Process for preparation of pharmaceutical dosage forms comprising TASK-1 and TASK-3 channel inhibitors and their use in treatment of respiratory disorders

Abstract

The present invention relates to a process for the preparation of a pharmaceutical dosage form comprising effective and selective TASK-1 and / or TASK-3 channel inhibitors, and the use of the dosage form obtained by said process for the treatment and / or prevention of respiratory disorders, including sleep-related respiratory disorders, such as obstructive and central sleep apnea and snoring.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980077910.0, whose application date is November 20, 2019 and invention name is “Method for preparing a pharmaceutical dosage form containing TASK-1 and TASK-3 channel inhibitors and use thereof in the treatment of respiratory disorders”.

[0002] This application was filed on November 20, 2019 as a PCT international patent application with application number PCT / EP2019 / 081950, and claims priority to European patent application No. 18208601.7 filed on November 27, 2018, the entire disclosure of which is hereby incorporated by reference into this specification.

[0003] The present application relates to a method for preparing a pharmaceutical dosage form comprising an effective and selective TASK-1 and / or TASK-3 channel inhibitor, and the use of the dosage form obtained by the preparation method for treating and / or preventing breathing disorders, including sleep-related breathing disorders, such as obstructive and central sleep apnea and snoring.

[0004] Potassium channels are almost ubiquitous membrane proteins that are involved in a large number of different physiological processes. This also includes the regulation of membrane potential and the electrical excitability of neurons and muscle cells. Potassium channels are divided into three major categories, with different numbers of transmembrane domains (2, 4 or 6). The class of potassium channels in which two pore-forming domains are flanked by four transmembrane domains is called a K2P channel (two pore domain K2P channel). + Functionally, K2P channels mediate K + The K2P channel family consists of 15 members that are divided into six subfamilies based on sequence, structural and functional similarities: 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) and TRESK (TWIK-related spinal cord K + aisle).

[0005] Of particular interest is TASK (TWIK-associated acid-sensitive K +The TASK channels are classified into TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 or K2P9.1) of the subfamily of TASK channels. Functionally, these channels are characterized by a "leak" or "background" current flowing through them in the maintenance of voltage-independent kinetics, in which they respond to many physiological and pathological influences by increasing or decreasing their activity. TASK channels are characterized by a sensitive response to changes in extracellular pH: the channels are inhibited at acidic pH and activated at alkaline pH.

[0006] TASK-1 and TASK-3 channels play a role in respiratory regulation. Both channels are expressed in respiratory neurons of the respiratory center of the brainstem, especially in neurons that generate respiratory rhythm (with pre- The TASK channel is expressed in the ventral respiratory group of the ventral respiratory complex, in the noradrenergic locus caeruleus, and in the serotonergic neurons of the raphe nucleus. Due to its pH dependence, the TASK channel has a sensor function here, which converts changes in extracellular pH into corresponding cellular signals [Bayliss et al., Pflugers Arch. 467 , 917-929 (2015)]. TASK-1 and TASK-3 are also expressed in the Glomus caroticum (a paraganglionic nerve that measures the pH and O2 and CO2 content of the blood and transmits signals to the respiratory center in the brainstem to regulate breathing). TASK-1 knockout mice have been shown to have reduced ventilatory responses to hypoxia and normoxic hypercapnia (increased respiratory rate and tidal volume) [Trapp et al., J. Neurosci. 28 , 8844-8850 (2008)]. In addition, TASK-1 and TASK-3 channels have been found in the motor neurons of the Nervus hypoglossus (the XII cranial nerve that plays an important role in maintaining upper airway patency) [Berg et al., J. Neurosci. 24 ,6693-6702(2004)].

[0007] In a sleep apnea model in anesthetized pigs, nasal administration of potassium channel blockers that block TASK-1 channels in the nanomolar range resulted in inhibition of collapse of the pharyngeal airway musculature and sensitization of the negative pressure reflex of the upper airway. It is speculated that nasal administration of potassium channel blockers depolarizes the mechanoreceptors in the upper airway and leads to increased activity of the upper airway musculature via activation of the negative pressure reflex, thereby stabilizing the upper airway and preventing collapse. TASK channel blockade is very important for obstructive sleep apnea and snoring via this stabilization of the upper airway [Wirth et al., Sleep 36, 699-708(2013); Kiper et al., Pflugers Arch. 467 ,1081-1090(2015)].

[0008] Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction. When inhaling, the patency of the upper airway is ensured by the interaction of two opposing forces. The dilation of the musculature of the upper airway counteracts the negative pressure in the cavity that causes the cavity to contract. The active contraction of the diaphragm and other auxiliary respiratory muscles creates negative pressure in the airway, which constitutes the driving force for breathing. The stability of the upper airway depends greatly on the coordination and contraction properties of the dilator muscles of the upper airway.

[0009] The genioglossus muscle plays a decisive role in the pathogenesis of OSA. In the sense of a dilation compensation mechanism, the activity of the genioglossus muscle increases as the intrapharyngeal pressure decreases. Innervated by the hypoglossal nerve, it drives the tongue forward and downward, thereby widening the pharyngeal airway [Verse et al., Somnologie 3 , 14-20 (1999)]. The tension of the dilator muscles of the upper respiratory tract is regulated in particular by means of mechanoreceptors / stretch receptors in the nasal cavity / pharynx [Brouillette et al., J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 49 , 772-779 (1979)]. In sleep patients with severe sleep apnea, additional reductions in genioglossus muscle activity were observed with local anesthesia of the upper airway [Berry et al., Am. J. Respir. Crit. Care Med. 156 , 127-132 (1997)]. OSA patients have high mortality and morbidity due to cardiovascular diseases such as hypertension, myocardial infarction and stroke [Vrints et al., Acta Clin.Belg. 68 ,169-178(2013)].

[0010] In the case of central sleep apnea, there is a paroxysmal suppression of the respiratory drive due to impaired brain function or impaired respiratory regulation. Central respiratory disorders cause mechanical respiratory arrest, i.e., there is no respiratory activity during these episodes; all respiratory muscles, including the diaphragm, are temporarily silent. In the case of central sleep apnea, there is no obstruction of the upper airway.

[0011] In the case of primary snoring, there is also no obstruction of the upper airway. However, due to the constriction of the upper airway, the flow rate of the inhaled and exhaled air increases. This combined with the relaxed muscle tissue causes the soft tissue of the oral cavity and pharynx to vibrate in the air flow. This slight vibration then produces the typical snoring noise.

[0012] Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This causes increased airway resistance and thus increased work of breathing, accompanied by significant fluctuations in intrathoracic pressure. During inspiration, the development of negative intrathoracic pressure can reach values ​​similar to those encountered due to complete airway obstruction during OSA. The pathophysiological consequences on the heart, circulation, and sleep quality are comparable to those of obstructive sleep apnea. As in OSA, it can be speculated that the pathogenesis is impaired reflex mechanisms of the pharyngeal dilator muscles during inspiration during sleep. Obstructive snoring is usually the primary stage of OSA [Hollandt et al., HNO 48 ,628-634(2000)].

[0013] The current therapeutic possibilities available for snoring and OSA are limited. Mixtures of surfactants intended to reduce upper airway resistance and snoring have been known since the 1980s [Widdicombe et al., Eur Resp J 1 , 785-791 (1988)]. These mixtures contain sodium chloride, glycerol, polysorbate 80, and benzalkonium chloride. From experiments in dogs, where these mixtures were administered by injection into the pharynx of dogs, it was concluded that these mixtures reduced upper airway resistance, increased genioglossus muscle activity during inspiration and expiration, and reduced snoring noise. OSA was not mentioned in Widdicombe's article, and upper airway collapse leading to apnea was not shown to be prevented in this model. Therefore, the model of Widdicombe and Davies does not predict OSA.

[0014] A composition based on glycerol, polysorbate 80, sodium chloride and 0.15% potassium sorbate (without benzalkonium chloride) is marketed as As a treatment for snoring. In a study at the University State Hospital in Copenhagen, the effect of polysorbate 80 on snoring was investigated in patients with Compared with nasal administration Effective in improving snoring. and without polysorbate 80 The effect of nasal application of and Polyglycoside 80on snoring and sleep apnoea,1989,[http: / / www.chrapat.sk / img / klinicka-dokumentacia.pdf].

[0015] WO-A 2012 / 010358 claims a pharmaceutical product comprising a container containing a liquid anti-snoring substance, wherein the container comprises a liquid outlet portion configured to deliver the liquid anti-snoring substance directly into the nasal passages in the form of a jet. The liquid anti-snoring substance is an anti-snoring solution comprising sodium chloride, glycerol, polysorbate and sodium ethylenediaminetetraacetate and optionally potassium sorbate as a preservative. WO-A 2012 / 010358 does not disclose a treatment for apnea or OSA. EP-B 2595685 describes the use of the substance for the treatment of snoring and respiratory arrest (apnea).

[0016] There are currently no pharmacological therapies for OSA. Surgery and oral devices have limited efficacy. The standard of care is therapy with a continuous positive airway pressure (CPAP) system. However, due to patient discomfort, compliance rates are only 50-70%, and the system is used for an average of no more than 4 hours per night.

[0017] Novel substances are known from WO-A 2017 / 097792 and WO-A 2017 / 097671, WO-A 2018 / 015196, EP 17176046.5 (unpublished) and PCT / CN2017 / 088237 (unpublished) which can be used as potent and selective TASK-1 and / or TASK-3 channel inhibitors, particularly suitable for the treatment and / or prevention of breathing disorders as such, including sleep-related breathing disorders, such as obstructive and central sleep apnea and snoring and other disorders. Therefore, the potent and selective TASK-1 and / or TASK-3 channel inhibitors disclosed therein represent an alternative to CPAP systems for the treatment of sleep-related breathing disorders, such as obstructive and central sleep apnea and snoring. Thus, potent and selective TASK-1 and / or TASK-3 channel inhibitors may improve patient compliance rates for the treatment and / or prevention of breathing disorders, including sleep-related breathing disorders such as obstructive and central sleep apnea and snoring, compared to the current standard of care (OSA therapy: CPAP system). To this end, such an alternative therapy should be simple and comfortable to use and should not disturb a person's sleep. Furthermore, such an alternative therapy should allow for an undisturbed night's sleep, require no repeated dosing, and require only a single daily dose at bedtime.

[0018] TASK-1 and / or TASK-3 channel inhibitors known from WO-A 2017 / 097792 and WO-A 2017 / 097671, WO-A 2018 / 015196, EP 17176046.5 (unpublished) and PCT / CN2017 / 088237 (unpublished) are active compounds that are sensitive to light, temperature and oxidation, and they undergo undesirable degradation during the preparation of the formulation and during storage in non-buffered aqueous solutions. In addition, the known effective and selective TASK-1 and / or TASK-3 channel inhibitors have poor solubility in water, which is insufficient to accommodate the amount of active ingredient required for pharmacological activity in a limited dosage amount (about 50 to 300 μl for nasal administration). The desired solubility can be achieved using solubilizing agents approved and / or known for nasal and pharyngeal routes of administration, such as co-solvents (e.g., polyethylene glycol 400 (PEG400)) or surfactants (e.g., polysorbate 80); however, despite the presence of known solubilizing agents, low dissolution rates of known potent and selective TASK-1 and / or TASK-3 channel inhibitors are observed in aqueous solutions, which results in significantly prolonged processing times during preparation and associated undesirable degradation of the active compounds used.

[0019] Aqueous formulations of potent and selective TASK-1 and / or TASK-3 channel inhibitors known from WO-A 2018 / 114501 and WO-A 2018 / 114503 contain polyethylene glycol 400 or glycerol, at least one auxiliary selected from pH regulators, at least one auxiliary selected from solubilizers, at least one auxiliary selected from stabilizers.

[0020] The disadvantages of the preparations described in the prior art which contain TASK-1 and / or TASK-3 channel inhibitors are that degradation products of the active compound may already be formed during the preparation process and undesirable discoloration may occur. In addition, the degradation of the active compound may increase during storage. In addition, the preparation of the preparation - even in small amounts of about 100 ml - takes a long time (>24 h) simply due to the insufficient solubility of the active compound.

[0021] Furthermore, the pharmacologically active substance for the treatment and / or prevention of respiratory disorders should be present in a pharmaceutical preparation which is considered to have a neutral taste, in particular also when pharmaceutical preparations comprising the pharmacologically active substance (verum) are compared with those not comprising any pharmacologically active substance (placebo).

[0022] The object of the present invention was therefore to provide an improved process for the preparation of stable aqueous formulations based on potent and selective TASK-1 and / or TASK-3 channel inhibitors for the treatment and / or prevention of breathing disorders, including sleep-related breathing disorders, such as obstructive and central sleep apnea and snoring, which process ensures sufficient stability of the active compound in the resulting aqueous formulation during preparation and storage and also allows the active compound to be dissolved in sufficiently high concentrations without any undesirably high time consumption during the preparation process.

[0023] Furthermore, it is another object of the present invention to provide aqueous formulations based on potent and selective TASK-1 and / or TASK-3 channel inhibitors for use in the treatment and / or prevention of breathing disorders, including sleep-related breathing disorders, such as obstructive and central sleep apnea and snoring, which aqueous formulations are considered to have a neutral taste.

[0024] Surprisingly, it has been found that when TASK-1 and / or TASK-1 channel inhibitors are pre-dissolved in surfactants (e.g., polysorbate 80) and / or cosolvents (e.g., PEG 400), the dissolution rate of potent and selective TASK-1 and / or TASK-3 channel inhibitors can be shortened, thereby significantly reducing the time to prepare aqueous formulations. Herein, it has also been found that when stabilizers are also pre-dissolved in a mixture of surfactants and / or cosolvents before adding TASK-1 and / or TASK-3 channel inhibitors, undesirable discoloration and degradation products during preparation and storage of the formulation can be avoided.

[0025] Another unexpected effect of the preparation according to the invention is that it can mask the taste of the surfactant and pharmacologically active substance components used by using a sweetener.

[0026] The present invention provides a method for preparing a stable pharmaceutical preparation, characterized in that:

[0027] In the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added as a solubilizer and / or PEG 400 is first added as a co-solvent, at least one antioxidant and a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof are dissolved therein, and then at least one pH adjuster, water and optionally glycerol, polyoxyethylene sorbitan fatty acid ester or PEG400 and optionally at least one sweetener are added, and the pH of the resulting solution is 6.8 to 8.2, preferably 6.8 to 7.8.

[0028] The present invention provides a pharmaceutical formulation obtainable by the process of the present invention.

[0029] In a preferred embodiment of the method of the present invention, at least one polyoxyethylene sorbitan fatty acid ester is first added as a solubilizer and / or PEG 400 is added as a co-solvent, then an antioxidant is added, and then a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof is dissolved therein.

[0030] In another preferred embodiment of the method of the present invention, first:

[0031] - preparing a primary solution (A) comprising at least one polyoxyethylene sorbitan fatty acid ester (polysorbate) and / or PEG 400 and at least one antioxidant, in a further step dissolving a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof in said mixture, and adding said mixture to the following solutions,

[0032] a solution (B) comprising at least one pH adjusting agent, water and optionally glycerol or PEG 400 and optionally at least one sweetener, the resulting solution having a pH of 6.8 to 8.2,

[0033] Preferred is 6.8 to 7.8.

[0034] Preferably, the addition of the primary solution (A) to the solution (B) is carried out within a period of 15 to 30 min, preferably within 30 min. The solution (B) can also be transferred into the pre-solution (A).

[0035] In a particularly preferred embodiment of the method of the present invention, in the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added, then an antioxidant is added, and then a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is dissolved therein, and then at least one pH regulator, optionally at least one sweetener and water are added.

[0036] In a very particularly preferred embodiment of the process according to the invention, in a first step, first at least one polyoxyethylene sorbitan fatty acid ester is added, then an antioxidant is added, subsequently a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is dissolved therein, and then at least one pH regulator, at least one sweetener and water are added.

[0037] In a likewise very particularly preferred embodiment of the process according to the invention, in a first step, firstly at least one polyoxyethylene sorbitan fatty acid ester is added, then an antioxidant is added, subsequently a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is dissolved therein, and then at least one pH regulator and water are added.

[0038] In another particularly preferred embodiment of the method according to the invention, in the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added, then an antioxidant is added, then a therapeutically effective amount of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone is dissolved, and then at least one pH adjuster, glycerol or PEG 400, optionally a sweetener and water are added.

[0039] In another particularly preferred embodiment of the method of the present invention, in the first step, PEG400 is first added, then an antioxidant is added, and then a therapeutically effective amount of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone is dissolved, and then at least one pH adjuster, at least one polyoxyethylene sorbitan fatty acid ester, an optional sweetener and water are added.

[0040] In another particularly preferred embodiment of the method of the present invention, in the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added, then an antioxidant is added, and then a therapeutically effective amount of (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone is dissolved, and then at least one pH adjuster, glycerol or PEG 400, at least one sweetener and water are added.

[0041] The pharmaceutical formulation of the present invention comprises at least one polyoxyethylene sorbitan fatty acid ester, at least one antioxidant and a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof, optionally glycerol or PEG 400 and optionally at least one sweetener, at least one pH adjuster and water, and the pH of the resulting solution is 6.8 to 8.2, preferably 6.8 to 7.8.

[0042] Preferably, the pharmaceutical formulation of the present invention comprises at least one polyoxyethylene sorbitan fatty acid ester (polysorbate) as a solubilizer and / or cosolvent, at least one antioxidant and a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, at least one sweetener, optionally at least one pH adjuster and water, and the pH of the resulting solution is 6.8 to 8.2, preferably 6.8 to 7.8.

[0043] Particularly preferably, the pharmaceutical formulation according to the invention comprises at least one polyoxyethylene sorbitan fatty acid ester (polysorbate) as a solubilizer and / or cosolvent, at least one antioxidant and a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, at least one sweetener, at least one pH regulator and water, the pH of the resulting solution being 6.8 to 8.2, preferably 6.8 to 7.8.

[0044] Particularly preferably, the pharmaceutical formulation according to the invention comprises at least one polyoxyethylene sorbitan fatty acid ester (polysorbate) as a solubilizer and / or cosolvent, at least one antioxidant and a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, optionally a sweetener, at least one pH regulator and water, the pH of the resulting solution being from 6.8 to 8.2, preferably from 6.8 to 7.8.

[0045] In one embodiment (A), the formulation of the invention comprises:

[0046] - 1 to 21% by weight of polyoxyethylene sorbitan fatty acid esters,

[0047] - 0.001 to 0.20% by weight of antioxidants,

[0048] - 0.002 to 0.10% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0049] - 0.3 to 25% by weight of glycerol, and

[0050] - 53.5 to 98% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0051] Preferably, the preparation (A) of the present invention comprises:

[0052] - 2.5 to 16% by weight of polyoxyethylene sorbitan fatty acid esters,

[0053] - 0.002 to 0.1% by weight of antioxidants,

[0054] - 0.005 to 0.07% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0055] - 1 to 12% by weight of glycerol, and

[0056] - 71 to 96% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0057] Very particularly preferably, the preparation (A) according to the invention comprises:

[0058] - 5 to 13% by weight of polyoxyethylene sorbitan fatty acid esters,

[0059] - 0.005 to 0.05% by weight of antioxidants,

[0060] - 0.006 to 0.06% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0061] - 2 to 6% by weight of glycerol, and

[0062] 80.5 to 92% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0063] In another embodiment (B), the formulation of the present invention comprises:

[0064] - 1 to 20% by weight of polyoxyethylene sorbitan fatty acid esters,

[0065] - 0.001 to 0.2% by weight of antioxidants,

[0066] - 0.002 to 0.10% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0067] - 3.0 to 60 wt. % PEG 400, and

[0068] - 19 to 95.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0069] Preferably, the preparation (B) of the present invention comprises

[0070] - 2.5 to 15% by weight of polyoxyethylene sorbitan fatty acid esters,

[0071] - 0.002 to 0.10% by weight of antioxidants,

[0072] - 0.005 to 0.07% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0073] - 6 to 36% by weight of PEG 400, and

[0074] - 48 to 91% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0075] Particularly preferably, the preparation (B) according to the invention comprises:

[0076] - 5 to 13% by weight of polyoxyethylene sorbitan fatty acid esters,

[0077] - 0.005 to 0.05% by weight of antioxidants,

[0078] - 0.006 to 0.06% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0079] - 12 to 23.5 wt. % PEG 400, and

[0080] - 63 to 82.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0081] Very particularly preferably, the preparations (A) and (B) according to the invention comprise 4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone as TASK-1 and / or TASK-3 channel inhibitor.

[0082] In another embodiment (C), the formulation of the present invention comprises:

[0083] - 1 to 21% by weight of polyoxyethylene sorbitan fatty acid esters,

[0084] - 0.001 to 0.2% by weight of antioxidants,

[0085] - 0.002 to 0.1% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0086] - 0.01 to 6% by weight of sweeteners, and

[0087] - 72 to 98.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0088] Preferably, the preparation (C) of the present invention comprises:

[0089] - 2.5 to 16% by weight of polyoxyethylene sorbitan fatty acid esters,

[0090] - 0.002 to 0.1% by weight of antioxidants,

[0091] - 0.005 to 0.07% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0092] - 0.02 to 1% by weight of sweeteners, and

[0093] 82.5 to 97% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0094] Particularly preferably, the preparation (C) according to the invention comprises:

[0095] - 5 to 13% by weight of polyoxyethylene sorbitan fatty acid esters,

[0096] - 0.005 to 0.05% by weight of antioxidants,

[0097] - 0.006 to 0.06% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0098] - 0.05 to 0.2% by weight of sweeteners, and

[0099] - 86 to 94% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0100] Very particularly preferably, the preparation (C) according to the invention comprises (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as TASK-1 and / or TASK-3 channel inhibitor.

[0101] In another embodiment (C'), the formulation of the invention comprises:

[0102] - 1.4 to 22.7% by weight of polyoxyethylene sorbitan fatty acid esters,

[0103] - 0.001 to 0.2% by weight of antioxidants,

[0104] - 0.002 to 0.1% by weight of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0105] - 0 to 4% by weight of sweeteners, and

[0106] - 73 to 98.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0107] Preferably, the formulation (C') of the present invention comprises:

[0108] - 2.9 to 15.8% by weight of polyoxyethylene sorbitan fatty acid esters,

[0109] - 0.002 to 0.1% by weight of antioxidants,

[0110] - 0.005 to 0.07% by weight of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0111] - 0.01 to 2% by weight of sweeteners, and

[0112] - 82 to 97% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0113] Particularly preferably, the preparation (C') according to the invention comprises:

[0114] - 5.4 to 13% by weight of polyoxyethylene sorbitan fatty acid esters,

[0115] - 0.005 to 0.05% by weight of antioxidants,

[0116] - 0.006 to 0.05% by weight of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0117] - 0.02 to 1% by weight of sweeteners, and

[0118] 85.9 to 94.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0119] In another embodiment (D), the formulation of the present invention comprises:

[0120] - 1 to 21% by weight of polyoxyethylene sorbitan fatty acid esters,

[0121] - 0.001 to 0.2% by weight of antioxidants,

[0122] - 0.002 to 0.1% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0123] - 0.3 to 25% by weight of glycerol,

[0124] - 0.01 to 5.5% by weight of sweeteners, and

[0125] - 48 to 98% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0126] Preferably, the preparation (D) of the present invention comprises:

[0127] - 2.5 to 16% by weight of polyoxyethylene sorbitan fatty acid esters,

[0128] - 0.002 to 0.1% by weight of antioxidants,

[0129] - 0.005 to 0.07% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0130] - 1 to 12% by weight of glycerol,

[0131] - 0.02 to 1% by weight of sweeteners, and

[0132] - 70 to 96% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0133] Particularly preferably, the preparation (D) according to the invention comprises:

[0134] - 5 to 13% by weight of polyoxyethylene sorbitan fatty acid esters,

[0135] - 0.005 to 0.05% by weight of antioxidants,

[0136] - 0.006 to 0.06% by weight of a therapeutically effective amount of at least one TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof,

[0137] - 2.5 to 6% by weight of glycerol,

[0138] - 0.05 to 0.3% by weight of sweeteners, and

[0139] 80 to 92% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

[0140] Very particularly preferably, the preparation (D) according to the invention comprises 4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone as TASK-1 and / or TASK-3 channel inhibitor.

[0141] Suitable polyoxyethylene sorbitan fatty acid esters of the present invention are, for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80. Polysorbate 80 is preferred.

[0142] Suitable antioxidants are, for example, butylated hydroxyanisole or butylated hydroxytoluene. Butylated hydroxyanisole is preferred.

[0143] Suitable sweeteners according to the invention are, for example, sucralose or sorbitol. Sucralose is preferred.

[0144] In a preferred embodiment, the antioxidant, preferably butylated hydroxyanisole, is present in pulverized form; particularly preferably, the diameter of the crystals is less than 1 mm.

[0145] In a preferred embodiment, the TASK-1 and / or TASK-3 channel inhibitor or its hydrate, solvate, polymorph or metabolite or pharmaceutically acceptable salt is present in a micronized form with an average particle size (x50 ) is 1 to 8 μm and the upper limit (x 90 ) is 20μm.

[0146] Preferably, a buffer solution selected from the group consisting of phosphate buffer, 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid (HEPES), 2-amino-2-(hydroxymethyl)propane-1,3-diol (TRIS) and 3-(N-morpholino)propanesulfonic acid (MOPS) is used.

[0147] Particularly preferably, the phosphate buffer solution comprises sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate and water and has a pH of 7.0.

[0148] Particularly preferably, the HEPES buffer solution comprises 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid and water, and is adjusted to pH 7.6 with aqueous sodium hydroxide solution.

[0149] Particularly preferably, the TRIS buffer solution comprises 2-amino-2-(hydroxymethyl)propane-1,3-diol and water, and is adjusted to pH 8.0 with hydrochloric acid.

[0150] Particularly preferably, the MOPS buffer solution comprises 3-(N-morpholino)propanesulfonic acid and water, adjusted to pH 7.5 with aqueous sodium hydroxide solution.

[0151] Very particularly preferably, the pH regulator is a phosphate buffer solution or 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid (HEPES).

[0152] The present invention provides a pharmaceutical preparation for nasal or pharyngeal administration obtainable by the method of the present invention.

[0153] The stable pharmaceutical formulation of the present invention may optionally contain other adjuvants.

[0154] Examples of auxiliaries in the context of the present invention are stabilizers, thickeners, preservatives, substances for adjusting tonicity, aromatic substances, fragrances or dyes.

[0155] In the context of the present invention, thickeners are, for example, natural rubber, alginic acid, pectin, starch and starch derivatives, gelatin, poloxamers (polyoxypropylene / polyoxyethylene block copolymers), cellulose derivatives, acrylic acid polymers or vinyl polymers.

[0156] In the context of the present invention, an active ingredient is defined as a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or metabolite thereof or a pharmaceutically acceptable salt thereof.

[0157] The stable pharmaceutical formulations of the present invention are, for example, those formulations, wherein the at least one TASK-1 and / or TASK-3 channel inhibitor is selected from compounds of formula (I) and salts thereof, solvates and solvates of salts thereof described in WO 2017 / 097671, WO 2017 / 097792, WO 2018 / 015196 and EP17176046.5 and PCT / CN2017 / 088237. The synthesis of these compounds is described in WO 2017 / 097792.

[0158] Preferred compounds of formula (I) are selected from Table 1 Compounds:

[0159] From WO 2017 / 097671, WO 2017 / 097792, WO 2018 / 015196, and

[0160] Compounds of EP17176046.5 and PCT / CN2017 / 088237 and hydrates, solvates, polymorphs or metabolites thereof, or pharmaceutically acceptable salts thereof.

[0161]

[0162]

[0163]

[0164] Particularly preferred are compounds selected from the following compounds, and hydrates, solvates, polymorphs or metabolites thereof, or pharmaceutically acceptable salts thereof.

[0165]

[0166]

[0167] Very particular preference is given to compounds selected from the group consisting of the following compounds, and hydrates, solvates, polymorphs or metabolites thereof, or pharmaceutically acceptable salts thereof.

[0168]

[0169]

[0170] The stable pharmaceutical formulations according to the invention are also those wherein the at least one TASK-1 and / or TASK-3 channel inhibitor is selected from the group consisting of:

[0171] (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone and / or (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone and their hydrates, solvates, polymorphs or metabolites or pharmaceutically acceptable salts thereof.

[0172] Stable pharmaceutical formulations according to the invention are also those wherein the at least one TASK-1 and / or TASK-3 channel inhibitor is (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone.

[0173] The stable pharmaceutical formulations of the present invention are also those in which the at least one TASK-1 and / or TASK-3 channel inhibitor is (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone.

[0174] Another embodiment of the present invention is a stable pharmaceutical formulation according to the present invention for nasal or pharyngeal administration for the treatment and / or prevention of diseases.

[0175] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for the treatment and / or prevention of breathing disorders, sleep-related breathing disorders, obstructive sleep apnea, central sleep apnea, snoring, arrhythmias, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmune diseases.

[0176] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for use in a method for the treatment and / or prevention of breathing disorders, sleep-related breathing disorders, obstructive sleep apnea, central sleep apnea, snoring, cardiac arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmune diseases, wherein the nasal or pharyngeal administration is assisted by nasal sprays, nasal drops, nasal solutions, powder inhalers, nebulizers, metered sprays or semisolid gels.

[0177] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for the treatment and / or prevention of breathing disorders, sleep-related breathing disorders, obstructive sleep apnea, central sleep apnea, snoring, arrhythmias, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmune diseases.

[0178] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for the treatment and / or prevention of breathing disorders, sleep-related breathing disorders, obstructive sleep apnea, central sleep apnea, snoring, arrhythmias, cardiac arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmune diseases.

[0179] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for treating and / or preventing obstructive sleep apnea or snoring, the pharmaceutical formulation comprising:

[0180] A therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone or (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3 .2.1] oct-8-yl)methanone and / or its hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof in 1.0 to 21 wt % of polysorbate 80, 0.001 wt % to 0.2 wt % of butylated hydroxyanisole and at least one other auxiliary agent, which are dissolved in a phosphate or HEPES buffer solution with a substance concentration of 25 to 200 mM, and the pH of the preparation is adjusted to 6.8 to 8.2.

[0181] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for treating and / or preventing obstructive sleep apnea or snoring, the pharmaceutical formulation comprising:

[0182] A therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone and / or its hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof is dissolved in 1.0 to 21 wt % of polysorbate 80, 0.001 wt % to 0.2 wt % of butylated hydroxyanisole, 0.3 to 24.5 wt % of glycerol and at least one other auxiliary agent, which is dissolved in a phosphate or HEPES buffer solution with a substance concentration of 25 to 200 mM, and the pH of the preparation is adjusted to 6.8 to 8.2, preferably 6.8 to 7.8.

[0183] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for treating and / or preventing obstructive sleep apnea or snoring, the pharmaceutical formulation comprising:

[0184] A therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone and / or its hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof is dissolved in 1.0 to 21 wt % of polysorbate 80, 0.001 wt % to 0.2 wt % of butylated hydroxyanisole, 3 to 60 wt % of PEG 400 and at least one other auxiliary agent, which is dissolved in a phosphate or HEPES buffer solution with a substance concentration of 25 to 200 mM, and the pH of the preparation is adjusted to 6.8 to 8.2, preferably 6.8 to 7.8.

[0185] Another embodiment of the present invention is a stable pharmaceutical formulation of the present invention for nasal or pharyngeal administration for use in a method for treating and / or preventing obstructive sleep apnea or snoring, the pharmaceutical formulation comprising:

[0186] A therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone and / or its hydrate, solvate, polymorph or metabolite or a pharmaceutically acceptable salt thereof in 1.0 to 21% by weight of polysorbate 80, 0.001% to 0.2% by weight of butylated hydroxyanisole, 0.05 to 0.25% by weight of sucralose and at least one other auxiliary agent, which is dissolved in a phosphate or HEPES buffer solution with a substance concentration of 25 to 200 mM, and the pH of the preparation is adjusted to 6.8 to 8.2, preferably 6.8 to 7.8.

[0187] The preparations of the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. Therefore, the present invention also provides a medicament comprising at least one preparation of the invention and one or more other active ingredients, which is particularly useful for treating and / or preventing the above-mentioned diseases. Preferred examples of combined active ingredients suitable for this purpose include:

[0188] respiratory stimulants, for example and preferably theophylline, doxapram, Nikethamide or caffeine;

[0189] Psychostimulant compounds, for example and preferably Modafinil or Armodafinil;

[0190] Amphetamine and amphetamine derivatives, for example and preferably amphetamine or methylphenidate;

[0191] Serotonin reuptake inhibitors, for example and preferably fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone;

[0192] a serotonin precursor, for example and preferably L-tryptophan;

[0193] - a selective serotonin norepinephrine reuptake inhibitor, for example and preferably venlafaxine or duloxetine;

[0194] Noradrenergic and specifically serotonergic antidepressants, for example and preferably mirtazapine;

[0195] - Selective norepinephrine reuptake inhibitors, for example and preferably reboxetine;

[0196] tricyclic antidepressants, for example and preferably amitriptyline, protriptyline, doxepine, trimipramine, imipramine, clomipramine or desipramine;

[0197] α2-adrenergic agonists, for example and preferably clonidine;

[0198] GABA agonists, for example and preferably Baclofen;

[0199] alpha sympathomimetics, for example and preferably xylometazoline, oxymetazoline, phenylephrine, naphazoline, tetrahydrozoline or tramazoline;

[0200] Glucocorticoids, for example and preferably Fluticasone, Budesonide, Beclometasone, Mometasone, Tixocortol or Triamcinolone;

[0201] Cannabinoid receptor agonists;

[0202] Carboanhydrase inhibitors, for example and preferably acetazolamide, methazolamide or diclofenamide;

[0203] Opioid and benzodiazepine receptor antagonists, for example and preferably Flumazenil, Naloxone or Naltrexone;

[0204] - cholinesterase inhibitors, for example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or rivastigmine;

[0205] N-methyl-D-aspartate and glutamate antagonists, for example and preferably Amantadine, Memantine or Sabeluzole;

[0206] Nicotinic receptor agonists;

[0207] Leukotriene receptor antagonists, for example and preferably Montelukast or Tripelukast;

[0208] dopamine receptor antagonists, for example and preferably dromperidon, metoclopramide or benzamide-, butyrophenone- or phenothiazine-derivatives;

[0209] Appetite suppressants, for example and preferably Topiramate, Phentermine, lipase inhibitors or cannabinoid receptor antagonists;

[0210] proton pump inhibitors, for example and preferably pantoprazole, omeprazole, esomeprazole, lansoprazole or rabeprazole;

[0211] Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine, or SIN-1, and inhaled NO;

[0212] Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors, such as Sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil;

[0213] NO- and heme-independent soluble guanylate cyclase (sGC) activators, such as, in particular, the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;

[0214] NO-independent but heme-dependent soluble guanylate cyclase (sGC) stimulators, such as, in particular, Riociguat, Vericiguat, and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549;

[0215] Prostacyclin analogs and IP receptor agonists, for example and preferably Iloprost, Beraprost, Treprostinil, Epoprostenol or Selexipag;

[0216] - Endothelin receptor antagonists, for example and preferably Bosentan, Darusentan, Ambrisentan or Sitaxsentan;

[0217] Compounds which inhibit human neutrophil elastase (HNE), for example and preferably Sivelestat or DX-890 (Reltran);

[0218] Compounds which inhibit the degradation and modification of the extracellular matrix, for example and preferably inhibitors of matrix metalloproteinases (MMPs), in particular inhibitors of matrilysins, collagenases, gelatinases and aggrecanases (in the present context in particular MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and metalloelastase (MMP-12);

[0219] Compounds that block the binding of serotonin to its receptors, such as and preferably 5-HT 2B Receptor antagonists, such as PRX-08066;

[0220] Antagonists of growth factors, cytokines and chemokines, for example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

[0221] Rho kinase inhibiting compounds, for example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

[0222] Compounds which influence cardiac energy metabolism, for example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

[0223] Compounds which inhibit the signal transduction cascade, for example and preferably selected from kinase inhibitors, in particular from tyrosine kinase and / or serine / threonine kinase inhibitors, for example and preferably Nintedanib, Dasatinib, Nilotinib, Bosutinib, Regorafenib, Sorafenib, Sunitinib, Cediranib, Axitinib, Telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, or tandutinib;

[0224] anti-obstructive agents, for example for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably selected from inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics) and inhaled anti-muscarinic substances;

[0225] anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, for example and preferably selected from systemically or inhaled corticosteroids and dimethyl fumarate, fingolimod, glatiramer acetate, beta-interferon, natalizumab, teriflunomide, mitoxantrone, immunoglobulins, acetylcysteine, Montelukast, Tripelukast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, interferon-gamma, pirfenidone or etanercept;

[0226] Antifibrotic agents, for example and preferably lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β antagonists or pirfenidone;

[0227] antithrombotic agents, for example and preferably selected from the group consisting of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;

[0228] blood pressure lowering active ingredients, for example and preferably selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha blockers, beta blockers, mineralocorticoid receptor antagonists and diuretics; and / or

[0229] Active ingredients which alter fat metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymerized bile acids Adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.

[0230] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a beta-adrenergic receptor agonist, for example and preferably albuterol, isoproterenol, metaproterenol, terbutalin, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0231] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an antimuscarinic substance, for example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0232] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a corticosteroid, for example and preferably Prednisone, Prednisolone, Methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone, Beclomethasone, Flunisolide, Budesonide or Fluticasone.

[0233] Antithrombotic agents are preferably understood to mean compounds selected from the group consisting of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

[0234] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

[0235] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a thrombin inhibitor, for example and preferably Ximelagatran, Melagatran, Dabigatran, Bivalirudin or Clexane.

[0236] In a preferred embodiment of the invention, the preparation according to the invention is administered in combination with a GPIIb / IIIa antagonist, such as for example and preferably Tirofiban or Abciximab.

[0237] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a factor Xa inhibitor, for 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.

[0238] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[0239] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a vitamin K antagonist, such as for example and preferably coumarin.

[0240] Antihypertensives are preferably understood to mean compounds selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

[0241] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0242] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an alpha-1 receptor blocker, such as for example and preferably prazosin.

[0243] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a beta-blocker, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, razalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol, or bucindolol.

[0244] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an angiotensin AII antagonist, for example and preferably Losartan, Candesartan, Valsartan, Telmisartan or Embusartan.

[0245] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an ACE inhibitor, for example and preferably Enalapril, Captopril, Lisinopril, Ramipril, Delapril, Fosinopril, Quinopril, Perindopril or Trandopril.

[0246] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an endothelin antagonist, for example and preferably Bosentan, Darusentan, Ambrisentan or Sitaxsentan.

[0247] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a renin inhibitor, for example and preferably Aliskiren, SPP-600 or SPP-800.

[0248] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as for example and preferably spironolactone, eplerenone or Finerenon.

[0249] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a diuretic, for example and preferably Furosemide, Bumetanide, Torsemide, Bendroflumethiazide, Chlorothiazide, Hydrochlorothiazide, Hydroflumethiazide, Methyclothiazide, Polythiazide, Trichlormethiazide, Chlorthalidone, Indapamide, Metolazone, Quinethazone, Acetazolamide, Dichlorphenamide, Methazolamide, Glycerolin, Isosorbide, Mannitol, Amiloride or Triamterene.

[0250] Lipid metabolism regulators are preferably understood to mean compounds selected from the group consisting of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

[0251] In a preferred embodiment of the invention, the preparation according to the invention is administered in combination with a CETP inhibitor, for example and preferably Torcetrap (CP-529 414), JJT-705 or a CETP vaccine (Avant).

[0252] In a preferred embodiment of the invention, the preparation according to the invention is administered in combination with a thyroid receptor agonist, for example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or Axitirome (CGS26214).

[0253] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an HMG-CoA reductase inhibitor selected from the group consisting of statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0254] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a squalene synthesis inhibitor, such as for example and preferably BMS-188494 or TAK-475.

[0255] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with an ACAT inhibitor, for example and preferably Avasimibe, Melinamide, Pactimibe, Eflucimibe or SMP-797.

[0256] In a preferred embodiment of the invention, the preparations 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.

[0257] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a PPAR-gamma agonist, such as for example and preferably pioglitazone or rosiglitazone.

[0258] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a PPAR-delta agonist, such as for example and preferably GW501516 or BAY 68-5042.

[0259] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a cholesterol absorption inhibitor, such as for example and preferably ezetimibe, tiqueside or pamaqueside.

[0260] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a lipase inhibitor, such as for example and preferably orlistat.

[0261] In a preferred embodiment of the invention, the preparations according to the invention are administered in combination with a polymeric bile acid adsorbent, for example and preferably Cholestyramine, Colestipol, Colesolvam, CholestaGel or Colestimid.

[0262] In a preferred embodiment of the invention, the preparation according to the invention is administered in combination with a bile acid reabsorption inhibitor, for example and preferably an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0263] In a preferred embodiment of the invention, the preparation according to the invention is administered in combination with a lipoprotein(a) antagonist, such as for example and preferably Gemcabene calcium (CI-1027) or niacin.

[0264] Particularly preferred are combinations of the preparations according to the invention with one or more further active substances selected from the group consisting of respiratory stimulants, psychostimulants, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulants, mineralocorticoid receptor antagonists, anti-inflammatory agents, immunomodulators, immunosuppressants and cytotoxic agents.

[0265] If necessary, the preparations according to the invention can also be used in combination with one or more medical technology devices or auxiliary devices, as long as this does not cause undesirable and unacceptable side effects. Suitable medical devices and auxiliary devices for such combined use are, for example and preferably:

[0266] Devices for positive airway pressure ventilation, such as and preferably CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Biphasic Positive Airway Pressure) devices and IPPV (Intermittent Positive Airway Pressure) devices;

[0267] Neurostimulator for the hypoglossal nerve;

[0268] Intraoral aids, for example and preferably protrusion splints;

[0269] Disposable nasal valve;

[0270] Nose supporter.

[0271] In one embodiment, in the case of nasal administration, the dosage is about 0.1 μg to 500 μg per day. In another embodiment, in the case of nasal administration, the dosage is about 1 μg to 250 μg per day. In another embodiment, in the case of nasal administration, the dosage is about 1 μg to 100 μg per day. In another embodiment, a dosage of about 0.1 μg to 500 μg per day, or about 1 μg to 250 μg per day, or about 1 μg to 100 μg per day is administered by the nasal route once a day before bedtime. In one embodiment, a dosage of about 0.1 μg to 500 μg per day, or about 1 μg to 250 μg per day, or about 1 μg to 100 μg per day is administered once a day, half in each nostril. In one embodiment, a dosage of about 0.1 μg to 500 μg per day, or about 1 μg to 250 μg per day, or about 1 μg to 100 μg per day is administered once a day before bedtime, half in each nostril.

[0272] However, in some cases it may be necessary to deviate from the stated amounts, in particular depending on body weight, route of administration, individual response to the active ingredient, properties of the formulation and time or interval of administration. It may therefore be sufficient to administer less than the above minimum amount in some cases, while in other cases it may be necessary to exceed the upper limit mentioned. If larger amounts are administered, it may be advisable to divide them into several single doses over the day. Example

[0273] List of abbreviations

[0274]

[0275]

[0276] HPLC method

[0277] Method 1 (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxy Pyridin-2-yl)methanone

[0278] Undiluted samples were analyzed by reverse phase HPLC on a Hewlett-Packard / Agilent HPLC and UHPLC instrument (DE). 2.0 μl of the sample solution was then applied to a stainless steel metal column, such as Agilent Eclipse PlusRRHD C18 (150 mm x 3.0 mm, particle size 1.8 μm), which was maintained at a temperature of 25° C. (flow rate 0.5 ml / min).

[0279] The samples were analyzed using a B gradient of 10-45% (v / v) in 10 min, followed by 45-80% (v / v) in 5 min, and then 80% (v / v) in 5 min. The mobile phase consisted of solvent A (H2O containing 1 ml of trifluoroacetic acid) and solvent B (acetonitrile; Riedel-de DE, containing 1 ml of trifluoroacetic acid). The preparation was checked by external standard method (ESTD) using UV detector at 238 nm.

[0280] Method 2 (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine- 3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone

[0281] The sample is diluted with a mixture of water and methanol and then analyzed by reverse phase HPLC on a Hewlett-Packard / Agilent HPLC or UHPLC instrument (DE). 3.0 μl of the sample solution is then applied to a stainless steel metal column, such as Waters Acquity UPLC HSS T3 (50 mm x 2.1 mm, particle size 1.8 μm), which is maintained at a temperature of 40° C. (flow rate 10 ml / min).

[0282] The samples were analyzed using a B gradient of 5-30% (v / v) in 2.5 min, followed by 30-50% (v / v) in 5.5 min, followed by 50-80% (v / v) in 1 min, and then 80% (v / v) in 1 min, with the mobile phase consisting of solvent A (0.77 g ammonium acetate / 1 l H2O, pH adjusted to about 9 with ammonia) and solvent B (acetonitrile; Riedel-de The content and area percentage of degradation products of the formulations were checked by external standard method (ESTD) using a UV detector at 220 nm.

[0283] Method 3 (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine- 3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone

[0284] The sample is diluted with a mixture of water and acetonitrile and then analyzed by reverse phase HPLC on a Hewlett-Packard / Agilent HPLC or UHPLC instrument (DE). 4.0 μl of the sample solution is then applied to a stainless steel metal column, such as Waters Acquity UPLC BEH Phenyl (100 mm x 2.1 mm, particle size 1.7 μm), which is maintained at a temperature of 50° C. (flow rate 0.5 ml / min).

[0285] The samples were analyzed using a B gradient of 5-51% (v / v) in 10 min, followed by 51-68% (v / v) in 7 min, followed by 68-90% (v / v) in 3 min, and then 90% (v / v) in 10 min, wherein the mobile phase consisted of solvent A (114 mg ammonium acetate and 0.49 ml glacial acetic acid / 1 l H2O, pH about 4) and solvent B (acetonitrile; Riedel-de The preparation was checked by external standard method (ESTD) using UV detector at 238 nm.

[0286] Example of preparation sequence

[0287] Example 1 Adding (primary solution A) to B) (present invention)

[0288] For the amphiphilic phase, a suitable container is selected that allows stirring with a magnetic stirring bar or a blade stirrer at a stirring speed of 200 to 300 rpm. First, 10% by volume of polysorbate 80 (accounting for the total material to be prepared) is charged into the container. Subsequently, 0.02% (weight / volume) of butylated hydroxyanisole (BHA) is added under stirring and dissolved. By pre-crushing BHA in a mortar, the dissolution time can be significantly reduced. Only after the BHA is completely dissolved, 0.015% (weight / volume) of micronized active compound (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazine-1-yl)(6-methoxypyridin-2-yl)methanone is added under stirring.

[0289] Prepare the aqueous phase in another container that is large enough to hold the entire batch and must also be equipped with a stirrer. Start by adding about 70% of the desired WFI. Dissolve the buffer salts disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total 0.063 mM phosphate, pH 7.0) under stirring at 200 to 300 rpm. Once the buffer salts are completely dissolved, add 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2, 3, 4 ), and stir the mixture until homogeneous.

[0290] When the active compound is completely dissolved in the amphiphilic phase, the amphiphilic phase is added to the aqueous phase within 30 minutes.

[0291] The container for the amphiphilic phase was rinsed 3 times with WFI to ensure that the transfer of the amphiphilic phase was quantitative. The pH of the overall preparation was then adjusted to 6.8 to 7.2 using 10% HCl or 1 N NaOH if necessary.

[0292] The entire formulation was then made up to final mass using WFI.

[0293] Embodiment 2 (present invention)

[0294] For the amphiphilic phase, a suitable container is selected that allows stirring with a magnetic stirring bar or a blade stirrer at a stirring speed of 200 to 300 rpm and is large enough to accommodate the entire batch. The container is first charged with 10% by volume of polysorbate 80 (of the total material to be prepared). Subsequently, 0.02% (weight / volume) of BHA is added under stirring and allowed to dissolve. The dissolution time can be significantly reduced by pre-crushing the BHA in a mortar. Only after the BHA is completely dissolved, 0.015% (weight / volume) of the micronized active compound (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazine-1-yl)(6-methoxypyridin-2-yl)methanone is added under stirring.

[0295] Prepare the aqueous phase in another container, which must also be equipped with a stirrer. Start by adding about 70% of the desired WFI. Dissolve the buffer salts disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total 0.063 mM phosphate, pH 7.0) under stirring at 200 to 300 rpm. Once the buffer salts are completely dissolved, add 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2 ), and stir the mixture until homogeneous.

[0296] When the active compound is completely dissolved in the amphiphilic phase, the entire aqueous phase is added to the amphiphilic phase within 30 minutes.

[0297] If necessary, adjust the pH to 6.8 to 7 using 10% HCl or 1 N NaOH.

[0298] The entire formulation was then made up to final mass using WFI.

[0299] Example 3 (Comparative Example)

[0300] First, about 70% of the required WFI is charged into a suitable container that is large enough to hold the entire batch and allows stirring using a magnetic stir bar or blade stirrer at a stirring speed of 200 to 300 rpm. Under stirring, the buffer salts of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total amount of 0.063 mM phosphate, pH 7.0) are introduced into the container. Once the buffer salts are completely dissolved, 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2, 3, 4) and the mixture was stirred until homogeneous. Subsequently, 10% by volume of polysorbate 80 was added under stirring over a period of 30 minutes. Once the polysorbate was completely dissolved, 0.02% (weight / volume) of BHA was added and allowed to dissolve. The dissolution time can be significantly reduced by pre-crushing the BHA in a mortar. Only after the BHA was completely dissolved, 0.015% (weight / volume) of micronized active compound (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazine-1-yl)(6-methoxypyridin-2-yl)methanone was added under stirring. After the active compound was also completely dissolved, if necessary, the pH of the overall formulation was adjusted to 6.8 to 7.2 using 10% concentration of HCl or 1N NaOH.

[0301] The entire formulation was then made up to final mass using WFI.

[0302] Embodiment 4 (present invention)

[0303] First, 20% by volume of PEG 400 (see Table 2 ) is loaded into a suitable container that is large enough to accommodate the entire material of the batch and allows stirring using a magnetic stirring bar or a blade stirrer at a stirring speed of 200 to 300 rpm. 0.02% (weight / volume) of BHA is added to the container under stirring and dissolved. The dissolution time can be significantly reduced by pre-crushing the BHA in a mortar. Subsequently, 0.015% (weight / volume) of micronized active compound (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazine-1-yl)(6-methoxypyridin-2-yl)methanone is added under stirring. Once the active compound is also completely dissolved, about 70% of the required WFI is added and the mixture is stirred until uniform. Subsequently, the buffer salts disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total amount of 0.063mM phosphate, pH 7.0) are dissolved. Then 10% by volume of polysorbate 80 was added with stirring over a period of 30 minutes. Once the polysorbate was also completely dissolved, the pH of the overall formulation was adjusted to 6.8 to 7.2 using 10% HCl or 1 N NaOH if necessary.

[0304] The entire formulation was then made up to final mass using WFI.

[0305] Embodiment 5 (present invention)

[0306] First, 10% by volume of polysorbate 80 is charged to a suitable container that is large enough to hold the entire batch and allows stirring using a magnetic stir bar or blade stirrer at a stirring speed of 200 to 300 rpm. 0.02% (weight / volume) of BHA is added to the container under stirring and allowed to dissolve. By pre-crushing the BHA in a mortar, the dissolution time can be significantly reduced. Subsequently, 0.015% (weight / volume) of micronized active compound (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone is added under stirring. Once the active compound is also completely dissolved, 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2 ) and the mixture is stirred until homogeneous. Subsequently, about 70% of the required WFI is added. Once a homogeneous solution is formed, the buffer salts of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total amount of 0.063 mM phosphate, pH 7.0) are added under stirring. Once the buffer salts are also dissolved, if necessary, the pH of the overall formulation is adjusted to 6.8 to 7.2 using 10% concentration HCl or 1N NaOH.

[0307] The entire formulation was then made up to final mass using WFI.

[0308] Embodiment 6 (present invention)

[0309] First, 10% by volume of polysorbate 80 is charged into a suitable container that is large enough to hold all the materials of the batch and allows stirring using a magnetic stirring bar or a blade stirrer at a stirring speed of 200 to 300 rpm. 0.02% (weight / volume) of BHA is added to the container under stirring and allowed to dissolve. The dissolution time can be significantly reduced by pre-crushing the BHA in a mortar. Then 0.015% (weight / volume) of micronized active compound is added under stirring. Once the active compound is also completely dissolved, about 70% of the required WFI is added and the mixture is stirred until uniform. Subsequently, the buffer salts disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total amount of 0.063mM phosphate, pH 7.0) are added and dissolved. Then 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2, 3, 4 ) and the mixture is stirred again until homogeneous. Once the buffer salts are also dissolved, check the pH of the entire preparation. If the pH is not between 6.8 and 7.2, readjust it with 10% HCl or 1N NaOH.

[0310] The entire formulation was then made up to final mass using WFI.

[0311] Example 7 (Comparative Example)

[0312] First, 10% by volume of polysorbate 80 is charged into a suitable container that is large enough to hold all the materials of the batch and allows stirring using a magnetic stir bar or blade stirrer at a stirring speed of 200 to 300 rpm. 0.015% (weight / volume) of the micronized active compound is added to this container under stirring. Once the active compound is completely dissolved, about 70% of the required WFI is added. Once a homogeneous solution is formed, the buffer salts of disodium hydrogen phosphate and sodium dihydrogen phosphate dihydrate (total amount of 0.063 mM phosphate, pH 7.0) are added under stirring. Then 2.5% by volume of glycerol or 20% by volume of PEG 400 (see Table 2, 3, 4 ) and the mixture was stirred again until homogeneous. Subsequently, 0.02% (w / v) BHA was added under stirring and allowed to dissolve. The dissolution time can be significantly reduced by pre-crushing the BHA in a mortar. Once the BHA is also dissolved, check the pH of the overall formulation. If the pH is not between 6.8 and 7.2, readjust it with 10% HCl or 1N NaOH.

[0313] The entire formulation was then made up to final mass using WFI.

[0314] Table 2:

[0315] Active compounds used: (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone

[0316]

[0317] *Comparative Example

[0318] For other embodiments of the method of the present invention, preparation examples 1, 3, 6 and 7 were performed to evaluate the preparation time. Two methods of the present invention were experimented according to examples 1 and 6 and comparative examples 3 and 7. In each case, sucralose was added after the addition of the buffer salt.

[0319] Table 3:

[0320] Active compound used: (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazine-1- 2-(6-methoxypyridin-2-yl)methanone

[0321]

[0322] Table 4:

[0323] Active compounds used:(3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone

[0324]

Claims

1. A method for preparing a stable pharmaceutical preparation, characterized in that: In the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added as a solubilizer and / or PEG 400 is first added as a co-solvent, at least one antioxidant and a therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof are dissolved therein, and then at least one pH adjuster, water and optionally glycerol, polyoxyethylene sorbitan fatty acid ester or PEG400 and optionally at least one sweetener are added, and the pH of the resulting solution is 6.8 to 8.2, Wherein, the TASK-1 and / or TASK-3 channel inhibitor is (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone.

2. The method according to claim 1, characterized in that: First, at least one polyoxyethylene sorbitan fatty acid ester is added as a solubilizer and / or PEG 400 is added as a co-solvent, then an antioxidant is added, and then a therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof is dissolved therein.

3. The method according to claim 1, characterized in that: first - preparing a primary solution (A) comprising at least one polyoxyethylene sorbitan fatty acid ester (polysorbate) and / or PEG 400 and at least one antioxidant, in a further step dissolving a therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof in said mixture, and adding said mixture to the following solutions, - a solution (B) comprising at least one pH adjusting agent, water and optionally glycerol or PEG 400 and optionally at least one sweetener, the resulting solution having a pH of 6.8 to 8.

2.

4. The method according to claim 1, characterized in that: In the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added, then an antioxidant is added, and then a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is dissolved therein, and then at least one pH adjuster, at least one sweetener and water are added.

5. The method according to claim 1, characterized in that: In the first step, at least one polyoxyethylene sorbitan fatty acid ester is first added, then an antioxidant is added, and then a therapeutically effective amount of (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is dissolved therein, and then at least one pH adjuster and water are added.

6. A pharmaceutical preparation obtained according to any one of claims 1 to 5.

7. The pharmaceutical preparation according to claim 6, characterized in that It contains: - 1 to 21% by weight of polyoxyethylene sorbitan fatty acid esters, - 0.001 to 0.2% by weight of antioxidants, - 0.002 to 0.1% by weight of a therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof, - 0.01 to 6% by weight of sweeteners, and - 72 to 98.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

8. The pharmaceutical preparation according to claim 6, characterized in that It contains: - 1.4 to 22.7% by weight of polyoxyethylene sorbitan fatty acid esters, - 0.001 to 0.2% by weight of antioxidants, - 0.002 to 0.1% by weight of a therapeutically effective amount of a TASK-1 and / or TASK-3 channel inhibitor or a hydrate, solvate, polymorph or pharmaceutically acceptable salt thereof, - 0 to 4% by weight of sweeteners, and - 73 to 98.5% by weight of a buffer solution with a substance concentration of 25 to 200 mM.

9. The pharmaceutical preparation according to any one of claims 1 to 8, which is used for nasal or pharyngeal administration for the treatment and / or prevention of diseases.

10. A pharmaceutical formulation according to any one of claims 1 to 8 for nasal or pharyngeal administration for use in a method for the treatment and / or prevention of breathing disorders, sleep-related breathing disorders, obstructive sleep apnea, central sleep apnea, snoring, arrhythmias, arrhythmias, neurodegenerative diseases, neuroinflammatory diseases and neuroimmune diseases.

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