Method for preventing, ameliorating, or treating sleep disorders and / or sleep disorder-related diseases

Abstract

An aspect of the present invention relates to a method for ameliorating, preventing, or treating sleep disorders and / or sleep disorder-related diseases with an increased risk of onset in sleep disorder patients, the method comprising a step of administering to a subject with sleep disorder a therapeutically effective amount of a norepinephrine selective reuptake inhibitor (NSRI) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an antiplatelet agent.

Description

Methods for preventing, improving, or treating sleep disorders and / or sleep disorder-related diseases The present invention relates to a composition, pharmaceutical composition, or combination comprising a norepinephrine selective reuptake inhibitor (NSRI) or a pharmaceutically acceptable salt thereof and an antiplatelet agent; uses thereof; and kits comprising the same. The composition, pharmaceutical composition, or combination has the effect of preventing, improving, or treating sleep disorders and / or sleep disorder-related diseases (e.g., hypertension, dementia, etc.) in a subject. Sleep disorders are a common condition characterized by alterations in the sleep-wake cycle, affecting approximately 20% of the population. Sleep disorders are also observed in children aged 3 to 6, as well as adults. Meanwhile, partial obstruction of the airway during sleep causes snoring, and repeated episodes of apnea (lasting about 20 to 30 seconds at a time) or hypopnea due to complete obstruction of the airway during sleep are classified as obstructive sleep apnea (OSA). Apnea or hypopnea during sleep cause hypoxia, which causes the body to temporarily awaken and tense muscles to try to remove the respiratory impediment. These temporary awakenings can occur hundreds of times during sleep. Therefore, patients with OSA repeatedly experience hypoxia, sleep fragmentation, arousals, and sympathetic nervous system stimulation during sleep. Furthermore, OSA causes various symptoms such as daytime fatigue, drowsiness, decreased concentration, and memory impairment, which interfere with daily life; decreased libido or erectile dysfunction; and cardiovascular complications such as hypertension, arrhythmia, and cardiac ischemia. When analyzing the results of polysomnography for patients with sleep apnea, it is confirmed that in most cases, the oxygen saturation is low, below 85%, or even in the 70% range, indicating that hypoxia has occurred. In addition, drug-resistant hypertension and congestive heart failure were observed in 80% of OSA patients, type 2 diabetes was observed in 72% of OSA patients, and atrial fibrillation, hypertension, coronary artery disease (CAD), and angina were also reported to be observed in a significant number of OSA patients (JH Kim et al., Journal of Clinical Sleep Medicine, vol. 9, No. 10, 2013). Furthermore, OSA patients are known to have a high risk of developing cardiovascular disease and metabolic syndrome. The prevalence of OSA in Korean men is 4.5%, and in Korean women it is 3.2%, making OSA a very common sleep disorder. In the past, anatomical causes such as structural problems of the upper airway, narrowing of the pharynx due to obesity, and narrowing of the upper airway due to fat accumulation in the soft tissues and tongue were pointed out as the main causes of OSA. However, recent studies have shown that non-anatomical causes contribute to the development of OSA patients. For example, the responsiveness of upper airway muscles to negative pressure respiratory stimulation and the rhythmic repetition of sleep and wakefulness according to the arousal threshold (the degree of respiratory effort that causes arousal during an apnea event when an increase in negative pressure in the thoracic cavity reaches a certain threshold) have been suggested as one of the causes. In addition, it is known that 40% of OSA is associated with polymorphisms in the serotonin transporter gene (AD Maierean et al., Nat Sci Sleep. 2021; 13: 125-139). Typically, positive airway pressure (PAP), preferably continuous positive airway pressure (CPAP), oral appliances (mandibular advancement devices (MADs), or surgical procedures (e.g., airway dilation surgery, glossoplasty, palatal advancement pharyngoplasty, genioglossus advancement, hyoid fixation, submucosal glossoplasty) are used for OSA treatment. However, CPAP devices are expensive, difficult to carry and adapt to, and have low compliance. Furthermore, oral airway dilation devices, while having the advantage of fewer side effects, are expensive, have limitations in cases of jaw disease or dentition, and cause oral discomfort after sleep. Furthermore, surgical treatments such as airway dilation surgery involve complex procedures targeting two or more areas of the obstructed airway. Postoperative side effects such as pain, dysphagia, dysphonia, and xerostomia can occur for 2 to 3 weeks, and the effects diminish after 6 to 12 months, with most patients experiencing a recurrence of symptoms. Meanwhile, medications approved to treat excessive sleepiness associated with narcolepsy (e.g., Provigil (modafinil), Nuvigil (armodafinil)) are sometimes prescribed off-label for the treatment of OSA, but no product has received approval from the US FDA and / or EMA for the treatment of OSA. Therefore, much research is being conducted on treatments and therapies for sleep disorders such as OSA. For example, treatment with ondansetron and fluoxetine has been studied (see patent US63765504), and patent publication No. 2021-0125507 discusses the treatment of OSA using a combination of atomoxetine and a 5-HT2A inverse agonist and a combination of atomoxetine and oxybutynin. However, ondansetron can cause immediate hypersensitivity side effects, including rash, itching, and rarely anaphylaxis. Therefore, careful observation is recommended during administration, and immediate discontinuation of administration is recommended if such symptoms occur. In addition, the combination of ondansetron and fluoxetine is warned to cause serious adverse events, such as cardiovascular acceleration, increased blood pressure, ST segment depression, chest pain, arrhythmia, hypotension, and bradycardia. Therefore, the combination of ondansetron and fluoxetine is not suitable for use as a treatment to alleviate OSA symptoms. In addition, atomoxetine is difficult to use in patients with OSA or those with both cardiovascular disease and OSA because it is difficult to prevent related diseases that increase the risk of developing due to persistent sleep disorders or to alleviate the symptoms of such accompanying diseases due to its insufficient effect to completely improve and alleviate sleep disorders including OSA. Pimavanserin, a 5-HT2A inverse agonist, is a treatment for Parkinson's disease. In addition to common side effects such as facial and limb swelling, it also has serious side effects such as delayed bowel movement, changes in walking and balance ability. This raises safety concerns when taken long-term. It is also difficult to expect preventative effects for diseases that increase the risk of developing due to persistent sleep disturbances (such as hypertension, diabetes, dementia, myocardial infarction, stroke, and sudden death). Oxybutynin is responsible for one axis of the sleep cycle and has the problem of suppressing REM sleep, which helps enhance memory, regulate emotions, and restore the brain. It can also increase the risk of cognitive impairment and dementia, making it difficult to use long-term. Moreover, the combination of atomoxetine and oxybutynin is known to increase blood nitrogen and fail to reduce arousals during sleep. Therefore, although active research is being conducted on treatments for sleep disorders, including OSA, there are still many issues that must be overcome in the treatment currently being studied to ensure safety and improve sleep disorder symptoms when taken long-term. There is a need for methods and / or drugs for preventing, improving, or treating sleep disorders in patients with sleep disorders at high risk for cardiovascular disease or those with both cardiovascular disease and sleep disorders. These drugs have minimal side effects and do not suppress REM sleep, even when taken long-term. Furthermore, in addition to preventing, improving, and treating sleep disorders, there is a need for methods and / or drugs that can prevent, improve, or treat sleep-related diseases (e.g., cardiovascular disease, metabolic syndrome) that are at increased risk in patients with sleep disorders. [1] One aspect of the present invention relates to a composition comprising a norepinephrine selective reuptake inhibitor (NSRI) or a pharmaceutically acceptable salt thereof; and an antiplatelet agent. [2] In the above [1], the composition may have an effect of improving, preventing or treating sleep disorders and / or sleep disorder-related diseases that have an increased risk of developing in patients with sleep disorders. [3] In the above [2], the sleep disorder may be one or more diseases selected from the group consisting of insomnia, sleep disordered breathing (SDB), hypersomnia, sleep-wake cycle disorders, parasomnias, conditions associated with pharyngeal airway collapse during sleep, and Prader-Willi Syndrome (PWS) with sleep apnea. [4] In the above [2] or [3], the sleep disorder may be sleep apnea. [5] In the above [2], the sleep disorder may be one or more diseases selected from the group consisting of simple snoring, obstructive snoring, upper airway resistance syndrome, obstructive sleep apnea (OSA), central sleep apnea, hypopnea, and Prader-Willi syndrome. [6] In the above [5], the obstructive sleep apnea may be obstructive sleep apnea associated with pharyngeal airway muscle narrowing during sleep and / or obstructive sleep apnea with an apnea-hypopnea index (AHI) of 5 or higher on polysomnography. [7] In any one of the above [2] to [6], the sleep disorder-related disease may be one or more diseases selected from the group consisting of cardiovascular disease, metabolic syndrome, cognitive decline, dementia, Parkinson's disease, myocardial infarction, sexual dysfunction, depression, anxiety, stroke, sudden death, headache, glaucoma, sleep-induced injury, cancer, kidney disease, osteoporosis, visual loss, neurodegenerative disorder, neuroinflammatory disorder, and neuroimmunological disorder. [8] In any one of the above [1] to [7], the NSRI may be selected from the group consisting of amedalin, atomoxetine, CP-39,332, dalledalin, edibuxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. [9] In any one of the above [1] to [8], the NSRI may be selected from the group consisting of atomoxetine and reboxetine.

[0010] In any one of the above [1] to [9], the antiplatelet agent may be sarpogrelate, an active metabolite thereof, an optically active substance thereof, or a pharmaceutically acceptable salt thereof.

[0011] In any one of the above [1] to

[0010] , the content ratio of NSRI to antiplatelet agent may be 20:1 to 1:20.

[0012] In any one of the above [1] to

[0011] , the content of the NSRI may be 10 to 100 mg, 20 to 100 mg, or 25 to 80 mg.

[0013] In any one of the above [1] to

[0012] , the content of the antiplatelet agent may be 30 to 300 mg, 50 to 100 mg, or 150 to 300 mg.

[0014] In any one of the above [1] to

[0013] , the composition may be a formulation for oral administration.

[0015] In the above

[0014] , the oral administration formulation may be selected from syrup, pill, tablet, troche, film or capsule.

[0016] Another aspect of the present invention relates to a pharmaceutical composition for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases at increased risk of developing in patients with sleep disorders, comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent.

[0017] In the above

[0016] , the antiplatelet agent may be included in an amount of 30 to 300 mg, 50 to 100 mg, or 150 to 300 mg.

[0018] Another aspect of the present invention relates to a method for improving, preventing, or treating a sleep disorder and / or a sleep disorder-related disease at an increased risk of developing in a patient with a sleep disorder, comprising administering to a subject having a sleep disorder and / or a sleep disorder-related disease at an increased risk of developing in a patient with a sleep disorder, an effective amount of an NSRI or a pharmaceutically acceptable salt thereof; and an effective amount of an antiplatelet agent.

[0019] In the above

[0018] , the antiplatelet agent can be administered to the subject in the form of an immediate-release oral formulation containing an effective dose of 50 to 100 mg of the antiplatelet agent.

[0020] In the above

[0018] , the antiplatelet agent can be administered to the subject in a sustained-release oral formulation containing an effective dose of 150 to 300 mg of the antiplatelet agent.

[0021] One aspect of the present invention relates to the use of any one of the compositions [1] to

[0015] above for the manufacture of a medicament for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases at an increased risk of developing in patients with sleep disorders.

[0022] Another aspect of the present invention relates to a combination of an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent.

[0023] In the above

[0022] , the antiplatelet agent may be an immediate-release oral formulation containing an effective dose of 50 to 100 mg of the antiplatelet agent, or a sustained-release oral formulation containing an effective dose of 150 to 300 mg of the antiplatelet agent.

[0024] Another aspect of the present invention relates to a kit comprising a composition, pharmaceutical composition or combination comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent; and instructions for use. The inventors of the present invention have completed the present invention by discovering a new drug combination and dosage that can be safely taken for a long period of time without concerns about side effects and that can prevent sleep disorders (particularly, OSA) and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders. It has been confirmed that a combination of NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent has the effect of improving and / or treating sleep disorders in subjects with sleep disorders including OSA. definition The term "sleep" refers to a behavioral state in which one is unaware of one's surroundings and unresponsive to stimuli. Sleep is divided into rapid eye movement (REM) sleep and non-REM sleep, depending on the presence or absence of rapid eye movement (REM). During a single night's sleep, non-REM and REM sleep repeat in cycles of approximately 90-120 minutes, with a normal night having approximately five cycles. It is known that the types of neurotransmitters that function in REM and non-REM sleep differ. During non-REM sleep, most physiological functions are impaired. Non-REM sleep is classified into stages 1 to 3 based on sleep depth. Stage 1 sleep typically begins when you first fall asleep, and progresses to deeper stages 2 and 3. Sufficient sleep in stages 2 and 3 is crucial for restoring bodily functions. REM sleep is the state in which dreams occur most frequently, and occurs most frequently in the latter half of sleep, near dawn. During REM sleep, physiological conditions such as blood pressure, heart rate, and breathing are elevated to levels similar to those during waking hours, while muscles are completely relaxed and motionless. The term "sleep disorder" refers to a behavioral condition that interferes with proper sleep, such as irregular sleep, sleep apnea, and abnormal sleep behaviors. According to the International Classification of Sleep Disorders, sleep disorders are categorized into insomnia, sleep disordered breathing (SDB), hypersomnia, sleep-wake cycle disorders, and parasomnias. In addition, the sleep disorder may be one or more diseases selected from the group consisting of insomnia, sleep disordered breathing (SDB), hypersomnia, sleep-wake cycle disorders, parasomnias, conditions associated with pharyngeal airway collapse during sleep, and Prader-Willi Syndrome (PWS) with sleep apnea. The above Prader-Willi syndrome is a developmental disorder accompanied by severe sleep apnea. Insomnia is a condition in which it takes too long to fall asleep, you wake up frequently after falling asleep, you wake up too early in the morning and have difficulty falling back to sleep, or you don't feel refreshed after waking up. It can also be accompanied by emotional symptoms such as depression or anxiety, insomnia accompanied by physical symptoms such as nocturnal dyspnea or nocturnal asthma attacks, or primary insomnia with no known cause. Sleep-disordered breathing (SAD) is a general term for breathing abnormalities that occur during sleep due to increased upper airway resistance. SAD includes, but is not limited to, simple snoring, obstructive snoring (severe snoring, hypopnea syndrome), upper airway resistance syndrome, obstructive sleep apnea (OSA), central sleep apnea, and hypopnea. Central sleep apnea is caused by brain dysfunction or breathing control disorders and includes altitude-induced periodic breathing, idiopathic central sleep apnea (ICSA), opioid-induced central apnea, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes breathing (CSB). Hypersomnia is characterized by excessive daytime sleepiness, and representative examples include narcolepsy and behaviorally induced sleep deprivation syndrome. Disorders of the sleep-wake cycle are conditions in which the biological clock rhythm does not match the environmental day-night rhythm, making it difficult to sleep at appropriate times and causing excessive sleepiness during times when one wants to be awake. Examples include delayed sleep phase syndrome, jet lag syndrome, shift work sleep disorder, and sleep-wake disorder in environments with prolonged white nights or polar nights. Parasomnias are abnormal behaviors or physiological events that occur during sleep or while still half asleep, such as sleepwalking, night terrors, sleep paralysis, sleep eating disorder, nightmare disorder, enuresis, REM sleep behavior disorder, and restless legs syndrome. The above sleep disorder causes extreme drowsiness while walking, driving, or performing work activities during the day, which increases the risk of injury from various accidents, including traffic accidents. The term "sleep-related disorders at increased risk in patients with sleep disorders" refers to disorders that are at increased risk for developing in patients with sleep disorders due to their persistence. Persistent sleep disturbances increase the risk of developing cardiovascular complications due to recurrent asphyxiation and neuropsychiatric complications due to repeated awakenings from deep sleep. The above sleep disorder-related diseases include, but are not limited to, hypertension (including pulmonary hypertension and systemic hypertension), bradycardia, congestive heart failure, arrhythmia, angina pectoris, arteriosclerosis, atherosclerosis, cardiovascular diseases such as ischemic symptoms, metabolic syndrome, cognitive decline, dementia, Parkinson's disease, myocardial infarction, sexual dysfunction, depression, anxiety, stroke, sudden death, headache, glaucoma, sleep-related injuries, cancer, kidney disease, osteoporosis, visual loss, neurodegenerative disorders, neuroinflammatory disorders, and neuroimmunological disorders. For example, sleep apnea increases the risk of dementia, depression, anxiety, heart disease, osteoporosis, kidney disease, visual loss, and stroke. The term "prevention" refers to a method of inhibiting the onset of a disease and / or its accompanying symptoms or preventing a subject from developing a disease. The terms “improvement” and “treatment” mean alleviation of one or more symptoms or effects associated with a disease and / or a decrease in the severity or frequency of one or more symptoms or effects of a disease. The term "subject" refers to an animal, preferably a mammal, most preferably a human. The term "pharmaceutically acceptable" refers to something useful in preparing a pharmaceutical composition, including something that is generally safe, non-toxic, and acceptable for pharmaceutical use for animals or humans. The term "pharmaceutically acceptable salt" refers to any organic or inorganic compound that is non-toxic to the subject of administration and yet has an effective effect, and that does not cause side effects resulting from the salt to affect the efficacy of the drug, does not cause serious irritation to the subject of administration, and does not impair the biological activity and physical properties of the compound. Acids that can be used to form pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besilicic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, para-bromophenylsulfonic acid), lactic acid, oxalic acid, malic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid. Compositions, pharmaceutical compositions and combinations In one aspect of the present invention, the present invention relates to a composition comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent. In another aspect of the present invention, the present invention relates to a pharmaceutical composition for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases at increased risk of developing in patients with sleep disorders, comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent. In another aspect of the present invention, the present invention relates to a combination of an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent. In one embodiment of the present invention, the composition, pharmaceutical composition, and combination may have an ameliorating, preventing, or treating effect on sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders. Furthermore, the composition, pharmaceutical composition, and combination may effectively inhibit the onset of sleep disorders during the sleep phase. In another embodiment of the present invention, the sleep disorder may be one or more diseases selected from the group consisting of insomnia, sleep disordered breathing (SDB), hypersomnia, sleep-wake cycle disorders, parasomnias, conditions associated with pharyngeal airway collapse during sleep, and Prader-Willi Syndrome (PWS) with sleep apnea. In another embodiment of the present invention, the sleep disorder may be a disease in which hypopnea or apnea symptoms occur during sleep. The disease in which hypopnea or apnea symptoms occur during sleep may be a condition related to apnea during sleep or may be a sleep apnea disorder, and may be at least one disease selected from the group consisting of simple snoring, obstructive snoring (severe snoring, hypopnea syndrome), upper airway resistance syndrome, obstructive sleep apnea (OSA), central sleep apnea, hypopnea, and PWS. In one embodiment of the present invention, the sleep disorder may be one or more diseases selected from the group consisting of snoring during sleep, pathological conditions associated with pharyngeal airway collapse during sleep, OSA, and PWS, preferably OSA. In one embodiment of the present invention, the OSA refers to a disease in which the apnea-hypopnea index (AHI) is 5 or higher in a polysomnography test when apnea symptoms are present during sleep, or the AHI or respiratory disturbance index (RDI) is 15 or higher when apnea symptoms do not appear during sleep. The AHI is the number of apneas and hypopneas per hour of sleep, while the RDI is the number of apneas, hypopneas, and respiratory effort-related arousals (RERAs) per hour of sleep. OSA severity is classified as mild (AHI ≥ 5 but < 15 per hour), moderate (AHI 15 to 30 per hour), or severe (AHI > 30 per hour). In another embodiment of the present invention, the OSA may be OSA associated with pharyngeal airway muscle stenosis during sleep and / or OSA having an AHI of 5 or higher. Additionally, the OSA may be OSA having an AHI of 10 or higher. In one embodiment of the present invention, the sleep disorder-related disease that is at increased risk of developing in the sleep disorder patient may be at least one disease selected from the group consisting of hypertension, cardiovascular disease, cognitive decline, dementia, Parkinson's disease, depression, anxiety, stroke, sudden death, headache, glaucoma, sleep-induced injury, cancer, kidney disease, osteoporosis, metabolic syndrome, visual loss, neurodegenerative disorder, neuroinflammatory disorder, and neuroimmunological disorder. The cardiovascular disease is a vascular disorder such as hypertension, congestive heart failure, arrhythmia, angina pectoris, ischemic symptom, and myocardial infarction. The metabolic syndrome is central obesity, impaired fasting glucose, dyslipidemia, and / or type 2 diabetes, or a pathological state that increases the risk of developing these diseases. Specifically, persistent sleep disturbances (e.g., OSA) can cause hypertension, arrhythmia, and ischemic symptoms due to cardiovascular complications, and are known to significantly increase the risk of developing life-threatening diseases such as myocardial infarction, stroke, sudden death, cancer, and dementia (Yaggi HK et al., N ENGL J Med 2005 353, 2034-2041 and FC Rodriguezet et al., AM J Respir Crit Care Med 2013, 187(1): 99-105). In addition, sleep apnea has been reported to increase blood viscosity, resulting in a decrease in blood flow and an increase in blood pressure, which can lead to various vascular disorders including cardiovascular disease and cause blood clots, which can lead to vascular disease (DM Toraldo et al., 2013 Feb;191(1):1-7 and C Liak & M Fitzpatrick. Can Respir J. 2011,18(6), 338-348). Additionally, it has been reported that cognitive decline may occur due to reduced blood flow to the cerebral cortex in patients with REM sleep behavior disorder, which may lead to cognitive decline diseases such as dementia and Parkinson's disease (S Weber & B Mollenhauer. Nature reviews neurology, 2021,17,329-330). Furthermore, OSA causes extreme drowsiness during the day while walking, driving, or performing other occupational activities, which increases the risk of injury from various accidents, including traffic accidents. In one embodiment of the present invention, the individual having the sleep disorder and / or sleep disorder-related disease at increased risk of developing in a sleep disorder patient may be an adult or a child aged 3 to 6 years, depending on the mechanism of the disease. In one aspect of the present invention, the NSRI may be selected from the group consisting of, for example, amedalin, atomoxetine, CP-39,332, dalledalin, edibuxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. In one embodiment of the present invention, the NSRI may be at least one selected from the group consisting of atomoxetine and reboxetine. Preferably, the NSRI may be atomoxetine having the following structure: In another embodiment of the present invention, the pharmaceutically acceptable salt of the NSRI refers to an organic or inorganic salt having the same biological activity as the NSRI, and having side effects resulting from the salt that do not reduce the efficacy of the NSRI. In one embodiment of the present invention, the antiplatelet agent may be sarpogrelate, an active metabolite thereof, an optically active substance thereof, or a pharmaceutically acceptable salt thereof. The above sapogrylate active metabolite refers to a substance that is metabolized in the body after taking sapogrylate and has the same biological activity as sapogrylate. In addition, the sapogrylate optically active substance refers to a substance that is an optical isomer of sapogrylate and is a compound that has physicochemical stability and has the same biological activity as sapogrylate. The above sapogrelate and its active metabolites and optically active substances are as shown below, but are not limited thereto. The pharmaceutically acceptable salt of the above sarpogrelate refers to an organic or inorganic salt of sarpogrelate that has the same biological activity as sarpogrelate and does not reduce the efficacy of sarpogrelate due to side effects caused by the salt. The pharmaceutically acceptable salt of the above sarpogrelate may be a salt prepared using an acid such as hydrochloric acid, hydrobromic acid, sulfonic acid, nitrate, phosphoric acid, acetate, citric acid, tartaric acid, fumarate, maleate, toluenesulfonate, oxalic acid, malic acid, and methanesulfonate, but is not limited thereto. The above-mentioned sarpogrelate is an antiplatelet agent with a widely established safety profile. Sarpogrelate is known to increase red blood cell deformability and exert a protective effect against the mechanical shear stresses red blood cells experience as they pass through narrow vascular spaces, thereby inhibiting shear-induced hemolysis and improving red blood cell migration into the peripheral bloodstream. In another aspect of the present invention, the content ratio of NSRI to antiplatelet agent included in the composition, pharmaceutical composition or combination may be 20:1 to 1:20. Preferably, the content ratio of the NSRI to the antiplatelet agent may be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20. In another aspect of the present invention, the content of NSRI included in the composition, pharmaceutical composition or combination may be 10 mg to 100 mg, 20 to 100 mg, 25 to 80 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg. In another aspect of the present invention, the content of the antiplatelet agent included in the composition, pharmaceutical composition or combination may be 30 to 300 mg, 150 to 300 mg, 100 to 300 mg, 50 to 100 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg. In another aspect of the present invention, the content of the antiplatelet agent included in the composition, pharmaceutical composition or combination may be 30 to 300 mg, 50 to 100 mg or 150 to 300 mg. In one aspect of the present invention, the composition or pharmaceutical composition may be prepared as a dosage form for oral administration. Furthermore, the combination may be a combination of dosage forms for oral administration. In one embodiment of the present invention, the oral administration formulation may be selected from syrup, pill, tablet, troche, film or capsule. In another embodiment of the present invention, the NSRI or a pharmaceutically acceptable salt thereof and the antiplatelet agent can form a single dose formulation. In another embodiment of the present invention, the composition, pharmaceutical composition or combination may comprise a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutically acceptable carrier, diluent or excipient may include, but is not limited to, water, a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose. In one aspect of the present invention, the antiplatelet agent included in the combination may be an immediate-release oral formulation containing an effective dose of 50 to 100 mg of the antiplatelet agent, or a sustained-release oral formulation containing an effective dose of 150 to 300 mg of the antiplatelet agent. Medicinal uses In one aspect of the present invention, the present invention relates to a method for improving, preventing, or treating a sleep disorder and / or a sleep disorder-related disease at an increased risk of developing in a patient with a sleep disorder, comprising the step of administering to a subject having a sleep disorder and / or a sleep disorder-related disease at an increased risk of developing in a patient with a sleep disorder, an effective amount of an NSRI or a pharmaceutically acceptable salt thereof; and an effective amount of an antiplatelet agent. In another aspect of the present invention, the present invention relates to the use of the composition for the manufacture of a medicament for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders. In one embodiment of the present invention, the NSRI or a pharmaceutically acceptable salt thereof and the antiplatelet agent can be administered orally. In another embodiment of the present invention, the dosage ratio of the NSRI or a pharmaceutically acceptable salt thereof to the antiplatelet agent is 20:1 to 1:20, preferably 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, It could be 1:18, 1:19 or 1:20. In another embodiment of the present invention, the effective amount of the NSRI or a pharmaceutically acceptable salt thereof may be 10 mg to 100 mg, 20 to 100 mg, 25 to 80 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg. In another embodiment of the present invention, the effective amount of the antiplatelet agent may be 30 to 300 mg, 150 to 300 mg, 100 to 300 mg, 50 to 100 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg. In one embodiment of the present invention, the antiplatelet agent may be administered in an immediate-release formulation or a sustained-release formulation. In this case, the immediate-release formulation may contain an effective dose of 50 to 100 mg of the antiplatelet agent, and the sustained-release formulation may contain an effective dose of 150 to 300 mg of the antiplatelet agent. In another embodiment of the present invention, a combination of 80 mg of an NSRI or a pharmaceutically acceptable salt thereof (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and 300 mg of an antiplatelet agent (e.g., sarpogrelate) is administered orally with a sufficient amount of water 15 to 60 minutes, 20 to 45 minutes, 15 to 25 minutes, or 20 to 30 minutes prior to sleep onset; a combination of 40 mg of an NSRI or a pharmaceutically acceptable salt thereof (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and 100 mg of an antiplatelet agent (e.g., sarpogrelate); a combination of 25 mg of an NSRI or a pharmaceutically acceptable salt thereof (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and 100 mg of an antiplatelet agent (e.g., sarpogrelate); Alternatively, a combination of 25 mg of an NSRI or a pharmaceutically acceptable salt thereof (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and 50 mg of an antiplatelet agent (e.g., sarpogrelate) may be administered. In one embodiment of the present invention, a combination of 25 to 80 mg of an NSRI or a pharmaceutically acceptable salt thereof (e.g., atomoxetine or a pharmaceutically acceptable salt thereof) and 50 to 300 mg of an antiplatelet agent (e.g., sarpogrelate) may be administered. Kit In one aspect of the present invention, the present invention relates to a kit comprising (a) a composition, pharmaceutical composition, or combination comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent; and (b) instructions for use. Definitions and structures of the NSRI, antiplatelet agent, composition, pharmaceutical composition, and combination are as described above. The instructions for use may be a pharmaceutical product information sheet containing information on indications, usage, dosage, and contraindications related to the use of the composition, pharmaceutical composition, or combination. Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention. Example 1. Effect of the combination of atomoxetine and sarpogrelate on improving / treating sleep disorders To determine the sleep disorder improvement / treatment effect of the combination of atomoxetine and sarpogrelate in an animal model of chronic intermittent hypoxia (CIH). Purchase C57BL (B6) mice and stabilize them by keeping them in a 23±2℃ breeding room with free access to food and water. Place the stabilized B6 mice in a 30X20X20 inch chamber with air circulation of 60 L / min and expose them to chronic intermittent hypoxia conditions for 8 hours per day for 10 days (one cycle is alternating between normal air conditions (21% oxygen) and 5% oxygen conditions, and the cycle is changed 10 times per hour). As a control group, B6 mice were continuously exposed to normal air containing 21% oxygen, and the experimental group mice were administered the drugs or drug combinations in Table 1 for 10 days. Drug type and dosage Administration groupDrug type and dosage Group 1 Atomoxetine 80 mg (PO, once daily) Group 2 Sarpogrelate 300 mg (PO, once daily) Group 3 [Atomoxetine and sarpogrelate dosage ratio 4:15] Atomoxetine 80 mg (PO, once daily) and sarpogrelate 300 mg (PO, once daily) Group 4 [Atomoxetine and sarpogrelate dosage ratio 2:5] Atomoxetine 40 mg (PO, once daily) and sarpogrelate 100 mg (PO, once daily) Group 5 [Atomoxetine and sarpogrelate dosage ratio 1:4] Atomoxetine 25 mg (PO, once daily) and Sarpogrelate 100 mg (PO, once daily) Group 6 [group with a dosage ratio of atomoxetine and sarpogrelate of 1:2] Atomoxetine 25 mg (PO, once daily) and sarpogrelate 50 mg (PO, once daily) After administering the combination of atomoxetine and sarpogrelate, the improvement in hypoxia was confirmed by examining the recovery of blood oxygen saturation, and the improvement in sleep quality was confirmed by examining changes in EEG and EMG during the circadian rhythm cycle. The experimental results showed that the combination of atomoxetine and sarpogrelate was more effective in improving hypoxia and sleep quality than atomoxetine or sarpogrelate alone. Example 2. Therapeutic effect of atomoxetine and sarpogrelate combination on OSA We conducted a trial to determine the efficacy of a combination of atomoxetine and sarpogrelate in treating patients with obstructive sleep apnea (OSA). Patients with OSA who had an apnea-hypopnea index (AHI) of 10 or higher on polysomnography and were not treated with positive airway pressure (CPAP) were recruited (n=6). Polysomnography was performed 1 day before the study. Each group was administered the drugs or drug combinations listed in Table 2 at home 60 minutes before sleep onset for 6 days. On the 7th day of the study, patients in Groups 1 to 6 were administered the drugs at a hospital and then slept. Sleep studies were conducted during the patients' sleep. Sleep studies were performed using standard methods used in routine sleep studies, including electroencephalography, electrooculography, airflow measurements using nasal cannulas and thermometers, blood viscosity, and oxygen saturation. Meanwhile, the OSA improvement effect was confirmed by measuring the degree of AHI reduction, blood viscosity, and improvement in daytime sleepiness symptoms on the 7th day of the trial compared to the AHI before the trial began. The test results are presented in Table 3. Drug type and dosage Administration group Drug type and dosage Group 1 (n=1) Atomoxetine 80 mg (PO, once daily) Group 2 (n=1) Sarpogrelate 300 mg (PO, once daily) Group 3 (n=1) [Atomoxetine and sarpogrelate dosage ratio 4:15] Atomoxetine 80 mg (PO, once daily) and sarpogrelate 300 mg (PO, once daily) Group 4 (n=1) [Atomoxetine and sarpogrelate dosage ratio 2:5] Atomoxetine 40 mg (PO, once daily) and sarpogrelate 100 mg (PO, once daily) Group 5 (n=1) [Atomoxetine and sarpogrelate dosage ratio 1:4] Administration group] Atomoxetine 25 mg (PO, once daily) and sarpogrelate 100 mg (PO, once daily) Group 6 (n=1) [Administration group with an atomoxetine and sarpogrelate dosage ratio of 1:2] Atomoxetine 25 mg (PO, once daily) and sarpogrelate 50 mg (PO, once daily) Test results Administration group AHI (relief level %) Blood viscosity (relief level %) Sleepiness (1-5) Nausea (1-5) Group 1 (n=1) 40% 3% 33 Group 2 (n=1) 16% 12% 32 Group 3 (n=1) 68% 17% 1-23 Group 4 (n=1) 66% 15% 1-22 Group 5 (n=1) 67% 14% 1-21 Group 6 (n=1) 67% 14.5% 1-21 As confirmed in Table 3, the AHI reduction in groups 3 to 6 administered with combination of atomoxetine and sarpogrelate was confirmed to be 1.5 times higher than the AHI reduction observed in group 1 administered with atomoxetine alone, and the blood viscosity improvement effect observed in groups 3 to 6 administered with combination of atomoxetine and sarpogrelate was approximately 5 times higher than the blood viscosity improvement effect observed in group 1 administered with atomoxetine alone. In addition, the drowsiness and nausea improvement effects observed in groups 3 to 6 administered with combination of atomoxetine and sarpogrelate were found to be superior to the drowsiness and nausea improvement effects observed in group 1 administered with atomoxetine alone. Furthermore, it was confirmed that the AHI reduction in groups 3 to 6 administered with atomoxetine and sarpogrelate in combination was more than 4 times higher than the AHI reduction observed in group 2 administered with sarpogrelate alone, and the blood viscosity improvement effect and the drowsiness and nausea improvement effect observed in groups 3 to 6 administered with atomoxetine and sarpogrelate in combination were more superior than the blood viscosity improvement effect and the drowsiness and nausea improvement effect observed in group 2 administered with sarpogrelate alone. Therefore, it was confirmed that co-administration of atomoxetine and sarpogrelate had a greater effect on improving OSA than when atomoxetine or sarpogrelate was administered alone. Additionally, the AHI reduction effect observed in the low-dose combination of atomoxetine and sarpogrelate (Groups 4 to 6) was similar to that observed in the high-dose combination of atomoxetine and sarpogrelate (Group 3). Therefore, this suggests that the combination of atomoxetine and sarpogrelate may exhibit excellent efficacy in preventing, improving, or treating OSA or mild OSA, even at low doses.

Claims

1. Norepinephrine selective reuptake inhibitor (NSRI) or a pharmaceutically acceptable salt thereof; and A composition comprising an antiplatelet agent.

2. In the first paragraph, the composition has an effect of improving, preventing, or treating sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders.

3. In the second paragraph, the sleep disorder is at least one disease selected from the group consisting of insomnia, sleep disordered breathing (SDB), hypersomnia, sleep-wake cycle disorders, parasomnias, conditions associated with pharyngeal airway collapse during sleep, and Prader-Willi Syndrome (PWS) with sleep apnea.

4. In the second or third paragraph, the sleep disorder is sleep apnea disorder, the composition.

5. In the second paragraph, the sleep disorder is at least one disease selected from the group consisting of simple snoring, obstructive snoring, upper airway resistance syndrome, obstructive sleep apnea (OSA), central sleep apnea, hypopnea, and Prader-Willi syndrome.

6. In the fifth paragraph, the composition is obstructive sleep apnea associated with pharyngeal airway muscle narrowing during sleep and / or obstructive sleep apnea with an apnea-hypopnea index (AHI) of 5 or higher on polysomnography.

7. A composition according to any one of claims 2 to 6, wherein the sleep disorder-related disease is at least one disease selected from the group consisting of cardiovascular disease, metabolic syndrome, cognitive decline, dementia, Parkinson's disease, myocardial infarction, sexual dysfunction, depression, anxiety, stroke, sudden death, headache, glaucoma, drowsiness-induced injury, cancer, kidney disease, osteoporosis, visual loss, neurodegenerative disorder, neuroinflammatory disorder, and neuroimmunological disorder.

8. A composition according to any one of claims 1 to 7, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, dalledalin, edibuxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine.

9. A composition according to any one of claims 1 to 8, wherein the NSRI is selected from the group consisting of atomoxetine and reboxetine.

10. A composition according to any one of claims 1 to 9, wherein the antiplatelet agent is sarpogrelate, an active metabolite thereof, an optically active substance thereof, or a pharmaceutically acceptable salt thereof.

11. A composition according to any one of claims 1 to 10, wherein the content ratio of NSRI to antiplatelet agent is 20:1 to 1:

20.

12. A composition according to any one of claims 1 to 11, wherein the content of the NSRI is 10 to 100 mg, 20 to 100 mg, or 25 to 80 mg.

13. A composition according to any one of claims 1 to 12, wherein the content of the antiplatelet agent is 30 to 300 mg, 50 to 100 mg, or 150 to 300 mg.

14. A composition according to any one of claims 1 to 13, which is a formulation for oral administration.

15. A composition according to claim 14, wherein the oral administration formulation is selected from syrup, pill, tablet, troche, film or capsule. 16.NSRI or pharmaceutically acceptable salt thereof and Containing antiplatelet agents, A pharmaceutical composition for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders.

17. A pharmaceutical composition comprising 30 to 300 mg, 50 to 100 mg, or 150 to 300 mg of an antiplatelet agent according to claim 16.

18. Subjects with sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders, Comprising a step of administering an effective amount of NSRI or a pharmaceutically acceptable salt thereof; and an effective amount of an antiplatelet agent; A method for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases that are at increased risk of developing in patients with sleep disorders.

19. A method for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases with an increased risk of developing in patients with sleep disorders, wherein the antiplatelet agent is administered in an immediate-release oral formulation containing an effective dose of 50 to 100 mg of the antiplatelet agent in accordance with claim 18.

20. A method for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases with an increased risk of developing in patients with sleep disorders, wherein the antiplatelet agent is administered in a sustained-release oral formulation containing an effective dose of 150 to 300 mg of the antiplatelet agent in accordance with claim 18.

21. Use of the composition of any one of claims 1 to 15 for the manufacture of a medicament for improving, preventing or treating sleep disorders and / or sleep disorder-related diseases at increased risk of developing in patients with sleep disorders.

22. A combination of NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent.

23. In paragraph 22, the antiplatelet agent A combination, which is an immediate-release oral dosage form comprising an effective dose of 50 to 100 mg of an antiplatelet agent, or a sustained-release oral dosage form comprising an effective dose of 150 to 300 mg of an antiplatelet agent. 24.(a) a composition, pharmaceutical composition or combination comprising an NSRI or a pharmaceutically acceptable salt thereof and an antiplatelet agent; and (b) A kit including instructions for use.

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