Semi-fluorinated alkane compositions containing 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 semi-fluorinated alkane.

Description

[Background technology]

[0001] The stability of an active pharmaceutical compound during storage under various conditions is a common concern during formulation development of that compound. This aspect is particularly relevant for liquid formulations of isomerizable pharmaceutically active compounds, as the isomerization process introduces structural changes to the compound that can significantly affect its properties, including its pharmacological and pharmacokinetic profiles.

[0002] For example, in enantiomer compounds, only one of a pair of enantiomers can be active or can provide desired pharmacological effect, while the other enantiomer is often less active or even harmful.However, for some active drug compounds, there may also be significant differences in the physiological activity between two enantiomers.For example, one enantiomer has pharmacological activity, while the other enantiomer shows significant drug toxicity characteristics to the extent that it may be unsafe for clinical use.

[0003] Therefore, for pharmaceutical formulations that contain only one, or primarily one, isomer, such as a single enantiomer of an active compound, it is important not only that the integrity of the compound is maintained during storage and that degradation of the compound is avoided or minimized, but also that there is no loss or change in the stereochemical purity of the compound in the composition.

[0004] Atropine is a racemic mixture of the enantiomers (S)-hyoscyamine and (R)-hyoscyamine, with (S)-hyoscyamine being the active enantiomeric 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 myopia progression, but these high doses also have a very high incidence of adverse events, typically resulting in discontinuation of treatment. To optimize safety versus efficacy, progressively lower doses of atropine have been tested, and it has been found that a 0.01% (w / v) atropine administered once daily retains virtually the same efficacy as the highest dose but with fewer side effects. Because 0.01% (w / v) atropine formulations are not approved anywhere in the world, physicians must write off-label prescriptions to compounding pharmacies to supply their patients. However, formulated (0.01% w / v) atropine tends to be pharmacologically unstable, resulting in a product with a short shelf life (e.g., approximately 30 days). Formulations closer to physiological pH (approximately 7.4) and with lower atropine concentrations have been observed to degrade at faster rates. As noted above, unstable pharmaceuticals pose concerns not only from the perspective of therapeutic efficacy (loss or reduction of accuracy during administration) but also from the perspective of patient safety. Formulations developed to counteract or slow atropine degradation include adjusting the pH to a lower level, which does not match the physiological pH of the eye or tears and is therefore less compatible with or potentially irritating to the eye.

[0005] Alternative formulations of atropine have been formulated. For example, International Publication No. 20200160493 describes 8-methyl-9-azabicyclo[3.2.1]octan-3-yl and pyridin-r-yl metanil ester and amide compounds, and compositions containing such compounds or atropine and a semi-fluorinated alkane, such as perfluorohexyl octane or perfluorohexyl nonane.

[0006] U.S. Patent No. 1,191,751 describes a topical ophthalmic composition containing atropine (free base) and a semi-fluorinated alkane as a liquid vehicle for use in treating myopia. However, the disclosed composition contains only atropine, a racemic mixture of two hyoscyamine enantiomers. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 20200160493 [Patent Document 2] U.S. Patent No. 1,119,1751 Summary of the Invention [Problem to be solved by the invention]

[0008] It is therefore an object of the present invention to provide compositions comprising an isomerizable compound, e.g. an enantiomer of a compound, e.g. (S)-hyoscyamine, which improve the stability of the aforementioned active compounds, particularly during storage, but which are also directly applicable for therapeutic use, such as topical ocular administration.

[0009] Further objects of the present invention will become apparent based on the following description of the invention, examples and claims. [Means for solving the problem]

[0010] In one aspect, the present invention provides 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 semi-fluorinated alkane and, optionally, one or more excipients, and the semi-fluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, structural isomers of these semi-fluorinated alkanes, or any combination thereof. The present disclosure also relates to a method for stabilizing (S)-hyoscyamine in a composition, the method comprising dissolving (S)-hyoscyamine in the semi-fluorinated alkane.

[0011] In still a further aspect, the present disclosure also provides the use of these pharmaceutical compositions for use as medicaments, such as for the treatment of ophthalmic conditions or disorders.

[0012] In a further 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 semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated 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 methods for stabilizing, preventing, or reducing loss (e.g., of enantiomeric excess or enantiomeric purity) of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition. [Brief explanation of the drawings]

[0013] [Figure 1]1 shows an HPLC chromatogram obtained for a composition containing 0.1 mg / mL (S)-hyoscyamine in F4H5, which contains (S)-hyoscyamine in an enantiomeric excess of 81.6% (enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine: 9.87). DETAILED DESCRIPTION OF THE INVENTION

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

[0016] The isomerizable pharmaceutically active compound is preferably a compound containing at least one chiral stereocenter. In one embodiment, the compound contains one chiral stereocenter. The compound can be one of a pair of stereoisomers, for example, an enantiomer. In other embodiments, the isomerizable compound according to the present disclosure can contain two or more chiral stereocenters. In other embodiments, the compound can be a diastereomer.

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

[0018] In a related aspect, the 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 semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated alkane and one or more excipients.

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

[0020] In another aspect, the disclosure relates to a liquid pharmaceutical composition comprising enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the ratio of a first enantiomer to a 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, and wherein the enantiomers are dissolved or suspended in a semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated alkane and one or more excipients.

[0021] As understood herein, a liquid pharmaceutical composition containing an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof refers to a composition containing a pair of enantiomers of the same compound that are mirror image stereoisomers. For example, the enantiopurity or stereochemical purity of a compound, which reflects the degree or amount of an enantiomer or stereoisomer in a sample or composition of the compound, can be defined or expressed, for example, by a ratio (i.e., enantiomeric ratio) or enantiomeric excess (ee) as defined herein. In some embodiments, the aforementioned compounds according to the present disclosure contain one chiral stereocenter. In some embodiments, the compound contains a chiral stereocenter on a carbon atom, and at least one of the substituents 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.

[0022] With regard to the enantiomers of the pharmaceutically active compounds featured in the compositions according to the present disclosure, they may be selected from the list consisting of compounds 1a to 49a in column A or compounds 1b to 49b in column B of Table 1 below.

[0023] [Table 1-1] [Table 1-2]

[0024] With respect to a pair of enantiomers (first or second enantiomers), Column A refers to the first enantiomer and Column B refers to the second enantiomer of the enantiomer pair. In some embodiments, a 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, and wherein the enantiomers are dissolved or suspended in a semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated 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 (included in Row A) to the second enantiomer (included in Row 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, and the enantiomers are dissolved or suspended in a semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated alkane and one or more excipients. Here, the mixture of two enantiomers consists of the first enantiomer (included in column A) and the corresponding second enantiomer (included in column B) in the same row of Table 1 (e.g., the mixture of two enantiomers consists of the first enantiomer 3a [(R)-azelastine] and the second enantiomer 3b [(S)-azelastine]).

[0025] In some embodiments, the (first) enantiomer is (S)-hyoscyamine (1a), (S)-(-)-alprenolol (2a), (R)-azelastine (3a), (S)-azelastine (4a), (S)-bisoprolol (5a), (R)-(-)-bufuranol (6a), (S)-carprofen (7a), (S)-carvedilol (8a), (R)-carvedilol (9a), (S)-(-)-celiprolol (10a), (S)-chloroquine (11a), (S)-(+)-dimethindene (12a), (R)-(+)-dimethindene (13a), (R)-(+)-dimethindene (14a), (R)-(+)-dimethindene (15a), (R)-(+)-dimethindene (16a), (R)-(+)-dimethindene (17a), (R)-(+)-dimethindene (18a), (R)-(+)-dimethindene (19a), (R)-(+)-dimethindene (20a), (R)-(+)-dimethindene (21a), (R)-(+)-dimethindene (22a), (R)-(+)-dimethindene (23a), (R)-(+)-dimethindene (24a), (R)-(+)-dimethindene (25a), (R)-(+)-dimethindene (26a), (R)-(+)-dimethindene (27a), (R)-(+)-dimethindene (28a), (R)-(+)-dimethindene (29a), (R)-(+)-dimethindene (30a), (R)-(+)-dimethindene (3 -(-)-Dimethindene (13a), (S)-Ecadotril (14a), (2S,3R)-Epoxiconazole (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)-(+)-genaconazole (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), (S) The compound is selected from the list consisting of -(-)-moprolol (38a), S-(-)-nadifloxacin (39a), (D)-nebivolol (40a), (L)-nebivolol (41a), (S)-(-)-oxprenolol (42a), (+)-pemedrac (43a), (S)-(-)-propranolol (44a), (R)-(+)-propranolol (45a), (R)-sertaconazole (46a), (R)-(-)-sotalol (47a), (-)-terconazole (48a), and (+)-terconazole (49a).

[0026] In some embodiments, the (second) enantiomer is (R)-hyoscyamine (1b), (R)-(+)-alprenolol (2b), (S)-azelastine (3b), (R)-azelastine (4b), (R)-bisoprolol (5b), (S)-(+)-bufuranol (6b), (R)-carprofen (7b), (R)-carvedilol (8b), (S)-carvedilol (9b), (R)-(+)-celiprolol (10b), (R)-chloroquine (11b), (R)-(-)-dimethindene (12b), (S)-(+)-dimethindene (13b), (S)-(+)-dimethindene (14b), (S)-(+)-dimethindene (15b), (S)-(+)-dimethindene (16b), (S)-(+)-dimethindene (17b), (S)-(+)-dimethindene (18b), (S)-(+)-dimethindene (19b), (S)-(+)-dimethindene (20b), (S)-(+)-dimethindene (21b), (S)-(+)-dimethindene (22b), (S)-(+)-dimethindene (23b), (S)-(+)-dimethindene (24b), (S)-(+)-dimethindene (25b), (S)-(+)-dimethindene (26b), (S)-(+)-dimethindene (27b), (S)-(+)-dimethindene (28b), (S)-(+)-dimethindene (29b), (S)-(+)-dimethindene (30b), (S)-(+)-dimethindene (3 -(+)-Dimethindene (13b), (R)-Ecadotril (14b), (2R,3S)-Epoxiconazole (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), (R)-Gemifloxacin (25b), (SS)-(-)-genaconazole (26b), (R)-hydroxychloroquine (27b), (R)-(-)-ibuprofen (28b), (R)-indoprofen (29b), (S)-ketamine (30b), (R)-ketoprofen (31b), (R)-ketorolac (32b), (R)-lolomefloxacin (33b), (S)-lolomefloxacin (34b), (R)-(+)-metoprolol (35b), (S)-(-)-metoprolol (36b), (S)-(+)-miconazole (37b), (R)- The compound is selected from the list consisting of (+)-moprolol (38b), R-(+)-nadifloxacin (39b), (L)-nebivolol (40b), (D)-nebivolol (41b), (R)-(+)-oxprenolol (42b), (-)-pemedrac (43b), (R)-(+)-propranolol (44b), (S)-(-)-propranolol (45b), (S)-sertaconazole (46b), (S)-(+)-sotalol (47b), (+)-terconazole (48b) and (-)-terconazole (49b).

[0027] Preferably, the first and second enantiomeric pairs 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, 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:50b, 51a:51b, 52a:52b, 53a:53b, 54a:54b, 55a:55b, 56a:56b, 57a:57b, 58a:58b, 59 24b, 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.

[0028] As described above, the composition of the present disclosure is a composition containing a semi-fluorinated alkane. A semi-fluorinated alkane is a linear or branched alkane in which some of the hydrogen atoms are replaced with fluorine atoms. In one embodiment, the semi-fluorinated alkane (which can be abbreviated as SFA) described and used according to the present disclosure comprises one linear non-fluorinated hydrocarbon segment and one linear perfluorocarbon segment, and the perfluorocarbon segment is bonded to the non-fluorinated hydrocarbon segment. In a preferred embodiment, the semi-fluorinated alkane used in connection with the present disclosure is preferably a liquid semi-fluorinated alkane.

[0029] In one embodiment, the semi-fluorinated alkane has the formula F(CF2) n (CH2) m H, where n and m are integers defining the number of carbon atoms in the fully fluorinated hydrocarbon segment and the non-fluorinated hydrocarbon segment, respectively. In further embodiments, the one or more semi-fluorinated alkanes included in the composition according to the present disclosure have the formula F(CF2) n (CH2) mH, where n is an integer selected from 4 to 6 and m is an integer selected from 2 to 10. In a further embodiment, the one or more semi-fluorinated alkanes have the formula F(CF2) n (CH2) m H, where n is an integer selected from 4 to 6, and m is an integer selected from 4 to 8.

[0030] A nomenclature frequently used for linear semifluorinated alkanes is to designate the perfluorocarbon segment as RF and the non-fluorinated segment as RH, i.e., RFRH. Alternatively, the compound may be referred to as FnHm, where F refers to the perfluorocarbon segment, H refers to the non-fluorinated segment, and n and m define the number of carbon atoms in each segment. For example, F3H3 is used for perfluoropropylpropane, F(CF2)3(CH2)3H. Furthermore, this type of nomenclature is typically 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 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

[0031] In one embodiment of the present disclosure, the composition or composition vehicle may comprise one or more semi-fluorinated alkanes selected from the group consisting of F4H4, F4H5, F4H6, F4H8, F6H2, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof, and mixtures thereof, which have the chemical formulas 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), respectively. 10H. In another embodiment, the vehicle comprises a semi-fluorinated alkane selected from F4H5, F4H6, F6H4, F6H6, F6H10, or structural isomers thereof, or any mixture or combination of these semi-fluorinated alkanes. In yet another embodiment, the composition or vehicle comprises a semi-fluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, structural isomers thereof, and any mixture thereof.

[0032] In still further embodiments, the semi-fluorinated alkane is F4H5 (1-perfluorobutyl-pentane), F6H8 (1-perfluorohexyl-octane), structural isomers thereof, or any mixture of these semi-fluorinated 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, where F represents a linear perfluorinated alkane segment containing 4 carbon atoms and H represents a linear non-fluorinated alkane segment of 5 carbon atoms. Preferably, 1-perfluorobutyl-pentane is substantially free of water.

[0033] Optionally, the formulation may include two or more semi-fluorinated alkanes. As understood herein, the term "a" semi-fluorinated alkane does not exclude a plurality unless the context otherwise provides. In other words, a composition or method according to the present disclosure may, in some embodiments, relate to the use or characteristics of one or more semi-fluorinated alkanes. For example, it may be useful to combine semi-fluorinated alkanes to achieve a specific target property, such as a specific density or viscosity. When a mixture of semi-fluorinated alkanes is used, it is preferred that the mixture include at least one of F4H5, F4H6, F6H4, F6H6, and F6H10. In one embodiment, the composition or vehicle includes at least two selected from the group consisting of F4H5, F4H6, F6H4, F6H6, and F6H10. In one embodiment, the composition or vehicle comprises a mixture of 1-perfluorobutyl-pentane and 2-perfluorobutyl-pentane, optionally wherein the 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 in an amount of 0.1% to 2% (w / w), or 0.01% to 1% (w / w), or 0.5% to 5% (w / w), based on the total weight of the mixture of semi-fluorinated alkanes. In still further embodiments, the vehicle of a composition according to the present disclosure comprises a mixture of 1-perfluorohexyl-octane and 2-perfluorohexyl-octane, optionally wherein the 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), based on the total weight of the mixture of semi-fluorinated alkanes.

[0034] In another embodiment, the vehicle of a composition according to the present disclosure consists essentially of one or more semi-fluorinated alkanes described herein, without the presence of additional excipients such as co-solvents (e.g., ethanol). For example, in one embodiment, the vehicle consists essentially of a semi-fluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, or structural isomers thereof, and any combination or mixture of these semi-fluorinated alkanes. Or, in other words, the vehicle consists essentially of 100% (w / w) semi-fluorinated alkane or a mixture of semi-fluorinated alkanes as defined above.

[0035] As used herein, the term "consists," and the related terms "consisting" or "consist," should be understood to mean that no other features are present other than those listed preceding the term. In the context of a composition, if any other component or ingredient other than that listed preceding such term is present in the composition, it will be present only in a minor or residual amount that does not confer technical advantage or relevance for purposes of the present invention, and such may be further understood by the terms "essentially" or "substantially" (e.g., "essentially consisting") used in conjunction with these terms. 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 may be present in the composition other than those listed preceding the term.

[0036] As understood herein, the vehicle of the composition according to the present disclosure comprises at least one semi-fluorinated alkane. The aforementioned vehicle may optionally further comprise one or more excipients as further described herein below. In one embodiment, the vehicle comprises two or more semi-fluorinated alkanes. In another embodiment, the vehicle consists of one or more semi-fluorinated alkanes and optionally one or more pharmaceutically acceptable excipients, preferably excipients that are miscible or soluble in the semi-fluorinated alkane or semi-fluorinated alkane mixture. In one embodiment, the amount of the semi-fluorinated alkane or semi-fluorinated alkane mixture in the composition is at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.8% (w / w) based on the total weight of the composition.

[0037] In other embodiments according to the present disclosure, the pharmaceutical composition comprises about 95 to about 99% (w / w), more preferably about 98 to about 99% (w / w), and even more preferably about 98 to about 99.9% (w / w) of a semi-fluorinated 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 2-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w / w) 1-perfluorobutyl-pentane (F4H5) and up to about 0.2%, 0.3%, 0.4%, 0.5%, or up to about 1% (w / w) 2-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition.

[0038] In another embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, 99%, or at least 99.5% (w / w) 1-perfluorohexyl-octane (F6H8), and optionally 2-perfluorohexyl-octane, based on the total weight of the pharmaceutical composition. In a further embodiment, the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w / w) 1-perfluorohexyl-octane (F6H8) and up to about 0.2%, 0.3%, 0.4%, 0.5% (w / w), or up to about 1% (w / w) 2-perfluorohexyl-octane, based on the total weight of the pharmaceutical composition.

[0039] 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 dissolved under room temperature conditions, i.e., between 15 and 25°C. A clear solution does not contain any particulate or solid phase components and preferably has a refractive index close to that of water (i.e., 1.333) at room temperature.

[0040] In one embodiment, the composition according to the present disclosure is in the form of a solution or suspension. As understood herein, the term "solution" or "clear solution" refers to a liquid solution in which all solutes are completely soluble or dissolved under room temperature conditions, i.e., between 15 and 25°C. The resulting solution does not contain 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 more of the semi-fluorinated alkanes defined herein, or a combination thereof, and optionally one or more excipients defined herein, and 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, e.g., selected from Table 1, dissolved in a vehicle comprising any one or more of the semi-fluorinated alkanes defined herein, or a combination thereof, and optionally one or more excipients defined herein, and the composition is in the form of a clear solution.

[0041] On the other hand, a "suspension" can be defined as a type of dispersion, which is a system having at least one continuous (or coherent) phase and at least one discontinuous (or inner) phase dispersed in the continuous phase. In a suspension, the dispersed phase is in a solid state. For example, 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 those provided in Table 1, can be suspended in a liquid vehicle of the composition. Suspensions useful in practicing the present invention are preferably liquid suspensions in which the continuous phase is liquid, and are formulated to be suitable for administration as a pharmaceutical.

[0042] In another embodiment, a 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 one or more of any one or combination of semi-fluorinated alkanes as defined herein. In another embodiment, a pharmaceutical composition according to the present disclosure consists of an enantiomer (a 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 (included in Row A) to the second enantiomer (included in Row 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, and wherein the enantiomer (a mixture of two enantiomers) is suspended in one or more of any one or combination of semi-fluorinated alkanes as defined herein.

[0043] Optionally, compositions according to the present disclosure may include a vehicle containing one or more excipients in addition to at least one semi-fluorinated alkane. In one embodiment, the vehicle of the composition consists of at least one semi-fluorinated alkane and one or more excipients. As used herein, the term "excipient" refers to any pharmaceutically acceptable natural, synthetic, or semi-synthetic substance, compound, or component that may be included in the vehicle, and thus in the compositions described herein, to enhance or otherwise modify, for example, the physical or chemical makeup or stability of the composition. Pharmaceutically acceptable means that the excipient is safe, non-toxic, biocompatible, and physiologically acceptable, e.g., for human pharmaceutical use. Preferably, the excipient is suitable and safe for topical application to the human eye or associated ocular tissues.

[0044] Examples of excipients that may be included in compositions according to the present disclosure include, but are not limited to, cosolvents, antioxidants, preservatives, lipids, oily excipients, surfactants, lubricants, or combinations thereof. In one embodiment, the excipient is a liquid that is miscible with the semi-fluorinated alkane and, if two or more excipients are included in the vehicle, is miscible with any of the other excipients included in the vehicle of the composition. In one embodiment, the excipient may function as a cosolvent, i.e., a compound suitable for increasing the solubility or solubilizing the active compound and / or other excipients included in the composition. The cosolvent is preferably a liquid that is completely miscible with the semi-fluorinated alkane, i.e., it forms a coherent single phase upon mixing with the semi-fluorinated alkane. In another embodiment, the excipient may be dissolved in the semi-fluorinated alkane.

[0045] In some embodiments, the excipient is a co-solvent. The co-solvent may be an alcohol, such as an alkyl alcohol. In one embodiment, the alcohol is selected from ethanol, 1-propanol, isopropanol, and phenylethyl alcohol, or more preferably, from ethanol and phenylethyl alcohol. Alternatively, the vehicle of the composition may comprise or consist of at least one excipient in addition to a semi-fluorinated alkane (or a mixture of semi-fluorinated alkanes) as defined herein, provided that the excipient is not an alcohol, and / or is not a medium-chain triglyceride (MCT), and / or is not light liquid paraffin.

[0046] In some embodiments, the excipient contained in the vehicle is an oily excipient. Examples of oily excipients include triglycerides, mineral oil, and liquid paraffin. In one embodiment, in addition to the semi-fluorinated alkane, the vehicle includes an oily excipient selected from medium-chain triglycerides (MCT) and light liquid paraffin.

[0047] In some embodiments, the vehicle of the composition comprises or consists of a combination of at least one semi-fluorinated alkane and any one of the co-solvents or oily excipients described herein above.

[0048] In some embodiments, the one or more excipients are optionally independently present in the composition in an amount of up to 0.1%, 0.5%, 0.75%, 1.0%, 1.25%, 1.4%, 1.5%, 1.8%, 2.0%, 3.0%, 4.0%, or up to 5.0% by weight (w / w), or preferably up to 1% or up to 1.4% by weight, based on the total weight of the composition. In other embodiments, the composition optionally independently comprises one or more excipients in an amount of 0.1-5.0% by weight, or 0.1-2.0% by weight, or 0.01-1.4% by weight, based on the total weight of the composition. In other embodiments, one or more excipients are optionally independently present in the composition in an amount of up to 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 up to 5.0% (v / v) (w / w), or preferably up to 1% (v / v) or up to 1.4% (v / v), based on the total volume of the composition. In other embodiments, the composition optionally independently comprises one or more excipients in an amount of 0.1-5.0% (v / v), or 0.1-2.0% (v / v), or 0.01-1.4% (v / v), based on the total volume of the composition.

[0049] In some embodiments, when the pharmaceutically active compound is hyoscyamine, the composition is essentially free of a) water, or b) preservatives, or c) one or more hyoscyamine degradation products selected from tropic acid, tropine, and apoatropine, or d) any combination of a), b), and c).

[0050] In other embodiments, the composition is essentially free of a) water, or b) preservatives.

[0051] As used herein, the term "up to about" or "up to," when used in connection with a parameter such as those relating herein 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., selected from Table 1, or the amount of one or more excipients in a composition, refers to any value greater than 0 up to and including the defined parameter, taking into account any degree of variability typically observed in measuring or determining this parameter using standard techniques and equipment known in the relevant art.

[0052] As understood herein, unless otherwise specified, the term "% (w / v)" refers to the amount of a component of a composition as a weight percentage relative to the total volume of the composition ("w" represents weight, and "v" represents volume). For example, 0.1% (w / v) corresponds to 1.0 mg of a component in 1 mL of the composition. As used herein, the term "% (w / w)" or "wt%" refers to the amount of a component of a composition as a weight percentage relative to the total weight of the composition, with "w" representing weight, unless otherwise specified. As used herein, the term % (v / v) or volume percent refers to the volume of a component of a composition relative to the total volume of the composition, unless otherwise specified.

[0053] As understood herein, the terms "essentially free" or "substantially free" or "component-free" with respect to a component or ingredient of a composition refer to the presence of said ingredient in trace amounts or less, where the ingredient provides no technical or material benefit to the composition. In one embodiment, the compositions described herein are essentially free of water. In another embodiment, the compositions described herein may be essentially free of preservatives, such as antimicrobial preservatives.

[0054] As used herein, the term "about," when used in reference to or in connection with, for example, the amount or concentration of a compound dissolved or suspended in a composition, includes the exact value defined, 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.

[0055] Also, as understood herein, a pharmaceutically acceptable salt is a salt of a compound as provided herein that retains its biological properties, is non-toxic, and is compatible with pharmaceutical use. Salts can be formed, for example, from the addition of an organic or mineral acid, such as sulfuric or hydrochloric acid.

[0056] The compositions of the present disclosure are compositions containing a higher enantiomeric ratio, or predominantly one enantiomer, of a pharmaceutically active compound, such as those defined herein above. These are formulated in a semi-fluorinated alkane and can remain stable under long-term storage conditions with minimal or reduced degradation or loss of the enantiopurity or stereochemical purity of the compound in the composition. For example, because maintaining the stereochemical purity of the desired enantiomer can be difficult due to stability issues and / or the tendency of the compound to gradually racemize under storage conditions, the pharmaceutically active compound can be provided as a racemate, where only one of the compounds may have the desired pharmacological or therapeutic effect. From the perspective of therapeutic efficacy, loss or reduction in dosing precision is undesirable. Furthermore, the absence or much lower amount of therapeutically irrelevant enantiomers in a pharmaceutical product can be advantageous in that it reduces or avoids unnecessary exposure of the subject to this compound, to which the subject's physiology may still be (harmfully) reactive, despite its non-therapeutic effects (or as yet unknown adverse effects).

[0057] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising (S)-hyoscyamine or a pharmaceutically acceptable salt thereof dissolved or suspended in a vehicle comprising a semi-fluorinated alkane, wherein the (S)-hyoscyamine is dissolved or suspended in a vehicle comprising the semi-fluorinated alkane and optionally one or more excipients as defined above.

[0058] Atropine (CAS 51-55-8), also known as (±)-hyoscyamine or benzeneacetic acid, α-(hydroxymethyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo(±), is a racemic mixture (50:50 enantiomeric ratio) of two isomers, (S)-hyoscyamine and (R)-hyoscyamine. Atropine is a tropane alkaloid compound used as an antimuscarinic and anticholinergic agent. However, (S)-hyoscyamine, also known as (-)-hyoscyamine or (L)-hyoscyamine, is believed to be the active enantiomeric species of atropine, which produces the physiological effects of atropine. The chemical structure of (S)-hyoscyamine is: [ka] is.

[0059] 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). Low-dose formulations of 0.01% (w / v) atropine have been found to be effective, but physicians currently must write off-label prescriptions to compounding pharmacies to supply patients. However, these compounded formulations of atropine, especially low-dose formulations (e.g., 0.01% (w / v)), tend to be pharmacologically unstable, resulting in a product with a short shelf life. As mentioned above, unstable pharmaceuticals are a concern not only from the perspective of therapeutic efficacy (loss or reduction in accuracy during administration) but also from the perspective of patient safety. Formulations have been developed to counteract or delay the degradation of atropine, including adjusting the aqueous formulation to a lower pH, but this does not match the physiological pH of the eye or tears and is therefore incompatible with or irritating to the eye. In the treatment of conditions such as myopia, which may require application over long periods of time, patient compliance is key to successful treatment.

[0060] It has been discovered that compositions containing a higher enantiomeric ratio, or primarily the active enantiomer (S)-hyoscyamine, can be formulated in semi-fluorinated alkanes and remain stable under long-term storage conditions. The observed stability relates to minimal or no degradation of the hyoscyamine compound, as is often observed with aqueous formulations of this compound or its sulfate salt, and unexpectedly, to a decrease in the enantiomeric ratio due to racemization or formation of the (R)-hyoscyamine enantiomer over time, providing improved storage stability.

[0061] Furthermore, it has been found that storage-stable, low-concentration compositions of (S)-hyoscyamine can also be formulated in semi-fluorinated alkanes according to the present disclosure, avoiding the drawback of the presence, or at least equivalent amounts, of the (R)-hyoscyamine enantiomer, which may be considered an impurity. While (R)-hyoscyamine has little or no pharmacological effect with respect to its intended therapeutic use, for example, for the treatment of myopia, the absence or much lower amount of this enantiomer in the composition can be advantageous in that it reduces or avoids unnecessary exposure of a subject in need of treatment to a compound to which the subject's physiology may still be reactive.

[0062] In one embodiment, a composition according to the present disclosure comprises an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, where the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is not 50:50. Or, in other words, the composition does not comprise atropine or a racemic mixture of the two enantiomers, but rather comprises a majority or preponderance of 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.

[0063] In one embodiment, the composition contains (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 used for chiral substances. It reflects the degree to which a sample contains more of one enantiomer (i.e., (S)-hyoscyamine (Table 1, above, 1a)) than the other enantiomer (i.e., (R)-hyoscyamine (Table 1, above, 1b)). A racemic mixture has an ee of 0%, while a single, completely pure enantiomer has an ee of 100%. A sample containing 70% (S)-hyoscyamine and 30% (R)-hyoscyamine has an ee of 40% (70% - 30%).

[0064] 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. The enantiomeric ratio is the percentage ratio of one enantiomer to the other and can alternatively be expressed as a numerical value. For example, in the case of a racemate, the enantiomeric ratio is 1 (50:50), or in the case of an enantiomeric ratio of 90:10, this can 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.

[0065] For example, the enantiomeric ratio or enantiomeric excess (ee) of hyoscyamine, or generally the stereochemical purity of the compounds, or specifically the enantiomers listed in Table 1 herein, and the relative or other quantification of the amounts of active compounds, their isomers, or degradation products contained in compositions according to the present disclosure, can be determined by several methods in the art, including, but not limited to, chromatographic methods such as HPLC, capillary electrophoresis, LC-MS, or gas chromatography, and / or spectroscopic methods such as circular dichroism or NMR. In one embodiment, the enantiomeric ratio is determined by HPLC, preferably from quantification of the peak areas of the respective compounds.

[0066] In addition to the low amount or concentration of (R)-hyoscyamine in the composition, pharmaceutical compositions containing (S)-hyoscyamine may also contain only small amounts of, or be essentially free of, degradation products of hyoscyamine, such as those derived from hydrolysis of the compound's esters or dehydration of hydroxyl substituents. Preferably, the composition is essentially free of any one or combination of tropic acid (also known as 3-hydroxy-2-phenylpropanoic acid), atropic acid, tropine, apoatropine (i.e., the dehydration products of hyoscyamine), or any salts thereof.

[0067] 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 hyoscyamine, based on the total weight of the composition, preferably wherein the compounds are selected from the group consisting of tropic acid, tropine, atropic acid, apoatropine or salts thereof.

[0068] In a further embodiment, the pharmaceutical composition comprises each or any combination of compounds resulting from the degradation of hyoscyamine of 0.05, 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6 or 7% or less, as a percentage derived from quantification of the peak area of ​​the compound in the respective analytical chromatographic method (e.g., HPLC), preferably said compounds are selected from the group consisting of tropic acid, atropic acid, apoatropine or a salt thereof.

[0069] Alternatively or additionally, the compositions of the present disclosure may contain about 0.0001-0.001% (w / v), or 0.004-0.006% (w / v) or less of (R)-hyoscyamine. The compositions may also be substantially free of (R)-hyoscyamine.

[0070] 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 of 0.001% to 1.0% (w / v), 0.001% to 0.5% (w / v), 0.001% to 0.015%, 0.002% to 0.012%, 0.004% to 0.012%, 0.005% to 0.01%, 0.01% to 0.1% (w / v), 0.02% to 0.07% (w / v), 0.002% to 0.006% (w / v), 0.004% to 0.006% (w / v), or 0.0045 to 0.0055% (w / v).

[0071] In some embodiments, (S)-hyoscyamine is present in the composition at a concentration of up to 0.003%, 0.005%, 0.0055%, 0.0075%, 0.01%, 0.02%, 0.03%, 0.05%, 0.1%, 0.5%, 1.0% (w / v).

[0072] In some embodiments, (S)-hyoscyamine is present in the composition at a concentration of 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1% (w / v).

[0073] In some embodiments, a composition according to the present disclosure comprises or consists of: a) 0.004 to 0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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% by weight of 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; after storage at 5°C for 1, 2 or 3 months, the total amount of hyoscyamine is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 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% by weight 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; d) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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 enantiomeric ratio is at least 90:10, at least 95:5, at least 96:4, or at least 98:2, and ... or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 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% by weight 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; f) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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, and the hyoscyamine is maintained at 25°C for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 9 or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by 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% by weight 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; h) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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, and the hyoscyamine is maintained at 25°C for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 9 or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0074] Compositions a), b), c), d), e), f), g), and h) are clear solutions, i.e., hyoscyamine is dissolved in a vehicle comprising or consisting of 1-perfluorobutyl-pentane and optionally up to 1% by weight of ethanol. In related embodiments, the semi-fluorinated alkane contained in these compositions may be a mixture of 1-perfluorobutyl-pentane and its structural isomers, such as 2-perfluorobutyl-pentane, according to the present disclosure.

[0075] In further embodiments, the composition according to the present disclosure comprises or consists of: j) 0.004 to 0.006% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1% by weight 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; k) 0.004 to 0.006% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1% by weight 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; after storage at 5°C for 1, 2 or 3 months, the total amount of hyoscyamine is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%; l) 0.005% (w / v) hyoscyamine, 1-perfluorohexyloctane, and optionally up to 1% by weight 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; m) 0.005% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1% by weight 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 enantiomeric ratio ... or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%. n) 0.01% (w / v) hyoscyamine, 1-perfluorohexyloctane, and optionally up to 1% by weight 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; o) 0.01% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1% by weight 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 enantiomeric ratio ... or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%. p) 0.02% (w / v) hyoscyamine, 1-perfluorohexyloctane, and optionally up to 1% by weight 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; q) 0.02% (w / v) hyoscyamine, 1-perfluorohexyl octane, and optionally up to 1% by weight 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, at 25°C, After storage for 2 to 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% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0076] Compositions j), k), l), m), n), o), p), and q) are clear solutions, i.e., hyoscyamine is dissolved in a vehicle comprising or consisting of 1-perfluorohexyl octane and optionally up to 1% by weight of ethanol. In related embodiments, the semi-fluorinated alkane contained in these compositions may be a mixture according to the present disclosure of 1-perfluorohexyl octane and its structural isomers, such as 2-perfluorohexyl octane.

[0077] In some embodiments, a liquid pharmaceutical composition according to the present disclosure comprises an enantiomer (or a mixture of the two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from the enantiomers set forth in Table 1 herein, wherein the concentration of the compound in the liquid pharmaceutical composition is 0.01-5% (w / v), 0.05-5% (w / v), 0.05-2% (w / v), 0.1-2% (w / v), 0.1-1% (w / v), or the concentration of the compound in the liquid pharmaceutical composition is 0.5-1.0% (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 enantiomer pairs set out in Table 1 herein, and 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 enantiomers or enantiomer pairs set forth 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 0.01% (w / v).

[0078] In some embodiments, after storage at 0-60°C, e.g., at 25°C, for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the amount of (S)-hyoscyamine in a composition according to the present disclosure is at least 90%, or at least 95%, or at least 99%, of the initial amount of (S)-hyoscyamine in the composition as determined, e.g., by HPLC.

[0079] In other embodiments, the concentration or amount of (S)-hyoscyamine in a composition according to the present disclosure after storage at 0-60°C, e.g., at 25°C, for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months is in the range of 90-110%, or 95-105%, of the initial concentration of (S)-hyoscyamine in the composition as determined, e.g., by HPLC. In other embodiments, the concentration of (S)-hyoscyamine after storage of the composition at 25°C for at least 3 months is in the range of about 90-110%, or is 90% or more (e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99%), or 100% or less (e.g., 101, 102, 103, 104, 105, 106, 107, 108, or 109% or less), as determined, e.g., by HPLC, preferably by quantitation of the peak area of ​​each compound. If the determined percentage exceeds 100%, it should be understood that the measurement does not relate to an increase in the amount of (S)-hyoscyamine, but rather corresponds to a loss of vehicle over time, for example, during storage. In further related embodiments, the amount of (S)-hyoscyamine, or preferably the initial concentration of (S)-hyoscyamine in the composition, is 90% or 95% or more, or 110%, 105%, or 100% or less of the initial concentration of (S)-hyoscyamine in the composition.

[0080] In some embodiments, the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in a composition according to the present disclosure after storage at 25° C. for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months does not decrease by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%. For example, in a composition comprising hyoscyamine dissolved in a semi-fluorinated alkane and optional excipients, where the hyoscyamine has an initial enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine of 90:10, i.e., 9, before storage or aging, a decrease of about 1% corresponds to a decrease in the enantiomeric ratio to 8.91%, or about 89.91:10.09.

[0081] In other embodiments, the amount of a compound in a composition according to the present disclosure, i.e., an enantiomer listed in Table 1 or any of the lists provided in this disclosure, after storage at 0-60°C, e.g., 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%, of the initial amount of enantiomer determined for the composition, e.g., by HPLC.

[0082] 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 of the lists provided herein, after storage at 0-60°C, e.g., at 25°C, for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months, is in the range of 80-120%, 85-115%, 90-110%, or 95-105% of the initial concentration of the enantiomer in the composition, as determined, e.g., by HPLC. In other related embodiments, the concentration of the enantiomers after storage of the composition for at least 3 months at 25° C. is within the range of about 90-110%, or is 90% or greater (e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99%), or 100% or less (e.g., 101, 102, 103, 104, 105, 106, 107, 108, or 109%), as determined, for example, by HPLC, preferably by quantitation of the peak area of ​​each compound. When the determined percentage exceeds 100%, it should be understood that the measurement does not relate to an increase in the amount of enantiomer, but rather corresponds to, for example, loss of vehicle over time during storage. In further related embodiments, the amount of enantiomer, or preferably the initial concentration of enantiomer in the composition, is 80%, 85%, or 90% or 95% or more, or 120%, 115%, 110%, 105% or 100% or less of the initial concentration of enantiomer in the composition.

[0083] In some embodiments, the enantiomeric ratio of the first enantiomer (see Table 1 above) to the second enantiomer in a liquid pharmaceutical composition according to the present disclosure after storage at 25° C. for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months does not decrease by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%. For example, in a composition comprising a first enantiomer and optional excipients dissolved in a semi-fluorinated alkane, where the initial enantiomeric ratio to the second enantiomer is 90:10, or 9, before storage or aging, a decrease of about 1% corresponds to a decrease in the enantiomeric ratio to 8.91%, or about 89.91:10.09.

[0084] In another aspect, the present disclosure relates to a method for preparing a liquid pharmaceutical composition as defined according to any one of the embodiments described herein, comprising dissolving or suspending an enantiomeric compound or enantiomer (or a mixture of two enantiomers) described herein above, e.g., in Table 1, in a semi-fluorinated alkane, or a non-aqueous vehicle comprising or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof, and any combination thereof.

[0085] In another aspect, the present disclosure relates to a method for preparing a composition as defined according to any one of the embodiments described herein, comprising dissolving (S)-hyoscyamine in a non-aqueous vehicle comprising or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof, and any combination thereof.

[0086] 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, comprising dissolving or suspending the compound in a semi-fluorinated alkane, or a vehicle consisting of a semi-fluorinated alkane and one or more excipients.

[0087] The isomerizable pharmaceutical agent may be a compound as defined herein 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., by HPLC). Preferably, the isomerizable compound contains at least one chiral stereocenter. The chiral stereocenter may be susceptible to racemization, inversion, or epimerization, and preferably, the chiral stereocenter may be susceptible to racemization, inversion, or epimerization under basic or acidic conditions.

[0088] In some embodiments of this method, after storing the composition at 0-60°C (e.g., at 25°C) for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the amount of other isomers (e.g., undesired enantiomers or epimers) of the isomerizable pharmaceutical compound 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., by HPLC).

[0089] In a related aspect, the disclosure provides a method for stabilizing, preventing, or reducing the loss of stereochemical or enantiomeric purity of an enantiomer of a pharmaceutically active compound, or a pharmaceutically acceptable salt thereof, in a liquid composition, the method comprising dissolving or suspending the enantiomer in a semi-fluorinated alkane, or a vehicle comprising a semi-fluorinated alkane and one or more excipients. In some embodiments, the purity of the enantiomer in the composition, when formulated in the semi-fluorinated alkane or vehicle, is at least 90%, or at least 95%, or at least 97% (e.g., by HPLC).

[0090] In related embodiments, methods are provided for stabilizing, 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, the methods comprising dissolving or suspending the enantiomer (provided at a defined optical purity) in a vehicle comprising a semi-fluorinated alkane, or a semi-fluorinated alkane and one or more excipients. In some embodiments, 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., by HPLC) when formulated in a semi-fluorinated alkane, or a vehicle comprising (or consisting of) a semi-fluorinated alkane and one or more excipients as defined herein. Thus, the methods provide a way to maintain or prevent significant changes in the enantiomeric purity of the compound.

[0091] In related embodiments, methods are provided for stabilizing, preventing, or losing the enantiomeric ratio for one enantiomer (pair of enantiomers or mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition, the method comprising dissolving or suspending the enantiomer (or mixture of two enantiomers) in a vehicle comprising a semi-fluorinated alkane described herein, or a semi-fluorinated alkane and one or more excipients. In some embodiments, the ratio of the first enantiomer to the second enantiomer, for example, when dissolved or suspended in the semi-fluorinated 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 in Table 1, and the corresponding second enantiomer is selected from compounds 1b to 49b.

[0092] The methods may provide for preventing or reducing the rate of decomposition (e.g., hydrolysis and / or dehydration) and / or preventing or reducing the rate of isomerization, e.g., preventing or reducing the rate of racemization or epimerization of an enantiomer in the composition into a different stereoisomer or enantiomer thereof. In some embodiments, these methods, the enantiomer, or the first enantiomer comprises a chiral stereocenter on a carbon atom, and at least one of the substituents of the chiral stereocenter is i) a hydrogen moiety susceptible to deprotonation under basic conditions, and / or ii) an alcohol moiety susceptible to dehydration under acidic conditions, and / or susceptible to racemization, isomerization, or epimerization.In other embodiments, the enantiomer or first enantiomer is (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuranol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S)-(-)-celiprolol, (S)-chloroquine, (S)-(+)-dimethicone ndene, (R)-(-)-dimethindene, (S)-ecadotril, (2S,3R)-epoxiconazole, (S)-esmolol, (S)-(-)-esmolol, (R)-etodolac, (S)-fenoprofen, (R)-fexofenadine, (S)-fexofenadine, (S)-(+)-flurbiprofen, (R)-(-)-flurbiprofen, (S)-gatifloxacin, (S)-gemifloxacin Syn, (R,R)-(+)-genaconazole, (S)-hydroxychloroquine, (S)-(+)-ibuprofen, (S)-indoprofen, (R)-ketamine, (S)-ketoprofen, (S)-ketorolac, (S)-lonofloxacin, (R)-lonofloxacin, (S)-(-)-metoprolol, (R)-(+)-metoprolol, (R)-(-)-miconazole, (S)-(-)-moprolol , S-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxoprenolol, (+)-pemedrac, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole and (+)-terconazole, or from column A or B of Table 1. Additionally, the compositions of such methods can correspond to any one or combination of the compositions described herein with respect to, for example, semi-fluorinated alkanes, excipients, etc.

[0093] In some embodiments of these methods, storage of the composition at 0-60° C. (e.g., at 25° C.) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months is provided, and over said period: i) the concentration of the enantiomer in the composition remains essentially 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 its initial concentration in the composition before storage (e.g., by HPLC); and / or ii) the enantiomeric excess of the enantiomers remains essentially 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 the value originally determined before storage; and / or iii) The enantiomeric ratio of the first enantiomer 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.

[0094] In a further related aspect, the present disclosure relates to a method for stabilizing and / or preventing isomerization of (S)-hyoscyamine in a composition, the method comprising dissolving (S)-hyoscyamine (of a particular optical purity) in a semi-fluorinated alkane, or a non-aqueous vehicle comprising a semi-fluorinated alkane and, optionally, one or more excipients, wherein the semi-fluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof, and any combination thereof. In some embodiments of this method, 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., by HPLC). In other embodiments, the enantiomeric purity or ratio of (S)-hyoscyamine can be as defined above.

[0095] The method provides for preventing or slowing the rate of decomposition (e.g., hydrolysis and / or dehydration) and / or isomerization (e.g., racemization) of (S)-hyoscyamine in the composition. In particular, the method may be effective in any one or combination of preventing or reducing the decomposition of (S)-hyoscyamine, such as that resulting in the formation or increase of tropic acid, tropine, or apoatropine in the composition, or preventing or reducing the conversion of (S)-hyoscyamine to (R)-hyoscyamine in the composition after storage of the composition at 0-60°C, e.g., 25°C, for at least 1, 2, 3, 4, 5, 6, 9, or 12 months.

[0096] In some embodiments of these methods, after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0-60°C (e.g., 25°C), the amount of any one or more degradation products of hyoscyamine (e.g., tropic acid, tropine, or apoatropine, or any salt thereof) is independently less than 5%, 4%, 3%, 2%, 1%, or 0.5% (e.g., by HPLC). In some embodiments of these methods, after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0-60°C (e.g., 25°C), the amount of (R)-hyoscyamine in the composition is less than 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% (e.g., by HPLC). In other embodiments, after storage at 0-60°C (e.g., 25°C) for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, 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).

[0097] In still further aspects, pharmaceutical compositions according to the present disclosure are useful or provided as medicaments for use in the treatment or prevention of a disease or medical condition, preferably in a human subject, or optionally in a veterinary subject, and in the manufacture of a medicament.

[0098] In some embodiments, the composition is a topical ophthalmic composition, or in other words, a composition that can be applied or administered topically to the surface of a subject's eye or to tissues related to the eye, such as the cornea or conjunctiva of the eye, or the cul-de-sac of the conjunctiva. In related embodiments, the composition is in the form of a clear solution. In another embodiment, the pharmaceutical composition is formulated or adapted for intravitreal, subcutaneous, intramuscular, or intravenous injection or infusion. In yet another embodiment, the composition is adapted for topical application to the surface of a tissue or organ, such as the skin or mucosal tissue, for example, to the eye.

[0099] In one embodiment, a composition according to any one or combination of embodiments according to the present disclosure is used to treat and / or prevent an ocular disease or condition, for example, affecting one or both eyes of a subject.

[0100] In one embodiment, a composition according to an embodiment of the present disclosure comprising (S)-hyoscyamine is used for the treatment, prevention, and / or control of myopia. Myopia, also known as short- or near-sightedness, is a refractive condition or error of the eye, typically characterized by blurred vision of distant objects, particularly as a result of the image falling or focusing in front of the photoreceptors on the retina or retinal surface. Among various factors and causes, myopia can arise, for example, because the axial length of the eye is not properly correlated with the refractive power or curvature of the lens.

[0101] In one embodiment, the disclosed composition comprising (S)-hyoscyamine is for use in a method for preventing or alleviating the onset of myopia, or for use in a method for reducing the progression of myopia in a human subject, such as a child and / or young subject. In a further embodiment, the composition is a topical ophthalmic composition for use in a method for reducing (e.g., slowing) the progression or rate of progression of myopia. A reduction in the progression of myopia can be determined, for example, by a decrease in the rate of change of one or more parameters typically used in the art to measure the myopic refractive error of the eye.

[0102] In another embodiment, a composition according to an embodiment of the present disclosure containing (S)-hyoscyamine is used to treat amblyopia or prevent the progression of amblyopia. Amblyopia, sometimes known as "lazy eye," is a condition that typically manifests in infants and children and can result in a disruption of the visual axis and loss of monocular vision. Conditions or symptoms associated with amblyopia include refractive errors, such as differences in visual acuity between the eyes or misalignment of the eyes, which can result in blurred vision and nonuse or suppression of the affected eye's visual field or visual input. Treatment of amblyopia itself or prevention of its progression according to the present disclosure can include penalization of a healthy, non-amblyopic, or good-vision eye. In one embodiment, a composition according to the present disclosure can be used to treat amblyopia in addition to other treatments, such as refractive correction or occlusion.

[0103] In other embodiments, the compositions may be used for cycloplegic refraction, temporary paralysis of the ciliary muscles, or pupil dilation, which may also be called mydriasis.

[0104] In yet another embodiment, the compositions can be used to treat (e.g., as an antidote) a subject, preferably a human subject, who has been exposed to a toxin, such as an organophosphate compound (e.g., a pesticide, or a nerve agent).

[0105] The use of the pharmaceutical composition described in any one of the above embodiments in the manufacture or preparation of a medicament or medicament for treating a subject in need thereof in connection with any one of the diseases or medical conditions described herein is also provided in the context of the present disclosure.Further provided in connection with the present disclosure is a method for treating a subject having or suffering from any medical condition or disorder described herein, or a method for preventing or ameliorating a medical condition or disorder in a subject, which may include administering (e.g., topically, for example, topically ocularly) a composition described herein to the subject.

[0106] In yet another aspect, the present disclosure relates to a kit comprising a composition according to any one or combination of the embodiments described herein, a container adapted to hold the composition, and optionally a means for dispensing the composition and / or instructions for use, wherein the instructions include any one of the uses or methods of treatment described herein.

[0107] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. [Example]

[0108] Example 1 Hyoscyamine solutions were prepared in F4H5 (1-perfluorobutylpentane) or in 1% (v / v) 2-propanol in 1-perfluorobutylpentane.

[0109] (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 containing 1% (v / v) 2-propanol was then added to the vial, and the resulting mixture was stirred at 300 rpm overnight to obtain a clear solution.

[0110] The (S)-hyoscyamine (CAS101-31-5, Abcam Pharmatech, Changzhou, China) used consisted of 90.8% (S)-hyoscyamine and 9.2% (R)-hyoscyamine, i.e., an enantiomeric excess (ee) of (S)-hyoscyamine of 81.6%, or an enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine of approximately 9.87.

[0111] The following solutions were prepared: (1) 0.1 mg / mL atropine in 1% (v / v) 2-propanol in F4H5 (i.e., a solution containing 0.05 mg / mL (S)-hyoscyamine) (2): 0.4 mg / ml atropine in 1% (v / v) 2-propanol in F4H5 (i.e., a solution containing 0.2 mg / ml (S)-hyoscyamine) (3) 0.1 mg / mL (S)-hyoscyamine in F4H5 (4) 0.1 mg / mL (S)-hyoscyamine in 1% (v / v) 2-propanol in F4H5 (5) 0.05 mg / mL (S)-hyoscyamine in 1% (v / v) ethanol in F4H5 (6) 0.05 mg / mL (S)-hyoscyamine in 1% (v / v) ethanol in F6H8

[0112] HPLC simultaneously detected the (R)- and (S)-hyoscyamine enantiomers in these solutions using a chiral HPLC column (Lux Cellulose-2, Phenomenex). As shown in Figure 1, the two enantiomers were clearly distinguishable (see Figure 1).

[0113] Example 2 Solutions of 0.1 mg / mL (S)-hyoscyamine in 1% (v / v) 2-propanol in F4H5 and 0.1 mg / mL (S)-hyoscyamine in F4H5, prepared according to Example 1, are checked for stability and racemization of (S)-hyoscyamine during storage at room temperature (25°C).

[0114] The ratio of (S)- to (R)-hyoscyamine in the infused solution was found to not change by 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.

[0115] Stability studies continued for 1.5 months at room temperature (25°C) confirmed that the ratio of (S)- to (R)-hyoscyamine in these compositions remained unchanged, demonstrating improved shelf life for the (S)-hyoscyamine compositions.

[0116] The stability of the solution at elevated temperatures is also tested.

[0117] Solutions of 0.1 mg / mL (S)-hyoscyamine in 1% (v / v) 2-propanol in F4H5 and 0.1 mg / mL in F4H5 were heated at 60°C for 1 hour. HPLC analysis to confirm solution stability and racemization revealed that the initial enantiomeric purity of 90.8% (S)-hyoscyamine was maintained in both solution formulations, and no other degradation products were produced. This demonstrated that compositions containing (S)-hyoscyamine and semifluorinated alkanes were stable under the experimental conditions and did not undergo racemization or decomposition, even at elevated temperatures.

[0118] Example 3 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 was monitored at room temperature (25°C) for 6 months. The ratio of the two enantiomers (i.e., the enantiomeric ratio of (R)- to (S)-hyoscyamine), as determined by HPLC based on peak area, was shown to be effectively stable over this period, with no isomerization or change in the enantiomeric ratio. The enantiomeric excess of S-hyoscyamine (1a) was shown to be stable at 94% ee over the 6-month period in both F4H5 and F6H8.

[0119] [Table 2]

[0120] Example 4 A solution or suspension of a semi-fluorinated alkane (e.g., F6H8 or F4H5) described herein, or any one of the enantiomeric compounds characterized in Table 1 herein (Column A or B) in a vehicle comprising a semi-fluorinated alkane (e.g., F6H8 or F4H5) and optionally one or more excipients, is prepared according to the following general method.

[0121] An amount of compound is weighed into a container, e.g., a vial, and a semi-fluorinated alkane, or a semi-fluorinated alkane in admixture with one or more excipients, is added to the container to obtain the desired concentration of compound in the composition, which is then treated, e.g., by stirring, to obtain a solution or suspension.

[0122] The enantiomeric excess or ratio of the 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 for a period of time (e.g., 2 weeks, 1 month, or up to 6 months), and optionally, the stability of the compound in the composition is determined during or at the end of this period to determine racemization or loss of stereochemical purity. The stability and percentage of the enantiomers in the composition are measured by sampling the composition and performing, for example, chiral HPLC based on peak area, or by using the same analytical method used to determine the purity of the compound in the composition at the beginning of the study.

[0123] The initial enantiomeric purity (e.g., enantiomeric excess, enantiomeric ratio) of the compounds is expected to be essentially maintained upon formulation in the semi-fluorinated alkanes or vehicles with minimal formation of degradation products, racemization, or changes in the enantiomeric purity of the enantiomers, demonstrating that semi-fluorinated alkanes can provide stable vehicles or formulations for liquid compositions of enantiomeric compounds.

Claims

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

2. 1. A liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein said enantiomer is present in said 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 said enantiomer is dissolved or suspended in a semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated alkane and one or more excipients.

3. 1. A liquid pharmaceutical composition comprising multiple enantiomers of a pharmaceutically active compound or pharmaceutically acceptable salts thereof, wherein the ratio of a first enantiomer to a 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, and wherein the enantiomers are dissolved or suspended in a semi-fluorinated alkane or in a vehicle comprising a semi-fluorinated alkane and one or more excipients.

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the compound comprises a chiral stereocenter on a carbon atom and at least one of the substituents 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.

5. The enantiomer or the first enantiomer is (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuranol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S)-(-)-celiprolol, (S)-chloroquine, (S)-(+)-dimethindene, (R )-(-)-Dimethindene, (S)-Ecadotril, (2S,3R)-Epoxiconazole, (S)-Esmolol, (S)-(-)-Esmolol, (R)-Etodolac, (S)-Fenoprofen, (R)-Fexofenadine, (S)-Fexofenadine, (S)-(+)-Flurbiprofen, (R)-(-)-Flurbiprofen, (S)-Gatifloxacin, (S)-Gemifloxacin, (R, R)-(+)-genaconazole, (S)-hydroxychloroquine, (S)-(+)-ibuprofen, (S)-indoprofen, (R)-ketamine, (S)-ketoprofen, (S)-ketorolac, (S)-lonofloxacin, (R)-lonofloxacin, (S)-(-)-metoprolol, (R)-(+)-metoprolol, (R)-(-)-miconazole, (S)-(-)-moprolol, S-(-) 5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the medicament is selected from the list consisting of (S)-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxoprenolol, (+)-pemedrac, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole and (+)-terconazole.

6. The second enantiomer is (R)-hyoscyamine, (R)-(+)-alprenolol, (S)-azelastine, (R)-azelastine, (R)-bisoprolol, (S)-(+)-bufuranol, (R)-carprofen, (R)-carvedilol, (S)-carvedilol, (R)-(+)-celiprolol, (R)-chloroquine, (R)-(-)-dimethindene, (S)-(+)-dimethindene. ndene, (R)-ecadotril, (2R,3S)-epoxiconazole, (R)-esmolol, (R)-(+)-esmolol, (S)-etodolac, (R)-fenoprofen, (S)-fexofenadine, (R)-fexofenadine, (R)-(-)-flurbiprofen, (S)-(+)-flurbiprofen, (R)-gatifloxacin, (R)-gemifloxacin, (S,S)-(-) -Genaconazole, (R)-hydroxychloroquine, (R)-(-)-ibuprofen, (R)-indoprofen, (S)-ketamine, (R)-ketoprofen, (R)-ketorolac, (R)-lolomefloxacin, (S)-lolomefloxacin, (R)-(+)-metoprolol, (S)-(-)-metoprolol, (S)-(+)-miconazole, (R)-(+)-moprolol, R-(+)-nadiazole 6. The pharmaceutical composition of any one of claims 2 to 5, wherein the active ingredient is selected from the list consisting of floxacin, (L)-nebivolol, (D)-nebivolol, (R)-(+)-oxoprenolol, (-)-pemedrac, (R)-(+)-propranolol, (S)-(-)-propranolol, (S)-sertaconazole, (S)-(+)-sotalol, (+)-terconazole and (-)-terconazole.

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

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

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

10. 10. The composition of claim 9, wherein the semi-fluorinated alkanes are 1-perfluorobutyl-pentane, and optionally 2-perfluorobutyl-pentane, and the 2-perfluorobutyl-pentane 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 up to 0.2% (w / w), based on the total weight of the mixture of semi-fluorinated alkanes.

11. 11. The composition of claim 10, wherein the semi-fluorinated alkanes are 1-perfluorohexyl-octane and, optionally, 2-perfluorohexyl-octane, and the 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), based on the total weight of the mixture of semi-fluorinated alkanes.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the vehicle consists of the semi-fluorinated alkane or a mixture of semi-fluorinated alkanes.

13. 13. The composition of any one of claims 1 to 12, wherein the semi-fluorinated alkane is present in an amount of at least 90%, 95%, 96%, 97%, 98%, 99% (w / w), based on the total weight of the composition.

14. 14. The composition of any one of claims 1 to 13, wherein the semi-fluorinated 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. 14. The composition of any one of claims 1 to 13, wherein the semi-fluorinated alkane is 1-perfluorobutyl-pentane (F4H5), and optionally 2-perfluorobutyl-pentane, 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 vehicle comprises or consists of the semi-fluorinated alkane and one or more excipients, the one or more excipients being: a) a co-solvent, which is preferably an alcohol selected from ethanol, 1-propanol, isopropanol, and phenylethyl alcohol, or more preferably selected from ethanol and phenylethyl alcohol; b) optionally an oily excipient selected from triglycerides, mineral oil, and liquid paraffin, preferably selected from medium chain triglycerides (MCT) and light liquid paraffin; and c) any combination of co-solvents or oily excipients as defined in a) or b). The composition according to any one of claims 1 to 15, selected from:

17. 17. The composition of any one of claims 1 to 16, wherein the vehicle consists of a semi-fluorinated alkane, and optionally a structural isomer 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 paraffins.

18. 18. The composition of any one of claims 1 to 17, 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. 19. The composition of any one of claims 1 to 18, wherein the composition comprises at least 89% (S)-hyoscyamine or at least 90% (S)-hyoscyamine, based on the total amount of hyoscyamine in the composition.

20. 20. The composition of any one of claims 1 to 19, 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. 21. The composition of any one of claims 1 to 20, 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. 22. A pharmaceutical composition according to any one of claims 1 to 21, comprising (S)-hyoscyamine, said composition being essentially free of any one or combination of tropic acid, atropic acid, tropine, apoatropine or salts thereof, and / or comprising about 0.0001 to 0.001% (w / v), or 0.004 to 0.006% (w / v)% (R)-hyoscyamine.

23. 23. A pharmaceutical composition according to any one of claims 1 to 22, comprising each or any combination of compounds resulting from the degradation of hyoscyamine of no more than 0.05, 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6 or 7% (e.g. by HPLC), preferably wherein the compounds are selected from the group consisting of tropic acid, atropic acid, apoatropine or a salt thereof.

24. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the composition comprises about 0.0001 to 0.001% (w / v), or 0.004 to 0.006% (w / v)% (R)-hyoscyamine.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the composition is substantially free of (R)-hyoscyamine.

26. (S)-hyoscyamine, a) 0.001% to 1.0% (w / v), 0.001% to 0.5% (w / v), 0.001% to 0.015%, 0.002% to 0.012%, 0.004% to 0.012%, 0.005% to 0.01%, 0 .01% to 0.1% (w / v), 0.02% to 0.07% (w / v), 0.002% to 0.006% (w / v), 0.004 to 0.006% (w / v), 0.0045 to 0.0055% (w / v), or b) up to 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) 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1% (w / v) The composition of any one of claims 1 to 25, wherein the composition is present in a concentration of

27. 27. The composition of any one of claims 1 to 26, wherein the one or more excipients are present in an amount of up to 0.1%, 0.5%, 0.75%, 1.0%, 1.25%, 1.4%, 1.5%, 1.8%, 2.0%, 3.0%, 4.0% or up to 5.0% by weight (w / w), preferably up to 1% or up to 1.4% by weight, based on the total weight of the composition.

28. 28. The composition of any one of claims 1 to 27, wherein the composition is essentially free of a) water, or b) preservatives, or c) one or more hyoscyamine degradation products selected from tropic acid, atropic acid, tropine, and apoatropine, or d) any combination of a), b), and c).

29. The composition comprises: a) 0.004-0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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) 0.004-0.006% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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. after 1, 2, or 3 months of storage at 25°C, the total amount of hyoscyamine is at least 99.9%, 99.5%, 99%, 98%, 97%, 96%, or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by 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% by weight 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; d) 0.005% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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, at 25°C. after 1, 2 or 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by 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% by weight 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; f) 0.01% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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 enantiomeric ratio is at least 90:10, at least 95:5, at least 96:4, or at least 98:2, and ... or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by 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% by weight 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; h) 0.02% (w / v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1% by weight 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 enantiomeric ratio is at least 90:10, at least 95:5, at least 96:4, or at least 98:2, and ... or after 3 months of storage, the total amount of hyoscyamine in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% of the initial amount of hyoscyamine in the composition, and optionally the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine does not decrease by more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

29. The composition according to any one of claims 1 to 28, comprising or consisting of:

30. 30. A composition according to any one of claims 1 to 29, wherein the amount of (S)-hyoscyamine after storage of the composition at 0 to 60°C, for example 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% of the initial amount of (S)-hyoscyamine in the composition.

31. 29. A composition according to claim 28, wherein the amount of (S)-hyoscyamine, 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)-hyoscyamine in the composition, or preferably is greater than or equal to 90% or 95% of the initial amount of (S)-hyoscyamine in the composition, or is less than or equal to 110%, 105% or 100% of the initial amount of (S)-hyoscyamine in the composition.

32. 32. A composition according to any one of claims 1 to 31, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine in said composition after storage at 25°C for at least 1, 2, 3, 4, 5, 6, 9, 12 months does not decrease by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

33. 33. A pharmaceutical composition according to any one of claims 1 to 32, wherein the active compound, e.g. (S)-hyoscyamine, is dissolved in the vehicle and / or the semi-fluorinated alkane, and the composition is in the form of a clear solution, preferably wherein the composition is a topical ophthalmic composition.

34. 34. The pharmaceutical composition of any one of claims 1 to 33, wherein the composition is formulated or adapted for intravitreal, subcutaneous, intramuscular, or intravenous injection or infusion, or for topical application to the surface of a tissue or organ, for example the skin.

35. A pharmaceutical composition according to any one of claims 1 to 34 for use as a medicament.

36. 36. A composition for use according to claim 35 for use in the treatment or prevention of an ocular disease or disorder.

37. A composition for use according to any one of claims 35 to 36 for use in the treatment, prevention or slowing the rate of progression of myopia and / or amblyopia.

38. A composition for use according to any one of claims 35 to 38 for use in pupil dilation.

39. 36. A composition for use according to claim 35 for use in the treatment of a subject, preferably a human subject, exposed to a toxicant such as an organophosphate compound (e.g. a pesticide or a nerve agent).

40. 40. A kit comprising the composition of any one of claims 1 to 39, comprising a container adapted to hold said composition and, optionally, means for dispensing said composition and / or instructions for use.

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

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

43. 43. A method according to 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% or at least 95% or at least 97% (e.g. by HPLC).

44. 44. A method according to any one of claims 42 to 43, which provides for the prevention or slowing down of decomposition (e.g. hydrolysis and / or dehydration) and / or isomerisation (e.g. racemisation) of the (S)-hyoscyamine in the composition.

45. 45. A method according to any one of claims 42 to 44, which is effective in preventing or reducing the formation of any one of tropic acid, atropic acid, tropine, apoatropine or combinations thereof, and / or is effective in preventing or reducing the conversion of (S)-hyoscyamine to (R)-hyoscyamine in the composition after a storage period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months at 0 to 60°C (e.g. 25°C).

46. 46. ​​A method according to any one of claims 42 to 45, wherein the amount of any one or more degradation products of hyoscyamine (e.g. tropic acid, tropine or apoatropine or salts 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. by HPLC) after a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months at 0-60°C (e.g. 25°C).

47. 47. A method according to any one of claims 42 to 46, wherein 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), 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. by HPLC).

48. 48. A method according to any one of claims 42 to 47, wherein after storage at 0 to 60°C (e.g. 25°C) for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, 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%.

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

50. A method for stabilizing, 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, the method comprising dissolving or suspending the enantiomer in a vehicle comprising a semi-fluorinated alkane, or a semi-fluorinated alkane and one or more excipients.

51. 51. The method of claim 50, wherein the enantiomeric excess of the enantiomers 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., by HPLC).

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

53. 53. The method of claim 52, 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.

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

55. 55. The method of claim 54, wherein the purity of the enantiomer in the composition is at least 90%, or at least 95%, or at least 97% (e.g., by HPLC).

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

57. The enantiomer or first enantiomer is (S)-hyoscyamine, (S)-(-)-alprenolol, (R)-azelastine, (S)-azelastine, (S)-bisoprolol, (R)-(-)-bufuranol, (S)-carprofen, (S)-carvedilol, (R)-carvedilol, (S)-(-)-celiprolol, (S)-chloroquine, (S)-(+)-dimethindene, (R) -(-)-Dimethindene, (S)-Ecadotril, (2S,3R)-Epoxiconazole, (S)-Esmolol, (S)-(-)-Esmolol, (R)-Etodolac, (S)-Fenoprofen, (R)-Fexofenadine, (S)-Fexofenadine, (S)-(+)-Flurbiprofen, (R)-(-)-Flurbiprofen, (S)-Gatifloxacin, (S)-Gemifloxacin, (R, R)-(+)-genaconazole, (S)-hydroxychloroquine, (S)-(+)-ibuprofen, (S)-indoprofen, (R)-ketamine, (S)-ketoprofen, (S)-ketorolac, (S)-lonofloxacin, (R)-lonofloxacin, (S)-(-)-metoprolol, (R)-(+)-metoprolol, (R)-(-)-miconazole, (S)-(-)-moprolol, S-(-) 57. The method of any one of claims 50 to 56, wherein the medicament is selected from the list consisting of (S)-(-)-nadifloxacin, (D)-nebivolol, (L)-nebivolol, (S)-(-)-oxoprenolol, (+)-pemedrac, (S)-(-)-propranolol, (R)-(+)-propranolol, (R)-sertaconazole, (R)-(-)-sotalol, (-)-terconazole and (+)-terconazole.

58. The second enantiomer is (R)-hyoscyamine (1b), (R)-(+)-alprenolol (2b), (S)-azelastine (3b), (R)-azelastine (4b), (R)-bisoprolol (5b), (S)-(+)-bufuranol (6b), (R)-carprofen (7b), (R)-carvedilol (8b), (S)-carvedilol (9b), (R)-(+)-celiprolol (10b), (R)-chloroquine (11b), (R)-(-)-dimethindene (12b), (S)-(+)-dimethindene (13b). , (R)-ecadotril (14b), (2R,3S)-epoxiconazole (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), (R)-gemifloxacin (25b), (SS)-(-)-gemifloxacin Naconazole (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-(+) 58. The method of any one of claims 50 to 57, wherein the active ingredient is selected from the list consisting of (R)-(+)-nadifloxacin (39b), (L)-nebivolol (40b), (D)-nebivolol (41b), (R)-(+)-oxprenolol (42b), (-)-pemedrac (43b), (R)-(+)-propranolol (44b), (S)-(-)-propranolol (45b), (S)-sertaconazole (46b), (S)-(+)-sotalol (47b), (+)-terconazole (48b) and (-)-terconazole (49b).

59. After storing the composition at 0-60°C (e.g., 25°C) for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, i) the concentration of said enantiomer is essentially 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% (e.g., as determined by HPLC) relative to its initial concentration in the composition before storage; and / or ii) the enantiomeric excess of said enantiomer or said first enantiomer is essentially 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 the value originally determined before storage; and / or iii) the enantiomeric ratio of the first enantiomer to the second enantiomer is the same or does not decrease by 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25% relative to the value initially determined before storage.

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

Images