Dexmedetomidine for treating sleep disorders

Abstract

The present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in treating or preventing a sleep disorder in a subject, wherein the dexmedetomidine or the pharmaceutically acceptable salt thereof is administered to the subject via a transmucosal administration route at a dose of 10 μg to 120 μg. The dexmedetomidine or the pharmaceutically acceptable salt thereof according to the present invention is preferably formulated as an orally dispersible tablet and is particularly useful in treating insomnia.

Description

[Technical Field]

[0001] The present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in treating or preventing a sleep disorder in a subject, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is administered to the subject via a transmucosal route at a dose of 10 μg to 120 μg. The dexmedetomidine or pharmaceutically acceptable salt thereof is preferably formulated as an orally dispersible tablet and is particularly useful in treating insomnia. [Background technology]

[0002] Sleep accounts for one-third of our lives, and there is evidence that sleep has multiple important functions, including detoxification, development, memory consolidation, and synaptic plasticity. Unfortunately, sleep disorders are the second most common reason patients visit a doctor, and current treatments for insomnia have several side effects. Dexmedetomidine is a sedative used during surgery. It may also have anxiolytic, sympatholytic, and analgesic effects. Furthermore, dexmedetomidine has been shown to attenuate overactivity of wake-promoting pathways. Therefore, dexmedetomidine is considered a promising drug for treating sleep disorders, especially insomnia.

[0003] Sleep problems are the second most common reason patients visit a doctor, after pain (Mahowald & Schenck, (2005). Insights from studying human sleep disorders. Nature, 437(7063), 1279-1285. (Non-Patent Document 1)). Patients suffering from sleep problems complain of dissatisfaction with the quality of their sleep and the negative impact it has on their social, educational, or professional lives. Furthermore, sleep deprivation is associated with diabetes mellitus and impaired glucose tolerance (Gottlieb, DJ, Punjabi, NM, Newman, AB, Resnick, HE, Redline, S., Baldwin, CM, & Nieto, FJ (2005). Association of Sleep Time With Diabetes Mellitus and Impaired Glucose Tolerance. Archives of Internal Medicine, 165(8), 863-867 (Non-Patent Document 2)), coronary heart disease (Ayas, NT, White, DP, Manson, JE, Stampfer, MJ, Speizer, FE, Malhotra, A., & Hu, FB (2003). A Prospective Study of Sleep Duration and Coronary Heart Disease in Women. Archives of Internal Medicine, 163(2), 205-209 (Non-Patent Document 3)), and depression (Ford, DE, & Kamerow, DB (1989). Epidemiological Study of Sleep It has been shown that it increases the probability of developing other diseases such as Disturbances and Psychiatric Disorders: An Opportunity for Prevention? JAMA, 262(11), 1479-1484 (Non-Patent Document 4).Sleep problems can also be caused by other diseases, such as cancer (Savard, J., & Savard, M.-H. (2013). Insomnia and cancer: prevalence, nature, and nonpharmacologic treatment. Sleep Medicine Clinics, 8(3), 373-387) and HIV (human immunodeficiency virus) (Norman, SE, Chediak, AD, Kiel, M., & Cohn, MA (1990). Sleep disturbances in HIV-infected homosexual men. AIDS, 4(8), 775-782). There is also a clear link between sleepiness and accidents related to sleep deprivation, such that patients with sleep problems are more likely to make mistakes or cause accidents, which can even lead to death (Dinges, DF (1995). An overview of sleepiness and accidents. J Sleep Res, 4(S2), 4-14).

[0004] The American Academy of Sleep Medicine (AASM) has published the International Classification of Sleep Disorders (ICSD). Based on the ICSD-3 (3rd edition), there are six major groups of sleep disorders. The first group is insomnia, which includes problems with sleep onset, sleep duration, sleep integration, and poor sleep quality (Sateia, 2014, International Classification of Sleep Disorders (3rd ed.). American Academy of Sleep Medicine. p. 19 (Non-Patent Document 8)). The second group is sleep-related breathing disorders, which are characterized by abnormal breathing during sleep (Sateia, 2014, p. 49). The third group is central hypersomnia, also known as hypersomnia or excessive daytime somnolence (EDS) (Chokroverty, S. (2010). Overview of sleep & sleep disorders. The Indian Journal of Medical Research, 131(2), 126-140; Sateia, 2014, p. 143 (Non-Patent Document 9)). The fourth group is circadian rhythm sleep-wake disorders, characterized by the inability to fall asleep at the desired time (Sateia, 2014, p. 189). The fifth group is parasomnias, characterized by unwanted physical events or experiences during sleep (Sateia, 2014, p. 225). The last group is sleep-related movement disorders, characterized by simple movements that disrupt sleep or its onset (Sateia, 2014, p. 281).

[0005] Insomnia is considered the most common sleep disorder. Treatments for insomnia can be divided into non-pharmacological and pharmacological treatments (Cunnington et al., 2013). Non-pharmacological treatments include establishing good sleep hygiene and cognitive behavioral therapy (CBT-i) (Cunnington et al., 2013, pp. 90-93; Stuck et al., 2021). Primary pharmacological treatments include benzodiazepines, melatonin, and modified forms of antidepressants, antipsychotics, and antihistamines (Cunnington, D., Junge, MF, & Fernando, AT (2013). Insomnia: prevalence, consequences, and effective treatment. Medical Journal of Australia, 199(8), 36-40 (Non-Patent Document 10)).

[0006] Good sleep hygiene aims to reduce sleep-incompatible behaviors and introduce sleep-promoting behaviors. Examples include creating a comfortable bedroom atmosphere, limiting alcohol and caffeine intake, and avoiding stimulating activities such as working, playing sports, or watching television late into the night (Stuck et al., 2021, Practice of Sleep Medicine: Sleep Disorders in Children and Adults (1st ed.). Springer International Publishing AG. pp. 91-92 (Non-Patent Document 11)). CBT-i is a psychotherapeutic intervention that targets maladaptive behaviors and thoughts that patients may have acquired due to insomnia (Cunnington et al., 2013; Stuck et al., 2021, p. 93). Morin et al. reviewed 37 psychological and behavioral treatment studies. They found that good sleep hygiene and CBT-i can change several sleep parameters and reduce psychological symptoms. However, there is limited evidence that they improve sleep quality or reduce physiological symptoms such as daytime fatigue (Morin, C.M., Koetter, U., Bastien, C., Ware, J.C., & Wooten, V. (2005). Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep, 28(11), 1465-1471 (Non-Patent Document 12)).

[0007] Benzodiazepines are hypnotic drugs, raising concerns about dependence and tolerance (Cunnington et al., 2013). Curran et al. investigated the effects of benzodiazepine withdrawal on long-term users (over 10 years) by having them complete various tasks and questionnaires. They found that patients who withdrew from benzodiazepines performed better during the tasks than those who continued taking them. However, sleep ratings between the two groups were not significantly different, indicating that benzodiazepines are not effective for long-term treatment (Curran, HV, Collins, R., Fletcher, S., Kee, SCY, Woods, B., & Iliffe, S. (2003). Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood, and quality of life. Psychological Medicine, 33(7), 1223-1237 (Non-Patent Document 13)). De Wit and Griffiths reviewed the abuse liability of anxiolytics and hypnotics in humans. They found that individuals with a history of drug abuse are particularly likely to become dependent on these drugs (de Wit, H., & Griffiths, RR (1991). Testing the abuse liability of anxiolytic and hypnotic drugs in humans. Drug and Alcohol Dependence, 28(1), 83-111 (Non-Patent Document 14)).Kales et al. have shown that abrupt cessation of benzodiazepines causes rebound insomnia, which encourages drug-taking behavior and increases the likelihood of drug dependence (Kales, A., Manfredi, RL, Vgontzas, AN, Bixler, EO, Vela-Bueno, A., & Fee, EC (1991). Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clinical Pharmacology & Therapeutics, 49(4), 468-476 (Non-Patent Document 15)).

[0008] Kennaway reviewed the use of melatonin as an over-the-counter treatment for insomnia. Melatonin is an endogenous hormone that has been shown to be effective in treating insomnia at high doses. However, it is not limited to the sleep process; it is also involved in the cardiovascular system and glucose metabolism (Kennaway, DJ (2022). What do we really know about the safety and efficacy of melatonin for sleep disorders? Current Medical Research and Opinion, 38(2), 211-227 (Non-Patent Document 16)). For example, Cagnacci et al. showed that administration of melatonin to young, healthy women affected arterial blood flow and reduced blood pressure, providing a rationale for the clinical use of melatonin (Cagnacci, A., Arangino, S., Angiolucci, M., Maschio, E., & Melis, GB (1998). Influences of melatonin administration on the circulation of women. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 274(2), R335-R338 (Non-Patent Document 17)). However, there have been cases in which high doses of melatonin have caused severe hypotension (Johnson, HE, Dotson, JM, Ellis, CS, & Hill, KK (2019). Severe Hypotension in an Adolescent After a Melatonin Overdose. Journal of child and adolescent psychopharmacology, 29(9), 726-727 (Non-Patent Document 18)). Melatonin may be a potential treatment for insomnia. However, there is still a need to study the effects of high doses of melatonin on other systems and clarify possible side effects (Kennaway, 2022).Antidepressants (e.g., doxepin and mirtazapine) (Hajak, G., Rodenbeck, A., Voderholzer, U., Riemann, D., Cohrs, S., Hohagen, F., Berger, M., & Ruther, E. (2000). Doxepin in the treatment of primary insomnia - A placebo-controlled, double-blind, polysomnographic study. European Neuropsychopharmacology, 10, 248-249 (Non-Patent Document 19); Karsten, J., Hagenauw, L.A., Kamphuis, J., & Lancel, M. (2017). Low doses of mirtazapine or quetiapine for transient insomnia: A randomized, double-blind, cross-over, placebo-controlled trial. Journal of Psychopharmacology, 31(3), 327-337 (Non-Patent Document 20)), antipsychotics (e.g., quetiapine) (Karsten et al., 2017), and antihistamines (e.g., diphenhydramine) (Morin et al., 2005) are effective treatments for insomnia. Unfortunately, they also have many side effects. An overview of the side effects of antidepressants has been reported by Khawam et al. Some of the side effects include anxiety, nausea, vomiting, sedation, daytime sleepiness, weight gain, and somnolence (Khawam, EA, Laurencic, G., & Malone, DA, Jr. (2006). Side effects of antidepressants: an overview. Cleveland Clinical Journal of Medicine, 73(4), 351-353, 356-361 (Non-Patent Document 21)). Ucok and Gaebel have reviewed the side effects of antipsychotics.Antipsychotics can lead to weight gain and increase the likelihood of developing conditions such as diabetes mellitus, hyperlipidemia (high blood lipid levels), and myocarditis (inflammation of the heart muscle) (Ucok, A., & Gaebel, W. (2008). Side effects of atypical antipsychotics: a brief overview. World psychiatry: official journal of the World Psychiatric Association (WPA), 7(1), 58-62 (Non-Patent Document 22)). First-generation antihistamines such as diphenhydramine have been shown to significantly impair performance during tasks requiring divided attention, working memory, alertness, and speed, and therefore taking them the night before may impair daytime performance (Kay, GG (2000). The effects of antihistamines on cognition and performance. Journal of Allergy and Clinical Immunology, 105(6, Part 2), S622-S627 (Non-Patent Document 23)). Current treatments have several side effects, including the risk of developing other diseases.

[0009] Therefore, new treatments need to be investigated, and dexmedetomidine is a potential treatment.

[0010] Dexmedetomidine not only has sedative effects, but also anxiolytic, sympatholytic, and analgesic effects (Bloor, Byron C., Ward, Denham S., Belleville, Jon P., & Maze, M. (1992). Effects of Intravenous Dexmedetomidine in Humans: II. Hemodynamic Changes. Anesthesiology, 77(6), 1134-1142 (Non-Patent Document 24)). Patients sedated with dexmedetomidine can be easily awakened and therefore cooperate during treatment (Venn, RM, & Grounds, RM (2001). Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions. British journal of anesthesia, 87(5), 684-690 (Non-Patent Document 25)). This unique sedative response is also known as "awakenable sedation" or "cooperative sedation" (Lee, S. (2019). Dexmedetomidine: present and future directions. Korean Journal of Anesthesiology, 72(4), 323-330 (Non-Patent Document 26)). Hall et al. compared the effects of low and medium doses of dexmedetomidine in seven subjects. After the specified period, the subjects underwent various tests and measurements. The results showed significant sedation, allowing the subjects to easily awaken and perform tasks. The cold pressure test (immersing one hand in ice-cold water and assessing subjective pain sensation using a visual analog scale (VAS)) showed a significant decrease in pain sensation. No impairment was observed in the cardiovascular or respiratory systems.Although performance on psychomotor tasks and global memory tests was impaired, retrograde memory was not impaired (Hall, JE, Uhrich, TD, Barney, JA, Arain, SR, & Ebert, TJ (2000). Sedative, Amnestic, and Analgesic Properties of Small-Dose Dexmedetomidine Infusions. Anesthesia and analgesia, 90(3), 699-705. (Non-Patent Document 27)). The two most common side effects of dexmedetomidine are bradycardia (a slow heart rate) and hypotension (a drop in blood pressure) (Paris, A., & Tonner, PH (2005). Dexmedetomidine in anesthesia. Current Opinion in Anesthesiology, 18(4) (Non-Patent Document 28)). It has been shown that dexmedetomidine sedation is dose-dependent (Sim, JH, Yu, HJ, & Kim, ST (2014). The effects of different loading doses of dexmedetomidine on sedation. Korean Journal of Anesthesiology, 67(1), 8-12 (Non-Patent Document 29)). Because the response to dexmedetomidine is dose-dependent, any side effects can be considered an overreaction of the normal sedative effect of dexmedetomidine caused by high doses of dexmedetomidine (Paris & Tonner, 2005).

[0011] WO 2018 / 126182 (Patent Document 1) discloses the specific use of sublingual dexmedetomidine for treating agitation.

[0012] International Publication No. 2020 / 006092 (Patent Document 2) discloses a film formulation containing dexmedetomidine and a method for producing the same. This document teaches that sublingual tablets tend to be swallowed before they are completely dissolved and delivered transmucosally, leading to waste of the active substance due to hepatic first-pass metabolism. As a result, sublingual tablets may not achieve therapeutic levels of dexmedetomidine in plasma.

[0013] International Publication No. 2016 / 061413 (Patent Document 3) discloses the prevention or treatment of sleep disorders using a dexmedetomidine formulation, in which dexmedetomidine is administered in a therapeutically effective amount of about 0.1 mg to about 5 mg.

[0014] U.S. Patent Application Publication No. 2017 / 239221 (Patent Document 4) provides a composition suitable for oral transmucosal administration (sublingually) containing dexmedetomidine. This composition is useful for treating sleep disorders such as insomnia and can provide sleep on demand. This composition contains an effective amount of dexmedetomidine or a pharmaceutically acceptable salt, solvate, or derivative thereof formulated to deliver dexmedetomidine across the oral mucosa of a subject.

[0015] U.S. Patent Application Publication No. 2022 / 226288 (Patent Document 5) discloses a method for administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject. The disclosed method is particularly suitable for treating agitation, particularly when associated with neurodegenerative and / or neuropsychiatric diseases or disorders such as dementia and delirium. US Patent Application Publication No. 2010 / 196286 (Patent Document 6) discloses devices and kits for treating sleep disorders, anxiety disorders, and developmental disorders and / or for inducing a wakeful sedative state in a subject. US Patent Application Publication No. 2005 / 025807 (Patent Document 7) provides a hardened porous calcium phosphate material, a substitute biological tissue material, a scaffold for tissue engineering, and a drug-carrying medium for DDS using the same. [Prior art documents]

Charter Documents

[0016] [Patent Document 1] International Publication No. 2018 / 126182 [Patent Document 2] International Publication No. 2020 / 006092 [Patent Document 3] International Publication No. 2016 / 061413 [Patent Document 4] U.S. Patent Application Publication No. 2017 / 239221 [Patent Document 5] U.S. Patent Application Publication No. 2022 / 226288 [Patent Document 6] U.S. Patent Application Publication No. 2010 / 196286 [Patent Document 7] U.S. Patent Application Publication No. 2005 / 025807

Non-licensed literature

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[0018] The objective technical problem was to provide a drug for treating sleep disorders with fewer side effects, which problem is solved by the embodiments described herein and characterized in the claims.

[0019] We studied the sleep of 17 healthy subjects, recording data over three nights. Subjects were administered either placebo, 20 μg dexmedetomidine, or 40 μg dexmedetomidine. These recordings allowed us to determine whether dexmedetomidine affected sleep physiology. Subjects also completed three questionnaires, allowing us to determine how dexmedetomidine affected subjective sleep quality. Thus, we demonstrated that dexmedetomidine decreased sleep latency, increased REM latency, and increased time spent in NREM sleep (N2 + N3), with these effects being more pronounced in the 40 μg condition compared to the 20 μg condition. Therefore, dexmedetomidine at the doses described herein contributes to deeper sleep without causing any residual effects, such as sedation or cardiovascular effects, the next day. Table 4 summarizes the effects of dexmedetomidine on sleep architecture. FIG. 9 shows the slow wave sleep enhancing effect of dexmedetomidine in a representative subject.

[0020] The inventors further demonstrated that the proposed administration scheme achieves plasma concentrations of dexmedetomidine sufficient to achieve efficacy, i.e., approximately 0.2 ng / mL after 1-2 hours of buccal administration of an orodispersible tablet containing 40 μg of dexmedetomidine and approximately 0.1 ng / mL after 1-2 hours of buccal administration of an orodispersible tablet containing 20 μg of dexmedetomidine. The inventors further demonstrated, surprisingly, that the plasma concentrations thus obtained were very similar across different subjects. Thus, surprisingly, transmucosal administration of dexmedetomidine according to the present invention can minimize inter-subject differences in dexmedetomidine bioavailability compared with orally administered dexmedetomidine. Pharmacokinetic profiles following sublingual administration of 20 / 40 μg (Figure 1, Part 1), 50 μg (Figure 1, Part 2 and Figure 2, Parts 1 / 2), and 150 μg (Figure 1, Part 2) of dexmedetomidine are shown.

[0021] We also surprisingly found in this study that bedtime sublingual doses of dexmedetomidine resulting in plasma concentrations greater than 0.15 ng / mL are likely to cause carryover effects upon awakening, particularly orthostatic intolerance and dizziness. Based on these findings, we suggest that bedtime sublingual doses greater than 120-150 μg are likely to cause next-day residual effects.

[0022] Thus, the present inventors have surprisingly found that the therapeutic window for sublingual administration of dexmedetomidine for treating sleep disorders is 10-120 μg.

[0023] The present invention is summarized in the following embodiments.

[0024] In a first embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a sleep disorder in a subject, wherein the dexmedetomidine or salt thereof is administered to the subject via a transmucosal administration route at a dose of between 10 μg and 120 μg.

[0025] In a second embodiment, the present invention relates to a method for treating or preventing a sleep disorder in a subject in need thereof, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject via a transmucosal administration route at a dose of 10 μg to 120 μg.

[0026] In a third embodiment, the present invention relates to the use of dexmedetomidine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a sleep disorder in a subject, wherein the dexmedetomidine or salt thereof is administered to the subject via a transmucosal administration route at a dose of 10 μg to 120 μg.

[0027] In certain embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein dexmedetomidine or a salt thereof is administered at a dose of 40 μg to 120 μg, preferably at a dose of 40 μg to 80 μg.

[0028] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein dexmedetomidine or a salt thereof is administered at a dose of 60 μg to 80 μg.

[0029] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein dexmedetomidine or a salt thereof is administered at a dose of 10 μg to 40 μg, preferably 20 μg to 40 μg.

[0030] In further specific embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein dexmedetomidine or a salt thereof is administered sublingually or bucally to a subject.

[0031] In further specific embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein dexmedetomidine or a salt thereof is administered bucally to a subject.

[0032] In further specific embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the dexmedetomidine or a salt thereof is administered to the subject in the form of an orally dispersible tablet.

[0033] In further particular embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the invention, the method according to the invention, or the use according to the invention, wherein said dexmedetomidine (in particular said orodispersible tablet) is formulated by using templated carrier particles, preferably templated inverted particles, preferably comprising calcium phosphate and / or magnesium phosphate.

[0034] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the sleep disorder is selected from insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance- or medication-induced sleep disorder.

[0035] In further specific embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the subject is suffering from depression and / or anxiety.

[0036] In further specific embodiments, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the subject suffers from a cardiac or pulmonary disorder (e.g., congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (e.g., Alzheimer's disease or Parkinson's disease), or a musculoskeletal disorder.

[0037] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method of the present invention, or the use of the present invention, wherein the sleep disorder is an insomnia disorder. In a specific embodiment, the insomnia disorder is selected from insomnia associated with depression, insomnia associated with anxiety disorder, insomnia associated with post-traumatic stress disorder (PTSD), insomnia associated with schizophrenia, insomnia associated with Parkinson's disease, insomnia associated with Alzheimer's disease, insomnia associated with multiple sclerosis, and insomnia associated with stroke.

[0038] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein said sleep disorder is hypersomnia or narcolepsy.

[0039] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the sleep disorder is a circadian rhythm sleep disorder, preferably characterized by a delayed sleep-wake phase, shift work, a non-24-hour sleep-wake rhythm, or an irregular sleep-wake rhythm.

[0040] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein the sleep disorder is REM sleep behavior disorder.

[0041] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, the method according to the present invention, or the use according to the present invention, wherein said sleep disorder is restless legs syndrome.

[0042] The term "preferably" is used to describe features or embodiments that are not essential to the invention but may lead to improved technical effects and are therefore preferred, but not required. [Brief explanation of the drawings]

[0043] [Figure 1-1] Part 1 shows plots of the plasma concentration of dexmedetomidine over time when 20 μg and 40 μg dexmedetomidine were administered transmucosally to subjects as orally dispersible tablets (average values measured for 17 subjects in each case are shown). [Figure 1-2] Part 2 shows the plasma profile of DEX after sublingual administration of 50 μg DEX at 24:00 and 50 μg / 150 μg DEX at 4:30. [Figure 2-1] Part 1 shows a plot of the plasma concentration of dexmedetomidine over time when 50 μg of dexmedetomidine was administered transmucosally as an orally dispersible tablet to subjects once at 24:00 ("long" label) and once at 4:30 ("short" label). [Figure 2-2]The average of the values measured for the four subjects in each case is shown in Part 2. [Figure 3] EEG electrode positions are shown (Klem et al., 1999). [Figure 4] Indicates the electrode positions for EOG (Berry, 2020, p. 18). [Figure 5] Indicates EMG electrode locations (Berry, 2020, p. 19). [Figure 6] ECG electrode positions are shown (Caples et al., 2007). [Figure 7] A screenshot of the program "Embla Rembrandt Manager" is shown. [Figure 8] Exemplary EEG, EOG, and EMG signal traces are shown for various sleep and wakefulness stages (Kandel et al., 2021, p. 1080). [Figure 9] Deep sleep-promoting properties of dexmedetomidine as indicated by increased slow wave activity following administration of 40 μg dexmedetomidine (bottom panel) compared to placebo (top panel). [Figure 10] The difference in cortisone emergence response (CAR) between placebo, 20 mg and 40 mg DEX is shown. [Figure 11]

[0023] Figure 1 shows the PK profiles following oral administration of 300 μg (bottom curve), 500 μg (middle curve), and 700 μg (top curve) of dexmedetomidine. The plasma curves are characterized by high inter-subject variability. [Figure 12] The effects of 20 and 40 μg dexmedetomidine on sleep onset latency are shown. Both 20 μg and 40 μg dexmedetomidine (DEX) significantly shortened sleep onset latency compared to placebo. This is remarkable considering that the drug was administered exactly at the intended bedtime (no premedication). Therefore, dexmedetomidine has a very rapid onset of action and can be taken immediately at bedtime, without the need for any premedication. [Figure 13]The effects of 20 and 40 μg dexmedetomidine on REM latency are shown. Both 20 μg and 40 μg dexmedetomidine (DEX) significantly increased REM latency compared to placebo. This effect was most likely due to the enhanced consolidation of NREM sleep in the first half of the night, supporting the notion of dexmedetomidine-mediated overall sleep improvement. Furthermore, pathological reductions in REM latency, known as sleep-onset REM episodes (SOREM), are associated with various sleep disorders, including narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS), and brainstem lesions. [Figure 14] Figure 1 shows the effect of 20 and 40 μg dexmedetomidine on the percentage of REM stage. 40 μg dexmedetomidine (DEX) significantly reduced the percentage of time spent in REM stage compared to placebo. This effect was most likely driven by a stronger consolidation of NREM sleep in the first half of the night, supporting the notion of dexmedetomidine-mediated overall sleep improvement. [Figure 15] Figure 1 shows the effect of 20 and 40 μg dexmedetomidine on the percentage of stage N2. Both 20 μg and 40 μg dexmedetomidine (DEX) significantly increased the percentage of time spent in stage N2, supporting the notion of dexmedetomidine-mediated overall sleep improvement. [Figure 16] A cumulative plot of NREM sleep stages is shown. This plot shows the proportion of deep sleep (N2 + N3) as a percentage of total sleep time for each hour of the night (1-8). This graph demonstrates a significant and dose-dependent increase in the proportion of deep sleep for hours 7-8 of the night with dexmedetomidine (20 / 40) compared to placebo (P; see statistical summary below; 1 = 11-12 pm; 2 = 12 pm-1 am; 3 = 1-2 am; 4 = 2-3 am; 5 = 3-4 am; 6 = 4-5 am; 7 = 5-6 am; 8 = 6-7 am). [Figure 17]Hypnograms and spectral plots are shown for a representative individual after placebo (top) and dexmedetomidine (40 μg; bottom). As shown, dexmedetomidine consolidates NREM sleep in the first half of the night and REM sleep in the second half of the night, indicating less fragmentation of NREM and REM sleep episodes (fewer gray columns). Therefore, dexmedetomidine may be particularly suitable for treating conditions associated with significant REM sleep fragmentation, including psychiatric and neurological conditions such as depression, anxiety, PTSD, schizophrenia, psychosis, ADHD, periodic limb movement disorder, restless legs syndrome, Parkinson's disease, Alzheimer's disease, and REM sleep behavior disorder. [Figure 18] Time course of slow wave activity (SWA) following placebo (top panel) and dexmedetomidine (40 μg; bottom panel) administration in a representative individual. Dexmedetomidine consolidates NREM sleep epochs and increases overall SWA. [Figure 19] Figure 1 shows slow wave energy (SWE) in stages N1, N2, and N3 after placebo and 20 μg and 40 μg dexmedetomidine administration. The figure shows the most pronounced increase in SWE activity during N3 sleep, indicating enhanced restorative sleep function. [Figure 20] Drug effects on SWE during the first (A) and second (B) parts of the night are shown. The plot shows that SWE was highly significantly increased during the first part of the night, but the effect was not stronger at 40 μg compared with the 20 μg condition. SWE during the second part of the night was unaffected by the drug. The fact that DEX selectively increased SWE during the first part of the night (despite higher exposure levels in the second part of the night), given that physiological slow-wave sleep is more prevalent in the first part of the night compared with the second part of the night, highlights the notion that DEX is a biomimetic sleep enhancer that does not disrupt physiological sleep architecture. [Figure 21] Cortisol awakening response (CAR; saliva) is shown: no drug effect on HPA axis activity after awakening; x-axis: 1 = awakening, 2 = 15 min, 3 = 30 min, 4 = 45 min, 5 = 60 min, 6 = 75 min. [Figure 22]Plasma melatonin release profile is shown: Drug administration has no effect on the melatonin release profile. [Figure 23] The number of awakenings during REM sleep is shown. As indicated by the asterisk, both 20 μg and 40 μg of DEX significantly reduced the number of awakenings during REM sleep, indicating REM sleep consolidation. This indicates that DEX has the ability to reduce REM sleep fragmentation (also known as restless REM sleep), which is typically caused by phasic bursts of noradrenergic activity, by blocking the locus coeruleus. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention will be described in the following embodiments, and it is understood that all disclosed features can be combined with each other.

[0045] In a first embodiment, the present invention relates to dexmedetomidine, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a sleep disorder in a subject.

[0046] Dexmedetomidine has the formula: [ka] This refers to a compound obtained by

[0047] Dexmedetomidine is also known as Precedex, Dexdol, and Igarumi. Preferably, the configuration of the asymmetric carbon atoms is as shown in the formula above. Therefore, preferably, the present invention encompasses only the enantiomer depicted in the formula above. Dexmedetomidine may also be referred to herein by the abbreviations Dex., dex., or DEX.

[0048] Those skilled in the art will recognize that dexmedetomidine can exist in different isomeric forms, particularly prototropic tautomeric forms. All such tautomeric forms are considered to be encompassed by the present invention. It is understood that dexmedetomidine may exhibit tautomerism. Thus, the formulas provided above explicitly represent only one of the possible tautomeric forms. The formulas and chemical names provided herein are intended to encompass any tautomeric form of the corresponding compound and are not limited to the specific tautomeric form merely depicted in the drawings or identified in the compound name.

[0049] In particular, as will be recognized by those skilled in the art, dexmedetomidine exists in two tautomeric forms, (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole and (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, which differ in the position of the H on the imidazole ring. Thus, when referring to dexmedetomidine, neither of these tautomeric forms is excluded; it is understood that both forms remain in equilibrium.

[0050] The term "pharmaceutically acceptable" indicates that a compound or composition, typically and preferably a salt or carrier, when typically and preferably used in a formulation or when typically and preferably used to treat an animal, preferably a human, must be chemically or toxicologically compatible with the other ingredient(s), typically and preferably a composition of the invention or part of a kit-of-parts of the invention. Preferably, the term "pharmaceutically acceptable" indicates that a compound or composition, typically and preferably a salt or carrier, when typically and preferably used in a formulation or when typically and preferably used to treat an animal, preferably a human, must be chemically and toxicologically compatible with the other ingredient(s), typically and preferably a composition of the invention or part of a kit-of-parts of the invention. Pharmaceutical compositions can be prepared using techniques known to those skilled in the art, for example, "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 2002. nd It should be noted that the formulation can be carried out according to techniques published in the US Pat. No. 6,629,499.

[0051] Thus, the scope of the present invention includes all pharmaceutically acceptable salt forms of dexmedetomidine that can be formed, for example, by protonation of an atom bearing a lone pair of electrons susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example, alkali metal salts such as sodium salts or potassium salts; alkaline earth metal salts such as calcium salts or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts.Exemplary acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, Organic acid salts such as glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate.

[0052] Preferred pharmaceutically acceptable salts of dexmedetomidine include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. A particularly preferred pharmaceutically acceptable salt of dexmedetomidine is hydrochloride. The present invention also relates to dexmedetomidine in particular in its non-salt form.

[0053] Furthermore, the scope of the present invention includes dexmedetomidine in any solvated form, including, for example, solvates with water (i.e., as hydrates) or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs) of dexmedetomidine, are also encompassed within the scope of the present invention. It is understood that such solvates and physical forms of pharmaceutically acceptable salts of dexmedetomidine are also encompassed within the present invention.

[0054] The scope of the present invention also preferably encompasses analogs of dexmedetomidine in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the present invention encompasses compounds according to the above formula in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by a deuterium atom (i.e., 2H; also referred to as "D"). Accordingly, the present invention also encompasses corresponding deuterium-enriched compounds. Naturally occurring hydrogen is an isotopic mixture containing approximately 99.98 mol% hydrogen-1 (1H) and approximately 0.0156 mol% deuterium (2H or D). The deuterium content at one or more hydrogen positions of the corresponding compounds can be increased using deuteration techniques known in the art. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise specifically specified, compounds of formula (I) are preferably not deuterium-enriched. Thus, naturally occurring hydrogen atoms or 1H hydrogen atoms are preferably present in compounds according to the above formula.

[0055] The term "treatment" of a disorder or disease, as used herein, is well known in the art. "Treatment" of a disorder or disease means that a subject is suspected of or diagnosed with the disorder or disease. A subject suspected of suffering from a disorder or disease typically exhibits specific clinical and / or pathological symptoms that one skilled in the art can readily attribute to a specific pathological condition (i.e., the disorder or disease can be diagnosed).

[0056] "Treatment" of a disorder or disease may, for example, result in the cessation of progression of the disorder or disease (e.g., symptoms do not worsen) or a slowing of progression of the disorder or disease (if the cessation of progression is only transient). "Treatment" of a disorder or disease may also result in partial remission (e.g., improvement of symptoms) or complete remission (e.g., disappearance of symptoms) in a subject / patient afflicted with a disorder or disease. Thus, "treatment" of a disorder or disease may refer to the amelioration of the disorder or disease, which may, for example, result in the cessation of progression of the disorder or disease or a slowing of progression of the disorder or disease. Such partial or complete remission may be followed by relapse. It is understood that a subject / patient may experience a wide range of responses to treatment (such as the exemplary responses described above in this specification). Treatment of a disorder or disease may include, inter alia, curative treatment (preferably leading to complete remission, and ultimately to a cure, of the disorder or disease) and symptomatic treatment (including alleviation of symptoms).

[0057] The term "prevention" of a disorder or disease, as used herein, is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may particularly benefit from prevention of that disorder or disease. A subject / patient may have a susceptibility or predisposition to a disorder or disease, including, but not limited to, a genetic predisposition. Such a predisposition can be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It is understood that the disorder or disease prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the subject (e.g., the subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of dexmedetomidine or a salt thereof in accordance with the present invention before any clinical and / or pathological symptoms have been diagnosed or determined or can be diagnosed or determined by the attending physician.

[0058] Preferably, the treatment or prevention of a sleep disorder in a subject according to the present invention is treatment of a sleep disorder in a subject.

[0059] As understood herein, a subject preferably refers to a human subject.

[0060] It is understood that dexmedetomidine or its salt is administered to a subject via a transmucosal administration route at a dose of 10 μg to 120 μg. It is understood that the dose of dexmedetomidine refers to the amount of pure dexmedetomidine, e.g., pure dexmedetomidine in a salt or solvate of dexmedetomidine. For example, in certain cases where dexmedetomidine is present in the form of a pharmaceutically acceptable salt, such amount may differ from the amount of the dexmedetomidine salt. As used herein, "mcg" stands for microgram, and μg or 10 -6 Also called g.

[0061] Preferably, dexmedetomidine or a salt thereof is administered at a dose of 20 μg to 120 μg, more preferably 40 μg to 120 μg.

[0062] Unless otherwise specified, the dose of dexmedetomidine described herein refers to a single bolus dose administered before sleep, i.e., before going to bed (for example, late at night).Therefore, the dose can be considered as a daily dose, and the daily dose is administered before the subject falls asleep.Therefore, preferably, in the present invention, dexmedetomidine is administered as a single bolus dose before falling asleep.

[0063] More preferably, dexmedetomidine or a salt thereof is administered at a dose of 40 μg to 80 μg.

[0064] Even more preferably, dexmedetomidine or a salt thereof is administered at a dose of 60 μg to 80 μg.

[0065] According to the present invention, dexmedetomidine or a salt thereof is administered to a subject via a transmucosal route. Transmucosal administration involves placing dexmedetomidine directly in contact with a mucous membrane, through which it is absorbed into the subject's bloodstream. Mucous membranes are membranes that line various cavities within an organism's body and cover the surfaces of internal organs. Mucous membranes consist of one or more layers of epithelial cells overlying a layer of loose connective tissue. Most are of endodermal origin and are continuous with the skin at body openings, such as the eyes, eyelids, ears, inside the nose, inside the mouth, lips, genitals, urethral opening, and anus. Transmucosal routes of administration therefore include intranasal, buccal, sublingual, vaginal, and rectal routes. These are non-invasive systemic drug delivery routes that can be self-administered or administered by a family caregiver. These administration methods are known to those skilled in the art. Those skilled in the art will appreciate that transmucosal administration may result in increased bioavailability and more rapid onset of action for some drugs compared to oral administration because the drug is absorbed directly into the bloodstream and does not pass through the digestive system, thereby avoiding first-pass metabolism.

[0066] Thus, preferably, dexmedetomidine or a salt thereof is administered to a subject via a transmucosal administration route selected from intranasal, buccal, sublingual, vaginal, and rectal administration routes.

[0067] Particularly preferred is transmucosal administration through the oral cavity. Thus, preferably, dexmedetomidine or a salt thereof is administered sublingually or bucally to a subject. As understood herein, sublingual administration of a medicament preferably refers to placing the medicament under the subject's tongue so that the medicament dissolves at that location and can be absorbed through the mucosa. As understood herein, buccal administration of a medicament preferably refers to placing the medicament between the subject's gums and cheek so that the medicament dissolves at that location and can be absorbed through the mucosa.

[0068] More preferably, dexmedetomidine or a salt thereof is administered to the subject buccally, which is less likely than sublingual administration to result in accidental oral administration due to the subject swallowing saliva containing dissolved medication.

[0069] Those skilled in the art can formulate dexmedetomidine or a pharmaceutically acceptable salt thereof into a form suitable for transmucosal administration, particularly by mixing appropriately selected and pharmaceutically acceptable excipients, vehicles, adjuvants, additives, surfactants, desiccants, or diluents. Suitable pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter. The pharmaceutically acceptable carriers of the present invention can be solid, semi-solid, or liquid.

[0070] Thus, dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated in accordance with the present invention as a tablet, orally dispersible tablet, mucoadhesive film, lyophilized agent, sachet, powder, granule, pellet, suppository, ointment, cream, lotion, gel, or paste. As will be apparent to those skilled in the art, the formulation may contain liposomes, micelles, and / or microspheres. Dexmedetomidine can also be formulated in the form of a film or patch, e.g., a buccal film, a buccal patch, a sublingual film, or in the form of droplets, e.g., droplets for sublingual administration, or a buccal spray. The film or patch formulation is prepared to be both mucus-adherent and soluble, so that the drug, dexmedetomidine, is released through the mucosa and then solubilized and eliminated, e.g., from the oral cavity.

[0071] Tablets or sachets are typically provided in dosage units and may contain conventional excipients, such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, colorants, flavoring agents, and wetting agents. Tablets may be coated according to methods well known in the art. Suitable fillers include or are preferred cellulose, mannitol, lactose, and similar agents. Suitable disintegrants include or are preferred starch, polyvinylpyrrolidone, and starch derivatives, such as sodium starch glycolate. Suitable lubricants include or are preferred, for example, magnesium stearate. Suitable wetting agents include or are preferred sodium lauryl sulfate. These solid compositions can be prepared by conventional blending, filling, or tableting methods. Blending operations may be repeated to disperse the active agent in compositions containing large amounts of filler. These operations are well known to those skilled in the art.

[0072] Liquid compositions may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats and oils; emulsifying agents, for example, lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol, or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; penetration enhancers, for example, dimethyl sulfoxide (DMSO); pH buffer systems, for example, phosphate buffers, carbonate buffers, citrate buffers, citrate-phosphate buffers, and other pharmaceutically acceptable buffer systems; solubilizing agents, for example, β-cyclodextrin, and, if desired, conventional flavorings or colorings.

[0073] Formulations for administration to the oral cavity may optionally further comprise a taste-masking component to optimize taste perception, examples of such taste-masking components may be citrus, licorice, mint, grape, blackcurrant, or eucalyptus flavors known to those skilled in the art.

[0074] Dosage forms for intranasal administration can include solutions, suspensions, or emulsions of the active compound in a liquid carrier in the form of nasal drops. Suitable liquid carriers include water, propylene glycol, and other pharmaceutically acceptable alcohols. When administered in the form of drops, the formulation can be conveniently placed in a container equipped with a conventional dropper / closure device, including, for example, a pipette, which preferably delivers a substantially constant volume of the composition / drops. The dosage form can be sterilized as needed. The dosage form can optionally contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying osmotic pressure, or buffers. Buffer systems can include, for example, phosphate buffers, carbonate buffers, citrate buffers, citrate-phosphate buffers, and other pharmaceutically acceptable buffer systems. The intranasal formulation can further include an optional odor-masking component to optimize odor.

[0075] Preferably, dexmedetomidine or a salt thereof is administered to a subject in the form of an orally dispersible tablet. An orally dispersible tablet, sometimes referred to as an orally disintegrating tablet (ODT), is herein preferably understood as a tablet configured to disintegrate (e.g., through effervescence or dissolution, preferably through dissolution) when placed in the oral cavity, for example, on the tongue, under the tongue, or between the gums and cheek, and release the medicament in the oral cavity as appropriate. As known to those skilled in the art, such tablets can be obtained by freeze-drying (lyophilizing) a solution containing dexmedetomidine or a pharmaceutically acceptable salt thereof and excipients. One typical excipient used in orally dispersible tablets is mannitol, which is known to those skilled in the art to increase binding and / or reduce the dissolution rate. Mannitol (which can be replaced by another sugar) typically serves as the primary diluent in orodispersible tablets and is also the primary factor responsible for their smooth, creamy mouthfeel. Other processes known to those skilled in the art for preparing orodispersible tablets include loose compression tableting, in which tablets are compressed with much less force (4-20 kN) than conventional tablets because they must be soft enough to disintegrate rapidly in the mouth. A lubricant, such as magnesium stearate, is added to the blend to reduce the amount of material that may stick to the die walls. Additionally, disintegration aids, such as crospovidone, and binders to improve mouthfeel, such as microcrystalline cellulose, are also typically used in formulating orodispersible tablets. Exemplary formulations of orodispersible tablets containing dexmedetomidine or a pharmaceutically acceptable salt thereof are provided in the Examples section.

[0076] The present invention further encompasses embodiments wherein dexmedetomidine (or an orodispersible tablet comprising same) is formulated by using templated carrier particles, preferably templated inverted particles, preferably comprising calcium phosphate and / or magnesium phosphate.

[0077] Therefore, as encompassed by the present invention, dexmedetomidine is preferably formulated using carrier particles. The carrier particles are not particularly limited, and any carrier particles known to those skilled in the art can be used within the present invention.

[0078] The term "carrier particles," as used herein, refers to a substance that is non-toxic or substantially non-toxic to a subject and can be used to improve the desired drug delivery properties of a solid pharmaceutical composition. The carrier particles described herein have no or substantially no therapeutic effect upon administration to a subject unless they are loaded with a therapeutic agent. In some embodiments, the carrier particles described herein are pharmacologically inactive unless they are loaded with a therapeutic agent. In some embodiments, the carrier particles described herein are insoluble or substantially insoluble in water. The desired drug delivery properties of a solid pharmaceutical composition described herein include, but are not limited to, efficacy, safety, pharmacokinetic properties (e.g., bioavailability), physical stability, chemical stability, drug loading capacity, and / or disintegration time. In some embodiments, the desired drug delivery properties of a solid pharmaceutical composition are physical stability, drug loading capacity, and disintegration time. In some embodiments, the desired drug delivery properties of the solid pharmaceutical composition include a high drug loading capacity of the solid pharmaceutical composition (e.g., a drug loading capacity of v / v ≥ 50%, ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, preferably ≥ 60%, more preferably 60% to 85%), a short disintegration time of the solid pharmaceutical composition (e.g., ≤ 15 s, ≤ 14 s, ≤ 13 s, ≤ 12 s, ≤ 11 s, ≤ 10 s, preferably ≤ 10 s), and / or physical stability (e.g., ≥ 200 N, ≥ 210 N, ≥ 220 N, ≥ 230 N, ≥ 240 N, or ≥ 250 N for an 11 mm tablet). For 1 / 2 mm tablets, the tablet hardness is ≧40N, ≧50N, ≧60N, preferably ≧50N for 6 mm tablets. The carrier particles as described herein can have any shape, and preferably the carrier particles described herein have a shape similar to a sphere, a spheroid, and / or a bead. Removal of the template material can result in at least one pore in an otherwise substantially uniform structure. The carrier particles can preferably form a hollow structure in a dry environment. Thus, the carrier particles described herein do not disintegrate or do not substantially disintegrate when dried.

[0079] It is understood that dexmedetomidine formulated as carrier particles can be formulated as an orodispersible tablet. Thus, the carrier particles loaded with dexmedetomidine can be compressed together to form a tablet. Depending on the disintegration properties of the tablet, the tablet may be orodispersible. Those skilled in the art can formulate and / or administer the orodispersible particles.

[0080] Preferably, as referred to herein, the carrier particles are templated carrier particles, preferably templated inversion particles, sometimes referred to as TIP particles. The techniques for producing and using TIP particles are described in detail in International Patent Application No. PCT / EP2022 / 051799, which is incorporated herein by reference in its entirety. The techniques for producing and using TIP particles are also described below. Preferably, in the event of any discrepancy between the following description and the description contained in International Application No. PCT / EP2022 / 051799 (which is incorporated herein by reference), the latter shall prevail.

[0081] The templated inverted particles are sometimes referred to as support particles having a secondary internal structure. As described in International Patent Application No. PCT / EP2022 / 051799, a method for producing support particles having a secondary internal structure includes the steps of: a) combining a support material with a template material, wherein the support material forms a primary structure around the template material; b) deforming the template material; c) removing the deformed template material; and d) obtaining support particles having a secondary internal structure.

[0082] Surprisingly, it has been found that when produced using template materials that have undergone modification as described herein, carrier particles exhibit desirable drug delivery properties.

[0083] Therefore, whenever reference is made to the above-mentioned support particles, it is preferably meant to refer to particles that can be obtained according to the above-mentioned method for producing support particles with a secondary internal structure.

[0084] The term "primary structure," as used herein, refers to a layer of support material that encompasses the template material. In some embodiments, the primary structure includes additional structural elements (e.g., petals as) that increase the surface area of the support particle.

[0085] The term "secondary internal structure," as used herein, means a hollow internal structure having a high concentration of crystallization initiation sites on the inner surface of the hollow internal structure, thus allowing crystallization within the support particle.

[0086] The term "support material," as used herein, refers to a material or mixture that constitutes the raw material for the support particles described herein. In some embodiments, the support materials described herein are inorganic salts or comprise inorganic salts to a substantial extent. In some embodiments, the support materials described herein are insoluble or sparingly soluble in water. In some embodiments, the support materials are soluble in a solvent. In some embodiments, the support materials or precursors to the support materials are liquids. In some embodiments, the support materials described herein are non-polymeric or comprise non-polymeric to a substantial extent. The term "template material," as used herein, refers to a solid material comprising particles suitable for functioning as a template to enable the formation of the primary structure of the support particles. The particles in the template material preferably have a spherical, spheroidal, and / or beaded shape. In some embodiments, the template materials described herein are non-polymeric or comprise non-polymeric to a substantial extent. In some embodiments, the template materials described herein have a uniform or nearly uniform particle size distribution. In some embodiments, the template materials described herein have a distribution width (defined by the formula (D90-D10) / D50) of about ≦5, about ≦4.5, about ≦4, about ≦3.5, about ≦3, about ≦2.8, about ≦2.4, about ≦2, about ≦1.8, about ≦1.6, about ≦1.4, about ≦1.2, about ≦1, about ≦0.9, about ≦0.8, about ≦0.7, about ≦0.6, about ≦0.5, about ≦0.4, about ≦0.3, about ≦0.2, or about ≦0.1. Thus, the template material can be any material that is deformable and stable enough to hold the support material. To avoid dissolution of the template material during the process of combining the support material with the template material, a template material that is poorly soluble in the combination liquid should be used. In some embodiments, the template materials described herein are sparingly soluble in at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran.In some embodiments, the template materials described herein are poorly soluble in water. In some embodiments, the template materials described herein are poorly soluble in aqueous solutions containing a solubility modifier (e.g., salt water). In some embodiments, the term "poorly soluble" as used herein refers to a solubility at 25°C of about <100 mg / L, <80 mg / L, <60 mg / L, <40 mg / L, <20 mg / L, <10 mg / L, <9 mg / L, <8 mg / L, <7 mg / L, <6 mg / L, <5 mg / L, <4 mg / L, <3 mg / L, <2 mg / L, <1 mg / L, <0 mg / L, .9mg / L, <0.8mg / L, <0.7mg / L, <0.6mg / L, <0.5mg / L, <0.4mg / L, <0.3mg / L, <0.2mg / L, <100μg / L, < 90μg / L, <80μg / L, <70μg / L, <60μg / L, <50μg / L, <40μg / L, <30μg / L, <25μg / L, or <20μg / L.

[0087] In some embodiments, the template materials described herein comprise a salt. In some embodiments, the template materials described herein comprise an organic salt. In some embodiments, the template materials described herein are or comprise to a substantial extent a carbonate. In some embodiments, the template materials described herein comprise a basic oxide.

[0088] The term "transforming," as used herein, refers to changing the properties of a template material through at least one physical process and at least one chemical process that, when combined, allow for the removal of the template material. The physical process of "transforming" involves providing energy to the material. In some embodiments, the energy is applied in the form of an increase in temperature and / or a change in pressure. In some embodiments, the physical process of "transforming" involves inducing an endothermic chemical reaction in the template material. The chemical process of "transforming" involves providing a chemical reactant to the template material. In some embodiments, the reactant provided in the chemical process of "transforming" reacts with the template material but does not or does not substantially react with the support material. In some embodiments, the chemical reactant provided in the chemical process of "transforming" is provided in liquid, dissolved, and / or gaseous form.

[0089] Thus, the carrier particles described herein are carrier particles with a secondary internal structure. In some embodiments, without being bound by theory, these secondary internal structures enable high drug loading because the carrier particles can load drugs not only on the surface of the carrier particles but also within the secondary internal structure. The loaded agent or drug can leave the carrier by diffusing through the porous carrier walls. In some embodiments, the carrier particles have a certain stability at the target site (e.g., on the mucosa of a patient). Thus, these carrier particles can remain at the target site (e.g., by adhering to the mucosa), enabling specific drug delivery. In some embodiments, the carrier particles mask the unpleasant taste of the loaded agent because the loaded agent is continuously released at the absorption site. The release rate of the loaded agent can be controlled by the shape of the template material and / or a diffusion rate modifier such as a disintegrant. Therefore, the diffusion of the unpleasant taste to the perceived location (e.g., the tongue) is reduced.

[0090] The secondary internal structure described herein allows for efficient drug loading within the carrier particles. Furthermore, the secondary internal structure is accessible via pores, for example, for solvent loading. In some embodiments, the carrier particles can be loaded with less effort and / or have particularly high loading capacity.

[0091] In some embodiments, the carrier particles have a particularly large surface area that is beneficial to interparticle forces. These interparticle forces act between the carrier particles in the absence of water, increasing the mechanical stability of the carrier particle mass. This increased mechanical stability reduces the need for additional stabilizing materials when the carrier particles are used in solid pharmaceutical compositions, such as tablets. In some embodiments, the interparticle forces acting between the carrier particles can be attenuated by water, thereby shortening the disintegration time of solid pharmaceutical compositions, such as tablets, that include the carrier particles described herein.

[0092] In certain embodiments, the support material is or consists primarily of an inorganic material.

[0093] The term "consisting essentially of," when used herein in the context of a material, refers to consisting of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the material.

[0094] In certain embodiments, the support material and template material are or consist primarily of inorganic salts.

[0095] The carrier particles described herein have secondary internal structures that are beneficial for enhancing one or more desired drug delivery properties.

[0096] In the process of producing the particles, the template material is preferably suspended in a liquid before combining the support material with the template material.

[0097] The template material can be suspended in a combination liquid (e.g., water) with stirring in a reaction vessel. A set stirring speed ensures stable turbulent mixing that prevents particle aggregation, allowing the particles to be individually processed.

[0098] In certain embodiments, combining the support material with the template material comprises adding the template material described herein and the support material described herein to a combined solution. In some embodiments, the combined solution described herein is at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran. In some embodiments, the combined solution described herein is water. In some embodiments, the combined solution described herein is an aqueous solution containing a solubility modifier (e.g., salt water).

[0099] To avoid dissolution of the template material during the process of combining the support material with the template material, an appropriate ratio of the amount of template material to the amount of combination liquid should be used, which depends on the solubility of the template material in the combination liquid. In some embodiments, the amounts of template material and combined liquid are selected such that less than about 0.05% (w / w), less than about 0.04% (w / w), less than about 0.03% (w / w), less than about 0.02% (w / w), less than about 0.01% (w / w), less than about 0.0095% (w / w), less than about 0.009% (w / w), less than about 0.0085% (w / w), less than about 0.0008% (w / w), less than about 0.0075% (w / w), less than about 0.007% (w / w), less than about 0.0065% (w / w), less than about 0.06% (w / w), less than about 0.0055% (w / w), or less than about 0.005% (w / w) of the template material is soluble in the combined liquid.

[0100] In certain embodiments, combining the support material with the template material comprises chemical precipitation, deposition, and / or crystallization of the support material onto the template material. The term "chemical precipitation," as used herein, refers to the process of converting a chemical substance from a solution into a solid by converting the substance into an insoluble form.

[0101] In certain embodiments, a precursor of the support material is combined to form the support material in a chemical reaction with the surface of the template material, hi some embodiments, the soluble precursor of the support material described herein is phosphoric acid.

[0102] Conversion grade refers to embodiments in which precursors of the support material are combined to form the support material upon chemical reaction with the surface of the template material. Too low a conversion grade can result in particles with holes or broken shells, while too high a conversion can reduce the size of the internal cavities and produce more external crystals, such as dicalcium phosphate, which further transform into hydroxyapatite slabs. In some embodiments, the conversion grades described herein are between about 30% and about 60%, between about 35% and about 55%, or between about 40% and about 50%.

[0103] The temperature during chemical precipitation described herein can have a substantial effect on the material. For example, dicalcium phosphate, as it is, is a less thermodynamically stable form than hydroxyapatite. Therefore, too low a temperature and too rapid or uncontrolled addition of orthophosphate to calcium carbonate can induce its precipitation, producing more dicalcium phosphate and, consequently, more discrete crystals that are more difficult to process. In some embodiments, the temperature during chemical precipitation is about 60°C or higher, preferably about 60°C to about 100°C, more preferably about 70°C to about 95°C, and even more preferably about 80°C to about 95°C.

[0104] In certain embodiments, a soluble precursor of the support material is added to the template material in solution and distributed onto the template material by the addition of a reactant that converts the soluble precursor of the support material to an insoluble support material. In some embodiments, the soluble precursor of the support material described herein is sodium phosphate or calcium chloride (e.g., Despotovie, R., et al., 1975, Calc. Tis Res. 18, 13-26).

[0105] The term "lamination," as used herein, refers to the technique of adding at least one layer of support onto the template material.

[0106] Any lamination technique known in the art can be used (see, for example, Decher, GHJD, et al., 1992, Thin solid films, 210, 831-835; Donath, E., et al., 1998, Angewandte Chemie International Edition, 37(16), 2201-2205; Caruso, F, et al., 1998, Science, 282(5391), 1111-1114). In some embodiments, for preparing at least one layer on the template material, and in particular for preparing a multilayer film on the template material, electrostatic interactions (e.g., as described in Decher, GHJD, et al., 1992, Thin solid films, 210, 831-835), hydrogen bonds (e.g., as described in Such, GK et al., 2010, Chemical Society Reviews, 40(1), 19-29), hydrophobic interactions (e.g., as described in Serizawa, T., Kamimura, S., et al., 2002, Langmuir, 18(22), 8381-8385), and / or covalent bonds (e.g., as described in Zhang, Y., et al., 2003, Macromolecules, 36(11), 4238-4240), electroplating and electrodeposition (e.g., Chandran, R., Panda, SK & Mallik, AA short review on the advancements in electroplating of CuInGaSe2 thin films (as described in Mater Renew Sustain Energy 7, 6 (2018)) are used.

[0107] The term "crystallization," as used herein, refers to the process of conversion of a chemical substance from a supersaturated solution.

[0108] In certain embodiments, the support material is added to the template material in a supersaturated solution and distributed onto the template material by initiating chemical precipitation.

[0109] In certain embodiments, combining the support material with the template material comprises chemical precipitation and crystallization of the support material onto the template material.

[0110] In certain embodiments, combining the support material with the template material includes chemical deposition and crystallization of the support material onto the template material.

[0111] In certain embodiments, combining the support material with the template material comprises chemical precipitation and lamination of the support material onto the template material.

[0112] The chemical precipitation process can be carried out by delivering a solution of a precursor of the template material onto the support material or into a liquid containing the support material. During this process, the support material can begin to grow (e.g., in the form of a crystalline lamellar structure) on the surface of the template material, thereby forming a stratum layer. In certain embodiments, the template material described herein is converted to the support material. In certain embodiments, the template material described herein is at least about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% converted to the support material.

[0113] Chemical precipitation, layering, and / or crystallization can provide a fine and / or uniform distribution of the support material on the template material, which influences the formation of secondary internal structures.

[0114] Thus, the support particles produced as described herein exhibit a particularly fine and / or uniform secondary internal structure through the use of chemical precipitation, layering, and / or crystallization of the support material onto the template material.

[0115] In certain embodiments, transforming the template material comprises heating to a temperature of about 600°C to about 1200°C, preferably about 600°C to about 900°C, preferably about 600°C to about 839°C, preferably about 650°C to about 700°C.

[0116] In certain embodiments, transforming the template material comprises heating to a temperature between 840°C and 1200°C.

[0117] Conditions can be optimized to avoid interparticle condensation during the heating step, which can lead to redispersibility problems. In some embodiments, no additional agent is required to prevent interparticle condensation, while in other embodiments, an agent to prevent interparticle condensation (e.g., a calcination inhibitor) is added during and / or before the heating step described herein. Such calcination inhibitors are described, for example, in Okada, M., et al., 2014, Journal of nanoparticle research, 16(7), 1-9.

[0118] The deformation of the template material described herein can be carried out at any suitable temperature or in any suitable temperature range. To enable the deformation of the template material described herein, the minimum optimum temperature for deformation is set to a specific temperature, such as about 210°C (e.g., when silver carbonate and gold carbonate are used as the template material), about 840°C (e.g., when calcium carbonate is used as the template material), about 900°C, about 1000°C, or about 1200°C (e.g., when potassium carbonate and / or sodium carbonate are used as the template material). Those skilled in the art can identify an appropriate minimum optimum temperature based on the decomposition temperature of the template material. Increasing the temperature can shorten the deformation time, but melting the support material may have undesirable effects on the support particles, such as the formation of incomplete support particles or a decrease in the hardness of the support particles. To avoid melting the support material, the maximum optimum temperature for deformation of the template material described herein is set below the melting temperature of the support material. Distortion and / or loss of desired structures (e.g., petals on the surface of the support particle) that increase the surface area of the support particle may already occur at temperatures below the melting temperature of the support material. Thus, in certain embodiments, the maximum suitable temperature for the transformation of the template material described herein is set to about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C below the melting temperature of the support material.

[0119] In certain embodiments, transforming the template material comprises heating from about a decomposition temperature of the template material to about a melting temperature of the support material, preferably from about a decomposition temperature of the template material to about 400° C. below the melting temperature of the support material, and more preferably from about a decomposition temperature of the template material to about 500° C. below the melting temperature of the support material.

[0120] In certain embodiments, transforming the template material comprises heating to a temperature between 840°C and 1600°C, preferably between 840°C and 1200°C, and more preferably around 1100°C.

[0121] The duration of heating to transform the template material described herein depends on various factors, such as the template material, the support material, the temperature range, the particle size, and / or the desired support particle surface area.

[0122] The duration of heating to transform the template materials described herein can be, for example, about 1 hour. In certain embodiments, the duration of heating to transform the template materials described herein is from about 5 minutes to about 24 hours, from about 10 minutes to about 12 hours, or from 20 minutes to about 4 hours.

[0123] Heating to transform the template material described herein (e.g., to a specific temperature range, e.g., 840°C to 1200°C or 600°C to 900°C) can be accomplished by any heating pattern, such as a linear increase in temperature, or with one or more preheating steps. The preheating steps described herein can include holding the temperature at a specific temperature level for a period of time before heating the template material to a specific temperature range, e.g., 840°C to 1200°C or 600°C to 900°C. Preheating can remove undesirable volatile components, such as solvents.

[0124] In some embodiments, the pressure is reduced during heating to a temperature range, for example, 840° C. to 1200° C., to deform the template material.

[0125] In some embodiments, the pressure is increased during heating to a temperature range, for example, 840° C. to 1200° C., to deform the template material.

[0126] In some embodiments, the application of heat to transform the template material induces an endothermic chemical reaction.

[0127] In some embodiments, an inert substance (e.g., a noble gas) is provided to avoid side reactions during heating to a specific temperature range, e.g., 840°C to 1200°C, to transform the template material.

[0128] In some embodiments, the application of heat to transform the template material induces evaporation of a volatile fraction of the template material.

[0129] Heating to a certain temperature range, e.g., 840°C to 1200°C, can initiate deformation of the template material while leaving the carrier material unchanged, or not to the same extent. This allows for removal of the deformed template material based on its altered properties. Lower temperatures (e.g., about 600°C to about 839°C or about 600°C to about 900°C) can be used to better preserve the petal structure, thereby increasing the hardness of the resulting tablet.

[0130] If the temperature is higher than the recommended range, the fine petal structure of the particles melts and reduces, reducing the flexibility of the petals, resulting in a significant decrease in the hardness of tablets produced using such overheated materials. Pharmaceutical compacts made using overheated materials exhibit capping and lamination and cannot be used equally well in pharmaceutical formulations.

[0131] Thus, the heating step to deform the template material allows for the production of carrier particles with secondary internal structures beneficial for enhancing one or more desired drug delivery properties.

[0132] In certain embodiments, the step of transforming the template material comprises calcination.

[0133] The term "calcination," as used herein, refers to heating a solid or a mixture containing a solid to an elevated temperature (e.g., a temperature between 840°C and 1200°C or between 600°C and 900°C) while supplying air or oxygen to the solid or mixture.

[0134] In some embodiments, the calcination described herein induces the decomposition of a template material that includes a carbonate (eg, a carbonate such as calcium carbonate) to carbon dioxide.

[0135] In some embodiments, the calcination described herein induces the decomposition of template materials containing metal carbonates into metal oxides, preferably basic oxides.

[0136] In some embodiments, the calcination described herein induces decomposition of the hydrated template material by removing water.

[0137] In some embodiments, the calcination described herein induces decomposition of volatiles in the template material.

[0138] Thus, the calcination process to transform the template material allows for the production of carrier particles with secondary internal structures beneficial for enhancing one or more desired drug delivery properties.

[0139] In certain embodiments, transforming the template material includes the subsequent addition of water.

[0140] Subsequent addition of water transforms the template material in a chemical reaction, but leaves the support material unchanged or substantially unchanged, allowing the transformed template material to be removed based on its altered properties.

[0141] In some embodiments, water that is subsequently added as described herein reacts with the metal oxide.

[0142] Thus, modified processing methods involving the addition of water allow for the production of carrier particles with secondary internal structures beneficial for enhancing one or more desired drug delivery properties.

[0143] In certain embodiments, the addition of water allows for an exothermic reaction.

[0144] The term "exothermic reaction," as used herein, refers to a reaction in which the overall standard enthalpy change is negative.

[0145] Subsequent addition of water as described herein transforms the template material in an exothermic chemical reaction, but does not or does not substantially transform the support material, allowing the transformed template material to be removed based on its altered properties.

[0146] The basic oxides described herein are non-toxic or substantially non-toxic at the dosages used as described herein. In some embodiments, water subsequently added as described herein reacts with the basic oxide. In some embodiments, water subsequently added as described herein reacts with at least one basic oxide selected from the group consisting of lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide, barium oxide, and bismuth (III) oxide. In some embodiments, water subsequently added as described herein reacts with magnesium oxide and / or calcium oxide.

[0147] The exothermic reactions described herein can facilitate subsequent removal of the template material. The forces released during the exothermic reaction and / or the properties of the products of the exothermic reaction can decrease density and / or increase solubility. For example, a density of 3.34 g / cm 3 The exothermic reaction of calcium oxide with water produces a solution with a density of 2.21 g / cm 3 of calcium hydroxide is produced.

[0148] Thus, the addition of water through an exothermic reaction aids in the formation of secondary structures and facilitates the subsequent removal of the template material.

[0149] In certain embodiments, removing the template material includes dissolving the transformed template material to form a secondary internal structure.

[0150] A secondary internal structure can be formed by removing the deformed template material by dissolving it in a solvent that dissolves the deformed template material but not the carrier material.

[0151] In some embodiments, removing the template material comprises dissolving the modified template material in water or an aqueous solution, hi some embodiments, the pH of the aqueous solution is altered prior to dissolving the modified template material to increase the solubility of the modified template material or decrease the solubility of the carrier material in the aqueous solution.

[0152] In some embodiments, removing the template material comprises dissolving the transformed template with an organic solvent.

[0153] Removal of the template material by dissolution is particularly gentle to the carrier material, thus helping to maintain the primary carrier material structure and allowing the formation of secondary internal structures that are particularly beneficial for crystallization during the drug loading process.

[0154] Thus, removing the template material includes dissolving the deformed template material to aid in the formation of the secondary internal structure.

[0155] In certain embodiments, the template material comprises a metal carbonate.

[0156] In certain embodiments, the template material is Li2CO3, LiHCO3, Na2CO 3、 NaHCO3, Na3H(CO3) 2、 MgCO 3、Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO 3、 It contains at least one metal carbonate selected from the group of Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3.

[0157] In certain embodiments, the template material comprises at least one metal selected from the group consisting of Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt, and Sn. In certain embodiments, the template material comprises at least one non-metal selected from the group consisting of Si, S, Sb, I, and C.

[0158] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% metal carbonate.

[0159] In certain embodiments, the template material is greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% Li2CO3, LiHCO3, Na2CO3 3、 NaHCO3, Na3H(CO3) 2、 MgCO 3、 The composition comprises at least one metal carbonate selected from the group consisting of Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO3, Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3.

[0160] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% magnesium carbonate.

[0161] In certain embodiments, the template material comprises calcium carbonate.

[0162] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% calcium carbonate.

[0163] In some embodiments, calcium carbonate described herein includes anhydrous calcium carbonate, complexes containing calcium carbonate, and / or hydrated calcium carbonate, such as CaCO3·H2O, and / or calcium carbonate hexahydrate.

[0164] In some embodiments, the calcium carbonate described herein is anhydrous calcium carbonate.

[0165] The metal carbonates described herein can be used as a basis to generate support materials with well-defined properties on the surface of a template material (e.g., insoluble metal phosphates by reaction of the metal carbonate with H3PO4), which can be modified as described herein.

[0166] In certain embodiments, the carrier material comprises at least one salt and / or complex selected from the group of calcium phosphate and magnesium phosphate.

[0167] In certain embodiments, the support material comprises at least one salt and / or complex of magnesium phosphate.

[0168] In certain embodiments, the carrier material comprises at least one salt and / or complex of calcium phosphate.

[0169] Calcium and magnesium phosphates have particularly low solubility in water and moderate heat resistance. Furthermore, calcium and magnesium phosphates are generally pharmacologically inactive and non-toxic. Therefore, calcium and magnesium phosphates are robust and non-toxic, allowing for the transformation of the template materials described herein without decomposition.

[0170] Thus, the production of carrier particles as described herein is particularly efficient when the carrier material comprises at least one salt and / or complex selected from the group of calcium phosphate and magnesium phosphate.

[0171] Preferably, carrier particles encompassed by the present invention comprise calcium phosphate and / or magnesium phosphate, more preferably, carrier particles encompassed by the present invention comprise calcium phosphate.

[0172] Preferably, the calcium phosphate is present in the form of hydroxyapatite. As referred to herein, hydroxyapatite is a material according to the formula Ca5(OH)(PO4)3.

[0173] Therefore, preferably, the carrier particles included in the present invention contain hydroxyapatite, and more preferably, the carrier particles included in the present invention further contain calcium hydroxide.

[0174] Preferably, therefore, the present invention relates to an embodiment in which dexmedetomidine (or an orodispersible tablet comprising dexmedetomidine) can be formulated by using carrier particles having a secondary internal structure, the carrier particles comprising hydroxyapatite and optionally calcium chloride. Preferably, the content of hydroxyapatite in the particles (not loaded with dexmedetomidine) is at least 80% w / w, preferably at least 90% w / w, more preferably at least 95% w / w, even more preferably at least 99% w / w, and even more preferably about 100% w / w.

[0175] The template material can have various structures, such as powders (e.g., powders having a D50 of approximately 1.9 μm, 2.3 μm, 3.2 μm, 4.5 μm, 5.5 μm, 6.5 μm, or 14 μm; powders having particle sizes ranging from approximately 1 to 100 μm, 100 μm to 300 μm, or 300 μm to 600 μm) or nanoparticles.

[0176] In certain embodiments, the template material comprises particles having a diameter of 1 to 300 μm. In certain embodiments, the template material consists of particles in which about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99% of the particles have a diameter of 1 to 300 μm. In certain embodiments, the template material comprises particles having a median particle size of about 1 to 300 μm, about 1 to 250 μm, about 1 to 200 μm, about 1 to 150 μm, about 1 to 100 μm, about 1 to 90 μm, about 1 to 80 μm, about 1 to 70 μm, about 1 to 60 μm, about 1 to 50 μm, about 1 to 40 μm, about 1 to 30 μm, or about 1 to 20 μm.

[0177] The particle size of the template material affects the diameter of the support particles. In certain embodiments, the particles of the template material have a median particle size that is approximately the same as the median particle size of the support particles. In embodiments in which the template material and support material are combined by layering and / or crystallization as described herein, the support particles have a similar or larger median particle size compared to the template material.

[0178] In embodiments where the template material and support material are combined by chemical precipitation as described herein, the support particles have a similar or smaller median particle size compared to the template material.

[0179] One skilled in the art can predict the support material from the template material, the support material, and the techniques used to combine the template material and the support material described herein.

[0180] In certain embodiments, the carrier particles have a diameter of between 1 and 300 μm.

[0181] Particles of a particular size can be obtained by methods known in the art, including grinding and sieving (see, for example, Patel, RP, et al., 2014, Asian Journal of Pharmaceutics (AJP), 2(4); David, J., and Peter, R., 2006, Fundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation, 247; U.S. Patent No. 5,376,347A). Particle size and shape measurements can be performed using any method known in the art, such as laser diffraction or in situ microscopy (Kempkes, M., Eggers, J., & Mazzotti, M., 2008, Chemical Engineering Science, 63(19), 4656-4675; Allen, T. (2013). Particle size measurement. Springer).

[0182] In some applications, particularly small carrier particle sizes are desirable. In certain embodiments, the carrier particles have diameters of about 1-20 μm, about 1-15 μm, about 1-10 μm, or about 1-5 μm for use in pulmonary and / or intranasal administration. In some applications, particularly small carrier particle sizes are desirable to increase the diffusion surface and facilitate release of the loaded agent.

[0183] In some applications, larger support particle sizes are desirable to improve the flowability of the support particles and facilitate further processing. In certain embodiments, the support particles have diameters of about 5-300 μm, about 10-250 μm, about 15-200 μm, or about 20-150 μm.

[0184] Thus, the methods of producing carrier particles described herein, in which the carrier particles have a particular range of diameters, may be particularly useful for further processing (e.g., flowability) and / or application (e.g., spreading surfaces) of the carrier particles produced according to the methods.

[0185] In certain embodiments, the carrier particles are 15 m2 / g~400m 2 / g or 30m 2 / g~400m 2 / g of surface area.

[0186] In certain embodiments, the support particles have a surface area of about 15 m as measured by five-point Brunnauer-Emmet-Teller (BET) surface area analysis using nitrogen as the gas. 2 / g~400m 2 / g approx. 30m 2 / g~400m 2 / g, approx. 50m 2 / g~350m 2 / g, approx. 70m 2 / g~320m 2 / g, approx. 90m 2 / g~300m 2 / g, or approximately 100m 2 / g~280m 2 / g of surface area.

[0187] Alternatively, the surface area of the carrier particles can be measured by any method known in the art (see, for example, Akashkina, LV, Ezerskii, ML, 2000, Pharm Chem J 34, 324-326; Bauer, JF, 2009, Journal of Validation Technology, 15(1), 37-45).

[0188] The surface area of the support particles can be varied, for example, by modifying the particle size of the support material, the support material, and / or the surface structure by the parameters described herein (eg, heat, duration of heating).

[0189] In certain embodiments, the carrier particles are used as adsorbents.

[0190] The larger specific surface area of the carrier particles described herein allows for stronger van der Waals interactions when the particles are brought into contact, which results in higher tensile strength in the final dosage form. These van der Waals interactions can be weakened by the addition of water, which can aid in the breakup of particle agglomerates.

[0191] Therefore, the method for producing carrier particles described herein is 2 / g~400m 2 / g, preferably 30m 2 / g~400m 2 / g provides mechanical stability and disintegration ability.

[0192] In certain embodiments, the secondary internal structure comprises pores having diameter sizes in the range of ≧0.2 μm and ≦1.5 μm.

[0193] In certain embodiments, the secondary internal structure comprises pores having a diameter size of ≧about 0.2 μm, ≧about 0.3 μm, ≧about 0.4 μm, ≧about 0.5 μm, ≧about 0.6 μm, ≧about 0.7 μm, ≧about 0.8 μm, ≧about 0.9 μm, ≧about 1 μm, ≧about 1.1 μm, ≧about 1.2 μm, ≧about 1.3 μm, or ≧about 1.5 μm.

[0194] In certain embodiments, the secondary internal structure comprises pores having diameter sizes ranging from about ≧0.2 μm to ≦1.5 μm, about ≧0.3 μm to ≦1.5 μm, about ≧0.4 μm to ≦1.5 μm, about ≧0.5 μm to ≦1.5 μm, about ≧0.6 μm to ≦1.5 μm, about ≧0.7 μm to ≦1.5 μm, about ≧0.8 μm to ≦1.5 μm, about ≧0.9 μm to ≦1.5 μm, about ≧1 μm to ≦1.5 μm, about ≧1.1 μm to ≦1.5 μm, about ≧1.2 μm to ≦1.5 μm, or about ≧1.3 μm to ≦1.5 μm.

[0195] The pore size of the carrier particles can be measured by any method known in the art (see, for example, Markl, D. et al., 2018, International Journal of Pharmaceutics, 538(1-2), 188-214).

[0196] The porous structure that can be formed by the methods of producing carrier particles described herein allows for particularly large pore sizes, which facilitate drug loading into the carrier particles and accelerate drug release from the carrier particles.

[0197] If the pore size diameter exceeds 90% of the particle size of the template material, the support particles become unstable. Therefore, the maximum pore size depends on the particle size of the template material.

[0198] In certain embodiments, the secondary internal structure comprises pores having diameter sizes of about ≦270 μm, about ≦225 μm, about ≦180 μm, about ≦135 μm, about ≦90 μm, about ≦81 μm, about ≦72 μm, about ≦63 μm, about ≦54 μm, about ≦45 μm, about ≦36 μm, about ≦27 μm, or about ≦18 μm in diameter. Thus, the methods of producing carrier particles described herein, in which the secondary internal structure comprises pores with particular diameter sizes, are particularly useful for subsequent drug loading and drug release of the carrier particles produced as described herein.

[0199] In certain embodiments, the total volume of the secondary internal structure in the resulting support particles having a secondary internal structure is in the range of ≧10% to ≦90% of the particle volume, as determined by SEM-FIB and SEM image analysis of cross-sectional images of the resin-embedded particles. Another analytical method for measuring the internal structure and particle volume ratio includes calculating the porosity as the ratio of the tapped bulk of the support material to the true crystalline density of the support material.

[0200] The total volume of secondary internal structures refers to the internal volume within the particle resulting from the removal of template material. In certain embodiments, the total volume of secondary internal structures described herein is the average internal volume of the support particle obtained as described herein.

[0201] In certain embodiments, the total volume of the secondary internal structure described herein is the central internal volume of the carrier particle obtained as described herein.

[0202] In certain embodiments, the total volume of the secondary internal structures in the resulting carrier particles having secondary internal structures is greater than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume.

[0203] In certain embodiments, the total volume of the secondary internal structures in the resulting carrier particles having secondary internal structures is greater than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume.

[0204] In certain embodiments, the total volume of the secondary internal structures in the resulting support particles having secondary internal structures is about ≧10% to ≦90%, about ≧15% to ≦90%, about ≧20% to ≦90%, about ≧25% to ≦90%, about ≧30% to ≦90%, about ≧35% to ≦90%, about ≧40% to ≦90%, about ≧45% to ≦90%, about ≧50% to ≦90%, about ≧55% to ≦90%, about ≧60% to ≦90% of the particle volume. %, approximately ≧65%~≦90%, approximately ≧70%~≦90%, approximately ≧10%~≦80%, approximately ≧15%~≦80%, approximately ≧20%~≦80%, approximately ≧25%~≦80%, approximately ≧30%~≦80%, approximately ≧35%~≦80%, approximately ≧40%~≦80%, approximately ≧45%~≦80%, approximately ≧50%~≦80%, approximately ≧55%~≦80%, approximately ≧60%~≦80%, approximately ≧65%~≦80%, approximately ≧70%~≦80%, approximately ≧ 10%~≦70%, approximately ≧15%~≦70%, approximately ≧20%~≦70%, approximately ≧25%~≦70%, approximately ≧30%~≦70%, approximately ≧35%~≦70%, approximately ≧40%~≦70%, approximately ≧45%~≦70%, approximately ≧50%~≦70%, approximately ≧55%~≦70%, approximately ≧60%~≦70%, approximately ≧65%~≦70%, approximately ≧10%~≦60%, approximately ≧15%~≦60%, approximately ≧20%~≦60%, approximately ≧25% ~≦60%, about ≧30%~≦60%, about ≧35%~≦60%, about ≧40%~≦60%, about ≧45%~≦60%, about ≧50%~≦60%, about ≧55%~≦60%, about ≧10%~≦50%, about ≧15%~≦50%, about ≧20%~≦50%, about ≧25%~≦50%, about ≧30%~≦50%, about ≧35%~≦50%, about ≧40%~≦50%, or about ≧45%~≦50%.

[0205] In certain embodiments of the carrier particles described herein and obtainable as described above, the carrier particles have a loading capacity of ≧72% v / v, ≧70% v / v, ≧68% v / v, ≧66% v / v, ≧64% v / v, ≧62% v / v, or ≧60% v / v.

[0206] In certain embodiments of the carrier particles described herein, the carrier particles have a loading capacity of ≧60% v / v.

[0207] The term "loading capacity" as used herein refers to the volume of a carrier particle that can be used to load an agent compared to the total volume of the carrier particle. Thus, a carrier particle with a loading capacity of 60% v / v can load 60% of the agent of the volume of the carrier particle. The volume of a carrier particle is calculated from the diameter of the carrier particle. Therefore, in this calculation, the volume of the internal structure is included in the volume of the carrier particle.

[0208] In some embodiments, the agent loaded onto the carrier particles is comprised of a loading solvent, which is removed to complete the loading.

[0209] The agent to be loaded is dissolved in a loading solvent and contacted with the carrier particles to ensure complete wetting of the loaded particles. The loading solvent can be removed by any solvent removal method known to those skilled in the art. In some embodiments, the loading solvent is removed by a method selected from the group consisting of evaporation, vacuum-assisted evaporation, atmospheric drying, vacuum freeze-drying, freeze-drying at atmospheric pressure, spray-drying, spray-drying in a fluidized bed device, microwave-assisted drying, electrospray-assisted drying, dielectric drying, fluidized bed-assisted drug loading, and solvent adsorption.

[0210] In the present invention, the agent carried on the carrier particles is dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the solvent adsorption method comprises high shear granulation.

[0212] Selection of an appropriate carrier solvent depends on the toxicity of the solvent, the partial vapor pressure of the solvent, the properties of the agent to be carried (eg, the pH stability and / or solubility of the agent to be carried), and / or the properties of the carrier material.

[0213] In some embodiments, the carrier solvent described herein comprises at least one organic solvent, preferably at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran. In some embodiments, the carrier solvent described herein is water.

[0214] Some loading solvents, such as water, have high surface tensions and may require additional measures to aid penetration into the pore(s) of the support particles described herein, despite their exceptionally large pore size. In some embodiments, the carrier solvents described herein include at least one surface active agent, such as a tenside. In some embodiments, the carrier solvent is added under high pressure to aid the carrier solvent in penetrating the interior of the support particles.

[0215] In some embodiments, the loading onto and in the carrier particles described herein includes the addition of an anti-solvent that reduces the solubility of the agent to be loaded in the loading solvent. In some embodiments, the anti-solvent is at least one anti-solvent selected from the group consisting of water, dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran.

[0216] In some embodiments, the carrier solvent is removed by evaporation, for example, by increasing the temperature and / or reducing the pressure. The maximum temperature for removing the carrier solvent depends on the thermal stability of the agent being carried.

[0217] Carrier particles having the secondary internal structure described herein can be compressed to provide compressed carrier particles.

[0218] The term "compressed support material," as used herein, refers to a mass of more than one support particle with adhesive forces acting between the support particles.

[0219] The term "compression" as used herein refers to applying pressure to one or more particles (e.g., carrier particles) to form a compressed carrier material, wherein the carrier particles remain at least partially attached to each other when the pressure is released.Compression techniques are known to those skilled in the art (see, for example, Odeku, OA et al., 2007, Pharmaceutical Reviews, 5(2)).Examples of compression techniques include, but are not limited to, tableting, roller compaction, slugging, briquetting, and / or centrifugation.

[0220] The compressed carrier material described herein is particularly stable and can be used to obtain a particularly stable pharmaceutical composition.During compression, the large surface area of the carrier particles described herein creates strong interparticle van der Waals adhesion forces, which allows for mechanical stability.When ingested, water penetrates between the particles (e.g., by capillary force), weakening the van der Waals adhesion forces in a distance-dependent manner, causing the compressed carrier material to collapse.

[0221] Thus, the compressed carrier materials described herein exhibit particular mechanical stability and / or fast disintegration times.

[0222] The inventors have surprisingly found that formulations of dexmedetomidine formulated with carrier particles exhibit improved bioavailability and / or reduced bitter taste, thereby leading to increased patient compliance.

[0223] Therefore, preferably, the carrier particles according to the present invention are compressed.

[0224] Therefore, preferably, the present invention relates to an embodiment in which dexmedetomidine (or an orodispersible tablet comprising dexmedetomidine) can be formulated by using carrier particles having a secondary internal structure, the carrier particles being compressed and comprising hydroxyapatite and optionally calcium chloride. Preferably, the content of hydroxyapatite in the particles (not loaded with dexmedetomidine) is at least 80% w / w, preferably at least 90% w / w, more preferably at least 95% w / w, even more preferably at least 99% w / w, and even more preferably about 100% w / w.

[0225] The sleep disorder that can be treated with dexmedetomidine according to the present invention is not particularly limited, and according to the inventors, any sleep disorder known to those skilled in the art can be treated with dexmedetomidine for use according to the present invention. Preferably, the sleep disorder is selected from insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance- or drug-induced sleep disorder. Therefore, in one embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, wherein the sleep disorder is selected from insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance- or drug-induced sleep disorder.

[0226] Those skilled in the art know that sleep disorders commonly coexist with other conditions that a subject may suffer from. These conditions may or may not be life-threatening. Those skilled in the art will appreciate that sleep disorders are often accompanied by depression, anxiety, and cognitive changes, which must be addressed in treatment planning and management. Sleep disorders are also established risk factors for the subsequent development of common mental illnesses and may represent a precursor to a psychotic episode, allowing for early intervention to prevent or alleviate a full-blown episode. Furthermore, sleep disorders provide a clinically useful indicator of medical and neurological disorders that often coexist with depression and other common mental disorders. Sleep-wake complaints can provide clinically actionable clues in breathing-related sleep disorders, cardiac and pulmonary disorders (e.g., congestive heart failure and chronic obstructive pulmonary disease), neurodegenerative disorders (Alzheimer's disease or Parkinson's disease), and musculoskeletal disorders, all of which are characterized by prominent sleep-wake complaints and are often associated with depression and anxiety disorders, respectively.

[0227] Conversely, psychiatrists should understand that some medical disorders may not only disrupt sleep (as in the examples above), but may themselves worsen during sleep. Thus, some patients may experience apnea or ECG arrhythmias during REM sleep, confusional awakenings due to dementia, hyperarousal associated with anxiety and insomnia, or REM sleep behavior disorder in alpha-synucleinopathies such as Parkinson's disease.

[0228] Thus, as disclosed herein and encompassed by the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof can be used to treat a subject suffering from depression and / or anxiety.

[0229] Further accordingly, as disclosed herein and encompassed by the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof can be used to treat a subject suffering from a cardiac or pulmonary disorder (e.g., congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (e.g., Alzheimer's disease or Parkinson's disease), or a musculoskeletal disorder.

[0230] Preferably, within the scope of the present invention, the sleep disorder is an insomnia disorder.

[0231] Insomnia is the most common complaint in the general population (Mahowald & Schenck, 2005). Ohayon reviewed over 50 epidemiological studies on insomnia and found that approximately one-third of the general population exhibits at least one of the criteria for insomnia defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Furthermore, 6% of the general population has been diagnosed with insomnia based on these criteria (Ohayon, MM (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews, 6(2), 97-111). Incidentally, the DSM classification of sleep-wake disorders has been updated to the 5th edition (DSM-V).

[0232] Insomnia can be an independent condition or can coexist with other psychiatric disorders (depression), medical conditions (pain), or other sleep disorders (American Psychiatric Association, 2013, p. 362). According to the DSM-V (2013, p. 362), the diagnostic criteria for insomnia are as follows: Dissatisfaction with sleep quality caused by difficulty initiating or maintaining sleep and being unable to return to sleep after waking up early in the morning The sleep disturbance interferes with social, occupational, educational, academic, behavioral, or other areas of functioning. Occurs at least three nights per week -It has been going on for at least 3 months Occurs despite normal sleep patterns Does not occur only during other sleep disorders -Not caused by the physiological effects of drugs or other substances The complaint is not explained by a coexisting medical or psychiatric condition

[0233] Another way to diagnose insomnia is through questionnaires. One example is the Insomnia Severity Index (ISI). It measures the severity of insomnia, allowing for understanding the course of the disorder. The ISI consists of seven items on a five-point Likert-type scale (0 to 4 points) that assess the severity of insomnia complaints over the past two weeks (Stuck et al., 2021, pp. 26-28). The scores are summed to obtain a score ranging from 0 to 28. The following interpretations are made based on the end scores: no insomnia (0-7), subthreshold insomnia (8-14), moderate insomnia (15-21), and severe insomnia (22-28) (Morin, C.M., Belleville, G., Belanger, L., & Ivers, H. (2011). The Insomnia Severity Index: Psychometric Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep, 34(5), 601-608).

[0234] As mentioned above, insomnia may be co-morbid with other pathologies. Thus, as disclosed herein and encompassed by the present invention, the insomnia to be treated according to the present invention is selected from insomnia associated with depression, insomnia associated with anxiety, insomnia associated with PTSD, insomnia associated with schizophrenia, insomnia associated with Parkinson's disease, insomnia associated with Alzheimer's disease, insomnia associated with multiple sclerosis, and insomnia associated with stroke.

[0235] In a specific embodiment, the insomnia is insomnia associated with PTSD. While current PTSD treatments are effective, preventive strategies have not produced satisfactory results. Therefore, there is an urgent need for effective preventive strategies targeting this debilitating mental disorder. Distressing intrusive memories are a core symptom of trauma-related disorders, characterized by repeated re-experiencing of traumatic memories after exposure to a traumatic event. The formation of such intrusions may be due to the insufficient consolidation of traumatic memories into the hippocampal-cortical memory network during slow-wave sleep (SWS)-dependent encoding due to the overwhelming negative emotional intensity of the traumatic event. Furthermore, post-traumatic stress-associated immune responses, which primarily involve increased cytokines but may also increase metabolites of the kynurenine pathway, are a pathological factor in PTSD and further impair sleep physiology and memory consolidation. Indeed, recent studies have revealed a close relationship between sleep physiology and the severity of intrusions, while poor sleep quality immediately after a traumatic event increases the likelihood of intrusive memories emerging. Furthermore, those skilled in the art are aware that sleep deprivation affects daytime physical and cognitive performance and mood.Similarly, sleep is known to have a significant impact on memory consolidation.Therefore, since PTSD is characterized by severe insomnia symptoms (including nightmares) and a lack of traumatic memory consolidation (which occurs particularly during deep sleep), it is plausible that treatment with dexmedetomidine as disclosed herein, intended to treat (or prevent) insomnia or its symptoms, may be effective in treating or preventing PTSD.

[0236] Thus, in one embodiment of the present invention, the treatment or prevention of a sleep disorder, in particular the treatment or prevention of insomnia, in a subject as defined herein constitutes the treatment or prevention of post-traumatic stress disorder.

[0237] The inventors have shown that administration of dexmedetomidine in accordance with the present invention reduces sleep latency, increases REM latency, and increases time spent in NREM sleep (N2 + N3). Furthermore, dexmedetomidine has been shown to increase slow-wave activity. Thus, dexmedetomidine at doses according to the present invention has been shown to contribute to deeper sleep. Furthermore, administration of dexmedetomidine in accordance with the present invention has been shown to achieve reproducible plasma levels in different subjects, thereby minimizing inter-subject variability and increasing the likelihood of reproducible therapeutic effects.

[0238] Furthermore, the inventors also found that bedtime sublingual doses of dexmedetomidine that result in plasma concentrations greater than 0.15 ng / mL at awakening time are likely to cause carryover effects upon awakening, particularly orthostatic intolerance and dizziness. Based on these findings, the inventors suggested that bedtime sublingual doses exceeding 120-150 μg are likely to cause next-day residual effects. Thus, the inventors found that the therapeutic concentration window for sublingual dexmedetomidine for treating sleep disorders is 10-120 μg.

[0239] Therefore, the inventors have plausibly demonstrated that dexmedetomidine used in accordance with the present invention can also be used to treat sleep disorders other than insomnia.

[0240] Thus, embodiments in which the sleep disorder is hypersomnia or narcolepsy are encompassed by the present invention. It is understood that dexmedetomidine or a salt thereof is administered in accordance with the present invention, i.e., as described herein.

[0241] Excessive sleepiness is understood to be the inability to stay awake and active during the day despite getting more than the appropriate amount of sleep at night. Excessive sleepiness interferes with work, social and family life.

[0242] Narcolepsy is herein understood to be a chronic sleep disorder that causes overwhelming daytime somnolence. Narcolepsy causes sudden sleep attacks. Sudden loss of muscle tone and hallucinations may also occur. The prolongation of REM sleep latency demonstrated by the present inventors may be particularly interesting for the treatment of disorders accompanied by a pathological shortening of REM sleep latency (also called sleep-onset REM episodes), which is very common not only in narcolepsy but also in affective disorders such as major depressive disorder.

[0243] Narcolepsy is characterized by fragmented NREM / REM sleep and shortened REM sleep latency. Furthermore, narcolepsy patients exhibit a higher REM density than healthy individuals. Narcolepsy is also characterized by excessive daytime sleepiness and nocturnal awakenings / nightmares due to non-restorative sleep. Interestingly, DEX 1) consolidates NREM and REM sleep, 2) significantly reduces REM sleep latency, 3) reduces REM sleep and increases NREM sleep, and 4) reduces daytime sleepiness. Furthermore, DEX has anxiolytic properties and is likely to effectively reduce nighttime anxiety (nightmares, abnormal thoughts). Therefore, DEX is likely to have a positive effect on several key pathological features of narcolepsy and therefore may be a promising treatment for this disorder.

[0244] The present invention further provides dexmedetomidine or a pharmaceutically acceptable salt thereof for use in treating a sleep disorder, wherein the sleep disorder is a circadian rhythm sleep disorder. Circadian rhythm sleep disorders include difficulty falling asleep, waking up in the middle of a sleep cycle, or waking too early and being unable to fall back asleep. Particularly preferred embodiments of the present invention relate to circadian rhythm sleep disorders characterized by delayed sleep-wake phases, shift work, a non-24-hour sleep-wake rhythm, or an irregular sleep-wake rhythm. It is understood that dexmedetomidine or a salt thereof is administered in accordance with the present invention, i.e., as described herein.

[0245] The present invention further provides dexmedetomidine for use in the treatment of REM sleep behavior disorder. Rapid eye movement (REM) sleep behavior disorder is a sleep disorder in which vivid, often disturbing dreams are physically enacted during REM sleep, accompanied by vocalizations and sudden, often violent movements of the arms and legs, sometimes referred to as dream actouts. As shown in the Examples, particularly Table 1, administration of dexmedetomidine according to the present invention can lead to a reduction in the time a subject spends in the REM phase, thus demonstrating the potential for administration of dexmedetomidine according to the present invention to treat REM disorders. It is understood that dexmedetomidine or a salt thereof is administered in accordance with the present invention, i.e., as described herein.

[0246] Dexmedetomidine for use in the present invention is further provided for the treatment of restless legs syndrome. Restless legs syndrome (RLS) is a condition that causes an irresistible urge to move the legs, usually due to an unpleasant sensation. It usually occurs in the evening or at night while sitting or lying down. Moving the legs temporarily relieves the discomfort. It is understood that dexmedetomidine or a salt thereof is administered in accordance with the present invention, i.e., as described herein.

[0247] Furthermore, the ability to increase REM sleep latency suggests the efficacy of dexmedetomidine in treating conditions associated with a pathological decrease in REM sleep latency. Such conditions include narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS), and brainstem lesions. Accordingly, in one embodiment, the present invention relates to dexmedetomidine for use in the present invention, where the sleep disorder is characterized by a pathological decrease in REM sleep latency. A pathological decrease in REM sleep latency is herein understood to be characterized by an increased prevalence of sleep-onset REM episodes (SOREM). This means that upon sleep onset, the patient transitions into REM sleep rather than NREM sleep, which is characteristic of a non-physiological sleep architecture. Those skilled in the art can measure REM sleep latency and thus select patient populations that would otherwise be unselectable for treatment with dexmedetomidine according to the present invention.

[0248] Furthermore, the ability of dexmedetomidine to improve sleep quality by reducing noradrenergic signaling confirms its effectiveness in treating conditions characterized by excessive noradrenergic signaling. Such disorders include anxiety, PTSD, depression, and ADHD. In the case of ADHD, patients often suffer from insomnia induced by stimulants (e.g., D-amphetamine, methylphenidate, atomoxetine, dislexamfetamine, etc.). Dexmedetomidine is believed to antagonize the excessive noradrenergic signaling induced by these stimulants, thereby alleviating the adverse effects on sleep. Thus, in one embodiment, the present invention relates to dexmedetomidine for use in the present invention, wherein the sleep disorder is characterized by excessive noradrenergic signaling.

[0249] Noradrenergic system overactivity, also known as noradrenergic overactivity, refers to excessive release and / or activity of the neurotransmitter noradrenaline (also called norepinephrine) within the central nervous system. Noradrenaline is a chemical messenger that plays an important role in regulating various physiological functions and behaviors, including the "fight or flight" response, attention, mood, and arousal. In neurological or psychiatric conditions, noradrenergic system overactivity can be associated with several disorders and symptoms: 1. Anxiety disorders: Excessive release of norepinephrine in certain areas of the brain can lead to increased alertness, arousal, and an increased anxiety response. 2. Post-traumatic stress disorder (PTSD): In PTSD individuals, the noradrenergic system is dysregulated and can contribute to a persistent state of hyperarousal and intrusive memories. 3. Panic Disorder: Noradrenergic overactivity is associated with the sudden and severe panic attacks experienced by individuals with panic disorder. 4. Attention Deficit Hyperactivity Disorder (ADHD): An imbalance in noradrenergic activity is thought to contribute to the impulsivity, hyperactivity, and inattention seen in ADHD. 5. Bipolar Disorder: During manic episodes in bipolar disorder, norepinephrine levels are elevated, which may contribute to elevated mood, increased energy, and agitation. 6. Major depressive disorder: Some research suggests that dysregulation of the noradrenergic system may play a role in depressive symptoms. 7. Schizophrenia: Noradrenergic abnormalities are involved in schizophrenia and likely contribute to cognitive deficits and disorganized thinking. 8. Autonomic Dysfunction: Overactivity of the noradrenergic system affects the autonomic nervous system, causing symptoms such as increased heart rate, sweating, and elevated blood pressure.

[0250] One skilled in the art can measure noradrenergic signals and accordingly select patient populations that would not otherwise be selected for treatment with dexmedetomidine according to the present invention.

[0251] In a first specific embodiment, dexmedetomidine or a salt thereof is administered at a dose of 60 μg to 80 μg.

[0252] In a second specific embodiment, dexmedetomidine or a salt thereof is administered at a dose of 20 μg to 40 μg.

[0253] In a third specific embodiment, the subject suffers from depression and / or anxiety.

[0254] In a fourth specific embodiment, the subject suffers from a cardiac or pulmonary disorder (e.g., congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (e.g., Alzheimer's disease or Parkinson's disease), or a musculoskeletal disorder.

[0255] Further examples and / or embodiments of the present invention are disclosed in the following numbered sections:

[0256] 1. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a sleep disorder in a subject, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject via a transmucosal route at a dose of between 10 μg and 120 μg.

[0257] 2. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 1, administered in a dose of 40 μg to 120 μg, preferably in a dose of 40 μg to 80 μg.

[0258] 3. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 1 or 2, administered at a dose of 60 μg to 80 μg.

[0259] 4. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 1, administered at a dose of 20 μg to 40 μg.

[0260] 5. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 4, administered sublingually or bucally to a subject.

[0261] 6. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 5, administered orally to a subject.

[0262] 7. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 6, to be administered to a subject in the form of an orally dispersible tablet.

[0263] 8. Dexmedetomidine or a pharmaceutically acceptable salt thereof according to item 7, wherein the orodispersible tablet is formulated by using templated carrier particles, preferably templated inverted particles, preferably comprising calcium phosphate and / or magnesium phosphate.

[0264] 9. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 8, wherein the sleep disorder is selected from insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance- or medication-induced sleep disorder.

[0265] 10. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 9, wherein the subject suffers from depression and / or anxiety.

[0266] 11. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 10, wherein the subject suffers from a cardiac or pulmonary disorder (e.g., congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (e.g., Alzheimer's disease or Parkinson's disease), or a musculoskeletal disorder.

[0267] 12. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 11, wherein the sleep disorder is insomnia disorder.

[0268] 13. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 12, wherein the insomnia disorder is selected from insomnia associated with depression, insomnia associated with anxiety, insomnia associated with PTSD, insomnia associated with schizophrenia, insomnia associated with Parkinson's disease, insomnia associated with Alzheimer's disease, insomnia associated with multiple sclerosis, and insomnia associated with stroke.

[0269] 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in any one of items 1 to 11, wherein the sleep disorder is hypersomnia or narcolepsy.

[0270] 15. The sleep disorder is a circadian rhythm sleep disorder, preferably characterized by delayed sleep-wake phases, shift work, a non-24-hour sleep-wake rhythm, or an irregular sleep-wake rhythm. or The sleep disorder is REM sleep behavior disorder. or 10. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as described in item 9, wherein the sleep disorder is restless legs syndrome.

[0271] The present invention is illustrated by the following examples, which should not be construed as limiting, however, since the scope of the invention is characterized by the appended claims. [Example]

[0272] The following five studies investigated the pharmacokinetics of various doses and formulations of dexmedetomidine and its effects on sleep physiology and next-day cardiovascular events in healthy young volunteers. The following experiments, summarized in Table 1, were performed:

[0273] Table 1. Study overview

[0274] [Table 1]

[0275] Preparation of the formulation: Test 1 - Preparation of ODT Dexmedetomidine melt tablets were obtained by lyophilization. Dextran FP40 was used as a bulking agent and dissolved in Dexdor™ injection solution (100 μg / mL; Orion Pharm AG, Zug, Switzerland). This solution was then volumetrically filled into aluminum blister molds (0.2 mL / cavity) using an Eppendorf micropipette and finally freeze-dried for 30 hours to obtain freeze-dried tablets with a strength of 20 μg each. Placebo melt tablets were obtained accordingly, except that Dexdor™ was replaced with 0.9% saline (B. Braun Medical AG, Sempach, Switzerland) to mimic the slight salty taste of the Dexdor™ solution. On each study day, placebo and verum tablets were combined to give a total dose of 40 μg (20 μg × 2), 20 μg (20 μg × 1 + placebo), or 0 μg (placebo × 2). All tablets were stored at room temperature under dry conditions (dessicator bags).

[0276] Study 2 - Preparation of TIP tablets (20 μg / tablet) The manufacturing procedures for the formulations used in Study 2 are outlined below in Table 2. The 20 μg condition received one 20 μg tablet of dexmedetomidine and one placebo tablet, while the 40 μg condition received two 20 μg tablets of dexmedetomidine. All tablets were stored at room temperature under dry conditions (dessicator bags).

[0277] Table 2. Preparation of dexmedetomidine-loaded G-TIP 210821 tablets for Study 2

[0278] [Table 2-1]

[0279] [Table 2-2]

[0280] Study 3 - 5 - Preparation of TIP tablets (50 μg / tablet) The manufacturing procedures for the formulations used in Studies 3-5 were the same as outlined in the table above, with the only difference being that tablets with a strength of 50 μg instead of 20 μg were produced by adjusting the amount of powder blend dosed into the 7 mm dye. In Studies 3 and 4, one tablet was administered. In Study 5, three tablets were administered. All tablets were stored at room temperature under dry conditions (dessicator bags).

[0281] Selection criteria for studies 1-5 A double-blind, placebo-controlled, randomized, balanced crossover study was conducted to examine the effects of dexmedetomidine on sleep architecture and subjective sleep quality. This report focuses on the second part of the main study, which included 10 healthy subjects. The first step was to recruit 10 subjects based on the following criteria: ·male 18-35 years old Body Mass Index (BMI) 18.5-24.9 kg / m² Moderate alcohol (less than 5 drinks / week) and caffeine (less than 3 drinks / day) consumption Drug-free Non-smokers Normal or corrected-to-normal vision ISI score 0-8 No sleep disorders No neurological, psychological, or clinical illnesses, and no regular use of medications that may interfere with the measurement No known severe allergies or sensitivities No night shifts - Have not exceeded more than two time zones in the past 30 days Not have participated in another clinical trial within the past 30 days

[0282] Subjects were invited to a one-night screening to check for possible sleep disorders and assess whether their sleep efficiency was sufficient to participate and whether they met all criteria. Subjects were then acclimatized to the experimental environment.

[0283] Experimental Procedures - Study 1+2 Subjects participated in the study for three nights, each one week apart. They received one of three treatments before bedtime: placebo, a 20 μg dose, or a 40 μg dose of dexmedetomidine. During sleep, ECG and polysomnography were recorded. The study followed a double-blind, randomized, crossover design. Manual scoring of polysomnography confirmed whether dexmedetomidine affected sleep architecture.

[0284] Blood collection and analysis Blood samples were collected during the study to determine the pharmacokinetic profile of the administered dexmedetomidine formulation. A Venflon intravenous catheter was placed in the median cubital vein of each participant's non-dominant arm the evening before the study night. Blood samples were collected 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after dexmedetomidine administration during sleep. To avoid disturbing the subjects' sleep, the catheter was connected to an adjacent room with a Heidelberg plastic tubing extension throughout the study. The intravenous line was kept open during each blood draw, with slow infusion (10 mL / h) of heparinized saline (1000 IU heparin in 0.9 g NaCl / dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland). Blood samples with a volume of 5.5 mL each were immediately centrifuged at 4700 RCF for 5 minutes, and plasma samples with a volume of 600 μL each were stored in a −28°C freezer. Analysis and quantification of dexmedetomidine concentrations in plasma were performed by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0285] EEG Setup - Studies 1 and 2 Polysomnography consists of various physiological monitoring methods that can be used to assess a patient's sleep quality and quantity. In our study, polysomnography was performed during 8 hours of sleep from midnight to 8:00 AM. For this purpose, we used the SIENNA ULTIMATE system (EMS Biomedical, Korneuburg, Austria). Prior to electrode placement, head circumference was measured to ensure accurate placement of the electrodes with appropriate EEG electrode caps. Skin preparation was performed with an abrasive skin preparation gel (NuPrep) to improve skin conductivity and reduce impedance. The electrodes were then secured with DermaPlast Grass EC2 Plus electrode cream and cut gauze bandages. The recording setup consisted of 23 EEG electrodes (Fp1, Fp2, F3, F4, F7, F8, Fz, T3, T4, T5, T6, C3, C4, Cz, P3, P4, Pz, O1, O2, Oz, M1, M2, and REF between Fz and Cz) in a 10-20 system, and binocular electroencephalography (EOG) for tracking eye movements. Muscle activity was tracked by tripartite electromyography (EMG) across two recording tracks on the face, with a PGND electrode serving as ground. Heart rate was measured using a two-channel electrocardiogram (ECG) with a sample rate of 512 Hz and recorded on two separate channels using two electrodes attached to the sternum and left lower rib cage. Pulse oximetry was also performed during sleep. Measurements of nasal breathing, thoracic and abdominal respiratory movements, and body position were not performed in this study.

[0286] Visual Sleep Stage Scoring - Studies 1 and 2 Sleep variables were visually scored based on 30-second epochs according to the American Academy of Sleep Medicine criteria (American Academy of Sleep Medicine Berry, 2020, p. 17; Berry, R.B. et al. AASM Scoring Manual Updates for 2017 (Version 2.4) J. Clin. Sleep Med. 13, 665-6 (2017)). Sleep was scored using the C3-A2 derivative. Movement- and wake-related artifacts were visually identified and excluded from analysis.

[0287] Figure 8 shows the specific characteristics of EEG, EOG, and EMG during wakefulness and various sleep stages. When a subject is still awake, the EEG shows alpha waves (8-13 Hz) in the occipital region, frequent eye movements occur in the EOG, and high muscle tone is observed in the EMG (Berry, 2020). During N1, the EEG shows waves in the theta range (4-7 Hz), slow rotational eye movements occur in the EOG, and muscle tone is lower than during wakefulness (Berry, 2020). N1 is also known as the photic sleep stage because light stimulation can quickly awaken a subject (Kandel, ER, Koester, JD, Mack, SH, & Siegelbaum, SA (2021). Principles of neural science (6 th(ed.). McGraw Hill, p. 1082). Two key markers of N2 are K-complexes (frontal origin) and spindles (central origin) in the EEG. Eye movements are absent or absent, and muscle tone is reduced compared to N1. N3, also known as deep sleep, is characterized by frontal-origin slow-wave (0.5–2 Hz and >75 μV) activity (hence the name SWS). Eye movements are typically absent and muscle tone is lower compared to N2 (Berry, 2020). As the name suggests, during REM sleep, the EOG shows rapid eye movements, the EEG displays a pattern similar to wakefulness, and muscle tone is at its lowest. Dreams during REM sleep are often vivid, unrealistic, and bizarre. Motor neurons are inhibited to prevent dream replay. This inhibition causes hypotonia (extremely low muscle tone) (Berry, 2020; Kandel et al., 2021, p. 1082).

[0288] Sherlong Test - Studies 1-5 Immediately after waking, the validated Schellong test was performed. In the two-part Schellong test, blood pressure and heart rate are measured for three minutes in the supine position, with a one-minute interval between measurements. The subject then stands, and five measurements are taken at one-minute intervals. The values measured during the test can be used to estimate whether and to what extent an orthostatic response occurs. Physiologically, when a person changes position, their systolic blood pressure decreases by 10 mmHg and their diastolic blood pressure increases by approximately 5 mmHg. In healthy individuals, a heart rate increase of 5 to 20 bpm can be expected (Moya, Angel, et al., Guidelines for the diagnosis and management of syncope (version 2009). European Heart Journal, Volume 30, Number 21, November 2009, pages 2631-2671. PubMed Central).

[0289] Questionnaire - Studies 1 and 2 Three questionnaires were assessed after awakening: PANAS (Positive and Negative Affect Schedule), SIQ-Acute (Sleep Inertia Questionnaire, Acute), and Morning Questionnaire (MQ). The questionnaires are described in detail below:

[0290] The Positive and Negative Affect Schedule (PANAS) (Appendix, p. 100) was developed by Watson and Clark in 1988 and is now a commonly used rating scale. It consists of 20 adjectives that subjects must rate on a 5-point Likert scale (1 = not at all or very little, 2 = a little, 3 = some, 4 = a great deal, 5 = very) according to how they feel at that moment. The adjectives are categorized as positive affect (PA) and negative affect (NA). Positive affect includes lively, interested, excited, energetic, motivated, proud, enthusiastic, alert, determined, and alert. Negative affect includes distress, embarrassment, guilt, fearful, hostile, irritable, embarrassed, nervous, confused, and anxious. The scores assigned to the adjectives are then summed. Thus, there is one score for each PA and one score for each NA (Watson, D., Clark, LA, & Tellegen, A. (1988). Development and validation of brief measures of positive and negative affect: The PANAS scales. Journal of Personality and Social Psychology, 54(6), 1063-1070). The adjectives for PA and NA are listed in Table PANAS. A high PA score indicates that the subject has high energy levels, is able to concentrate fully, and is in a happy mood. On the other hand, a low PA score is characterized by sadness and lethargy. A high NA score is associated with the subject feeling anger, contempt, disgust, guilt, fear, and irritability, while a high NA score indicates that the subject is in a calm and peaceful mood (Watson et al, 1988).

[0291] The Sleep Inertia Questionnaire (SIQ) (Appendix, pages 101-102) was developed by Kanady and Harvey in 2015. Sleep inertia is a state immediately after sleep characterized by decreased alertness and impaired performance. The SIQ allows for the assessment of the level of sleep inertia (Kanady, JC, & Harvey, AG (2015). Development and Validation of the Sleep Inertia Questionnaire (SIQ) and Assessment of Sleep Inertia in Analogue and Clinical Depression. Cognitive Therapy and Research, 39(5), 601-612). The original SIQ consists of 21 questions scored on a 5-point Likert scale. Landolt's group added two more questions and changed the scoring scale to a 7-point Likert scale (-3 = much less, -2 = slightly less, -1 = slightly less, 0 = equal, 1 = slightly more, 2 = slightly more, 3 = much more) for questions 1–22 and a visual analog scale (VSA) ranging from 0 (no effort) to 100 (extreme effort) for question 23, which they named the SIQ-Acute. For analysis, questions 22 and 23 are treated separately, while questions 1–21 are grouped into one of four factors (physiological, inertial, cognitive, and affective). A summary of the characteristics of each factor and questions 22 and 23 can be found in Table 2.

[0292] Morning Questionnaire The morning questionnaire was a short questionnaire that study participants completed 30 minutes after waking. The questionnaire was divided into two parts. In the first, study participants indicated the estimated length of time it took them to fall asleep (in minutes), how often they thought they woke up during the night, and the length of time they thought they woke during the night (in minutes, not including the time it took them to fall asleep). In the second part, participants recorded their mental state compared to a normal night and their usual mental state on seven visual scales. For example, study participants were asked how tired, calm, or focused they felt at that moment, or how deeply or superficially they slept compared to their usual sleep.

[0293] Cortisol awakening response Cortisone-D7 was purchased from Sigma Aldrich (Buchs, Switzerland), and 13C3-cortisol was purchased from Isoscience (Ambler, USA). Each subject's saliva was sampled at 08:00 (immediately after waking), 08:15, 08:30, 08:45, and 09:00. Participants were instructed to bite the cotton swab for 60 seconds and then return it to a Salivette® tube (Sarstedt, Germany). After sampling, the tube was immediately stored on ice until final storage at -80°C. For cortisol detection, the tube was thawed and centrifuged at 5000 rpm for 5 minutes to obtain clear saliva in a conical tube. The swab was then removed, and 50 μL of IS (0.1 ng / μL Cortison-D7) was added to the resulting saliva for further analysis. Automated supported liquid extraction (SLE) was performed by transferring 265 μL of saliva to a Biotage® Extrahera (Biotage, Uppsala, Sweden) column rack (24 × 6 mL) and adding 300 μL of water to the sample. After mixing, the extract was automatically loaded onto an Isolute SLE+ column and allowed to adsorb for 5 minutes. The analytes were then eluted twice with 1.5 mL of ethyl acetate, with a 5-minute waiting period between elutions. The extract was dried at 35°C in a Turbovap® (Biotage, Uppsala, Sweden). The dried residue was resuspended in 150 μL of methanol and 350 μL of ammonium formate (5 mM) solution and used for liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis according to a recently published method using 13C-labeled cortisol as a surrogate analyte for calibration. Saliva samples were analyzed using an LC-MS / MS system consisting of a Shimadzu Prominence UFLC (Shimadzu, Kyoto, Japan) high-pressure liquid chromatography (HPLC) system coupled to a Sciex QTRAP® 6500+ linear ion trap quadrupole mass spectrometer (Sciex, Darmstadt, Germany). 10 μL of sample was injected onto a Phenomenex® Kinetex® C18 column (2.6 μm, 50 × 2.10 mm).The mobile phase consisted of 10 mL of 1 M ammonium formate and 2 mL of formic acid in 2 L of water (A) and 10 mL of 1 M ammonium formate in 2 L of methanol (B). The flow rate was 0.3 mL / min, and the column oven temperature was set to 40 °C. Quantitation was performed using a mass spectrometer in multiple reaction monitoring (MRM) with an ion spray voltage of -4500 V. Cortisol was measured as the formate adduct [(MH)+46]- in negative electrospray ionization mode. The method was validated according to the guidelines of the German Society for Toxicology and Forensic Chemistry (GTFCh). Calibrators were prepared by spiking saliva with 13C3-cortisol at concentrations ranging from 0.55 nmol / mL to 55 nmol / mL. QC samples were prepared at a lower concentration (1.5 nmol / L). The detection limit for cortisol was 0.55 nmol / L, and the quantification limit was 1.1 nmol / L.

[0294] result Pharmacokinetic Results: Study 1 The results are presented in Table 3 below and Figure 1, Part 1. Note the significantly smaller standard error observed in the PK profiles shown in Figure 1, Part 1, when compared to the plasma profiles after oral administration of 300 / 500 / 700 μg DEX (Figure 11; Akeju et al., 2018, Neurophysiology—as reported in https: / / pubmed.ncbi.nlm.nih.gov / 29154132 / ). We also found that DEX bioavailability is significantly improved after sublingual administration compared to oral administration, in that similar mean plasma values were obtained with 40 μg sublingual DEX and 300 / 500 μg oral DEX. Therefore, the sublingual approach not only improves the predictability of systemic exposure levels after DEX administration, but also significantly reduces the risk of overdosing poor metabolizers when administering high-dose DEX orally.

[0295] Table 3. PK parameters of dexmedetomidine administration (Study 1).

[0296] [Table 3]

[0297] Pharmacokinetic Results: Studies 3 and 4 The results are presented in Figure 2. Note the very low inter-subject variability observed in the PK profiles shown in Figure 2, particularly when compared to the plasma profiles after oral administration of 300 / 500 / 700 μg of DEX (Figure 11; Akeju et al., 2018, Neurophysiology). Interestingly, compared to the ODT formulation used in Study 1, the formulations used in Studies 2 and 3 produced a slightly more sustained-release profile, with slightly lower Cmax values (mean: 0.16 ng / mL), but a pronounced plateau. This was particularly surprising because sustained-release profiles are not typically observed with sublingual formulations. The formation of a plateau may be particularly useful for use in therapeutic settings where maintaining dexmedetomidine levels overnight is of paramount importance. Even more interestingly, despite the pronounced plateau, plasma levels declined to the same level (approximately 0.6 ng / mL) observed during the 40 μg condition in Study 1.

[0298] Pharmacokinetic Results: Study 5 The results are presented in Figure 1, part 2. The observed Cmax after a 150 μg dose was approximately 0.5 ng / mL, and therefore approximately three-fold higher than in studies 3 and 4, where the same formulation was administered at 50 μg, highlighting the ability of the formulation to accurately deliver dexmedetomidine via the sublingual route.

[0299] Relationship between morning plasma concentrations and side effects Figure 1, Part 2, shows the plasma profiles of DEX after sublingual administration of 50 μg DEX at midnight and 50 μg / 150 μg DEX at 4:30 AM. The Schellong task was performed at 8:00 AM immediately after awakening. When the 50 μg dose was administered at midnight, no participants (0 of 4) experienced orthostatic intolerance or dizziness. In contrast, when the 50 μg dose was administered at 4:30 AM, 3 of 4 participants experienced dizziness, orthostatic dysregulation, and nausea at 8:00 AM. Similarly, participants who received the 150 μg dose at 4:30 AM experienced severe side effects, including syncope, nausea, hypotonia, bradycardia, and cognitive impairment, after awakening at 8:00 AM. Based on this data, we suggest that morning plasma concentrations of 0.18 ng / mL are associated with adverse effects that must be avoided in the treatment of insomnia. This can be achieved by selecting a bedtime dose of sublingual DEX that results in post-awakening concentrations (after 8 hours of sleep) of less than 0.15 ng / mL. Our data suggest that such a dose would be between 100 and 150 μg.

[0300] Sleep Physiology Results - Study 1 Table 4 below shows the effects of 20 and 40 μg dexmedetomidine ODT (Study 1) on visually scored sleep variables. As highlighted in orange, both doses were able to shorten sleep latency, prolong REM sleep latency, and increase time spent in stages N2+N3 (deep sleep). In particular, shortening sleep latency and prolonging deep sleep represent two clinically meaningful features because both sleep latency and deep sleep are impaired in most insomnia patients. Note that dexmedetomidine was able to dramatically shorten sleep latency despite being administered immediately before lights-out rather than prior to bedtime (e.g., 30–60 min before bedtime). This suggests that the onset of action on sleep latency is very rapid and efficient. Prolonging REM sleep latency may be of particular interest for the treatment of disorders associated with pathologically shortened sleep latency (also known as sleep-onset REM episodes), which is very common not only in narcolepsy but also in affective disorders such as MDD. It should be noted that the effect was more pronounced at 40 μg compared to 20 μg, and as a result, the 20 μg condition often only reached a statistical trend level. Based on these data, we therefore argue that the therapeutic window may begin somewhere between 20 and 40 μg, with lower doses likely resulting in reduced clinical efficacy. In any case, highly sensitive individuals or those with low body weight may respond even to 10 μg. Therefore, using this data, we have identified the lower limit of the therapeutic window of sublingual dexmedetomidine for treating insomnia.

[0301] Table 4. Visually scored sleep variables following administration of placebo, 20, and 40 μg of DEX (Study 1).

[0302] [Table 4]

[0303] Effects of DEX on slow wave activity - Study 1 Here, we investigated the effect of 40 μg of sublingual DEX on slow-wave activity, a well-established marker of sleep depth and restorative sleep, compared with placebo (see Figure 9). Higher levels of SWA were associated with deeper and more restorative sleep. As shown, 40 μg of sublingual DEX significantly increased slow-wave activity, most prominently during the first half of the night, but this effect disappeared just before awakening at 7:00 AM. Therefore, this dose of dexmedetomidine may be particularly suitable for improving nighttime sleep without inducing any carryover into the morning. Interestingly, most known hypnotics attenuate SWA and thus fail to restore physiological sleep and wakefulness. In contrast, dexmedetomidine may offer an innovative approach to improving both sleep and wakefulness quality by enhancing restorative SWA.

[0304] Sleep Physiology Results - Study 2 Study 2 included only eight subjects, resulting in a relatively small sample size. Based on the observed data, the program "G*Power" estimated that the minimum sample size required to obtain significant results was n ≥ 19. Therefore, the following table presents a descriptive summary of the effects of 20 and 40 μg dexmedetomidine TIP (Study 2) on visually scored sleep variables. As observed in Study 1, both doses administered in this study shortened sleep latency, prolonged REM sleep latency, and increased time spent in stages N2+N3 (deep sleep). Again, shortened sleep latency and prolonged deep sleep represent two clinically meaningful features, since both sleep latency and deep sleep are impaired in most insomnia patients. Note again that the dexmedetomidine formulation used in this study was able to dramatically shorten sleep latency despite being administered immediately before lights-out, rather than pre-administered (e.g., 30–60 min before bedtime). This suggests that the onset of action on sleep latency is very rapid and efficient. Prolongation of REM sleep latency may be of particular interest for the treatment of disorders accompanied by pathologically shortened REM sleep latency (also called sleep-onset REM episodes), which is very common not only in narcolepsy but also in affective disorders such as MDD. Again, it should be noted that the effect is more pronounced at 40 μg compared to the 20 μg condition.

[0305] Table 5. Descriptive statistics for sleep latency

[0306] [Table 5]

[0307] Table 6. Descriptive statistics for REM latency

[0308] [Table 6]

[0309] Table 7. Descriptive statistics for time spent in the awakening stage

[0310] [Table 7]

[0311] Table 8. Descriptive statistics for time spent in stage N1

[0312] [Table 8]

[0313] Table 9. Descriptive statistics for time spent in stage N2

[0314] [Table 9]

[0315] Table 10. Descriptive statistics for time spent in stage N3 over the course of a full night

[0316] [Table 10]

[0317] Table 11. Descriptive statistics for time spent in the REM stage

[0318] [Table 11]

[0319] Table 12. Descriptive statistics for time spent in stage N3 during the first half of the night.

[0320] [Table 12]

[0321] Table 13. Descriptive statistics for time spent in stage N3 during the second half of the night.

[0322] [Table 13]

[0323] Morning Questionnaire - Study 2 Study 2 included only 10 subjects, a relatively small sample size. Based on the observed data, the program "G*Power" estimated that the minimum sample size required to obtain significant results was n ≥ 19. Therefore, the following tables (14-23) present a descriptive summary of the effects of 20 and 40 μg dexmedetomidine TIP (Study 2) on morning questionnaires. Although no statistical analysis was performed on the data, the mean differences between the placebo condition and both dexmedetomidine conditions suggest a restorative effect of dexmedetomidine, as indicated by higher ratings of perceived sleep quality and improvements in mood, arousal, and concentration.

[0324] Table 14. Descriptive statistics for estimated sleep latency.

[0325] [Table 14]

[0326] Table 15. Descriptive statistics for estimated number of awakenings.

[0327] [Table 15]

[0328] Table 16. Descriptive statistics for estimated wake time.

[0329] [Table 16]

[0330] Table 17. Descriptive statistics for perceived sleep quality.

[0331] [Table 17]

[0332] Table 18. Descriptive statistics for perceived sleep depth.

[0333] [Table 18]

[0334] Table 19. Descriptive statistics for subjects' fatigue.

[0335] [Table 19]

[0336] Table 20. Descriptive statistics for subjects' moods.

[0337] [Table 20]

[0338] Table 21. Descriptive statistics for subject energies.

[0339] [Table 21]

[0340] Table 22. Descriptive statistics for subject arousal.

[0341] [Table 22]

[0342] Table 23. Descriptive statistics for subject concentration levels.

[0343] [Table 23]

[0344] Next-day residual effects of dexmedetomidine after bedtime administration The most common adverse reactions associated with DEX administration are cardiovascular dysregulation and sedation. This is due to DEX's antagonistic effect on the adrenergic system and its ability to reduce sympathetic nervous system activity. Therefore, at high doses, DEX can cause hypotonia, bradycardia, and ultimately orthostatic dysregulation and syncope. In our study, we examined orthostatic regulation immediately after awakening (8:00 a.m.) using the so-called Schellong test. This is because, as with other hypnotics, the occurrence of residual effects (carryover effects) after awakening, such as dizziness and hypotonia, is thought to determine the maximum dose (upper limit of the therapeutic window) that can be administered at bedtime.

[0345] Schellong test results: Study 1 Table 24 below shows the change in diastolic blood pressure during the Schellong study. Comparison with baseline measurement 3 shows a significant increase in diastolic blood pressure of 13-18 mmHg after standing (measurements 6-10), which is expected for a physiological orthostatic response. For 20 μg and 40 μg DMTN, no significant differences were detectable compared to placebo.

[0346] Table 24. Comparison of mean diastolic blood pressure values during the Shelong test

[0347] [Table 24]

[0348] Table 25 below shows the change in systolic blood pressure during the Shelong study. After standing, there is a significant increase in systolic blood pressure of approximately 7 mmHg only at baseline (measurement 6) compared to reference measurement 3. For 20 μg and 40 μg DMTN, there are no detectable significant differences compared to placebo.

[0349] Table 25. Comparison of mean systolic blood pressure values during the Shelong test

[0350] [Table 25]

[0351] Adverse Reactions During the Shelong Trial - Studies 1-5 As shown in Table 26 below, orthostatic intolerance after awakening (8:00 AM) during the Schelong test was reported in the 20 μg condition (1 of 17 subjects), 40 μg condition (2 of 17 subjects), and 50 μg condition (0 of 4 subjects) administered at bedtime (24:00 AM). This was similar to the number of orthostatic intolerances reported in the placebo condition (1 of 17 subjects). The DEX plasma concentrations at the time of the Schelong test were 0.03 ng / mL (20 μg), 0.06 ng / mL (40 μg), and 0.06 ng / mL (50 μg). Therefore, post-awakening plasma levels between 0.03 ng / mL (20 μg) and 0.06 ng / mL (40 / 50 μg) are considered to be well tolerated and therefore applicable for clinical use. Furthermore, it should be noted that when the 50 μg dose was administered at 4:30 AM, three of four volunteers reported moderate orthostatic dysregulation during the Schellong test at 4:30 AM. The mean plasma level for these subjects was 0.18 ng / mL. Another subject administered 150 μg at 4:30 AM reported more severe orthostatic dysregulation (bradycardia, hypotonia, syncope, and cognitive impairment), which resolved within 2–3 hours (5–6 hours after administration) of awakening. Upon awakening, this subject's plasma level was 0.45 ng / mL. Based on this data, we suggest that bedtime administration, which results in plasma levels higher than approximately 0.15–0.18 ng / mL upon awakening, may not be clinically useful due to excessive carryover effects. Therefore, based on our data, we estimate the upper limit of the therapeutic concentration range in the study sample (healthy young volunteers) to be approximately 80–100 μg.

[0352] Table 26.

[0353] [Table 26]

[0354] Cortisol Awakening Response – Study 1 Figure 10 shows the difference in cortisol awakening response (CAR) between placebo, 20 μg, and 40 μg dexmedetomidine. CAR reflects HPA axis activation after awakening and is thought to play an important role in replenishing psychological and physical resources to tackle the day's challenges. Because the HPA axis is tightly controlled by the noradrenergic system, it is an excellent biomarker of the carryover effects of dexmedetomidine on the HPA axis. As depicted in the plot, there was no difference between placebo, 20 μg, and 40 μg, indicating no relevant carryover effects of dexmedetomidine on the adrenergic system or the HPA axis in general.

[0355] conclusion Based on the above, the present inventors have surprisingly found that sublingual administration of 20 and 40 μg of dexmedetomidine at bedtime produces significant effects on sleep physiology, including significant reductions in sleep latency, prolongation of REM latency, and increase in time spent in NREM sleep (N2+N3). These effects indicate a deepening and integrating effect of dexmedetomidine on the sleep process, making it a promising treatment option for patients with sleep disorders such as insomnia. While the present inventors have suggested that higher doses may further amplify the observed effects, the present inventors have also surprisingly found that bedtime doses exceeding 120-150 μg may be associated with next-day residual effects, including orthostatic intolerance and dizziness, substantially limiting the use of such doses in patient treatment.

[0356] Furthermore, the inventors have surprisingly found that administration of dexmedetomidine via the sublingual route results in a substantially better pharmacokinetic profile than orally administered dexmedetomidine, such that the use of the sublingual route increases bioavailability and reduces inter-subject plasma level variability compared to oral delivery, and this effect was found using both lyophilized melt tablets (ODTs) and carrier particles.

[0357] Further Data: Summary and Clinical Implications Each 20 μg DEX ODT was prepared by lyophilization. Each ODT contained: DEX 20μg Dextran FP40 30mg 0.2 mL of dH2O

[0358] DEX and dextran FP40 were dissolved in dH2O, and the solution was volume-filled into aluminum molds and freeze-dried for 30 hours.

[0359] Dexmedetomidine reduces sleep onset latency (see FIG. 12 ), prolongs REM latency (see FIG. 13 ), and increases N2+N3 deep sleep (as seen through a decrease in REM stage length in FIG. 14 , an increase in stage N2 in FIG. 15 , and an increase in NREM stage length in FIG. 16 ). The latter is characterized by increased slow-wave activity and SWE, particularly in the first half of the night. Furthermore, dexmedetomidine reduces sleep fragmentation in both NREM and REM sleep (see FIGS. 17 and 23 ). In light of the sleep pharmacological profile presented herein, dexmedetomidine is proposed as a suitable treatment option for conditions associated with sleep onset insomnia, sleep maintenance insomnia, and the occurrence of restorative slow-wave deep sleep. These symptoms are commonly seen in psychiatric conditions, including depression, anxiety, PTSD, ADHD, schizophrenia, and psychosis, as well as neurological conditions, including neurodegenerative disorders (e.g., Parkinson's disease and Alzheimer's disease) and sleep-related neurological disorders, such as restless legs syndrome, REM sleep behavior disorder, and narcolepsy, as well as pain-induced insomnia. Furthermore, the ability to increase REM sleep latency suggests the efficacy of dexmedetomidine in treating conditions associated with a pathological decrease in REM sleep latency, including narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS), and brainstem lesions.

[0360] Furthermore, the ability of dexmedetomidine to improve sleep quality by reducing noradrenergic signaling (as outlined in the Results) suggests its clinical efficacy in treating conditions associated with excessive noradrenergic signaling, including anxiety, PTSD, depression, and ADHD. In the case of ADHD, patients often suffer from stimulant-induced insomnia (e.g., D-amphetamine, methylphenidate, atomoxetine, dislexamfetamine, etc.). Dexmedetomidine is thought to antagonize the excessive noradrenergic signaling induced by these stimulants, thereby reducing their adverse effects on sleep. Similarly, dexmedetomidine has been proposed to reduce the adverse effects of SSRIs and SNRIs on sleep by antagonizing noradrenergic-induced sleep disturbances.

[0361] Furthermore, the ability of dexmedetomidine to reduce NREM and REM sleep fragmentation translates into clinical efficacy in treating conditions associated with NREM and REM sleep fragmentation.

Claims

1. 1. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use in treating or preventing a sleep disorder in a subject, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject via a transmucosal administration route at a dose of 10 μg to 120 μg.

2. 2. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, administered at a dose of 40 μg to 120 μg.

3. 3. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 2, administered at a dose of 40 μg to 80 μg.

4. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 3, administered in a dose of 60µg to 80µg.

5. 2. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, administered at a dose of 20 μg to 40 μg.

6. 6. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 5, administered sublingually or bucally to a subject.

7. 7. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 6, which is administered bucally to a subject.

8. 8. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 7, which is administered to a subject in the form of an orally dispersible tablet.

9. 9. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 8, wherein the orally dispersible tablet is formulated by using templated carrier particles.

10. 10. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 9, wherein the templated carrier particles are templated inverted particles.

11. 11. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 9 or 10, wherein the particles comprise calcium phosphate and / or magnesium phosphate.

12. 12. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 9 to 11, wherein the templated carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity, and calcium hydroxide.

13. 13. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 12, wherein the sleep disorder is selected from insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-rapid eye movement (NREM) sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance- or drug-induced sleep disorder.

14. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the subject suffers from depression and / or anxiety.

15. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the subject suffers from a cardiac or pulmonary disorder, preferably congestive heart failure or chronic obstructive pulmonary disease.

16. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the subject is suffering from a neurodegenerative disorder, preferably, for example, Alzheimer's disease or Parkinson's disease.

17. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the subject is suffering from a musculoskeletal disorder.

18. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the subject is suffering from PTSD.

19. 19. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 18, wherein the sleep disorder is insomnia disorder.

20. 20. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 19, wherein the insomnia disorder is selected from insomnia associated with depression, insomnia associated with anxiety, insomnia associated with PTSD, insomnia associated with schizophrenia, insomnia associated with Parkinson's disease, insomnia associated with Alzheimer's disease, insomnia associated with multiple sclerosis, and insomnia associated with stroke.

21. 19. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 18, wherein the sleep disorder is hypersomnia or narcolepsy.

22. 19. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 18, wherein the sleep disorder is a circadian rhythm sleep disorder, preferably characterized by a delayed sleep-wake phase, shift work, a non-24-hour sleep-wake rhythm, or an irregular sleep-wake rhythm.

23. 19. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 18, wherein the sleep disorder is REM sleep behaviour disorder.

24. 19. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 18, wherein the sleep disorder is restless legs syndrome.

25. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the sleep disorder is characterized by a pathologically reduced REM sleep latency.

26. 26. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 25, wherein the disorder is selected from narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS), and brainstem lesions.

27. 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 13, wherein the sleep disorder is characterized by hyperactivity of noradrenergic signalling.

28. 28. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use as claimed in claim 27, wherein the disorder is selected from anxiety, PTSD, depression, and ADHD.

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