mentioned above, unstable drug products are a concern not only from the perspective of therapeutic efficacy (loss or reduction in dosing accuracy) but also from the perspective of patient safety. Formulations have been developed to counteract or slow the degradation of atropine, including by adjusting the aqueous formulation to a lower pH. However, this does not match the physiological pH of the eye or tears and, as a result, is less compatible with or irritating to the eye. In the treatment of conditions such as myopia, where application may be required over an extended period of time, patient compliance is key to successful treatment.

[0063] It has been discovered that compositions containing a higher enantiomeric ratio of the active enantiomer (S)-hyoscyamine or containing primarily the active enantiomer (S)-hyoscyamine can be formulated in semifluorinated alkanes and remain stable under long-term storage conditions. Stability was observed in terms of minimal to no degradation of the hyoscyamine compound (as often observed in aqueous formulations of the compound or its sulfate salt), and surprisingly, stability was also observed in terms of racemization or a reduction in the enantiomeric ratio formed relative to the (R)-hyoscyamine enantiomer over time, thereby providing improved shelf-stable compositions.

[0064] Furthermore, it has been found that, in particular, low-concentration (S)-hyoscine compositions that are shelf-stable can also be formulated in semifluorinated alkanes according to the present disclosure, also avoiding the disadvantages of the presence or at least an equivalent amount of the (R)-hyoscine enantiomer (which can be considered an impurity). Although (R)-hyoscine has a low or no pharmacological effect in its intended therapeutic use (e.g., for the treatment of myopia), the absence or a much lower amount of this enantiomer in the composition can be advantageous because it reduces or avoids unnecessary exposure of a subject in need of treatment to a compound to which the subject may still have a physiological response.

[0065] In one embodiment, the composition according to the present disclosure comprises an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is not 50:50. In other words, the composition does not comprise atropine or a racemic mixture of two enantiomers, but rather comprises a majority of the (S)-hyoscyamine enantiomer or predominantly the (S)-hyoscyamine enantiomer. In one embodiment, the composition comprises at least 89% (S)-hyoscyamine, at least 90% (S)-hyoscyamine, at least 93% (S)-hyoscyamine, or at least 95% (S)-hyoscyamine based on the total amount of hyoscyamine compounds in the composition.

[0066] In one embodiment, the composition comprises (S)-hyoscyamine in an enantiomeric excess of at least about 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%. Enantiomeric excess (ee) is a measure of purity for chiral substances. It reflects the extent to which a sample contains an amount of one enantiomer (i.e., (S)-hyoscyamine (1a in Table 1 above)) that is greater than the amount of the other enantiomer (i.e., (R)-hyoscyamine (1b in Table 1 above). A racemic mixture has an ee of 0%, while a completely pure single enantiomer has an ee of 100%. The sample with 70% (S)-hyoscyamine and 30% (R)-hyoscyamine had an ee of 40% (70% - 30%).

[0067] In one embodiment, the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1. An enantiomeric ratio is the ratio of the percentage of one enantiomer to the percentage of the other enantiomer and may alternatively be expressed as a number. For example, for a racemate, the enantiomeric ratio is 1 (50:50), or for an enantiomeric ratio of 90:10, this may be expressed as 9. In one embodiment, the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition is at least 8, 9, 10, 11, 12, 13, 15, 32, or at least 49.

[0068] For example, the enantiomeric ratio or enantiomeric excess (ee) of hyoscyamine, or the stereochemical purity of compounds in general or enantiomers as described in Table 1 herein in particular, and the relative amount or other amount of the active compound, its isomers or degradation products contained in the compositions according to the present disclosure can be determined by many methods in the art, such as, but not limited to, chromatography (such as HPLC), capillary electrophoresis, LC-MS or gas chromatography and / or spectrometry (such as circular dichroism or NMR). In one embodiment, the enantiomeric ratio is determined by HPLC, preferably by quantification of the peak areas of the corresponding compounds.

[0069] In addition to the low amount or concentration of (R)-hyoscyamine in the composition, the pharmaceutical composition comprising (S)-hyoscyamine may also contain only low amounts of, or may be substantially free of, any hyoscyamine degradation products, such as those resulting from hydrolysis of esters of the compound or dehydration of hydroxyl substituents. Preferably, the composition may be substantially free of any one or combination of tropic acid (also known as 3-hydroxy-2-phenylpropionic acid), atropic acid, tropine, anhydroatropine (i.e., a dehydration product of hyoscyamine), or any salt thereof.

[0070] In one embodiment, the pharmaceutical composition comprises no more than 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% or 5% (w / w) of each or any combination of compounds resulting from the degradation of scopolamine, based on the total weight of the composition; preferably wherein the compound is selected from tropic acid, tropine base, atropine, anhydroatropine or a salt thereof.

[0071] In another embodiment, the pharmaceutical composition comprises no more than 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6% or 7% of each or any combination of compounds resulting from the degradation of scopolamine; preferably wherein the compound is selected from tropic acid, atropic acid, anhydroatropine or a salt thereof; the percentages being derived from peak area quantification of the compound in the corresponding analytical chromatography method (e.g., HPLC).

[0072] Alternatively or additionally, the compositions of the present disclosure may be comprised of no more than about 0.0001% to 0.001% (w / v), or 0.004% to 0.006% (w / v)% (R)-hyoscyamine. The compositions may also be substantially free of (R)-hyoscyamine.

[0073] In some embodiments, a composition according to the present disclosure comprises (S)-hyoscyamine, wherein the (S)-hyoscyamine is present in the composition at a concentration between 0.001% and 1.0% (w / v), between 0.001% and 0.5% (w / v), between 0.001% and 0.015%, between 0.002% and 0.012%, between 0.004% and 0.012%, between 0.005% and 0.01%, between 0.01% and 0.1% (w / v), between 0.02% and 0.07% (w / v), between 0.002% and 0.006% (w / v), between 0.004% and 0.006% (w / v), between 0.0045% and 0.0055% (w / v).

[0074] In some embodiments, the concentration of (S)-hyoscyamine in the composition is at most 0.003%, 0.005%, 0.0055%, 0.0075%, 0.01%, 0.02%, 0.03%, 0.05%, 0.1%, 0.5%, 1.0% (w / v).

[0075] In some embodiments, the concentration of (S)-hyoscyamine in the composition is 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1% (w / v).

[0076] In some embodiments, according to the composition of the present disclosure, the composition comprises or consists of:

[0077] a) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, and the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0078] b) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein the hyoscyamine is stored at 25°C for 1, 2 or after 3 months, the total amount of hyoscine relative to the initial amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95%; and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%;

[0079] c) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0080] d) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, the total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%;

[0081] e) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0082] f) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, the total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%;

[0083] g) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0084] h) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, The total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0085] Compositions a), b), c), d), e), f), g), and h) are clear solutions, i.e., the scopolamine is dissolved in a vehicle comprising or consisting of 1-perfluorobutyl-pentane and optionally up to 1 wt% ethanol. In related embodiments, the semifluorinated alkane in these compositions can be a mixture of 1-perfluorobutyl-pentane and its structural isomers (e.g., 2-perfluorobutyl-pentane) according to the present disclosure.

[0086] In further embodiments, the composition according to the present disclosure, wherein the composition comprises or consists of:

[0087] j) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, and the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0088] k) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein the hyoscyamine is stored at 25°C for 1, 2, or 3 hours. After 1 month, the total amount of hyoscyamine is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscyamine in the composition; and optionally wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine has decreased by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%;

[0089] 1) 0.005% (w / v) hyoscyamine, 1-perfluorohexyl-octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0090] m) 0.005% (w / v) hyoscyamine, 1-perfluorohexyl-octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, The total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0091] n) 0.01% (w / v) hyoscyamine, 1-perfluorohexyl-octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0092] o) 0.01% (w / v) hyoscyamine, 1-perfluorohexyl-octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, The total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0093] p) 0.02% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2;

[0094] q) 0.02% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; and wherein after storage at 25°C for 1, 2, or 3 months, the The total amount of hyoscine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscine to (R)-hyoscine is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0095] Compositions j), k), l), m), n), o), p), and q) are clear solutions, i.e., the scopolamine is dissolved in a vehicle comprising or consisting of 1-perfluorohexyl octane and optionally up to 1 wt% ethanol. In related embodiments, the semifluorinated alkane in these compositions can be a mixture of 1-perfluorohexyl octane and its structural isomers (e.g., 2-perfluorohexyl octane) according to the present disclosure.

[0096] In some embodiments, the liquid pharmaceutical composition according to the present disclosure comprises an enantiomer (or a mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from the enantiomers as described in Table 1 herein, wherein the concentration of the compound in the liquid pharmaceutical composition is 0.01% to 5% (w / v), 0.05% to 5% (w / v), 0.05% to 2% (w / v), 0.1% to 2% (w / v), 0.1% to 1% (w / v), or wherein the concentration of the compound in the liquid pharmaceutical composition is 0.5% to 1.0% (w / v). Preferably, the liquid pharmaceutical composition comprises an enantiomer (or a mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from the enantiomers or pairs of enantiomers as described in Table 1 herein, wherein the concentration of the compound in the liquid pharmaceutical composition is at least 0.01% (w / v), 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v), 2% (w / v) or at least 5% (w / v). In some embodiments, the liquid pharmaceutical composition comprises an enantiomer (or a mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from the enantiomer or enantiomeric pair as described in Table 1 herein, wherein the concentration of the compound in the liquid pharmaceutical composition is less than 10% (w / v), 5% (w / v), 3% (w / v), 2% (w / v), 1% (w / v), 0.5% (w / v), 0.1% (w / v), 0.05% (w / v) or less than 0.01% (w / v).

[0097] In some embodiments, the amount of (S)-hyoscyamine in the composition according to the present disclosure is at least 90%, or at least 95%, or at least 99% relative to the initial amount of (S)-hyoscyamine in the composition, e.g., as determined by HPLC, after storage at 0 to 60°C (e.g., storage at 25°C) for at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

[0098] In other embodiments, the concentration or amount of (S)-hyoscine in a composition according to the present disclosure after storage at 0 to 60°C (e.g., storage at 25°C) for at least 1, 2, 3, 4, 5, 6, 9 or at least 12 months is in the range of 90% to 110% or 95% to 105% of the initial concentration of (S)-hyoscine in the composition, e.g., as determined by HPLC. In other embodiments, after storage of the composition at 25° C. for at least 3 months, the concentration of (S)-hyoscyamine is in the range of about 90%-110%; or not less than 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%); or not more than 100% (e.g., not more than 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108% or 109%), for example, as determined by HPLC (preferably by quantification of the peak area of ​​the corresponding compound). In the case where the determined percentage is greater than 100%, it should be understood that the measurement does not relate to an increase in the amount of (S)-hyoscyamine, but rather, for example, is a loss of the vehicle over time during storage. In further related embodiments, the amount of (S)-hyoscyamine is preferably equal to or greater than 90% or 95% of the initial concentration of (S)-hyoscyamine in the composition, or equal to or less than 110%, 105% or 100% of the initial concentration of (S)-hyoscyamine in the composition.

[0099] In some embodiments, the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in a composition according to the present disclosure decreases by no more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% after storage for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months at 25° C. For example, in a composition comprising hyoscyamine dissolved in a semifluorinated alkane and optionally one or more excipients, wherein the hyoscyamine has an initial enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine of 90:10 (i.e., 9) prior to storage or aging, a decrease of about 1% would correspond to a decrease in the enantiomeric ratio to 8.91% or about 89.91:10.09.

[0100] In other embodiments, the amount of the compound (i.e., the enantiomer as described in Table 1 or any list provided in the present disclosure) in the composition according to the present disclosure after storage at 0 to 60°C (e.g., storage at 25°C) for at least 1, 2, 3, 4, 5, 6, 9 or 12 months is at least 90%, or at least 95% or at least 99% relative to the initial amount of the enantiomer in the composition, e.g., as determined by HPLC.

[0101] In some embodiments, the concentration or amount of an enantiomer in a liquid composition according to the present disclosure (e.g., as described in Table 1 or any list provided in the present disclosure) after storage at 0 to 60°C (e.g., storage at 25°C) for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months is in the range of 80% to 120%, 85% to 115%, 90% to 110%, or 95% to 105% of the initial concentration of the enantiomer in the composition, e.g., as determined by HPLC. In other related embodiments, after the composition is stored at 25° C. for at least 3 months, the concentration of the enantiomer is in the range of about 90%-110%; or not less than 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%); or not more than 100% (e.g., not more than 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108% or 109%), for example, as determined by HPLC (preferably by quantification of the peak area of ​​the corresponding compound). In the case where the determined percentage is greater than 100%, it should be understood that the measurement does not relate to an increase in the amount of the enantiomer, but rather, for example, to a loss of the conversion vehicle over time during storage. In other related embodiments, the amount of the enantiomer is preferably equal to or greater than 80%, 85%, or 90% or 95% of the initial concentration of the enantiomer in the composition, or equal to or less than 120%, 115%, 110%, 105% or 100% of the initial concentration of the enantiomer in the composition.

[0102] In some embodiments, the enantiomeric ratio of the first enantiomer to the second enantiomer (see Table 1 above) in a liquid pharmaceutical composition according to the present disclosure decreases by no more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% after storage for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months at 25° C. For example, in a composition comprising the first enantiomer dissolved in a semifluorinated alkane and optionally one or more excipients, wherein the initial enantiomeric ratio to the second enantiomer prior to storage or aging is 90:10 (i.e., 9), a decrease of about 1% would correspond to a decrease in the enantiomeric ratio to 8.91% or about 89.91:10.09.

[0103] In another aspect, the present disclosure relates to a method for preparing a liquid pharmaceutical composition as defined in any one of the embodiments described herein; the method comprising the step of dissolving or suspending an enantiomeric compound or enantiomer (or a mixture of two enantiomers) as described above (e.g., in Table 1) in a semifluorinated alkane or a non-aqueous vehicle comprising or consisting of a semifluorinated alkane and optionally one or more excipients, wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10 or structural isomers thereof and any combination thereof.

[0104] In another aspect, the present disclosure relates to a method for preparing a composition as defined in any one of the embodiments described herein; the method comprising the step of dissolving (S)-hyoscyamine in a non-aqueous vehicle comprising or consisting of a semifluorinated alkane and optionally one or more excipients, wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10 or structural isomers thereof and any combination thereof.

[0105] In yet another aspect, the present disclosure relates to a method for stabilizing an isomerizable pharmaceutical compound or a pharmaceutically acceptable salt thereof in a composition or for preventing isomerization of an isomerizable pharmaceutical compound or a pharmaceutically acceptable salt thereof in a composition, wherein the method comprises the step of dissolving or suspending the compound in a semifluorinated alkane or a vehicle consisting of a semifluorinated alkane and one or more excipients.

[0106] The isomerizable drug may be a compound as defined above. In some embodiments, the isomerizable compound has a purity of at least 90%, or at least 92%, or at least 95%, or at least 97% (e.g., as determined by HPLC). Preferably, the isomerizable drug compound comprises at least one chiral stereocenter. The chiral stereocenter is susceptible to racemization, inversion, or epimerization; preferably, the chiral stereocenter is susceptible to racemization, inversion, or epimerization under alkaline or acidic conditions.

[0107] In some embodiments of the method, the amount of other isomers of the isomerizable drug compound (e.g., undesired enantiomers or epimers) in the composition is independently less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% (e.g., as determined by HPLC) after storage of the composition at 0 to 60°C (e.g., at 25°C) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

[0108] In a related aspect, the present disclosure provides a method for stabilizing, preventing or reducing the loss of stereochemical purity or enantiomeric purity of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, wherein the method comprises dissolving or suspending the enantiomer in a semifluorinated alkane or a vehicle comprising a semifluorinated alkane and one or more excipients. In some embodiments, when the composition is formulated in a semifluorinated alkane or vehicle, the enantiomeric purity of the composition is at least 90%, or at least 95%, or at least 97% (e.g., as determined by HPLC).

[0109] In a related embodiment, a method for stabilizing the enantiomeric excess, preventing or reducing the loss of enantiomeric excess of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition is provided, wherein the method comprises the step of dissolving or suspending the enantiomer (provided in a defined optical purity) in a semifluorinated alkane or in a vehicle comprising a semifluorinated alkane and one or more excipients. In some embodiments, when the liquid composition is formulated in a semifluorinated alkane or a vehicle comprising (or consisting of) a semifluorinated alkane and one or more excipients as defined herein, the enantiomeric excess of the enantiomer in the liquid composition is at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99% (e.g., as determined by HPLC). Thus, the method provides a means to maintain or prevent significant changes in the enantiomeric purity of a compound.

[0110] In a related embodiment, a method is provided for stabilizing the enantiomeric ratio of an enantiomer (enantiomer pair or mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, preventing or reducing the loss of the enantiomeric ratio of an enantiomer (enantiomer pair or mixture of two enantiomers) of an pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, wherein the method comprises dissolving or suspending the enantiomer (or mixture of two enantiomers) in a semifluorinated alkane or a vehicle comprising a semifluorinated alkane and one or more excipients, as described in the present disclosure. In some embodiments, the ratio of the first enantiomer relative to the second enantiomer, for example, when dissolved or suspended in the semifluorinated alkane, is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1. Preferably, the first enantiomer is selected from compounds 1a to 49a of Table 1, and the corresponding second enantiomer is selected from compounds 1b to 49b.

[0111] The methods can provide for the prevention or rate reduction of degradation (e.g., hydrolysis and / or dehydration) and / or for the prevention or rate reduction of isomerization (e.g., racemization or epimerization) of an enantiomer in a composition into a different stereoisomer or an enantiomer thereof. In some embodiments of these methods, the enantiomer or first enantiomer comprises a chiral stereocenter on a carbon atom, wherein at least one substituent of the chiral stereocenter is i) a hydrogen moiety that is susceptible to deprotonation under alkaline conditions and / or ii) an alcohol moiety that is susceptible to dehydration under acidic conditions; and / or is susceptible to racemization, isomerization, or epimerization. In other embodiments, the enantiomer or first enantiomer is selected from the list consisting of: (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuralol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S)-(-)-celiprolol, (S)-chlorpheniramine, Quinone, (S)-(+)-dimethylindine, (R)-(-)-dimethylindine, (S)-ecamprol, (2S,3R)-epiconazole, (S)-esmolol, (S)-(-)-esmolol, (R)-etodolac, (S)-fenoprofen, (R)-fexofenadine, (S)-fexofenadine, (S)-(+)-flurbiprofen, (R)-(-)-flurbiprofen, (S)- Gatifloxacin, (S)-gemifloxacin, (R,R)-(+)-ginaconazole, (S)-hydroxychloroquine, (S)-(+)-ibuprofen, (S)-indoprofen, (R)-ketamine, (S)-ketoprofen, (S)-ketorolac, (S)-lomefloxacin, (R)-lomefloxacin, (S)-(-)-metoprolol, (R)-(+)-metoprolol, (R)-(-)-miconazole, (S)-(-)-moprolol, S-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxprenolol, (+)-pemetrexate, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole, and (+)-terconazole, or selected from Table 1, Column A or Column B. In addition, the composition of such methods can be according to any one or combination of the compositions described herein, e.g., with respect to the semifluorinated alkanes, excipients, etc.

[0112] In some embodiments of these methods, there is provided storage of the composition at 0 to 60° C. (e.g., at 25° C.) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months, wherein over the period of time,

[0113] i) the concentration of one or more enantiomers in the composition remains substantially the same, or does not change or does not decrease by more than 10%, more than 5%, more than 4%, more than 3%, more than 2%, more than 1% or more than 0.5% relative to its initial concentration in the composition prior to storage (e.g., as determined by HPLC); and / or

[0114] ii) the enantiomeric excess of the enantiomer is substantially the same, or does not change or does not decrease by more than 10%, more than 5%, more than 4%, more than 3%, more than 2%, more than 1% or more than 0.5% relative to the value initially determined prior to storage; and / or

[0115] iii) the enantiomeric ratio of the first enantiomer relative to the second enantiomer is the same as or within 10%, or 5%, or 4%, or 3% or 1% of the enantiomeric ratio before storage.

[0116] In another related aspect, the present disclosure relates to a method for stabilizing (S)-hyoscyamine in a composition and / or preventing its isomerization, the method comprising dissolving (S)-hyoscyamine (having a certain optical purity) in a semifluorinated alkane or a non-aqueous vehicle comprising a semifluorinated alkane and optionally one or more excipients; wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, their structural isomers, and any combination thereof. In some embodiments according to the method, (S)-hyoscyamine has an enantiomeric excess of at least 80% ee, at least 80% ee, at least 90% 95% ee, or at least 97% ee, or a purity of at least 90%, at least 95%, or at least 97% (e.g., as determined by HPLC). In other embodiments, the enantiomeric purity or enantiomeric ratio of (S)-scopolamine may be as defined above.

[0117] The method provides for preventing or reducing the rate of degradation (e.g., hydrolysis and / or dehydration) and / or isomerization (e.g., racemization) of (S)-hyoscine in the composition. In particular, the method may be effective in any one or a combination of: preventing or reducing the degradation of (S)-hyoscine, such as, for example, causing an increased formation or presence of any one or a combination of tropic acid, tropine, anhydroatropine in the composition; or preventing or reducing the conversion of (S)-hyoscine to (R)-hyoscine in the composition after storage of the composition at 0 to 60° C. (e.g., 25° C.) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

[0118] In some embodiments of these methods, the amount of any one or more degradation products of hyoscyamine (e.g., tropic acid, tropine base, or anhydroatropine, or any salt thereof) is independently less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% (e.g., as determined by HPLC) after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0 to 60° C. (e.g., 25° C.). In some embodiments of these methods, the amount of (R)-hyoscyamine in the composition is less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% (e.g., as determined by HPLC) after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0 to 60° C. (e.g., 25° C.). In other embodiments, the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition decreases by less than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% (e.g., as determined by HPLC) after storage at 0 to 60°C (e.g., at 25°C) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

[0119] In yet another aspect, the pharmaceutical compositions according to the present disclosure can be used or provided as a medicament for use in the treatment or prevention of a disease or medical condition, preferably a disease or medical condition in a human subject or optionally a veterinary subject; and in the manufacture of a medicament.

[0120] In some embodiments, the composition is a topical ophthalmic composition, or in other words, a composition that can be applied topically or to the surface of a subject's eye or tissue associated with the eye, such as a composition applied to the cornea or conjunctiva of the eye or to the conjunctival fornix. In a related embodiment, the composition is in the form of a clear solution. In another embodiment, the pharmaceutical composition is formulated for or suitable for intravitreal, subcutaneous, intramuscular injection, or for intravenous injection or infusion. In yet another embodiment, the composition is suitable for topical administration to the surface of a tissue or organ (e.g., skin or mucosal tissue, such as that associated with the eye).

[0121] In one embodiment, a composition according to any one or combination of embodiments of the present disclosure is used to treat and / or prevent an ophthalmic disease or disorder, eg, affecting one or both eyes of a subject.

[0122] In one embodiment, a composition according to an embodiment of the present disclosure comprising (S)-hyoscyamine is used to treat, prevent, and / or control myopia. Myopia (also known as short-sightedness or near-sightedness) is a refractive condition or refractive error of the eye and is typically characterized by blurred vision, particularly blurred vision of distant objects due to images falling or focusing in front of photoreceptors on the retina or retinal plane. Myopia can arise, for example, due to an inappropriate correlation between the axial length of the eye and the refractive power or curvature of the lens, among a variety of factors and causes.

[0123] In one embodiment, a composition of the present disclosure comprising (S)-hyoscyamine is for use in a method of preventing or reducing the onset of myopia, or for use in a method of reducing the progression of myopia in a human subject (e.g., in a pediatric and / or juvenile subject). In another embodiment, the composition is a topically applied ophthalmic composition for use in a method of reducing the progression of myopia or reducing the rate of progression of myopia (e.g., slowing myopia). A reduction in myopia progression can be determined, for example, by a reduction in the rate of change of one or more parameters typically used in the art to measure the myopic refractive error of an eye.

[0124] In another embodiment, the composition according to the embodiment in the present disclosure comprising (S)-hyoscine is used to treat amblyopia or to prevent the progression of amblyopia. Amblyopia (amblyopia, sometimes referred to as "lazy eye") is a disease that typically occurs in infants and children and can cause visual axis interruption and monocular vision loss. The related conditions or symptoms of amblyopia include refractive errors, such as visual acuity differences or eye misalignment between eyes, resulting in blurred vision, and disuse or inhibition of the visual cortex or visual input of the affected eye. According to the present disclosure, the treatment of amblyopia itself or the prevention of the progression of amblyopia itself can include penalization of healthy, non-amblyopic or better-sighted eyes. In one embodiment, in addition to other treatment methods such as refractive correction or occlusion, the composition according to the present disclosure can also be used to treat amblyopia.

[0125] In other embodiments, the compositions may be used for cycloplegic refraction, temporary paralysis of the ciliary muscle, or pupil dilation (which may also be referred to as mydriasis).

[0126] In yet another embodiment, the composition can be used (eg, as an antidote) to treat a subject, preferably a human subject, who has been exposed to a toxin such as an organophosphate compound (eg, a pesticide or a nerve agent).

[0127] Also provided in the context of the present disclosure is the use of a pharmaceutical composition as described in any of the above embodiments in the manufacture or preparation of a medicament or drug for treating a subject in need thereof associated with any disease or medical condition described herein. Further provided in the context of the present disclosure is a method of treating a subject having or suffering from any medical condition or disorder described herein; or a method of preventing or ameliorating a medical condition or disorder in the subject, wherein the method may comprise the step of administering to the subject (e.g., topically, e.g., topically ophthalmologically) a composition as described herein.

[0128] In yet another aspect, the disclosure relates to a kit comprising a composition according to any one or combination of the embodiments described herein, a container suitable for containing the composition, and optionally a device for dispensing the composition and / or instructions for use, wherein the instructions for use include any of the therapeutic uses or methods as described herein.

[0129] The following examples are provided to illustrate the present invention, but should not be construed as limiting the scope of the present invention.

[0130] Example

[0131] Example 1

[0132] Hyoscyamine solutions were prepared in F4H5 (1-perfluorobutylpentane) or in 1% (v / v) 2-propanol in 1-perfluorobutylpentane.

[0133] (S)-hyoscyamine or atropine (a racemic mixture of (S)-hyoscyamine and (R)-hyoscyamine; CAS 5908-99; EDQM, Y0000878) was weighed into a 1.5 mL vial. F4H5 or F4H5 with 1% (v / v) 2-propanol was then added to the vial, and the resulting mixture was stirred at 300 rpm overnight to provide a clear solution.

[0134] The (S)-hyoscyamine used (CAS 101-31-5; Abcam Pharmatech, Changzhou, China) consists of 90.8% (S)-hyoscyamine and 9.2% (R)-hyoscyamine, i.e., the enantiomeric excess (ee) of (S)-hyoscyamine is 81.6%, or the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is about 9.87.

[0135] Prepare the following solutions:

[0136] (1) 0.1 mg / mL atropine in F4H5 with 1% (v / v) 2-propanol (i.e., a solution containing 0.05 mg / ml (S)-hyoscyamine)

[0137] (2): 0.4 mg / ml atropine in F4H5 with 1% (v / v) 2-propanol (i.e., a solution containing 0.2 mg / ml (S)-hyoscyamine)

[0138] (3) 0.1 mg / mL (S)-hyoscyamine in F4H5

[0139] (4) 0.1 mg / mL (S)-hyoscyamine in F4H5 with 1% (v / v) 2-propanol.

[0140] (5) 0.05 mg / mL (S)-hyoscyamine in F4H5 with 1% (v / v) ethanol.

[0141] (6) 0.05 mg / mL (S)-hyoscyamine in F6H8 with 1% (v / v) ethanol.

[0142] HPLC was used to simultaneously detect the (R)-hyoscyamine and (S)-hyoscyamine enantiomers in these solutions using a chiral HPLC column (Lux Cellulose-2; Phenomenex). As shown in Figure 1, the two enantiomers could be clearly distinguished (see Figure 1).

[0143] Example 2

[0144] Solutions of 0.1 mg / mL (S)-hyoscine in F4H5 with 1% (v / v) 2-propanol and 0.1 mg / mL (S)-hyoscine in F4H5 prepared according to Example 1 were examined for stability and racemization of (S)-hyoscine during storage at room temperature (25°C).

[0145] The ratio of (S)-hyoscyamine to (R)-hyoscyamine in the injected solution was found to vary by no more than 0.2% over 5 days for a 0.1 mg / mL solution in F4H5 + 1% (v / v) 2-propanol and over 4 days for a 0.1 mg / ml solution in F4H5 without 2-propanol, respectively.

[0146] Stability studies continued for 1.5 months at room temperature (25°C) and confirmed that the ratio of (S)-hyoscyamine to (R)-hyoscyamine in these compositions did not change, demonstrating that the shelf life of the (S)-hyoscyamine compositions was improved.

[0147] The stability of the solutions at elevated temperatures was also tested.

[0148] A solution of 0.1 mg / mL (S)-hyoscine in F4H5 with 1% (v / v) 2-propanol and a solution of 0.1 mg / ml solution in F4H5 were heated at 60°C for 1 hour. HPLC analysis to check solution stability and racemization revealed that in both solution formulations, 90.8% of the initial enantiomeric purity of (S)-hyoscine was maintained, and no other degradation products were produced. This demonstrates that the composition comprising (S)-hyoscine and a semifluorinated alkane is stable under the experimental conditions and does not undergo racemization or degradation even at elevated temperatures.

[0149] Example 3

[0150] The stability of solutions of 0.05 mg / ml (S)-hyoscyamine (1a) in F4H5, 0.05 mg / ml (S)-hyoscyamine in F6H8, and 0.10 mg / ml atropine in F4H5 were monitored at room temperature (25°C) over a period of 6 months. The results showed that the ratio of the two enantiomers (i.e., the ratio of (R)-hyoscyamine to (S)-hyoscyamine enantiomers) as measured by HPLC based on peak area was effectively stable over this period of time, with no isomerization or change in the enantiomeric ratio. The results showed that the enantiomeric excess of S-hyoscyamine (1a) was stable at 94% ee in F4H5 and F6H8 over a period of 6 months.

[0151]

[0152]

[0153] Example 4

[0154] Solutions or suspensions of any one of the enantiomeric compounds (column A or column B) as contained in Table 1 herein in a semifluorinated alkane (e.g., F6H8 or F4H5) or a vehicle comprising a semifluorinated alkane (e.g., F6H8 or F4H5) and optionally one or more excipients as described herein are prepared according to the following general method:

[0155] An amount of compound is weighed into a container (e.g., a vial), and the semifluorinated alkane or a mixture of the semifluorinated alkane and one or more excipients is added to the container to achieve the desired concentration of the compound in the composition, and then processed, for example, by stirring, to provide a solution or suspension.

[0156] The enantiomeric excess or enantiomeric ratio of one or more enantiomers of the compound in the composition is determined, for example, by chiral HPLC based on peak area or by another suitable analytical method capable of quantifying optically active compounds (such as enantiomers). The composition is then subjected to aging conditions over a period of time (e.g., 2 weeks or 1 month or up to 6 months) to determine the stability of the compound in the composition, and the loss of racemization or stereochemical purity; optionally during or at the end of the time period. The stability and percentage of the one or more enantiomers in the composition are measured by sampling the composition and performing, for example, chiral HPLC based on peak area or using the same analytical method used to determine the purity of the compound in the composition at the beginning of the study.

[0157] The initial enantiomeric purity (e.g., enantiomeric excess, enantiomeric ratio) of the desired compound is substantially maintained in the formulation in the semifluorinated alkane or vehicle, with minimal formation of degradation products, racemization, or enantiomeric purity of the enantiomers.

[0158] Changes, demonstrated that semifluorinated alkanes can provide liquid compositions of enantiomeric compounds

[0159] Stable vehicle or formulation.

Claims

1. A pharmaceutical composition comprising (S)-hyoscyamine or a pharmaceutically acceptable salt thereof dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients, wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10 or structural isomers thereof and any combination thereof.

2. A liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%, and wherein the enantiomer is dissolved or suspended in a semifluorinated alkane, or in a vehicle comprising a semifluorinated alkane and one or more excipients.

3. A liquid pharmaceutical composition comprising enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer to the second enantiomer is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:1, wherein the enantiomers are dissolved or suspended in a semifluorinated alkane; or dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients.

4. The pharmaceutical composition according to claim 2 or 3, wherein the compound comprises a chiral stereocenter at a carbon atom, wherein at least one substituent of the chiral stereocenter is i) a hydrogen moiety that is easily deprotonated under basic conditions and / or ii) an alcohol moiety that is easily dehydrated under acidic conditions.

5. The pharmaceutical composition according to claim 2 to 4, wherein the enantiomer or the first enantiomer is selected from the list consisting of: (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuralol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S )-(-)-celiprolol, (S)-chloroquine, (S)-(+)-dimethylindine, (R)-(-)-dimethylindine, (S)-ecamprol, (2S,3R)-epiconazole, (S)-esmolol, (S)-(-)-esmolol, (R)-etodolac, (S)-fenoprofen, (R)-fexofenadine, (S)-fexofenadine, (S)-(+)-flurbiprofen, (R )-(-)-Frbiprofen, (S)-Gatifloxacin, (S)-Gemifloxacin, (R,R)-(+)-Ginaconazole, (S)-Hydroxychloroquine, (S)-(+)-Ibuprofen, (S)-Indoprofen, (R)-Ketamine, (S)-Ketoprofen, (S)-Ketorolac, (S)-Lomefloxacin, (R)-Lomefloxacin, (S)-(-)-Metoprolol, (R)-(+)-Metoprolol , (R)-(-)-miconazole, (S)-(-)-moprolol, S-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxprenolol, (+)-pemetrexate, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole, and (+)-terconazole.

6. The pharmaceutical composition according to claims 2 to 5, wherein the second enantiomer is selected from the list consisting of: (R)-hyoscyamine, (R)-(+)-alprenolol, (S)-azelastine, (R)-azelastine, (R)-bisoprolol, (S)-(+)-bufuralol, (R)-carprofen, (R)-carvedilol, (S)-carvedilol, (R)-(+)- Celiprolol, (R)-chloroquine, (R)-(-)-dimethylindine, (S)-(+)-dimethylindine, (R)-ecamprol, (2R,3S)-epiconazole, (R)-esmolol, (R)-(+)-esmolol, (S)-etodolac, (R)-fenoprofen, (S)-fexofenadine, (R)-fexofenadine, (R)-(-)-flurbiprofen, (S)-(+ )-Frbiprofen, (R)-gatifloxacin, (R)-gemifloxacin, (S,S)-(-)-ginaconazole, (R)-hydroxychloroquine, (R)-(-)-ibuprofen, (R)-indoprofen, (S)-ketamine, (R)-ketoprofen, (R)-ketorolac, (R)-lomefloxacin, (S)-lomefloxacin, (R)-(+)-metoprolol, (S)-(-)-metoprolol, ( S)-(+)-miconazole, (R)-(+)-moprolol, R-(+)-nadifloxacin, (L)-nebivolol, (D)-nebivolol, (R)-(+)-oxprenolol, (-)-pemetrexate, (R)-(+)-propranolol, (S)-(-)-propranolol, (S)-sertaconazole, (S)-(+)-sotalol, (+)-terconazole, and (-)-terconazole.

7. The composition of claims 2 to 6, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, their structural isomers, and any combination thereof.

8. The composition of claims 1 to 7, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, their structural isomers, and any combination thereof.

9. The composition according to claim 8, wherein the semifluorinated alkane is selected from F4H5 (1-perfluorobutyl-pentane), F6H8 (1-perfluorohexyl-octane), their structural isomers and any combination thereof, preferably wherein the semifluorinated alkane is a combination of F4H5 (1-perfluorobutyl-pentane) and 2-perfluorobutyl-pentane.

10. The composition of claim 9, wherein the semifluorinated alkane is 1-perfluorobutyl-pentane and optionally 2-perfluorobutyl-pentane, wherein the 2-perfluorobutyl-pentane is present in an amount of at most 2% (w / w), or at most 1% (w / w), or at most 0.5% (w / w) or at most 0.2% (w / w), relative to the total weight of the semifluorinated alkane mixture.

11. The composition of claim 10, wherein the semifluorinated alkane is 1-perfluorohexyl-octane and optionally 2-perfluorohexyl-octane, wherein the 2-perfluorohexyl-octane is present in an amount of at most 2% (w / w), or at most 1% (w / w) or at most 0.5% (w / w), relative to the total weight of the semifluorinated alkane mixture.

12. The pharmaceutical composition according to claims 1 to 11, wherein the vehicle consists of the semifluorinated alkane or the mixture of semifluorinated alkanes.

13. The composition of claims 1 to 12, wherein the one or more semifluorinated alkanes are present in an amount of at least 90%, 95%, 96%, 97%, 98%, 99% (w / w) based on the total weight of the composition.

14. The composition of claims 1 to 13, wherein the semifluorinated alkane is 1-perfluorobutyl-pentane (F4H5) and is present in an amount of at least 90%, 95%, 96%, 97%, 98%, 99% (w / w) based on the total weight of the composition.

15. The composition of claims 1 to 13, wherein the semifluorinated alkane is 1-perfluorobutyl-pentane (F4H5), and optionally also 2-perfluorobutyl-pentane, and is present in an amount of at least 90%, 95%, 96%, 97%, 98%, 99% (w / w) based on the total weight of the composition.

16. The composition of any preceding claim, wherein the vehicle comprises or consists of the semifluorinated alkane and one or more excipients, wherein the one or more excipients are selected from: a) a cosolvent, optionally wherein the cosolvent is an alcohol; preferably wherein the alcohol is selected from ethanol, 1-propanol, isopropanol and phenylethanol; or more preferably wherein the alcohol is selected from ethanol and phenylethanol; b) an oily excipient, optionally wherein the oily excipient is selected from triglycerides, mineral oil and liquid paraffin; preferably, wherein the oily excipient is selected from medium chain triglycerides (MCT) and light liquid paraffin; and c) Any combination of cosolvents or oily excipients as defined in a) or b).

17. A composition according to any preceding claim, wherein the vehicle consists of a semifluorinated alkane and optionally structural isomers thereof and one or more excipients, wherein the one or more excipients are not alcohols and / or are not medium chain triglycerides (MCTs) and / or are not light liquid paraffin.

18. A composition according to any preceding claim, wherein the composition comprises an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is not 50:

50.

19. A composition according to any preceding claim, wherein the composition comprises at least 89% (S)-hyoscine or at least 90% (S)-hyoscine based on the total amount of hyoscine in the composition.

20. The composition of any preceding claim, comprising (S)-hyoscyamine in an enantiomeric excess of at least about 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%.

21. The composition of any preceding claim, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:

1.

22. A pharmaceutical composition comprising (S)-hyoscyamine according to any preceding claim, wherein the composition comprises substantially no one or a combination of tropic acid, atropine, tropine base, anhydroatropine, or salts thereof; and / or comprises no more than about 0.0001% to 0.001% (w / v), or 0.004% to 0.006% (w / v)% (R)-hyoscyamine.

23. A pharmaceutical composition according to any preceding claim, comprising no more than 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6% or 7% (e.g. as determined by HPLC) of each or any combination of compounds resulting from the degradation of scopolamine; preferably wherein the compound is selected from tropic acid, atropic acid, anhydroatropine or a salt thereof.

24. The pharmaceutical composition of any preceding claim, wherein the composition comprises no more than about 0.0001% to 0.001% (w / v), or 0.004% to 0.006% (w / v)% (R)-hyoscyamine.

25. The pharmaceutical composition of any preceding claim, wherein the composition is substantially free of (R)-hyoscyamine.

26. A composition according to any preceding claim, wherein (S)-hyoscyamine is present in the composition at a concentration of: a) between 0.001% and 1.0% (w / v), between 0.001% and 0.5% (w / v), between 0.001% and 0.015%, between 0.002% and 0.012%, between 0.004% and 0.012%, between 0.005% and 0.01%, between 0.01% and 0.1% (w / v), between 0.02% and 0.07% (w / v), between 0.002% and 0.006% (w / v), between 0.004% and 0.006% (w / v), between 0.0045% and 0.0055% (w / v); or b) at most 0.003%, 0.005%, 0.0055%, 0.0075%, 0.01%, 0.02%, 0.03%, 0.05%, 0.1%, 0.5%, 1.0% (w / v); or c) at concentrations of 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.01%, 0.02%, 0.025%, 0.05%, and 0.1% (w / v).

27. A composition according to any preceding claim, wherein the one or more excipients are present in an amount of at most 0.1 wt%, 0.5 wt%, 0.75 wt%, 1.0 wt%, 1.25 wt%, 1.4 wt%, 1.5 wt%, 1.8 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt% or at most 5.0 wt% (w / w), preferably at most 1 wt% or at most 1.4 wt%, based on the total weight of the composition.

28. A composition according to any preceding claim, wherein the composition is substantially free of a) water; or b) a preservative; or c) one or more scopolamine degradation products selected from tropic acid, atropine, tropine base and anhydroatropine; or d) any combination of a), b) and c).

29. A composition according to any preceding claim, wherein the composition comprises or consists of: a) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, and the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; b) 0.004% to 0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% of ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98: 2; and wherein after storage at 25°C for 1, 2, or 3 months, the total amount of hyoscyamine relative to the initial amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96%, or at least 95%; and optionally wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine decreases by no more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%; c) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; d) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98: 2; and wherein after storage at 25°C for 1, 2 or 3 months, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscyamine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine decreases by no more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%; e) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; f) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98: 2; and wherein after storage at 25°C for 1, 2 or 3 months, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscyamine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine decreases by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%; g) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98:2; h) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4, or at least 98: 2; and wherein after storage at 25°C for 1, 2 or 3 months, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of hyoscyamine in the composition, and optionally wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine decreases by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

30. A composition according to any preceding claim, wherein after storage of the composition at 0 to 60°C, such as at 25°C for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, the amount of (S)-hyoscine in the composition is at least 90%, or at least 95% or at least 99% relative to the initial amount of (S)-hyoscine in the composition.

31. The composition of claim 28, wherein the amount of (S)-hyoscine after storage at 0 to 60°C, for example after storage at 25°C for at least 1, 2, 3, 4, 5, 6, 9 or at least 12 months, is in the range of 90% to 110%, or 95% to 105% of the initial amount of (S)-hyoscine in the composition, or is preferably equal to or greater than 90% or 95% of the initial amount of (S)-hyoscine in the composition, or equal to or less than 110%, 105% or 100% of the initial amount of (S)-hyoscine in the composition.

32. The composition of any preceding claim, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition does not decrease by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% after storage at 25°C for at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

33. The pharmaceutical composition according to any preceding claim, wherein the active compound, e.g., (S)-hyoscyamine, is dissolved in the vehicle and / or the semifluorinated alkane, wherein the composition is in the form of a clear solution; preferably wherein the composition is a topical ophthalmic composition.

34. A pharmaceutical composition according to any preceding claim, wherein the composition is formulated or adapted for intravitreal, subcutaneous, intramuscular injection or for intravenous injection or infusion; or for topical application to the surface of a tissue or organ, such as the skin.

35. A pharmaceutical composition according to any preceding claim for use as a medicament.

36. The composition for use according to claim 35, for use in the treatment or prevention of an ophthalmic disease or disorder.

37. The composition for use according to claims 35 to 36, for use in treating, preventing, or reducing the rate of progression of myopia and / or amblyopia.

38. The composition for use according to claims 35 to 38, for use in pupil dilation.

39. The composition for use according to claim 35, for use in treating a subject, preferably a human subject, exposed to a toxin, such as an organophosphate compound (eg, a pesticide or a nerve agent).

40. A kit comprising a composition according to any preceding claim, said kit comprising a container suitable for containing said composition and optionally means for dispensing said composition and / or instructions for use.

41. A process for preparing a composition as defined in claims 1 to 34, said process comprising the step of dissolving (S)-hyoscyamine in a non-aqueous vehicle comprising or consisting of a semifluorinated alkane and optionally one or more excipients, wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10 or structural isomers thereof and any combination thereof.

42. A method for stabilizing (S)-hyoscyamine in a composition, the method comprising the step of dissolving (S)-hyoscyamine in a semifluorinated alkane or a non-aqueous vehicle comprising a semifluorinated alkane and optionally one or more excipients; wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, their structural isomers, and any combination thereof.

43. The method of claim 41 or 42, wherein the (S)-hyoscyamine has an enantiomeric excess of at least 80% ee, at least 80% ee, at least 90% 95% ee, or at least 97% ee, or a purity of at least 90%, at least 95%, or at least 97% (e.g., as determined by HPLC).

44. The method of claims 42 to 43, wherein the method provides for prevention or a reduction in the rate of degradation (e.g., hydrolysis and / or dehydration) and / or isomerization (e.g., racemization) of (S)-hyoscyamine in the composition.

45. The method of claims 42 to 44, wherein the method is effective to prevent or reduce the formation of any one or a combination of tropic acid, atropic acid, tropine, anhydroatropine after storage at 0 to 60°C (e.g., 25°C) for a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months and / or wherein the method is effective to prevent or reduce the conversion of (S)-hyoscyamine to (R)-hyoscyamine in the composition.

46. ​​The method of claims 42 to 45, wherein the amount of any one or more degradation products of scopolamine (e.g., tropic acid, tropine base, or anhydroatropine or a salt thereof) is independently less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% (e.g., as determined by HPLC) after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0 to 60°C (e.g., 25°C).

47. The method of claims 42 to 46, wherein the amount of (R)-hyoscyamine in the composition is less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% or less than 0.5% (e.g., as determined by HPLC) after a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months at 0 to 60°C (e.g., 25°C).

48. The method of claims 42 to 47, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in the composition decreases by less than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25% after storage at 0 to 60°C (e.g., at 25°C) for a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months.

49. A method according to claims 41 to 48, wherein the composition is as defined in any one or combination of claims 1 to 29.

50. A method for stabilizing the enantiomeric excess, preventing or reducing the loss of enantiomeric excess of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, wherein the method comprises the step of dissolving or suspending the enantiomer in a semifluorinated alkane or in a vehicle comprising a semifluorinated alkane and one or more excipients.

51. The method of claim 50, wherein the enantiomeric excess of the enantiomer in the liquid composition is at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98%, or 99% (e.g., as determined by HPLC).

52. A method of stabilizing, preventing or reducing the loss of the enantiomeric ratio of enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, wherein the method comprises the step of dissolving or suspending the enantiomer (or mixture of two enantiomers) in a semifluorinated alkane or in a vehicle comprising a semifluorinated alkane and one or more excipients, preferably wherein the enantiomer (or mixture of two enantiomers) comprises a first enantiomer and a second enantiomer.

53. The method of claim 52, wherein the ratio of the first enantiomer relative to the second enantiomer is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or at least 99:

1.

54. A method for stabilizing, preventing or reducing the loss of stereochemical purity or enantiomeric purity of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, wherein the method comprises the step of dissolving or suspending the enantiomer in a semifluorinated alkane or in a vehicle comprising a semifluorinated alkane and one or more excipients.

55. The method of claim 54, wherein the enantiomeric purity of the composition is at least 90%, or at least 95%, or at least 97% (eg, as determined by HPLC).

56. The method of claims 50 to 54, wherein the enantiomer or the first enantiomer comprises a chiral stereocenter at a carbon atom, wherein at least one substituent of the chiral stereocenter is i) a hydrogen moiety that is susceptible to deprotonation under basic conditions and / or ii) an alcohol moiety that is susceptible to dehydration under acidic conditions; and / or is susceptible to racemization, isomerization or epimerization.

57. The method of claims 50 to 56, wherein the enantiomer or the first enantiomer is selected from the list consisting of: (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuralol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S )-(-)-celiprolol, (S)-chloroquine, (S)-(+)-dimethylindine, (R)-(-)-dimethylindine, (S)-ecamprol, (2S,3R)-epiconazole, (S)-esmolol, (S)-(-)-esmolol, (R)-etodolac, (S)-fenoprofen, (R)-fexofenadine, (S)-fexofenadine, (S)-(+)-flurbiprofen, (R )-(-)-Frbiprofen, (S)-Gatifloxacin, (S)-Gemifloxacin, (R,R)-(+)-Ginaconazole, (S)-Hydroxychloroquine, (S)-(+)-Ibuprofen, (S)-Indoprofen, (R)-Ketamine, (S)-Ketoprofen, (S)-Ketorolac, (S)-Lomefloxacin, (R)-Lomefloxacin, (S)-(-)-Metoprolol, (R)-(+)-Metoprolol , (R)-(-)-miconazole, (S)-(-)-moprolol, S-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxprenolol, (+)-pemetrexate, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole, and (+)-terconazole.

58. The method of claims 50 to 57, wherein the second enantiomer is selected from the list consisting of: (R)-hyoscyamine (1b), (R)-(+)-alprenolol (2b), (S)-azelastine (3b), (R)-azelastine (4b), (R)-bisoprolol (5b), (S)-(+)-bufuralol (6b), (R)-carprofen (7b), (R)-carvedilol (8b), (S)-carvedilol (9b), (R)-(+)-celiprolol (10b), (R)-chloroquine (11b), ( R)-(-)-dimethylindine (12b), (S)-(+)-dimethylindine (13b), (R)-ecamprol (14b), (2R,3S)-epiconazole (15b), (R)-esmolol (16b), (R)-(+)-esmolol (17b), (S)-etodolac (18b), (R)-fenoprofen (19b), (S)-fexofenadine (20b), (R)-fexofenadine (21b), (R)-(-)-flurbiprofen (22b), (S)-(+)-flurbiprofen (23b), (R)-gadrone Tifloxacin (24b), (R)-gemifloxacin (25b), (SS)-(-)-jinaconazole (26b), (R)-hydroxychloroquine (27b), (R)-(-)-ibuprofen (28b), (R)-indoprofen (29b), (S)-ketamine (30b), (R)-ketoprofen (31b), (R)-ketorolac (32b), (R)-lomefloxacin (33b), (S)-lomefloxacin (34b), (R)-(+)-metoprolol (35b), (S)-(-)-metoprolol (36b), (S)-(+) -miconazole (37b), (R)-(+)-moprolol (38b), R-(+)-nadifloxacin (39b), (L)-nebivolol (40b), (D)-nebivolol (41b), (R)-(+)-oxprenolol (42b), (-)-pemetrexate (43b), (R)-(+)-propranolol (44b), (S)-(-)-propranolol (45b), (S)-sertaconazole (46b), (S)-(+)-sotalol (47b), (+)-terconazole (48b), and (-)-terconazole (49b).

59. The method of claims 50 to 58, wherein after storing the composition at 0 to 60°C (e.g., at 25°C) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months, i) the concentration of the enantiomer is substantially the same, or does not change or does not decrease by more than 10%, more than 5%, more than 4%, more than 3%, more than 2%, more than 1% or more than 0.5% relative to its initial concentration in the composition prior to storage (e.g., as determined by HPLC); and / or ii) the enantiomeric excess of the enantiomer or the first enantiomer is substantially the same, or does not change or decrease by more than 10%, more than 5%, more than 4%, more than 3%, more than 2%, more than 1% or more than 0.5% relative to an initially determined value prior to storage; and / or iii) the enantiomeric ratio of the first enantiomer relative to the second enantiomer is the same as, or has not decreased by 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% relative to an initially determined value prior to storage.

60. The method of claims 50 to 59, wherein the composition is as defined in any one or combination of claims 1 to 17.

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