Pharmaceutical dosage forms containing task-i and task-3 channel inhibitors, and the use of same in breathing disorder therapy

Patent metadata

Field	Value
Publication number	US-2020085734-A1
Application number	US-201716471263-A
Country	US
Kind code	A1
Filing date	Dec 13, 2017
Priority date	Dec 21, 2016
Publication date	Mar 19, 2020
Grant date	—

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.

First claim

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 8 -C 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),

wherein
R 1 is halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl;
R 2 is (C 4 -C 6 )-cycloalkyl, wherein a ring CH 2 group may be replaced by —O—,
or
R 2 is represents a phenyl group of formula (a) or a pyridyl group of formula (b)

wherein * marks the bond to the adjacent carbonyl group; and
R 3 is fluorine, chlorine, bromine, cyano, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy, wherein (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may be up to trisubstituted by fluorine;
R 4 is hydrogen, fluorine, chlorine, bromine or methyl;
R 5 is hydrogen, fluorine, chlorine, bromine or methyl;
and
R 6 is hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy or tetrahydro-2H-pyran-4-yloxy,
wherein (C 1 -C 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 p

Assignees

• Bayer Pharma AG

Inventors

• Anlahr Johanna
• Beck-Broichsitter Moritz
• Nicolai Janine
• Delbeck Martina
• Hahn Michael
• Albus Udo
• Gehring Doris
• Rosenstein Björn

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61K47/10 Primary

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title