WO2024133913A2 - Compositions d'alcane semi-fluoré comprenant de l'hyoscyamine - Google Patents

Compositions d'alcane semi-fluoré comprenant de l'hyoscyamine Download PDF

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Publication number
WO2024133913A2
WO2024133913A2 PCT/EP2023/087677 EP2023087677W WO2024133913A2 WO 2024133913 A2 WO2024133913 A2 WO 2024133913A2 EP 2023087677 W EP2023087677 W EP 2023087677W WO 2024133913 A2 WO2024133913 A2 WO 2024133913A2
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Prior art keywords
hyoscyamine
composition
enantiomer
semifluorinated alkane
enantiomeric
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PCT/EP2023/087677
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English (en)
Inventor
Frank LÖSCHER
Jörg HAISSER
Timo SMIATEK
Markus Beier
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Novaliq Gmbh
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Publication of WO2024133913A2 publication Critical patent/WO2024133913A2/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite

Definitions

  • NVL22P03PC1 SEMIFLUORINATED ⁇ ALKANE ⁇ COMPOSITIONS COMPRISING ⁇ HYOSCYAMINE Description BACKGROUND OF THE INVENTION
  • the stability of an active pharmaceutical compound during storage over a variety of conditions is a generally of concern during development of a formulation for the compound.
  • This aspect is especially relevant for liquid formulations of isomerizable pharmaceutically active compounds, as the isomerization processes will result in structural changes to the compound which can have significant impact on its properties, including its pharmacological properties and pharmacokinetic profile.
  • enantiomeric compounds it may often be the case that only one of a pair of enantiomers may be active or provide a desired pharmacological effect, while the other enantiomer is less active, or even harmful.
  • 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 been shown to be effective in treating the progression of myopia, however these high doses also have a very high incidence of adverse events that typically result in discontinuation of treatment.
  • Atropine Progressively lower doses of atropine have been tested to optimize the safety versus efficacy, and it has been found that 0.01 % (w/v) atropine given once a day retains virtually the same efficacy as the highest doses but with almost no side effects. As no formulations of 0.01 % (w/v) atropine are approved anywhere in the world, physicians have to write off-label prescriptions for compounding pharmacies to supply their patients. However, compounded (0.01% w/v) atropine tends to be pharmacologically unstable resulting in a product with short-term (e.g. ⁇ 30 day) shelf life.
  • WO20200160493 describes 8-methyl-9-azabicyclo[3.2.1]octan-3-yl and pyridine-r-ylmethanyl ester and amide compounds, and compositions comprising such compounds, or atropine and a semifluorinated alkane such as perfluorohexyloctane, or perfluorohexylnonane.
  • US11191751 describes a topical ophthalmological composition comprising atropine (free base) and a semifluorinated alkane as a liquid vehicle, for use in the treatment of myopia.
  • the compositions in this disclosure comprise only atropine i.e.
  • composition comprising an isomerizable compound e.g. an enantiomer of a compound, such as (S)-hyoscyamine which improves the stability of said active compound in particular during storage, but is also directly applicable for therapeutic use, such as for topical ophthalmic administration.
  • an isomerizable compound e.g. an enantiomer of a compound, such as (S)-hyoscyamine which improves the stability of said active compound in particular during storage, but is also directly applicable for therapeutic use, such as for topical ophthalmic administration.
  • the present invention provides for pharmaceutical composition
  • pharmaceutical composition comprising (S)- hyoscyamine or a pharmaceutically acceptable salt thereof, wherein the (S)-hyoscyamine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients; wherein the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, the structural isomers of these semifluorinated alkanes or any combination thereof.
  • the present disclosure also relates to methods for stabilizing (S)- hyoscyamine in a composition, the method comprising a step of dissolving (S)-hyoscyamine in a semifluorinated alkane.
  • the disclosure also provides for the use of these pharmaceutical compositions, e.g. for use as a medicine such as for the treatment of ophthalmological conditions or disorders.
  • the disclosure relates to a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is dissolved or suspended in a semifluorinated alkane, or dissolved or suspended in a vehicle comprising of a semifluorinated alkane and one or more excipients.
  • the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%.
  • the present disclosure also relates to methods for stabilizing, or preventing, or reducing the loss (e.g. of enantiomeric excess, or enantiomeric purity) of an enantiomer of a pharmaceutically active compound, or its pharmaceutically acceptable salt in a liquid composition.
  • DESCRIPTION OF THE DRAWINGS Figure 1 depicts an HPLC chromatograph obtained for a composition comprising 0.1 mg/mL (S)-hyoscyamine in F4H5, the composition comprising an enantiomeric excess of 81.6% of (S)-hyoscyamine (an enantiomeric ratio of 9.87, of (S)-hyoscyamine to (R)-hyoscyamine).
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (S)-hyoscyamine or a pharmaceutically acceptable salt thereof, wherein the (S)-hyoscyamine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients.
  • the semifluorinated alkane is in one embodiment, F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, the structural isomers of these semifluorinated alkanes or any combination or mixtures of these compounds.
  • said compositions are liquid compositions.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an isomerizable pharmaceutically active compound, or a pharmaceutically acceptable salt thereof dissolved or suspended in a vehicle comprising a semifluorinated alkane.
  • the isomerizable pharmaceutically active compound is preferably a compound which comprises at least one chiral stereocenter.
  • the compound comprises one chiral stereocenter.
  • Said compound may be one of a pair of stereoisomers, e.g. an enantiomer.
  • the isomerizable compound according to the present disclosure may comprise more than one chiral stereocenter.
  • the compound may be a diastereomer.
  • the chiral stereocenter may be one that is labile, or susceptible to racemization, or inversion, or in the case the compound is a diastereomeric compound, prone to epimerization at one of its chiral stereocenters.
  • the chiral stereocenter is on an acidic or basic carbon.
  • the present disclosure relates to a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%, and wherein the enantiomer is dissolved or suspended in a semifluorinated alkane, or dissolved or suspended in a vehicle comprising of a semifluorinated alkane and one or more excipients.
  • Enantiomeric excess is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer (i.e. (S)-hyoscyamine, 1a in reference to the list of enantiomeric compounds in Table 1 below) in greater amounts than its mirror image stereoisomer (i.e. (R)-hyoscyamine, 1b in reference to the list of enantiomeric compounds in Table 1 below).
  • a racemic mixture has an ee of 0%, while a single completely pure enantiomer (e.g. an enantiopure compound) has an ee of 100%.
  • a sample with 70% of (S)-hyoscyamine (1a) and 30% of (R)-hyoscyamine (1b) has an ee of 40% (70% ⁇ 30%).
  • the present disclosure relates to a liquid pharmaceutical composition comprising enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the ratio of the first enantiomer relative to the second enantiomer is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, wherein the enantiomer or enantiomers are dissolved or suspended in a semifluorinated alkane; or are dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients.
  • a liquid pharmaceutical composition comprising enantiomers of a pharmaceutically active compound, or a pharmaceutically acceptable salt thereof refers to a composition that comprises a pair of enantiomers of the same compound which are mirror image stereoisomers.
  • the enantiopurity or stereochemical purity of the compound reflecting the extent or the amount of an enantiomer or a stereoisomer e.g. in a sample of the compound, or in the composition may be defined or expressed for example by ratios (i.e. enantiomeric ratios), or the enantiomeric excess (ee) as defined herein.
  • said compound according to the present disclosure comprises one chiral stereo center.
  • the compound comprises a chiral stereocenter on a carbon atom, wherein at least one of the substituents of the chiral stereocenter is i) a hydrogen moiety prone to deprotonation under basic conditions and/or ii) is an alcohol moiety prone to dehydration under acidic conditions.
  • substituents of the chiral stereocenter is i) a hydrogen moiety prone to deprotonation under basic conditions and/or ii) is an alcohol moiety prone to dehydration under acidic conditions.
  • these may be selected from the list consisting of the compounds 1a to 49a featured in the Column A, or compounds 1b to 49b featured in the Column B in Table 1 below. Table 1 Column ⁇ A Column ⁇ B No. Compound No.
  • the liquid pharmaceutical composition comprises enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof selected from any row of Table 1, wherein the ratio of the first enantiomer (column A) relative to the second enantiomer (column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, wherein the enantiomers are dissolved or suspended in a semifluorinated alkane; or are dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients.
  • the liquid pharmaceutical composition comprises a mixture of two enantiomers of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof selected from any row of Table 1, wherein the ratio of the first enantiomer (featured in column A) relative to the second enantiomer (featured in column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, wherein the enantiomers are dissolved or suspended in a semifluorinated alkane; or are dissolved or suspended in a vehicle comprising a semifluorinated alkane and one or more excipients.
  • the mixture of the two enantiomers consists of the first enantiomer (featured in column A) and the corresponding second enantiomer (featured in column B) in the same row of Table 1 (for example the mixture of two enantiomers consist of first enantiomer 3a [(R)-azelastine] and second enantiomer 3b [(S)-azelastine]).
  • the (first) enantiomer is selected from the list consisting of (S)- hyoscyamine (1a), (S)-(-)-alprenolol (2a), (R)-azelastine (3a), (S)-azelastine (4a), (S)- bisoprolol (5a), (R)-(-)-bufuranol (6a), (S)-carprofen (7a), (S)-carvedilol (8a), (R)-carvedilol (9a), (S)-(-)-celiprolol (10a), (S)-chloroquine (11a), (S)-(+)-dimethindene (12a), (R)-(-)- dimethindene (13a), (S)-ecadotril (14a), (2S,3R)-epoxiconazole (15a), (S)-esmolol (16a), (S)- (-)-esmol
  • the (second) enantiomer is selected from the list consisting of (R)- hyoscyamine (1b), (R)-(+)-alprenolol (2b), (S)-azelastine (3b), (R)-azelastine (4b), (R)- bisoprolol (5b), (S)-(+)-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)-(+)-esmol
  • the pairs of the first and second enantiomers are respectively 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
  • compositions of the disclosure are compositions comprising a semifluorinated alkane.
  • Semifluorinated alkanes are linear or branched alkanes where some of the hydrogen atoms are replaced by fluorine atoms.
  • the semifluorinated alkane (which may be abbreviated as SFAs) described and used according to the present disclosure comprises of one linear non-fluorinated hydrocarbon segment and of one linear perfluorinated hydrocarbon segment with the perfluorinated hydrocarbon segment attached to the non-fluorinated hydrocarbon segment.
  • the semifluorinated alkanes used in the context of the present disclosure are preferably liquid semifluorinated alkanes.
  • the semifluorinated alkanes have the chemical formula F(CF2)n(CH2)mH, wherein n and m are integers defining the number of carbons in the perfluorinated hydrocarbon segment and non-fluorinated hydrocarbon segment respectively.
  • the one or more semifluorinated alkanes featured in the compositions according to the present disclosure is a semifluorinated alkane of formula F(CF2)n(CH2)mH, wherein n is an integer selected from 4 to 6 and m is an integer selected from 2 to 10.
  • the one or more semifluorinated alkanes is a semifluorinated alkane of formula F(CF2)n(CH2)mH, wherein n is an integer selected from 4 to 6 and m is an integer selected from 4 to 8.
  • a nomenclature which is also frequently used for linear semifluorinated alkanes designates a perfluorinated hydrocarbon segment as RF and a non-fluorinated segment as RH, i.e. RFRH.
  • the compounds may be referred to as FnHm, wherein F means a perfluorinated hydrocarbon segment, H means a non-fluorinated segment, and n and m define the number of carbon atoms of the respective segment.
  • F3H3 is used for perfluoropropylpropane, F(CF 2 ) 3 (CH 2 ) 3 H.
  • this type of nomenclature is usually used for compounds having linear i.e. unbranched segments. Therefore, unless otherwise indicated, it should be assumed that F3H3 means 1-perfluoropropylpropane, rather than its structural isomers e.g. branched isomers such as 2-perfluoropropylpropane, 1- perfluoroisopropylpropane or 2-perfluoroisopropylpropane.
  • the composition or the vehicle of the composition may comprise of one or more semifluorinated alkanes selected from the group consisting of F4H4, F4H5, F4H6, F4H8, F6H2, F6H4, F6H6, F6H8, F6H10, or their structural isomers, and mixtures thereof.
  • the chemical formula of these semifluorinated alkanes may be expressed, respectively as F(CF 2 ) 4 (CH 2 ) 4 H, F(CF 2 ) 4 (CH 2 ) 5 H, F(CF 2 ) 4 (CH 2 ) 6 H, F(CF 2 ) 4 (CH 2 ) 8 H, F(CF 2 ) 6 (CH 2 ) 2 H, F(CF 2 ) 6 (CH 2 ) 4 H, F(CF 2 ) 6 (CH 2 ) 6 H, F(CF 2 ) 6 (CH 2 ) 8 H and F(CF 2 ) 6 (CH 2 ) 10 H.
  • the vehicle comprises a semifluorinated alkane selected from F4H5, F4H6, F6H4, F6H6, F6H10, or their structural isomers, or any mixture or combination of these semifluorinated alkanes.
  • the composition, or the vehicle comprises a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, their structural isomers, and any mixtures thereof.
  • the semifluorinated alkane is F4H5 (1-perfluorobutyl-pentane), F6H8 (1-perfluorohexyl-octane), their structure isomers or any mixtures for these semifluorinated alkanes.1-perfluorobutyl-pentane, with the chemical formula F(CF2)4(CH2)5H, is an inert, water-insoluble liquid, with a density of 1.284 g/cm 3 at 25 °C and refractive index of 1.3204 at 20 °C.
  • the 1-perfluorobutyl-pentane is substantially free of water.
  • the formulation may comprise more than one semifluorinated alkane.
  • the term ‘a’ semifluorinated alkane does not exclude the plurality, unless context provides otherwise.
  • the compositions or methods according to the present disclosure may, in some embodiments, relate to the use or feature of one or more semifluorinated alkanes.
  • the composition, or the vehicle comprise at least two members selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10.
  • the composition, or the vehicle comprises a mixture of 1- perfluorobutyl-pentane and 2-perfluorobutyl-pentane, optionally wherein the 2- perfluorobutyl-pentane is present in the vehicle 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) in respect total weight of the mixture of semifluorinated alkane.
  • 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) in respect total weight of the mixture of semifluorinated alkane.
  • the vehicle of a composition according to the present disclosure essentially consists only of one or more semifluorinated alkanes as described herein, with no further excipients such as a cosolvent (e.g. ethanol) present.
  • a cosolvent e.g. ethanol
  • the vehicle consists only of a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H10, or their structural isomers and any combination or mixtures of these semifluorinated alkanes.
  • the vehicle essentially consists of 100 % (w/w) of a semifluorinated alkane, or a mixture of semifluorinated alkane such as defined above.
  • the term “consists” and related terms “consisting” or “consist” is to be understood as meaning that no other features, other than those prefaced by the term are present.
  • any other constituent or component is present in the composition other than those prefaced by such term, then it is present only in trace or residual amounts such as to confer no technical advantage or relevance in respect of the object of the invention, such as may be further understood by the term ‘essentially” or “substantially” used in conjunction with these terms (e.g. ‘essentially consisting of”).
  • the term ‘comprising” or related terms “comprises” or “comprise” in the context of compositions, is to be understood as meaning that other features, other than those prefaced by the term may be present in the composition.
  • the vehicle of a composition according to the present disclosure comprises at least one semifluorinated alkane.
  • Said vehicle may optionally further comprise one or more excipients, as such as further described herein below.
  • the vehicle comprises more than one semifluorinated alkane.
  • the vehicle consists of one or more semifluorinated alkanes and optionally one or more pharmaceutically acceptable excipients, preferably excipients which are miscible, or soluble in the semifluorinated alkane or semifluorinated alkane mixture.
  • the amount of semifluorinated alkane or mixture of semifluorinated alkanes in the composition is in an amount of at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.8% (w/w) with respect to the total weight of the composition.
  • the pharmaceutical composition comprises from about 95 to about 99% (w/w), more preferably from about 98 to about 99% (w/w), even more preferably from about 98 to about 99.9% (w/w) of a semifluorinated alkane as based on the total weight of the composition.
  • 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 also optionally 2-perfluorobutyl- pentane, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w/w) of 1-perfluorobutyl-pentane (F4H5), and up to about 0.2%, 0.3%, 0.4%, 0.5% or up to about 1% (w/w) of 2-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition.
  • F4H5 1-perfluorobutyl-pentane
  • 2-perfluorobutyl-pentane based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, 99% or at least 99.5% (w/w) of 1-perfluorohexyl-octane (F6H8), and optionally 2-perfluorohexyl-octane, based on the total weight of the pharmaceutical composition.
  • F6H8 1-perfluorohexyl-octane
  • 2-perfluorohexyl-octane based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w/w) of 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) of 2- perfluorohexyl-octane, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the present disclosure is a solution.
  • the term a “clear” solution refers to a liquid solution in which all solutes are fully dissolvable or dissolved under room temperature conditions i.e. between 15 and 25 °C.
  • the clear solution does not comprise of any particulate or solid phase components and preferably has a refractive index approximate to that of water (i.e.1.333) at room temperature.
  • the composition according to the present disclosure is in the form of a solution, or alternatively a suspension.
  • solution or “clear solution” as such, as understood herein, refers to a liquid solution in which all solutes are fully dissolvable or dissolved under room temperature conditions i.e. between 15 and 25 °C.
  • the resulting solution does not comprise of any particulate or solid phase components.
  • the pharmaceutical composition according to the present disclosure comprises (S)- hyoscyamine dissolved in a vehicle comprising one or more of any one or combination of semifluorinated alkane as defined herein, and optionally one or more excipients as defined herein, and is in the form of a clear solution.
  • the pharmaceutical composition according to the present disclosure comprises an enantiomer of a compound e.g. selected from the Table 1, dissolved in a vehicle comprising one or more of any one or combination of semifluorinated alkane as defined herein, and optionally one or more excipients as defined herein, wherein the composition is in the form of a clear solution.
  • a ‘suspension’ on the other hand may be defined as a type of a dispersion, a dispersion being a system having at least one continuous (or coherent) phase and at least one discontinuous (or inner) phase which is dispersed in the continuous phase.
  • the dispersed phase is in the solid state.
  • a particle i.e. in a solid state
  • comprising, or consisting of an isomerizable pharmaceutically active compound or a pharmaceutically acceptable salt thereof e.g. as provided for in Table 1 may be suspended in the liquid vehicle of the composition.
  • the suspensions useful for practising the present invention are preferably liquid suspensions, wherein the continuous phase is a liquid, and are formulated so as to be suitable administration as a medicament.
  • the pharmaceutical composition according to the present disclosure consists of an enantiomer of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, wherein the enantiomer is present in the composition in an enantiomeric excess of at least 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99%, and wherein the enantiomer is suspended in one or more of any one or combination of semifluorinated alkane as defined herein.
  • the pharmaceutical composition according to the present disclosure consist of (a mixture of two) enantiomers of a compound or a pharmaceutically acceptable salt thereof selected from any row of Table 1, wherein the ratio of the first enantiomer (featured in column A) relative to the second enantiomer (featured in column B) is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, wherein the (mixture of two) enantiomers are suspended in one or more of any one or combination of semifluorinated alkane as defined herein.
  • compositions according to the present disclosure may comprise of a vehicle comprising, in addition to the at least one semifluorinated alkane, one or more excipients.
  • vehicle of the composition consists of at least one semifluorinated alkane and one or more excipients.
  • excipients refers to any pharmaceutically acceptable, natural, synthetic or semi-synthetic substance, compound or component that may be included in the vehicle and thus the composition as described herein, for example to enhance or otherwise modify the physical or chemical constitution or stability of the composition.
  • Pharmaceutically acceptable means that the excipient is safe, non-toxic, biocompatible and physiologically tolerated e.g.
  • the excipient is suitable and safe for topical administration to a human eye or its associated ophthalmic tissues.
  • excipients which may be featured in the compositions according to the present disclosure include, but are not limited to, co-solvents, antioxidants, a preservative, lipids, oily excipients, surfactants, lubricant or combinations thereof.
  • the excipient is a liquid which is miscible with a semifluorinated alkane, and in case of more than one excipient being featured in the vehicle, also miscible with any of the other excipients featured in the vehicle of the composition.
  • the excipient in one embodiment may function as a co- solvent, i.e.
  • the co-solvent is preferably a liquid that is fully miscible with the semifluorinated alkane, i.e. it mixes with the semifluorinated alkane to form a coherent and single phase.
  • the excipient may be dissolved in the semifluorinated alkane.
  • the excipient is a co-solvent.
  • the co-solvent may be an alcohol, such as an alkyl alcohol.
  • the alcohol is selected from ethanol, 1-propanol, isopropanol, and phenylethyl alcohol; or more preferably from ethanol and phenylethyl alcohol.
  • the vehicle of the composition may comprise, or consists in addition to a semifluorinated alkane (or mixture of semifluorinated alkanes) as defined herein, at least one excipient, with the proviso that the excipient is not an alcohol, and/or is not medium chain triglycerides (MCT) and/or is not light liquid paraffin.
  • the excipient featured in the vehicle is an oily excipient. Examples of oily excipients are triglycerides, mineral oil, and liquid paraffin.
  • the vehicle in addition to a semifluorinated alkane the vehicle comprises an oily excipient is selected from medium chain triglycerides (MCT) and light liquid paraffin.
  • MCT medium chain triglycerides
  • the vehicle of the composition comprises, or consists of at least one semifluorinated alkane and a combination of any one of a co-solvent or oily excipient as described herein above.
  • the one or more excipients is present in the composition, optionally independently, in an amount of up to 0.1 wt %, 0.5 wt%, 0.75 wt%, 1.0 wt%, 1.25 wt%, 1.4 wt%, 1.5 wt%, 1.8 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt% or up to 5.0 wt% (w/w), or preferably up to 1 wt% or up to 1.4 wt%, based on the total weight of the composition.
  • the composition comprises one or more excipients, optionally independently, in an amount of between 0.1 to 5.0 wt%, or between 0.1 to 2.0 wt% or between 0.01 to 1.4 wt%, based on the total weight of the composition.
  • the one or more excipients is present in the composition, optionally independently, 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.
  • the composition comprises one or more excipients, optionally independently, in an amount of between 0.1 to 5.0 % (v/v), or between 0.1 to 2.0 % (v/v) or between 0.01 to 1.4 % (v/v), based on the total volume of the composition.
  • the pharmaceutically active compound is hyoscyamine
  • the composition is essentially free of a) water; or b) a preservative; or c) one or more hyoscyamine degradation products selected from tropic acid, tropine and apoatropine; or d) any combination of a), b), and c).
  • the composition is essentially free of a) water; or b) a preservative.
  • a parameter such as in relation to the concentration or amount of (S)-hyoscyamine or an isomerizable active compound, e.g. any one of the enantiomer compounds as disclosed herein, e.g. as selected from Table 1, or presently in relation to the amount of the one or more excipient in the composition, refers to any value of the parameter greater than zero and up to, and inclusive of, the defined parameter, taking into account any degree of variability usually observed in measuring or determining this parameter, using the standard techniques and equipment known in the relevant field.
  • % (w/v) refers to the amount of a component of a composition as a weight percentage in relation to the total volume of the composition (with “w” denoting weight and “v” denoting volume). For example, a 0.1 % (w/v) would correspond to 1.0 mg of a component in 1 mL of the composition.
  • % (w/w) or alternatively, “wt %” as used herein and unless otherwise indicated refers to the amount of a component of a composition as a weight percentage in relation to the total weight of the composition with ‘w’ denoting weight.
  • compositions described herein are, in one embodiment, essentially free of water. In another embodiment, the composition described herein may be essentially free of a preservative, such as an anti-microbial preservative.
  • a pharmaceutically acceptable salt is a pharmaceutically acceptable salt is a salt of a compound such as provided herein, which retains its biological properties, and which is non-toxic and is compatible for pharmaceutical use. Salts, for example, may result from an addition of an acid, such as an organic acid or a mineral acid, such as sulfuric acid, or hydrochloric acid.
  • compositions of the present disclosure are compositions containing higher enantiomeric ratio, or predominantly one enantiomer of an active pharmaceutically active compound, such as a compound as defined in herein above. These are formulated in a semifluorinated alkane and may remain stable also under long term storage conditions, with minimal or reduced degradation or loss of the enantiopurity or stereochemical purity of the compound in the composition.
  • Pharmaceutically active compounds may be provided as racemate form where only one of the compounds may have the desirable pharmacological or therapeutic effect, as maintaining stereochemical purity of e.g. the desired enantiomer may be difficult due to stability issues and/or propensity of the compound under storage conditions towards gradual racemization.
  • a loss or diminished accuracy in dosing is not desirable.
  • the absence, or else a much lower amount of a non- therapeutically relevant enantiomer in a medicament may be advantageous in that this reduces or avoids unnecessary exposure of a subject to this compound which despite its non- therapeutic effect (or not yet known adverse effect), a subject’s physiology could still be (adversely) reactive to.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (S)-hyoscyamine (or a pharmaceutically acceptable salt thereof), wherein the (S)- hyoscyamine is dissolved or suspended in a vehicle comprising a semifluorinated alkane and optionally one or more excipients such as defined above.
  • Atropine (CAS 51-55-8), also known as ( ⁇ )-hyoscyamine, or benzeneacetic acid, alpha- (hydroxymethyl)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo( ⁇ ), is a racemate (enantiomeric ratio 50:50) of the two isomers (S)-hyoscyamine and (R)-hyoscyamine.
  • Atropine is a tropane alkaloid compound which is used as an antimuscarinic agent and anticholinergic agent.
  • (S)-hyoscyamine also referred to as (-)-hyoscyamine, or (L)- hyoscyamine
  • (S)-hyoscyamine is however attributed as the active enantiomeric species of atropine which gives rise to the physiological effects of atropine.
  • the chemical structure of (S)-hyoscyamine is Aqueous formulations of the racemate atropine are based on the atropine sulfate salt (CAS 5908-99-6). As noted above, aqueous formulations of atropine are commercially available at a concentrations of 1.0 % and 0.5% (w/v).
  • Formulations have been developed to counteract or slow down degradation of atropine including adjustment of the aqueous formulations to a lower pH, however this does not match physiological pH of the eye or tears and so are less compatible or irritable to the eye.
  • patient compliance is key for a successful treatment. It has been found that a composition containing higher enantiomeric ratio, or predominantly of the active enantiomer (S)-hyoscyamine may be formulated in a semifluorinated alkane and remain stable also under long term storage conditions.
  • the stability observed is in respect of minimal to no degradation of the hyoscyamine compound, such as often observed in aqueous formulations of this compound or its sulfate salt, and unexpectedly, also in respect to racemization or reduction in enantiomeric ratio in respect to the formation of the (R)- hyoscyamine enantiomer over time, providing for an improved shelf-stable composition.
  • shelf -stable low concentration compositions of (S)-hyoscyamine may also be formulated in the semifluorinated alkanes according to the present disclosure, also avoiding the disadvantage of presence or at least equivalent amounts of the (R)-hyoscyamine enantiomer which may be considered as an impurity.
  • the composition according to the disclosure comprises an enantiomeric mixture of (S)-hyoscyamine and (R)-hyoscyamine, wherein the enantiomeric ratio of (S)- hyoscyamine to (R)-hyoscyamine is not 50:50.
  • the composition does not comprise atropine, or a racemic mixture of the two enantiomers, but rather a majority or predominance of the (S)-hyoscyamine enantiomer.
  • 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 compound in the composition.
  • the composition comprises (S)-hyoscyamine in at least about 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98% or 99% enantiomeric excess.
  • the enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer (i.e. (S)- hyoscyamine (1a in Table 1 above)) in greater amounts than the other (i.e. (R)-hyoscyamine (1b in Table 1 above)).
  • a racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%.
  • a sample with 70% of (S)-hyoscyamine and 30% of (R)- hyoscyamine has an ee of 40% (70% ⁇ 30%).
  • 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.
  • Enantiomeric ratio is the ratio of the percentage of one enantiomer to that of the other, and may alternatively also be expressed numerically. For example, for a racemate the enantiomeric ratio is 1 (50:50), or for an enantiomeric ratio of 90:10, this may be expressed as 9.
  • 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.
  • hyoscyamine or in general, stereochemical purity of a compound, or specifically an enantiomer as described herein in Table 1, and the quantification of the amount, relative or otherwise, of the active compound, their isomers or degradation products featured in a composition according to the present disclosure may be determined via a number of methods in the art, for example, but not limited to chromatography methods such as HPLC, capillary electrophoresis, LC-MS or gas chromatography, and/or spectroscopic methods such as circular dichroism or NMR.
  • the enantiomeric ratio is determined by HPLC, preferably from quantification of the peak areas of the respective compounds.
  • the pharmaceutical composition comprising (S)-hyoscyamine may also comprise only low amounts of, or may be essentially free of any degradation products of hyoscyamine, e.g. as derived from hydrolysis of the ester or dehydration of the hydroxyl substituent of the compound.
  • the composition may be essentially free of any one or a combination of tropic acid (also known as 3-hydroxy-2-phenylpropanoic acid), atropic acid, tropine, apoatropine (i.e. the dehydration product of hyoscyamine) or any salts thereof.
  • the pharmaceutical composition comprises no more than 0.05, 0.1, 0.5, 1, 2, 3, 4 or 5 % (w/w), based on the total weight of the composition of each or any combination of a compound resulting from the degradation of hyoscyamine; preferably wherein the compound is selected from the group consisting of tropic acid, tropine, atropic acid, apoatropine or a salt thereof.
  • the pharmaceutical composition comprises no more than 0.05, 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6 or 7 % of each or any combination of a compound resulting from the degradation of hyoscyamine; preferably wherein the compound is selected from the group consisting of tropic acid, atropic acid, apoatropine or a salt thereof; with the percentages derived from quantification of the peak area of the compounds in the respective analytical chromatography method (e.g. HPLC).
  • the compositions of the present disclosure may comprise of no more than about 0.0001 to 0.001 %(w/v), or 0.004 to 0.006% (w/v) % (R)-hyoscyamine.
  • the composition may also be substantially free of (R)-hyoscyamine.
  • the composition according to the present disclosure comprises (S)- hyoscyamine, wherein the (S)-hyoscyamine is present in the composition at a concentration of between 0.001% and 1.0% (w/v), between 0.001% and 0.5 % (w/v), between 0.001% and 0.015%, between 0.002% and 0.012%, between 0.004% and 0.012%, between 0.005% and 0.01%, between 0.01% and 0.1% (w/v), between 0.02% and 0.07 % (w/v), between 0.002% and 0.006 % (w/v), between 0.004 and 0.006% (w/v), between 0.0045 and 0.0055% (w/v).
  • (S)-hyoscyamine is 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). In some embodiments, (S)-hyoscyamine is 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).
  • the composition according to the present disclosure wherein the composition comprises or consists of: a) 0.004 to 0.006 % (w/v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% 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; b) 0.004 to 0.006 % (w/v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-
  • hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; f) 0.01% (w/v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt % ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric ratio of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric ratio of (S)-hyoscyamine and (R)-
  • hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine, wherein the enantiomeric ratio of (S)-hyoscyamine to (R)-hyoscyamine is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; h) 0.02% (w/v) hyoscyamine, 1-perfluorobutyl-pentane, and optionally up to 1 wt % ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric ratio of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric ratio of (S)-hyoscyamine and (R)-
  • compositions a), b) c), d), e), f), g) and h) are clear solutions, i.e. the hyoscyamine is dissolved in a vehicle which comprises or consists of 1-perfluorobutyl-pentane and optionally up to 1 wt % ethanol.
  • the semifluorinated alkane featured in these compositions may be a mixture according to the present disclosure of 1-perfluorobutyl- pentane and a structural isomer thereof, such as 2-perfluorobutyl-pentane.
  • the composition according to the present disclosure wherein the composition comprises or consists of: j) 0.004 to 0.006 % (w/v) hyoscyamine, 1-perfluorohexyloctane and optionally up to 1 wt% 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; k) 0.004 to 0.006 % (w/v) hyoscyamine, 1-perfluorohexyloctane, and optionally up to 1 wt% ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscy
  • 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; o) 0.01% (w/v) hyoscyamine, 1-perfluorohexyl-octane, and optionally up to 1 wt % ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric
  • 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; q) 0.02% (w/v) hyoscyamine, 1-perfluorohexyloctane, and optionally up to 1 wt % ethanol, wherein the hyoscyamine is an enantiomeric mixture of (S)-hyoscyamine and (R)- hyoscyamine wherein the enantiomeric ratio of (S)-
  • compositions j), k), l), m), n), o), p) and q) are clear solutions, i.e. the hyoscyamine is dissolved in a vehicle which comprises or consists of 1-perfluorohexyloctane and optionally up to 1 wt % ethanol.
  • the semifluorinated alkane featured in these compositions may be a mixture, according to the present disclosure, of 1-perfluorohexyl- octane and a structural isomer thereof, such as 2-perfluorohexyl-octane.
  • the liquid pharmaceutical composition according to the present disclosure comprises the enantiomer (or the mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from an enantiomer as described herein in Table 1, wherein the concentration of the compound in the liquid pharmaceutical composition is 0.01 to 5% (w/v), 0.05 to 5% (w/v), 0.05 to 2% (w/v), 0.1 to 2% (w/v), 0.1 to 1% (w/v), or wherein the concentration of the compound in the liquid pharmaceutical composition is 0.5 to 1.0% (w/v).
  • the liquid pharmaceutical composition comprises the enantiomer (or the mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from an enantiomer or enantiomer pair as described herein in Table 1, wherein the concentration of the compound in the liquid pharmaceutical composition is at least 0.01% (w/v), 0.05% (w/v), 0.1% (w/v), 0.5% (w/v), 1% (w/v), 2% (w/v) or at least 5% (w/v).
  • the liquid pharmaceutical composition comprises the enantiomer (or the mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof, preferably selected from an enantiomer or enantiomer pair as described herein in Table 1, wherein the concentration of the compound in the liquid pharmaceutical composition is below 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 below 0.01% (w/v).
  • the concentration or amount of (S)-hyoscyamine in a composition according to the present disclosure, after storage at 0 to 60°C, e.g. storage at 25°C for at least 1, 2, 3, 4, 5, 6, 9 or at least 12 months is in the range of 90 to 110%, or 95 to 105 % of the initial concentration of (S)-hyoscyamine in the composition e.g. as determined by HPLC.
  • 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 not less than 90% (e.g.91, 92 ,93 ,94, 95 ,96, 97, 98, 99%); or is not higher than 100% (e.g. not higher than 101, 102, 103, 104, 105, 106, 107, 108, or 109%), e.g. as determined by HPLC, preferably by quantification of the peak areas of the respective compounds. Where the percentage determined is greater than 100%, it is to be understood that the measurement does not relate to an increase in amount of (S)-hyoscyamine, but e.g.
  • 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 has not decreased by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%.
  • a decrease of about 1% would amount in a decrease of the enantiomeric ratio to 8.91%, or about 89.91 : 10.09.
  • the amount of a compound in a composition according to the present disclosure i.e.
  • an enantiomer as described in Table 1 or any of the lists as provided in the current disclosure after storage at 0 to 60°C, e.g. storage at 25 °C for at least 1, 2, 3, 4, 5, 6, 9, or 12 months is at least 90%, or at least 95% or at least 99% relative to the initial amount of the enantiomer as determined for the composition, e.g. by HPLC.
  • the concentration of enantiomer after storage of the composition at 25°C for at least 3 months is in the range of about 90-110%; or is not less than 90% (e.g.91, 92 ,93 ,94, 95 ,96, 97, 98, 99%); or is not higher than 100% (e.g. not higher than 101, 102, 103, 104, 105, 106, 107, 108, or 109%), e.g.
  • the enantiomeric ratio of first enantiomer to the second enantiomer (ref.
  • 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 has not decreased by more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%.
  • a composition comprising a first enantiomer dissolved in a semifluorinated alkane and optional excipient(s), wherein the initial enantiomeric ratio to the second enantiomer is 90:10, i.e.9, prior to storage or aging, a decrease of about 1% would amount in a decrease of the enantiomeric ratio to 8.91%, or about 89.91 : 10.09.
  • the disclosure relates to a method for the preparation of a liquid pharmaceutical composition as defined according to any one of the embodiments described herein; said method comprising a step of dissolving or suspending an enantiomeric compound or enantiomers (or mixture of two enantiomers) as described herein above, e.g. in Table 1 in semifluorinated alkane or a non-aqueous vehicle comprising, or consisting of a semifluorinated alkane, and optionally one or more excipients, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, or their structural isomers and any combination thereof.
  • the disclosure relates to a method for the preparation of a composition as defined according to any one of the embodiments described herein; said method comprising a step of dissolving (S)-hyoscyamine in a non-aqueous vehicle comprising, or consisting of a semifluorinated alkane, and optionally one or more excipients, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, or their structural isomers and any combination thereof.
  • the disclosure relates to a method for stabilizing an isomerizable pharmaceutical compound or a pharmaceutically acceptable salt thereof in a composition, or for preventing the isomerization of an isomerizable pharmaceutical compound or a pharmaceutically acceptable salt thereof in a composition, wherein the method comprises a step of dissolving or suspending the compound in a semifluorinated alkane, or a vehicle consisting of a semifluorinated alkane and one or more excipients.
  • the isomerizable pharmaceutical may be a compound as defined herein above.
  • 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).
  • the isomerizable pharmaceutical compound comprises at least one chiral stereocenter.
  • the chiral stereocenter may be susceptible to racemization, inversion or epimerization; preferably the chiral stereocenter may be susceptible to racemization, inversion or epimerization under basic or acidic conditions.
  • the amount of the other isomer e.g.
  • 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, wherein the method comprises a step of dissolving or suspending the enantiomer in a semifluorinated alkane, or in a vehicle comprising a semifluorinated alkane and one or more excipients.
  • the purity of the enantiomer in the composition is at least 90% or at least 95% or at least 97% (e.g. by HPLC) when it is formulated in the semifluorinated alkane or the vehicle.
  • a method of 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 wherein the method comprises a step of dissolving or suspending the enantiomer (provided at defined optical purity) in a semifluorinated alkane, or in a vehicle comprising a semifluorinated alkane and one or more excipients.
  • 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 it is formulated in the semifluorinated alkane, or the vehicle comprising (or consisting) the semifluorinated alkane and one or more excipients as defined herein.
  • HPLC semifluorinated alkane
  • the method thus provides for a way of maintaining, or preventing significant changes with respect to the enantiopurity of the compound.
  • a method of stabilizing, preventing, or loss of enantiomeric ratio with respect to enantiomers (an enantiomer pair or mixture of two enantiomers) of a pharmaceutically active compound or a pharmaceutically acceptable salt thereof in a liquid composition wherein the method comprises a step of dissolving or suspending the enantiomers (or mixture of two enantiomers) in a semifluorinated alkane, or in a vehicle comprising a semifluorinated alkane and one or more excipients, as described in the present disclosure.
  • the ratio of the first enantiomer relative to the second enantiomer is at least 89:11, 90:10, 91:8, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2 or at least 99:1, e.g. when it is dissolved or suspended in the semifluorinated alkane.
  • the first enantiomer is selected from the compounds 1a to 49a, and the corresponding second enantiomer is selected from compounds 1b to 49b of Table 1. Said methods may provide for the prevention of, or reduction in the rate of degradation (e.g.
  • the enantiomer, or the first enantiomer comprises a chiral stereocenter on a carbon atom, wherein at least one of the substituents of the chiral stereocenter is i) a hydrogen moiety prone to deprotonation under basic conditions and/or ii) is an alcohol moiety prone to dehydration under acidic conditions; and/or is susceptible to racemization, isomerization or epimerization.
  • the enantiomer or first enantiomer is selected from the list consisting of (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)-fex
  • compositions of such methods may be in accordance with any one or combination of the compositions as described herein e.g in respect to the semifluorinated alkane, excipients, etc.
  • the storage of the composition for a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months at 0 to 60 °C (e.g. at 25 °C), wherein over said period, i) the concentration of the enantiomer(s) in the composition remains essentially the same, or has not changed or decreased 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.
  • the enantiomeric excess of the enantiomer is essentially the same, or has not changed or decreased by more than 10%, more than 5%, more than 4% , more than 3%, more than 2%, more than 1% or more than 0.5% with respect to the initially determined value prior to storage; and/or iii) the enantiomeric ratio of the first enantiomer with respect to the second enantiomer is the same, or within 10% or 5% or 4%, or 3% or 1% of the enantiomeric ratio prior to storage.
  • the disclosure relates to a method for stabilizing and/or preventing isomerization of (S)-hyoscyamine in a composition, the method comprising a step of dissolving (S)-hyoscyamine (of certain optical purity) in a semifluorinated alkane, or a non- aqueous vehicle comprising a semifluorinated alkane, and optionally one or more excipients; wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H4, F6H6, F6H8, F6H10, their structural isomers, and any combination thereof.
  • 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).
  • the enantiomeric purity or ratio of the (S)-hyoscyamine may be as defined above.
  • the method provides for the prevention of, or reduction in the rate of degradation (e.g. hydrolysis and/or dehydration) and/or isomerization (e.g. racemization) of the (S)- hyoscyamine in the composition.
  • the method may be effective in any one or combination of: preventing or reducing the degradation of (S)-hyoscyamine, e.g. such as resulting in the formation or increase in the presence of any one or combination of tropinic acid, tropine, apoatropine in the composition; or preventing or reducing the conversion of (S)-hyoscyamine to (R)-hyoscyamine in the composition, after a period of storage of the composition for at least 1, 2, 3, 4, 5, 6, 9 or 12 months at 0 to 60 °C, e.g.25 °C.
  • the amount of any one or more of a degradation product of hyoscyamine 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).
  • 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).
  • 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).
  • after storage at 0 to 60 °C e.g.
  • compositions according to the present disclosure are useful or are provided as a medicine, for use in the treatment or prevention of disease or medical conditions, preferably of a human subjects, or optionally, veterinary subjects; and in the manufacture of a medicament.
  • the composition is a topical ophthalmic composition, or in other words, a composition which may be topically applied or administered to the surface of a subject’s eye, or tissues associated with the eye, such as to the cornea or conjunctiva of the eye, or to the cul-de-sac of the conjunctiva.
  • said composition is in the form of a clear solution.
  • the pharmaceutical composition is formulated or adapted for intravitreal, subcutaneous, intramuscular injection, or for intravenous injection or infusion.
  • the composition is adapted for topical administration to a surface of a tissue or organ, e.g. the skin or a mucosal tissue, for example in relation to the eye.
  • the composition according to any one or combination of embodiments according to the present disclosure is used for the treatment, and/or prevention of an ophthalmic disease or condition, e.g. affecting one or both eyes of a subject.
  • the composition according to the embodiments in the present disclosure comprising (S)-hyoscyamine is used for treatment, prevention and /or for the control of myopia.
  • Myopia also known as short- or near-sightedness is a refractive condition or a refractive error of the eye, and is typically characterized by blurred vision, in particular of images of distant objects as a result of the image falling or focusing in front of the photoreceptors of the retina or retinal plane.
  • the composition of the present disclosure comprising (S)-hyoscyamine is for use in a method of preventing or reducing the onset of myopia, or for use in a method of reducing the progression of myopia in human subjects, for example, in paediatric and/or in juvenile subjects.
  • the composition is a topically applied ophthalmic composition, for use in a method of reducing the progression, or the rate of progression (e.g. slowing down) of myopia.
  • the reduction in progression of myopia may be determined for example by a decrease in the rate of change of one or more parameters typically used in the art for measuring myopic refractive error of an eye.
  • the composition according to the embodiments in the present disclosure comprising (S)-hyoscyamine is used for the treatment of amblyopia, or for preventing the progression of amblyopia.
  • Amblyopia sometimes known as ‘lazy eye’ is a condition typically presenting in infants and children, may result in disruption of the visual axis and loss of monocular vision.
  • Associated conditions or symptoms of amblyopia include refractive errors e.g.
  • the treatment or the prevention of the progression of amblyopia as such, according to the present disclosure may include penalization of a healthy, non-amblyopic, or else better- seeing eye.
  • the compositions according to the present disclosure may be used for treating amblyopia in addition to other treatment methods such as refractive correction or occlusion.
  • the compositions may be used for cycloplegic refraction, for temporary paralysis of the ciliary muscle, or for pupil dilation, which may also be referred to as mydriasis.
  • the composition may be used (e.g. as an antidote) for treating a subject, preferably a human subject, who has been exposed to a poison such as an organophosphate compound (e.g. an insecticide, or nerve agent).
  • a poison such as an organophosphate compound (e.g. an insecticide, or nerve agent).
  • kits comprising a composition according to any one or combination of embodiments described herein, a container adapted for holding the composition and optionally a means for dispensing the composition and/or instructions for use, wherein the instructions for use comprise any one of the uses or methods of treatment as described herein.
  • Hyoscyamine solutions were prepared in F4H5 (1-perfluorobutylpentane) or in 1% (v/v) 2- propanol in 1-perfluorobutylpentane.
  • the (S)-hyoscyamine, or atropine racemic mixture of (S)-hyoscyamine and (R)- hyoscyamine; CAS 5908-99; EDQM, Y0000878) was weighed into 1.5 mL vials.
  • the (S)-hyoscyamine used (CAS 101-31-5; Abcam Pharmatech, Changzhou, China) comprised of 90.8% (S)-hyoscyamine and 9.2% (R)-hyoscyamine, i.e. an enantiomeric excess (ee) of 81.6% of (S)-hyoscyamine, or an enantiomeric ratio of (S)-hyoscyamine to (R)- hyoscyamine of about 9.87.
  • 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) over a period of 6 months. It was shown that the ratio of the two enantiomers (i.e. (R)- to (S)-hyoscyamine enantiomeric ratio) as measured by HPLC on the basis of peak area was effectively stable over this period, with no isomerization and change in the enantiomeric ratio.
  • R room temperature
  • F6H8, or F4H5 or a vehicle comprising a semifluorinated alkane (e.g. F6H8, or F4H5) and optionally one or more excipients as described herein are prepared according to the general method as follows: Weighing an amount of the compound into a container e.g. a vial, and adding a semifluorinated alkane, or a semifluorinated alkane in mixture with one or more excipients, to the container to obtain a desired concentration of the compound in the composition and then processing, for example by stirring so as to provide the solution, or the suspension. The enantiomeric excess or ratio of the enantiomer(s) of the compound in the composition is determined, e.g.
  • composition is then subjected to aging conditions over a period of time (for example, 2 weeks, or 1 month, or up to 6 months) to determine the stability of the compound in the composition, and for racemization, or loss of stereochemical purity; optionally during, or at the end of this period of time.
  • the stability and percentage of the enantiomer(s) in the composition is measured by sampling the composition and performing e.g. chiral HPLC on the basis of peak area or using the same analytical method utilized to determine compound purity in the composition at the start of the study.
  • the initial enantiomeric purity (such as enantiomeric excess, enantiomeric ratio) of the compound is essentially maintained in the formulations in the semifluorinated alkane or vehicle with minimal formation of degradation products, racemization, or change in enantiomeric purity of the enantiomer, demonstrating that the semifluorinated alkane may provide a stable vehicle or formulation for liquid compositions of the enantiomeric compound.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant de l'hyoscyamine ou un sel pharmaceutiquement acceptable de celle-ci dissous ou en suspension dans un véhicule comprenant un alcane semi-fluoré.
PCT/EP2023/087677 2022-12-23 2023-12-22 Compositions d'alcane semi-fluoré comprenant de l'hyoscyamine WO2024133913A2 (fr)

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EP22216345.3 2022-12-23
EP22216345 2022-12-23

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WO2024133913A2 true WO2024133913A2 (fr) 2024-06-27

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