EP3558380A1 - Pharmaceutical dosage forms containing task-1 and task-3 channel inhibitors, and the use of same in breathing disorder therapy - Google Patents

Pharmaceutical dosage forms containing task-1 and task-3 channel inhibitors, and the use of same in breathing disorder therapy

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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Withdrawn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
Other languages
German (de)
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/en
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3558380A1 publication Critical patent/EP3558380A1/en
Withdrawn legal-status Critical Current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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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 apnea and snoring.

Description

Pharmazeutische Darreichungsformen enthaltend Inhibitoren von TASK-1 und TASK-3 Kanälen und deren Verwendung für die Therapie von Atemstörungen  Pharmaceutical dosage forms containing inhibitors of TASK-1 and TASK-3 channels and their use for the treatment of respiratory disorders
Die vorliegende Anmeldung betrifft neue pharmazeutische Darreichungsformen enthaltend potente und selektive Inhibitoren von TASK-1 und/oder TASK-3 Kanälen und ihre Verwendung für die Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen. 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.
Kaliumkanäle sind nahezu ubiquitär vorkommende Membranproteine, die an einer Vielzahl von unterschiedlichen physiologischen Prozessen beteiligt sind. Dazu gehört auch die Regulation des Membranpotentials und der elektrischen Erregbarkeit von Neuronen und Muskelzellen. Kaliumkanäle werden in drei größere Gruppen unterteilt, welche sich in der Zahl der Transmembrandomänen (2, 4 oder 6) unterscheiden. Die Gruppe von Kaliumkanälen, bei der zwei porenbildende Domänen von vier Transmembrandomänen flankiert werden, wird K2P-Kanäle (Two-pore domain K") genannt. Funktionell vermitteln die K2P-Kanäle weitgehend zeit- und spannungsunabhängig K+-Hintergrundströme und tragen entscheidend zur Aufrechterhaltung des Ruhemembranpotentials bei. Die Familie der K2P- Kanäle umfasst 15 Mitglieder, die in sechs Subfamilien untergliedert sind, basierend auf Ähnlichkeiten in Sequenz, Struktur und Funktion: TWIK (Tandem pore domain halothane inhibited K+ Channel), TREK (TWIK-related K+ Channel), TASK (TWIK-related acid-sensitive K+ Channel), TALK (TWIK- related alkaline pH activated K+ Channel), THIK (Tandem pore domain halothane inhibited K+ Channel) und TRESK (TWIK-related spinal cord K+ Channel). 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). 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 ").) Functionally, 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).
Von besonderem Interesse sind TASK-1 (KCNK3 oder K2P3.1) und TASK-3 (KCNK9 oder K2P9.1) der TASK {TWIK-related acid-sensitive K+ c/za««e/)-Subfamüie. Diese Kanäle sind funktionell dadurch gekennzeichnet, dass durch sie bei Erhaltung der spannungsunabhängigen Kinetik sogenannte "Leck"- oder "Hintergrund"-Ströme fließen, wobei sie auf eine Vielzahl von physiologischen und pathologischen Einflüssen mit einer Zu- oder Abnahme der Aktivität reagieren. Charakteristisch für TASK-Kanäle ist die sensitive Reaktion auf eine Änderung des extrazellulären pH- Wertes: Die Kanäle werden bei saurem pH- Wert inhibiert und bei alkalischem pH- Wert aktiviert. Of particular interest are TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 or K2P9.1) of the TASK {TWIK-related acid-sensitive K + c / za "" e) subfamie. 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- und TASK-3-Kanäle spielen eine Rolle bei der Regulation der Atmung. Beide Kanäle werden in den respiratorischen Neuronen des Atemzentrums im Hirnstamm exprimiert, unter anderem in Neuronen, die den Atemrhythmus generieren (ventrale respiratorische Gruppe mit dem prä-Bötzinger- Komplex), und im noradrenergen Locus caeruleus sowie in serotonergen Neuronen der Raphe-Kerne. Aufgrund der pH-Abhängigkeit übernehmen die TASK-Kanäle hier die Funktion eines Sensors, der extrazelluläre pH- Wert-Änderungen in entsprechende zelluläre Signale übersetzt [Bayliss et al, Pflugers Arch. 467, 917-929 (2015)]. Auch im Glomus caroticum, einem Paraganglion, das den pH- Wert und den O2- und C02-Gehalt des Blutes misst und Signale an das Atemzentrum im Hirnstamm übermittelt, um die Atmung zu regulieren, werden TASK-1 und TASK-3 exprimiert. Es wurde gezeigt, dass TASK-1 knock- out-Mäuse eine verringerte ventilatorische Reaktion (Anstieg der Atemfrequenz und des Atemzugvolumens) auf Hypoxie und normoxische Hyperkapnie aufweisen [Trapp et al, J. Neurosci. 28, 8844-8850 (2008)]. Des Weiteren wurden TASK-1- und TASK-3-Kanäle in Motoneuronen des Nervus hypoglossus, dem XII. Hirnnerv, nachgewiesen, der eine wichtige Funktion für die Offenhaltung der oberen Atemwege hat [Berg et al, J. Neurosci. 24, 6693-6702 (2004)]. 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)]. Also in the carotid body, a paraganglion that measures the pH and O2 and C0 2 content of the blood and sends signals to the respiratory center in the brain stem To regulate respiration, 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)]. Furthermore, 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)].
In einem Schlafapnoe-Modell am anästhesierten Schwein führte die nasale Gabe eines Kaliumkanal- Blockers, der im nanomolaren Bereich den TASK-1 -Kanal blockiert, zu einer Hemmung der Kollapsibilität der pharyngealen Atemwegsmuskulatur und zu einer Sensibilisierung des negativen Druckreflexes der oberen Atemwege. Man vermutet, dass die nasale Gabe des Kaliumkanal-Blockers Mechanorezeptoren in den oberen Atemwegen depolarisiert und über Aktivierung des negativen Druckreflexes zu einer verstärkten Aktivität der Muskulatur der oberen Atemwege führt, wodurch eine Stabilisierung der oberen Atemwege erfolgt und ein Kollaps verhindert wird. Über eine solche Stabilisierung der oberen Atemwege kann die TASK-Kanal-Blockade für obstruktive Schlafapnoe und auch Schnarchen von großer Bedeutung sein [Wirth et al, Sleep 36, 699-708 (2013); Kiper et al, Pflugers Arch. 467, 1081-1090 (2015)]. In a sleep apnea model on the anesthetized pig, the nasal administration of 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. Over such upper airway stabilization, 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)].
Die obstruktive Schlafapnoe (OSA) ist eine schlafbedingte Atemstörung, die gekennzeichnet ist durch wiederholte Episoden der Obstruktion der oberen Atemwege. Bei der Einatmung wird die Durchgängigkeit der oberen Atemwege durch das Zusammenspiel zweier Gegenkräfte gewährleistet. Die diktierenden Effekte der Muskulatur der oberen Atemwege wirken dem das Lumen verengenden negativen intraluminaren Druck entgegen. Die aktive Kontraktion des Zwerchfells und der anderen Atemhilfsmuskeln erzeugt einen Unterdruck in den Atemwegen und stellt so die treibende Kraft für die Atmung dar. Die Stabilität der oberen Atemwege wird maßgeblich von der Koordination und Kontraktionseigenschaft der diktierenden Muskeln der oberen Atemwege bestimmt. Der Musculus genioglossus spielt bei der Pathogenese der OSA eine entscheidende Rolle. Die Aktivität des Musculus genioglossus nimmt mit abnehmendem Druck im Pharynx im Sinne eines diktierenden Kompensationsmechanismus zu. Innerviert vom Nervus hypoglossus zieht er die Zunge nach vorne und unten und erweitert auf diese Weise den pharyngealen Luftweg [Verse et al, Somnologie 3, 14-20 (1999)]. Die Anspannung der diktierenden Muskeln der oberen Atemwege wird unter anderem über Mechanorezeptoren/Dehnungsrezeptoren im Nasen-Rachen-Raum moduliert [Bouillette et al, J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]. Durch Lokalanästhesie des oberen Luftwegs kann bei Patienten mit schwerer Schlafapnoe im Schlaf eine zusätzliche Reduktion der Aktivität des Musculus genioglossus beobachtet werden [Berry et al, Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]. Patienten mit OSA haben eine hohe Mortalität und Morbidität infolge von Herz- Kreislauf-Erkrankungen wie z. B. Bluthochdruck, Herzinfarkt und Schlaganfall [Vrints et al., Acta Clin. Belg. 68, 169-178 (2013)]. Obstructive sleep apnea (OSA) 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)]. Local anesthesia of the upper airway may cause an additional reduction in the activity of the genioglossus muscle in patients with severe sleep apnea during sleep [Berry et al, Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]. Patients with OSA have high mortality and morbidity due to cardiac Circulatory diseases such. Hypertension, myocardial infarction and stroke [Vrints et al., Acta Clin. Belg. 68, 169-178 (2013)].
Bei der zentralen Schlafapnoe kommt es infolge einer gestörten Hirnfunktion bzw. einer gestörten Atemregulation zu episodischen Hemmungen des Atemantriebs. Zentral bedingte Atemstörungen führen zu mechanischen Atemstillständen, d.h. es findet während dieser Episoden keine Atmungsaktivität statt, sämtliche Atemmuskeln einschließlich Zwerchfell stehen vorübergehend still. Bei der zentralen Schlafapnoe liegt keine Obstruktion der oberen Atemwege vor. In 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. In central sleep apnea, there is no upper airway obstruction.
Beim primären Schnarchen kommt es ebenfalls nicht zu einer Obstruktion der oberen Atemwege. Durch die Verengung der oberen Atemwege erhöht sich allerdings die Strömungsgeschwindigkeit der ein- und ausgeatmeten Luft. Dies bewirkt im Verbund mit der erschlafften Muskulatur, dass die weichen Gewebe des Mund- und Rachenraumes im Luftstrom flattern. Dieses leichte Vibrieren erzeugt dann die typischen Schnarchgeräusche. Primary snoring also does not cause upper airway obstruction. However, the narrowing of the upper respiratory tract increases the flow rate of the inhaled and exhaled air. This, in conjunction with the relaxed muscles, causes the soft tissues of the mouth and throat to flutter in the airstream. This slight vibration then generates the typical snoring sounds.
Das obstruktive Schnarchen (upper airway resistance Syndrome, heavy snoring, Hypopnoe-Syndrom) wird durch eine wiederkehrende partielle Obstruktion der oberen Atemwege im Schlaf verursacht. Hierdurch kommt es zu einer Erhöhung des Atemwegswiderstands und somit zu einem Anstieg der Atemarbeit mit erheblichen intrathorakalen Druckschwankungen. Die negative intrathorakale Druckentwicklung während der Inspiration kann dabei Werte erreichen, wie sie infolge einer kompletten Atemwegsobstruktion bei der OSA auftreten. Die pathophysiologischen Auswirkungen auf Herz, Kreislauf und Schlafqualität entsprechen denen bei der obstruktiven Schlafapnoe. Die Pathogenese ist wie bei der OSA in einem gestörten Reflexmechanismus der Pharynx- dilatierenden Muskeln im Schlaf während der Inspiration anzunehmen. Das obstruktive Schnarchen stellt häufig die Vorstufe für die OSA dar [Hollandt et al., HNO 48, 628-634 (2000)]. 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)].
Die derzeit verfügbaren Therapiemöglichkeiten von Schnarchen und von OSA sind begrenzt. Aus den 1980er Jahren sind Mischungen von oberflächenaktiven Substanzen bekannt, die den Widerstand der oberen Atemwege und das Schnarchen reduzieren sollen [Widdicombe and Davies, Eur Resp J \ , 785- 791 (1988)]. Diese Mischungen enthalten NaCl, Glycerol, Polysorbat 80 und Benzalkoniumchlorid. Aus Versuchen an Hunden, denen diese Mischungen per Injektion in den Pharynx verabreicht wurden, wurde gefolgert, dass diese Mischungen den Widerstand der oberen Atemwege reduzieren, die Aktivität des Musculus genioglossus während der Einatmung und Ausatmung erhöhen und Schnarchgeräusche reduzieren. OSA wird in dem Artikel von Widdicombe nicht erwähnt und es wurde in diesem Modell auch nicht gezeigt, dass ein Kollaps der oberen Luftwege, der zu einer Apnoe führt, verhindert werden konnte. Das Modell von Widdicombe und Davies ist damit nicht prädiktiv für OSA. The currently available treatment options for snoring and OSA are limited. From the 1980's, blends of surfactants are known which are said to reduce upper respiratory tract resistance and snoring [Widdicombe and Davies, Eur Resp J \, 785-791 (1988)]. These mixtures contain NaCl, glycerol, polysorbate 80 and benzalkonium chloride. From experiments on dogs given these injections into the pharynx, it was concluded that these mixtures reduce the resistance of the upper respiratory tract, increase the activity of the genioglossus muscle during inhalation and exhalation, and reduce snoring sounds. OSA is not mentioned in the article by Widdicombe, nor has it been shown in this model that a collapse of the upper airways leading to apnea could be prevented. The model of Widdicombe and Davies is therefore not predictive of OSA.
Eine Zusammensetzung bestehend aus: 0.26% Glycerol, 0.2% Polysorbat 80, 0.9%> Natriumchlorid und 0.15%) Kaliumsorbat (ohne Benzalkoniumchlorid) ist als Asonor® zur Therapie des Schnarchens auf dem Markt. In einer Studie des University State Hospital in Kopenhagen wurde die Wirksamkeit einer nasalen Gabe von Asonor® im Vergleich zu„Asonor®" ohne Polysorbat 80 im Hinblick auf eine Verbesserung des Schnarchens untersucht. Sowohl Asonor® als auch„Asonor®" ohne Polysorbat 80 bewirkten eine signifikante Verbesserung des Schnarchens [Report from the Departement of Neurology, University State Hospital, Copenhagen, Denmark. The effect of nasal application of Asonor® and Polyglycoside 80 on snoring and sleep apnoea, 1989, http://www.chrapat.sk/img/klinicka- dokumentacia.pdf] . 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. In a study by the University State Hospital in Copenhagen, the efficacy of 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. The effect of nasal application of Asonor ® and polyglycosides 80 on snoring and sleep apnea, 1989, http://www.chrapat.sk/img/klinicka- dokumentacia.pdf].
EP 2595685 Bl (U.S. Patent No. 9,132,243 Bl) beansprucht ein pharmazeutisches Produkt umfassend einen Behälter, der eine flüssige Anti-Schnarch-Substanz enthält, wobei der Behälter einen Flüssigkeitsauslassabschnitt enthält, der konfiguriert ist, um die flüssige Anti-Schnarch-Substanz direkt in einen Nasengang in der Form eines Strahlstroms abzugeben. Die flüssige Anti-Schnarch-Substanz ist eine Anti-Schnarch-Lösung, die Natriumchlorid, Glycerol, Polysorbat und Natriumedetat und wahlweise Kaliumsorbat als Konservierungsstoff umfasst. Eine Therapie von Apnoe oder OSA ist in den ursprünglich eingereichten Anmeldeunterlagen von EP 2595685 Bl und U.S. Patent No. 9,132,243 Bl nicht offenbart. In der EP 2595685 Bl ist die beschriebene Anti-Schnarch-Substanz für eine Verwendung in der Behandlung von Schnarchen und Atemstillstand (Apnoe) beansprucht. 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. In EP 2595685 Bl the anti-snoring substance described is claimed for use in the treatment of snoring and respiratory arrest (apnea).
Für die Therapie der OSA ist derzeit keine pharmakologische Therapie verfügbar. Operationen und orale Vorrichtungen sind nur eingeschränkt wirksam. Behandlungsstandard ist die Therapie mit dem Continuous Positive Airway Pressure (CPAP) System. Die Rate der Einhaltung dieser Therapie liegt aber aufgrund der Unannehmlichkeit bei nur 50-70% und das System wird im Schnitt nicht mehr als 4 Stunden pro Nacht getragen. No pharmacological therapy is currently available for the treatment of OSA. Surgeries and oral devices have limited effectiveness. Standard of care is therapy with the Continuous Positive Airway Pressure (CPAP) system. However, due to the inconvenience, the rate of adherence to this therapy is only 50-70% and the system is worn on average no more than 4 hours per night.
Neue Substanzen, die als potente und selektive Inhibitoren von TASK-1- und/oder TASK-3 -Kanälen agieren und sich als solche insbesondere zur Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen, sowie anderer Erkrankungen eignen, sind bekannt aus PCT/EP2016/079973 und PCT/EP2016/079544 (unveröffentlicht) . 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).
Die Wirkdauer der in der EP 15199270.8 und EP 15199268.2 offenbarten potenten und selektiven Inhibitoren von TASK-1- und/oder TASK-3 -Kanälen ist bei nasaler Verabreichung nicht immer ausreichend, was eine Nachdosierung während der Nacht und damit eine Unterbrechung der Nachtruhe bzw. des Schlafs erforderlich macht. 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.
Aufgabe der vorliegenden Erfindung ist es daher, eine wirkungsvolle pharmakologische Therapie zur Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen zur Verfügung zu stellen, die eine Alternative zur Behandlung mit dem CPAP System darstellt. Eine weitere Aufgabe der vorliegenden Erfindung ist es, die Rate der Einhaltung einer Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen gegenüber dem derzeitigen Therapiestandard (Therapie von OSA: CPAP System) durch den Patienten zu erhöhen. Dazu sollte diese alternative Therapie einfach und bequem anwendbar sein und den Schlafenden nicht stören. Außerdem sollte diese alternative Therapie mit einer einmal täglichen Dosierung vor dem Schlafengehen eine ungestörte Nachtruhe ohne erneute Medikation ermöglichen. 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). In addition, this alternative therapy should be easy and convenient to use and not disturb the sleeping. In addition, this alternative regimen of once-a-day dosing should allow for undisturbed sleep without re-medication.
Eine weitere Aufgabe der vorliegenden Erfindung ist es daher, die pharmakologisch wirksamen Substanzen zur Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen in einer Applikationsform zur Verfügung zu stellen, die für eine einmal tägliche nasale oder pharyngeale Gabe vor dem Schlafengehen geeignet ist. Insbesondere ist es eine Aufgabe der vorliegenden Erfindung, eine pharmakologisch wirksame Therapie zur Behandlung und/oder Prävention von Atemstörungen, einschließlich schlafbedingter Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen zur Verfügung zu stellen, die eine Wirkdauer von mindestens 4 Stunden aufweist. 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. In particular, it is an object of the present invention to provide a pharmacologically effective therapy for the treatment and / or prevention of respiratory disorders, including sleep-disordered breathing such as obstructive and central sleep apnea and snoring, having a duration of action of at least 4 hours.
Die Verlängerung der Wirkdauer von nasal verabreichten Wirkstoffen ist schwierig. Aufgrund physiologischer Gegebenheiten ist die Verweilzeit von Wirkstoffen, Partikeln, Kapseln und Ähnlichem an den Epithelzellen kurz. Das Epithel besteht zum Teil aus Flimmerzellen, welche haarförmige Strukturen, die Zilien aufweisen. Diese sind von einer Schleimschicht (Mukus) bedeckt, welche durch eine koordinierte Bewegung der Zilien in Richtung Rachen abtransportiert wird. Auf der Mukusschicht bleiben Fremdpartikel und Mikroorganismen nach nasaler Aufnahme haften und werden durch die mukoziliäre Clearance gemeinsam mit dem Mukus in Richtung Rachen und Oesophagus transportiert. Dadurch wirkt die mukoziliäre Clearance der nasalen Absorption von Wirkstoffen entgegen und stellt insbesondere eine Herausforderung für das Erreichen einer Wirkverlängerung dar. Die Flussrate des Mukus beträgt ungefähr 5 mm pro Minute, so dass sie alle 15-20 min erneuert wird. Für nasal applizierte Lösungen und Pulver wurden daher auch Cfearance-Halbwertszeiten von 15 min bestimmt [Illum et al, Int J Pharm. 39, 189-199 (1987)], so dass Wirkstoffe prinzipiell nur kurz an der Mukosa verweilen, um eine Wirkung zu erzielen. 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. As a result, 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.
Eine Methode zur Erreichung einer Wirkverlängerung nach nasaler Applikation ist, die Kontaktzeit zwischen Wirkstoff und dem Absorptionsort in der Nase, den Epithelzellen, zu verlängern. Durch eine verlängerte Kontaktzeit wird die Absorption von Arzneistoffen in der Nase gesteigert. Die Wirkstoffaufnahme kann über einen längeren Zeitraum erfolgen, so dass zum einen eine verlängerte Wirkung bzw. Wirkdauer erreicht und zum anderen die insgesamt aufgenommene Arzneistoffmenge gesteigert werden kann. Methoden, um die Kontaktzeit zwischen dem Wirkstoff und den Epithelzellen zu erhöhen, sind unter anderem die Erhöhung der Viskosität, die Verwendung von bioadhäsiven Polymeren oder der Einsatz von Mikropartikeln. 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. konnten bereits 1988 zeigen, dass durch die Erhöhung der Viskosität von nasal applizierten Lösungen mit Hydroxypropylmethylcellulose die Clearance-Rate reduziert wird [Pennington et al, Int J Pharm. 43, 221-224 (1988)]. Mit ansteigendem Polymeranteil und damit steigender Viskosität verlängerte sich die Halbwertszeit von 1 Stunde auf 2.2 Stunden. Verglichen mit den von lllum et al. [Illum et al, Int J Pharm. 39, 189-199 (1987)] beobachteten Halbwertszeiten für Lösungen von 15 min führte die Viskositätserhöhung somit zu einer deutlichen Verlängerung der Halbwertszeit. Viskose Lösungen und halbfeste Systeme wie Gele, Cremes und Salben lassen sich allerdings schwieriger applizieren als niedrig- viskose Formulierungen. Die Zerstäubung über ein Spray ist nicht mehr möglich und eine genaue Dosierung mit Hilfe von Applikatoren im Falle von halbfesten Systemen ist erschwert. Zudem können nasal applizierte halbfeste Systeme zu einer Blockade führen, die die nasale Atmung stören können. Neben der Verabreichung von höher-viskosen Lösungen und applikationsfertigen Gelen ist auch die Verabreichung von in situ Gelen denkbar [Majithiya et al., AAPS PharmSciTech 7 (3), Article 67 (2006)]. Hier wird die Gelierung erst innerhalb der Nase ausgelöst, z. B. durch eine Temperaturveränderung, eine Änderung des pH- Wertes oder die Anwesenheit von Ionen. Dadurch kann eine niedrig- viskose Lösung appliziert werden und die viskose Formulierung steht nach Gelierung am Depositionsort, der Nasenschleimhaut, mit ihren positiven Effekten zur Verfügung. Dadurch können Dosiersysteme für die Applikation verwendet werden, die eine genaue und einfache Applikation ermöglichen. Allerdings handelt es sich um komplexe und aufwändige Darreichungsformen, da die Gelbildung genau abgestimmt werden muss. Wird die Gelierung z. B. durch eine Temperaturänderung hervorgerufen, muss gewährleistet werden, dass die Gelierung erst bei physiologischen Temperaturen ausgelöst wird, bei der Lagerung allerdings noch unterbunden wird. Damit sind einerseits besondere Anforderungen an die Lagerung und Handhabung gestellt, um eine vorzeitige Gelierung zu vermeiden, andererseits ist der Entwicklungs- und Herstellungsaufwand eines solchen, sensitiven Systems sehr hoch. 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. However, 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. In addition, nasally-applied semi-solid systems can lead to blockage that can interfere with nasal breathing. In addition to the administration of higher-viscous solutions and ready-to-use gels, the administration of in situ gels is also conceivable [Majithiya et al., AAPS PharmSciTech 7 (3), Article 67 (2006)]. Here, 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. As a result, a low-viscosity solution can be applied and the viscous formulation is available after gelation at the deposition site, the nasal mucous membrane, with its positive effects. As a result, dosing systems for the application can be used, which enable precise and simple application. However, these are complex and expensive forms of administration, since the gel formation must be precisely coordinated. If the gelation z. B. caused by a change in temperature, it must be ensured that the gelation is triggered only at physiological temperatures, however, is still prevented during storage. Thus, on the one hand special requirements are placed on the storage and handling in order to avoid premature gelation, on the other hand, the development and production cost of such a sensitive system is very high.
Als bioadhäsive Polymere finden Stärke und Chitosan häufig Verwendung [Illum et al, J Controlled Release 87, 187-198 (2003)]. Chitosan ist ein bioadhäsives Polysaccharid und kann ausgeprägt mit den Epithelzellen und der Mukusschicht interagieren. Dadurch wird eine längere Kontaktzeit hervorgerufen, die für den Wirkstofftransport durch die Membran zur Verfügung steht. In der Literatur ist Chitosan weit verbreitet, allerdings handelt es sich hier vorwiegend um in vitro Versuche. Bisher ist Chitosan nicht für die nasale Applikation zugelassen (FDA Drag Databases, Inactive Ingredient Search for Approved Drag Products) und die potentielle Langzeit-Toxizität für eine chronische nasale Applikation ist nicht vollständig untersucht. Eine weitere Möglichkeit, die Wirkung nach nasaler Wirkstoffverabreichung zu verlängern, stellt die Verkapselung des Wirkstoffs in polymere Mikropartikel dar [Cerchiara et al, Eur J Pharm Biopharm. 61, 195-200 (2005)]. Hierzu wird der Wirkstoff in einem geeigneten Polymer, das eine geringe Löslichkeit in Wasser aufweist, oder einer Polymerkombination, die zusätzlich noch eine Adhäsion der wirkstoffbeladenen Mikropartikel an die Nasenschleimhaut ermöglicht, eingebettet. Nach Einbringen dieser Darreichungsform in die Nase wird der Wirkstoff aus den Mikropartikeln je nach Eigenschaft des eingesetzten Polymers mittels Diffusion und/oder Polymerabbau/-erosion verzögert freigegeben, was zu einer verlängerten Wirkdauer des Wirkstoffs am Wirkort führt. Verfügt die verwendete Polymerkombination, aus der die Mikropartikel aufgebaut sind, zusätzlich noch über die Eigenschaft, an der Nasenschleimhaut anzuhaften, so ist mit einer verlängerten Verweildauer und damit Wirkdauer der nasal eingebrachten Medikation zu rechnen. Gerade die Kombination aus Mikropartikeln und bioadhäsiven Polymeren stellt daher einen viel beschriebenen Ansatz zur Verlängerung der Wirkdauer bei nasaler Applikation dar, da hier zwei Prinzipien - die verzögerte Freisetzung und die Erhöhung der Kontaktzeit - kombiniert werden. Dabei können die Mikropartikel direkt aus einem bioadhäsiven Polymer hergestellt werden [Illum et al, Int J Pharm. 39, 189-199 (1987)] oder es können andere Polymere wie Poly(lactid-co-glycolid (PLGA) für die Herstellung der Mikropartikel verwendet werden, die dann in einem weiteren Schritt mit dem bioadhäsiven Polymer überzogen werden [Pawar et al., Am Assoc Pharmac Sei J 12, 130-137 (2010)]. 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. Another way to prolong the effect after nasal drug administration, the encapsulation of the active ingredient in polymeric microparticles is [Cerchiara et al, Eur J Pharm Biopharm. 61, 195-200 (2005)]. For this purpose, 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. After introducing this dosage form into the nose, 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. If 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. Especially 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. In this case, the microparticles can be prepared directly from a bioadhesive polymer [Illum et al, Int J Pharm. 39, 189-199 (1987)] or other polymers such as poly (lactide-co-glycolide (PLGA) for the preparation of microparticles which are then coated with the bioadhesive polymer in a further step [Pawar et al., Am Assoc Pharmac. Ji J 12, 130-137 (2010)].
Neben der Verwendung der oben beschriebenen Mikropartikel kann eine Verlängerung der Wirkstofffreisetzung auch durch die Verwendung von suspendiertem statt gelöstem Wirkstoff erzeugt werden. Der eingesetzte Wirkstoff wird hierfür z. B. mikronisiert (Zerkleinerung zu Wirkstoffmikropartikeln) und in eine flüssige Phase eingearbeitet (suspendiert). Nach Applikation in die Nase, lösen sich die Wirkstoffpartikel am Wirkort verzögert auf. Erst der gelöste Wirkstoff kann über die Nasenschleimhaut absorbiert werden und dann wirksam werden. Die Auflösungskinetik, die über die Verlängerung des Wirkeffekts entscheidet, hängt u.a. von den physikochemischen Eigenschaften (z. B. Löslichkeit, Partikelgröße) des eingesetzten Wirkstoffs ab. Durch eine Verabreichung von Kristallsuspensionen von Glucocorticoiden konnte so beispielsweise eine lokale Wirkungsverlängerung erzielt werden [Rygg et al, Pharm Res. 33, 909-921(2016)]. In addition to using the microparticles described above, 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. By administration of crystal suspensions of glucocorticoids, for example, a local extension of activity could be achieved [Rygg et al, Pharm Res. 33, 909-921 (2016)].
Die Verarbeitung von Wirkstoffen in Kristallsuspensionen sowie die Verkapselung von Wirkstoffen in polymere Mikropartikel mit dem Ziel einer Wirkungsverlängerung nach nasaler Applikation ist mit zahlreichen Nachteilen verbunden. The processing of active ingredients in crystal suspensions and the encapsulation of active ingredients in polymeric microparticles with the aim of prolonging the action after nasal administration has numerous disadvantages.
Einerseits ist die Herstellung derartiger Darreichungsformen im Vergleich zu beispielsweise Wirkstofflösungen technisch um ein vielfaches komplexer. So erfordert die Herstellung von Kristallsuspensionen und polymeren Mikropartikeln eine Vielzahl von aufeinanderfolgenden Prozessschritten, die die Qualität der fertigen Darreichungsform signifikant beeinflussen. Die Funktionalität dieser komplexen Darreichungsformen kann aufgrund mangelnder Lagerstabilität ungünstig beeinflusst werden. So weisen Kristallsuspensionen beispielsweise Partikelsedimentation (inkl. Sedimentbildung) und/oder Veränderungen der Primärpartikelgröße während der Lagerung auf, was zu Inhomogenität innerhalb der Darreichungsform und damit Fehldosierungen führt. Andererseits wird für die Herstellung von Kristallsuspensionen und polymeren Mikropartikeln der Einsatz zahlreicher Stabilisatoren und polymerer Matrixbildner benötigt, die nach nasaler Applikation zu lokalen Unverträglichkeiten/Reizungen führen können. So ist beispielsweise bekannt, dass zahlreiche Stabilisatoren zu einer unerwünschten Beeinflussung der Zilienbeweglichkeit, Zellyse und Inaktivierung von Enzymen führen können [Schinichiro et al, Int J Pharm. 9, 173-184 (1981)]. Während des hydrolytischen Abbaus von Polymeren wie etwa bioresorbierbaren Polyestern (z. B. PLGA), die häufig als Matrixbildner für Mikropartikel eingesetzt werden, kommt es zu einer Freisetzung von Abbauprodukten (z. B. Milch- und Glykolsäure), die den lokalen pH- Wert stark absenken können, wodurch es zu einer lokalen Irritation kommen kann. Lokale Irritationen können auch durch die Partikel selbst ausgelöst werden. Darüber hinaus kann gerade die Verwendung von partikulären Systemen wie Kristallsuspensionen und polymeren Mikropartikeln, die mit einer verzögerten Freisetzung und Auflösung des Wirkstoffes einhergehen, dazu führen, dass bedingt durch die mukoziliäre Clearance ein nicht reproduzierbarer Anteil der Dosis vor der Absorption bereits als ungelöste Partikel abtransportiert und abgeschluckt wird. Das Verschlucken von Wirkstoff kann dann wiederrum zu einer großen Variabilität der Exposition führen [Malinovsky et al., Br J Anaesthesia 77, 203-207 (1996)]. On the one hand, the production of such dosage forms is technically many times more complex compared to, for example, drug solutions. Thus, the preparation of crystal suspensions and polymeric microparticles requires 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. For example, 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. On the other hand, 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. It is known, for example, that numerous stabilizers can lead to an undesired effect on ciliary mobility, cell lysis and inactivation of enzymes [Schinichiro et al, Int J Pharm. 9, 173-184 (1981)]. During the hydrolytic degradation of polymers such as bioresorbable polyesters (eg PLGA), which are often used as matrix formers for microparticles, degradation products (eg, lactic and glycolic acid) are released which interfere with local pH. Can greatly lower the value, which can cause local irritation. Local irritations can also be triggered by the particles themselves. In addition, especially the use of 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. In turn, ingestion of active ingredient can lead to high variability of exposure [Malinovsky et al., Br J Anesthesia 77, 203-207 (1996)].
Weiterhin ist der Einsatz von Kristallsuspensionen und polymeren Mikropartikeln mit komplexeren Anwendungshinweisen verbunden, die zu Anwendungsfehlern führen können, die wiederum den gewünschten Therapieerfolg gefährden. Furthermore, the use of crystal suspensions and polymeric microparticles is associated with more complex instructions for use, which can lead to application errors, which in turn endanger the desired therapeutic success.
Nachteile der beschriebenen Ansätze zur Verlängerung der Wirkung nasal verabreichter Wirkstoffe, wie viskose Systeme, Kristallsuspensionen und Mikropartikel, sind demnach der hohe Aufwand in der Herstellung, die Komplexität dieser Darreichungsformen, das Risiko für große Variabilität in der Exposition und nicht zuletzt die mangelnde Unbedenklichkeit der eingesetzten Hilfsstoffe (z. B. Polymere) für die nasale Applikation. Disadvantages of the approaches described for prolonging the action of nasally administered active substances, such as viscous systems, crystal suspensions and microparticles, are therefore the high production costs, the complexity of these administration forms, the risk of great variability in exposure and not least the lack of safety of the used Excipients (eg polymers) for nasal application.
Überraschenderweise wurde in der vorliegenden Erfindung gezeigt, dass eine nasale Gabe einer Formulierung enthaltend eine therapeutisch wirksamen Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in 1% bis 100% w/v Glycerol die Wirkdauer des Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in Abhängigkeit von deren Dosis deutlich verlängert. Surprisingly, it has been demonstrated in the present invention that 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.
Ein Gegenstand der vorliegenden Erfindung sind stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation enthaltend: eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in 1% bis 100% w/v Glycerol und gegebenenfalls mindestens einen Hilfsstoff, wobei die Formulierung einen pH- Wert von 4 bis 8 aufweist. 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.
Eine nasale oder pharyngeale Gabe einer therapeutisch wirksamen Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in einer Formulierung enthaltend einen pH-Regulator und einen Lösungsvermittler ohne Zusatz von Glycerol führte auch bei Steigerung der Dosis des Inhibitors des TASK-1 und/oder TASK-3 Kanals nicht zu einer Verlängerung der Wirkdauer. A nasal or pharyngeal administration of 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 a formulation containing a pH regulator and a solubilizer without the addition of glycerol, even increasing the dose of the inhibitor of the TASK-1 and / or TASK-3 channel did not prolong the duration of action.
Überraschenderweise zeigten auch Formulierungen enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon und enthaltend 20% w/v des dem Glycerol strukturell sehr ähnlichen Propylenglykols (statt Glycerol) und einen pH-Regulator und einen Lösungsvermittler keine Verlängerung der Wirkdauer des Inhibitors des TASK-1 und/oder TASK-3 Kanals. Auch Formulierungen enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon und 1.25% w/v der Viskositäts-erhöhenden Substanz Na-Carboxymethylcellulose (Na-CMC) (statt Glycerol) und einen pH-Regulator und einen Lösungsvermittler zeigten keine Verlängerung der Wirkdauer des Inhibitors des TASK-1 und/oder TASK-3 Kanals. Dies weist darauf hin, dass eine durch die Zugabe von Glycerol bewirkte Viskositätserhöhung nicht der entscheidende Grund für die mit den erfindungsgemäßen Formulierungen beobachtete Verlängerung der Wirkdauer sein kann. Surprisingly, 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. Also 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. This indicates that a viscosity increase caused by the addition of glycerol can not be the decisive reason for the prolongation of the duration of action observed with the formulations according to the invention.
Auch eine Zusammensetzung enthaltend einen Lösungsvermittler und 2.13%> w/v Glycerol in einem pH- Regulator ohne Wirkstoff zeigte in der vorliegenden Erfindung keine Wirkung. Dies ist insofern überraschend, als für die oben erwähnte unter dem Handelsnamen Asonor® verfügbare Zusammensetzung bestehend aus 0.26% Glycerol, 0.2% Polysorbat 80, 0.9%> Natriumchlorid und 0.15% Kaliumsorbat eine signifikante Verbesserung des Schnarchens beobachtet wurde. Der gleiche Effekt wurde auch für eine Zusammensetzung bestehend aus 0.26% Glycerol, 0.9% Natriumchlorid und 0.15% Kaliumsorbat, d.h. in Abwesenheit von Polysorbat 80, beobachtet [Report from the Departement of Neurology, University State Hospital, Copenhagen, Denmark. The effect of nasal application of Asonor® and Polyglycoside 80 on snoring and sleep apnoea, 1989, http://www.chrapat.sk/img/klinicka- dokumentacia.pdf] . Widdicombe et al. vermuten, dass die genannte Mischung enthaltend Natriumchlorid, Glycerol, Polysorbat 80 und Benzalkoniumchlorid, die sowohl bei der Einatmung als auch bei der Ausatmung die Spannung der Muskulatur der oberen Atemwege erhöht, direkt oder sekundär Reflexe in den oberen Atemwegen beeinflusst, die die Dilatator-Muskeln des Pharynx kontrahieren. Der genaue Stimulus oder mögliche Rezeptoren, die beeinflusst werden, sind nicht bekannt. In dem der vorliegenden Erfindung zugrunde liegenden Schlafapnoe-Modell am anästhesierten Schwein führte die nasale Gabe der erfindungsgemäßen Zusammensetzungen dagegen nur während der Inspiration zu einer erhöhten Aktivität des Musculus genioglossus, bedingt durch eine Sensibilisierung des negativen Druckreflexes der oberen Atemwege, was zu einer vollständigen Hem-mung der Kollapsibilität der pharyngealen Atemwegsmuskulatur bei jeder Einatmung führte. Also, a composition containing a solubilizer and 2.13%> w / v glycerol in a pH regulator without active ingredient showed no effect in the present invention. This is surprising, as for the above-mentioned available under the trade name 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. The effect of nasal application of Asonor ® and polyglycosides 80 on snoring and sleep apnea, 1989, http://www.chrapat.sk/img/klinicka- dokumentacia.pdf]. Widdicombe et al. suggest that the said mixture containing sodium chloride, glycerol, polysorbate 80 and benzalkonium chloride, which increases the tension of the upper airway muscles both during inhalation and exhalation, directly or secondarily affects reflexes in the upper airways affecting the dilator muscles of the pharynx. The exact stimulus or potential receptors that are affected are unknown. However, in the anesthetized pig sleep apnea model of the present invention, 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.
Der Fachmann hatte keinen Ansatzpunkt dafür, die physikalische Therapie von OSA mittels CPAP zu ersetzen, da eine pharmakologische Alternative erstmals in der unveröffentlichten PCT/EP2016/079973 beschrieben ist. Auch gegen Schnarchen gibt es derzeit keine bzw. nur sehr begrenzte pharmakologische Therapien, so dass der Fachmann auch hier keinen Ansatzpunkt gehabt hätte, zur vorliegenden Erfindung zu gelangen. Auch wenn die in der PCT/EP2016/079973 beschriebenen TASK-1 und/oder TASK-3 Inhibitoren bekannt gewesen wären, hätte der Fachmann keine Veranlassung gehabt zu vermuten, dass die geschilderte, sehr einfach handhabbare Lösung zur Verlängerung der Wirkdauer des Inhibitors des TASK-1 und/oder TASK-3 Kanals erfolgreich ist. The skilled person had no starting point for replacing the physical therapy of OSA by means of CPAP, since a pharmacological alternative is described for the first time in unpublished PCT / EP2016 / 079973. Even against snoring there are currently no or only very limited pharmacological therapies, so that the skilled person would have had no starting point to get to the present invention. Even if the TASK-1 and / or TASK-3 inhibitors described in PCT / EP2016 / 079973 had been known, the skilled person would have had no reason to suspect that the described, very easy to handle solution for extending the duration of action of the TASK inhibitor -1 and / or TASK-3 channel is successful.
Im Stand der Technik gibt es keinen Hinweis darauf, dass eine Verlängerung der Wirkung von Inhibitoren des TASK-1 und/oder TASK-3 Kanals um mehrere Stunden im Hinblick auf OSA mit dem Einsatz des Standardformulierungshilfsstoffes Glycerol, aber nicht mit dem in seinen chemisch- physikalischen Eigenschaften dem Glycerol nahe verwandten Propylenglykol, erreicht werden kann. Auch gibt es im Stand der Technik keinen Hinweis, dass eine Wirkverlängerung von mehreren Stunden ohne die Verwendung von im Stand der Technik zur Wirkverlängerung von nasal verabreichten Wirkstoffen beschriebenen, aufwändigen Ansätzen wie Mikropartikeln, Kristallsuspensionen oder bioadhäsive Systeme erreicht werden kann. Darüber hinaus gibt es im Stand der Technik keinen Hinweis darauf, dass die Wirkverlängerung mit Hilfe der erfindungsgemäßen Formulierungen nur in einem spezifischen Konzentrationsbereich des Formulierungsbestandteils Glycerol erreicht werden kann. Auch ein Hinweis auf geeignete Konzentrationsbereiche der Formulierungsbestandteile ist dem Stand der Technik nicht zu entnehmen. Im Rahmen der vorliegenden Erfindung wird die stabile pharmazeutische Formulierung nasal oder pharyngeal appliziert. There is no indication in the prior art that prolonging the effect of inhibitors of the TASK-1 and / or TASK-3 channel by several hours with respect to OSA with the use of the standard formulation adjuvant glycerol, but not with its chemical physical properties of the glycerol closely related propylene glycol, can be achieved. There is also no indication in the prior art that an activity prolongation of several hours can be achieved without the use of elaborate approaches such as microparticles, crystal suspensions or bioadhesive systems described in the prior art for extending the action of nasally administered active ingredients. In addition, there is no indication in the prior art that the action prolongation with the aid of the formulations according to the invention can be achieved only in a specific concentration range of the formulation component glycerol. Also, an indication of suitable concentration ranges of the formulation components is not apparent from the prior art. In the context of the present invention, the stable pharmaceutical formulation is administered nasally or pharyngeally.
Im Rahmen der vorliegenden Erfindung werden die Begriffe „nasal" und „intranasal" synonym verwendet. Im Rahmen der vorliegenden Erfindung sind stabile pharmazeutische Formulierungen, die für die nasale Applikation geeignet sind, Formulierungen in flüssiger, halbfester oder fester Form, beispielsweise Nasentropfen, Nasenlösungen, Nasengele, Nasensalben, Nasencremes oder pulverformige Darreichungsformen. In the context of the present invention, the terms "nasal" and "intranasal" are used interchangeably. In the context of the present invention, 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.
Im Rahmen der vorliegenden Erfindung kann eine nasale Applikation beispielsweise mittels Nasenspray, Tropfpipette, Quetschflasche, COMOD® System, Flüssigzerstäubern (z. B. piezoelektrischen Verneblern, Düsen- oder Ultraschall-Aerosolgeneratoren, Soft-Mist-Inhalern) oder Dosieraerosolen, bzw. Nasenapplikatoren für halbfeste Formulierungen (Tubenspitzen, Spatel) und/oder feste Formulierungen (Pulver) erfolgen. Gemäß einer Ausführungsform der vorliegenden Erfindung erfolgt die Applikation mittels Nasenspray. Im Rahmen der vorliegenden Erfindung sind stabile pharmazeutische Formulierungen, die für die pharyngeale Applikation geeignet sind, Formulierungen in flüssiger, halbfester oder fester Form, beispielsweise Lösungen, Gele oder Pulver. In the present invention, a nasal application, for example, by means of nasal spray, dropper, squeeze bottle, COMOD ® System, Flüssigzerstäubern (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. According to one embodiment of the present invention, the application is carried out by means of nasal spray. In the context of the present invention, stable pharmaceutical formulations which are suitable for pharyngeal administration are formulations in liquid, semisolid or solid form, for example solutions, gels or powders.
Im Rahmen der vorliegenden Erfindung kann eine pharyngeale Applikation mittels Inhalation unter Verwendung von Flüssigzerstäubern (z. B. piezoelektrischen Verneblern, Düsen- oder Ultraschall- Aerosolgeneratoren, Pumpsprays) oder Dosieraerosolen, oder mittels lokaler Applikation unter Verwendung eines Bronchoskops (Instillation), einer Tropfpipette, Quetschflasche oder ähnlichem erfolgen. In the context of the present invention, a pharyngeal administration by inhalation using liquid atomizers (eg piezoelectric nebulizers, jet or ultrasonic aerosol generators, pump sprays) or metered aerosols, or by local application using a bronchoscope (instillation), a dropper pipette, Squeeze bottle or the like.
Die therapeutische Wirkung im Sinne der vorliegenden Erfindung ist definiert als eine Reduktion des Apnoe- Hypopnoe Index (AHI) eines Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon. 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.
Gemäß einer Ausführungsform der vorliegenden Erfindung ist die therapeutische Wirkung definiert als eine Reduktion des Apnoe-Hypopnoe Index (AHI) eines Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon um mindestens 20%. According to one embodiment of the present invention, 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%.
Gemäß einer Ausführungsform der vorliegenden Erfindung ist die therapeutische Wirkung definiert als eine Reduktion des Apnoe-Hypopnoe Index (AHI) eines Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon um mindestens 20%, mindestens 25%, mindestens 30%, mindestens 35%, mindestens 40%, mindestens 45%, mindestens 50%), mindestens 55%, mindestens 60%, mindestens 65%, mindestens 70%, mindestens 75% oder mindestens 80%. According to one embodiment of the present invention, 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%.
Die Wirkdauer im Sinne der vorliegenden Erfindung ist definiert als die Zeit nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon an einen Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen, in der der Apnoe-Hypopnoe Index (AHI) dieses Patienten reduziert wird. 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.
Gemäß einer Ausführungsform der vorliegenden Erfindung ist die Wirkdauer definiert als die Zeit nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon an einen Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen, in der der Apnoe-Hypopnoe Index (AHI) dieses Patienten um mindestens 20% reduziert wird. Gemäß einer Ausführungsform der vorliegenden Erfindung ist die Wirkdauer definiert als die Zeit nach nasaler oder pharyngealer Gabe einer erfindungsgemäßen Formulierung enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon an einen Patienten mit schlafbedingten Atemstörungen wie obstruktiven und zentralen Schlafapnoen und Schnarchen, in der der Apnoe-Hypopnoe Index (AHI) dieses Patienten um mindestens 20%, mindestens 25%), mindestens 30%, mindestens 35%, mindestens 40%), mindestens 45%), mindestens 50%), mindestens 55%), mindestens 60%), mindestens 65%), mindestens 70%), mindestens 75%) oder mindestens 80%) reduziert wird. Im Sinne der vorliegenden Erfindung beträgt die Wirkdauer mindestens 3 Stunden oder mindestens 3.5 Stunden oder mindestens 4 Stunden oder mindestens 4.5 Stunden oder mindestens 5 Stunden oder mindestens 5.5 Stunden oder mindestens 6 Stunden oder mindestens 6.5 Stunden oder mindestens 7 Stunden oder mindestens 7.5 Stunden oder mindestens 8 Stunden. Gemäß einer Ausführungsform der vorliegenden Erfindung beträgt die Wirkdauer mindestens 3 Stunden. Gemäß einer Ausführungsform der vorliegenden Erfindung beträgt die Wirkdauer mindestens 4 Stunden. Gemäß einer Ausführungsform der vorliegenden Erfindung beträgt die Wirkdauer mindestens 5 Stunden. Gemäß einer Ausführungsform der vorliegenden Erfindung beträgt die Wirkdauer mindestens 6 Stunden. According to one embodiment of the present invention, 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%. According to one embodiment of the present invention, 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%). For the purposes of the present invention, the duration of action is at least 3 hours or at least 3.5 hours or at least 4 hours or at least 4.5 hours or at least 5 hours or at least 5.5 hours or at least 6 hours or at least 6.5 hours or at least 7 hours or at least 7.5 hours or at least 8 hours. According to one embodiment of the present invention, the duration of action is at least 3 hours. According to one embodiment of the present invention, the duration of action is at least 4 hours. According to one embodiment of the present invention, the duration of action is at least 5 hours. According to one embodiment of the present invention, the duration of action is at least 6 hours.
Eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon im Sinne der vorliegenden Erfindung ist definiert als die Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon, die bei nasaler oder pharyngealer Applikation eine Wirkdauer von mindestens 3 Stunden oder mindestens 3.5 Stunden oder mindestens 4 Stunden oder mindestens 4.5 Stunden oder mindestens 5 Stunden oder mindestens 5.5 Stunden oder mindestens 6 Stunden oder mindestens 6.5 Stunden oder mindestens 7 Stunden oder mindestens 7.5 Stunden oder mindestens 8 Stunden zeigt. 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.
Eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon im Sinne der vorliegenden Erfindung ist definiert als die Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon, die bei nasaler oder pharyngealer Applikation eine Wirkdauer von mindestens 3 Stunden zeigt. 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.
Eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon im Sinne der vorliegenden Erfindung ist definiert als die Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon, die bei nasaler oder pharyngealer Applikation eine Wirkdauer von mindestens 4 Stunden zeigt. Eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon im Sinne der vorliegenden Erfindung ist definiert als die Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon, die bei nasaler oder pharyngealer Applikation eine Wirkdauer von mindestens 5 Stunden zeigt. 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.
Eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon im Sinne der vorliegenden Erfindung ist definiert als die Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon, die bei nasaler oder pharyngealer Applikation eine Wirkdauer von mindestens 6 Stunden zeigt. 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.
Im Rahmen der vorliegenden Erfindung sind Hilfsstoffe Stoffe, die in der stabilen pharmazeutischen Formulierung zum Beispiel dazu dienen, den pH- Wert einzustellen oder zu stabilisieren, die Löslichkeit des Wirkstoffs zu erhöhen, die Zubereitung mikrobiologisch und physikalisch zu stabilisieren, die Viskosität der Formulierung zu verändern oder den Geschmack oder das Aussehen zu verbessern. In the context of the present invention, 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.
Beispiele für Hilfsstoffe im Sinne der vorliegenden Erfindung sind pH-Regulatoren, Lösungsvermittler, Antioxidantien, Stabilisatoren, Verdickungsmittel, Konservierungsmittel, Tonizitäts-einstellende Substanzen, Aromen, Duftstoffe oder Farbstoffe. Examples of auxiliaries for the purposes of the present invention are pH regulators, solubilizers, antioxidants, stabilizers, thickeners, preservatives, tonicity-adjusting substances, flavors, fragrances or dyes.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei der gegebenenfalls mindestens eine Hilfsstoff ausgewählt ist aus der Gruppe bestehend aus mindestens einem pH-Regulator, mindestens einem Lösungsvermittler, mindestens einem Antioxidans, mindestens einem Stabilisator, mindestens einem Verdickungsmittel, mindestens einem Konservierungsmittel, mindestens einer Tonizitäts- einstellenden Substanz, mindestens einem Aroma, mindestens einem Duftstoff, und mindestens einem Farbstoff. pH-Regulatoren im Sinne der vorliegenden Erfindung sind beispielsweise Puffer, wie Citronensäure und ihre Salze, Essigsäure und ihre Salze und Phosphorsäure und ihre Salze, oder anorganische Säuren wie beispielsweise Salzsäure, Borsäure, Carbonsäuren, Bicarbonsäuren, Aminosäuren oder organische Säuren wie beispielsweise Monocarbonsäuren wie Oxocarbonsäuren oder Polycarbonsäuren, oder Basen wie beispielsweise Natriumhydroxid, Kaliumhydroxid, Natriumcarbonat, Natriumhydrogencarbonat. 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. 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.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei der gegebenenfalls mindestens eine pH-Regulator ausgewählt ist aus der Gruppe bestehend aus Citronensäure und ihren Salzen, Essigsäure und ihren Salzen, Phosphorsäure und ihren Salzen, Salzsäure, Borsäure, Carbonsäuren, Bicarbonsäuren, Aminosäuren, Oxocarbonsäuren, Polycarbonsäuren, Natriumhydroxid, Kaliumhydroxid, Natriumcarbonat, und Natriumhydrogencarbonat. Gemäß einer Ausführungsform der Erfindung ist der pH-Regulator ein Phosphatpuffer. Gemäß einer Ausführungsform der Erfindung ist der pH-Regulator ein Phosphatpuffer, der die Lösung im Sinne der vorliegenden Erfindung auf einen pH- Wert zwischen 4 und 8 puffert. Der bevorzugte pH-Bereich ist zwischen 7 und 8. Gemäß einer Ausführungsform beträgt der pH- Wert der erfindungsgemäßen Formulierungen 7. 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. According to one embodiment of the invention, the pH regulator is a phosphate buffer. According to one embodiment of the invention, the pH regulator is a phosphate buffer which buffers the solution for the purposes of the present invention to a pH of between 4 and 8. The preferred pH range is between 7 and 8. According to one embodiment, the pH of the formulations according to the invention is 7.
Lösungsvermittler im Sinne der vorliegenden Erfindung sind beispielsweise Komplexbildner (beispielsweise Cyclodextrine und Natrium EDTA (Natriumethylendiamintetraessigsäure)), Cosolventien (beispielsweise Ethanol, Propylenglykol, Dimethylacetamid,) und Tenside. In die Gruppe der Tenside fallen beispielsweise Fettalkohole (beispielsweise Cetylalkohol), Phospholipide (beispielsweise Lecithin), Sterole (beispielsweise Cholesterol), Gallensäuresalze, Saponine, Glycerolfettsäureester (beispielsweise Glycerolmonostearat), Polyoxyethylen-fettsäureester (beispielsweise Polyoxyethylenstearat), Polyoxyethylensorbitanfettsäureester (wie Tween®, beispielsweise Polysorbat 20 (Polyoxyethylen-(20)-sorbitanmonolaurat), Polysorbat 21 (Polyoxyethylen-(4)-sorbitanmonolaurat), Polysorbat 40 (Polyoxyethylen-(20)-sorbitanmonopalmitat), Polysorbat 60 (Polyoxyethylen-(20)-sorbitanmonostearat), Polysorbat 61 (Polyoxyethylen-(4)- sorbitanmonostearat), Polysorbat 65 (Polyoxyethylen-(20)-sorbitantristearat), Polysorbat 80 (Polyoxyethylen-(20)-sorbitanmonooleat), Polysorbat 81 (Polyoxyethylen-(5)-sorbitanmonooleat), Polysorbat 85 (Polyoxyethylen-(20)-sorbitantrioleat), Polysorbat 120 (Polyoxyethylen-(20)- sorbitanmonoisostearat)), Sorbitanfettsäureester (wie Span®, beispielsweise Sorbitanmonolaurat (Span® 20), Sorbitanmonopalmitat (Span® 40), Sorbitanmonostearat (Span® 60) Sorbitantristearat (Span® 65) Sorbitanmonooleat (Span® 80), Sorbitansesquioleat (Span® 83), Sorbitantrioleat (Span® 85), Polyoxyethylenglycerolfettsäureester (beispielsweise Polyoxyethylenglycerolmonostearat,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. 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. glycerol monostearate), 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), sorbitan fatty acid ester (as Span ® , for example sorbitan monolaurate (Span ® 20), sorbitan monopalmitate (Span ® 40), sorbitan monostearate (Span ® 60) sorbitan tristearate (Span ® 65) sorbitan monooleate (Span ® 80), sorbitan sesquioleate (Span ® 83), sorbitan trioleate (Span ® 85), Polyoxyethylene glycerol fatty acid ester (for example, polyoxyethylene glycerol monostearate,
Polyoxyethylenglycerolricinoleat, Polyoxyethylen-glyceroltriricinoleat), Polyoxyethylenfettalkoholether (beispielsweise Polyoxyethylenlaurylether, Polyoxyethylencetylstearylether), Polyoxypropylen- Polyoxyethylen-Blockcopolymere (beispielsweise Poloxamer), Alkylsulfate (beispielsweise Natriumlaurylsulfat, Natriumcetylstearylsulfat), Alkaliseifen (beispielsweise Natriumpalmitat, Natriumstearat) und Saccharose-Fettsäureester. Gemäß einer Ausführungsform der Erfindung ist der Lösungsvermittler ausgewählt aus der Gruppe bestehend aus Ethanol, Polysorbat 20, Polyoxyethylen(8)- stearat und Polysorbat 80. Gemäß einer Ausführungsform der Erfindung ist der Lösungsvermittler Polysorbat 80. 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), and sucrose fatty acid esters. According to one embodiment of the invention, the solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80. According to one embodiment of the invention, the solubilizer is polysorbate 80.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei der gegebenenfalls mindestens eine Lösungsvermittler ausgewählt ist aus der Gruppe bestehend aus Ethanol, Polysorbat 20, Polyoxyethylen(8)-stearat und Polysorbat 80. Sofern als Lösungsvermittler ein Tensid in den erfindungsgemäßen Formulierungen enthalten ist, beträgt die Konzentration dieses Tensids minimal seine kritische Mizellenbildungskonzentration (CMC, critical micelle concentration) und maximal die für die nasale oder pharyngeale Applikation maximal zugelassene Menge. Die CMC von Polysorbat 80 beträgt 0.001% w/v, die maximal pharmazeutisch zugelassene Konzentration beträgt 10%> w/v. Bei Verwendung von Polysorbat 80 als Lösungsvermittler ist Polysorbat 80 in einer Konzentration von 0.001 -10%) w/v, oder 0.1 -10%) w/v, oder 1 -10% w/v oder 5- 10%o w/v in den erfindungsgemäßen Formulierungen enthalten. Alternativ kann Polysorbat 80 auch in Konzentrationen bis 15%> w/v oder bis 20%> w/v in den erfindungsgemäßen Formulierungen enthalten sein. Antioxidantien im Sinne der vorliegenden Erfindung sind beispielsweise Citronensäure, Butylhydroxyanisol, Butylhydroxytoluol, EDTA, eine Begasung mit Stickstoff, Tocopherol, Ascorbinsäure, Glutathion, Cystein, Sulfite (beispielsweise Natriumsulfit, Natriumhydrogensulfit), Disulfite (beispielsweise Natriumpyrosulfit), Ascorbinsäureester oder Gallate. Gemäß einer Ausführungsform der Erfindung ist das Antioxidans ausgewählt aus der Gruppe bestehend aus Citronensäure, Butylhydroxyanisol, Butylhydroxytoluol, EDTA und einer Begasung mit Stickstoff. Gemäß einer Ausführungsform der Erfindung ist das Antioxidans Butylhydroxyanisol. 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. If 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. The CMC of polysorbate 80 is 0.001% w / v, the maximum pharmaceutically approved concentration is 10%> w / v. 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. According to one embodiment of the invention, the antioxidant is selected from the group consisting of citric acid, butylhydroxyanisole, butylhydroxytoluene, EDTA and a gasification with nitrogen. According to one embodiment of the invention, the antioxidant is butylhydroxyanisole.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei das gegebenenfalls mindestens eine Antioxidans ausgewählt ist aus der Gruppe bestehend aus Citronensäure, Butylhydroxyanisol, Butylhydroxytoluol, EDTA und einer Begasung mit Stickstoff. 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.
Eine Ausführungsform der vorliegenden Erfindung betrifft stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation enthaltend eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in 1%> bis 100% w/v Glycerol und ein Antioxidans und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Formulierung einen pH- Wert von 4 bis 8 aufweist. 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.
Konservierungsmittel im Sinne der vorliegenden Erfindung sind beispielsweise phenolische Substanzen wie Phenol oder Kresol, Alkohole wie Ethanol, Chlorbutanol, Phenylethanol, oder Propylenglycol, Invertseifen wie Benzalkoniumchlorid oder Benzethoniumchlorid, Benzoesäure und deren Salze, Sorbinsäure und deren Salze, Dehydroessigsäure und Schwefelsäure und deren Salze, Natriumhydrogensulfit, Parabene, einschließlich Methylparaben und Propylparaben oder Thiomersal. Gemäß einer Ausführungsform der Erfindung ist das Konservierungsmittel ausgewählt aus der Gruppe bestehend aus Cs-Cis Alkoniumchlorid, Methylparaben, Propylparaben, Sorbinsäure, Chlorbutanol und Benzalkoniumchlorid. Gemäß einer Ausführungsform der Erfindung ist das Konservierungsmittel B enzalkoniumchlorid. 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. According to one embodiment of the invention, the preservative is selected from the group consisting of Cs-Cis alkonium chloride, methylparaben, propylparaben, sorbic acid, chlorobutanol and Benzalkonium chloride. According to one embodiment of the invention, the preservative B is enalkonium chloride.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei das gegebenenfalls mindestens eine Konservierungsmittel ausgewählt ist aus der Gruppe bestehend aus Cs-Cis Alkoniumchlorid, Methylparaben, Propylparaben, Sorbinsäure, Chlorbutanol und Benzalkoniumchlorid. 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.
Tonizitäts-einstellende Substanzen im Sinne der vorliegenden Erfindung sind beispielsweise Salze (z. B. von Plasmakationen mit physiologisch tolerierbaren Gegenionen), Zucker (z. B. Glucose, Saccharose), Zuckeralkohole (z. B. Mannitol, Sorbitol), Glykole (z. B. Propylenglykole) und andere nichtionische Polyolmaterialien. 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.
Verdickungsmittel im Sinne der vorliegenden Erfindung sind beispielsweise natürliche Gummis, Alginsäure, Pektine, Stärke und Stärkederivate, Gelatine, Poloxamere (Blockcopolymere Ethylenoxid und Propylenoxid) Zellulosederivate, Acrylsäurepolymere, oder Vinylpolymere. 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.
Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens einen pH-Regulator. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens ein Antioxidans. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens einen Lösungsvermittler. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens einen pH-Regulator und mindestens einen Lösungsvermittler. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens ein Antioxidans und mindestens einen Lösungsvermittler. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens einen pH-Regulator, mindestens einen Lösungsvermittler und mindestens ein Antioxidans. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen als Hilfsstoffe mindestens einen pH-Regulator, mindestens einen Lösungsvermittler, mindestens ein Antioxidans und mindestens einen Konservierungsstoff. According to one embodiment of the present invention, 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. 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 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.
Gegenstand der vorliegenden Erfindung sind auch erfindungsgemäße stabile pharmazeutische Formulierungen zur nasalen oder pharyngealen Applikation, wobei die Formulierung 2 bis 50% w/v Glycerol, 1 bis 10% eines Lösungsvermittlers, bis 97% w/v eines pH-Regulators und gegebenenfalls mindestens einen weiteren Hilfsstoff enthält. 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.
Eine Ausführungsform der vorliegenden Erfindung ist eine erfindungsgemäße stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation, wobei die Formulierung 1% w/v bis 100%) w/v Glycerol enthält und gegebenenfalls mindestens einen pH-Regulator und gegebenenfalls mindestens einen Lösungsvermittler und gegebenenfalls mindestens einen weiteren Hilfsstoff enthält. 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%). contains w / v glycerol and optionally contains at least one pH regulator and optionally at least one solubilizer and optionally at least one further excipient.
Im Rahmen der vorliegenden Erfindung liegt die dynamische Viskosität (bei 20°C) der erfindungsgemäßen Formulierungen zwischen 0.5 und 1480 mPa*s, bevorzugt zwischen 1.0 und 140 mPa*s. Erfindungsgemäße Formulierungen für die nasale Applikation mittels Nasenspray haben eine bevorzugte dynamische Viskosität (bei 20°C) zwischen 1.0 und 140 mPa*s. Erfindungsgemäße Formulierungen für die nasale Applikation mittels Nasentropfen haben eine bevorzugte dynamische Viskosität (bei 20°C) zwischen 1.0 und 1480 mPa*s. In the context of the present invention, the dynamic viscosity (at 20 ° C.) of the formulations according to the invention is between 0.5 and 1480 mPa * s, preferably between 1.0 and 140 mPa * s. 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.
Eine Ausführungsform der vorliegenden Erfindung ist eine erfindungsgemäße stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation, wobei die Formulierung eine Viskosität bei 20 °C von 0.5 - 200 mPa*s, bevorzugt 1 - 20 mPa*s aufweist. 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.
Eine erfindungsgemäße Formulierung enthaltend 2.5% w/v einer 85%igen Glycerollösung und 10% w/v Polysorbat 80 in Phosphatpuffer hat eine dynamische Viskosität von ca. 2 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.
Im Rahmen der vorliegenden Erfindung liegt die bevorzugte Tröpfchengröße (angegeben als medianer Volumendurchmesser) bei einer zerstäubten Formulierung zwischen 5 und 300 μιη, bevorzugt zwischen 30 und 100 μιη. Dies ist unabhängig davon, ob die Gabe nasal oder pharyngeal erfolgt. In the context of the present invention, the preferred droplet size (expressed as median volume diameter) in an atomized formulation is between 5 and 300 μm, preferably between 30 and 100 μm. This is independent of whether the administration is nasal or pharyngeal.
Eine Ausführungsform der vorliegenden Erfindung ist eine erfindungsgemäße stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation, wobei die Formulierung als Nasenspray verabreicht wird und eine Tröpfchengröße als medianer Volumendurchmesser von 5 - 300 μηι, bevorzugt 30 - 100 μιη aufweist. 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 μm, preferably 30 to 100 μm.
Im Rahmen der vorliegenden Erfindung wird der Begriff Glycerol synonym mit Glycerin verwendet. In the context of the present invention, the term glycerol is used synonymously with glycerol.
Im Sinne der vorliegenden Erfindung bedeutet die Angabe „1%> w/v Glycerol" eine absolute Glycerolkonzentration von 1%> w/v, welche einer Konzentration von 1.18% w/v einer 85%igen Glycerollösung entspricht. For the purposes of the present invention, the term "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.
Weitere Konzentrationen an Glycerol (absolut) [% w/v] entsprechen den folgenden Konzentrationen einer 85%igen Glycerollösung: Further concentrations of glycerol (absolute) [% w / v] correspond to the following concentrations of an 85% glycerol solution:
Glycerol (absolut) [% w/v] 85%ige Glycerollösung [% w/v] Glycerol (absolute) [% w / v] 85% glycerol solution [% w / v]
0.85 1  0.85 1
1 1.18  1 1.18
1.5 1.76  1.5 1.76
2.13 2.5  2.13 2.5
2.5 2.95  2.5 2.95
4.25 5 Glycerol (absolut) [% w/v] 85%ige Glycerollösung [% w/v] 4.25 5 Glycerol (absolute) [% w / v] 85% glycerol solution [% w / v]
5 5.9  5 5.9
10 1 1.8  10 1 1.8
20 23.6  20 23.6
50 59  50 59
70 82.6  70 82.6
100 1 18  100 1 18
Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsgemäßen Formulierungen 1% w/v bis 100% w/v oder 1%> w/v bis 90%> w/v oder 1%> w/v bis 80% w/v oder 1% w/v bis 70%) w/v oder 1% w/v bis 60% w/v oder 1% w/v bis 50% w/v oder 1% w/v bis 40% w/v oder 1%) w/v bis 30%) w/v oder 1% w/v bis 20% w/v oder 1% w/v bis 10% w/v oder 1% w/v bis 5% w/v oder 2% w/v bis 100% w/v oder 2% w/v bis 90% w/v oder 2% w/v bis 80% w/v oder 2% w/v bis 70% w/v oder 2% w/v bis 60% w/v oder 2% w/v bis 50% w/v oder 2% w/v bis 40% w/v oder 2% w/v bis 30% w/v oder 2% w/v bis 20% w/v oder 2% w/v bis 10% w/v oder 2% w/v bis 5% w/v oder 2% w/v oder 5% w/v Glycerol. Gemäß einer Ausführungsform der vorliegenden Erfindung enthalten die erfindungsmäßen Formulierungen 2.5-5% w/v einer 85%>igen Glycerollösung. Gemäß einer weiteren Ausführungsform der vorliegenden Erfindung enthalten die erfindungsmäßen Formulierungen 2.5% w/v einer 85%>igen Glycerollösung. According to one embodiment of the present invention, 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 80% w / v or 2% w / v to 70% w / v or 2% w / v v to 60% w / v or 2% w / v to 50% w / v or 2% w / v to 40% w / v or 2% w / v to 30% w / v or 2% w / v to 20% w / v or 2% w / v to 10% w / v or 2% w / v to 5% w / v or 2% w / v or 5% w / v glycerol. According to one embodiment of the present invention, 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.
Im Rahmen der vorliegenden Erfindung ist ein Wirkstoff definiert als ein Inhibitor des TASK-1 und/oder TASK-3 Kanals oder ein Hydrat, Solvat, Polymorph, oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salzes hiervon. In the context of the present invention, an active ingredient is defined as an inhibitor of the TASK-1 and / or TASK-3 channel or a hydrate, solvate, polymorph, or metabolite thereof or a pharmaceutically acceptable salt thereof.
Erfindungsgemäße stabile pharmazeutische Formulierung sind beispielsweise solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus den in der PCT/EP2016/079973 beschriebenen Verbindungen. Erfindungsgemäße stabile pharmazeutische Formulierung sind beispielsweise solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der allgemeinen Formel (I), 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)
(I), in welcher (I) in which
R1 für Halogen, Cyano, (Ci-C4)-Alkyl, Cyclopropyl oder Cyclobutyl steht und R 1 is halogen, cyano, (C 1 -C 4) -alkyl, cyclopropyl or cyclobutyl and
R2 für (C4-C6)-Cycloalkyl steht, worin eine Ring-CH2-Gruppe gegen -O- ausgetauscht sein kann, oder für eine Phenyl-Gruppe der Formel (a) oder eine Pyridyl-Gruppe der Formel (b) 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 )
steht, stands,
worin * die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert und R3 Fluor, Chlor, Brom, Cyano, (Ci-C3)-Alkyl oder (Ci-C3)-Alkoxy bedeutet, wobei (Ci-C3)-Alkyl und (Ci-C3)-Alkoxy bis zu dreifach mit Fluor substituiert sein können, R4 Wasserstoff, Fluor, Chlor, Brom oder Methyl bedeutet, R5 Wasserstoff, Fluor, Chlor, Brom oder Methyl bedeutet und in which * denotes the linkage to the adjacent carbonyl group and 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, and
R6 Wasserstoff, (Ci-C3)-Alkoxy, Cyclobutyloxy, Oxetan-3-yloxy, Tetrahydrofuran-3-yloxy oder Tetrahydro-2H-pyran-4-yloxy bedeutet, wobei (Ci-C3)-Alkoxy bis zu dreifach mit Fluor substituiert sein kann, sowie ihre Salze, Solvate und Solvate der Salze. 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.
Erfindungsgemäße stabile pharmazeutische Formulierung sind beispielsweise solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der oben angegebenen Formel (I), worin 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
R1 für Fluor, Chlor, Brom, Methyl, Isopropyl, tert. -Butyl oder Cyclopropyl steht und R 2 für Cyclobutyl, Cyclopentyl oder Cyclohexyl steht oder eine Phenyl-Gruppe der Formel (a) oder eine Pyridyl-Gruppe der Formel (b) 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)
steht, stands,
worin * die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert und where * denotes the link to the adjacent carbonyl group and
R3 Fluor, Chlor, Cyano, (Ci-C3)-Alkyl, (Ci-C3)-Alkoxy oder Trifluormethoxy bedeutet, R 3 is fluorine, chlorine, cyano, (C 1 -C 3) -alkyl, (C 1 -C 3) -alkoxy or trifluoromethoxy,
R4 Wasserstoff, Fluor oder Chlor bedeutet, R 4 is hydrogen, fluorine or chlorine,
R5 Wasserstoff, Fluor, Chlor, Brom oder Methyl bedeutet und R6 Wasserstoff oder (Ci-C3)-Alkoxy, das bis zu dreifach mit Fluor substituiert sein kann, bedeutet, sowie ihre Salze, Solvate und Solvate der Salze. 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.
Erfindungsgemäße stabile pharmazeutische Formulierung sind beispielsweise solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin R1 für Chlor oder Brom steht, sowie ihre Salze, Solvate und Solvate der Salze. 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.
Erfindungsgemäße stabile pharmazeutische Formulierung sind beispielsweise solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin für Methyl, Isopropyl, tert. -Butyl oder Cyclopropyl steht, sowie ihre Salze, Solvate und Solvate der Salze. Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin 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
R2 für Cyclobutyl, Cyclopentyl oder Cyclohexyl steht, sowie ihre Salze, Solvate und Solvate der Salze. R 2 is cyclobutyl, cyclopentyl or cyclohexyl, and their salts, solvates and solvates of the salts.
Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin 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
R2 für eine Phenyl-Gruppe der Formel (a) R 2 represents a phenyl group of the formula (a)
steht, stands,
worin * die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert, R3 Fluor, Chlor, Cyano, (Ci-C3)-Alkyl oder (Ci-C3)-Alkoxy bedeutet und in which * denotes the linkage to the adjacent carbonyl group, R 3 denotes fluorine, chlorine, cyano, (C 1 -C 3 ) -alkyl or (C 1 -C 3 ) -alkoxy and
R4 Wasserstoff, Fluor oder Chlor bedeutet, sowie ihre Salze, Solvate und Solvate der Salze. R 4 is hydrogen, fluorine or chlorine, and their salts, solvates and solvates of the salts.
Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin 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
R2 für eine Pyridyl-Gruppe der Formel (b) R 2 for a pyridyl group of the formula (b)
steht, stands,
worin die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert, R5 Wasserstoff, Chlor oder Brom bedeutet und wherein the linkage to the adjacent carbonyl group marks, R 5 is hydrogen, chlorine or bromine and
R6 (Ci-C3)-Alkoxy, das bis zu dreifach mit Fluor substituiert sein kann, bedeutet, sowie ihre Salze, Solvate und Solvate der Salze. Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Formel (I), worin R 6 (C 1 -C 3) -alkoxy, which may be substituted up to three times by fluorine, 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
R1 für Chlor, Brom, Isopropyl oder Cyclopropyl steht und R2 für Cyclobutyl, Cyclopentyl oder Cyclohexyl steht oder für eine Phenyl-Gruppe der Formel (a) oder eine Pyridyl-Gruppe der Formel (b) 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)
steht, stands,
worin * die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert und where * denotes the link to the adjacent carbonyl group and
R3 Fluor, Chlor, Cyano, Methyl, Isopropyl, Methoxy oder Ethoxy bedeutet, R 3 is fluorine, chlorine, cyano, methyl, isopropyl, methoxy or ethoxy,
R4 Wasserstoff, Fluor oder Chlor bedeutet, R 4 is hydrogen, fluorine or chlorine,
R5 Wasserstoff, Chlor oder Brom bedeutet und R 5 is hydrogen, chlorine or bromine and
R6 Methoxy, Difluormethoxy, Trifluormethoxy oder Isopropoxy bedeutet, sowie ihre Salze, Solvate und Solvate der Salze. Die in den jeweiligen Kombinationen bzw. bevorzugten Kombinationen von Resten im einzelnen angegebenen Reste-Definitionen werden unabhängig von den jeweiligen angegebenen Kombinationen der Reste beliebig auch durch Reste-Definitionen anderer Kombinationen ersetzt. 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.
Ganz besonders bevorzugt sind Kombinationen von zwei oder mehreren der oben genannten Vorzugs- bereiche. Very particular preference is given to combinations of two or more of the preferred ranges mentioned above.
Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus Verbindungen der Tabelle 1. Die Synthese dieser Verbindungen ist in der PCT/EP2016/079973 beschrieben. 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.
Tabelle 1: Verbindungen aus PCT/EP2016/079973 Table 1: Compounds from PCT / EP2016 / 079973
Beispiel Name Example name
1 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclopentyl)- methanon  1 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclopentyl) methanone
2 (4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclopentyl)- methanon  2 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclopentyl) methanone
3 (4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6- methoxypyridin-2-yl)methanon  3 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxypyridin-2-yl) methanone
4 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-fluorphenyl)- methanon  4 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-fluorophenyl) -methanone
5 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(3- methoxyphenyl)methanon  5 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (3-methoxyphenyl) methanone
6 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-chlor-5- fluorphenyl)methanon  6 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-chloro-5-fluorophenyl) methanone
7 (4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-fluorphenyl)- methanon  7 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-fluorophenyl) -methanone
8 (4- {[2-(4-Fluorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(cyclohexyl)- methanon  8 (4- {[2- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (cyclohexyl) -methanone
9 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclohexyl)- methanon  9 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclohexyl) methanone
10 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(tetrahydrofuran- 10 (4- {[2- (4-bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (tetrahydrofuran).
3-yl)methanon 3-yl) methanone
11 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclobutyl)- methanon  11 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclobutyl) -methanone
12 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2- methoxyphenyl)methanon  12 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-methoxyphenyl) methanone
13 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(5-fluor-2- methoxyphenyl)methanon  13 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (5-fluoro-2-methoxyphenyl) methanone
14 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2- methylphenyl)methanon  14 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-methylphenyl) methanone
15 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(5-fluor-2- methylphenyl)methanon  15 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (5-fluoro-2-methylphenyl) methanone
16 (2-Chlor-5-fluorphenyl)(4- {[2-(4-chlorphenyl)imidazo[l,2-a]pyridin-3- yljmethyl} piperazin- 1 -yl)methanon  16 (2-chloro-5-fluorophenyl) (4- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-ylmethyl} piperazine-1-yl) methanone
17 (4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclohexyl)- methanon  17 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclohexyl) methanone
18 ((4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclobutyl)- methanon Beispiel Name 18 ((4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclobutyl) -methanone Example name
19 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(3 -methoxy- phenyl)methanon  19 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (3-methoxyphenyl) methanone
20 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(2- methoxyphenyl)methanon  20 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-methoxyphenyl) methanone
21 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazm-l-yl)(5-fluor-2- methoxyphenyl)methanon  21 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazm-1-yl) (5-fluoro-2-methoxyphenyl) -methanone
22 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(2- methylphenyl)methanon  22 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-methylphenyl) methanone
23 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(5-fluor-2- methylphenyl)methanon  23 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (5-fluoro-2-methylphenyl) -methanone
24 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl) [3 - (trifluormethoxy)phenyl] methanon  24 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) [3- (trifluoromethoxy) phenyl] methanone
25 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl) [3 - (trifluormethyl)phenyl] methanon  25 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) [3- (trifluoromethyl) phenyl] methanone
26 ((4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(pyridin-2-yl)- methanon  26 ((4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (pyridin-2-yl) -methanone
27 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-fluor-5- methoxyphenyl)methanon  27 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-fluoro-5-methoxyphenyl) -methanone
28 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(2- ethoxyphenyl)methanon  28 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-ethoxyphenyl) methanone
29 (2-Chlor-5-methoxyphenyl)(4- {[2-(4-chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}- piperazin- 1 -yl)methanon  29 (2-chloro-5-methoxyphenyl) (4- {[2- (4-chloro-1-yl) -imidazo [1,2-a] pyridin-3-yl] -methyl} -piperazine-1-yl) -methanone
30 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(tetrahydro-2H- pyran-2-yl)methanon  30 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (tetrahydro-2H-pyran-2-yl) -methanone
31 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(3-isopropoxy- phenyl)methanon  31 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (3-isopropoxyphenyl) methanone
32 2-[(4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l - yl)carbonyl]benzonitril  32 2 - [(4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) carbonyl] benzonitrile
33 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(3 - isopropylphenyl)methanon  33 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (3-isopropyl-phenyl) -methanone
34 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(2- isopropylphenyl)methanon  34 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (2-isopropyl-phenyl) -methanone
35 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(tetrahydrofura  35 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (tetrahydrofuran
2-yl)methanon  2-yl) methanone
36 (3-Chlo^henyl)(4- {[2-(4-chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)- methanon  36 (3-chlorobenzene) (4- {[2- (4-chloro-1-yl) -imidazo [1,2-a] pyridin-3-yl] -methyl} -piperazin-1-yl) -methanone
37 (2-Chlo^henyl)(4- {[2-(4-chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)- methanon  37 (2-chlorobenzene) (4- {[2- (4-chloro-1-yl) -imidazo [1,2-a] pyridin-3-yl] -methyl} -piperazin-1-yl) -methanone
38 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)[6-(2,2,2-trifluor- ethoxy)pyridin-2-yl]methanon  38 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) [6- (2,2,2-trifluoroethoxy ) pyridin-2-yl] -methanone
39 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-isopropoxy- pyridin-2-yl)methanon  39 (4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-isopropoxypyridin-2-yl) -methanone
40 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-methoxy-4- methylpyridin-2-yl)methanon  40 (4- {[2- (4-chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxy-4-methylpyridin-2-yl) methanone
41 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl) [6-(cyclobutyl- oxy)pyridin-2-yl]methanon  41 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl] [6- (cyclobutyl-oxy) -pyridin-2-yl] -methanone
42 (3-Brom-6-methoxypyridin-2-yl)(4- {[2-(4-chlorphenyl)imidazo[l,2-a]pyridin-3- yl]methyl} piperazin- 1 -yl)methanon  42 (3-bromo-6-methoxypyridin-2-yl) (4- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) methanone
43 (3-Chlor-6-methoxypyridin-2-yl)(4- {[2-(4-chlorphenyl)imidazo[l,2-a]pyridin-3- yl]methyl} piperazin- 1 -yl)methanon  43 (3-chloro-6-methoxypyridin-2-yl) (4- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) methanone
44 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)[6-(difluor- methoxy)pyridin-2-yl]methanon Beispiel Name 44 (4- {[2- (4-chlorobenzene) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) [6- (difluoromethoxy) pyridin-2-yl ] methanone Example name
45 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6- ethoxypyridin-2 -yl)methanon  45 (4- {[2- (4-Chloroyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-ethoxypyridine-2-yl) methanone
46 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl) [6-(tetrahydro- 2H-pyran-4-yloxy)pyridin-2-yl]methanon  46 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) [6- (tetrahydro-2H-pyran-4-yloxy) pyridine methanone -2-yl]
47 (4- {[2-(4-Bromphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6- methoxypyridin-2-yl)methanon  47 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxypyridin-2-yl) methanone
48 (4- {[2-(4-Fluo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(cyclopentyl)- methanon  48 (4- {[2- (4-Fluorohexyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (cyclopentyl) -methanone
49 (4- {[2-(4-Fluo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(cyclobutyl)- methanon  49 (4- {[2- (4-Fluorohexyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (cyclobutyl) -methanone
50 (5-Fluor-2-methoxyphenyl)(4- {[2-(4-fluo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}- piperazin- 1 -yl)methanon  50 (5-Fluoro-2-methoxyphenyl) (4- {[2- (4-fluoro-1-yl) -imidazo [1,2-a] pyridin-3-yl] -methyl} -piperazin-1-yl) -methanone
51 (2-Chlor-5-fluorphenyl)(4- {[2-(4-fluorphenyl)imidazo[l,2-a]pyridin-3- yl]methyl} piperazin- 1 -yl)methanon  51 (2-chloro-5-fluorophenyl) (4- {[2- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) methanone
52 (4- {[2-(4-Fluo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(2-methoxy- phenyl)methanon  52 (4- {[2- (4-Fluorohexyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (2-methoxyphenyl) methanone
53 (2-Fluo^henyl)(4- {[2-(4-isopropylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin- 53 (2-Fluorohexyl) (4- {[2- (4-isopropylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine
1 -yl)methanon 1 -yl) methanone
54 Cyclopentyl(4- {[2-(4-isopropylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl} piperazin- 1-yl)- methanon  54 cyclopentyl (4- {[2- (4-isopropylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) -methanone
55 (4- { [2-(4-Isopropylphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(6-methoxy- pyridin-2-yl)methanon  55 (4- {[2- (4-Isopropylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxypyridin-2-yl) methanone
56 Cyclopentyl(4- { [2-(4-methylphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)- methanon  56 Cyclopentyl (4- {[2- (4-methylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) -methanone
57 Cyclohexyl(4- {[2-(4-methylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)- methanon  57 Cyclohexyl (4- {[2- (4-methylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) methanone
58 (2-Methoxyphenyl)(4- { [2-(4-methylphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 58 (2-methoxyphenyl) (4- {[2- (4-methylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine
1 -yl)methanon 1 -yl) methanone
59 (6-Methoxypyridin-2-yl)(4- {[2-(4-methylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}- piperazin- 1 -yl)methanon  59 (6-methoxypyridin-2-yl) (4- {[2- (4-methylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} -piperazin-1-yl) methanone
60 (4-(3- {[4-(2-Fluorbenzoyl)piperazin-l-yl]methyl}imidazo[l,2-a]pyridin-2-yl)benzonirril 60 (4- (3- {[4- (2-Fluorobenzoyl) piperazin-1-yl] methyl} imidazo [1,2-a] pyridin-2-yl) benzonitrile
61 4- [3 -( {4- [(6-Methoxypyridin-2-yl)carbonyl]piperazin- 1 -yl} methyl)imidazo [ 1 ,2-a]pyridin-61 4- [3 - ({4- [(6-methoxypyridin-2-yl) carbonyl] piperazine-1-yl} methyl) imidazo [1,2-a] pyridine
2-yl]benzonitril 2-yl] benzonitrile
62 4-(3 - { [4-(Cyclopentylcarbonyl)piperazin- 1 -yljmethyl} imidazo[ 1 ,2-a]pyridin-2- yl)benzonirril  62 4- (3 - {[4- (cyclopentylcarbonyl) piperazine-1-ylmethyl} imidazo [1,2-a] pyridin-2-yl) benzonitrile
63 4-(3- {[4-(Cyclohexylcarbonyl)piperazin-l-yl]methyl}imidazo[l,2-a]pyridin-2- yl)benzonirril  63 4- (3- {[4- (Cyclohexylcarbonyl) piperazin-1-yl] methyl} imidazo [1,2-a] pyridin-2-yl) benzonitrile
64 (4- {[2-(4-tert.-Butylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-methoxy- pyridin-2-yl)methanon  64 (4- {[2- (4-tert-butylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxypyridin-2-yl) methanone
65 (4- {[2-(4-tert.-Butylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-fluor- phenyl)methanon  65 (4- {[2- (4-tert-butylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-fluoro-phenyl) -methanone
66 (4- {[2-(4-tert.-Butylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(cyclo- pentyl)methanon  66 (4- {[2- (4-tert-butylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (cyclopentyl) methanone
67 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yljmethyl} piperazin- 1 -yl) [6- (trifluormethoxy)pyridin-2-yl]methanon  67 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridine-3-ylmethyl} piperazine-1-yl) [6- (trifluoromethoxy) pyridin-2-yl] methanone
68 (4- {[2-(4-Chlo^henyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(3-fluor-6- methoxypyridin-2-yl)methanon  68 (4- {[2- (4-chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (3-fluoro-6-methoxypyridin-2-yl) methanone
69 (4- {[2-(4-Cyclopropylphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(2-fluor- phenyl)methanon  69 (4- {[2- (4-Cyclopropylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (2-fluorophenyl) methanone
70 4-(3- {[4-(2-Fluor-5-methoxybenzoyl)piperazin-l-yl]methyl}imidazo[l,2-a]pyridin-2- yl)benzonirril Beispiel Name 70 4- (3- {[4- (2-Fluoro-5-methoxybenzoyl) piperazin-1-yl] methyl} imidazo [1,2-a] pyridin-2-yl) benzonitrile Example name
71 4- [3 -( {4- [(6-Methoxy-3 -methylpyridin-2-yl)carbonyl]piperazin- 1 - yl} methyl)imidazo [ 1 ,2-a]pyridin-2-yl]benzonitril  71 4- [3 - ({4- [(6-Methoxy-3-methylpyridin-2-yl) carbonyl] piperazin-1-yl} methyl) imidazo [1,2-a] pyridin-2-yl] benzonitrile
72 (4- { [2-(4-Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(6-methoxy-3 - methylpyridin-2-yl)methanon  72 (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxy-3-methyl-pyridin-2-yl) -methanone
73 (4- {[2-(4-tert. -Butylphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(6-methoxy- 73 (4- {[2- (4-tert-butylphenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxy)
3 -methylpyridin-2-yl)methanon 3-methylpyridin-2-yl) methanone
74 (4- {[2-(4-Bromphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(6-methoxy-3- methylpyridin-2-yl)methanon  74 (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxy-3-methylpyridin-2-yl) methanone
Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus der Gruppe bestehend aus 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
sowie ihre Salze, Solvate und Solvate der Salze. and their salts, solvates and solvates of the salts.
Erfindungsgemäße stabile pharmazeutische Formulierung sind auch solche Formulierungen, in denen der mindestens eine Inhibitor des TASK- 1 und/oder TASK-3 Kanals (4- {[2-(4- Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yl]methyl} piperazin- 1 -yl)(6-methoxypyridin-2-yl)methanon ist. Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Behandlung und/oder Prävention von Krankheiten. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen, wobei die nasale oder pharyngeale Applikation mit Hilfe von Nasensprays, Nasentropfen, Nasenlösungen, Pulverinhalatoren, Nebulizern, Dosieraerosolen oder halbfesten Gelen erfolgt. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atem- Störungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen verwendet, wobei die Wirkdauer mindestens 3 Stunden beträgt. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen verwendet, wobei die Wirkdauer mindestens 4 Stunden beträgt. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen verwendet, wobei die Wirkdauer mindestens 5 Stunden beträgt. Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuro- immunologischen Erkrankungen verwendet, wobei die Wirkdauer mindestens 6 Stunden beträgt. 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.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2-(4-Chlo^henyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(6-methoxy-pyridin-2-yl) methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in 2% bis 5% w/v Glycerol und 1 bis 10% w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 3 Stunden oder mindestens 4 Stunden oder mindestens 5 Stunden oder mindestens 6 Stunden oder mindestens 7 Stunden oder mindestens 8 Stunden beträgt. 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. 3 channels 4- {[2- (4-Chloro) -yl] imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (6-methoxy-pyridin-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 pharyngeal administration is at least 3 hours or at least 4 hours or at least 5 hours or at least 6 hours or at least 7 hours or at least 8 hours.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend: eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2-(4- Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yljmethyl} piperazin- 1 -yl)(6-methoxypyridin-2-yl)-methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in 2% bis 5% w/v Glycerol und 1 bis 10%> w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 3 Stunden beträgt. 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 pharyngeal application is at least 3 hours.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend: eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2-(4- Chlorphenyl)imidazo [ 1 ,2-a]pyridin-3 -yljmethyl} piperazin- 1 -yl)(6-methoxypyridin-2-yl)-methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in 2% bis 5% w/v Glycerol und 1 bis 10% w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 4 Stunden beträgt. Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2-(4-Chlorphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(6-methoxy-pyridin-2-yl)- methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in 2% bis 5% w/v Glycerol und 1 bis 10% w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 5 Stunden beträgt. 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 pharyngeal application is at least 4 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. 3 channels of 4- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} 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 - value of 7, and optionally at least one further adjuvant, wherein the duration of action of the stable pharmaceutical formulation after nasal or pharyngeal application is at least 5 hours.
Eine weitere Ausführungsform der vorliegenden Erfindung sind die erfindungsgemäßen stabilen pharmazeutischen Formulierungen zur nasalen oder pharyngealen Applikation zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2-(4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-methoxy-pyridin-2-yl)- methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in 2% bis 5% w/v Glycerol und 1 bis 10%> w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 6 Stunden beträgt. 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. 3 channels of 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 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 pharyngeal application is at least 6 hours.
Die erfindungsgemäßen Formulierungen können allein oder bei Bedarf in Kombination mit einer oder mehreren anderen pharmakologisch wirksamen Substanzen eingesetzt werden, solange diese Kombination nicht zu unerwünschten und inakzeptablen Nebenwirkungen führt. Weiterer Gegenstand der vorliegenden Erfindung sind daher Arzneimittel, enthaltend mindestens eine der erfindungsgemäßen Formulierungen und einen oder mehrere weitere Wirkstoffe, insbesondere zur Behandlung und/oder Prävention der zuvor genannten Erkrankungen. Als hierfür geeignete Kombinationswirkstoffe seien beispielhaft und vorzugsweise genannt: 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:
• Atemstimulantien, wie beispielhaft und vorzugsweise Theophyllin, Doxapram, Nicethamid oder Coffein; Respiratory stimulants, such as by way of example and preferably theophylline, doxapram, nicethamide or caffeine;
· psychostimulierende Verbindungen, wie beispielhaft und vorzugsweise Modafinil oder Armodafinil; Psycho-stimulatory compounds, such as by way of example and preferably modafinil or armodafinil;
• Amphetamine und Amphetamin-D erivate, wie beispielhaft und vorzugsweise Amphetamin, Met- amphetamin oder Methylphenidat; Amphetamines and amphetamine derivatives, such as by way of example and preferably amphetamine, metamphetamine or methylphenidate;
• Serotonin- Wiederaufnahmehemmer, wie beispielhaft und vorzugsweise Fluoxetin, Paroxetin, Citalopram, Escitalopram, Sertralin, Fluvoxamin oder Trazodon;  Serotonin reuptake inhibitors such as, by way of example and by way of illustration, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone;
· Serotonin-Präkursoren, wie beispielhaft und vorzugsweise L-Tryptophan; Serotonin precursors, such as by way of example and preferably L-tryptophan;
• selektive Serotonin-Noradrenalin- Wiederaufnahmehemmer, wie beispielhaft und vorzugsweise Venlafaxin oder Duloxetin; • noradrenerge und spezifisch serotonerge Antidepressiva, wie beispielhaft und vorzugsweise Mir- tazapin; 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;
• selektive Noradrenalin- Wiederaufhahmehemmer, wie beispielhaft und vorzugsweise Reboxetin; Selective noradrenaline reuptake inhibitors, such as by way of example and preferably reboxetine;
• tricyclische Antidepressiva, wie beispielhaft und vorzugsweise Amitriptylin, Protriptylin, Doxepin, Trimipramin, Imipramin, Clomipramin oder Desipramin; Tricyclic antidepressants such as, by way of example and by way of illustration, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine;
• alpha2-adrenerge Agonisten, wie beispielhaft und vorzugsweise Clonidin; Alpha2-adrenergic agonists, such as, by way of example and by way of illustration, clonidine;
• GABA- Agonisten, wie beispielhaft und vorzugsweise Baclofen;  GABA agonists, such as by way of example and preferably baclofen;
• alpha-Sympathomimetika, wie beispielhaft und vorzugsweise Xylometazolin, Oxymetazolin, Phenyl- ephrin, Naphazolin, Tetryzolin oder Tramazolin; · Glucocorticoide, wie beispielhaft und vorzugsweise Fluticason, Budesonid, Beclometason, Mometason, Tixocortol oder Triamcinolon;  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;
• Cannabinoid-Rezeptor- Agonisten;  • cannabinoid receptor agonists;
• Carboanhydrase-Hemmer, wie beispielhaft und vorzugsweise Acetazolamid, Methazolamid oder Diclofenamid; Carbonic anhydrase inhibitors, such as by way of example and preferably acetazolamide, methazolamide or diclofenamide;
· Opioid- und Benzodiazepin-Rezeptor- Antagonisten, wie beispielhaft und vorzugsweise Flumazenil, Naloxon oder Naltrexon; · Opioid and benzodiazepine receptor antagonists, such as by way of example and preferably flumazenil, naloxone or naltrexone;
• Cholinesterase-Hemmer, wie beispielhaft und vorzugsweise Neostigmin, Pyridostigmin, Physo- stigmin, Donepezil, Galantamin oder Rivastigmin;  Cholinesterase inhibitors, such as by way of example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine;
• N-Methyl-D-Aspartat- und Glutamat-Antagonisten, wie beispielhaft und vorzugsweise Amantadin, Memantin oder Sabeluzol;  N-methyl-D-aspartate and glutamate antagonists, such as by way of example and preferably amantadine, memantine or sabeluzol;
• Nikotin-Rezeptor-Agonisten;  Nicotine receptor agonists;
• Leukotrien-Rezeptor- Antagonisten, wie beispielhaft und vorzugsweise Montelukast oder Tripelukast;  Leukotriene receptor antagonists, such as by way of example and preferably montelukast or tripelukast;
• Dopamin-Rezeptor-Antagonisten, wie beispielhaft und vorzugsweise Dromperidon, Metoclopramid oder Benzamid-, Butyrophenon- oder Phenothiazin-Derivate; Dopamine receptor antagonists, such as by way of example and preferably dromperidone, metoclopramide or benzamide, butyrophenone or phenothiazine derivatives;
· Appetitzügler, wie beispielhaft und vorzugsweise Sibutramin, Topiramat, Phentermin, Lipase- Inhibitoren oder Cannabinoid-Rezeptor-Antagonisten; Appetite suppressants, such as by way of example and preferably sibutramine, topiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists;
• Protonenpumpen-Inhibitoren, wie beispielhaft und vorzugsweise Pantoprazol, Omeprazol, Esome- prazol, Lansoprazol oder Rabeprazol; Proton pump inhibitors, such as by way of example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;
• organische Nitrate und NO-Donatoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO; Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) und/oder cyclischem Adenosinmonophosphat (cAMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2, 3, 4 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil oder Lodenafil; • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil , Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil;
NO- und Häm-unabhängige Aktivatoren der löslichen Guanylatcyclase (sGC), wie insbesondere die in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 und WO 02/070510 beschriebenen Verbindungen; NO and heme-independent activators of soluble guanylate cyclase (sGC), in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
NO-unabhängige, jedoch Häm-abhängige Stimulatoren der löslichen Guanylatcyclase (sGC), wie insbesondere Riociguat, Vericiguat sowie die in WO 00/06568, WO 00/06569, WO 02/ 42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 und WO 2012/ 059549 beschriebenen Verbindungen; NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), such as, in particular, riociguat, vericiguat and those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549 described compounds;
Prostacyclin- Analoga und IP-Rezeptor-Agonisten, wie beispielhaft und vorzugsweise Iloprost, Bera- prost, Treprostinil, Epoprostenol oder Selexipag;  Prostacyclin analogs and IP receptor agonists such as, by way of example and by way of preference, iloprost, berastone, treprostinil, epoprostenol or selexipag;
Endothelin-Rezeptor-Antagonisten, wie beispielhaft und vorzugsweise Bosentan, Darusentan, Ambrisentan oder Sitaxsentan;  Endothelin receptor antagonists, such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;
Verbindungen, die die humane neutrophile Ekstase (HNE) inhibieren, wie beispielhaft und vorzugsweise Sivelestat oder DX-890 (Reltran);  Compounds that inhibit human neutrophilic ecstasy (HNE), such as by way of example, and preferably Sivelestat or DX-890 (Reltran);
Verbindungen, die den Ab- und Umbau der Extrazellulärmatrix inhibieren, beispielhaft und vorzugsweise Inhibitoren der Matrix-Metalloproteasen (MMPs), insbesondere Inhibitoren von Stromelysin, Kollagenasen, Gelatinasen und Aggrecanasen (hierbei vor allem von MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 und MMP-13) sowie der Metallo-Elastase (MMP-12);  Exemplary and preferably inhibitors of the matrix metalloproteases (MMPs), 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);
Verbindungen, die die Bindung von Serotonin an dessen Rezeptor blockieren, beispielhaft und vorzugsweise Antagonisten des 5-HT2B-Rezeptors wie PRX-08066;  Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT2B receptor such as PRX-08066;
Antagonisten von Wachstumsfaktoren, Zytokinen und Chemokinen, beispielhaft und vorzugsweise Antagonisten von TGF-ß, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL- 13 und Integrinen; die Rho-Kinase inhibierende Verbindungen, wie beispielhaft und vorzugsweise Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 oder BA-1049;  Antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, 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;
den Energiestoffwechsel des Herzens beeinflussende Verbindungen, wie beispielhaft und vorzugsweise Etomoxir, Dichloracetat, Ranolazin oder Trimetazidin; die Signaltransduktionskaskade inhibierende Verbindungen, beispielhaft und vorzugsweise aus der Gruppe der Kinase-Inhibitoren, insbesondere aus der Gruppe der Tyrosinkinase- und/oder Serin/Threoninkinase-Inhibitoren, wie beispielhaft und vorzugsweise Nintedanib, Dasatinib, Nilo- tinib, Bosutinib, Regorafenib, Sorafenib, Sunitinib, Cediranib, Axitinib, Telatinib, Imatinib, Brivanib, Pazopanib, Vatalanib, Gefitinib, Erlotinib, Lapatinib, Canertinib, Lestaurtinib, Pelitinib, Semaxanib oder Tandutinib; 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, semaxanib or tandutinib;
• anti-obstruktiv wirkende Mittel, wie sie z. B. zur Therapie der chronisch-obstruktiven Lungenerkrankung (COPD) oder eines Asthma bronchiale eingesetzt werden, beispielhaft und vorzugsweise aus der Gruppe der inhalativ oder systemisch angewendeten beta-adrenergen Rezeptor-Agonisten • 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
(beta-Mimetika) und der inhalativ angewendeten anti-muscarinergen Substanzen; (beta-mimetics) and the inhaled anti-muscarinergen substances;
• entzündungshemmende, immunmodulierende, immunsuppressive und/oder zytotoxische Mittel, beispielhaft und vorzugsweise aus der Gruppe der systemisch oder inhalativ angewendeten Cortico- steroide sowie Dimethylfumarat, Fingolimod, Glatirameracetat, ß-Interferone, Natalizumab, Teriflunomid, Mitoxantron, Immunglobuline, Acetylcystein, Montelukast, Tripelukast, Azathioprin,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,
Cyclophosphamid, Hydroxycarbamid, Azithromycin, Interferon-γ, Pirfenidon oder Etanercept; Cyclophosphamide, hydroxycarbamide, azithromycin, interferon-γ, pirfenidone or etanercept;
• antifibrotisch wirkende Mittel, wie beispielhaft und vorzugsweise Lysophosphatidsäure-Rezeptor 1 (LPA-1)- Antagonisten, CTGF-Inhibitoren, IL-4-Antagonisten, IL-13-Antagonisten, TGF-ß- Antagonisten oder Pirfenidon; · antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien und der profibrinolytischen Substanzen; 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-β antagonists or pirfenidone; Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;
• den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium- Antagonisten, Angiotensin All- Antagonisten, ACE-Hemmer, Vasopeptidase-Inhibitoren, Endothelin- Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker, Mineralo- corticoid-Rezeptor- Antagonisten sowie der Diuretika; und/oder 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
• den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie beispielhaft und vorzugsweise HMG-CoA-Reduktase- oder Squalensynthese- Inhibitoren, der ACAT-Inhibitoren, CETP-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin- Absorptionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-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
Reabsorptionshemmer und Lipoprotein(a)-Antagonisten. Reabsorptionshemmer and lipoprotein (a) antagonists.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem beta-adrenergen Rezeptor-Agonisten, wie beispielhaft und vorzugsweise Albuterol, Isoproterenol, Metaproterenol, Terbutalin, Fenoterol, Formoterol, Reproterol, Salbutamol oder Salmeterol, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einer anti-muscarinergen Substanz, wie beispielhaft und vorzugsweise Ipratropiumbromid, Tiotropiumbromid oder Oxitropiumbromid, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Corticosteroid, wie beispielhaft und vorzugsweise Prednison, Prednisolon, Methylprednisolon, Triamcinolon, Dexamethason, Betamethason, Beclometason, Flunisolid, Budesonid oder Fluticason, verabreicht. Unter antithrombotisch wirkenden Mittel werden vorzugsweise Verbindungen aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien und der profibrinolytischen Substanzen verstanden. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Thrombozytenaggregationshemmer, wie beispielhaft und vorzugsweise Aspirin, Clopidogrel, Ticlopidin oder Dipyridamol, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Thrombin-Inhibitor, wie beispielhaft und vorzugsweise Ximelagatran, Melagatran, Dabigatran, Bivalirudin oder Clexane, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem GPIIb/IIIa- Antagonisten, wie beispielhaft und vorzugsweise Tirofiban oder Abciximab, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Faktor Xa-Inhibitor, wie beispielhaft und vorzugsweise 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 oder SSR- 128428, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit Heparin oder einem low molecular weight (LMW)-Heparin-Derivat verabreicht. In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Vitamin K-Antagonisten, wie beispielhaft und vorzugsweise Coumarin, verabreicht. In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
Unter den Blutdruck senkenden Mitteln werden vorzugsweise Verbindungen aus der Gruppe der Calcium- Antagonisten, Angiotensin All- Antagonisten, ACE-Hemmer, Endothelin- Antagonisten, Renin- Inhibitoren, alpha-Rezeptoren-B locker, beta-Rezeptoren-Blocker, Mineralocorticoid-Rezeptor- Antagonisten sowie der Diuretika verstanden. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Calcium-Antagonisten, wie beispielhaft und vorzugsweise Nifedipin, Amlodipin, Verapamil oder Diltiazem, verabreicht. Among 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. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem alpha- 1 -Rezeptoren-Blocker, wie beispielhaft und vorzugsweise Prazosin, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem beta-Rezeptoren-B locker, wie beispielhaft und vorzugsweise 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 oder Bucindolol, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Angiotensin AII-Antagonisten, wie beispielhaft und vorzugsweise Losartan, Candesartan, Valsartan, Telmisartan oder Embusartan, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem ACE-Hemmer, wie beispielhaft und vorzugsweise Enalapril, Captopril, Lisinopril, Ramipril, Delapril, Fosinopril, Quinopril, Perindopril oder Trandopril, verabreicht. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Endothelin-Antagonisten, wie beispielhaft und vorzugsweise Bosentan, Darusentan, Ambrisentan oder Sitaxsentan, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Renin-Inhibitor, wie beispielhaft und vorzugsweise Aliskiren, SPP-600 oder SPP-800, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Mineralocorticoid-Rezeptor- Antagonisten, wie beispielhaft und vorzugsweise Spironolacton, Eplerenon oder Finerenon, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Diuretikum, wie beispielhaft und vorzugsweise Furosemid, Bumetanid, Torsemid, Bendroflumethiazid, Chlorthiazid, Hydrochlorthiazid, Hydroflumethiazid, Methyclothiazid, Polythiazid, Trichlormethiazid, Chlorthalidon, Indapamid, Metolazon, Quinethazon, Acetazolamid, Dichlorphenamid, Methazolamid, Glycerin, Isosorbid, Mannitol, Amilorid oder Triamteren, verabreicht. Unter den Fettstoffwechsel verändernden Mitteln werden vorzugsweise Verbindungen aus der Gruppe der CETP-Inhibitoren, Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie HMG-CoA- Reduktase- oder Squalensynthese-Inhibitoren, der ACAT-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer, Lipase-Inhibitoren sowie der Lipoprotein(a)- Antagonisten verstanden. In a preferred embodiment of the invention, 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. Among the 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem CETP-Inhibitor, wie beispielhaft und vorzugsweise Torcetrapib (CP-529 414), JJT-705 oder CETP -Vaccine (Avant), verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Thyroidrezeptor-Agonisten, wie beispielhaft und vorzugsweise D-Thyroxin, 3,5,3'-Triiodothyronin (T3), CGS 23425 oder Axitirome (CGS 26214), verabreicht. In a preferred embodiment of the invention, 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). In a preferred embodiment of the invention, 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).
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem HMG-CoA-Reduktase-Inhibitor aus der Klasse der Statine, wie beispielhaft und vorzugsweise Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin oder Pitavastatin, verabreicht. In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Squalensynthese-Inhibitor, wie beispielhaft und vorzugsweise BMS-188494 oder TAK-475, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem ACAT-Inhibitor, wie beispielhaft und vorzugsweise Avasimibe, Melinamide, Pactimibe, Eflucimibe oder SMP-797, verabreicht. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem MTP-Inhibitor, wie beispielhaft und vorzugsweise Implitapid, BMS-201038, R- 103757 oder JTT-130, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem PPAR-gamma-Agonisten, wie beispielhaft und vorzugsweise Pioglitazon oder Rosiglitazon, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem PPAR-delta-Agonisten, wie beispielhaft und vorzugsweise GW 501516 oder BAY 68-5042, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Cholesterin- Absorptionshemmer, wie beispielhaft und vorzugsweise Ezetimibe, Tiqueside oder Pamaqueside, verabreicht. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Lipase-Inhibitor, wie beispielhaft und vorzugsweise Orlistat, verabreicht. In a preferred embodiment of the invention, the formulations according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem polymeren Gallensäureadsorber, wie beispielhaft und vorzugsweise Cholestyramin, Colestipol, Colesolvam, CholestaGel oder Colestimid, verabreicht. In a preferred embodiment of the invention, 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.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Gallensäure-Reabsorptionshemmer, wie beispielhaft und vorzugsweise ASBT (= IBAT)-Inhibitoren wie z. B. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 oder SC-635, verabreicht. In a preferred embodiment of the invention, the formulations according to the invention in combination with a bile acid reabsorptionshemmer, such as by way of example and preferably ASBT (= IBAT) inhibitors such. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Formulierungen in Kombination mit einem Lipoprotein(a)-Antagonisten, wie beispielhaft und vorzugsweise Gemcabene calcium (CI- 1027) oder Nicotinsäure, verabreicht. In a preferred embodiment of the invention, 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.
Besonders bevorzugt sind Kombinationen der erfindungsgemäßen Formulierungen mit einem oder mehreren weiteren Wirkstoffen ausgewählt aus der Gruppe bestehend aus Atemstimulantien, psycho- stimulierenden Verbindungen, Serotonin- Wiederaufnahmehemmern, noradrenergen, serotonergen und tricyclischen Antidepressiva, sGC-Stimulatoren, Mineralocorticoid-Rezeptor-Antagonisten, entzündungshemmend wirkenden Mitteln, immunmodulierend wirkenden Mitteln, immunsuppressiv wirkenden Mitteln und zytotoxisch wirkenden Mitteln. Particularly preferred are combinations of the formulations 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.
Die erfindungsgemäßen Formulierungen können bei Bedarf auch in Zusammenhang mit dem Einsatz eines oder mehrerer medizinisch-technischer Geräte oder Hilfsmittel verwendet werden, solange dies nicht zu unerwünschten und inakzeptablen Nebeneffekten führt. Für eine solche Kombinations- anwendung in Betracht kommende medizinische Geräte und Hilfsmittel sind beispielhaft und vorzugsweise: If necessary, the 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:
• Geräte zur Atemwegs-Überdruckbeatmung, wie beispielhaft und vorzugsweise CPAP (continuous positive airway pressure)-Geräte, BiPAP (bilevel positive airway pressure)-Geräte und IPPV (intermittent positive pressure ventilation)-Geräte; • Positive airway pressure (CPAP) devices, such as positive airway pressure (CPAP) devices, positive airway pressure (BIPAP) devices, and intermittently positive pressure ventilation (IPPV) devices;
· Neurostimulatoren des Nervus hypoglossus; Neurostimulators of the hypoglossal nerve;
• intraorale Hilfsmittel, wie beispielhaft und vorzugsweise Protrusionsspangen; • nasale Einwegventile; Intraoral aids, such as by way of example and preferably protrusion clips; • nasal one-way valves;
• Nasenstents.  • Nasal stents.
Gemäß einer Ausführungsform beträgt die Dosierung bei intranasaler Applikation etwa 0.1 μg bis 500 μg pro Tag. Gemäß einer weiteren Ausführungsform beträgt die Dosierung bei intranasaler Appli- kation etwa 1 μg bis 250 μg pro Tag. Gemäß einer weiteren Ausführungsform beträgt die Dosierung bei intranasaler Applikation etwa 1 μg bis 120 μg pro Tag. Gemäß einer weiteren Ausführungsform wird die Dosis von etwa 0.1 μg bis 500 μg pro Tag oder von etwa 1 μg bis 250 μg pro Tag oder von etwa 1 μg bis 120 μg pro Tag, einmal täglich vor dem Schlafen intranasal appliziert. Gemäß einer Ausführungsform wird die Dosis von etwa 0.1 μg bis 500 μg pro Tag oder von etwa 1 μg bis 250 μg pro Tag oder von etwa 1 μg bis 120 μg pro Tag, einmal täglich je zur Hälfte in jede Nasenöffnung appliziert. Gemäß einer Ausführungsform wird die Dosis von etwa 0.1 μg bis 500 μg pro Tag oder von etwa 1 μg bis 250 μg pro Tag oder von etwa 1 μg bis 120 μg pro Tag, einmal täglich vor dem Schlafen je zur Hälfte in jede Nasenöffnung appliziert. According to one embodiment, the dosage for intranasal administration is about 0.1 μg to 500 μg per day. According to a further embodiment, the dosage for intranasal administration is about 1 μg to 250 μg per day. According to a further embodiment, the dosage for intranasal administration is about 1 μg to 120 μg per day. In another embodiment, the dose is applied intranasally from about 0.1 μg to 500 μg per day or from about 1 μg to 250 μg per day, or from about 1 μg to 120 μg per day once a day before sleep. According to one embodiment, the dose of about 0.1 micrograms to 500 micrograms per day or from about 1 micrograms to 250 micrograms per day or from about 1 micrograms to 120 micrograms per day, once a day each half applied in each nostril. According to one embodiment, the dose of about 0.1 .mu.g to 500 .mu.g per day or of about 1 .mu.g to 250 .mu.g per day or of about 1 .mu.g to 120 .mu.g per day, once a day before sleeping each half applied in each nostril.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
Bewertung der pharmakologischen Wirksamkeit Evaluation of pharmacological activity
Abkürzungsverzeichnis List of abbreviations
Die pharmakologische Aktivität der in den erfindungsgemäßen Formulierungen enthaltenen Inhibitoren des TASK-1 und/oder TASK-3 Kanals wurde in der PCT/EP2016/079973 durch in vitro Versuche gezeigt. Die pharmakologische Aktivität der erfindungsgemäßen Formulierungen kann durch in vivo- Untersuchungen, wie sie dem Fachmann bekannt sind, nachgewiesen werden. Die nachfolgenden Anwendungsbeispiele beschreiben die biologische Wirkung der erfindungsgemäßen Verbindungen, ohne die Erfindung auf diese Beispiele zu beschränken. Tiermodell der obstruktiven Schlafapnoe am Schwein 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. Animal model of obstructive sleep apnea in pigs
Die Wirkungen der erfindungsgemäßen Formulierungen der Inhibitoren von TASK-1 und/oder TASK-3 Kanälen auf die Aktivierungsschwelle des Genioglossusmuskels durch negativen Druck und die Kollapsibilität der oberen Atemwege wurden an einem Schweinemodell für obstruktive Schlafapnoe untersucht. Durch den Einsatz von Unterdruck kann bei anästhesierten, spontan-atmenden Schweinen ein Kollaps und damit ein Verschluss der oberen Atemwege ausgelöst werden [Wirth et al, Sleep 36, 699-708 (2013)]. The effects of the formulations according to the invention of the inhibitors of TASK-1 and / or TASK-3 channels on the activation threshold of the genioglossus muscle by negative pressure and the collapseibility of the upper respiratory tract were investigated in a pig model for obstructive sleep apnea. The use of negative pressure can cause a collapse of the upper respiratory tract in anesthetized, spontaneously breathing pigs [Wirth et al, Sleep 36, 699-708 (2013)].
Für das Modell wurden Deutsche Landschweine verwendet. Da sich beim Menschen in liegender, schlafender Position die nasale Achse in einer fast vertikalen Position befindet, wurden die Schweine bei den Versuchen in einer sitzenden Position (70 Grad) fixiert, wobei die Nase nach oben zeigte. Dadurch floss die Formulierung nach nasaler Gabe nach unten über alle Bereiche der oberen Atemwege. Die Schweine wurden anästhesiert und tracheotomiert. In den rostralen und kaudalen Teil der Trachea wurde jeweils eine Kanüle eingebunden. Die rostrale Kanüle wurde mittels eines T-Stückes einerseits mit einem Gerät verbunden, welches Unterdruck generiert, und andererseits mit der kaudalen Kanüle. Die kaudale Kanüle war mittels eines T-Stückes mit der rostralen Kanüle verbunden sowie mit einem Schlauch, der unter Umgehung der oberen Atemwege eine spontane Atmung erlaubte. Durch entsprechendes Verschließen und Öffnen der Schläuche war es so möglich, dass das Schwein von einer normalen Nasenatmung zu einer Atmung über die kaudale Kanüle wechseln konnte, während die oberen Atemwege isoliert und mit dem Gerät zur Erzeugung des Unterdrucks verbunden waren. Die Muskel- aktivität des Musculus genioglossus wurde mittels Elektromyogramm (EMG) registriert. 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).
Zu bestimmten Zeitpunkten wurde die Kollapsibilität der oberen Atemwege getestet, indem das Schwein über die kaudale Kanüle atmete und an die oberen Atemwege Unterdrücke von -50, -100 und -150 mbar (entsprechend -50, -100 und -150 cm Wassersäule (cm H2O)) angelegt wurden. Hierdurch kollabierten die oberen Atemwege, was durch Unterbrechung des Luftstroms und einen Druckabfall im Schlauchsystem angezeigt wurde. Dieser Test wurde durchgeführt vor Gabe der Testsubstanz und in bestimmten Abständen nach Gabe die Testsubstanz. Eine entsprechend wirksame Testsubstanz konnte diesen Kollaps der Atemwege in der inspiratorischen Phase verhindern. Nach dem Wechsel von nasaler Atmung zur Atmung durch die kaudale Kanüle war keine EMG- Aktivität des Musculus genioglossus beim anästhesierten Schwein messbar. Als ein weiterer Test wurde dann der Unterdruck ermittelt, bei dem die EMG-Aktivität wieder einsetzte. Dieser Schwellenwert wurde bei Wirksamkeit einer Testsubstanz zu positiveren Werten verschoben. Die Untersuchung wurde ebenfalls vor Gabe der Testsubstanz und zu bestimmten Zeitpunkten nach Gabe der Testsubstanz durchgeführt. Die Gabe der Testsubstanz erfolgte nasal. At certain times, 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. After switching from nasal breathing to respiration through the caudal cannula, no EMG activity of the genioglossus muscle was measurable in the anesthetized pig. As a further test, the negative pressure was determined in which the EMG activity started again. This threshold was shifted to more positive values when a test substance was effective. The examination was also carried out before administration of the test substance and at certain times after administration of the test substance. The administration of the test substance was nasal.
Die in den folgenden Tabellen gezeigten Ergebnisse wurden mit den in Tabelle 1 als Beispiel 1, Beispiel 3 und Beispiel 4 aufgeführten Verbindungen durchgeführt. Soweit nicht anders angegeben, wurden die Daten bei einem Unterdruck von -100 mbar (entsprechend -100 cm Wassersäule (cm H2O)) auf die oberen Atemwege gemessen. 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.
Die in Tabelle 1 als Beispiel 1, Beispiel 3 und Beispiel 4 aufgeführten Wirkstoffe wurden in den in der folgenden Tabelle 2 aufgeführten verschiedenen Formulierungen gelöst und in einer Menge von 0 μg, 3 μg, 10 μg,30 μg bzw. 100 μg pro Schwein verabreicht. Die Wirkstoffformulierung bzw. das reine Vehikel wurde mit einer Pipette in einem Volumen von je 400 μΐ in jede Nasenöffnung appliziert. 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 μg, 3 μg, 10 μg, 30 μg or 100 μg per pig , The active ingredient formulation or the pure vehicle was administered with a pipette in a volume of 400 μΐ in each nostril.
Tabelle 2: Zusammensetzungen der Formulierungen für die nasale Gabe, in der die in Tabelle 1 als Beispiel 3 aufgeführte Verbindung verabreicht wurde: Table 2: Compositions of the formulations for nasal administration in which the compound listed in Table 1 as Example 3 was administered:
Optional enthalten die Formulierungen von Tabelle 2 zusätzlich Butylhydroxyanisol in einer Konzentration von 0.02% w/v. Die Herstellung des Phosphatpuffers pH 7, 0.063 M erfolgte nach European Pharmacopoeia 8.7: 5.18 g wasserfreies Dinatrium-Hydrogenphosphat und 3.65 g Natrium-Dihydrogenphosphat Monohydrat wurden in 950 mL Wasser gelöst, der pH- Wert wurde mit Phosphorsäure eingestellt und es wurde auf 1000 mL mit Wasser aufgefüllt. Alternativ wurde für die Herstellung des Phosphatpuffers Dinatrium- Hydrogenphosphats Dihydrat und Natrium-Dihydrogenphosphat Dihydrat anstelle des wasserfreien Dinatrium-Hydrogenphosphats und des Natrium-Dihydrogenphosphat Monohydrats verwendet. Hierfür wurden 6.49 g Dinatrium-Hydrogenphosphats Dihydrat und 4.13 g Natrium-Dihydrogenphosphat Dihydrat in 950 mL Wasser gelöst, der pH- Wert wurde mit Phosphorsäure eingestellt und es wurde auf 1000 mL mit Wasser aufgefüllt. Optionally, 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. Alternatively, 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.
Die Wirkdauer ist in diesem Schweinemodell definiert als die Zeit [min], in der bei keinem Tier ein Kollaps der oberen Atemwege beobachtet wurde, als Mittelwert der angegebenen Anzahl von Tieren. Eine Wirkdauer, die als„>" X min angegeben ist bedeutet, dass der Versuch bei X min beendet wurde und bis dahin noch bei keinem Tier ein Kollaps der oberen Atemwege beobachtet wurde. 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.
Tabelle 3: Wirkdauer von Beispiel 3/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80 mit Glvcerol 85% (Formulierung 3) oder mit Glvcerol 85% und PEG400 (Formulierung 5) im Vergleich zu der Wirkdauer von Beispiel 3/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80 (Formulierung 1) 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)
*Bei Versuchen, bei denen die Nasengänge der Schweine durch Schleim verlegt waren, worauf stark verrauschte Kurven des Trachealdruckes und des Luftflusses hinwiesen, betrug der Mittelwert der Wirkdauer von 30 μg Beispiel 3 in Formulierung 1 120 min. Tabelle 4: Wirkdauer von Beispiel 3/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80/Glycerol, Vergleich verschiedener Glycerolkonzentrationen  * In experiments in which the nasal passages of pigs were misplaced by mucus, followed by strongly noisy curves of tracheal pressure and air flow, the mean duration of action of 30 μg of 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
Tabelle 5: Wirkdauer von Beispiel 3/Tabelle 1 in Phosphatpuffer pH7/Polvsorbat 80 (90/10) + Na-  Table 5: duration of action of example 3 / table 1 in phosphate buffer pH7 / polysorbate 80 (90/10) + sodium
Formulierung Na-CMC Beispiel 3 aus Wirkdauer Formulation Na-CMC Example 3 from duration of action
nach Tabelle 2 [% w/v] Tabelle 1 [min]  according to Table 2 [% w / v] Table 1 [min]
[μ§] Mittelwert  [μ§] mean
7 1.25 Na-CMC 3 120 Tabelle 6: Wirkdauer von Beispiel 3/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80 mit Glvcerol (87.5/10/2.5) oder Propylenglycol (70/10/20) 7 1.25 Na-CMC 3 120 Table 6: Duration of action of Example 3 / Table 1 in phosphate buffer pH7 / polysorbate 80 with glvcerol (87.5 / 10 / 2.5) or propylene glycol (70/10/20)
Tabelle 7: Wirkdauer von Beispiel 1/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80/Glvcerol (Formulierung 3) im Vergleich zu der Wirkdauer von Beispiel 1/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80 (Formulierung 1) bei einem Unterdruck von -100 mbar und -50 mbar  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
Tabelle 8: Wirkdauer von Beispiel 4/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80/Glvcerol (Formulierung 3) im Vergleich zu der Wirkdauer von Beispiel 4/Tabelle 1 in Phosphatpuffer pH7/Polysorbat 80 (Formulierung 1) bei einem Unterdruck von -100 mbar und -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

Claims

Patentansprüche claims
1. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation enthaltend: eine therapeutisch wirksame Menge mindestens eines Inhibitors des TASK-1 und/oder TASK-3 Kanals oder eines Hydrats, Solvats, Polymorphs oder Metaboliten hiervon oder eines pharmazeutisch verwendbaren Salzes hiervon in 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
1% bis 100% w/v Glycerol und gegebenenfalls mindestens einen Hilfsstoff, wobei die Formulierung einen pH- Wert von 4 bis 8 aufweist. 1% to 100% w / v glycerol and optionally at least one excipient, the formulation having a pH of 4 to 8.
2. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach Anspruch 1 , wobei der gegebenenfalls mindestens eine Hilfsstoff ausgewählt ist aus der Gruppe bestehend aus mindestens einem pH-Regulator, mindestens einem Lösungsvermittler, mindestens einem Antioxidans, mindestens einem Stabilisator, mindestens einem Verdickungsmittel, mindestens einem Konservierungsmittel, mindestens einer Tonizitäts- einstellenden Substanz, mindestens einem Aroma, mindestens einem Duftstoff und mindestens einem Farbstoff. 2. A stable pharmaceutical formulation for nasal or pharyngeal application according to claim 1, 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 a preservative, at least one tonicity adjusting substance, at least one flavor, at least one perfume and at least one dye.
3. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach Anspruch 1 oder 2, wobei der gegebenenfalls mindestens eine pH-Regulator ausgewählt ist aus der Gruppe bestehend aus Citronensäure und ihren Salzen, Essigsäure und ihren Salzen, Phosphorsäure und ihren Salzen, Salzsäure, Carbonsäuren, Bicarbonsäuren, Aminosäuren, Oxocarbonsäuren, Polycarbonsäuren, Natriumhydroxid, Kaliumhydroxid, Natriumcarbonat und3. Stable pharmaceutical formulation for nasal or pharyngeal application according to claim 1 or 2, 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, carboxylic acids, Bicarboxylic acids, amino acids, oxocarboxylic acids, polycarboxylic acids, sodium hydroxide, potassium hydroxide, sodium carbonate and
Natriumhydrogencarbonat. Sodium bicarbonate.
4. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 3, wobei der gegebenenfalls mindestens eine Lösungs vermittler ausgewählt ist aus der Gruppe bestehend aus Ethanol, Polysorbat 20, Polyoxyethylen(8)-stearat und Polysorbat 80. 4. A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 3, wherein the optionally at least one solubilizer is selected from the group consisting of ethanol, polysorbate 20, polyoxyethylene (8) stearate and polysorbate 80th
5. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 4, wobei das gegebenenfalls mindestens eine Antioxidans ausgewählt ist aus der Gruppe bestehend aus Citronensäure, Butylhydroxyanisol, Butylhydroxytoluol, EDTA und einer Begasung mit Stickstoff. 5. A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 4, wherein the optionally at least one antioxidant is selected from the group consisting of citric acid, butylated hydroxyanisole, butylated hydroxytoluene, EDTA and a gasification with nitrogen.
6. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 5, wobei das gegebenenfalls mindestens eine Konservierungsmittel ausgewählt ist aus der Gruppe bestehend aus Cs-Cis Alkoniumchlorid, Methylparaben, Propylparaben, Sorbinsäure, Chlorbutanol und Benzalkoniumchlorid. 6. A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 5, 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.
7. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 6, wobei die Formulierung 2 bis 50% w/v Glycerol, 1 bis 10%> eines Lösungsvermittlers, bis 97% w/v eines pH-Regulators und gegebenenfalls mindestens einen weiteren Hilfsstoff enthält. 7. Stable pharmaceutical formulation for nasal or pharyngeal application according to any one of claims 1 to 6, wherein the formulation 2 to 50% w / v glycerol, 1 to 10%> of a solubilizer, to 97% w / v of a pH regulator and optionally contains at least one other excipient.
8. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 7, wobei der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus einer Verbindun der Formel (I), 8. A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 7, wherein the at least one inhibitor of the TASK-1 and / or TASK-3 channel is selected from a Verbindun of formula (I),
in welcher  in which
R1 für Halogen, Cyano, (Ci-C4)-Alkyl, Cyclopropyl oder Cyclobutyl steht und R 1 is halogen, cyano, (C 1 -C 4) -alkyl, cyclopropyl or cyclobutyl and
R2 für (C4-C6)-Cycloalkyl steht, worin eine Ring-CH2-Gruppe gegen -O- ausgetauscht kann, oder für eine Phenyl-Gruppe der Formel (a) oder eine Pyridyl-Gruppe der Formel (b) R 2 is (C 4 -C 6 ) -cycloalkyl, in which one ring-CH 2 group can be replaced by -O-, or represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)
steht, stands,
worin * die Verknüpfung zur angrenzenden Carbonyl-Gruppe markiert und  where * denotes the link to the adjacent carbonyl group and
R3 Fluor, Chlor, Brom, Cyano, (Ci-C3)-Alkyl oder (Ci-C3)-Alkoxy bedeutet, wobei (Ci-C3)-Alkyl und (Ci-C3)-Alkoxy bis zu dreifach mit Fluor substituiert sein können, R 3 is fluorine, chlorine, bromine, cyano, (C 1 -C 3 ) -alkyl or (C 1 -C 3 ) -alkoxy, where (C 1 -C 3) -alkyl and (C 1 -C 3) -alkoxy can be substituted up to three times by fluorine,
R4 Wasserstoff, Fluor, Chlor, Brom oder Methyl bedeutet, R5 Wasserstoff, Fluor, Chlor, Brom oder Methyl bedeutet und R 4 is hydrogen, fluorine, chlorine, bromine or methyl, R 5 is hydrogen, fluorine, chlorine, bromine or methyl, and
R6 Wasserstoff, (Ci-C3)-Alkoxy, Cyclobutyloxy, Oxetan-3-yloxy, Tetrahydrofuran- 3-yloxy oder Tetrahydro-2H-pyran-4-yloxy bedeutet, wobei (Ci-C3)-Alkoxy bis zu dreifach mit Fluor substituiert sein kann, sowie einem Hydrat, Solvat, Polymorph oder Metabolit hiervon oder einem pharmazeutisch verwendbaren Salz hiervon. 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 a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof.
9. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 8, wobei der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals ausgewählt ist aus 9. A stable pharmaceutical formulation for nasal or pharyngeal application according to any one of claims 1 to 8, wherein the at least one inhibitor of the TASK-1 and / or TASK-3 channel is selected from
(4- {[2-(4-Chlorphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-methoxypyridin-2- yl)Tnethanon, (4- {[2- (4-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazin-1-yl) (6-methoxypyridin-2-yl) -ethanethanone
(4- {[2-(4-Bromphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(2-fluorphenyl)- methanon, (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (2-fluorophenyl) -methanone,
(4- {[2-(4-Bromphenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(cyclopentyl)- methanon, und (4- {[2- (4-Bromophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (cyclopentyl) -methanone, and
(4- {[2-(4-Chlorophenyl)imidazo[l ,2-a]pyridin-3-yl]methyl}piperazin-l -yl)(cyclopentyl)- methanon, sowie einem Hydrat, Solvat, Polymorph oder Metabolit hiervon oder einem pharmazeutisch verwendbaren Salz hiervon. (4- {[2- (4-Chlorophenyl) imidazo [1,2-a] pyridin-3-yl] methyl} piperazine-1-yl) (cyclopentyl) -methanone, as well as a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof.
10. Stabile pharmazeutische Formulierung nach einem der Ansprüche 1 bis 9, wobei der mindestens eine Inhibitor des TASK-1 und/oder TASK-3 Kanals (4- {[2-(4-Chlorphenyl)imidazo[l ,2- a]pyridin-3-yl]methyl}piperazin-l -yl)(6-methoxy-pyridin-2-yl)methanon ist oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon. 10. Stable pharmaceutical formulation according to one of claims 1 to 9, wherein the at least one inhibitor of TASK-1 and / or TASK-3 channel (4- {[2- (4-chlorophenyl) imidazo [l, 2 a] pyridine 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. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 9 zur Behandlung und/oder Prävention von Krankheiten. 11. Stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 9 for the treatment and / or prevention of diseases.
12. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmusstörungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuroimmunologischen Erkrankungen. 12. Stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 9 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 neuroimmunological diseases.
13. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmus Störungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuroimmunologischen Erkrankungen, wobei die nasale oder pharyngeale Applikation mit Hilfe von Nasensprays, Nasentropfen, Nasenlösungen, Pulverinhalatoren, Nebulizern, Dosieraerosolen oder halbfesten Gelen erfolgt. A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 9 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 neuroimmunologic diseases, where nasal or pharyngeal administration is by nasal sprays, nasal drops, nasal solutions, powder inhalers, nebulizers, metered aerosols or semi-solid gels.
14. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von Atemstörungen, schlafbedingten Atemstörungen, obstruktiven Schlafapnoen, zentralen Schlafapnoen, Schnarchen, Herzrhythmus Störungen, Arrhythmien, neurodegenerativen Erkrankungen, neuroinflammatorischen Erkrankungen und neuroimmunologischen Erkrankungen, wobei die Wirkdauer mindestens 4 Stunden beträgt. 14. Stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 9 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 neuroimmunological disorders, with a duration of action of at least 4 hours.
15. Stabile pharmazeutische Formulierung zur nasalen oder pharyngealen Applikation nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung und/oder Prävention von obstruktiven Schlafapnoen oder Schnarchen, enthaltend: eine therapeutisch wirksame Menge des Inhibitors des TASK-1 und/oder TASK-3 Kanals 4- {[2- (4-Chlorphenyl)imidazo[l,2-a]pyridin-3-yl]methyl}piperazin-l-yl)(6-methoxypyridin-2-yl)- methanon oder ein Hydrat, Solvat, Polymorph oder Metabolit hiervon oder ein pharmazeutisch verwendbares Salz hiervon in A stable pharmaceutical formulation for nasal or pharyngeal administration according to any one of claims 1 to 9 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] 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
2% bis 5% w/v Glycerol und 2% to 5% w / v glycerol and
1 bis 10% w/v Polysorbat 80 und bis 97% w/v eines Phosphatpuffers, der einen pH- Wert von 7 aufweist, und gegebenenfalls mindestens einen weiteren Hilfsstoff, wobei die Wirkdauer der stabilen pharmazeutischen Formulierung nach nasaler oder pharyngealer Applikation mindestens 5 Stunden beträgt. 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 pharyngeal administration is at least 5 hours.
EP17822216.2A 2016-12-21 2017-12-13 Pharmaceutical dosage forms containing task-1 and task-3 channel inhibitors, and the use of same in breathing disorder therapy Withdrawn EP3558380A1 (en)

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PCT/EP2017/082542 WO2018114501A1 (en) 2016-12-21 2017-12-13 Pharmaceutical dosage forms containing task-1 and task-3 channel inhibitors, and the use of same in breathing disorder therapy

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