Hemifluorinated alkane compositions comprising rilmenidene

Abstract

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

Description

[0001] describe Background Technology

[0002] The stability of active pharmaceutical compounds during storage under various conditions is generally a concern during the development of compound formulations. This aspect is particularly relevant for liquid formulations of pharmaceutically active compounds that are isomerizable, as isomerization processes lead to structural changes in the compound, which can significantly affect the compound's properties, including its pharmacological and pharmacokinetic characteristics.

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

[0004] Therefore, for pharmaceutical formulations containing only one or primarily one isomer (such as a single enantiomer of the active compound), it is important not only to maintain the integrity of the compound and avoid or minimize its degradation during storage, but also to ensure that the stereochemical purity of the compound in the composition is not lost or altered.

[0005] Rifelast is an active compound used to treat dry eye disease (keratoconjunctivitis sicca) and is an optically active compound with a chiral stereocenter. It has the following chemical structure: The formulation of rifetast in the commercially available product Xiidra® is an isotropic and buffered aqueous solution and contains sodium thiosulfate as an antioxidant.

[0006] The discovery of rifemilast's oxidative instability was a challenge in the clinical development of the investigational new drug (Xiidra®), an aqueous ophthalmic composition containing rifemilast, and required a formulation modification mid-clinical initiation by adding sodium thiosulfate as an antioxidant. US11058677 also discloses the need to add thiosulfate to overcome the instability of rifemilast due to oxidation.

[0007] In addition, Kumar also studied the stability of rifaspirant under various hydrolysis conditions (acidic, alkaline, neutral / water, oxidative, photolytic, and thermal) (Anal. Chem. Lett. 12 (6) 2022, 730-744), which revealed that rifaspirant is highly sensitive to alkaline degradation, sensitive to acidic degradation, and also degrades under oxidative conditions.

[0008] Stereocenters can have the potential to racemic, for example, under acidic or alkaline conditions, and especially in aqueous environments.

[0009] Therefore, the object of this disclosure is to provide a composition comprising rifamil that, among other advantages, is stable during long-term storage with respect to potential loss of stereochemical purity and overall stability with respect to loss or degradation of the compound, but is also a composition suitable for direct application and therapeutic use (such as for topical ophthalmic administration to the eye). For example, an object may be to provide a rifamil composition that can have improved acceptability in terms of administration to a prescribed treatment procedure and patient adherence to it.

[0010] Other objects of the invention will become clear from the following description of the invention, its embodiments, and the claims. Summary of the Invention

[0011] In one aspect, the present invention provides a pharmaceutical composition comprising rifelast or a pharmaceutically acceptable salt thereof, wherein the rifelast is dissolved or suspended in a medium comprising a semi-fluorinated alkane and optionally one or more excipients; wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, structural isomers of these semi-fluorinated alkanes, and any combination thereof.

[0012] This disclosure also relates to a method for stabilizing rifaspirate in a composition, the method comprising the step of suspending rifaspirate in a liquid semi-fluorinated alkane.

[0013] In another aspect, this disclosure also provides for the use of these pharmaceutical compositions, such as as a medicine, and for use in the treatment of dry eye diseases. Detailed Implementation

[0014] In a first aspect, this disclosure relates to pharmaceutical compositions comprising rifetazone or a pharmaceutically acceptable salt thereof, wherein the rifetazone is dissolved or suspended in a medium comprising a semi-fluorinated alkane and optionally one or more excipients.

[0015] In one embodiment, the semifluorinated alkane is F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, structural isomers of these semifluorinated alkane, or any combination or mixture of these compounds.

[0016] Semi-fluorinated alkanes are straight-chain or branched alkanes in which some hydrogen atoms are replaced by fluorine atoms. In one embodiment, a semi-fluorinated alkane (which may be abbreviated as SFA) described and used according to this disclosure consists of a straight-chain non-fluorinated hydrocarbon segment and a straight-chain perfluorinated hydrocarbon segment, wherein the perfluorinated hydrocarbon segment is attached to the non-fluorinated hydrocarbon segment. In a preferred embodiment, the semi-fluorinated alkane used in the context of this disclosure is preferably a liquid semi-fluorinated alkane.

[0017] In one embodiment, the semi-fluorinated alkane has the chemical formula F(CF2). n (CH2) m H, where n and m are integers defining the number of carbon atoms in the perfluorinated hydrocarbon segment and the nonfluorinated hydrocarbon segment, respectively. In another embodiment, one or more semi-fluorinated alkanes included in the composition according to this disclosure are of the formula F(CF2). n (CH2) m H is a semi-fluorinated alkane, wherein n is an integer selected from 4 to 6, and m is an integer selected from 2 to 10. In another embodiment, the one or more semi-fluorinated alkanes are of the formula F(CF2). n (CH2) m H is a semi-fluorinated alkane, where n is an integer selected from 4 to 6, and m is an integer selected from 4 to 8.

[0018] This nomenclature, also commonly used for straight-chain semi-fluorinated alkanes, designates the perfluorinated segment as RF and the nonfluorinated segment as RH, i.e., RFRH. Alternatively, compounds can be named FnHm, where F indicates the perfluorinated segment, H indicates the nonfluorinated segment, and n and m define the number of carbon atoms in the respective segment. For example, F3H3 is used for perfluoropropylpropane, and F(CF2)3(CH2)3H. Furthermore, this type of nomenclature is generally used for compounds with straight-chain, i.e., unbranched segments. Therefore, unless otherwise indicated, F3H3 should be assumed to refer to 1-perfluoropropylpropane, not its structural isomers, such as branched isomers like 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

[0019] In one embodiment of this disclosure, the mediator may be composed of one or more semi-fluorinated 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 formulas of these semi-fluorinated alkanes may be represented as F(CF2)4(CH2)4H, F(CF2)4(CH2)5H, F(CF2)4(CH2)6H, F(CF2)4(CH2)8H, F(CF2)6(CH2)2H, F(CF2)6(CH2)4H, F(CF2)6(CH2)6H, F(CF2)6(CH2)8H, and F(CF2)6(CH2). 10 H. In another embodiment, the mediator comprises a semi-fluorinated alkane selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, or their structural isomers, or any mixture or combination of these semi-fluorinated alkanes. In yet another embodiment, the mediator consists of a semi-fluorinated alkane selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H10, their structural isomers, or any mixture thereof.

[0020] In yet another embodiment, the semi-fluorinated alkane is F4H5 (1-perfluorobutylpentane), F6H8 (1-perfluorohexyloctane), their structural isomers, or any mixture of these semi-fluorinated alkanes. 1-Perfluorobutylpentane, having the chemical formula F(CF2)4(CH2)5H, is an inert, water-insoluble liquid with a density of 1.284 g / cm³ at 25ºC. 3 It has a refractive index of 1.3204 at 20ºC. Alternative nomenclature for this compound includes F4H5, where F represents a straight-chain perfluorinated alkane segment containing 4 carbon atoms, and H represents a straight-chain and nonfluorinated alkane segment containing 5 carbon atoms. Preferably, 1-perfluorobutylpentane is substantially anhydrous.

[0021] Optionally, the formulation may contain more than one semi-fluorinated alkane. For example, combining semi-fluorinated alkanes may be useful to achieve specific target properties, such as a particular density or viscosity. If a mixture of semi-fluorinated alkanes is used, it is preferred that the mixture contains at least one of the following: F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10. In one embodiment, the medium contains at least two members selected from the following: F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10. In one embodiment, the medium comprises a combination or mixture of 1-perfluorobutylpentane and 2-perfluorobutylpentane, optionally wherein 2-perfluorobutylpentane is present in the medium 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) relative to the total weight of the mixture of semi-fluorinated alkanes. In yet another embodiment, the mediator of the composition according to this disclosure comprises a combination or mixture of 1-perfluorohexyl-octane and 2-perfluorohexyl-octane, optionally wherein 2-perfluorohexyl-octane is present in an amount of up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w), or up to 0.2% (w / w) relative to the total weight of the mixture of semi-fluorinated alkanes, or from 0.1% to 2% (w / w), or from 0.01% to 1% (w / w), or from 0.5% to 5% (w / w).

[0022] In another embodiment, the mediator of the composition according to this disclosure consists essentially only of one or more semi-fluorinated alkanes or combinations thereof as described herein. In other words, no additional excipients such as cosolvents (e.g., ethanol) are present. For example, in one embodiment, the mediator consists only of semi-fluorinated alkanes selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers, and any combination or mixture of these semi-fluorinated alkanes. Or in other words, the mediator consists essentially of 100% (w / w) of semi-fluorinated alkanes (as defined above) or mixtures of semi-fluorinated alkanes. In some embodiments, the pharmaceutical composition comprises rifelast or a pharmaceutically acceptable salt thereof dissolved or suspended in semi-fluorinated alkanes.

[0023] As used herein, the term "consists" and related terms "consisting" or "consist" should be understood to mean that no other features exist besides those that begin with the term. In the context of compositions of this disclosure, if any other ingredient or component is present in the composition besides those that begin with the term, it is present only in trace or residual amounts to such an extent that it does not provide any technical advantage or relevance to the purposes of this disclosure, and may be further understood, for example, by the terms "substantially" or " substantially" used in conjunction with these terms (e.g., "substantially constitutes"). In contrast, in the context of compositions, the term "comprising" or related terms "comprises" or "comprise" should be understood to mean that other features besides those that begin with the term may be present in the composition.

[0024] As used herein, unless the context clearly indicates or requires otherwise, the terms “a”, “an”, or “the” in relation to any component or part of a semifluorinated alkane or excipient or composition do not exclude a plurality of. Unless otherwise defined or clearly indicated by the context, the terms “a”, “an”, and “the” may be understood to correspond to “at least one” or “one or more”.

[0025] As understood herein, the mediator of the compositions according to this disclosure comprises one or more semi-fluorinated alkanes. However, the mediator may optionally further comprise one or more excipients, as further described below. In one embodiment, the mediator comprises more than one semi-fluorinated alkane. In another embodiment, the mediator consists of one or more semi-fluorinated alkanes and optionally one or more pharmaceutically acceptable excipients, preferably excipients miscible or soluble in the semi-fluorinated alkanes or mixtures thereof. In one embodiment, the amount of the semi-fluorinated alkanes or mixtures thereof in the composition is at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.8% (w / w) relative to the total weight of the composition.

[0026] In other embodiments according to this disclosure, the pharmaceutical composition comprises, based on the total weight of the composition, from about 95% to about 99% (w / w), more preferably from about 98% to about 99% (w / w), and even more preferably from about 98% to about 99.9% (w / w) of a semi-fluorinated alkane. In one embodiment, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, at least about 90%, 95%, 96%, 97%, 98%, 99%, or at least 99.5% (w / w) of 1-perfluorobutylpentane (F4H5), and optionally 2-perfluorobutylpentane. In another embodiment, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, at least about 90%, 95%, 96%, 97%, 98%, or at least 99% (w / w) of 1-perfluorobutylpentane (F4H5) and at most about 0.2%, 0.3%, 0.4%, 0.5%, or at most 1% (w / w) of 2-perfluorobutylpentane.

[0027] In another embodiment, 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. In another embodiment, 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 at most about 0.2%, 0.3%, 0.4%, 0.5% (w / w), or at most about 1% (w / w) of 2-perfluorohexyl-octane.

[0028] In one embodiment, the pharmaceutical composition of this disclosure is a solution. As understood herein, the term "clarified" solution refers to a liquid solution in which all solutes are completely soluble or have been completely soluble at room temperature (i.e., between 15ºC and 25ºC). A clarified solution does not consist of any particulate or solid phase components and preferably has a refractive index at room temperature close to that of water (i.e., 1.333).

[0029] In one embodiment, the pharmaceutical composition according to this disclosure comprises rifaspirate dissolved in a carrier comprising one or more semi-fluorinated alkanes as defined herein and optionally one or more excipients as defined herein, wherein the composition is in the form of a clear solution.

[0030] In another embodiment, the pharmaceutical composition according to this disclosure comprises solid particles of rifelilast suspended in a liquid medium, or solid particles containing or substantially consisting of rifelilast, said liquid medium comprising one or more semi-fluorinated alkanes as defined herein and optionally one or more excipients as defined herein. In other words, the pharmaceutical composition is in the form of a suspension. In related embodiments, the pharmaceutical composition according to this disclosure comprises rifelilast suspended in a liquid semi-fluorinated alkanes as disclosed herein. Preferably, the composition is suitable for topical ophthalmic application.

[0031] In one embodiment, the pharmaceutical composition according to this disclosure comprises rifelast or a pharmaceutically acceptable salt thereof suspended in a semi-fluorinated alkane or suspended in a carrier, said carrier comprising a semi-fluorinated alkane and optionally one or more excipients, wherein said semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0032] A "suspension" can be defined as a dispersion, that is, a dispersion of a system having at least one continuous phase (or coherent phase) and at least one discontinuous phase (or internal phase) dispersed within the continuous phase. In a suspension, the dispersed phase is solid. For example, and in the context of this disclosure, particles (i.e., solid) comprising, or substantially comprising, rifaspire or a pharmaceutically acceptable salt thereof, or composed of, or substantially composed of, rifaspire can be suspended in a liquid medium of the composition. The suspension used for carrying out the invention is preferably a liquid suspension, wherein the continuous phase is liquid, i.e., the medium is liquid, and furthermore, the suspension is formulated or adjusted to be suitable for administration as a pharmaceutical agent or as a topical ophthalmic agent.

[0033] As understood herein, the term “suspended” or “suspension” refers to a composition in which a solid phase (i.e., particles) is suspended or dispersed within a continuous phase. It is possible that a suspension may undergo phase separation, with particles floating or settling, upon standing or storage of the composition, but as understood herein, a suspension as defined in this disclosure may be redispersible.

[0034] In some embodiments, rifetazone particles suspended in a semi-fluorinated alkane or a medium comprising a semi-fluorinated alkane and optionally one or more excipients as described herein have an average diameter of less than 50 µm or less than 30 µm, as determined by laser diffraction. In other embodiments, the average diameter of rifetazone particles in a suspension formulation as described herein may be less than 20 µm, 30 μm, 15 μm, 10 μm, or less than 5 μm, as determined by laser diffraction. In other embodiments according to this disclosure, at least 90% of the rifetazone particles suspended in a semi-fluorinated alkane or a medium comprising a semi-fluorinated alkane and optionally one or more excipients have an average diameter between 1 and 15 µm, or between 1 and 20 µm, or between 1 and 30 µm, or between 1 and 50 µm, as determined by laser diffraction. Optionally, the particle size distribution basis on which the particle size of the suspension composition depends can be determined by laser diffraction, and may be volume. In such cases, "average diameter" can be understood as volume average diameter.

[0035] In an alternative embodiment, the pharmaceutical composition according to this disclosure comprises rifaspirate dissolved in a carrier comprising one or more semi-fluorinated alkanes as defined herein and optionally one or more excipients as defined herein, wherein the carrier comprises at least two (immiscible) liquid phases.

[0036] In relevant embodiments, the medium of the pharmaceutical composition comprises an aqueous phase or water. This liquid aqueous phase may be supplemented to another liquid phase (e.g., a liquid non-aqueous phase or a non-aqueous miscible phase, i.e., a semi-fluorinated alkane phase), which may comprise or consist of one or more semi-fluorinated alkanes as described herein and optionally one or more excipients (such as surfactants). The pharmaceutical composition in such embodiments is in the form of an emulsion.

[0037] As understood herein, an emulsion is a liquid system comprising a dispersed (or internal, emulsified, or discontinuous) liquid phase within a continuous (or external, or coherent) liquid phase. The two liquid phases are immiscible. In an o / w emulsion (also known as an oil-in-water emulsion), a water-immiscible organic liquid phase (which need not be any specifically defined "oil") (e.g., a liquid semi-fluorinated alkane phase, i.e., a liquid phase comprising one or more semi-fluorinated alkanes and optional excipients (such as surfactants) or substantially composed thereof) is dispersed in a water-miscible continuous phase, which may or may not be substantially composed of water itself.

[0038] In some embodiments, when the pharmaceutical composition is in emulsion form, the emulsion is an o / w emulsion, for example, wherein the dispersed phase comprises or is substantially composed of one or more semi-fluorinated alkanes and optionally one or more excipients, and the aqueous phase, which substantially comprises water (with optionally one or more excipients), is the continuous phase. Alternatively, the emulsion may be a w / o emulsion, i.e., a water-in-oil emulsion, for example, wherein the continuous phase comprises or is substantially composed of one or more semi-fluorinated alkanes and optionally one or more other excipients, and the aqueous phase (e.g., containing rifelast dissolved in said phase (and optionally one or more excipients)) is the dispersed phase of the emulsion.

[0039] In some implementations, rifaspire is dissolved in the aqueous phase of the medium.

[0040] In some embodiments of the pharmaceutical composition, such as when the composition is in emulsion form, the carrier comprises between 30 vol% and 70 vol%, or between 40 vol% and 60 vol% of a semi-fluorinated alkane or semi-fluorinated alkane phase. As understood herein, vol% refers to a percentage relative to the total volume of the carrier. Alternatively, the carrier may comprise between 30 wt% and 70 wt%, or between 40 wt% and 60 wt% of a semi-fluorinated alkane or semi-fluorinated alkane phase relative to the total weight of the carrier.

[0041] In some embodiments of the pharmaceutical compositions described herein, for example when the composition is in emulsion form, the carrier comprises an aqueous phase of 30 to 70 vol% or 40 to 60 vol% relative to the total volume of the carrier. Alternatively, the carrier may comprise an aqueous phase of 30 to 70 wt% or 40 to 60 wt% relative to the total weight of the carrier.

[0042] Pharmaceutical compositions in emulsion form and comprising an aqueous phase may contain rifaspire (e.g., dissolved in said phase) and / or one or more components selected from any one or a combination of the following: (i) Surfactants; (ii) Buffer salts; (iii) Preservatives.

[0043] One or more of the components can also be dissolved or solubilized in the aqueous phase. The surfactant is preferably a polyethoxylated dehydrated sorbitan fatty acid ester, such as polysorbate 20, polysorbate 60, and polysorbate 80 (i.e., Tween). 20 / 60 / 80).

[0044] The buffer salt may be selected from phosphates, citrates, borates, or Tris-HCl (Tris). In some preferred embodiments, the buffer salt is a phosphate (e.g., selected from disodium hydrogen phosphate pentahydrate, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate).

[0045] The preservative may be selected from benzalkonium chloride or other quaternary ammonium compounds, such as polyquad, sodium perborate, and preservative systems, such as oxychlorine complexes, like Purite®; or sofZia®. In a preferred embodiment, the preservative is benzalkonium chloride.

[0046] In some embodiments, the surfactant is included in the medium in an amount of 3 wt% to 5 wt% relative to the total weight of one or more semi-fluorinated alkanes in the medium. In some embodiments, the medium comprises (i) between 3 wt% and 5 wt% of polysorbate 80 (e.g., Tween® 80) or (ii) between 3 wt% and 4 wt% of polysorbate 20 (e.g., Tween® 20) relative to the total weight of one or more semi-fluorinated alkanes in the medium.

[0047] In some embodiments, the compositions according to this disclosure may consist of a carrier that, in addition to comprising at least one semi-fluorinated alkane, comprises one or more excipients. In one embodiment, the carrier of the composition consists of at least one semi-fluorinated alkane and one or more excipients. As used herein, the term "excipient" means any pharmaceutically acceptable, natural, synthetic, or semi-synthetic substance, compound, or component that may be included in the carrier and therefore in the compositions as described herein, for example, to enhance or otherwise modify the physical or chemical composition or stability of the composition. Pharmaceutically acceptable means that the excipient is safe, non-toxic, biocompatible, and physiologically tolerable, for example, for human pharmaceutical use; preferably, the excipient is suitable and safe for topical application to the human eye or its associated ocular tissue.

[0048] Examples of excipients that may be included in compositions according to this 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 miscible with semi-fluorinated alkanes, and in cases where more than one excipient is included in the medium, it may also be miscible with any other excipient included in the medium of the composition. In one embodiment, the excipient may be used as a cosolvent, i.e., a compound suitable for enhancing solubility or solubilizing active compounds (e.g., lifexat) and / or another excipient included in the composition. The cosolvent is preferably a liquid completely miscible with semi-fluorinated alkanes, i.e., it is mixed with semi-fluorinated alkanes to form a coherent phase and a single phase. In another embodiment, the excipient may be dissolved in semi-fluorinated alkanes.

[0049] In some embodiments, the excipient is a cosolvent. The cosolvent may be an alcohol, such as an alkyl alcohol. In one embodiment, the alcohol is selected from ethanol, 1-propanol, isopropanol, and phenethyl alcohol; or more preferably from ethanol and phenethyl alcohol. Alternatively, the medium of the composition may comprise at least one excipient, and a semi-fluorinated alkane as defined herein and optionally its structural isomers or a mixture of two different semi-fluorinated alkanes, or consist thereof, provided that the excipient is not an alcohol.

[0050] In embodiments of this disclosure, the composition is a suspension of rifaspirant, and one or more excipients are not cosolvents. In related embodiments, the excipients (if present in the composition) are not surfactants and / or antioxidants.

[0051] In some embodiments, the excipients included in the medium are oily excipients. Examples of oily excipients are triglycerides, mineral oils, and liquid paraffins. In one embodiment, in addition to semi-fluorinated alkanes, the medium also contains an oily excipient selected from medium-chain triglycerides (MCTs) and light liquid paraffins.

[0052] In some implementations, the excipients contained in the medium are aqueous components selected from water, aqueous buffers (i.e., phosphate buffers), and salt solutions (i.e., saline solutions).

[0053] In embodiments of this disclosure, the composition is an emulsion comprising rifelast and a semi-fluorinated alkane, and one or more excipients are selected from aqueous components (e.g., water, buffer solutions, salt solutions), surfactants, preservatives, and antioxidants. In said embodiments, the aqueous component may be present in an amount such that it forms the bulk or continuous phase of the emulsion, or vice versa, depending on the relative amount of the semi-fluorinated alkane; the aqueous component may form the dispersed phase of the emulsion or be contained within the dispersed phase of the emulsion.

[0054] In some embodiments, the medium of the composition comprises at least one semi-fluorinated alkane and any one or a combination thereof of the cosolvent or oily excipient as described above.

[0055] In some embodiments, the one or more excipients are optionally present independently in the composition in amounts 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. In other embodiments, the composition comprises one or more excipients, the amounts of which are optionally present independently based on the total weight of the composition in amounts between 0.1 wt% and 5.0 wt%, between 0.1 wt% and 2.0 wt%, or between 0.01 wt% and 1.4 wt%. In other embodiments, the one or more excipients are optionally present independently in the composition in amounts 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), 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 comprises one or more excipients, the amount of which is optionally independently between 0.1% and 5.0% (v / v), or between 0.1% and 2.0% (v / v), or between 0.01% and 1.4% (v / v) based on the total volume of the composition.

[0056] In some embodiments, the composition is substantially free of a) water; or b) preservatives; or c) antioxidants; d) surfactants and / or e) any one or a combination of a), b), c) and d). In related embodiments, the composition is substantially free of one or more rifaspire degradation products.

[0057] In some embodiments, the composition is substantially free of antioxidants, such as antioxidants (or combinations of antioxidants) used to prevent or reduce the oxidative degradation rate of rifaspirant. Preferably, the composition is free of antioxidants selected from: propyl gallate, octyl gallate and lauryl gallate, butylated hydroxyanisole (BHA), green tea extract, uric acid, cysteine, pyruvate, nordihydroguaiac acid, ascorbic acid, ascorbate salts (such as ascorbate palmitate and sodium ascorbate, ascorbate glucosamine), vitamin E (i.e., tocopherol, such as α-tocopherol), vitamin E derivatives (e.g., tocopherol acetate), retinoids (such as retinoic acid, retinol, trans-retinol, cis-retinol, trans-retinol). The compositions of this disclosure are: mixtures of cis-retinol, 3-dehydroretinol and vitamin A derivatives (e.g., retinyl acetate, retinaldehyde and retinyl palmitate), sodium citrate, sodium sulfite, lycopene, anthocyanins, bioflavonoids (e.g., hesperidin, naringin, rutin and quercetin), superoxide dismutase, glutathione peroxidase, butylated hydroxytoluene (BHT), indole-3-methanol, pycnogenol, melatonin, sulforaphane, pregnenolone, lipoic acid and 4-hydroxy-5-methyl-3[2H]-furanone, acetylcysteine, thioglycerol, vitamin E TPGS, thiosulfates (e.g., sodium thiosulfate), metabisulfites (e.g., sodium metabisulfite), and bisulfites (e.g., sodium bisulfite). More preferably, the compositions of this disclosure are free of thiosulfates, such as sodium thiosulfate.

[0058] In some embodiments, the compositions of this disclosure consist of rifelast dissolved or suspended in a medium comprising or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the compositions are substantially free of antioxidants.

[0059] In some embodiments, the composition comprises rifelast dissolved or suspended in a medium comprising one or more semi-fluorinated alkanes and optionally one or more excipients, provided that the composition is substantially free of antioxidants, preferably wherein the antioxidants are selected from propyl gallate, octyl gallate and lauryl gallate, butylated hydroxyanisole (BHA), green tea extract, uric acid, cysteine, pyruvate, nordihydroguaiac acid, ascorbic acid, ascorbate salts (such as ascorbate palmitate and sodium ascorbate, ascorbyl glucosamine), vitamin E (i.e., tocopherol, such as α-tocopherol), vitamin E derivatives (e.g., acetic acid). Tocopherol), retinoids (such as retinoic acid, retinol, trans-retinol, cis-retinol, a mixture of trans-retinol and cis-retinol), 3-dehydroretinol and vitamin A derivatives (e.g., retinyl acetate, retinaldehyde and retinyl palmitate), sodium citrate, sodium sulfite, lycopene, anthocyanins, bioflavonoids (e.g., hesperidin, naringin, rutin and quercetin), superoxide dismutase, glutathione peroxidase, butylated hydroxytoluene (BHT), indole-3-methanol, pycnogenol, melatonin, sulforaphane, pregnenolone, lipoic acid and 4-hydroxy-5-methyl-3[2H]-furanone, acetylcysteine, thioglycerol, vitamin E TPGS, thiosulfates (e.g., sodium thiosulfate), metabisulfites (e.g., sodium metabisulfite) and bisulfites (e.g., sodium bisulfite).

[0060] Preferably, the composition comprises rifelast dissolved or suspended in a medium comprising one or more semi-fluorinated alkanes and optionally one or more excipients or thereof, wherein the one or more semi-fluorinated alkanes are selected from 1-perfluorobutylpentane (F4H5), 2-perfluorobutylpentane, 1-perfluorohexyloctane (F6H8), and 2-perfluorohexyloctane, provided that the composition is substantially free of thiosulfates (e.g., sodium thiosulfate).

[0061] In a preferred embodiment, the composition comprises 5% (w / v) rifelast dissolved or suspended in a medium comprising one or more semi-fluorinated alkanes and optionally one or more excipients or thereof, wherein the one or more semi-fluorinated alkanes are selected from (i) a mixture of 1-perfluorobutylpentane and 2-perfluorobutylpentane, and (ii) a mixture of 1-perfluorohexyloctane and 2-perfluorohexyloctane; and the condition is that the composition is substantially free of thiosulfates (e.g., sodium thiosulfate).

[0062] In another embodiment, the composition comprises 5% (w / v) rifelast dissolved or suspended in a medium comprising or consisting of one or more semi-fluorinated alkanes and optionally one or more excipients, wherein the one or more semi-fluorinated alkanes are selected based on: (i) a mixture of at least 97 wt% 1-perfluorobutylpentane and 3 wt% or less 2-perfluorobutylpentane, and (ii) a mixture of at least 97 wt% 1-perfluorohexyloctane and 3 wt% or less 2-perfluorohexyloctane; and provided that the composition is substantially free of thiosulfates (e.g., sodium thiosulfate).

[0063] Surprisingly, it was found that oxidative degradation (and related losses) of rifaspirant was reduced or substantially avoided in the compositions of this disclosure, despite a high oxygen saturation of up to about 8% by volume (equivalent to an oxygen concentration of about 10 mg / ml) in the medium or in the compositions comprising one or more semi-fluorinated alkanes and optionally one or more excipients or thereof. Preferredly, bubbling the medium with an inert gas (such as nitrogen) to replace the high oxygen content prior to the addition of rifaspirant is not necessary for reducing or substantially avoiding oxidative degradation of rifaspirant in the composition. Furthermore, the addition of antioxidants is not necessary to prevent oxidative degradation of rifaspirant.

[0064] In some embodiments according to this disclosure, the oxygen content in the pharmaceutical composition containing rifaspire is not less than 3%, 4%, 5%, 6%, 7%, or not less than 8% of the total volume of the composition.

[0065] In some embodiments, the composition comprises or consists of rifelast suspended in a medium composed of one or more semi-fluorinated alkanes selected from 1-perfluorobutylpentane (F4H5), 2-perfluorobutylpentane, 1-perfluorohexyloctane (F6H8), and 2-perfluorohexyloctane, wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, or at most about 8 vol% relative to the volume of the composition. More preferably, the compositions of this disclosure comprise or consist of rifelast suspended in a medium composed of (i) a mixture of 1-perfluorobutylpentane and 2-perfluorobutylpentane, or (ii) a mixture of 1-perfluorohexyloctane and 2-perfluorohexyloctane, wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, or at most about 8 vol%. Even more preferably, the compositions of this disclosure comprise or consist of solid particles of rifelast suspended in a medium, said medium being composed of: (i) at least 97 wt% of 1-perfluorobutylpentane and 3 wt% or less of 2-perfluorobutylpentane, or (ii) at least 97 wt% of 1-perfluorohexyloctane and 3 wt% or less of 2-perfluorohexyloctane, and wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, or more about 8 vol% relative to the volume of the composition.

[0066] In some embodiments, the composition comprises or consists of rifelast suspended in a medium composed of one or more semi-fluorinated alkanes selected from 1-perfluorobutylpentane (F4H5), 2-perfluorobutylpentane, 1-perfluorohexyloctane (F6H8), and 2-perfluorohexyloctane, wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, 8 vol%, 9 vol%, or at most about 10 vol%, or wherein the oxygen content in the composition is between 4 vol% and 5 vol%, and wherein the composition is substantially free of antioxidants. More preferably, the composition of this disclosure comprises rifelast suspended in a medium comprising: (i) a mixture of 1-perfluorobutyl-pentane and 2-perfluorobutyl-pentane, or (ii) a mixture of 1-perfluorohexyl-octane and 2-perfluorohexyl-octane, wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, 8 vol%, 9 vol%, or at most about 10 vol%, or wherein the oxygen content in the composition is between 4 vol% and 5 vol%, and wherein the composition is substantially free of antioxidants. Even more preferably, the compositions of this disclosure may consist of solid particles of rifelast suspended in a medium composed of: (i) at least 97 wt% of 1-perfluorobutylpentane and 3 wt% or less of 2-perfluorobutylpentane, or (ii) at least 97 wt% of 1-perfluorohexyloctane and 3 wt% or less of 2-perfluorohexyloctane, based on the weight of the medium, and wherein the oxygen content in the composition is at most about 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol%, 8 vol%, 9 vol%, or at most about 10 vol%, relative to the volume of the composition, or wherein the oxygen content in the composition is between 4 vol% and 5 vol%, provided that the composition is substantially free of antioxidants. The oxygen content can be determined using methods in the art, for example using a chemioptic oxygen microsensor, such as one with a measurement range of 0-250% air saturation.

[0067] As used herein, the term “at most about” or “at most” in the context of parameters relating to the concentration or amount of rifaspirant or the amount of one or more excipients in a composition means any value greater than zero and at most the defined parameter (including the end values ​​of the defined parameter), taking into account any degree of variability typically observed when measuring or determining the parameter using standard techniques and equipment known in the relevant field.

[0068] As understood herein, unless otherwise indicated, the term "% (w / v)" means the amount of a component in the composition expressed as a weight percentage relative to the total volume of the composition (where "w" represents weight and "v" represents volume). For example, 0.1% (w / v) would correspond to 1.0 mg of component in 1 mL of the composition. As used herein and unless otherwise indicated, the term "% (w / w)" or alternatively "wt %" means the amount of a component in the composition expressed as a weight percentage relative to the total weight of the composition, where "w" represents weight. As used herein and unless otherwise indicated, the term % (v / v) or volume % or volume percentage means the volume of a component in the composition relative to the total volume of the composition.

[0069] As understood herein, the terms "substantially free of" or alternatively "substantially free of" or "free of component" regarding a compositional ingredient or component mean that the presence of said component is in trace amounts and, if present in trace amounts, that component does not provide any technical contribution or material advantage to the composition. In one embodiment, the composition described herein is substantially free of water. In another embodiment, the composition described herein may be substantially free of preservatives (such as antimicrobial preservatives or antioxidants). In other embodiments, the composition described herein is substantially free of surfactants.

[0070] The term “about” as used herein and in connection with parameters (such as the amount or concentration of a compound dissolved or suspended in a composition) includes both the defined precise value and any value falling within the degree of variability observed when measuring or determining these parameters using standard techniques and equipment known in the art.

[0071] As understood herein, pharmaceutically acceptable salts are salts of compounds (as provided herein) that retain their biological properties, are non-toxic, and are compatible with pharmaceutical use. For example, salts can be produced by adding an acid (such as an organic acid or an inorganic acid (such as sulfuric acid or hydrochloric acid)).

[0072] Rifelast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist with the following chemical formula: The chemical names of rifelast include (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methanesulfonyl)phenyl)propionic acid, or (2S)-2-{[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-yl]formamido}-3-(3-methanesulfonylphenyl)propionic acid.

[0073] As discussed above, this disclosure relates to pharmaceutical compositions comprising rifelilast or a pharmaceutically acceptable salt thereof, wherein the rifelilast is dissolved or suspended in a medium comprising a semi-fluorinated alkane and optionally one or more excipients (as defined above). Compositions containing a high enantiomeric ratio or primarily rifelilast can be formulated in a semi-fluorinated alkane, and said compositions remain stable under long-term storage conditions, particularly long-term storage conditions. Stability may include reducing or even substantially eliminating any degradation (and loss) of rifelilast, for example, this may be the case for aqueous formulations, which may require sophisticated buffering systems and / or single-use packaging to control or mitigate the compound’s exposure to environmental factors and changes and / or require the presence of antioxidants to control the oxidation of the compound. Additionally, improvements in stability may also relate to a reduction in racemization potential and / or a decrease in the change in the enantiomeric ratio of rifelilast’s enantiomeric or (R)-isomer formation over time and during storage. Overall, this disclosure provides improvements in the storage stability of rifelilast and maintains the long-term integrity of the concentration of the active ingredient in relation to its intended therapeutic use. Thus, storage-resistant rifelilast compositions can be formulated in semi-fluorinated alkanes according to this disclosure, avoiding the disadvantages of the presence or formation of large quantities of its enantiomer (rifelilast(R)-isomer) (which can be considered an impurity). Although the rifelilast(R)-isomer has low or no pharmacological effect in relation to its intended therapeutic use (particularly for the treatment of dry eye disease), the absence or significantly reduced amount of this enantiomer in the composition may be advantageous, as this reduces or avoids unnecessary exposure of subjects requiring treatment to compounds to which they may still have a physiological response.

[0074] In one embodiment, the composition according to this disclosure comprises rifaspirant and a mixture of its enantiomers (i.e., its (R)-enantiomers), said (R)-enantiomers may also be defined as (R)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methanesulfonyl)phenyl)propionic acid, or (2R)-2-{[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-yl]formamido}-3-(3-methanesulfonyl)phenyl)propionic acid. The molecular structure of this isomer is: This isomer may also be referred to as "impurity 8", and as used herein, the term "rifestar(R)-isomer" can be understood to refer to this enantiomer of rifestar.

[0075] In one embodiment, the enantiomer ratio of rifetazone to its enantiomer (rifetazone(R)-isomer) is not 50:50. In other words, the composition does not contain, is not, or will not become a racemic mixture of these two enantiomers. In one embodiment, based on the total amount of the compound and its enantiomers in the composition, the composition comprises at least 80% rifetazone, at least 89% rifetazone, at least 90% rifetazone, at least 93% rifetazone, or at least 95% rifetazone, or at least 96% rifetazone, or at least 97% rifetazone, or at least 98% rifetazone, or at least 99% or at least 99.5% rifetazone.

[0076] In one embodiment, the composition contains lifacitin in an enantiomer excess of at least about 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98%, 99%, or 99.5%. Enantiomer excess (ee) is used for the purity measurement of chiral substances. It reflects the extent to which a sample contains a higher amount of one enantiomer (i.e., lifexazone) than its (R)-enantiomer, specifically a greater proportion of (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid than (R)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid. Racemic mixtures have 0% ee, while completely pure single enantiomers have 100% ee. Samples containing 70% lifexazone and 30% lifexazone (R)-enantiomers have 40% (70% - 30%) ee.

[0077] In some embodiments, after storage at 0 to 60ºC, for example, at 25ºC for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the enantiomeric excess of rifelast in the composition relative to its enantiomer (rifelast(R)-isomer) is at least 90%, at least 95%, or at least 99% relative to the initial enantiomer excess of rifelast in the composition.

[0078] In some embodiments, based on the total amount of rifelast and its enantiomers (rifelast(R)-isomers) in the composition, the composition according to this disclosure comprises less than 10% of rifelast enantiomers (rifelast(R)-isomers), or less than 5% of rifelast enantiomers (rifelast(R)-isomers), or less than 2% of rifelast enantiomers (rifelast(R)-isomers), or less than 1% of rifelast enantiomers (rifelast(R)-isomers), or less than 0.5% of rifelast enantiomers (rifelast(R)-isomers).

[0079] In some embodiments, the enantiomer ratio of rifexar to its enantiomer (rifexar(R)-isomer) in the composition is at least 89:11, 90:10, 91:8, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, 99.7:0.3, or at least 99.9:0.1. The enantiomer ratio is a percentage of one enantiomer to another, and may alternatively be expressed numerically. For example, for the racemic mixture, the enantiomer ratio is 1 (50:50), or for a 90:10 enantiomer ratio, this may be expressed as 9. In one embodiment, the enantiomeric ratio of rifetaste to its isomers in the composition is at least 8, 9, 10, 11, 12, 13, 15, 32, 50, 100 or at least 250.

[0080] The enantiomer ratio or enantiomer excess (ee) of rifaspirant, or generally its stereochemical purity, and the relative or other amounts of rifaspirant, its enantiomers, or rifaspirant-related degradation products contained in the compositions according to this disclosure, can be determined by a number of methods in the art, such as, but not limited to, chromatography (e.g., HPLC), capillary electrophoresis, LC-MS, or gas chromatography and / or spectrometry (e.g., circular dichroism or NMR). In one embodiment, the enantiomer ratio is preferably determined by HPLC from the quantification of the peak area of ​​the respective compound.

[0081] In addition to low amounts or low concentrations of the rifelast(R)-isomer in the composition, pharmaceutical compositions containing rifelast may also contain only low amounts of any degradation products or substantially no degradation products. Degradation products of rifelast may include any products formed when rifelast (e.g., formulated in a liquid composition) is exposed to any or a combination of heat, oxidation, photolysis, alkaline, or acidic conditions. Rifelast degradation products include, but are not limited to, the rifelast(R)-isomer or any degradation products formed upon exposure to heat, oxidation, photolysis, alkaline, or acidic stress conditions, as included in Examples 5 and 6; for example, the degradation products listed in Table 1, or... Figure 1 or Figure 2 The chromatogram contains degradation products.

[0082] Alternatively or additionally, the compositions of this disclosure may contain no more than about 0.0001% to 0.001% (w / v) or 0.004% to 0.006% (w / v) of rifelast(R)-isomer. The compositions may also be substantially free of rifelast(R)-isomer.

[0083] In some embodiments, the composition according to this disclosure comprises rifaspirant, wherein rifaspirant is present in the composition at a concentration between 2% and 8% (w / v), or between 3% and 7% (w / v), or between 4% and 6% (w / v), or about 5% (w / v).

[0084] In some embodiments, the concentration of rifaspirant in the composition is up to 8% (w / v), or up to 7% (w / v), or up to 6% (w / v), or up to 5% (w / v).

[0085] Further embodiments of the compositions according to this disclosure may include, but are not limited to, suspensions of rifaspirate in semi-fluorinated alkanes or mixtures of semi-fluorinated alkanes as defined herein, wherein the composition comprises or is composed of the following: a) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifexister suspended in semi-fluorinated alkanes; b) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of lifexate suspended in a semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof; c) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast suspended in a semi-fluorinated alkane, wherein the semi-fluorinated alkane is optionally combined with 2-perfluorobutylpentane to form 1-perfluorobutylpentane, wherein the 2-perfluorobutylpentane 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) relative to the total weight of the combination of the semi-fluorinated alkane; or d) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of lifexito suspended in a semi-fluorinated alkane, wherein the semi-fluorinated alkane is optionally combined with 2-perfluorohexyl-octane to form 1-perfluorohexyl-octane, 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 about 0.2% (w / w) of the total weight of the combination of the semi-fluorinated alkane.

[0086] In some embodiments, the liquid composition according to this disclosure comprises or consists of the following: a) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast, 1-perfluorobutylpentane, and optionally one or more excipients; b) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast, 1-perfluorobutyl-pentane, and optionally one or more excipients, optionally combined with 2-perfluorobutyl-pentane, wherein 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) by weight relative to the total weight of the combination of semi-fluorinated alkanes. c) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast and an enantiomeric mixture of rifelast(R)-isomer, 1-perfluorobutylpentane, and optionally one or more excipients, wherein the enantiomeric ratio of rifelast to rifelast(R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2.

[0087] d) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifexalate and an enantiomer of rifexalate(R)-isomer, 1-perfluorobutylpentane, and optionally one or more excipients, wherein: - The enantiomeric ratio of rifexist to its (R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2, and - After storage at 25ºC for 1, 2, or 3 months, the total amount of rifelast and rifelast(R)-isomer relative to their initial amount in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96%, or at least 95%; and - Optionally, the ratio of rifexister to the enantiomeric form of rifexister(R)-isomer is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%; e) about 5% (w / v) of rifelast and an enantiomeric mixture of rifelast(R)-isomer, 1-perfluorobutylpentane and optionally one or more excipients, wherein the enantiomeric ratio of rifelast to rifelast(R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2 or at least 99:1; or at least 99.8:0.2; f) Approximately 5% (w / v) of rifexalate and an enantiomer mixture of rifexalate(R)-isomers, 1-perfluorobutylpentane, and optionally one or more excipients, wherein the enantiomer ratio of rifexalate to rifexalate(R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2 or at least 99:1; or at least 99.8%. :0.2, and wherein after storage at 25ºC for 1, 2 or 3 months, the total amount of rifelast in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96% or at least 95% relative to the initial amount of rifelast in the composition, and optionally, wherein the enantiomeric ratio of rifelast to the rifelast(R)-isomer decreases by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0088] g) About 5% (w / v) of a mixture of enantiomers of rifelast and rifelast(R)-isomer, 1-perfluorobutylpentane, and optionally up to 1 wt% of one or more excipients (e.g., ethanol), wherein the enantiomer ratio of rifelast to rifelast(R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2 or at least 99:1; or at least 99.8:0.2.

[0089] In some embodiments, compositions a), b), c), d), e), f), and g) are suspensions, wherein rifelast (and its (R)-isomers) are particles suspended in a liquid medium comprising or consisting of 1-perfluorobutylpentane and optional excipients. In relevant embodiments, the semi-fluorinated alkane in these compositions may be a mixture of 1-perfluorobutylpentane and its structural isomers (e.g., 2-perfluorobutylpentane) according to this disclosure.

[0090] According to another embodiment, this disclosure also relates to liquid compositions comprising or containing the following: j) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast, 1-perfluorohexyl-octane, and optionally one or more excipients. k) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast, 1-perfluorohexyl-octane, and optionally one or more excipients, optionally combined with 2-perfluorohexyl-octane, wherein 2-perfluorohexyl-octane is present in an amount of up to 2% (w / w), or up to 1% (w / w), or up to 0.5% (w / w), or up to 0.2% (w / w) by weight relative to the total weight of the combination of semi-fluorinated alkanes. l) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifexalate and an enantiomer mixture of rifexalate(R)-isomers, 1-perfluorohexyloctane, and optionally one or more excipients, wherein the enantiomer ratio of rifexalate to rifexalate(R)-isomer present in the composition is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2, or m) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast and an enantiomer of rifelast(R)-isomer, 1-perfluorohexyl-octane, and optionally one or more excipients, wherein: - The enantiomer ratio of rifexist to its (R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2; and - After storage at 25ºC for 1, 2, or 3 months, the total amount of rifaspirin relative to the initial amount of rifaspirin in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96%, or at least 95%; and - Optionally, the ratio of rifexister to the enantiomer of rifexister(R)-isomer is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%; n) Approximately 5% (w / v) of rifelast and an enantiomeric mixture of rifelast(R)-isomers, 1-perfluorohexyl-octane, and optionally one or more excipients, wherein the enantiomeric ratio of rifelast to rifelast(R)-isomers is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2.

[0091] o) Approximately 5% (w / v) of rifelast and an enantiomer of rifelast(R)-isomer, 1-perfluorohexyl-octane, and optionally one or more excipients, wherein - The enantiomeric ratio of rifexist to its (R)-isomer is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2, and - After storage at 25ºC for 1, 2, or 3 months, the total amount of rifaspirant in the composition relative to the initial amount of rifaspirant in the composition is at least 99.9%, 99.5%, 99%, 98%, 97%, 96%, or at least 95%, and - Optionally, the ratio of rifelast to the enantiomeric form of the rifelast(R)-isomer is reduced by no more than 0.25%, 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20% or 25%.

[0092] p) Approximately 5% (w / v) of rifelast and an enantiomeric mixture of rifelast(R)-isomers, 1-perfluorohexyl-octane, and optionally up to 1 wt% of one or more excipients (e.g., ethanol), wherein the enantiomeric ratio of rifelast to rifelast(R)-isomers is at least 90:10, at least 95:5, at least 96:4; or at least 98:2; or at least 99:1; or at least 99.8:0.2.

[0093] In some embodiments, compositions j), k), l), m), n), o), and p) are suspensions in which rifelast (and its isomers) are suspended as particles in a liquid medium comprising or consisting of 1-perfluorohexyloctane and optional excipients. In related embodiments, the semi-fluorinated alkane in these compositions may be a mixture of 1-perfluorohexyloctane and its structural isomers (e.g., 2-perfluorohexyloctane).

[0094] In some embodiments, the composition comprises rifelast suspended in a medium composed of one or more semi-fluorinated alkanes selected from 1-perfluorobutylpentane (F4H5), 2-perfluorobutylpentane, 1-perfluorohexyloctane (F6H8), and 2-perfluorohexyloctane. In other embodiments, the composition of this disclosure comprises rifelast suspended in a medium composed of (i) a mixture of 1-perfluorobutylpentane and 2-perfluorobutylpentane, or (ii) a mixture of 1-perfluorohexyloctane and 2-perfluorohexyloctane. In a preferred embodiment, the composition of this disclosure comprises solid particles of rifelast suspended in a medium consisting of: (i) at least 97 wt% of 1-perfluorobutylpentane and 3 wt% or less of 2-perfluorobutylpentane, or (ii) at least 97 wt% of 1-perfluorohexyloctane and 3 wt% or less of 2-perfluorohexyloctane, based on the weight of the medium.

[0095] In some embodiments, after being stored at 0 to 60ºC (e.g., at 25ºC) for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the amount of rifelast in the composition according to this disclosure is at least 90%, at least 95%, or at least 99% relative to the initial amount of rifelast in the composition, as determined, for example, by HPLC.

[0096] In other embodiments, after storage at 0 to 60ºC (e.g., at 25ºC) for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months, the concentration or amount of rifelast in the composition according to this disclosure is in the range of 90% to 110% or 95% to 105% of the initial concentration of rifelast in the composition, for example, as determined by HPLC. In other embodiments, after storing the composition at 25ºC for at least 3 months, the concentration of rifelast is in the range of about 90% to 110%; or not less than 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%); or not more than 100% (e.g., not more than 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, or 109%), for example, as determined by HPLC (preferably by quantification of the peak area of ​​the respective compound). When the determined percentage is greater than 100%, it should be understood that the measurement does not involve an increase in the amount of rifaspirant, but rather, for example, a loss of the medium over time during storage. In another related embodiment, the amount of rifaspirant is preferably equal to or greater than 90% or 95% of the initial concentration of rifaspirant in the composition, or equal to or less than 110%, 105%, or 100% of the initial concentration of rifaspirant in the composition.

[0097] In some embodiments, after storage at 25ºC for at least 1, 2, 3, 4, 5, 6, 9, or at least 12 months, the enantiomeric ratio of rifelast to the rifelast(R)-isomer in the compositions according to this disclosure decreases by no more than 0.5%, 1.0%, 2.0%, 2.5%, 5%, 7.5%, 10%, 15%, 20%, or 25%. For example, in a composition comprising rifelast and its(R)-isomer suspended and dissolved in a semi-fluorinated alkane and optionally one or more excipients, if the initial enantiomeric ratio of rifelast to the rifelast(R)-isomer was 90:10 (i.e., 9) prior to storage or aging, a decrease of about 1% would be equivalent to a reduction in the enantiomeric ratio to 8.91% or about 89.91:10.09.

[0098] In some embodiments, after the composition has been stored at 0 to 60°C, for example at 25°C for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the amount of rifelast in the composition is at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99% relative to the initial amount of rifelast in the composition, wherein the oxygen content in the composition is not less than 3%, 4%, 5%, 6%, 7%, or not less than 8% of the total volume of the composition.

[0099] In another aspect, this disclosure relates to a method for preparing a composition as defined in any of the embodiments described herein; the method comprising the step of dissolving or suspending rifelast in a non-aqueous medium comprising or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0100] In other embodiments, this disclosure relates to a method for preparing a composition, wherein the composition is in the form of an emulsion, wherein the method includes the step of dissolving rifelast in an aqueous phase, the aqueous phase optionally containing one or more excipients, and combining the aqueous phase with a liquid phase comprising a semi-fluorinated alkane and optionally one or more excipients, or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0101] In some embodiments of these methods, after storing the composition at 0 to 60ºC (e.g., at 25ºC) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the amount of the (R)-isomer of rifelast 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., determined by HPLC).

[0102] In a related aspect, this disclosure relates to a method for stabilizing rifaspirant in a composition, the method comprising the step of dissolving or suspending rifaspirant (having a certain optical purity) in a semi-fluorinated alkane or a non-aqueous medium comprising a semi-fluorinated alkane and optionally one or more excipients; wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, their structural isomers, and any combination thereof. In some embodiments according to this method, rifaspirant has an enantiomer excess of at least 80% ee, at least 80% ee, at least 90%, 95%, 97% ee, or at least 99% ee, or a purity of at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99% (e.g., determined by HPLC). In other embodiments, the enantiomer purity or enantiomer ratio of rifaspirant may be as defined above.

[0103] In another related aspect, this disclosure provides a method for stabilizing rifaspirant in a composition, the method comprising the step of dissolving or suspending rifaspirant in a semi-fluorinated alkane as defined in any of the embodiments described herein. Further, a method for stabilizing rifaspirant in a composition is provided, wherein the method comprises the step of dissolving or suspending rifaspirant in a medium comprising a semi-fluorinated alkane as defined in any of the embodiments described herein and optionally one or more excipients.

[0104] These methods include, for example, a) preventing or reducing the rate of degradation (e.g., hydrolysis and / or dehydration and / or oxidation) of rifelast in the composition; and / or b) preventing or reducing the rate of isomerization (e.g., racemization) of rifelast in the composition; and / or c) preventing or reducing an excess of enantiomers of rifelast in the composition; and / or d) preventing or reducing the formation of enantiomers of rifelast (rifelast(R)-isomers) in the composition; and / or e) preventing or reducing the formation of rifelast degradation products, preferably preventing or reducing the formation of rifelast degradation products formed by exposure to any one or a combination of heat, oxidation, photolysis, alkaline or acidic conditions. In particular, the method is effective in any one or a combination of the following: preventing or reducing the degradation of rifelast in the composition after storing the composition at 0 to 60ºC (e.g., 25ºC) for a period of at least 1, 2, 3, 4, 5, 6, 9 or 12 months; or preventing or reducing the conversion of rifelast in the composition to the rifelast(R)-isomer.

[0105] In some embodiments of these methods, after a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months at 0 to 60ºC (e.g., 25ºC), the amount of any one or more degradation products of rifelast (e.g., oxidative degradation products) is independently less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% (e.g., determined 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 to 60ºC (e.g., 25ºC), the amount of rifelast(R)-isomer 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., determined by HPLC). In other embodiments, after storage at 0 to 60ºC (e.g., at 25ºC) for a period of at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the enantiomeric ratio of rifelast to the rifelast(R)-isomer 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).

[0106] In some embodiments, the method includes the step of suspending rifaspirant in a medium comprising at least 90 wt%, 93 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, or at least 99.5 wt% of F6H8 (1-perfluorohexyl-octane) and optionally up to 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 2 wt%, or up to 3 wt% of 2-perfluorohexyl-octane or composed thereof.

[0107] The method can effectively reduce the amount of the one or more rifelast degradation products to less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, or less than 0.1% relative to the initial amount of rifelast in the composition. In some embodiments, after storing the composition at 0 to 60ºC, for example at 25ºC for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the method effectively maintains the amount of rifelast in the composition at at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99% relative to the initial amount of rifelast in the composition.

[0108] In some embodiments, the composition comprises less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, or less than 0.1% of rifaspirant degradation products relative to the initial amount of rifaspirant in the composition. The rifaspirant degradation products can be formed by exposing the composition to one or more of heat, oxidation, photolysis, alkaline, or acidic conditions. In some embodiments, the rifaspirant degradation products are formed due to exposure to heat, oxidation, or photolysis conditions. In other embodiments, the rifaspirant degradation products are formed due to exposure to oxidizing conditions.

[0109] In another aspect, the pharmaceutical compositions according to this disclosure may be used as a medicine or provided as a medicine for use in the treatment or prevention of a disease or medical condition, preferably in a human subject or optionally in a mammalian or veterinary subject; and in the manufacture of a pharmaceutical preparation.

[0110] In some embodiments, the composition is a topical ophthalmic composition, or in other words, a composition adapted and formulated for topical application to the eye, particularly for application to the surface of a subject's eye or to eye-related tissues, such as the cornea and / or conjunctiva, or to the conjunctival fornix. In one related embodiment, the composition is in the form of a clear solution. In another related embodiment, the composition is a topically applicable ophthalmic suspension; a suspension of solid particles comprising or composed of rifaspirant suspended (or suspendable) in a liquid medium and / or a liquid semi-fluorinated alkane (as described herein).

[0111] In one aspect, a composition of any one or a combination thereof according to embodiments of this disclosure is used to treat and / or prevent, for example, an ophthalmic disease or condition affecting one or both eyes of a subject.

[0112] In another aspect, compositions comprising rifaspirant or a pharmaceutically acceptable salt thereof according to embodiments of this disclosure are used to treat, prevent, and / or reduce dry eye disease; or to treat, prevent, and / or alleviate signs or symptoms of dry eye disease; or to treat, prevent, or alleviate ocular surface diseases, preferably ocular surface diseases affecting the cornea and / or conjunctiva, or ocular surface diseases associated with inflammation of the cornea and / or conjunctiva; or to increase tear production in at least one or both eyes of a subject suffering from dry eye disease; or to treat autoimmune disorders of the ocular surface. In some embodiments, the compositions according to this disclosure are used to treat signs and symptoms of dry eye disease.

[0113] Dry eye disease (also abbreviated as DED, and synonymous with or referred to as keratoconjunctivitis sicca, tear film instability syndrome, or dry eye syndrome) is a complex condition that causes discomfort, visual disturbances, and tear film instability, and can lead to ocular surface damage. It may be accompanied by increased tear film osmolality and ocular surface inflammation. Patients with dry eye disease may experience any one or a combination of tear hyperosmolarity, tear film instability, or abnormalities in the composition of the tear film lipid layer.

[0114] Dry eye disease (DED), or keratoconjunctivitis sicca, can be divided into two main categories: dehydrating dry eye disease and evaporative dry eye disease. Additional subtypes can be classified within these two categories. Subjects with dehydrating dry eye disease typically exhibit insufficient or low levels of tear production, such as due to lacrimal gland insufficiency, lacrimal duct obstruction, or reflexive hypotonia.

[0115] Evaporative dry eye disease is also heterogeneous to some extent and can develop due to different underlying causes. One of the main causes is meibomian gland disease or dysfunction, eyelid aperture disorder, blinking disorder, or other ocular surface disorders.

[0116] Signs of dry eye disease may include corneal surface damage, conjunctival surface damage, corneal surface inflammation, conjunctival surface inflammation, reduced tear production, and any combination thereof. These signs can be determined by performing objective clinical measurements of the subject's eyes for such signs using characterization methods and tests developed in the art for quantifying such signs, such as corneal fluorescein staining (e.g., for grading and assessing corneal damage and / or inflammation), conjunctival staining (e.g., for grading and assessing conjunctival damage and / or inflammation), or Schirmer's Test I (e.g., for assessing tear production levels).

[0117] Symptoms of dry eye disease can include dryness, itching, a gritty or sandy feeling in the eyes; a foreign body sensation; pain or soreness; stinging or burning; itching; increased blinking; eye fatigue; photophobia; blurred vision; redness; mucus discharge; contact lens intolerance; excessive reflex tearing; or any combination thereof. These can be assessed, for example, through a patient questionnaire.

[0118] As described herein, the compositions herein are preferably used for the treatment of mammals, or more preferably human subjects. Furthermore, in the context of this disclosure, the use of the pharmaceutical compositions as described in any of the foregoing embodiments in the manufacture or preparation of an agent or medicine for the treatment of a subject in need of any of the diseases or medical conditions described herein is also provided. In the context of this disclosure, methods for treating a subject having or suffering from any of the medical conditions or disorders described herein; or methods for preventing or improving the medical conditions or disorders of said subject, wherein said methods may include the step of administering (e.g., topically, such as topical ophthalmic application) the compositions as described herein to said subject.

[0119] In another aspect, this disclosure relates to a kit comprising a composition of any one or a combination of embodiments described herein, a container adapted to contain the composition, and optionally means for dispensing the composition and / or instructions for use, wherein the instructions for use include any of the therapeutic uses or methods described herein.

[0120] In some embodiments of the kit, the kit includes a device for dispensing the composition, which may be attached to or reversibly attached to a container. The device for dispensing the composition may be a dropper or the like, or adapted to administer a single drop of the composition in a volume of about 9 to 12 µl, or about 10 to 11 µl, or about 9 µl, or about 10 µl, or about 11 µl to the subject's eye.

[0121] In some embodiments of the kit, the container is adapted to contain a single dose of the composition or a multiple dose of the composition, preferably without any preservatives for preventing or reducing microbial growth.

[0122] In another aspect, this disclosure relates to reducing the dosage of a commercially available aqueous rifetaste product (Xiidra®), administered as a single dose of 2.5 mg rifetaste per eye or as a (total) daily dose of 5 mg per eye. Reducing the dose or amount of exposure of a subject to the active compound can be beneficial, for example, in terms of reducing the overall risk of adverse reactions.

[0123] In some embodiments of this aspect of the present disclosure, a composition comprising 5% (w / v) rifelast dissolved or suspended in a medium containing a semi-fluorinated alkane as disclosed herein is topically administered to the eye of a subject with dry eye disease in a single dose of about 0.40 to 0.60 mg, or about 0.45 to 0.55 mg, or about 0.50 mg of rifelast per eye. Preferably, a composition comprising 5% (w / v) rifelast dissolved or suspended in a medium containing a semi-fluorinated alkane is topically administered to the eye of a subject with dry eye disease twice daily, providing a single dose of about 0.40 to 0.60 mg, or about 0.45 to 0.55 mg, or about 0.50 mg of rifelast per eye twice daily. In the context of the use of the composition described in any of the embodiments herein in the manufacture of an agent for treating dry eye disease, in some embodiments the agent may comprise at least one or more unit doses of rifelast, wherein the unit dose is about 0.40 to 0.60 mg, or about 0.45 to 0.55 mg, or about 0.50 mg of rifelast per eye.

[0124] In another embodiment of this aspect of the present disclosure, a composition comprising 5% (w / v) rifelast dissolved or suspended in a medium comprising a semi-fluorinated alkane as disclosed herein is topically administered to the eye of a subject suffering from dry eye disease at a total daily dose of about 0.80 to 1.20 mg, or about 0.90 to 1.10 mg, or about 1.0 mg of rifelast per eye. Preferably, the total daily dose per eye is provided by topically administering the composition to the subject's eye twice daily.

[0125] In another embodiment of this aspect of the present disclosure, a composition comprising 5% (w / v) rifelast is applied topically to the eye of a human subject with dry eye disease in a single dose of about 9 to 12 µl, or about 10 to 11 µl, or about 10 µl volume of droplets per eye. Preferably, the composition comprising 5% (w / v) rifelast as described herein is applied topically to the eye of a human subject with dry eye disease twice daily in a single dose of about 9 to 12 µl, or about 10 to 11 µl, or about 10 µl volume of droplets per eye. Attached Figure Description

[0126] Figure 1HPLC chromatograms of 5% (w / v) rifelast compositions (A), (B), and (C) as described in Example 6 after oxidative stress were plotted. The major degradation product peak of (A) is shown at a relative retention time (RRT) of 0.67; the major degradation product peaks of (B) are shown at RRTs of 0.42, 0.60, and 0.73. For (C), the major degradation product is not shown.

[0127] Figure 2 HPLC chromatograms of 5% (w / v) rifelast compositions (A), (B), and (C) as described in Example 6 after photodegradation stress were plotted. The major degradation product peak of (A) is shown at a relative retention time (RRT) of 0.88; the major degradation product peak of (B) is shown at RRTs of 0.73 and 0.88. For (C), the major degradation product is not shown.

[0128] Figure 3 HPLC chromatograms of 5% (w / v) rifelast composition (C) were plotted, derived from chiral HPLC as described in Example 7. Chromatograms labeled (a), (b), (c), (d), (e), (f), (g), and (h) are chiral HPLC chromatograms of composition (C) subjected to the following conditions: (a) darkness (control for photodegradation stress); (b) photodegradation stress (200 W); (c) room temperature (RT) control; (d) heat stress, 2ºC–8ºC; (e) heat stress, 80ºC; (f) acid stress, 80ºC; (g) alkaline stress, 80ºC; and (h) oxidative stress, 80ºC. Under these stress conditions, no peaks of rifelast (R)-isomers (which should be found at RRT 5.03) or degradation products were detected.

[0129] This disclosure further includes the following items 1 through 54, including: 1. A pharmaceutical composition comprising rifelast or a pharmaceutically acceptable salt thereof dissolved or suspended in a carrier, the carrier comprising a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0130] 2. The composition according to Item 1, wherein the semifluorinated alkane is selected from F4H5 (1-perfluorobutylpentane), F6H8 (1-perfluorohexyloctane), their structural isomers, and any combination thereof.

[0131] 3. The composition according to item 2, wherein the semi-fluorinated alkane is a combination of F4H5 (1-perfluorobutyl-pentane) and 2-perfluorobutyl-pentane.

[0132] 4. The composition according to item 2, wherein the semi-fluorinated alkane is a combination of F6H8 (1-perfluorohexyl-octane) and 2-perfluorohexyl-octane.

[0133] 5. The composition according to item 3, wherein the medium comprises 1-perfluorobutyl-pentane and optionally 2-perfluorobutyl-pentane, wherein the 2-perfluorobutyl-pentane is present in an amount of up to 2% (w / w), up to 1% (w / w), up to 0.5% (w / w), or up to 0.2% (w / w) relative to the total weight of the semi-fluorinated alkane mixture.

[0134] 6. The composition according to item 4, wherein the medium comprises 1-perfluorohexyl-octane and optionally 2-perfluorohexyl-octane, 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 up to 0.2% (w / w) by weight relative to the total weight of the combination of the semi-fluorinated alkanes.

[0135] 7. The pharmaceutical composition according to items 1 to 6, wherein the mediator comprises the semi-fluorinated alkane or a combination of the semi-fluorinated alkane.

[0136] 8. The composition according to items 1 to 7, wherein the one or more semi-fluorinated alkanes are present in an amount of at least 90%, 95%, 96%, 97%, 98%, or 99% (w / w) based on the total weight of the composition.

[0137] 9. The composition according to items 1 to 8, wherein the semi-fluorinated alkane is 1-perfluorobutylpentane (F4H5) and optionally also 2-perfluorobutylpentane, and the one or more semi-fluorinated alkanes are present in an amount of at least 90%, 95%, 96%, 97%, 98%, or 99% (w / w) based on the total weight of the composition.

[0138] 10. The composition according to items 1 to 8, wherein the semi-fluorinated alkane is 1-perfluorohexyl-octane (F6H8) and optionally also 2-perfluorohexyl-octane, and the one or more semi-fluorinated alkanes are present in an amount of at least 90%, 95%, 96%, 97%, 98%, or 99% (w / w) based on the total weight of the composition.

[0139] 11. The composition according to any of the preceding items, wherein the medium comprises or consists of the semi-fluorinated alkane and one or more excipients, wherein the one or more excipients are selected from: a) A co-solvent, optionally wherein the co-solvent is an alcohol; preferably wherein the alcohol is selected from ethanol, 1-propanol, isopropanol and phenethyl alcohol; or more preferably wherein the alcohol is selected from ethanol and phenethyl alcohol; b) An oily excipient, optionally wherein the oily excipient is selected from triglycerides, mineral oils, and liquid paraffins; preferably, wherein the oily excipient is selected from medium-chain triglycerides (MCTs) and light liquid paraffins; and c) Any combination of cosolvents or oily excipients as defined in a) or b).

[0140] 12. The composition according to any of the preceding items, wherein the medium comprises a semi-fluorinated alkane and optionally its structural isomers, and one or more excipients, wherein the one or more excipients are not alcohols.

[0141] 13. The composition according to any of the preceding items, wherein the composition comprises rifelast and a mixture of enantiomers of its enantiomers (rifelast(R)-isomers), wherein the enantiomer ratio of rifelast to its enantiomers is not 50:50.

[0142] 14. The composition according to any of the preceding items, wherein the composition comprises at least 80% rifelast and at least 90% rifelast, or at least 95% rifelast, or at least 97% rifelast, or at least 98% rifelast, or at least 99% rifelast based on the total amount of rifelast and its enantiomers (rifelast(R)-isomers) in the composition.

[0143] 15. The composition according to any of the preceding items, wherein, based on the total amount of rifelast and its enantiomers (rifelast(R)-isomers) in the composition, the composition comprises less than 10% of the rifelast enantiomers (rifelast(R)-isomers), or less than 5% of the rifelast enantiomers (rifelast(R)-isomers), or less than 2% of the rifelast enantiomers (rifelast(R)-isomers), or less than 1% of the rifelast enantiomers (rifelast(R)-isomers), or less than 0.5% of the rifelast enantiomers (rifelast(R)-isomers).

[0144] 16. The composition according to any of the preceding items, wherein the composition contains rifexatri in excess of at least about 78%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 96%, 97%, 98%, 99%, or 99.5% of the enantiomers.

[0145] 17. The composition according to any of the preceding items, wherein the enantiomer ratio of rifelast to its enantiomer (rifelast(R)-isomer) in the composition is at least 89:11, 90:10, 91:8, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, 99.7:0.3, 99.8:0.2 or at least 99.9:0.1.

[0146] 18. The pharmaceutical composition according to any of the preceding items, wherein the pharmaceutical composition comprises rifaspirate, wherein the composition substantially comprises no more than about 0.0001% to 0.001% (w / v) or 0.004% to 0.006% (w / v) of its enantiomers.

[0147] 19. The pharmaceutical composition according to any of the preceding items, wherein the composition is substantially free of the enantiomers of the rifaspirant.

[0148] 20. The composition according to any of the preceding items, wherein rifetazone is present in the composition at a concentration of between 2% and 8% (w / v), between 3% and 7% (w / v), between 4% and 6% (w / v), or about 5% (w / v).

[0149] 21. The composition according to any of the preceding items, wherein, based on the total weight of the composition, the one or more excipients are optionally present independently in an amount of up to 0.1%, 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), preferably up to 1 wt% or up to 1.4 wt%.

[0150] 22. The composition according to any of the preceding items, wherein the composition is substantially free of a) water; or b) preservatives; or c) antioxidants; d) surfactants and / or e) any combination of a), b), c) and d).

[0151] 23. The composition according to any of the preceding items, wherein the composition is a suspension of rifaspirant in the semi-fluorinated alkane or mixture of semi-fluorinated alkane, and wherein the composition comprises or is composed of the following: a) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifexister suspended in the semi-fluorinated alkane; b) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast suspended in the semi-fluorinated alkane, wherein the semi-fluorinated alkane is selected from F4H5, F6H8, their structural isomers, and any combination thereof. c) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of rifelast suspended in the semi-fluorinated alkane, wherein the semi-fluorinated alkane is optionally 1-perfluorobutylpentane combined with 2-perfluorobutylpentane, wherein the 2-perfluorobutylpentane is present in an amount of up to 2% (w / w), or up to 1% (w / w), or up to 0.5% or up to 0.2% (w / w) relative to the total weight of the combination of the semi-fluorinated alkane; or d) 2% to 8% (w / v), or 3% to 7% (w / v), or 4% to 6% (w / v), or about 5% (w / v) of lifexito suspended in the semi-fluorinated alkane, wherein the semi-fluorinated alkane is optionally 1-perfluorohexyl-octane in combination with 2-perfluorohexyl-octane, 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 up to 0.2% (w / w) relative to the total weight of the combination of the semi-fluorinated alkane.

[0152] 24. The composition according to any of the preceding items, wherein after storing the composition at 0 to 60ºC, for example at 25ºC for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, the amount of rifelast in the composition is at least 90%, or at least 95%, or at least 97%, or at least 98% or at least 99% relative to the initial amount of rifelast in the composition.

[0153] 25. The composition according to any of the preceding items, wherein after storage at 0 to 60ºC, for example after storage at 25ºC for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the enantiomeric excess of rifelast in the composition relative to its enantiomer (rifelast(R)-isomer) is at least 90%, or at least 95%, or at least 99% of the initial enantiomer excess of rifelast in the composition.

[0154] 26. The pharmaceutical composition according to any of the preceding items, wherein the composition is a suspension of solid particles comprising or consisting of rifaspirate suspended in the liquid medium and / or the liquid semi-fluorinated alkane; preferably, wherein the composition is a topically applied ophthalmic suspension.

[0155] 27. The pharmaceutical composition according to items 1 to 26, wherein the oxygen content in the composition is not less than 3%, 4%, 5%, 6%, 7% or not less than 8% of the total volume of the composition.

[0156] 28. The pharmaceutical composition according to any of the preceding items, wherein the composition is formulated for or suitable for topical application to the surface of the eye, such as the conjunctiva and / or cornea.

[0157] 29. The pharmaceutical composition according to any of the preceding items, wherein the medium comprises an aqueous phase (or water).

[0158] 30. The pharmaceutical composition according to item 29, wherein the rifaspire is dissolved in the aqueous phase of the medium.

[0159] 31. The pharmaceutical composition according to items 29 to 30, wherein the composition is in the form of an emulsion, preferably selected from o / w emulsions or w / o emulsions.

[0160] 32. The pharmaceutical composition according to items 29 to 31, wherein the carrier comprises 30 vol% to 70 vol%, or 40 vol% to 60 vol% of the semi-fluorinated alkane relative to the total volume of the carrier; or wherein the carrier comprises 30 wt% to 70 wt%, or 40 wt% to 60 wt% of the semi-fluorinated alkane relative to the total weight of the carrier.

[0161] 33. The pharmaceutical composition according to items 29 to 32, wherein the carrier comprises an aqueous phase of 30 vol% to 70 vol%, or 40 vol% to 60 vol% relative to the total volume of the carrier; or wherein the carrier comprises an aqueous phase of 30 wt% to 70 wt%, or 40 wt% to 60 wt% relative to the total weight of the carrier.

[0162] 34. The pharmaceutical composition according to items 29 to 33, wherein the aqueous phase comprises one or more components selected from: i.) Surfactants, such as polysorbate 80 and polysorbate 20; ii.) Buffer salts, such as phosphates, citrates, borates, Tris-HCl (Tris), for example, wherein the buffer salt is a phosphate, such as selected from disodium hydrogen phosphate pentahydrate, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate; iii.) Preservatives, such as benzalkonium chloride, polyquad, sodium perborate, or preservative complexes, such as Purite®, SofZia®.

[0163] 35. The pharmaceutical composition according to items 29 to 34, wherein the mediator comprises a surfactant in an amount of 3 wt% to 5 wt% relative to the total weight of the semi-fluorinated alkanes in the mediator.

[0164] 36. The pharmaceutical composition according to items 29 to 35, wherein the carrier comprises, by weight relative to the total weight of the semi-fluorinated alkane in the carrier, i.) 3 wt% to 5 wt% of polysorbate 80, or ii.) 3 wt% to 4 wt% of polysorbate 20.

[0165] 37. The pharmaceutical composition according to any of the preceding items, wherein the pharmaceutical composition is used as a medicine.

[0166] 38. The composition according to item 37 for the stated purpose, the composition being used in: a) To treat, prevent, or alleviate dry eye disease; or b) To treat, prevent, or alleviate the signs or symptoms of dry eye disease; or c) Treatment, prevention, or relief of ocular surface diseases, preferably those affecting the cornea and / or conjunctiva, or ocular surface diseases associated with inflammation of the cornea and / or conjunctiva; or d) Increase tear production in at least one or both eyes of a subject with dry eye disease; or e) Treatment of autoimmune disorders of the ocular surface.

[0167] 39. The composition for the stated use according to item 38, wherein the signs of said dry eye disease include damage to the corneal surface, damage to the conjunctival surface, inflammation of the corneal surface, inflammation of the conjunctival surface, reduced tear production, and any combination thereof, and wherein the symptoms of said dry eye disease include dry eyes, itching, gritty or sandy feeling; foreign body sensation; pain or soreness; stinging or burning; pruritus; increased blinking; eye fatigue; photophobia; blurred vision; redness; mucus discharge; contact lens intolerance; excessive reflex tearing, or any combination thereof.

[0168] 40. The composition for the stated purpose according to items 37 to 39, the composition being used in the treatment of mammalian subjects, preferably human subjects.

[0169] 41. The composition for the stated use according to items 37 to 40, wherein the composition is intended for use in a treating human subject, wherein the composition is applied topically to the subject's eye daily to provide a daily dose of about 0.80 to 1.20 mg of rifelast, or about 0.90 to 1.10 mg or about 1.0 mg of rifelast per eye, optionally wherein the composition is applied topically twice daily in a single dose of about 0.40 to 0.60 mg, or about 0.45 to 0.55 mg or about 0.50 mg of rifelast per eye.

[0170] 42. A kit comprising a composition according to any one of the preceding items, the kit comprising a container adapted to contain the composition and optionally means for dispensing the composition and / or instructions for use.

[0171] 43. The kit according to item 42, wherein the dispensing device is adapted to administer a single drop of about 9 to 12 µl of the composition into the eye of the subject.

[0172] 44. A method for preparing compositions as defined in items 1 to 28, the method comprising the step of dissolving or suspending rifelast in a non-aqueous medium comprising or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0173] 45. A method for preparing a composition as defined in items 29 to 36, the method comprising the steps of dissolving rifelast in an aqueous phase, the aqueous medium optionally comprising one or more excipients, and combining the aqueous phase with a liquid phase comprising a semi-fluorinated alkane and optionally one or more excipients, or consisting of a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0174] 46. ​​A method for stabilizing rifaspirant in a composition, the method comprising the steps of dissolving or suspending rifaspirant in a semi-fluorinated alkane as defined in any of the above items, or dissolving or suspending rifaspirant in a medium comprising a semi-fluorinated alkane as defined in any of the above items and optionally one or more excipients.

[0175] 47. The method according to item 44, 45 or 46, wherein the rifelast has an enantiomer excess of at least 80% ee, at least 90%, at least 95% ee or at least 97% ee, or a purity of at least 90%, at least 95%, at least 97% or at least 99% (e.g., determined by HPLC).

[0176] 48. The method according to items 44 to 47, wherein the method: - To prevent the degradation (e.g., hydrolysis and / or dehydration and / or oxidation) of rifaspirant in the composition or to reduce the rate of degradation (e.g., hydrolysis and / or dehydration and / or oxidation); and / or - To prevent isomerization (e.g., racemization) of rifaspire in the composition or to reduce the rate of isomerization (e.g., racemization); and / or - Prevent or reduce the excess of the enantiomer of rifaspirant in the composition; and / or - To prevent the formation of the rifaspirant enantiomer (rifaspirant(R)-isomer) in the composition or to reduce the rate of formation; and / or - To prevent the formation of rifetacal degradation products or reduce the rate of formation, preferably to prevent the formation of rifetacal degradation products or reduce the rate of formation caused by exposure to any one or a combination of heat, oxidation, photolysis, alkaline or acidic conditions.

[0177] 49. The method according to items 44, 46 to 48, the method comprising the step of suspending rifelast in a medium comprising at least 90 wt%, 93 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt% or at least 99.5 wt% of F6H8 (1-perfluorohexyl-octane) and optionally up to 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 2 wt% or up to 3 wt% of 2-perfluorohexyl-octane or composed thereof.

[0178] 50. The method according to items 44, 46 to 49, wherein the method effectively reduces the amount of the one or more rifelast degradation products to less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25% or less than 0.1% relative to the initial amount of rifelast in the composition.

[0179] 51. The method according to items 44, 46 to 50, wherein after storing the composition at 0 to 60ºC, for example at 25ºC for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, the method effectively maintains the amount of rifelast in the composition at at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99% of the initial amount of rifelast in the composition.

[0180] 52. The composition according to items 1 to 36, wherein the composition comprises less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, or less than 0.1% of rifecista degradation products relative to the initial amount of rifecistasta in the composition.

[0181] 53. The composition according to item 52, wherein the degradation products of said rifelast are formed due to exposure of said composition to one or more of heat, oxidation, photolysis, alkaline or acidic conditions, preferably wherein said degradation products of said rifelast are formed due to exposure to heat, oxidation or photolysis conditions; more preferably, wherein said degradation products of said rifelast are formed due to exposure to oxidative conditions.

[0182] 54. The composition according to items 1 to 36, wherein after storing the composition at 0 to 60ºC, for example at 25ºC for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, the amount of rifelast in the composition is at least 90%, or at least 95%, or at least 97%, or at least 98% or at least 99% relative to the initial amount of rifelast in the composition, wherein the oxygen content in the composition is not less than 3 vol%, 4 vol%, 5 vol%, 6 vol%, 7 vol% or not less than 8 vol% relative to the total volume of the composition.

[0183] This disclosure further includes the following items 1 through 15, including: 1. A pharmaceutical composition comprising rifelast or a pharmaceutically acceptable salt thereof dissolved or suspended in a carrier, the carrier comprising a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

[0184] 2. A method for stabilizing rifelast or a pharmaceutically acceptable salt thereof in a pharmaceutical composition, the method comprising the step of dissolving or suspending rifelast in a semi-fluorinated alkane or a medium comprising a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof and any combination thereof.

[0185] 3. The pharmaceutical composition according to item 1 or 2, wherein the semifluorinated alkane is selected from F4H5 (1-perfluorobutylpentane), F6H8 (1-perfluorohexyloctane), their structural isomers, and any combination thereof.

[0186] 4. The pharmaceutical composition according to items 1 to 3, wherein the mediator comprises the semi-fluorinated alkane or a combination of the semi-fluorinated alkane.

[0187] 5. The pharmaceutical composition according to any of the preceding items, wherein rifaspire is present in the composition at a concentration between 2% and 8% (w / v).

[0188] 6. The pharmaceutical composition according to any of the preceding items, wherein the composition is substantially free of a) water; or b) preservatives; or c) antioxidants; d) surfactants and / or e) any combination of a), b), c) and d).

[0189] 7. The pharmaceutical composition according to any of the preceding items, wherein after the composition is stored at 0 to 60ºC, for example at 25ºC for at least 1, 2, 3, 4, 5, 6, 9 or 12 months, the amount of rifelast in the composition is at least 90%, at least 95% or at least 99% relative to the initial amount of rifelast in the composition.

[0190] 8. The pharmaceutical composition according to any of the preceding items, wherein after storage at 0 to 60ºC, for example after storage at 25ºC for at least 1, 2, 3, 4, 5, 6, 9, or 12 months, the enantiomeric excess of rifelast in the composition relative to its enantiomer (rifelast(R)-isomer) is at least 90%, at least 95%, or at least 99% of the initial enantiomer excess of rifelast in the composition.

[0191] 9. The pharmaceutical composition according to any of the preceding items, wherein the oxygen content in the composition is not less than 3% by volume, 4% by volume, 5% by volume, 6% by volume, 7% by volume, or not less than 8% by volume.

[0192] 10. The pharmaceutical composition according to any of the preceding items, wherein the composition is formulated for or suitable for topical application to the surface of the eye, such as the conjunctiva and / or cornea.

[0193] 11. The pharmaceutical composition according to any of the preceding items, wherein the carrier comprises an aqueous phase, and wherein the rifaspire is dissolved in the aqueous phase of the carrier.

[0194] 12. The pharmaceutical composition according to item 11, wherein the composition is in the form of an emulsion.

[0195] 13. The pharmaceutical composition according to item 11 or 12, wherein the mediator comprises a surfactant in an amount of 3 wt% to 5 wt% relative to the total weight of the one or more semi-fluorinated alkanes in the mediator, optionally wherein the mediator comprises polysorbate 80 or polysorbate 20 in an amount of 3 wt% to 5 wt% relative to the total weight of the one or more semi-fluorinated alkanes in the mediator.

[0196] 14. The pharmaceutical composition according to items 1 to 10, wherein the composition comprises 5% (w / v) rifelast suspended in a medium consisting of F6H8 and optionally one or more excipients.

[0197] 15. The pharmaceutical composition according to any of the preceding items, wherein the pharmaceutical composition is used as a medicine; optionally wherein the composition is used for: a) treating, preventing or alleviating dry eye disease; or b) treating, preventing or alleviating signs or symptoms of dry eye disease; or c) increasing tear production in at least one or both eyes of a subject suffering from dry eye disease.

[0198] The following examples are used to illustrate the present invention; however, they should not be construed as limiting the scope of the invention.

[0199] Example Example 1: Preparation of an ophthalmic suspension composition containing rifaspirate and semi-fluorinated alkanes To prepare a 5% (w / v) rifexalate composition in F6H8 or F4H5, 50 mg of rifexalate was weighed into a clear glass capped vial, and 1 ml of F6H8 (or F4H5) was added. A Teflon-coated magnetic stir bar was then added to the vial, which was subsequently capped and placed on a magnetic stirrer set to 500 rpm for 2 hours. Visual inspection revealed that both formulations of rifexalate in F6H8 and F4H5 exhibited a surprisingly uniform distribution of suspended rifexalate particles within the semi-fluorinated alkanes.

[0200] Both formulations were stored overnight. Visual inspection the following day showed that the vast majority of API particles remained free-floating and suspended in semi-fluorinated alkanes. Slight shaking of the suspension formulation resulted in uniform redistribution and redispersibility of the rifafloxacin particles, and no clumping or aggregation of particles was observed.

[0201] Visual inspection of the composition after 2, 4, 6, and 8 weeks still demonstrated that the composition remained unchanged; both suspension compositions remained easily redispersible.

[0202] Similar studies were conducted on suspension compositions of rifamil at concentrations ranging from 10 to 90 mg / mL (i.e., 1% to 9% (w / v) rifamil suspensions in F6H8 or F4H5). Suspensions of 10 mg / mL, 25 mg / mL, 30 mg / mL, 70 mg / mL, and 90 mg / mL rifamil suspended in F6H8 or F4H5 were prepared. All formulations within these concentration ranges exhibited the same visual-physical properties as described above.

[0203] Example 2: Preparation of an ophthalmic composition comprising rifaspirant, semi-fluorinated alkanes and excipients The following formulations were prepared according to the procedure described in Example 1: - Rifalast at concentrations of 10, 25, 30, 50, 70, and 90 mg / ml suspended in a medium containing F6H8 and 1 wt% ethanol. Example 3: Determination of oxygen content in a composition containing rifaspirant Shortly after preparation, the oxygen content of the formulation containing a 50 mg / mL rifelast in F6H8 was determined and compared with that of the mediator F6H8 alone. The oxygen content of the formulation was determined using a chemioptic oxygen microsensor (PreSens—Precision Sensing GmbH; Regensburg, Germany; the microsensor has a measurement range of 0–250% air saturation, equivalent to 0–22.5 mg / L dissolved oxygen). No difference was observed in the oxygen content measurements between the F6H8 mediator and the rifelast / F6H8 combination (50 mg / mL). Both measurements yielded the same value, 22% oxygen saturation, which translates to approximately 4.61% by volume of oxygen (or 1.9 mg / mL).

[0204] Example 4: Preparation of an ophthalmic emulsion composition containing rifaspirant and semi-fluorinated alkanes An ophthalmic emulsion composition was prepared according to the following procedure: First, rifelast and a surfactant were mixed in equal amounts in an aqueous buffer to form an aqueous phase. Then, a semi-fluorinated alkane phase was slowly added to the aqueous phase under vigorous stirring. The pre-emulsion was stirred at 2000 rpm for more than 1 hour. The turbid pre-emulsion was then sonicated at maximum amplitude (UP400S, Hielscher) for 5 min under ice bath cooling to obtain the emulsion. The prepared emulsion was physically stable upon visual examination.

[0205] The following emulsion compositions were prepared according to this general procedure: Note: * = Concentration relative to the total weight of the semi-fluorinated alkane phase (the total weight of one or more semi-fluorinated alkane phases in the composition).

[0206] Example 5: Stability of ophthalmic suspension compositions containing rifaspirate and semi-fluorinated alkanes Forced degradation and stress studies were conducted to determine the stability of ophthalmic suspension compositions containing rifaspirate and semi-fluorinated alkanes. A 5% rifaspirate suspension in F6H8 was subjected to thermal, oxidative, acidic, and alkaline stresses, each at 80ºC for 24 hours. Additionally, photodegradation stress (1.2 million lux visible light and 200 wh / m² UV light) was performed at room temperature. The stressed samples were analyzed by UV (260 nm) and reversed-phase HPLC (C18 column, mobile phase A: phosphoric acid dilution, mobile phase B: acetonitrile with phosphoric acid, gradient system, flow rate 0.8 mL / min, column temperature 40ºC, UV detection at 210 nm and 260 nm).

[0207] These studies observed that compositions containing rifetazone suspended in F6H8 were highly stable. No significant degradation products were identified, which is unexpected considering the harsh stress conditions of 24 hours at 80ºC. Notably, the suspension of rifetazone in F6H8 did not show degradation under thermal stress, which already includes oxidative stress when considering the approximately 22% oxygen saturation of the formulation (see Example 3). Furthermore, no oxidative degradation was observed when additional oxidative stress was applied. This is unexpected and contrasts with the prior art teaching that aqueous rifetazone formulations are sensitive to oxidative stress (leading to the inclusion of antioxidants in commercially available aqueous rifetazone ophthalmic compositions). Therefore, the use of semi-fluorinated alkanes as a mediator not only supports overall stability but also eliminates the need for antioxidants.

[0208] Example 6: Stability and Degradation Products To further investigate the stability of the ophthalmic suspension composition containing rifaspirant, it was compared with an aqueous solution formulation of rifaspirant. The following three rifaspirant compositions were compared according to the forced degradation and stress study settings described in Example 5: (A) 5% (w / v) rifelast [aqueous] dissolved in 10 mM phosphate buffer (pH 9.2); (B) 5% (w / v) commercially available rifetazone eye drops (Xiidra) dissolved in phosphate buffer (pH 7-8) and containing sodium thiosulfate as an antioxidant. ® [Water-based]; (C) 5% (w / v) rifelast [non-aqueous] suspended in 1-perfluorohexyloctane.

[0209] Rifalast samples (A), (B), and (C) were subjected to thermal, photolytic, oxidative, and alkaline stress conditions and analyzed using the HPLC method described in Example 5. The peak areas of rifalast and its major degradation products were quantified (see [reference]). Figure 1 and Figure 2 ).

[0210] Under alkaline stress, the major degradation product with a relative retention time (RRT) of 0.67 and a relative total peak area of ​​1.38% was found only for composition (A).

[0211] When subjected to thermal stress, no major degradation products were identified for rifelast samples (B) and (C), while for the aqueous formulation (A), a major degradation product with an RRT of 0.67 and a relative total peak area of ​​3.48% was observed.

[0212] Conversely, key differences were observed among the three formulations under oxidative and photolytic conditions (see Table 1 below).

[0213] Under oxidative stress, for composition (A), the major degradation product was found to have a relative retention time (RRT) of 0.67 and a relative total peak area of ​​2.39%, while other impurities appeared between RRTs of 0.67 and 0.88. Commercially available 5% rifaspirant eye drops, Xiidra... ® (B) Major degradation products were observed at RRT 0.42, RRT 0.60, and RRT 0.73, with a relative total peak area of ​​6.48%. In contrast, the non-aqueous suspension of rifetastar in F6H8 (C) did not show major degradation products and was found to be stable under oxidative stress conditions.

[0214] The sample was subjected to photolysis stress. For composition (A), impurities with a relative total peak area of ​​1.38% and an RRT of 0.88, as well as other impurities, were detected. Commercially available rifaspirant eye drops Xiidra... ® (B) Two major degradation products were observed at RRT 0.73 (7.03 min) and RRT 0.88 (8.48 min), with a total relative peak area of ​​1.41%. More impurities were noted between RRT 0.40 and 0.56 (3.8–4.5 min). The non-aqueous suspension of rifelast in F6H8 (C) was found to be stable under photodegradation stress, and no major degradation products were detected.

[0215] In summary, the findings of Example 5 were confirmed, revealing that rifetaste (C) suspended in a semi-fluorinated alkane (F6H8) was more stable under applied stress conditions compared to two aqueous rifetaste formulations (A) and (B). When considering commercially available Xiidra... ® The above results are particularly surprising given that formulation (B) already contains an antioxidant (sodium thiosulfate) to prevent or at least reduce the oxidation of the active ingredient rifelast under oxidative stress. Furthermore, the difference in oxidative stress stability observed between the formulation and the aqueous formulation is even more surprising when considering the approximately 22% oxygen saturation of the non-aqueous rifelast suspension in the SFA (see Example 3). This highlights the advantage of rifelast's stability under oxidative stress and other environmental stresses as described herein when formulated, for example, in suspension in semi-fluorinated alkanes (such as 1-perfluorohexyloctane).

[0216] Table 1 RRT = Relative Retention Time (relative to the retention time determined by Rifaist). Example 7 Compositions (B) and (C) underwent the forced degradation and stress studies described in Example 5, and were analyzed by chiral HPLC (Chiralcel OJ-RH column, mobile phase A: formic acid, pH 3.0, mobile phase B: acetonitrile; isocratic (65:35), flow rate 1.0 mL / min, column temperature 40ºC, UV detection at 260 nm). This analysis confirmed the findings of Example 6, namely that under oxidative stress, a higher rate of rifelast conversion to degradation products was observed in the commercially available Xiidra® formulation (B), while the non-aqueous suspension of rifelast in F6H8 (C) was found to be stable, with no major degradation products detected. Furthermore, even under applied forced degradation and stress conditions, no conversion of rifaspirant to its enantiomer (rifaspirant(R)-isomer) was observed in the non-aqueous suspension (C) of rifaspirant in F6H8, demonstrating that the optical purity and enantiomer excess (ee) of rifaspirant in this formulation remained stable and were maintained. Figure 3 ).

Claims

1. A pharmaceutical composition comprising rifelast or a pharmaceutically acceptable salt thereof suspended in a carrier, the carrier comprising a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10 or their structural isomers and any combination thereof.

2. The pharmaceutical composition according to claim 1, wherein the semifluorinated alkane is selected from F4H5 (1-perfluorobutylpentane), F6H8 (1-perfluorohexyloctane), their structural isomers, and any combination thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the mediator comprises the semi-fluorinated alkanes or a combination of semi-fluorinated alkanes.

4. The pharmaceutical composition according to any of the preceding claims, wherein rifaspire is present in the composition at a concentration between 2% and 8% (w / v).

5. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is substantially free of a) water; or b) preservatives; or c) antioxidants; d) surfactants and / or e) any combination of a), b), c) and d).

6. The pharmaceutical composition according to any one of the preceding claims, wherein the oxygen content in the composition is not less than 3% by volume, 4% by volume, 5% by volume, 6% by volume, 7% by volume, or not less than 8% by volume.

7. The pharmaceutical composition according to any of the preceding claims, wherein the composition is formulated for or adapted for topical application to the surface of the eye, such as the conjunctiva and / or cornea.

8. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises 5% (w / v) rifelast suspended in a medium consisting of F6H8 and optionally one or more excipients.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is used as a medicine.

10. The pharmaceutical composition for the purpose according to claim 9, wherein the composition is used for: a) treating, preventing or alleviating dry eye disease; or b) treating, preventing or alleviating signs or symptoms of dry eye disease; or c) increasing tear production in at least one or both eyes of a subject suffering from dry eye disease.

11. A method for stabilizing rifelast or a pharmaceutically acceptable salt thereof in a pharmaceutical composition, the method comprising suspending rifelast in a semi-fluorinated alkane or a medium comprising a semi-fluorinated alkane and optionally one or more excipients, wherein the semi-fluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, F6H10, or structural isomers thereof and any combination thereof.

12. The method according to claim 11, wherein the semi-fluorinated alkane is selected from F4H5 (1-perfluorobutylpentane), F6H8 (1-perfluorohexyloctane), their structural isomers, and any combination thereof.

13. The method according to claim 11 or 12, wherein the medium comprises the semi-fluorinated alkane or a combination of the semi-fluorinated alkane.

14. The method according to any one of claims 11 to 13, wherein rifelast is present in the composition at a concentration between 2% and 8% (w / v).

15. The method according to any one of claims 11 to 14, wherein the medium is substantially free of a) water; or b) preservatives; or c) antioxidants; d) surfactants and / or e) any combination of a), b), c) and d).

16. The method according to any one of claims 11 to 15, wherein the oxygen content in the composition is not less than 3% by volume, 4% by volume, 5% by volume, 6% by volume, 7% by volume, or not less than 8% by volume.

17. The method according to any one of claims 11 to 16, wherein the method comprises suspending 5% (w / v) rifelast in a medium consisting of F6H8 and optionally one or more excipients.

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