EP3558380A1 - Pharmazeutische darreichungsformen enthaltend inhibitoren von task-1 und task-3 kanälen und deren verwendung für die therapie von atemstörungen - Google Patents

Pharmazeutische darreichungsformen enthaltend inhibitoren von task-1 und task-3 kanälen und deren verwendung für die therapie von atemstörungen

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Publication number
EP3558380A1
EP3558380A1 EP17822216.2A EP17822216A EP3558380A1 EP 3558380 A1 EP3558380 A1 EP 3558380A1 EP 17822216 A EP17822216 A EP 17822216A EP 3558380 A1 EP3558380 A1 EP 3558380A1
Authority
EP
European Patent Office
Prior art keywords
nasal
task
stable pharmaceutical
methyl
imidazo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17822216.2A
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German (de)
English (en)
French (fr)
Inventor
Johanna Anlahr
Moritz Beck-Broichsitter
Janine NICOLAI
Martina Delbeck
Michael Hahn
Udo Albus
Doris Gehring
Björn ROSENSTEIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
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Filing date
Publication date
Priority claimed from EP16205688.1A external-priority patent/EP3338764A1/de
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3558380A1 publication Critical patent/EP3558380A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present application relates to novel pharmaceutical dosage forms containing potent and selective inhibitors of TASK-1 and / or TASK-3 channels and their use for the treatment and / or prevention of respiratory disorders, including sleep-disordered breathing disorders such as obstructive and central sleep apnea and snoring.
  • Potassium channels are nearly ubiquitous membrane proteins involved in a variety of different physiological processes. This includes the regulation of the membrane potential and the electrical excitability of neurons and muscle cells. Potassium channels are divided into three larger groups, which differ in the number of transmembrane domains (2, 4, or 6).
  • K2P channels two-pore domain K ".
  • the group of potassium channels in which two pore-forming domains are flanked by four transmembrane domains, are called K2P channels (two-pore domain K ").
  • the K2P channels largely mediate K + background currents, independent of time and voltage, and contribute significantly to their maintenance
  • the family of K2P channels comprises 15 members subdivided into six subfamilies based on similarities in sequence, structure, and function: TWIK (Tandem pore domain halothane inhibited K + channel), TREK (TWIK-related K + Channel), TIKK (TWIK-related acid-sensitive K + channel), TALK (TWIK-related alkaline pH activated K + channel), THIK (tandem pore domain halothane inhibited K + channel) and TRESK (TWIK-related spinal cord K + channel).
  • TASK-1 KCNK3 or K2P3.1
  • TASK-3 KCNK9 or K2P9.1
  • These channels are functionally characterized by the flow of so-called “leak” or “background” currents as they maintain the voltage-independent kinetics, thereby responding to a variety of physiological and pathological influences with an increase or decrease in activity.
  • Characteristic for TASK channels is the sensitive reaction to a change in the extracellular pH: the channels are inhibited at acidic pH and activated at an alkaline pH.
  • TASK-1 and TASK-3 channels play a role in the regulation of respiration. Both channels are expressed in respiratory neurons of the respiratory center in the brain stem, among others in neurons that generate the respiratory rhythm (ventral respiratory group with the pre-Bötzinger complex), and in the noradrenergic locus caeruleus as well as in serotonergic neurons of the raphe nuclei. Due to the pH dependence, the TASK channels here take on the function of a sensor that translates extracellular pH changes into corresponding cellular signals [Bayliss et al, Pflugers Arch. 467, 917-929 (2015)].
  • TASK-1 and TASK-3 are expressed.
  • TASK-1 knockout mice have been shown to have a decreased ventilatory response (increase in respiratory rate and tidal volume) to hypoxia and normoxic hypercapnia [Trapp et al, J. Neurosci. 28, 8844-8850 (2008)].
  • TASK-1 and TASK-3 channels in motor neurons of the hypoglossal nerve, the XII. Cranial nerve, which has an important function for the maintenance of the upper respiratory tract [Berg et al, J. Neurosci. 24, 6693-6702 (2004)].
  • a potassium channel blocker blocking the TASK-1 channel in the nanomolar range inhibited the collapse of the pharyngeal airway muscles and sensitized the negative pressure reflex of the upper respiratory tract.
  • Nasal administration of the potassium channel blocker is thought to depolarize mechanoreceptors in the upper respiratory tract, and activation of the negative pressure reflex results in increased upper airway muscle activity, stabilizing the upper airways and preventing collapse.
  • TASK channel blockade may be of major importance for obstructive sleep apnea and even snoring [Wirth et al, Sleep 36, 699-708 (2013); Kiper et al, Pflugers Arch. 467, 1081-1090 (2015)].
  • Obstructive sleep apnea is a sleep-disordered breathing disorder characterized by repeated episodes of upper airway obstruction. During inhalation, the patency of the upper respiratory tract is ensured by the interaction of two opposing forces. The dictating effects of the upper airway muscles counteract the negative intraluminal pressure that narrows the lumen. The active contraction of the diaphragm and other respiratory auxiliaries creates a negative pressure in the airways and thus provides the driving force for breathing. The stability of the upper airways is largely determined by the coordination and contraction properties of the dictating muscles of the upper respiratory tract. The genioglossus muscle plays a crucial role in the pathogenesis of OSA.
  • the activity of the genioglossus muscle increases with decreasing pressure in the pharynx in the sense of a dictating compensatory mechanism. Innervated by the hypoglossal nerve, it pulls the tongue forward and down, thereby expanding the pharyngeal airway [Verse et al, Somnologie 3, 14-20 (1999)].
  • the tension of the upper airway dictating muscles is modulated by, among others, nasopharyngeal mechanoreceptors / extensor receptors [Bouillette et al, J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)].
  • central sleep apnea episodic inhibition of the respiratory drive occurs as a result of disturbed brain function or disturbed respiratory regulation.
  • Central respiratory disorders lead to mechanical respiratory arrest, i. no respiratory activity takes place during these episodes, all respiratory muscles, including the diaphragm, temporarily stand still.
  • central sleep apnea there is no upper airway obstruction.
  • Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by recurring partial upper airway obstruction during sleep. This leads to an increase of the airway resistance and thus to an increase in the work of breathing with considerable intrathoracic pressure fluctuations.
  • the negative intrathoracic pressure development during inspiration can reach values that occur as a result of complete airway obstruction in the OSA.
  • the pathophysiological effects on heart, circulatory system and sleep quality correspond to those in obstructive sleep apnea.
  • the pathogenesis, as in OSA is to be assumed in a disturbed reflex mechanism of the pharyngeal dilating muscles during sleep during inspiration.
  • Obstructive snoring is often the precursor to OSA [Hollandt et al., ENT 48, 628-634 (2000)].
  • a composition consisting of: 0.26% glycerol, 0.2% polysorbate 80, 0.9%> sodium chloride and 0.15%) potassium sorbate (without benzalkonium chloride) is used as Asonor ® for the treatment of snoring on the Market.
  • Asonor ® a nasal administration of Asonor ® compared to "Asonor ®" without polysorbate 80 in terms of an improvement of snoring was investigated.
  • Both Asonor ® and "Asonor ®” brought about without polysorbate 80 a significant improvement in snoring [Report from the Department of Neurology, University State Hospital, Copenhagen, Denmark.
  • EP 2595685 B1 (US Patent No. 9,132,243 B1) claims a pharmaceutical product comprising a container containing a liquid anti-snoring substance, the container containing a liquid outlet portion configured to directly insert the liquid anti-snoring substance into to deliver a nasal passage in the form of a jet stream.
  • the liquid anti-snoring substance is an anti-snoring solution comprising sodium chloride, glycerol, polysorbate and sodium edetate and optionally potassium sorbate as a preservative.
  • Apnea or OSA therapy is described in the originally filed application documents of EP 2595685 Bl and U.S. Pat. Patent No. 9,132,243 Bl not revealed.
  • the anti-snoring substance described is claimed for use in the treatment of snoring and respiratory arrest (apnea).
  • Novel substances that act as potent and selective inhibitors of TASK-1 and / or TASK-3 channels and, as such, in particular for the treatment and / or prevention of respiratory disorders, including sleep-disordered breathing such as obstructive and central sleep apnea and snoring, and others are known from PCT / EP2016 / 079973 and PCT / EP2016 / 079544 (unpublished).
  • the duration of action of the potent and selective inhibitors of TASK-1 and / or TASK-3 channels disclosed in EP 15199270.8 and EP 15199268.2 is not always sufficient in the case of nasal administration, which means a subsequent dosing during the night and thus an interruption of the night's sleep or of sleep is required.
  • the object of the present invention is therefore to provide an effective pharmacological therapy for the treatment and / or prevention of respiratory disorders, including sleep-related respiratory disorders such as obstructive and central sleep apnea and snoring, which is an alternative to treatment with the CPAP system.
  • Another object of the present invention is to increase the rate of compliance by a patient with treatment and / or prevention of respiratory disorders including sleep-related breathing disorders such as obstructive and central sleep apnea and snoring against the current standard of therapy (therapy of OSA: CPAP system).
  • this alternative therapy should be easy and convenient to use and not disturb the sleeping.
  • this alternative regimen of once-a-day dosing should allow for undisturbed sleep without re-medication.
  • a further object of the present invention is therefore to provide the pharmacologically active substances for the treatment and / or prevention of respiratory disorders, including sleep-related respiratory disorders such as obstructive and central sleep apnea and snoring in an application form suitable for once daily nasal or pharyngeal administration suitable for bedtime.
  • the extension of the duration of action of nasal administered drugs is difficult. Due to physiological conditions, the residence time of drugs, particles, capsules and the like on the epithelial cells is short.
  • the epithelium consists in part of ciliated cells, which have hair-like structures that contain cilia. These are covered by a mucous layer (mucus), which is transported away by a coordinated movement of the cilia in the direction of the throat. On the mucous layer, foreign particles and microorganisms remain attached after nasal uptake and are transported by the mucociliary clearance together with the mucus towards the pharynx and esophagus.
  • mucociliary clearance counteracts nasal absorption of drugs and, in particular, presents a challenge to achieving efficacy enhancement.
  • the flow rate of the mucus is approximately 5 mm per minute, so it is refreshed every 15-20 min. Cfearance half-lives of 15 min were therefore also determined for solutions and powders applied by nasal methods [Illum et al., Int J Pharm. 39, 189-199 (1987)], so that in principle the active ingredients linger only briefly on the mucosa in order to have an effect achieve.
  • One method to achieve nasal application prolongation is to extend the contact time between the drug and the site of absorption in the nose, the epithelial cells. Prolonged contact time increases the absorption of drugs in the nose.
  • the active ingredient intake can take place over a relatively long period of time, so that, on the one hand, a prolonged action or duration of action can be achieved and, on the other hand, the total amount of drug taken up can be increased.
  • Methods to increase the contact time between the drug and the epithelial cells Increases in viscosity include the use of bioadhesive polymers or the use of microparticles.
  • Pennington et al. were able to show as early as 1988 that by increasing the viscosity of nasally applied solutions with hydroxypropylmethylcellulose, the clearance rate is reduced [Pennington et al, Int J Pharm. 43, 221-224 (1988)]. With increasing polymer content and thus increasing viscosity, the half-life of 1 hour to 2.2 hours extended. Compared with those of lllum et al. [Illum et al, Int J Pharm. 39, 189-199 (1987)] for 15 min. Solutions, the increase in viscosity thus resulted in a marked increase in the half-life.
  • viscous solutions and semi-solid systems such as gels, creams and ointments are more difficult to apply than low-viscosity formulations. Atomization via a spray is no longer possible and precise metering with applicators in the case of semi-solid systems is more difficult.
  • nasally-applied semi-solid systems can lead to blockage that can interfere with nasal breathing.
  • in situ gels is also conceivable [Majithiya et al., AAPS PharmSciTech 7 (3), Article 67 (2006)].
  • the gelation is triggered only within the nose, z. Example by a change in temperature, a change in the pH or the presence of ions.
  • Chitosan As bioadhesive polymers, starch and chitosan are frequently used [Illum et al, J Controlled Release 87, 187-198 (2003)]. Chitosan is a bioadhesive polysaccharide and can interact well with the epithelial cells and mucosal layer. This produces a longer contact time available for drug delivery across the membrane. Chitosan is widely used in the literature, but these are mainly in vitro experiments. To date, chitosan has not been approved for nasal application (FDA Drag Databases, Inactive Ingredient Search for Approved Drag Products) and the potential long-term toxicity for chronic nasal application has not been fully investigated.
  • FDA Drag Databases Inactive Ingredient Search for Approved Drag Products
  • the encapsulation of the active ingredient in polymeric microparticles is [Cerchiara et al, Eur J Pharm Biopharm. 61, 195-200 (2005)].
  • the active ingredient is embedded in a suitable polymer which has a low solubility in water, or a polymer combination which additionally allows adhesion of the active ingredient-laden microparticles to the nasal mucous membrane.
  • the active ingredient is released from the microparticles depending on the nature of the polymer used by diffusion and / or polymer degradation / erosion delayed, resulting in a prolonged duration of action of the drug at the site of action.
  • the polymer combination used, from which the microparticles are composed additionally has the property of adhering to the nasal mucous membrane, then an extended residence time and thus duration of action of the nasally introduced medication can be expected.
  • the combination of microparticles and bioadhesive polymers is therefore a much-described approach for extending the duration of action in nasal administration, since two principles - the delayed release and the increase in contact time - are combined.
  • the microparticles can be prepared directly from a bioadhesive polymer [Illum et al, Int J Pharm.
  • prolongation of drug release may also be produced by the use of suspended rather than dissolved drug.
  • the active ingredient used is z. B. micronized (comminution to drug microparticles) and incorporated into a liquid phase (suspended). After application to the nose, the active ingredient particles dissolve at the site of action delayed. Only the dissolved drug can be absorbed through the nasal mucosa and then become effective.
  • the dissolution kinetics which determines the prolongation of the effect, depends i.a. from the physicochemical properties (eg solubility, particle size) of the active ingredient used.
  • crystal suspensions and polymeric microparticles require a large number of successive process steps which significantly influence the quality of the finished dosage form.
  • the Functionality of these complex forms of administration can be adversely affected due to lack of storage stability.
  • crystal suspensions have particle sedimentation (including sedimentation) and / or changes in primary particle size during storage, resulting in inhomogeneity within the dosage form and thus misdosing.
  • the preparation of crystal suspensions and polymeric microparticles requires the use of numerous stabilizers and polymeric matrix formers which, after nasal administration, can lead to local incompatibilities / irritations.
  • particulate systems such as crystal suspensions and polymeric microparticles, which are associated with a delayed release and dissolution of the active ingredient, lead to the fact that due to the mucociliary clearance, a non-reproducible portion of the dose before absorption already removed as undissolved particles and is swallowed.
  • ingestion of active ingredient can lead to high variability of exposure [Malinovsky et al., Br J Anesthesia 77, 203-207 (1996)].
  • crystal suspensions and polymeric microparticles are associated with more complex instructions for use, which can lead to application errors, which in turn endanger the desired therapeutic success.
  • nasal administration of a formulation 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 1% to 100% w / v glycerol the duration of action of the inhibitor of the TASK-1 and / or TASK-3 channel or a hydrate, solvate, polymorph or Metabolites thereof or a pharmaceutically acceptable salt thereof, depending on the dose significantly prolonged.
  • a subject of the present invention is 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 1% to 100% w / v glycerol and optionally at least one excipient, the formulation having a pH of 4 to 8.
  • formulations also containing 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 and containing 20% w / v of the glycerol structurally very similar propylene glycol (instead of glycerol) and a pH regulator and a solubilizer no prolongation of the duration of action of the inhibitor of the TASK-1 and / or TASK-3 channel.
  • formulations 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 and 1.25% w / v of the viscosity-increasing substance Na Carboxymethylcellulose (Na-CMC) (instead of glycerol) and a pH regulator and solubilizer did not increase the duration of action of the TASK-1 and / or TASK-3 channel inhibitor.
  • Na-CMC Na Carboxymethylcellulose
  • glycerol glycerol
  • a pH regulator and solubilizer did not increase the duration of action of the TASK-1 and / or TASK-3 channel inhibitor.
  • compositions containing a solubilizer and 2.13%> w / v glycerol in a pH regulator without active ingredient showed no effect in the present invention.
  • Asonor ® composition consisting of 0.26% to glycerol, 0.2% polysorbate 80, 0.9%> sodium chloride and potassium sorbate 0.15% to a significant improvement of snoring was observed.
  • the same effect was also observed for a composition consisting of 0.26% glycerol, 0.9% sodium chloride and 0.15% Potassium sorbate, ie in the absence of polysorbate 80, [Report from the Department of Neurology, University State Hospital, Copenhagen, Denmark.
  • nasal administration of the compositions of the present invention resulted in increased genioglossus activity only during inspiration due to sensitization of the negative pressure reflex of the upper respiratory tract, resulting in complete inhibition. the collapse of the pharyngeal airway muscles at each inhalation.
  • the stable pharmaceutical formulation is administered nasally or pharyngeally.
  • nasal and “intranasal” are used interchangeably.
  • stable pharmaceutical formulations which are suitable for nasal administration are formulations in liquid, semisolid or solid form, for example nose drops, nasal solutions, nasal gels, nasal ointments, nasal creams or powdered dosage forms.
  • a nasal application for example, by means of nasal spray, dropper, squeeze bottle, COMOD ® System, viassigzerstäubern (z. B. piezoelectric nebulizers, jet or ultrasonic aerosol generators, Soft Mist inhalers) or metered-dose inhalers, or Nasenapplikatoren for semi-solid formulations (tube tips, spatula) and / or solid formulations (powder) take place.
  • the application is carried out by means of nasal spray.
  • stable pharmaceutical formulations which are suitable for pharyngeal administration are formulations in liquid, semisolid or solid form, for example solutions, gels or powders.
  • a pharyngeal administration by inhalation using liquid atomizers eg piezoelectric nebulizers, jet or ultrasonic aerosol generators, pump sprays
  • liquid atomizers eg piezoelectric nebulizers, jet or ultrasonic aerosol generators, pump sprays
  • metered aerosols or by local application using a bronchoscope (instillation), a dropper pipette, Squeeze bottle or the like.
  • the therapeutic effect in the context of the present invention is defined as a reduction of the apnea-hypopnea index (AHI) of a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring after nasal or pharyngeal administration of a formulation according to the invention containing 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.
  • AHI apnea-hypopnea index
  • the therapeutic effect is defined as a reduction in the apnea-hypopnea index (AHI) of a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring after nasal or pharyngeal administration of a formulation according to the invention containing at least a therapeutically effective amount 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 by at least 20%.
  • AHI apnea-hypopnea index
  • the therapeutic effect is defined as a reduction in the apnea-hypopnea index (AHI) of a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring after nasal or pharyngeal administration of a formulation of the invention containing a therapeutically effective amount of at least one inhibitor the TASK-1 and / or TASK-3 channel or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof 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%.
  • AHI apnea-hypopnea index
  • the duration of action in the context of the present invention is defined as the time 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 of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, to a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (AHI) of that patient is reduced.
  • sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (AHI) of that patient is reduced.
  • the duration of action is defined as the time 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 of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, to a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (AHI) of that patient is reduced by at least 20%.
  • sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (AHI) of that patient is reduced by at least 20%.
  • the duration of action is defined as the time 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 of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof, to a patient with sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (AHI) of that patient 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%).
  • sleep-disordered breathing such as obstructive and central sleep apnea and snoring, in which the apnea-hypopnea index (A
  • 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. According to one embodiment of the present invention, the duration of action is at least 6 hours.
  • a therapeutically effective amount of at least one inhibitor of the TASK-1 and / or TASK-3 channel or of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof within the meaning of the present invention 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 have 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 nasal or pharyngeal administration 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.
  • a therapeutically effective amount of at least one inhibitor of the TASK-1 and / or TASK-3 channel or of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof within the meaning of the present invention 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 exhibits a duration of action of at least 3 hours during nasal or pharyngeal administration.
  • a therapeutically effective amount of at least one inhibitor of the TASK-1 and / or TASK-3 channel or of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof within the meaning of the present invention 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 exhibits a duration of action of at least 4 hours during nasal or pharyngeal administration.
  • a therapeutically effective amount of at least one inhibitor of the TASK-1 and / or TASK-3 channel or of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof within the meaning of the present invention is defined as the amount of at least one inhibitor of the TASK- 1 and / or TASK-3 channel or a hydrate, solvate, Polymorphs or metabolites thereof or a pharmaceutically acceptable salt thereof, which exhibits a duration of action of at least 5 hours in the case of nasal or pharyngeal administration.
  • a therapeutically effective amount of at least one inhibitor of the TASK-1 and / or TASK-3 channel or of a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof within the meaning of the present invention 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 exhibits a duration of action of at least 6 hours during nasal or pharyngeal administration.
  • adjuvants are substances which in the stable pharmaceutical formulation serve, for example, to adjust or stabilize the pH, to increase the solubility of the active ingredient, to microbiologically and physically stabilize the preparation, to change the viscosity of the formulation or to improve the taste or appearance.
  • auxiliaries for the purposes of the present invention are pH regulators, solubilizers, antioxidants, stabilizers, thickeners, preservatives, tonicity-adjusting substances, flavors, fragrances or dyes.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optionally at least one adjuvant 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 tonicity adjusting substance, at least one flavor, at least one perfume, and at least one dye.
  • the optionally at least one adjuvant 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 tonicity adjusting substance, at least one flavor, at least one perfume, and at least one dye.
  • pH regulators for the purposes of the present invention are, for example, buffers such as citric acid and its salts, acetic acid and its salts and phosphoric acid and its salts, or inorganic acids such as hydrochloric acid, boric acid, carboxylic acids, bicarboxylic 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 bicarbonate.
  • buffers such as citric acid and its salts, acetic acid and its salts and phosphoric acid and its salts
  • inorganic acids such as hydrochloric acid, boric acid, carboxylic acids, bicarboxylic 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 bicarbonate.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optionally at least one pH regulator is selected from the group consisting of citric acid and its salts, acetic acid and its salts, phosphoric acid and its salts, hydrochloric acid, boric acid, Carboxylic acids, bicarboxylic acids, amino acids, oxocarboxylic acids, polycarboxylic acids, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.
  • the pH regulator is a phosphate buffer.
  • the pH regulator is a phosphate buffer which buffers the solution for the purposes of the present invention to a pH of between 4 and 8.
  • the preferred pH range is between 7 and 8.
  • the pH of the formulations according to the invention is 7.
  • Solubilizers for the purposes of the present invention are, for example, complexing agents (for example cyclodextrins and sodium EDTA (sodium ethylenediaminetetraacetic acid)), cosolvents (for example ethanol, propylene glycol, dimethylacetamide) and surfactants.
  • complexing agents for example cyclodextrins and sodium EDTA (sodium ethylenediaminetetraacetic acid)
  • cosolvents for example ethanol, propylene glycol, dimethylacetamide
  • surfactants for example, fatty alcohols fall (for example, cetyl alcohol), phospholipids in the group of surfactants (e.g. lecithin), sterols (for example cholesterol), bile acid salts, saponins, glycerol fatty acid ester (e.g.
  • polyoxyethylene fatty acid ester e.g., polyoxyethylene stearate
  • polyoxyethylene sorbitan 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),
  • polyoxyethylene glycerol ricinoleate polyoxyethylene glycerol triricinoleate
  • polyoxyethylene fatty alcohol ethers e.g., polyoxyethylene lauryl ether, polyoxyethylene cetyl stearyl ether
  • polyoxypropylene-polyoxyethylene block copolymers e.g., poloxamer
  • alkyl sulfates e.g., sodium lauryl sulfate, sodium cetyl stearyl sulfate
  • alkali soaps e.g., sodium palmitate, sodium stearate
  • sucrose fatty acid esters e.g., the solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80.
  • the solubilizer is polysorbate 80.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optionally at least one solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80.
  • the solubilizer contains a surfactant in the formulations according to the invention, the concentration of this surfactant is at least its critical micelle concentration (CMC, critical micelle concentration) and, at most, the maximum permitted amount for nasal or pharyngeal administration.
  • CMC critical micelle concentration
  • the CMC of polysorbate 80 is 0.001% w / v
  • the maximum pharmaceutically approved concentration is 10%> w / v.
  • polysorbate 80 When polysorbate 80 is used as a solubilizer, polysorbate 80 is in a concentration of 0.001-10% w / v, or 0.1-10%) w / v, or 1-10% w / v or 5-10% ow / v in contain the formulations of the invention. Alternatively, polysorbate 80 can also be present in concentrations of up to 15%> w / v or up to 20%> w / v in the formulations according to the invention.
  • Antioxidants for the purposes of the present invention are, for example, citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA, a gasification with nitrogen, tocopherol, ascorbic acid, glutathione, cysteine, sulfites (for example sodium sulfite, sodium hydrogen sulfite), disulfites (for example sodium pyrosulfite), ascorbic acid esters or gallates.
  • the antioxidant is selected from the group consisting of citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA and a gasification with nitrogen.
  • the antioxidant is butylhydroxyanisole.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optionally at least one antioxidant is selected from the group consisting of citric acid, butylated hydroxyanisole, butylated hydroxytoluene, EDTA and a gassing with nitrogen.
  • the optionally at least one antioxidant is selected from the group consisting of citric acid, butylated hydroxyanisole, butylated hydroxytoluene, EDTA and a gassing with nitrogen.
  • One embodiment of the present invention relates to stable pharmaceutical formulations 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 1%> to 100% w / v glycerol and an antioxidant and optionally at least one further adjuvant, wherein the formulation has a pH of 4 to 8.
  • Preservatives for the purposes of the present invention 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 its salts, sorbic acid and its salts, dehydroacetic acid and sulfuric acid and salts thereof, sodium hydrogensulfite Parabens, including methylparaben and propylparaben or thiomersal.
  • the preservative is selected from the group consisting of Cs-Cis alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and Benzalkonium chloride.
  • the preservative B is enalkonium chloride.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the optionally at least one preservative is selected from the group consisting of Cs-Cis alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and benzalkonium chloride.
  • Tonicity-adjusting substances in the context of the present invention are, for example, salts (for example of plasma cations with physiologically tolerable counterions), sugars (for example glucose, sucrose), sugar alcohols (for example mannitol, sorbitol), glycols (eg B. propylene glycols) and other nonionic polyol materials.
  • salts for example of plasma cations with physiologically tolerable counterions
  • sugars for example glucose, sucrose
  • sugar alcohols for example mannitol, sorbitol
  • glycols eg B. propylene glycols
  • Thickening agents for the purposes of the present invention are, for example, natural gums, alginic acid, pectins, starch and starch derivatives, gelatin, poloxamers (block copolymers of ethylene oxide and propylene oxide), cellulose derivatives, acrylic acid polymers, or vinyl polymers.
  • the formulations according to the invention contain as adjuvants at least one pH regulator. According to one embodiment of the present invention, the formulations according to the invention contain as adjuvants at least one antioxidant. According to one embodiment of the present invention, the formulations according to the invention contain as auxiliary substances at least one solubilizer. According to one embodiment of the present invention, the formulations according to the invention contain as auxiliary substances at least one pH regulator and at least one solubilizer. According to one embodiment of the present invention, the formulations according to the invention contain as auxiliary substances at least one antioxidant and at least one solubilizer.
  • the formulations according to the invention contain as auxiliary substances at least one pH regulator, at least one solubilizer and at least one antioxidant. According to one embodiment of the present invention, the formulations according to the invention contain as auxiliary substances at least one pH regulator, at least one solubilizer, at least one antioxidant and at least one preservative.
  • the present invention also relates to stable pharmaceutical formulations according to the invention for nasal or pharyngeal administration, wherein the formulation contains 2 to 50% w / v glycerol, 1 to 10% of a solubilizer, up to 97% w / v of a pH regulator and optionally at least one other Contains adjuvant.
  • One embodiment of the present invention is a stable pharmaceutical formulation according to the invention for nasal or pharyngeal administration, the formulation being 1% w / v to 100%).
  • 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.
  • Nasal spray formulations according to the invention have a preferred dynamic viscosity (at 20 ° C.) of between 1.0 and 140 mPa * s.
  • Nasal administration formulations according to the invention for nasal administration have a preferred dynamic viscosity (at 20 ° C.) between 1.0 and 1480 mPa * s.
  • 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 to 200 mPa * s, preferably 1 to 20 mPa * s.
  • a formulation according to the invention containing 2.5% w / v of an 85% glycerol solution and 10% w / v polysorbate 80 in phosphate buffer has a dynamic viscosity of about 2 mPa * s.
  • the preferred droplet size (expressed 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.
  • 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 of median volume diameter of 5 to 300 ⁇ m, preferably 30 to 100 ⁇ m.
  • glycerol is used synonymously with glycerol.
  • 1%> w / v glycerol means an absolute glycerol concentration of 1%> w / v, which corresponds to a concentration of 1.18% w / v of an 85% glycerol solution.
  • the formulations according to the invention contain 1% w / v to 100% w / v or 1%> w / v to 90%> w / v or 1%> w / v to 80% w / v or 1 % w / v to 70%) w / v or 1% w / v to 60% w / v or 1% w / v to 50% w / v or 1% w / v to 40% w / v or 1% w / v to 30%) w / v or 1% w / v to 20% w / v or 1% w / v to 10% w / v or 1% w / v to 5% w / v or 2% w / v to 100% w / v or 2% w / v to 90% w / v or 2% w / v to 100% w / v or
  • the formulations according to the invention contain 2.5-5% w / v of an 85% glycerol solution. According to a further embodiment of the present invention, the formulations according to the invention contain 2.5% w / v of an 85% glycerol solution.
  • 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.
  • 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.
  • 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)
  • R 1 is halogen, cyano, (C 1 -C 4) -alkyl, cyclopropyl or cyclobutyl and
  • R 2 is (C 4 -C 6 ) -cycloalkyl, wherein a ring CH 2 group may be substituted with -O-, or a phenyl group of formula (a) or a pyridyl group of formula (b )
  • R 3 denotes fluorine, chlorine, bromine, cyano, (C 1 -C 3 ) -alkyl or (C 1 -C 3 ) -alkoxy, where (C 1 -C 3 ) -alkyl and ( Ci-C3) -alkoxy can be substituted up to three times with fluorine
  • R 4 is hydrogen, fluorine, chlorine, bromine or methyl
  • R 5 is hydrogen, fluorine, chlorine, bromine or methyl
  • R 6 is hydrogen, (Ci-C3) alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy or tetrahydro-2H-pyran-4-yloxy, where (Ci-C3) alkoxy up to three times with fluorine and their salts, solvates and solvates of the salts.
  • 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 above-indicated formula (I), wherein
  • R 1 is fluorine, chlorine, bromine, methyl, isopropyl, tert. Is butyl or cyclopropyl and R 2 is cyclobutyl, cyclopentyl or cyclohexyl or a phenyl group of the formula (a) or a pyridyl group of the formula (b)
  • R 3 is fluorine, chlorine, cyano, (C 1 -C 3) -alkyl, (C 1 -C 3) -alkoxy or trifluoromethoxy,
  • R 4 is hydrogen, fluorine or chlorine
  • R 5 is hydrogen, fluorine, chlorine, bromine or methyl and R 6 is hydrogen or (Ci-C3) alkoxy, which may be substituted up to three times with fluorine, and their salts, solvates and solvates of the salts.
  • 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 R 1 is chlorine or bromine, and their salts, solvates and solvates of salts.
  • 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) wherein for methyl, isopropyl, tert. Butyl or cyclopropyl, and their salts, solvates and solvates of the salts.
  • 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) wherein
  • R 2 is cyclobutyl, cyclopentyl or cyclohexyl, and their salts, solvates and solvates of the salts.
  • 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) wherein
  • R 2 represents a phenyl group of the formula (a)
  • R 3 denotes fluorine, chlorine, cyano, (C 1 -C 3 ) -alkyl or (C 1 -C 3 ) -alkoxy and
  • R 4 is hydrogen, fluorine or chlorine, and their salts, solvates and solvates of the salts.
  • 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) wherein
  • R 5 is hydrogen, chlorine or bromine
  • 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) wherein
  • R 1 represents chlorine, bromine, isopropyl or cyclopropyl and R 2 represents cyclobutyl, cyclopentyl or cyclohexyl or represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)
  • R 3 is fluorine, chlorine, cyano, methyl, isopropyl, methoxy or ethoxy,
  • R 4 is hydrogen, fluorine or chlorine
  • R 5 is hydrogen, chlorine or bromine
  • R 6 is methoxy, difluoromethoxy, trifluoromethoxy or isopropoxy, and their salts, solvates and solvates of the salts.
  • the residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.
  • 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.
  • 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
  • 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 (4- ⁇ [2- (4-chlorophenyl) imidazo [1,2-a] pyridine-3] yl] methyl ⁇ piperazine-1-yl) (6-methoxypyridin-2-yl) methanone.
  • Another 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.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory Diseases and neuro-immunological diseases.
  • a further embodiment of the present invention is 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-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuro-immunological disorders, wherein the nasal or pharyngeal application is by nasal sprays, nasal drops, Nasal solutions, powder inhalers, nebulizers, metered aerosols or semi-solid gels occurs.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases , Neuroinflammatory diseases and neuro-immunological diseases used, the duration of action is at least 3 hours.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory Diseases and neuro-immunological diseases used, the duration of action is at least 4 hours.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory Diseases and neuro-immunological disorders used, the duration of action is at least 5 hours.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of respiratory disorders, sleep-disordered breathing, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory Diseases and neuro-immunological disorders used, the duration of action is at least 6 hours.
  • a further embodiment of the present invention is 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 apnea or snoring, comprising a therapeutically effective amount of the inhibitor of TASK-1 and / or TASK.
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the present invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of obstructive sleep apnea or snoring, comprising: a therapeutically effective amount of the inhibitor of TASK-1 and / or TASK -3 channel 4- ⁇ [2- (4-chlorophenyl) imidazo [1,2-a] pyridine-3-ylmethyl ⁇ piperazine-1-yl) (6-methoxypyridin-2-yl) -methanone or a hydrate, solvate , Polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 2% to 5% w / v glycerol and 1 to 10%> w / v polysorbate 80 and up to 97% w / v of a phosphate buffer having a pH of 7 , and optionally at least one further adjuvant, wherein the duration of action of the stable pharmaceutical formulation after nasal or
  • Another embodiment of the present invention is the stable pharmaceutical formulations of the present invention for nasal or pharyngeal application for use in a method for the treatment and / or prevention of obstructive sleep apnea or snoring, comprising: a therapeutically effective amount of the inhibitor of TASK-1 and / or TASK -3 channel 4- ⁇ [2- (4-chlorophenyl) imidazo [1,2-a] pyridine-3-ylmethyl ⁇ piperazine-1-yl) (6-methoxypyridin-2-yl) -methanone or a hydrate, solvate , Polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof in 2% to 5% w / v glycerol and 1 to 10% w / v polysorbate 80 and up to 97% w / v of a phosphate buffer having a pH of 7, and optionally at least one further adjuvant, wherein the duration of action of the stable pharmaceutical formulation after nasal or phary
  • a further embodiment of the present invention is 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 apnea or snoring, comprising a therapeutically effective amount of the inhibitor of TASK-1 and / or TASK.
  • a further embodiment of the present invention is 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 apnea or snoring, comprising a therapeutically effective amount of the inhibitor of TASK-1 and / or TASK.
  • the formulations according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • the present invention therefore further relates to medicaments comprising at least one of the formulations according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the abovementioned disorders.
  • Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:
  • Respiratory stimulants such as by way of example and preferably theophylline, doxapram, nicethamide or caffeine;
  • Psycho-stimulatory compounds such as by way of example and preferably modafinil or armodafinil;
  • Amphetamines and amphetamine derivatives such as by way of example and preferably amphetamine, metamphetamine or methylphenidate;
  • Serotonin reuptake inhibitors such as, by way of example and by way of illustration, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone;
  • Serotonin precursors such as by way of example and preferably L-tryptophan;
  • Selective serotonin norepinephrine reuptake inhibitors such as, by way of example and preferably, venlafaxine or duloxetine; • noradrenergic and specific serotonergic antidepressants, such as, by way of example and preferably, mirtazapine;
  • Selective noradrenaline reuptake inhibitors such as by way of example and preferably reboxetine;
  • Tricyclic antidepressants such as, by way of example and by way of illustration, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine;
  • Alpha2-adrenergic agonists such as, by way of example and by way of illustration, clonidine;
  • GABA agonists such as by way of example and preferably baclofen;
  • Alpha-sympathomimetics such as, by way of example and by way of illustration, xylometazoline, oxymetazoline, phenylphrine, naphazoline, tetryzolin or tramazoline;
  • Glucocorticoids such as by way of example and preferably fluticasone, budesonide, beclomethasone, mometasone, tixocortol or triamcinolone;
  • Carbonic anhydrase inhibitors such as by way of example and preferably acetazolamide, methazolamide or diclofenamide;
  • Opioid and benzodiazepine receptor antagonists such as by way of example and preferably flumazenil, naloxone or naltrexone;
  • Cholinesterase inhibitors such as by way of example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine;
  • N-methyl-D-aspartate and glutamate antagonists such as by way of example and preferably amantadine, memantine or sabeluzol;
  • Nicotine receptor agonists Nicotine receptor agonists
  • Leukotriene receptor antagonists such as by way of example and preferably montelukast or tripelukast;
  • Dopamine receptor antagonists such as by way of example and preferably dromperidone, metoclopramide or benzamide, butyrophenone or phenothiazine derivatives;
  • Appetite suppressants such as by way of example and preferably sibutramine, topiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists;
  • Proton pump inhibitors such as by way of example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • PDE phosphodiesterases
  • sGC soluble guanylate cyclase
  • sGC soluble guanylate cyclase
  • Prostacyclin analogs and IP receptor agonists such as, by way of example and by way of preference, iloprost, berastone, treprostinil, epoprostenol or selexipag;
  • Endothelin receptor antagonists such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;
  • HNE human neutrophilic ecstasy
  • MMPs matrix metalloproteases
  • stromelysin in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (here in particular of MMP-1, MMP-3, MMP-8), inhibit the degradation and remodeling of the extracellular matrix , MMP-9, MMP-10, MMP-11 and MMP-13) as well as the metallo-elastase (MMP-12);
  • Antagonists of growth factors, cytokines and chemokines by way of example and preferably antagonists of TGF- ⁇ , CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; the Rho kinase inhibiting compounds, such as exemplified and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • the energy metabolism of the heart affecting compounds such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine; the signal transduction cascade inhibiting compounds, by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and preferably nintedanib, dasatinib, nilotibib, bosutinib, regorafenib, sorafenib, Sunitinib, cediranib, axitinib, telatinib, imatinib, Brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxani
  • anti-obstructive agents such as. B. for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma are used, by way of example and preferably from the group of inhaled or systemically applied beta-adrenergic receptor agonists
  • Antiinflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents by way of example and preferably from the group of systemically or inhalatively applied corticosteroids and dimethylfumarate, fingolimod, glatiramer acetate, beta-interferons, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, montelukast, tripelukast , Azathioprine,
  • Cyclophosphamide hydroxycarbamide, azithromycin, interferon- ⁇ , pirfenidone or etanercept
  • Antifibrotic agents such as, by way of example and by way of illustration, lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF- ⁇ antagonists or pirfenidone;
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Mineralocorticoid receptor antagonists and diuretics; and or
  • Lipid metabolism-modifying agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid
  • the formulations according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.
  • a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.
  • the formulations according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • an anti-muscarinergic substance such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • the formulations according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • the formulations according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the formulations according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • the formulations according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the formulations according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably 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.
  • a factor Xa inhibitor such as by way of example and preferably 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-12
  • the formulations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the formulations according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxer, beta-receptor blocker, mineralocorticoid receptor Understood antagonists and diuretics.
  • the formulations according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the formulations according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the formulations according to the invention are used in combination with a beta-receptor B, such as by way of example and preferably 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.
  • a beta-receptor B such as by way of example and preferably propranolol, atenolol, timolol
  • the formulations according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the formulations according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the formulations according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the formulations according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, by way of example and by way of preference, spironolactone, eplerenone or finerenone.
  • a mineralocorticoid receptor antagonist such as, by way of example and by way of preference, spironolactone, eplerenone or finerenone.
  • the formulations according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, Dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlorome
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, 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 lipoprotein (a) antagonists.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile
  • the formulations according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the formulations according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the formulations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the formulations according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the formulations according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the formulations according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapid, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapid, BMS-201038, R-103757 or JTT-130.
  • the formulations according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • the formulations according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • a PPAR delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the formulations according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the formulations according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • the formulations according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • the formulations according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions of the invention with one or more further active ingredients selected from the group consisting of respiratory stimulants, psycho-stimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, anti-inflammatory agents , immunomodulating agents, immunosuppressive agents and cytotoxic agents.
  • formulations according to the invention can also be used in conjunction with the use of one or more medical-technical devices or aids, as long as this does not lead to undesired and unacceptable side effects.
  • Medical devices and aids which are suitable for such a combination application are exemplary and preferably:
  • CPAP Positive airway pressure
  • CPAP positive airway pressure
  • BIPAP positive airway pressure
  • IPPV intermittently positive pressure ventilation
  • Intraoral aids such as by way of example and preferably protrusion clips; • nasal one-way valves;
  • the dosage for intranasal administration is about 0.1 ⁇ g to 500 ⁇ g per day. According to a further embodiment, the dosage for intranasal administration is about 1 ⁇ g to 250 ⁇ g per day. According to a further embodiment, the dosage for intranasal administration is about 1 ⁇ g to 120 ⁇ g per day. In another embodiment, the dose is applied intranasally from about 0.1 ⁇ g to 500 ⁇ g per day or from about 1 ⁇ g to 250 ⁇ g per day, or from about 1 ⁇ g to 120 ⁇ g per day once a day before sleep.
  • the pharmacological activity of the inhibitors of the TASK-1 and / or TASK-3 channel contained in the formulations according to the invention was demonstrated in PCT / EP2016 / 079973 by in vitro experiments.
  • the pharmacological activity of the formulations according to the invention can be demonstrated by in vivo studies, as are known to the person skilled in the art.
  • the following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.
  • German country pigs were used for the model. Since the human nasal axis is in an almost vertical position in a lying, sleeping position, the pigs were fixed in a sitting position (70 degrees) during the experiments with the nose pointing upwards. As a result, after nasal administration, the formulation flowed down all areas of the upper respiratory tract. The pigs were anesthetized and tracheotomized. In each of the rostral and caudal parts of the trachea a cannula was inserted. The rostral cannula was connected by means of a T-piece on the one hand to a device which generates negative pressure, and on the other hand to the caudal cannula.
  • the caudal cannula was connected by a T-piece to the rostral cannula and a tube allowing spontaneous respiration, bypassing the upper respiratory tract.
  • By appropriately closing and opening the hoses it was possible for the pig to switch from normal nasal breathing to respiration via the caudal cannula, while the upper respiratory tract was isolated and connected to the negative pressure device.
  • Muscle activity of the genioglossus muscle was recorded by electromyogram (EMG).
  • the upper airway collapse was tested by breathing the pig over the caudal cannula and suppressing upper respiratory tract pressures of -50, -100 and -150 mbar (corresponding to -50, -100 and -150 cm of water column (cm H2O )). This collapsed the upper airways, as indicated by the interruption of airflow and a drop in pressure in the tubing.
  • This test was performed before administration of the test substance and at certain intervals after administration of the test substance. A suitably effective test substance was able to prevent this collapse of the respiratory tract in the inspiratory phase.
  • Example 1 The results shown in the following tables were carried out with the compounds listed in Table 1 as Example 1, Example 3 and Example 4. Unless otherwise stated, the data were measured at a negative pressure of -100 mbar (corresponding to -100 cm water column (cm H2O)) to the upper respiratory tract.
  • Example 1 The active compounds 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 administered with a pipette in a volume of 400 ⁇ in each nostril.
  • Table 2 Compositions of the formulations for nasal administration in which the compound listed in Table 1 as Example 3 was administered:
  • the formulations of Table 2 additionally contain butylhydroxyanisole in a concentration of 0.02% w / v.
  • the phosphate buffer pH 7, 0.063 M was prepared according to European Pharmacopoeia 8.7: 5.18 g of anhydrous disodium hydrogen phosphate and 3.65 g of sodium dihydrogenphosphate monohydrate were dissolved in 950 ml of water, the pH was adjusted with phosphoric acid and it was combined with 1000 ml Water filled up.
  • disodium hydrogen phosphate dihydrate and sodium dihydrogen phosphate dihydrate were used instead of the anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate to prepare the phosphate buffer. Therefor 6.49 g of disodium hydrogen phosphate dihydrate and 4.13 g of sodium dihydrogen phosphate dihydrate were dissolved in 950 ml of water, the pH was adjusted with phosphoric acid and made up to 1000 ml with water.
  • the duration of action in this pig model is defined as the time [min] in which no collapse of the upper respiratory tract was observed in any animal, as an average of the indicated number of animals.
  • a duration of action indicated as ">" X min means that the experiment was terminated at X min and until then no collapse of the upper respiratory tract was observed in any animal.
  • Table 3 duration of action of example 3 / table 1 in phosphate buffer pH7 / polysorbate 80 with glvcerol 85% (formulation 3) or with glvcerol 85% and PEG400 (formulation 5) in comparison to the duration of action of example 3 / table 1 in phosphate buffer pH7 / Polysorbate 80 (Formulation 1)
  • Example 3 in Formulation 1 was 120 min.
  • Table 4 duration of action of Example 3 / Table 1 in phosphate buffer pH7 / polysorbate 80 / glycerol, comparison of different glycerol concentrations
  • Table 5 duration of action of example 3 / table 1 in phosphate buffer pH7 / polysorbate 80 (90/10) + sodium
  • Table 7 Duration of action of Example 1 / Table 1 in phosphate buffer pH7 / polysorbate 80 / Glvcerol (Formulation 3) compared to the duration of action of Example 1 / Table 1 in phosphate buffer pH7 / polysorbate 80 (Formulation 1) at a negative pressure of -100 mbar and -50 mbar
  • Table 8 duration of action of Example 4 / Table 1 in phosphate buffer pH7 / polysorbate 80 / Glvcerol (Formulation 3) compared to the duration of action of Example 4 / Table 1 in phosphate buffer pH7 / polysorbate 80 (Formulation 1) at a negative pressure of -100 mbar and -50 mbar

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CN103877288B (zh) * 2014-04-16 2016-01-20 广西信业生物技术有限公司 一种壳聚糖鼻咽生物医用膜及其制备方法

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JP2020502215A (ja) 2020-01-23
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MX2019007619A (es) 2019-09-06
CL2019001726A1 (es) 2019-11-29
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AU2017379245A1 (en) 2019-07-11
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CA3047426A1 (en) 2018-06-28
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CR20190299A (es) 2019-09-04
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