PHARMACEUTICAL DOSAGE FORMS CONTAINING TASK-I AND TASK-3 CHANNEL INHIBITORS, AND THE USE OF SAME IN BREATHING DISORDER THERAPY

Abstract

The invention relates to new pharmaceutical dosage forms containing potent and selective TASK-1 and/or TASK-3 channel inhibitors, and the use of same to treat and/or prevent breathing disorders including sleep-related breathing disorders such as obstructive and central sleep apnoea and snoring.

Claims

1. A stable pharmaceutical formulation for nasal or pharyngeal administration comprising: a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel or a hydrate, solvate, polymorph or metabolite thereof, or a pharmaceutically acceptable salt thereof, in >2.5% to 100% w/v polyethylene glycol, wherein the formulation has a pH of 4 to 8.

2. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 1, further comprising at least one auxiliary, wherein the at least one auxiliary is selected from the group consisting of at least one pH regulator, at least one solubilizer, at least one antioxidant, at least one stabilizer, at least one thickener, at least one preservative, at least one substance for adjusting tonicity, at least one aroma, at least one fragrance and at least one dye.

3. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 2, wherein the at least one auxiliary comprises at least one pH regulator, and wherein the at least one pH regulator is selected from the group consisting of citric acid and salts thereof, acetic acid and salts thereof, phosphoric acid and salts thereof, hydrochloric acid, carboxylic acids, dicarboxylic acids, amino acids, oxocarboxylic acids, polycarboxylic acids, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogencarbonate.

4. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 2, wherein the at least one auxiliary comprises at least one solubilizer, and wherein the at least one solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80.

5. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 2, wherein the at least one auxiliary comprises at least one antioxidant, wherein the at least one antioxidant is selected from the group consisting of citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA and purging with nitrogen.

6. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 2, wherein the at least one auxiliary comprises at least one preservative, and wherein the at least one preservative is selected from the group consisting of C.sub.8-C.sub.18 alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and benzalkonium chloride.

7. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 1, wherein the formulation comprises 5 to 100% w/v polyethylene glycol 400, 0 to 10% w/v of a solubilizer, and 0 to 95% w/v of a pH regulator.

8. The stable pharmaceutical formulation for nasal or pharyngeal administration according to claim 1, wherein the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from a compound of formula (I), ##STR00008## wherein R.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl; R.sup.2 is (C.sub.4-C.sub.6)-cycloalkyl, wherein a ring CH.sub.2 group may be replaced by O, or R.sup.2 is represents a phenyl group of formula (a) or a pyridyl group of formula (b) ##STR00009## wherein * marks the bond to the adjacent carbonyl group; and R.sup.3 is fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy, wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine; R.sup.4 is hydrogen, fluorine, chlorine, bromine or methyl; R.sup.5 is hydrogen, fluorine, chlorine, bromine or methyl; and R.sup.6 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy or tetrahydro-2H-pyran-4-yloxy, wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine, or a hydrate, solvate, polymorph or metabolite thereof, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical formulation for nasal or pharyngeal administration according to claim 8, wherein the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from the group consisting of: (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(2-fluorophenyl)methanone, (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, and (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, or a hydrate, solvate, polymorph or metabolite thereof, or a pharmaceutically acceptable salt thereof.

10. The stable pharmaceutical formulation according to claim 9, wherein the at least one inhibitor of the TASK-1 and/or TASK-3 channel is (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof, or a pharmaceutically acceptable salt thereof.

11. (canceled)

12. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical formulation according to claim 1.

13. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical formulation according to claim 1, wherein the formulation is by nasal sprays, nasal drops, nasal solutions, powder inhalers, nebulizers, metered dose aerosols or semisolid gels.

14. A method for treatment or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders or neuroimmunological disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical formulation according to claim 1, wherein the duration of action is at least 4 hours.

15. A method for treatment or prevention of obstructive sleep apnoeas or snoring, comprising administering to a patient in need thereof a stable pharmaceutical formulation according to claim 8, wherein the stable pharmaceutical formulation comprises: a therapeutically effective amount of the inhibitor of the TASK-1 and/or TASK-3 channel 4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, in 20% to 100% w/v PEG400, and 0 to 10% w/v polysorbate 80 and 0 to 80% w/v of a phosphate buffer having a pH of 7, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal administration is at least 5 hours.

16. The stable pharmaceutical formulation according to claim 7, wherein the stable pharmaceutical formulation comprises at least one further auxiliary.

17. The method according to claim 15, wherein the stable pharmaceutical formulation comprises at least one further auxiliary.

Description

[0051] According to one embodiment of the present invention, the duration of action is defined as the period in which the apnoea-hypopnoea index (AHI) of said patient is reduced by at least 20% after nasal or pharyngeal administration of a formulation according to the invention comprising a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, to a patient with sleep-related respiratory disorders such as obstructive and central sleep apnoeas and snoring.

[0052] According to one embodiment of the present invention, the duration of action is defined as the period in which the apnoea-hypopnoea index (AHI) of said patient is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% or at least 80% after nasal or pharyngeal administration of a formulation according to the invention comprising a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, to a patient with sleep-related respiratory disorders such as obstructive and central sleep apnoeas and snoring.

[0053] In the context of the present invention, the duration of action is at least 3 hours or at least 3.5 hours or at least 4 hours or at least 4.5 hours or at least 5 hours or at least 5.5 hours or at least 6 hours or at least 6.5 hours or at least 7 hours or at least 7.5 hours or at least 8 hours. According to one embodiment of the present invention, the duration of action is at least 3 hours. According to one embodiment of the present invention, the duration of action is at least 4 hours. According to one embodiment of the present invention, the duration of action is at least 5 hours.

[0054] In the context of the present invention, a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, is defined as the amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, which on nasal or pharyngeal administration shows a duration of action of at least 3 hours or at least 3.5 hours or at least 4 hours or at least 4.5 hours or at least 5 hours or at least 5.5 hours or at least 6 hours or at least 6.5 hours or at least 7 hours or at least 7.5 hours or at least 8 hours.

[0055] In the context of the present invention, a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, is defined as the amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, which on nasal or pharyngeal administration shows a duration of action of at least 3 hours.

[0056] In the context of the present invention, a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, is defined as the amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, which on nasal or pharyngeal administration shows a duration of action of at least 4 hours.

[0057] In the context of the present invention, a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, is defined as the amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, which on nasal or pharyngeal administration shows a duration of action of at least 5 hours.

[0058] In the context of the present invention, auxiliaries are substances which, in the stable pharmaceutical formulation serve the purpose, for example, of adjusting or stabilizing the pH, of increasing the solubility of the active ingredient, of microbiologically and physically stabilizing the preparation, of modifying the viscosity of the formulation or improving the taste or appearance.

[0059] Examples of auxiliaries in the context of the present invention are pH regulators, solubilizers, antioxidants, stabilizers, thickeners, preservatives, substances for adjusting tonicity, aromas, fragrances or dyes.

[0060] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optional at least one auxiliary is selected from the group consisting of at least one pH regulator, at least one solubilizer, at least one antioxidant, at least one stabilizer, at least one thickener, at least one preservative, at least one substance for adjusting tonicity, at least one aroma, at least one fragrance and at least one dye.

[0061] In the context of the present invention, pH regulators are, for example, buffers such as citric acid and salts thereof, acetic acid and salts thereof and phosphoric acid and salts thereof, or inorganic acids such as hydrochloric acid, boric acid, carboxylic acids, dicarboxylic acids, amino acids or organic acids such as monocarboxylic acids such as oxocarboxylic acids or polycarboxylic acids, or bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate.

[0062] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optional at least one pH regulator is selected from the group consisting of citric acid and salts thereof, acetic acid and salts thereof, phosphoric acid and salts thereof, hydrochloric acid, boric acid, carboxylic acids, dicarboxylic acids, amino acids, oxocarboxylic acids, polycarboxylic acids, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogencarbonate.

[0063] According to one embodiment of the invention, the pH regulator is a phosphate buffer. According to one embodiment of the invention, the pH regulator is a phosphate buffer which buffers the solution in the context of the present invention to a pH between 4 and 8. The preferred pH range is between 7 and 8. According to one embodiment, the pH of the formulations according to the invention is 7.

[0064] In the context of the present invention, solubilizers are, for example, chelating agents (for example cyclodextrins and sodium EDTA (sodium ethylenediaminetetraacetate)), cosolvents (for example ethanol, propylene glycol, dimethylacetamide), and surfactants. The group of surfactants includes, for example, fatty alcohols (for example cetyl alcohol), phospholipids (for example lecithin), sterols (for example cholesterol), bile acid salts, saponins, glycerol fatty acid esters (for example glycerol monostearate), polyoxyethylene fatty acid esters (for example polyoxyethylene stearate), polyoxyethylene sorbitan fatty acid esters (such as Tween, for example polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 21 (polyoxyethylene (4) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 61 (polyoxyethylene (4) sorbitan monostearate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), polysorbate 81 (polyoxyethylene (5) sorbitan monooleate), polysorbate 85 (polyoxyethylene (20) sorbitan trioleate), polysorbate 120 (polyoxyethylene (20) sorbitan monoisostearate)), sorbitan fatty acid esters (such as Span, for example sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60) sorbitan tristearate (Span 65) sorbitan monooleate (Span 80), sorbitan sesquioleate (Span 83), sorbitan trioleate (Span 85), polyoxyethylene glycerol fatty acid esters (for example polyoxyethylene glycerol monostearate, polyoxyethylene glycerol ricinoleate, polyoxyethylene glycerol triricinoleate), polyoxyethylene fatty alcohol ethers (for example polyoxyethylene lauryl ether, polyoxyethylene cetyl-stearyl ether), polyoxypropylene-polyoxyethylene block copolymers (for example poloxamer), alkyl sulfates (for example sodium lauryl sulfate, sodium cetyl-stearyl sulfate), alkali soaps (for example sodium palmitate, sodium stearate) and sucrose fatty acid esters. According to one embodiment of the invention, the solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80. According to one embodiment of the invention, the solubilizer is polysorbate 80.

[0065] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optional at least one solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80.

[0066] If a surfactant is present as solubilizer in the formulations according to the invention, the concentration of this surfactant is at least its critical micelle concentration (CMC) and at most the maximum approved amount for nasal or pharyngeal administration. The CMC of polysorbate 80 is 0.001% w/v and the maximum pharmaceutically approved concentration is 10% w/v. When using polysorbate 80 as solubilizer, polysorbate 80 is present in the formulations according to the invention at a concentration of 0.001-10% w/v, or 0.1-10% w/v, or 1-10% w/v or 5-10% w/v. Alternatively, polysorbate 80 may also be present in the formulations according to the invention at concentrations up to 15% w/v or up to 20% w/v.

[0067] In the context of the present invention, antioxidants are, for example, citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA, purging with nitrogen, tocopherol, ascorbic acid, glutathione, cysteine, sulfites (for example sodium sulfite, sodium hydrogensulfite), disulfites (for example sodium pyrosulfite), ascorbic acid esters or gallates. According to one embodiment of the invention, the antioxidant is selected from the group consisting of citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA and purging with nitrogen. According to one embodiment of the invention, the antioxidant is butylhydroxyanisole.

[0068] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optional at least one antioxidant is selected from the group consisting of citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA and purging with nitrogen.

[0069] One embodiment of the present invention relates to stable pharmaceutical formulations for nasal or pharyngeal administration comprising:

[0070] a therapeutically effective amount of at least one inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in >2.5% to 100% w/v polyethylene glycol and an antioxidant and optionally at least one further auxiliary, wherein the formulation has a pH of 4 to 8.

[0071] In the context of the present invention, preservatives are, for example, phenolic substances such as phenol or cresol, alcohols such as ethanol, chlorobutanol, phenylethanol, or propylene glycol, invert soaps such as benzalkonium chloride or benzethonium chloride, benzoic acid and salts thereof, sorbic acid and salts thereof, dehydroacetic acid and sulfuric acid and salts thereof, sodium hydrogensulfite, parabens, including methylparaben and propylparaben or thiomersal. According to one embodiment of the invention, the preservative is selected from the group consisting of C.sub.8-C.sub.18 alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and benzalkonium chloride. According to one embodiment of the invention, the preservative is benzalkonium chloride.

[0072] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optional at least one preservative is selected from the group consisting of C.sub.8-C.sub.18 alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and benzalkonium chloride.

[0073] In the context of the present invention, substances for adjusting tonicity are, for example, salts (e.g. of plasma cations with physiologically tolerable counterions), sugars (e.g. glucose, sucrose), sugar alcohols (e.g. mannitol, sorbitol), glycols (e.g. propylene glycols) and other non-ionic polyol materials.

[0074] In the context of the present invention, thickeners are, for example, natural rubbers, alginic acid, pectins, starch and starch derivatives, gelatins, poloxamers (block copolymers of ethylene oxide and propylene oxide) cellulose derivatives, acrylic acid polymers or vinyl polymers.

[0075] According to one embodiment of the present invention, the formulations according to the invention comprise at least one pH regulator as auxiliary. According to one embodiment of the present invention, the formulations according to the invention comprise at least one antioxidant as auxiliary. According to one embodiment of the present invention, the formulations according to the invention comprise at least one solubilizer as auxiliary. According to one embodiment of the present invention, the formulations according to the invention comprise at least one pH regulator and at least one solubilizer as auxiliaries. According to one embodiment of the present invention, the formulations according to the invention comprise at least one antioxidant and at least one solubilizer as auxiliaries. According to one embodiment of the present invention, the formulations according to the invention comprise at least one pH regulator, at least one solubilizer and at least one antioxidant as auxiliaries. According to one embodiment of the present invention, the formulations according to the invention comprise at least one pH regulator, at least one solubilizer, at least one antioxidant and at least one preservative as auxiliaries.

[0076] The present invention also provides stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the formulation comprises 5 to 100% w/v polyethylene glycol 400, 0 to 10% wv of a solubilizer, 0 to 95% w/v of a pH regulator and optionally at least one further auxiliary.

[0077] For the purpose of the present invention, polyethylene glycol is defined as a polyethylene glycol of the general formula (II)

##STR00001##

[0078] having a molar mass of 44 g/mol per repeat unit and additionally by weight of the incorporated water. The empirical formula of polyethylene glycol is C.sub.2nH.sub.4n+2O.sub.n+1.

[0079] In the context of the present invention, use may be made of polyethylene glycols having a mean molar mass of 200 to 3350 Da. According to a further embodiment, the present invention uses polyethylene glycols having a molecular weight of from 200 to 600 or 300 to 400 or 400. These are approved for nasal administration.

[0080] One embodiment of the present invention is a stable pharmaceutical formulation according to the invention for nasal or pharyngeal administration, wherein the formulation comprises >2.5% w/v to 100% w/v polyethylene glycol having a molecular weight of 200 to 600 and optionally comprises at least one pH regulator and optionally at least one solubilizer and optionally at least one further auxiliary.

[0081] S PEG 400 has an aver age molar mass of 400 glmol, PEG 300 has an average molar mass of 300 glmol.

[0082] In the context of the present invention, the dynamic viscosity (at 20 C.) of the formulations according to the invention is between 0.5 and 1480 mPa*s, preferably between 1.0 and 140 mPa*s. Formulations according to the invention for nasal administration by means of nasal spray preferably have a dynamic viscosity (at 20 C.) between 1.0 and 140 mPa*s. Formulations according to the invention for nasal administration by means of nasal drops preferably have a dynamic viscosity (at 20 C.) between 1.0 and 1480 mPa*s.

[0083] One embodiment of the present invention is a stable pharmaceutical formulation according to the invention for nasal or pharyngeal administration, wherein the formulation has a viscosity at 20 C. of 0.5-200 mPa*s, preferably 1-20 mPa*s.

[0084] One formulation according to the invention comprising 20% w/v PEG 400 and 10% w/v polysorbate 80 in phosphate buffer has a dynamic viscosity of ca. 6 mPa*s.

[0085] In the context of the present invention, the preferred droplet size (stated as median volume diameter) in an atomized formulation is between 5 and 300 m, preferably between 30 and 100 m. This is independent of whether the administration is nasal or pharyngeal.

[0086] One embodiment of the present invention is a stable pharmaceutical formulation according to the invention for nasal or pharyngeal administration, wherein the formulation is administered as a nasal spray and has a droplet size as median volume diameter of 5-300 m, preferably 30-100 m.

[0087] According to one embodiment of the present invention, the formulations according to the invention comprise >2.5% w/v to 100% w/v or 3% w/v to 100% w/v or 3% w/v to 90% w/v or 3% w/v to 80% w/v or 3% w/v to 70% w/v or 3% w/v to 60% w/v or 3% w/v to 50% w/v or 3% w/v to 40% w/v or 3% w/v to 30% w/v or 3% w/v to 20% w/v or 3% w/v to 10% w/v or 3% w/v to 5% w/v or 5% w/v to 100% w/v or 5% w/v to 90% w/v or 5% w/v to 80% w/v or 5% w/v to 70% w/v or 5% w/v to 60% w/v or 5% w/v to 50% w/v or 5% w/v to 40% w/v or 5% w/v to 50% w/v or 5% w/v to 20% w/v or 5% w/v to 10% w/v or 5% w/v PEG200 or PEG300 or PEG400 or PEG500 or PEG600.

[0088] According to one embodiment of the present invention, the formulations according to the invention comprise >2.5% w/v to 100% w/v or 3% w/v to 100% w/v or 3% w/v to 90% w/v or 3% w/v to 80% w/v or 3% w/v to 70% w/v or 3% w/v to 60% w/v or 3% w/v to 50% w/v or 3% w/v to 40% w/v or 3% w/v to 30% w/v or 3% w/v to 20% w/v or 3% w/v to 10% w/v or 3% w/v to 5% w/v or 5% w/v to 100% w/v or 5% w/v to 90% w/v or 5% w/v to 80% w/v or 5% w/v to 70% w/v or 5% w/v to 60% w/v or 5% w/v to 50% w/v or 5% w/v to 40% w/v or 5% w/v to 50% w/v or 5% w/v to 20% w/v or 5% w/v to 10% w/v or 5% w/v PEG400.

[0089] According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in >2.5 to 100% w/v PEG400. According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in 5 to 100% w/v PEG400. According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in 10 to 100% w/v PEG400. According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in 20 to 100% w/v PEG400. According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in 5 to 20% w/v PEG400. According to one embodiment of the present invention, the formulations according to the invention comprise the inhibitor of the TASK-1 and/or TASK-3 channel in 20% w/v PEG400.

[0090] In the context of the present invention, an active ingredient is defined as an inhibitor of the TASK-1 and/or TASK-3 channel, or a hydrate, solvate, polymorph, or metabolite thereof or a pharmaceutically acceptable salt thereof.

[0091] Stable pharmaceutical formulations according to the invention are, for example, those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from the compounds described in PCT/EP2016/079973.

[0092] Stable pharmaceutical formulations according to the invention are, for example, those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the general formula (I),

##STR00002##

[0093] in which

[0094] R.sup.1 represents halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl

[0095] and

[0096] R.sup.2 represents (C.sub.4-C.sub.6)-cycloalkyl in which a ring CH.sub.2 group may be replaced by O

[0097] or

[0098] represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

##STR00003##

[0099] in which * marks the bond to the adjacent carbonyl group and

[0100] R.sup.3 represents fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy,

[0101] where (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine,

[0102] R.sup.4 represents hydrogen, fluorine, chlorine, bromine or methyl,

[0103] R.sup.5 represents hydrogen, fluorine, chlorine, bromine or methyl,

[0104] and

[0105] R.sup.6 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy or tetrahydro-2H-pyran-4-yloxy,

[0106] where (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine,

[0107] and the salts, solvates and solvates of the salts thereof.

[0108] Stable pharmaceutical formulations according to the invention are, for example, those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I) given above, in which

[0109] R.sup.1 represents fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl or cyclopropyl and

[0110] R.sup.2 represents cyclobutyl, cyclopentyl or cyclohexyl

[0111] or

[0112] represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

##STR00004##

[0113] in which * marks the bond to the adjacent carbonyl group and

[0114] R.sup.3 represents fluorine, chlorine, cyano, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-alkoxy or trifluoromethoxy, [0115] R.sup.4 represents hydrogen, fluorine or chlorine, [0116] R.sup.5 represents hydrogen, fluorine, chlorine, bromine or methyl

[0117] and

[0118] R.sup.6 represents hydrogen or (C.sub.1-C.sub.3)-alkoxy which may be up to trisubstituted by fluorine,

[0119] and the salts, solvates and solvates of the salts thereof.

[0120] Stable pharmaceutical formulations according to the invention are, for example, those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0121] R.sup.1 represents chlorine or bromine,

[0122] and the salts, solvates and solvates of the salts thereof.

[0123] Stable pharmaceutical formulations according to the invention are, for example, those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0124] R.sup.1 represents methyl, isopropyl, tert-butyl or cyclopropyl,

[0125] and the salts, solvates and solvates of the salts thereof.

[0126] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0127] R.sup.2 represents cyclobutyl, cyclopentyl or cyclohexyl,

[0128] and the salts, solvates and solvates of the salts thereof.

[0129] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0130] R.sup.2 represents a phenyl group of the formula (a)

##STR00005##

[0131] in which * marks the bond to the adjacent carbonyl group,

[0132] R.sup.3 represents fluorine, chlorine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy

[0133] and

[0134] R.sup.4 represents hydrogen, fluorine or chlorine,

[0135] and the salts, solvates and solvates of the salts thereof.

[0136] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0137] R.sup.2 represents a pyridyl group of the formula (b)

##STR00006##

[0138] in which * marks the bond to the adjacent carbonyl group,

[0139] R.sup.5 represents hydrogen, chlorine or bromine

[0140] and

[0141] R.sup.6 represents (C.sub.1-C.sub.3)-alkoxy which may be up to trisubstituted by fluorine,

[0142] and the salts, solvates and solvates of the salts thereof.

[0143] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of the formula (I), in which

[0144] R.sup.1 represents chlorine, bromine, isopropyl or cyclopropyl

[0145] and

[0146] R.sup.2 represents cyclobutyl, cyclopentyl or cyclohexyl

[0147] or

[0148] represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

##STR00007##

[0149] in which * marks the bond to the adjacent carbonyl group and

[0150] R.sup.3 represents fluorine, chlorine, cyano, methyl, isopropyl, methoxy or ethoxy,

[0151] R.sup.4 represents hydrogen, fluorine or chlorine,

[0152] R.sup.5 represents hydrogen, chlorine or bromine

[0153] and

[0154] R.sup.6 represents methoxy, difluoromethoxy, trifluoromethoxy or isopropoxy,

[0155] and the salts, solvates and solvates of the salts thereof

[0156] The individual radical definitions specified in the respective combinations or preferred combinations of radicals are, independently of the respective combinations of the radicals specified, also replaced as desired by radical definitions of other combinations.

[0157] Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

[0158] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from compounds of Table 1. The synthesis of these compounds is described in PCT/EP2016/079973.

TABLE-US-00001 TABLE 1 Compounds of PCT/EP2016/079973 Example Name 1 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclopentyl)methanone 2 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclopentyl)methanone 3 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxypyridin-2-yl)methanone 4 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-fluorophenyl)methanone 5 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(3-methoxyphenyl)methanone 6 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-chloro-5-fluorophenyl)methanone 7 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-fluorophenyl)methanone 8 (4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclohexyl)methanone 9 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclohexyl)methanone 10 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(tetrahydrofuran-3-yl)methanone 11 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclobutyl)methanone 12 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-methoxyphenyl)methanone 13 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(5-fluoro-2-methoxyphenyl)methanone 14 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-methylphenyl)methanone 15 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(5-fluoro-2-methylphenyl)methanone 16 (2-chloro-5-fluorophenyl)(4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 17 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclohexyl)methanone 18 ((4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclobutyl)methanone 19 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(3-methoxyphenyl)methanone 20 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-methoxyphenyl)methanone 21 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(5-fluoro-2-methoxyphenyl)methanone 22 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-methylphenyl)methanone 23 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(5-fluoro-2-methylphenyl)methanone 24 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[3-(trifluoromethoxy)phenyl]methanone 25 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[3-(trifluoromethyl)phenyl]methanone 26 ((4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(pyridin-2-yl)methanone 27 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-fluoro-5-methoxyphenyl)methanone 28 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-ethoxyphenyl)methanone 29 (2-chloro-5-methoxyphenyl)(4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin- 3-yl]methyl}piperazin-1-yl)methanone 30 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(tetrahydro-2H-pyran-2-yl)methanone 31 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(3-isopropoxyphenyl)methanone 32 2-[(4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)carbonyl]benzonitrile 33 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(3-isopropylphenyl)methanone 34 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-isopropylphenyl)methanone 35 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(tetrahydrofuran-2-yl)methanone 36 (3-chlorophenyl)(4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 37 (2-chlorophenyl)(4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 38 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]methanone 39 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-isopropoxypyridin-2-yl)methanone 40 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxy-4-methylpyridin-2-yl)methanone 41 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[6-(cyclobutyloxy)pyridin-2-yl]methanone 42 (3-bromo-6-methoxypyridin-2-yl)(4-{[2-(4-chlorophenyl)imidazo[1,2- a]pyridin-3-yl]methyl}piperazin-1-yl)methanone 43 (3-chloro-6-methoxypyridin-2-yl)(4-{[2-(4-chlorophenyl)imidazo[1,2- a]pyridin-3-yl]methyl}piperazin-1-yl)methanone 44 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[6-(difluoromethoxy)pyridin-2-yl]methanone 45 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-ethoxypyridin-2-yl)methanone 46 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl]methanone 47 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxypyridin-2-yl)methanone 48 (4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclopentyl)methanone 49 (4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclobutyl)methanone 50 (5-fluoro-2-methoxyphenyl)(4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 51 (2-chloro-5-fluorophenyl)(4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 52 (4-{[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-methoxyphenyl)methanone 53 (2-fluorophenyl)(4-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 54 cyclopentyl(4-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 55 (4-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxypyridin-2-yl)methanone 56 cyclopentyl(4-{[2-(4-methylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 57 cyclohexyl(4-{[2-(4-methylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 58 (2-methoxyphenyl)(4-{[2-(4-methylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 59 (6-methoxypyridin-2-yl)(4-{[2-(4-methylphenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)methanone 60 (4-(3-{[4-(2-fluorobenzoyl)piperazin-1-yl]methyl}imidazo[1,2-a]pyridin-2- yl)benzonitrile 61 4-[3-({4-[(6-methoxypyridin-2-yl)carbonyl]piperazin-1- yl}methyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile 62 4-(3-{[4-(cyclopentylcarbonyl)piperazin-1-yl]methyl}imidazo[1,2-a]pyridin- 2-yl)benzonitrile 63 4-(3-{[4-(cyclohexylcarbonyl)piperazin-1-yl]methyl}imidazo[1,2-a]pyridin- 2-yl)benzonitrile 64 (4-{[2-(4-tert-butylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxypyridin-2-yl)methanone 65 (4-{[2-(4-tert-butylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(2-fluorophenyl)methanone 66 (4-{[2-(4-tert-butylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(cyclopentyl)methanone 67 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)[6-(trifluoromethoxy)pyridin-2-yl]methanone 68 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(3-fluoro-6-methoxypyridin-2-yl)methanone 69 (4-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin- 1-yl)(2-fluorophenyl)methanone 70 4-(3-{[4-(2-fluoro-5-methoxybenzoyl)piperazin-1-yl]methyl}imidazo[1,2- a]pyridin-2-yl)benzonitrile 71 4-[3-({4-[(6-methoxy-3-methylpyridin-2-yl)carbonyl]piperazin-1- yl}methyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile 72 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxy-3-methylpyridin-2-yl)methanone 73 (4-{[2-(4-tert-butylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxy-3-methylpyridin-2-yl)methanone 74 (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1- yl)(6-methoxy-3-methylpyridin-2-yl)methanone

[0159] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is selected from the group consisting of

TABLE-US-00002 Example Name 1 (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(cyclopentyl)methanone 2 (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(cyclopentyl)methanone 3 (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone 4 (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1-yl)(2-fluorophenyl)methanone

[0160] and the salts, solvates and solvates of the salts thereof.

[0161] Stable pharmaceutical formulations according to the invention are also those formulations in which the at least one inhibitor of the TASK-1 and/or TASK-3 channel is (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone.

[0162] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for the treatment and/or prevention of diseases.

[0163] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders.

[0164] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders, wherein the nasal or pharyngeal administration is aided by nasal sprays, nasal drops, nasal solutions, powder inhalers, nebulizers, metered dose aerosols or semisolid gels.

[0165] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders, wherein the duration of action is at least 3 hours.

[0166] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders, wherein the duration of action is at least 4 hours.

[0167] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders, wherein the duration of action is at least 5 hours.

[0168] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of obstructive sleep apnoeas or snoring, comprising:

[0169] a therapeutically effective amount of the inhibitor of the TASK-1 and/or TASK-3 channel 4-{[2-(4-chlorophenyl)imidazo[1,2-a] pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxy-pyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 20% to 100% w/v PEG400 and 0 to 10% w/v polysorbate 80 and 0 to 80% w/v of a phosphate buffer having a pH of 7, and optionally at least one further auxiliary, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal administration is at least 3 hours or at least 4 hours or at least 5 hours or at least 6 hours or at least 7 hours or at least 8 hours.

[0170] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of obstructive sleep apnoeas or snoring, comprising a therapeutically effective amount of the inhibitor of the TASK-1 and/or TASK-3 channel 4-{[2-(4-chlorophenyl)imidazo[1,2-a] pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 20% to 100% w/v PEG400 and 0 to 10% w/v polysorbate 80 and 0 to 80% w/v of a phosphate buffer having a pH of 7, and optionally at least one further auxiliary, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal administration is at least 3 hours.

[0171] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of obstructive sleep apnoeas or snoring, comprising:

[0172] a therapeutically effective amount of the inhibitor of the TASK-1 and/or TASK-3 channel 4-{[2-(4-chlorophenyl)imidazo[1,2-a] pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 20% to 100% w/v PEG400 and 0 to 10% w/v polysorbate 80 and 0 to 80% w/v of a phosphate buffer having a pH of 7, and optionally at least one further auxiliary, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal administration is at least 4 hours.

[0173] A further embodiment of the present invention are the stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration for use in a method for the treatment and/or prevention of obstructive sleep apnoeas or snoring, comprising:

[0174] a therapeutically effective amount of the inhibitor of the TASK-1 and/or TASK-3 channel 4-{[2-(4-chlorophenyl)imidazo[1,2-a] pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxy-pyridin-2-yl)methanone or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 20% to 100% w/v PEG400 and 0 to 10% w/v polysorbate 80 and 0 to 80% w/v of a phosphate buffer having a pH of 7, and optionally at least one further auxiliary, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal administration is at least 5 hours.

[0175] The formulations of the invention can be used alone or, if required, in combination with one or more other pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects. The present invention therefore further provides medicaments comprising at least one of the formulations of the invention and one or more further active ingredients, especially for treatment and/or prevention of the aforementioned disorders. Preferred examples of combination active ingredients suitable for this purpose include: [0176] respiratory stimulants, by way of example and with preference theophylline, doxapram, nikethamide or caffeine; [0177] psychostimulants, by way of example and with preference modafinil or armodafinil; [0178] amphetamines and amphetamine derivatives, by way of example and with preference amphetamine, metamphetamine or methylphenidate; [0179] serotonin reuptake inhibitors, by way of example and with preference fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone; [0180] serotonin precursors, by way of example and with preference L-tryptophan; [0181] selective serotonin noradrenaline reuptake inhibitors, by way of example and with preference venlafaxine or duloxetine; [0182] noradrenergic and specifically serotonergic antidepressants, by way of example and with preference mirtazapine; [0183] selective noradrenaline reuptake inhibitors, by way of example and with preference reboxetine; [0184] tricyclic antidepressants, by way of example and with preference amitriptyline, protriptyline, doxepine, trimipramine, imipramine, clomipramine or desipramine; [0185] alpha2-adrenergic agonists, by way of example and with preference clonidine; [0186] GABA agonists, by way of example and with preference baclofen; [0187] alpha sympathomimetics, by way of example and with preference xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetryzoline or tramazoline; [0188] glucocorticoids, by way of example and with preference fluticasone, budesonide, beclometasone, mometasone, tixocortol or triamcinolone; [0189] cannabinoid receptor agonists; [0190] carboanhydrase inhibitors, by way of example and with preference acetazolamide, methazolamide or diclofenamide; [0191] opioid and benzodiazepine receptor antagonists, by way of example and with preference flumazenil, naloxone or naltrexone; [0192] cholinesterase inhibitors, by way of example and with preference neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine; [0193] N-methyl-D-aspartate and glutamate antagonists, by way of example and with preference amantadine, memantine or sabeluzole; [0194] nicotine receptor agonists; [0195] leukotriene receptor antagonists, by way of example and with preference montelukast or tripelukast; [0196] dopamine receptor antagonists, by way of example and with preference dromperidone, metoclopramide or benzamide, butyrophenone or phenothiazine derivatives; [0197] appetite suppressants, by way of example and with preference sibutramine, topiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists; [0198] proton pump inhibitors, by way of example and with preference pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole; [0199] organic nitrates and NO donors, for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; [0200] compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil; [0201] NO- and haem-independent activators of soluble guanylate cyclase (sGC), such as in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; [0202] NO-independent but haem-dependent stimulators of soluble guanylate cyclase (sGC), such as in particular riociguat, vericiguat and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549; [0203] prostacyclin analogues and IP receptor agonists, by way of example and with preference iloprost, beraprost, treprostinil, epoprostenol or selexipag; [0204] endothelin receptor antagonists, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan; [0205] compounds which inhibit human neutrophile elastase (HNE), by way of example and with preference sivelestat or DX-890 (reltran); [0206] compounds which inhibit the degradation and alteration of the extracellular matrix, by way of example and with preference inhibitors of the matrix metalloproteases (MMPs), especially inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (in this context particularly of MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase (MMP-12); [0207] compounds which block the binding of serotonin to its receptors, by way of example and with preference antagonists of the 5-HT.sub.2B receptor such as PRX-08066; [0208] antagonists of growth factors, cytokines and chemokines, by way of example and with preference antagonists of TGF-, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; [0209] Rho kinase-inhibiting compounds, by way of example and with preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; [0210] compounds which influence the energy metabolism of the heart, by way of example and with preference etomoxir, dichloroacetate, ranolazine or trimetazidine; [0211] compounds which inhibit the signal transduction cascade, by way of example and with preference from the group of the kinase inhibitors, in particular from the group of the tyrosine kinase and/or serine/threonine kinase inhibitors, by way of example and with preference nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib; [0212] anti-obstructive agents as used, for example, for treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and with preference from the group of the inhalatively or systemically administered agonists of the beta-adrenergic receptor (beta-mimetics) and the inhalatively administered anti-muscarinergic substances; [0213] antiinflammatory, immunomodulating, immunosuppressive and/or cytotoxic agents, by way of example and with preference from the group of the systemically or inhalatively administered corticosteroids and also dimethyl fumarate, fingolimod, glatiramer acetate, -interferons, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tripelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, interferon-, pirfenidone or etanercept; [0214] antifibrotic agents, by way of example and with preference lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF- antagonists or pirfenidone; [0215] antithrombotic agents, by way of example and with preference from the group of platelet aggregation inhibitors, the anticoagulants and the profibrinolytic substances; [0216] hypotensive active ingredients, by way of example and with preference from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists and also the diuretics; and/or [0217] active ingredients that alter lipid metabolism, by way of example and with preference from the group of the thyroid receptor agonists, cholesterol synthesis inhibitors, by way of example and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.

[0218] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with a beta-adrenergic receptor agonist, by way of example and with preference albuterol, isoproterenol, metaproterenol, terbutalin, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0219] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with an antimuscarinergic substance, by way of example and with preference ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0220] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with a corticosteroid, by way of example and with preference prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclometasone, flunisolide, budesonide or fluticasone.

[0221] Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants and the profibrinolytic substances.

[0222] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, ticlopidine or dipyridamole.

[0223] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, melagatran, dabigatran, bivalirudin or clexane.

[0224] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with a GPIIb/IIIa antagonist, by way of example and with preference tirofiban or abciximab.

[0225] In a preferred embodiment of the invention, the formulations of the invention are administered in combination with a factor Xa inhibitor, by way of example and with preference rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0226] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0227] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.

[0228] Hypotensive agents are preferably understood to mean compounds from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, and the diuretics.

[0229] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.

[0230] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an alpha-1 receptor blocker, by way of example and with preference prazosin.

[0231] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a beta receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0232] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an angiotensin AII antagonist, preferred examples being losartan, candesartan, valsartan, telmisartan or embusartan.

[0233] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0234] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.

[0235] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.

[0236] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone, eplerenone or finerenone.

[0237] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a diuretic, by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0238] Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

[0239] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-529 414), HT-705 or CETP vaccine (Avant).

[0240] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxine, 3,5,3-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0241] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0242] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS-188494 or TAK-475.

[0243] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0244] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an MTP inhibitor, by way of example and with preference implitapide, BMS-201038, R-103757 or JTT-130.

[0245] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.

[0246] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042.

[0247] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.

[0248] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a lipase inhibitor, by way of example and with preference orlistat.

[0249] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a polymeric bile acid adsorber, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0250] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a bile acid reabsorption inhibitor, by way of example and with preference ASBT (=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0251] In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.

[0252] Particular preference is given to combinations of the formulations according to the invention with one or more further active ingredients selected from the group consisting of respiratory stimulants, psychostimulants, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory agents, immunomodulators, immunosuppressants and cytotoxic agents.

[0253] If required, the formulations according to the invention can also be employed in conjunction with the use of one or more medical technical devices or auxiliaries, provided that this does not lead to unwanted and unacceptable side-effects. Medical devices and auxiliaries suitable for such a combined application are, by way of example and with preference: [0254] devices for positive airway pressure ventilation, by way of example and with preference CPAP (continuous positive airway pressure) devices, BiPAP (bilevel positive airway pressure) devices and IPPV (intermittent positive pressure ventilation) devices; [0255] neurostimulators of the Nervus hypoglossus; [0256] intraoral auxiliaries, by way of example and with preference protrusion braces; [0257] nasal disposable valves; [0258] nasal stents.

[0259] In one embodiment, the dosage in the case of intranasal administration is about 0.1 g to 500 g per day.

[0260] In a further embodiment, the dosage in the case of intranasal administration is about 1 g to 250 g per day. In a further embodiment, the dosage in the case of intranasal administration is about 1 g to 120 g per day. In a further embodiment, the dose of about 0.1 g to 500 g per day, or of about 1 g to 250 g per day, or of about 1 g to 120 g per day, is administered once daily by the intranasal route before sleeping. In one embodiment, the dose of about 0.1 g to 500 g per day, or of about 1 g to 250 g per day, or of about 1 g to 120 g per day, is administered once daily with half to each nostril. In one embodiment, the dose of about 0.1 g to 500 g per day, or of about 1 g to 250 g per day, or of about 1 g to 120 g per day, is administered once daily with half to each nostril before sleeping.

[0261] It may nevertheless be necessary in some cases to deviate from the stated amounts, and specifically as a function of body weight, route of administration, individual response to the active ingredient, nature of the preparation and time at which or interval over which administration takes place. Thus in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of greater amounts, it may be advisable to divide them into several individual doses over the day.

Assessment of the Pharmacological Activity List of Abbreviations

[0262]

TABLE-US-00003 AHI Apnoea-Hypopnoea Index Na-CMC Na carboxymethyl cellulose CMC Critical micelle concentration CPAP system Continuous positive airway pressure system EDTA Ethylenediaminetetraacetic acid EMG Electromyogram mPa * s Millipascal seconds OSA Obstructive sleep apnoea PEG Polyethylene glycol TASK TWIK-related acid-sensitive K.sup.+ channel

[0263] The pharmacological activity of the inhibitors of the TASK-1 and/or TASK-3 channel present in the formulations according to the invention was demonstrated by in vitro experiments in PCT/EP2016/079973.

[0264] The pharmacological activity of the formulations according to the invention can be demonstrated by in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples.

Animal Model of Obstructive Sleep Apnoea in the Pig

[0265] The effects of the formulations according to the invention of the inhibitors of TASK-1 and/or TASK-3 channels on the activation threshold of the genioglossus muscle by negative pressure and the collapsibility of the upper airways were investigated in a pig model for obstructive sleep apnoea.

[0266] Using negative pressure, it is possible to induce collapse and thus obstruction of the upper airways in anaesthetized, spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

[0267] German Landrace pigs were used for the model. Since the nasal axis is in an almost vertical position in humans in a horizontal sleeping position, the pigs in the experiments were fixed in a sitting position (70 degrees), wherein the nose pointed upwards. After nasal administration, the formulation therefore flowed downwards over all regions of the upper airways. The pigs were anaesthetized and tracheotomized. One cannula each was inserted into the rostral and the caudal part of the trachea. Using a T connector, the rostral cannula was connected on the one hand to a device generating negative pressure and on the other hand to the caudal cannula. Using a T connector, the caudal cannula was connected to the rostral cannula and to a tube which allowed spontaneous breathing circumventing the upper airways. By appropriate closing and opening of the tubes it was thus possible for the pig to change from normal nasal breathing to breathing via the caudal cannula during the time when the upper airways were isolated and were connected to the device for generating negative pressure. The muscle activity of the Musculus genioglossus was recorded by electromyogram (EMG).

[0268] At certain points in time, the collapsibility of the upper airways was tested by having the pig breathe via the caudal cannula and applying negative pressures of 50, 100 and 150 mbar (corresponding to 50, 100 and 150 cm water column (cm H.sub.2O)) to the upper airways. This caused the upper airways to collapse, which manifested itself in an interruption of the airflow and a pressure drop in the tube system. This test was conducted prior to administration of the test substance and at certain intervals after administration of the test substance. An appropriately effective test substance could prevent this collapse of the airways in the inspiratory phase.

[0269] After changeover from nasal breathing to breathing via the caudal cannula, it was not possible to measure any EMG activity of the Musculus genioglossus in the anaesthetized pig. As a further test, the negative pressure at which EMG activity restarted was then determined. This threshold value was, if a test substance was effective, shifted to more positive values. The test was likewise conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. The test substance was administered by the nasal route.

[0270] The results shown in the tables which follow were conducted with the compounds listed in Table 1 as Example 1, Example 3 and Example 4. Unless stated otherwise, the data were measured at a negative pressure of 100 mbar (corresponding to 100 cm water column (cm H.sub.2O)) on the upper airways.

[0271] The active ingredients listed in Table 1 as Example 1, Example 3 and Example 4 were dissolved in the various formulations listed in Table 2 below and administered in an amount of 0 g, 3 g, 10 g, 30 g or 100 g per pig. The active ingredient formulation or the pure vehicle was each administered with a pipette at a volume of 400 l in each nostril.

TABLE-US-00004 TABLE 2 Compositions of the formulations for nasal administration in which the compound listed in Table 1 as Example 3 was administered: Glycerol Phosphate Polysor- 85% buffer bate (absolute Propylene Na- Formu- pH 7 80 glycerol) PEG400 glycol CMC lation [% w/v] [% w/v] [% w/v] [% w/v] [% w/v] [% w/v] 1 90 10 2 100 3 70 10 20 4 85 10 5 5 87.5 10 2.5 6 67.5 10 2.5 20 (2.125) 7 70 10 20 8 68.75 10 20 1.25 9 88.75 10 1.25

[0272] The formulations of Table 2 optionally additionally comprise butylhydroxyanisole at a concentration of 0.02% w/v.

[0273] The phosphate buffer pH 7, 0.063 M was prepared according to the European Pharmacopoeia 8.7: 5.18 g of anhydrous disodium hydrogenphosphate and 3.65 g of sodium dihydrogenphosphate monohydrate were dissolved in 950 mL of water, the pH was adjusted with phosphoric acid and the solution made up to 1000 mL with water. Alternatively, the phosphate buffer was prepared using disodium hydrogenphosphate dihydrate and sodium dihydrogenphosphate dihydrate in place of the anhydrous disodium hydrogenphosphate and the sodium dihydrogenphosphate monohydrate. For this purpose, 6.49 g of disodium hydrogenphosphate dihydrate and 4.13 g of sodium dihydrogenphosphate dihydrate were dissolved in 950 mL of water, the pH was adjusted with phosphoric acid and the solution made up to 1000 mL with water.

[0274] The duration of action in this pig model is defined as the time [min] in which a collapse of the upper airways was not observed in any animal, as a mean value of the specified number of animals. A duration of action specified as > X min signifies that the experiment was terminated at X min and up to this point a collapse of the upper airways was still not observed in any animal

TABLE-US-00005 TABLE 3 Duration of action of Example 3/Table 1 in phosphate buffer pH 7/ polysorbate 80 with PEG400 (Formulation 3) or with 85% glycerol and PEG400 (Formulation 6) in comparison to the duration of action of Example 3/Table 1 in phosphate buffer pH 7/polysorbate 80 (Formulation 1) Glycerol 85% Example Formulation (absolute 3 from according to PEG400 glycerol) Tab. 1 Duration of action Table 2 [% w/v] [% w/v] [g] [min], mean value 1 0 0 3 150 1 0 0 30 180* 3 20 0 0 0 3 20 0 3 180 3 20 0 30 300 6 20 2.5 (2.125) 3 240 *In experiments in which the nasal passages of the pigs were blocked by mucous, which were suggested by very noisy curves of the tracheal pressure and air flow, the mean value of the duration of action of 30 g of Example 3 in Formulation 1 was 120 min.

TABLE-US-00006 TABLE 4 Duration of action of Example 3/Table 1 in phosphate buffer pH 7/polysorbate 80/PEG, comparison of various PEG concentrations Formulation Example 3 Duration of action according to PEG400 from Table 1 [min] Table 2 [% w/v] [g] mean value 2 100 3 >240 3 20 3 180 4 5 3 180 5 2.5 3 150 1 0 3 150

TABLE-US-00007 TABLE 5 Duration of action of Example 3/Table 1 in phosphate buffer pH 7/polysorbate 80 (90/10) + Na-CMC, Comparison with the duration of action of Example 3/Table 1 in phosphate buffer pH 7/ polysorbate 80/PEG400 (70/10/20) Formulation Example 3 Duration of according to Na-CMC/PEG400 from Table 1 action [min] Table 2 [% w/v] [g] mean value 9 1.25 Na-CMC 3 120 3 20 PEG 3 180

TABLE-US-00008 TABLE 6 Duration of action of Example 3/Table 1 in phosphate buffer pH 7/ polysorbate 80 with PEG (70/10/0) or propylene glycol (70/10/20) Formulation PEG400/propylene Duration of according to glycol Example 3 action [min] Table 2 [% w/v] [g] Mean value 3 20 PEG 30 300 7 20 propylene glycol 30 180

TABLE-US-00009 TABLE 7 Duration of action of Example 1/Table 1 in phosphate buffer pH 7/polysorbate 80/PEG400 (Formulation 3) in comparison to the duration of action of Example 1/Table 1 in phosphate buffer pH 7/polysorbate 80 (Formulation 1) at a reduced pressure of 100 mbar and 50 mbar Formulation Reduced Example 1 Duration of according to pressure PEG400 from Tab. 1 action[min], Table 2 [mbar] [% w/v] [g] mean value 1 50 0 10 150 1 100 0 10 120 3 50 20 10 >210 3 100 20 10 180

TABLE-US-00010 TABLE 8 Duration of action of Example 4/Table 1 in phosphate buffer pH 7/polysorbate 80/PEG400 (Formulation 3) in comparison to the duration of action of Example 4/Table 1 in phosphate buffer pH 7/polysorbate 80 (Formulation 1) at a reduced pressure of 100 mbar and 50 mbar Formulation Reduced Example 4 Duration of according to pressure PEG400 from Tab. 1 action [min], Table 2 [mbar] [% w/v] [g] mean value 1 50 0 100 180 1 100 0 100 180 3 50 20 100 >210 3 100 20 100 180