Dexmedetomidine for treatment of sleep disorders

Abstract

The present invention relates to the use of dexmedetomidine or a pharmaceutically acceptable salt thereof in the treatment or prevention of sleep disorders in a subject, wherein dexmedetomidine or a salt thereof is administered to the subject by a transmucosal administration route at a dose of from 10 mcg to 120 mcg. The dexmedetomidine or a pharmaceutically acceptable salt thereof is preferably formulated as an orally disintegrating tablet and is particularly useful in the treatment of insomnia.

Description

Technical Field

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

[0002] Sleep takes up one-third of our lives, and there is evidence that sleep has multiple important functions, such as detoxification, development, memory consolidation, and synaptic plasticity. Unfortunately, sleep problems are the second most common reason why patients seek medical help, and current treatments for insomnia have multiple side effects. Dexmedetomidine is a sedative used during surgery. In addition, dexmedetomidine also has anxiolytic, sympatholytic, and analgesic effects. In addition, studies have shown that dexmedetomidine can weaken overactive wake-promoting pathways. Therefore, dexmedetomidine is considered a potential drug for the treatment of sleep disorders, especially insomnia.

[0003] Sleep problems are the second most common reason for patients to seek medical help, second only to pain (Mahowald & Schenck, (2005). Insights from studying human sleep disorders. Nature, 437 (7063), 1279-1285.). Patients with sleep problems complain about being dissatisfied with their sleep quality and how sleep quality negatively affects their social, educational or professional life. In addition, insufficient sleep has been shown to increase the risk of other diseases such as diabetes 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), 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) and depression (Ford, DE, & Kamerow, DB (1989). Epidemiologic Study of Sleep Disturbances and Psychiatric Disorders: An Opportunity for Prevention? JAMA, 262(11), 1479-1484).Sleep problems may 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 a clear link between sleepiness associated with insufficient sleep and accidents, making patients with sleep problems more likely to make mistakes and cause accidents, which may be fatal (Dinges, DF (1995). An overview of sleepiness and accidents. J Sleep Res, 4 (S2), 4-14).

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

[0005] Insomnia is considered the most common sleep disorder. Treatment of insomnia can be divided into non-pharmacological treatment and pharmacological treatment (Cunnington et al., 2013). Non-pharmacological treatment includes establishing good sleep hygiene and cognitive-behavioral therapy (CBT-i) (Cunnington et al., 2013, pp.90-93; Stuck et al., 2021). The main pharmacological treatments include benzodiazepines. drugs, melatonin, and variants 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).

[0006] Good sleep hygiene aims to reduce behaviors that are incompatible with sleep and introduce behaviors that promote sleep. Measures that can be taken are: creating a comfortable atmosphere in the bedroom, reducing alcohol and caffeine intake, or reducing stimulating activities such as work, exercise, or watching TV in the evening (Stuck et al., 2021, Practice of Sleep Medicine: Sleep Disorders in Children and Adults (1st ed.). Springer International Publishing AG. pp. 91-92). CBT-i is a psychotherapeutic intervention. It targets maladaptive behaviors and thoughts that patients may have due to insomnia (Cunnington et al., 2013; Stuck et al., 2021, p. 93). Morin et al. reviewed 37 psychological and behavioral therapy studies. They found that good sleep hygiene and CBT-I can change multiple sleep parameters and reduce psychological symptoms. However, there is only limited evidence that they improve sleep quality and reduce physiological symptoms such as daytime fatigue (Morin, CM, Koetter, U., Bastien, C., Ware, JC, & Wooten, V. (2005). Valerian-hops combination and diphenhydramine for treating insomnia: arandomized placebo-controlled clinical trial. Sleep, 28(11), 1465-1471).

[0007] Benzodiazepines Benzodiazepines are hypnotic drugs, so they can cause dependence and tolerance (Cunnington et al., 2013). Curran et al. studied the effects of benzodiazepines on long-term users (>10 years) by asking them to perform different tasks and fill out different questionnaires. They found that compared with continuing to take benzodiazepines Compared with patients who were taking benzodiazepines, Patients taking benzodiazepines performed better on the task. However, there were no significant differences in sleep ratings between the two groups, suggesting that the benzodiazepines These drugs are ineffective 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). De Wit and Griffiths reviewed the potential for abuse of anxiolytic and hypnotic drugs in humans. They found that individuals with a history of drug abuse were more 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). Kales et al. showed that abrupt cessation of benzodiazepine use can Benzodiazepines can cause rebound insomnia, which encourages drug-taking behavior and increases the possibility 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).

[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, but 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). For example, Cagnacci et al. showed that the administration of melatonin to young healthy women affects arterial blood flow and lowers blood pressure, which provides evidence 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). However, there are cases where high-dose melatonin causes 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). Melatonin has the potential to treat insomnia. However, we still need to study the effects of high-dose melatonin on other systems and determine 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., & Rüther, E. (2000). Doxepin in the treatment of primary insomnia—A placebo-controlled, double-blind, polysomnographic study. European Neuropsychopharmacology, 10, 248-249; Karsten, J., Hagenauw, L. A., Kamphuis, J., & Lancel, M. (2017). Low doses of mirtazapine or quetiapine for transient insomnia: A randomised, double-blind, cross-over, placebo-controlled trial. Journal of Psychopharmacology, 31(3), 327-337), antipsychotics (e.g., quetiapine) (Karsten et al., 2017), and antihistamines (e.g., diphenhydramine) (Morin et al., 2005) are effective in treating insomnia. Unfortunately, they also have many side effects. Khawam et al. provide an overview of the side effects of antidepressants. Some side effects include anxiety, nausea, vomiting, sedation, daytime sleepiness, weight gain, and drowsiness (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). and Gaebel reviewed the side effects of antipsychotics. Antipsychotics increase the likelihood of weight gain and diseases such as diabetes, hyperlipidemia (high levels of lipids in the blood), and myocarditis (inflammation of the heart muscle). 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). Studies have shown that first-generation antihistamines such as diphenhydramine significantly reduce performance in tasks requiring divided attention, working memory, vigilance and speed, so if first-generation antihistamines are taken the night before, they may interfere with 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). Current treatments have a variety of side effects, including the risk of developing other diseases.

[0009] Therefore, new treatments need to be investigated. One drug that may be a potential treatment is dexmedetomidine.

[0010] Dexmedetomidine not only has a sedative effect, but also has anxiolytic, anti-sympathetic 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). Patients sedated with dexmedetomidine can be easily awakened, so that they can cooperate during surgery (Venn, RM, & Grounds, RM (2001). Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions. British journal of anaesthesia, 87 (5), 684-690). This unique sedative response is also called "awakenable sedation" or "cooperative sedation" (Lee, S. (2019). Dexmedetomidine: present and future directions. Korean Journal of Anesthesiology, 72 (4), 323-330). Hall et al. compared the effects of low-dose dexmedetomidine and medium-dose dexmedetomidine on 7 subjects. After a specific period of time, the subjects were subjected to different tests and measurements. The results showed a significant sedative effect, but the subjects could be easily awakened and perform tasks. The cold pressor test (placing one hand in ice water and assessing subjective pain with a visual analog scale (VAS)) showed a significant reduction in pain sensation. They did not find any interference with the cardiovascular or respiratory systems. Although they found a decrease in performance on psychomotor tasks and comprehensive memory tests, no impairment of retrograde memory was found (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.).The two most common side effects of dexmedetomidine are bradycardia (decreased heart rate) and hypotension (low blood pressure) (Paris, A., & Tonner, PH (2005). Dexmedetomidine in anaesthesia. Current Opinion in Anesthesiology, 18 (4)). The sedative effect of dexmedetomidine has been shown to be 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). Since the response to dexmedetomidine is dose-dependent, both side effects can be considered as an overreaction to the normal sedative effect of dexmedetomidine caused by high doses of dexmedetomidine (Paris & Tonner, 2005).

[0011] Document WO 2018 / 126182 discloses the specific use of sublingual dexmedetomidine for the treatment of agitation.

[0012] Document WO 2020 / 006092 discloses a film formulation containing dexmedetomidine and a method for producing the same. The document teaches that sublingual tablets are often swallowed before complete dissolution and transmucosal delivery, resulting in the active substance being wasted due to first-pass metabolism in the liver. Therefore, sublingual tablets may not be able to achieve therapeutic levels of dexmedetomidine in plasma.

[0013] Document WO 2016 / 061413 discloses the use of dexmedetomidine formulations to prevent or treat sleep disorders, wherein dexmedetomidine is administered in a therapeutically effective amount of about 0.1 mg to about 5 mg.

[0014] Document US2017 / 239221 provides a composition suitable for oral mucosal administration (sublingual) comprising dexmedetomidine. The composition is used to treat sleep disorders such as insomnia and can provide sleep on demand. The composition comprises an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a derivative thereof, which is formulated for delivering dexmedetomidine through the oral mucosa of a subject.

[0015] Document US2022 / 226288 discloses a method of administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject. The disclosed method is particularly suitable for treating anxiety, especially when associated with neurodegenerative diseases or disorders and / or neuropsychiatric diseases or disorders such as dementia and psychosis.

[0016] Document US 2010 / 196286 discloses devices and kits for treating sleep disorders, anxiety disorders and developmental disorders and / or for inducing a state of arousable sedation in a subject.

[0017] Document US2005 / 025807 provides a solidified porous calcium phosphate material, a replaceable living tissue material, a tissue engineering scaffold, and a drug support medium for DDS using the same. Summary of the invention

[0018] The objective technical problem is to provide a method for treating sleep disorders with reduced side effects. Said problem is solved by the embodiments described herein and having the features of the claims.

[0019] The inventors studied the sleep of 17 healthy subjects and recorded three nights. They took placebo, 20 μg dexmedetomidine or 40 μg dexmedetomidine. These records make it possible to observe whether dexmedetomidine affects sleep physiology. The subjects also filled out three questionnaires, which allowed the inventors to understand how dexmedetomidine affects subjective sleep quality. The inventors have thus demonstrated that dexmedetomidine shortens sleep latency, increases REM latency, and increases the time spent in NREM sleep (N2+N3), and the effect under 40 μg conditions is more significant than 20 μg. Therefore, it has been shown that dexmedetomidine at a dose according to the present invention contributes to deep sleep and does not cause residual effects the next day, such as sedation or cardiovascular effects. The effects of dexmedetomidine on sleep structure are summarized in Table 4. Fig. 9 Shown is the enhancing effect of dexmedetomidine on slow-wave sleep in a representative subject.

[0020] The inventors have also shown that the proposed dosing regimen can achieve plasma concentrations of dexmedetomidine sufficient to achieve therapeutic efficacy, i.e., about 0.2 ng / mL after 1 to 2 hours of buccal administration of an orally disintegrating tablet containing 40 μg of dexmedetomidine, and about 0.1 ng / mL after 1 to 2 hours of buccal administration of an orally disintegrating tablet containing 20 μg of dexmedetomidine. The inventors have also shown that, surprisingly, the plasma concentrations obtained are very similar in different subjects. Accordingly, it is therefore surprisingly shown that, compared with oral administration of dexmedetomidine, transmucosal administration of dexmedetomidine according to the present invention can minimize the variability in the bioavailability of dexmedetomidine between subjects. It is shown that sublingual administration of 20 / 40 μg dexmedetomidine ( Part 1 of Figure 1 )、50μg dexmedetomidine ( Figure 1, part 2 and Part 1 of Figure 2 / 2) and 150 μg dexmedetomidine ( Figure 1, part 2 ) after the pharmacokinetic curve.

[0021] The inventors also found in this study that, surprisingly, sublingual bedtime doses of dexmedetomidine that resulted in plasma concentrations above 0.15 ng / mL may lead to hangover effects upon awakening, particularly orthostatic dysregulation and dizziness. Based on these findings, the inventors propose that sublingual bedtime doses above 120 μg to 150 μg may lead to next-day residual effects.

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

[0023] The present invention will be 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 treating or preventing a sleep disorder in a subject, wherein the dexmedetomidine or a salt thereof is administered to the subject via a transmucosal administration route at a dose of 10 meg to 120 meg.

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

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

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

[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, to a method according to the present invention or to a use according to the present invention, wherein dexmedetomidine or a salt thereof is administered at a dose of 60mcg to 80mcg.

[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, to a method according to the present invention or to a use according to the present invention, wherein dexmedetomidine or a salt thereof is administered in a dose of 10mcg to 40mcg, preferably, in a dose of 20mcg to 40mcg.

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

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

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

[0033] In a further specific embodiment, the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, to a method according to the present invention or to a use according to the present invention, wherein the dexmedetomidine (in particular the orally disintegrating tablet) is formulated by using templated carrier particles, preferably templated reverse phase 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, to a method according to the present invention, or to a use according to the present invention, wherein the sleep disorder is selected from insomnia disorder, excessive sleepiness disorder, narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep disorder, a non-REM (NREM) sleep arousal disorder, a nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and a substance or drug-induced sleep disorder.

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

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

[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, to a method according to the present invention or to a use according to 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, 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, to a method according to the present invention or to a use according to the present invention, wherein the sleep disorder is excessive sleepiness disorder 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, to a method according to the present invention or to a use according to the present invention, wherein the sleep disorder is a circadian rhythm sleep disorder, preferably characterized by 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, to a method according to the present invention or to a 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, to a method according to the present invention or to a use according to the present invention, wherein the sleep disorder is restless legs syndrome.

[0042] The term "preferably" is used to describe features or embodiments that are not essential to the present invention, but may lead to an improved technical effect and are therefore desirable, but not essential. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Part 1 of Figure 1 A graph showing the plasma concentration of dexmedetomidine over time after transmucosal administration of 20mcg and 40mcg dexmedetomidine in the form of an orally disintegrating tablet to a subject (mean values ​​measured for 17 subjects are shown in each case). Part 2 shows the plasma profile of DEX after sublingual administration of 50mcg DEX at 24:00 and 50mcg / 150mcg DEX at 4:30.

[0044] Part 1 of Figure 2A graph showing the time course of plasma concentrations of dexmedetomidine after a single transmucosal administration of 50 mcg of dexmedetomidine in the form of an orally disintegrating tablet to a subject at 24:00 ("long" label) and 4:30 ("short" label), respectively. Part 2 shows the mean values ​​measured for 4 subjects in each case.

[0045] Figure 3 Electrode locations for EEG are shown (Klem et al., 1999).

[0046] Figure 4 The electrode locations for EOG are shown (Berry, 2020, p. 18).

[0047] Figure 5 Electrode locations for EMG are shown (Berry, 2020, p. 19).

[0048] Figure 6 Electrode locations for ECG are shown (Caples et al., 2007).

[0049] Figure 7 A screenshot of the program "Embla Rembrandt Manager" is shown.

[0050] Figure 8 Exemplary EEG, EOG, and EMG signal traces for different sleep and wakefulness phases are shown (Kandel et al., 2021, p. 1080).

[0051] Fig. 9 The deep sleep promoting properties of dexmedetomidine are shown with an increase in slow wave activity following administration of 40mcg dexmedetomidine (lower panel) compared to placebo (upper panel).

[0052] Fig.10 Shown are the differences in the Cortisol Awakening Response (CAR) between placebo, 20 mg DEX, and 40 mg DEX.

[0053] Fig.11 PK profiles following oral administration of 300mcg dexmedetomidine (lower curve), 500mcg dexmedetomidine (middle curve), and 700mcg dexmedetomidine (upper curve) are shown. The plasma profiles were characterized by high inter-subject variability.

[0054] Fig.12The effect of 20mcg dexmedetomidine and 40mcg dexmedetomidine on sleep onset latency is shown. Both 20μg dexmedetomidine (DEX) and 40μg DEX significantly shortened sleep onset latency compared to placebo. This is noteworthy considering that the drug is administered exactly at the scheduled bedtime (without premedication). Therefore, dexmedetomidine has a very rapid onset of action and can be taken immediately at bedtime and does not require any premedication.

[0055] Fig.13 The effect of 20mcg dexmedetomidine and 40mcg dexmedetomidine on REM latency is shown. Compared with placebo, 20μg dexmedetomidine (DEX) and 40μg DEX both significantly increased REM sleep latency. This drug effect is most likely driven by the strong consolidation of NREM sleep in the first half of the night, which supports the view that dexmedetomidine improves overall sleep. In addition, pathological shortening of REM sleep latency (the so-called sleep onset REM period (SOREM)) is associated with a variety of sleep disorders (including narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS), brainstem injury).

[0056] Fig.14 The effect of 20mcg dexmedetomidine and 40mcg dexmedetomidine on the percentage of REM stage is shown. Compared with placebo, 40μg dexmedetomidine (DEX) significantly reduced the percentage of time spent in REM stage. This drug effect is most likely driven by the strong consolidation of NREM sleep in the first half of the night, which supports the view that overall sleep is improved by dexmedetomidine.

[0057] Fig.15 The effect of 20mcg dexmedetomidine and 40mcg dexmedetomidine on the percentage of stage N2 is shown. Both 20μg dexmedetomidine (DEX) and 40μg DEX significantly increased the percentage of time spent in stage N2. This supports the idea that overall sleep is improved by dexmedetomidine.

[0058] Fig.16 Cumulative graphs of NREM sleep stages are shown. The figure shows the percentage of deep sleep (N2+N3) in total sleep time for each hour of the night (1 to 8). The figure shows that, compared with placebo, at 7 hours to 8 hours, the percentage of deep sleep increased significantly and was a dose-dependent increase of dexmedetomidine (20 / 40) (P; see statistical summary below; 1 = 11-12pm; 2 = 12pm-1am; 3 = 1-2am; 4 = 2-3am; 5 = 3-4am; 6 = 4-5am; 7 = 5-6am; 8 = 6-7am).

[0059] Fig.17 Hypnograms and spectrograms after administration of placebo (top) and dexmedetomidine (40 μg; bottom) to representative individuals are shown. As shown, dexmedetomidine consolidates NREM sleep in the first half of the night and REM sleep in the second half of the night, as shown by less fragmentation in NREM sleep and REM sleep (grey columns are less at 7 hours to 8 hours). Therefore, dexmedetomidine may be particularly suitable for treating disorders associated with strong REM sleep fragmentation, including psychiatric disorders and neurological disorders, such as depression, anxiety, PTSD, schizophrenia, psychosis, ADHD, periodic limb movement disorder, restless legs syndrome, Parkinson's disease (Morbus Parkinson), Alzheimer's disease (Morbus Alzheimer), REM sleep behavior disorder.

[0060] Fig.18 Shown is the time course of slow wave activity (SWA) in a representative subject following administration of placebo (upper panel) and dexmedetomidine (40 μg; lower panel). Dexmedetomidine consolidates NREM sleep sessions and increases overall SWA.

[0061] Fig.19 Slow wave energy (SWE) during N1, N2, and N3 following administration of placebo, 20 μg dexmedetomidine, and 40 μg dexmedetomidine is shown. The graph shows an increase in SWE activity, most pronounced during N3 sleep, indicating an increase in restorative sleep function.

[0062] Fig. 20 The effect of the drug on SWE in the first half of the night (A) and the second half of the night (B) is shown. The figure shows that SWE in the first half of the night is extremely significantly increased, while the effect under the 40μg condition is no stronger than 20μg. SWE in the second half of the night is not affected by the drug. Considering that physiological slow-wave sleep is more prevalent in the first half of the night than in the second half of the night, the fact that DEX selectively increases SWE in the first half of the night (despite high exposure levels in the second half of the night) emphasizes the concept that DEX is a biomimetic sleep enhancer that does not disrupt physiological sleep architecture.

[0063] Fig.21 Shown is the cortisol awakening response (CAR; saliva): drug had no effect on HPA axis activity after awakening; x-axis: 1 = awakening time point; 2 = 15 min; 3 = 30 min; 4 = 45 min; 5 = 60 min; 6 = 75 min.

[0064] Fig. 22 The plasma melatonin release profile is shown: administration of the drug had no effect on the melatonin release profile.

[0065] Fig.23The number of awakenings during REM sleep is shown. As shown by the asterisk, both 20 μg DEX and 40 μg DEX significantly reduced the number of awakenings during REM sleep, indicating that REM sleep is consolidated. This shows that DEX can reduce REM sleep fragmentation (also known as restless REM sleep) by blocking the locus coeruleus, which is usually caused by phasic bursts of noradrenergic activity. DETAILED DESCRIPTION

[0066] The present invention will be described in the following embodiments. It should be understood that all disclosed features can be combined with each other.

[0067] In a first embodiment, the present invention is directed to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in treating or preventing a sleep disorder in a subject.

[0068] Dexmedetomidine refers to the compound according to the formula:

[0069]

[0070] Dexmedetomidine is also known as Precedex, Dexdor, Igalmi. Preferably, the configuration of the chiral (stereogenic) carbon atom is as shown in the above formula. Therefore, preferably, the present invention only includes the enantiomers shown in the above formula. Dexmedetomidine may also be referred to herein as the abbreviation Dex., dex. or DEX.

[0071] The skilled person will recognize that dexmedetomidine can exist in the form of different isomers, particularly proton-modified tautomers. All such tautomers are considered to be included in the present invention. It should be understood that dexmedetomidine can exhibit tautomerism. Therefore, the formula provided above only explicitly describes one of the possible tautomeric forms. The formulas and chemical names provided herein are intended to include any tautomeric form of the corresponding compound, and are not limited to the specific tautomeric form shown in the figure or represented by the compound name.

[0072] In particular, as the skilled artisan will appreciate, dexmedetomidine exists in two tautomeric forms, namely (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. Therefore, when referring to dexmedetomidine, these tautomeric forms are not excluded; it is understood that these two forms remain in equilibrium.

[0073] The term "pharmaceutically acceptable" means a compound or composition (usually and preferably a salt or a carrier), which, when usually and preferably used in a formulation or when usually and preferably used to treat an animal (preferably, a human), must be chemically and toxicologically compatible with the other ingredients (usually and preferably with the composition of the invention or with the parts of the kit of parts of the invention). Preferably, the term "pharmaceutically acceptable" means a compound or composition (usually and preferably a salt or a carrier), which, when usually and preferably used in a formulation or when usually and preferably used to treat an animal (preferably, a human), must be chemically and toxicologically compatible with the other ingredients (usually and preferably with the composition of the invention or with the parts of the kit of parts of the invention). It should be noted that the pharmaceutical composition can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22nd edition.

[0074] Thus, the scope of the present invention includes all pharmaceutically acceptable salt forms of dexmedetomidine, which can be formed, for example, by protonation of an atom carrying an electron lone pair susceptible to protonation (e.g., an amino group) with an inorganic or organic acid, or as a salt of an acid group (e.g., a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, zinc salts, ammonium salts, fatty amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, meglumine salts, ethylenediamine salts or choline salts, arylalkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, phenethylbenzylamine salts, heterocyclic aromatic amine salts such as pyridinium salts, methylpyridinium 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 hydrochlorides, hydrobromides, hydroiodides, sulfates (such as, for example, sulfate or hydrogen sulfate), nitrates, phosphates (such as, for example, phosphate, hydrogen phosphate or dihydrogen phosphate), carbonates, bicarbonates, perchlorates, borates or thiocyanates, organic acid salts such as acetates, propionates, butyrates, valerates, hexanoates, heptanoates, octanoates, cyclopentanepropionates, decanoates, undecanoates, oleates, stearates, lactates, maleates, oxalates, fumarates, tartrates, malates, citrates, Succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, embonate, camphorate, glucoheptonate or pivalate, sulfonate such as methylsulfonate (mesylate), ethylsulfonate (ethanesulfonate), 2-hydroxyethylsulfonate (ethanesulfonate), phenylsulfonate (benzenesulfonate), p-toluenesulfonate (toluenesulfonate), 2-naphthylsulfonate (naphthalenesulfonate), 3-phenylsulfonate, or camphorsulfonate, glycerophosphate, and acidic amino acid salts such as aspartate or glutamate.

[0075] Preferred pharmaceutically acceptable salts of dexmedetomidine include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. A particularly preferred pharmaceutically acceptable salt of dexmedetomidine is hydrochloride. The present invention also particularly relates to dexmedetomidine in non-salt form.

[0076] In addition, the scope of the present invention includes any solvated form of dexmedetomidine, including, for example, solvates with water (i.e., as a hydrate) or solvates with organic solvents (e.g., for example, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO or acetonitrile). All physical forms of dexmedetomidine, including any amorphous form or crystalline form (i.e., polymorphs), are also included within the scope of the present invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of dexmedetomidine are also included in the present invention.

[0077] The scope of the present invention also preferably includes analogs of dexmedetomidine, wherein one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, the present invention includes compounds according to the above formula, wherein one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as "D"). Therefore, the present invention also includes corresponding deuterium-enriched compounds. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol% hydrogen 1 (1H) and about 0.0156 mol% deuterium (2H or D). Deuteration techniques known in the art can be used to increase the deuterium content of one or more hydrogen positions in the corresponding compounds. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise expressly stated, it is preferred that the compounds of formula (I) are not enriched in deuterium. Therefore, it is preferred that naturally occurring hydrogen atoms or 1H hydrogen atoms are present in the compounds according to the above formula.

[0078] As used herein, the term "treating" a disorder or disease is well known in the art. "Treating" a disorder or disease implies that the subject is suspected of or has been diagnosed with the disorder or disease. A subject suspected of having a disorder or disease typically exhibits specific clinical symptoms and / or pathological symptoms that a skilled person can readily attribute to a specific pathological condition (i.e., diagnose the disorder or disease).

[0079] "Treatment" of a disorder or disease can, for example, result in cessation of the progression of the disorder or disease (e.g., symptoms do not worsen) or a delay in the progression of the disorder or disease (if the cessation of progression is only temporary). "Treatment" of a disorder or disease can also result in a partial response (e.g., symptom improvement) or a complete response (e.g., symptom disappearance) in the subject / patient with the disorder or disease. Therefore, "treatment" of a disorder or disease can also refer to the improvement of the disorder or disease, which may, for example, result in cessation of the progression of the disorder or disease or a delay in the progression of the disorder or disease. This partial response or complete response may be followed by recurrence. It should be understood that the subject / patient may experience a wide range of responses to treatment (e.g., exemplary responses as described above). Treatment of a disorder or disease can include, in particular, curative treatment (preferably, resulting in a complete response to the disorder or disease and ultimately a cure) and palliative treatment (including symptom relief).

[0080] As used herein, the term "prevention" of a disorder or disease 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 the prevention of the disorder or disease. The subject / patient may have a susceptibility or tendency to the disorder or disease, including but not limited to a genetic tendency. This tendency can be determined by using, for example, standard methods or tests of genetic markers or phenotypic indicators. It should be understood that the disorder or disease to be prevented according to the present invention has not been diagnosed or cannot be diagnosed in the subject (for example, the subject does not show any clinical symptoms or pathological symptoms). Therefore, the term "prevention" includes the use of dexmedetomidine or its salt according to the present invention before any clinical symptoms and / or pathological symptoms are diagnosed or determined by the attending physician or can be diagnosed or determined by the attending physician.

[0081] Preferably, treating or preventing a sleep disorder in a subject according to the present invention is treating a sleep disorder in a subject.

[0082] As understood herein, the subject preferably refers to a human subject.

[0083] It is understood that dexmedetomidine or a salt thereof is administered to a subject by a transmucosal administration route at a dose of 10 meg to 120 meg. It is understood that the dose of dexmedetomidine refers to the amount of pure dexmedetomidine, such as pure dexmedetomidine in a dexmedetomidine salt or solvate. For example, if dexmedetomidine is present in the form of a pharmaceutically acceptable salt in a particular case, the amount may be different from the amount of the dexmedetomidine salt. As used herein, "mcg" stands for micrograms, also known as μg or 10 - 6 g.

[0084] Preferably, dexmedetomidine or a salt thereof is administered at a dose of 20mcg to 120mcg, more preferably, at a dose of 40mcg to 120mcg.

[0085] Unless expressly stated to the contrary, the doses of dexmedetomidine described herein refer to a single bolus dose administered before bedtime, i.e., before going to bed (e.g., midnight). Thus, the doses can be considered as daily doses, wherein the daily dose is administered before the subject falls asleep. Therefore and preferably, in the present invention, dexmedetomidine is administered as a single bolus dose before falling asleep.

[0086] More preferably, dexmedetomidine or a salt thereof is administered at a dose of 40mcg to 80mcg.

[0087] Even more preferably, dexmedetomidine or a salt thereof is administered at a dose of 60 meg to 80 meg.

[0088] According to the present invention, dexmedetomidine or its salt is administered to a subject via a transmucosal administration route. In transmucosal administration, dexmedetomidine is placed directly in contact with the mucosa and absorbed into the subject's blood via the mucosa. Mucosa (or a membrane that secretes mucus) is a membrane that is arranged in a variety of cavities in the body of an organism and covers the surface of an internal organ. Mucosa is composed of one or more layers of epithelial cells covering a loose connective tissue layer. Mucosa originates primarily from the endoderm and is connected to the skin at body openings such as eyes, eyelids, ears, inside the nasal cavity, inside the oral cavity, lips, genital area, urethral orifice, and anus. Therefore, transmucosal routes include intranasal, buccal, sublingual, vaginal, and rectal routes of administration. They are non-invasive routes for systemic drug delivery and can be administered by themselves or by a family caregiver. These methods of administration are known to technicians. The skilled artisan appreciates that the transmucosal route of administration may provide better bioavailability and more rapid onset of action for some drugs compared to oral administration because the drug is absorbed directly into the bloodstream without passing through the digestive system, thereby avoiding first-pass metabolism.

[0089] Thus, preferably, dexmedetomidine or a salt thereof is administered to the subject via a transmucosal administration route selected from the group consisting of intranasal, buccal, sublingual, vaginal and rectal administration routes.

[0090] Particularly preferred is transmucosal administration via the oral cavity. Thus preferably, dexmedetomidine or a salt thereof is administered to the subject sublingually or buccally. As understood herein, preferably, administering the drug sublingually means placing the drug under the tongue of the subject so that it can dissolve at that location and be absorbed through the mucosa. As understood herein, preferably, administering the drug buccally means placing the drug between the gums and cheek of the subject so that it can dissolve at that location and be absorbed through the mucosa.

[0091] More preferably, dexmedetomidine or a salt thereof is administered to the subject buccally. Compared to sublingual administration, buccal administration reduces the likelihood of accidental oral administration due to the subject swallowing saliva containing dissolved drug.

[0092] The skilled person is able to formulate dexmedetomidine or a pharmaceutically acceptable salt thereof into a form suitable for transmucosal administration, particularly by appropriately mixing selected and pharmaceutically acceptable excipients, carriers, adjuvants, additives, surfactants, desiccants or diluents. Suitable pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter. The pharmaceutically acceptable carrier of the present invention may be solid, semisolid or liquid.

[0093] Thus, dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated according to the present invention as a tablet, an orally disintegrating tablet, a mucoadhesive film, a lyophilisate, a sachet, a powder, a granule, a pill, a suppository, an ointment, a lotion, a gel or a paste. As will be apparent to the skilled person, the formulation may comprise liposomes, micelles and / or microspheres. Dexmedetomidine can also be formulated in the form of a film or patch, such as a buccal film, a buccal patch, a sublingual film, in the form of drops, such as drops for sublingual administration, or in the form of a spray. The film or patch formulation is prepared so that it adheres to the mucus and is soluble at the same time, so that they dissolve and disappear from, for example, the oral cavity, wherein the drug (herein dexmedetomidine) released by them passes through the mucus.

[0094] Tablets or sachets are usually provided in dosage units and may contain conventional excipients, such as binders, fillers, diluents, compressed tablets, lubricants, detergents, disintegrants, colorants, flavoring agents and wetting agents. Tablets can be coated according to methods well known in the art. Suitable fillers include or are preferably cellulose, mannitol, lactose and similar agents. Suitable disintegrants include or are preferably starch, polyvinyl pyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include or are preferably, for example, magnesium stearate. Suitable wetting agents include or are preferably sodium lauryl sulfate. These solid compositions can be prepared by conventional mixing, filling or tableting methods. The mixing operation can be repeated to disperse the active agent in a composition comprising a large amount of fillers. These operations are known to the technician.

[0095] 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, emulsifiers such as lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerides, propylene glycol or ethanol, preservatives such as methyl or propylparaben or sorbic acid, penetration enhancers such as dimethyl sulfoxide (DMSO), pH buffer systems such as phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer and other pharmaceutically acceptable buffer systems, solubilizers such as β-cyclodextrin, and, if desired, conventional flavoring or coloring agents.

[0096] Formulations for oral administration may optionally further include a taste-masking component to optimize taste perception. Examples of such taste-masking components may be citrus-based, liquorice-based, mint-based, grape-based, blackcurrant-based or eucalyptus-based flavorants known to those skilled in the art.

[0097] The dosage form for intranasal administration can include a solution, suspension or emulsion of the active compound in the form of nasal drops in a liquid carrier. Suitable liquid carriers include water, propylene glycol and other pharmaceutically acceptable alcohols. For the administration of drops, the preparation can be appropriately placed in a container, which is provided with, for example, a conventional dropper / closure device, such as a pipette, etc., preferably delivering a substantially fixed volume of the composition / drops. As required, the dosage form can be sterilized. As required, the dosage form can also include an adjuvant, such as a preservative, a stabilizer, an emulsifier or a suspending agent, a wetting agent, a salt or a buffer for changing the osmotic pressure. The buffer system can include, for example, a phosphate buffer, a carbonate buffer, a citrate buffer, a citrate-phosphate buffer and other pharmaceutically acceptable buffer systems. The intranasal preparation can optionally further include a taste masking component to optimize the smell.

[0098] Preferably, dexmedetomidine or a salt thereof is administered to the subject in the form of an orally disintegrating tablet. An orally disintegrating tablet, which may also be referred to as an orally disintegrating tablet (ODT), is preferably understood herein as a tablet that, once placed in the oral cavity, for example, on the tongue, under the tongue, or between the gums and the cheek, will disintegrate (e.g., by effervescence or by dissolution, preferably by dissolution), and accordingly release the drug into the oral cavity. As known to the skilled person, such tablets can be obtained by freeze drying (lyophilization) a solution comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and an excipient. A typical excipient for orally disintegrating tablets is mannitol, which is known to the skilled person to increase binding force and / or reduce dissolution rate. Mannitol (which may be replaced by another sugar) is usually used as the main diluent for orally disintegrating tablets and is also the main contributor to its smooth and creamy mouthfeel. Other processes known to the skilled person for preparing orally disintegrating tablets include loose tableting, in which the tablet is compressed with a much lower force (4 kN to 20 kN) than conventional tablets because the orally disintegrating tablets are required to be soft enough to disintegrate rapidly in the oral cavity. Lubricants such as magnesium stearate are added to the blend to reduce the amount of material that may stick to the die walls. In addition, disintegration aids such as crospovidone and binders that aid in mouth feel such as microcrystalline cellulose are often used in the formulation of orally disintegrating tablets. Exemplary formulations of orally disintegrating tablets containing dexmedetomidine or a pharmaceutically acceptable salt thereof are shown in the Examples section.

[0099] The present invention also includes embodiments in which dexmedetomidine (or an orally disintegrating tablet comprising the same) is formulated by using templated carrier particles, preferably templated reverse phase particles, preferably comprising calcium phosphate and / or magnesium phosphate.

[0100] Therefore and preferably, as encompassed by the present invention, dexmedetomidine is formulated by using carrier particles. The carrier particles are not particularly limited, and any carrier particles known to the skilled person can be used in the present invention.

[0101] As used herein, the term "carrier particles" refers to a material that is nontoxic or substantially nontoxic to a subject, which can be used to improve the desired drug delivery properties of a solid pharmaceutical composition. Unless the carrier particles are loaded with a therapeutic agent, the carrier particles described herein do not have or substantially have no therapeutic effect when applied. In some embodiments, unless the carrier particles are loaded with a therapeutic agent, the carrier particles described herein are pharmacologically inert. In some embodiments, the carrier particles described herein are insoluble in water or substantially insoluble in water. The desired drug delivery properties described herein of a solid pharmaceutical composition include, but are not limited to, effectiveness, 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 are high drug loading capacity of the solid pharmaceutical composition (e.g., drug loading capacity ≥50% v / v, ≥55% v / v, ≥60% v / v, ≥65% v / v, ≥70% v / v, ≥75% v / v, ≥80% v / v; preferably, ≥60% v / v; more preferably, 60% v / v to 85% v / v), low disintegration time ( For example, ≤15s, ≤14s, ≤13s, ≤12s, ≤11s, ≤10s; preferably, ≤10s), and / or physical stability (e.g., for 11 mm tablets, tablet hardness ≥200N, ≥210N, ≥220N, ≥230N, ≥240N or ≥250N; or for 6 mm tablets, tablet hardness ≥40N, ≥50N, ≥60N; preferably, for 6 mm tablets, tablet hardness ≥50N). The carrier particles described herein can have any shape, preferably, the carrier particles described herein have a shape similar to a sphere, a spheroid and / or a bead. The removal of the template material can produce at least one hole in an otherwise substantially uniform structure. The carrier particles can preferably form a hollow structure in a dry environment. Therefore, the carrier particles described herein do not collapse or substantially collapse when dried.

[0102] It should be understood that dexmedetomidine formulated with carrier particles can be formulated as an orally disintegrating tablet. Thus, the carrier particles loaded with dexmedetomidine can be compacted together to form a tablet. Depending on the disintegration properties of the tablet, the tablet can be orally disintegrating. A skilled person is able to formulate and / or administer the orally disintegrating particles.

[0103] Preferably, as described herein, the carrier particles are templated carrier particles, preferably templated reverse phase particles, which may also be referred to as TIP particles. The technology for preparing and using TIP particles is described in detail in patent application PCT / EP2022 / 051799, which is incorporated herein by reference in its entirety. The technology for preparing and using TIP particles is also described below. Preferably, in the event of a conflict between the description below and the description covered by PCT / EP2022 / 051799 (included herein by reference), the latter shall prevail.

[0104] The templated reverse phase particles may also be referred to as carrier particles with a secondary internal structure. As described in PCT / EP2022 / 051799, the method for producing carrier particles with a secondary internal structure comprises the following steps: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) transforming the template material; c) removing the transformed template material; and d) obtaining carrier particles with a secondary internal structure.

[0105] It has surprisingly been found that when carrier particles are produced using template materials that have undergone the transformation described herein, the carrier particles exhibit desirable drug delivery properties.

[0106] Therefore, whenever referring to the carrier particles as described above, it is preferably intended that the particles are obtained according to the method for producing the carrier particles having a secondary internal structure as described above.

[0107] As used herein, the term "primary structure" refers to a layer of support material that includes the template material. In some embodiments, the primary structure includes further structural elements (eg, petalsas) that increase the surface area of ​​the support particle.

[0108] As used herein, the term "secondary internal structure" refers to a hollow internal structure, wherein the inner surface of the hollow internal structure is dense at the crystallization starting point. Thus, the secondary internal structure enables crystallization of the interior of the carrier particle.

[0109] As used herein, the term "support material" refers to a material or mixture comprising raw materials for support particles described herein. In some embodiments, the support material described herein is an inorganic salt or mainly comprises an inorganic salt. In some embodiments, the support material described herein is insoluble in water or is poorly soluble in water. In some embodiments, the support material is soluble in a solvent. In some embodiments, the support material or the precursor of the support material is a liquid. In some embodiments, the support material described herein is a non-polymer or mainly comprises a non-polymer. As used herein, the term "template material" refers to a solid material comprising particles suitable for use as a template so that the primary structure of the support particles can be formed. The particles in the template material preferably have the shape of a sphere, a spheroid and / or a bead. In some embodiments, the template material described herein is a non-polymer or mainly comprises a non-polymer. In some embodiments, the template material described herein has a uniform or almost uniform particle size distribution. In some embodiments, the template materials described herein have a distribution width (as 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. Therefore, the template material is any material that is convertible and has sufficient stability to support the support material. In order to avoid dissolution of the template material in the step 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 poorly 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, olefins, dienes, 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 an aqueous solution comprising a solubility modifier (e.g., saline).In some embodiments, as used herein, the term "poorly soluble" refers to a solubility 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. 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.

[0110] In some embodiments, the template materials described herein comprise salts. In some embodiments, the template materials described herein comprise organic salts. In some embodiments, the template materials described herein are carbonates or comprise primarily carbonates. In some embodiments, the template materials described herein comprise basic oxides.

[0111] As used herein, the term "conversion" refers to changing the properties of a template material by combining at least one physical step and at least one chemical step that can remove the template material. The physical step of "conversion" includes providing energy to the material. In some embodiments, energy is applied in the form of increasing temperature and / or changing pressure. In some embodiments, the physical step of "conversion" induces an endothermic chemical reaction in the template material. The chemical step of "conversion" includes providing a chemical reactant to the template material. In some embodiments, the reactant provided in the chemical step of "conversion" reacts with the template material, but does not react with the support material or does not react substantially with the support material. In some embodiments, the chemical reactant provided in the chemical step of "conversion" is provided in liquid form, dissolved form and / or gaseous form.

[0112] Therefore, carrier particles described herein are carrier particles with a secondary internal structure. In some embodiments, these secondary internal structures can achieve high drug loading, because without being bound by theory, carrier particles can be in the secondary internal structure rather than just on the surface of the carrier particles. The loaded agent or drug can leave the carrier by diffusing through the porous carrier wall. In some embodiments, carrier particles have a certain stability at the target site (for example, on the patient's mucosa). Therefore, these carrier particles can stay at the target site (for example, by adhering to the mucosa), and enable specific drug delivery. In some embodiments, because the loaded agent is continuously released at the absorption site, the carrier particles cover up the bad taste of the loaded agent. The release rate of the loaded agent can be controlled by the geometry of the template material and / or by a diffusion rate regulator such as a disintegrant. Therefore, the degree to which the bad taste diffuses to the perception position (for example, tongue) is low.

[0113] The secondary internal structure described herein enables efficient loading of drugs within the interior of the carrier particles. In addition, the secondary internal structure can be accessed through, for example, pores for loading solvents. In some embodiments, the carrier particles can be loaded with less effort and / or have a particularly high loading capacity.

[0114] In some embodiments, the carrier particles have a particularly large surface area, which is conducive to inter-particle forces. These inter-particle forces act between the carrier particles in the absence of water and increase the mechanical stability of the carrier particle clusters. The increased mechanical stability reduces the need for additional stabilizing materials when the carrier particles are used in pharmaceutical compositions (e.g., solid pharmaceutical compositions, such as tablets). In some embodiments, the inter-particle forces acting between the carrier particles can be weakened by water, thereby shortening the disintegration time of pharmaceutical compositions (e.g., solid pharmaceutical compositions, such as tablets) containing the carrier particles described herein.

[0115] In certain embodiments, the support material is or consists essentially of an inorganic material.

[0116] As used herein, the term "consisting essentially of" in the context of a material means consisting of at least 50% of the material, at least 60% of the material, at least 70% of the material, at least 80% of the material, at least 90% of the material, at least 95% of the material, at least 96% of the material, at least 97% of the material, at least 98% of the material, or at least 99% of the material.

[0117] In certain embodiments, the support material and the template material are or consist essentially of inorganic salts.

[0118] The carrier particles described herein having a secondary internal structure facilitate enhancing one or more desired drug delivery properties.

[0119] During production of the particles, the template material is preferably suspended in a liquid prior to combining the support material with the template material.

[0120] The template material can be suspended in a binding liquid (eg, water) in a reaction vessel under stirring. The stirring speed is set to ensure stable turbulent mixing to prevent particle agglomeration, thereby enabling individual handling of the particles.

[0121] 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 liquid. In some embodiments, the combined liquid described herein is at least one organic solvent selected from the following: dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, olefins, dienes, fatty acids, glycerol, silicone oil, γ-butyrolactone and tetrahydrofuran. In some embodiments, the combined liquid described herein is water. In some embodiments, the combined liquid described herein is an aqueous solution comprising a solubility modifier (e.g., saline).

[0122] In order to avoid dissolution of the template material during the step of combining the support material with the template material, a suitable ratio of the amount of the template material to the amount of the combining liquid should be used. The suitable ratio depends on the solubility of the template material in the combining liquid. In some embodiments, the amount of template material and binding liquid is selected so 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 dissolved in the binding liquid.

[0123] In certain embodiments, combining the support material with the template material comprises chemical precipitation, delamination and / or crystallization of the support material onto the template material.As used herein, the term "chemical precipitation" refers to the process of converting a chemical substance from a solution to a solid by converting the substance into an insoluble form.

[0124] In certain embodiments, a precursor of a support material combines with the surface of a template material in a chemical reaction to form the support material. In some embodiments, a soluble precursor of a support material described herein is phosphoric acid.

[0125] In embodiments where a precursor of a support material combines with the surface of a template material in a chemical reaction to form the support material, the conversion level is relevant. A conversion level that is too low may result in a particle with a porous or broken shell, while a conversion level that is too high may reduce the size of the internal cavity and produce more external crystals, such as dicalcium phosphate, which further converts to hydroxyapatite plates. In some embodiments, the conversion level described herein is about 30% to about 60%, about 35% to 55%, or about 40% to about 50%.

[0126] The temperature during the chemical precipitation process described herein may have a significant impact on the material. For example, dicalcium phosphate is a form that is less thermodynamically stable than hydroxyapatite. Therefore, too low a temperature and rapid or uncontrolled addition of orthophosphoric acid to calcium carbonate will cause its precipitation, producing more dicalcium phosphate, producing more difficult to handle independent crystals. In some embodiments, the temperature during the chemical precipitation process is about 60°C or higher, preferably, about 60°C to about 100°C, more preferably, about 70°C to about 95°C, more preferably, about 80°C to about 95°C.

[0127] In certain embodiments, a soluble precursor of a support material is added to the template material in the form of a solution and distributed on the template material by adding a reactant for converting the soluble precursor of the support material into an insoluble support material. In some embodiments, the soluble precursor of the support material described herein is sodium phosphate or calcium chloride (e.g., R., et al., 1975, Calc. Tis Res. 18, 13–26).

[0128] As used herein, the term "layering" refers to a technique for adding at least one layer of a carrier to a template material.

[0129] Any delamination 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, electrostatic interactions (e.g., as described in Decher, GHJD, et al., 1992, Thin solid films, 210, 831-835), hydrogen bonding (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 coupling (e.g., as described in Zhang, Y., et al., 2003, Macromolecules, 36(11), 4238-4240), electroplating and electrodeposition (e.g., as described in Chandran, R., Panda, SK & Mallik, AA short review on the advances in electroplating of CuInGaSe2 thin films. Mater Renew Sustain Energy 7,6(2018)) is used to prepare at least one layer on a template material, in particular to prepare a multilayer film on a template material.

[0130] As used herein, the term "crystallization" refers to the process of transforming a chemical substance from a supersaturated solution.

[0131] In certain embodiments, the support material is added to the template material as a supersaturated solution and distributed on the template material by inducing chemical precipitation.

[0132] In certain embodiments, combining the support material with the template material comprises chemical precipitation and crystallization of the support material on the template material.

[0133] In certain embodiments, combining the support material with the template material comprises chemical delamination and crystallization of the support material on the template material.

[0134] In certain embodiments, combining the support material with the template material comprises chemical precipitation and delamination of the support material onto the template material.

[0135] The chemical precipitation process can be carried out by pumping a precursor solution of the template material onto a support material or into a liquid containing the support material. In this process, the support material can begin to grow (e.g., in the form of a crystalline lamella structure) on the surface of the template material, thereby forming a layer (stratum layer). In certain embodiments, the template material described herein is converted into a support material. In certain embodiments, at least about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% of the template material described herein is converted into a support material.

[0136] Chemical precipitation, delamination and / or crystallization allows the support material to be finely and / or evenly distributed on the template material. This fine distribution and / or even distribution affects the formation of the secondary internal structure.

[0137] Thus, by using chemical precipitation, delamination and / or crystallization of a support material on a template material, as described herein, support particles are produced that exhibit a particularly fine and / or uniform secondary internal structure.

[0138] In certain embodiments, converting 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 839°C, preferably, about 650°C to about 700°C.

[0139] In certain embodiments, converting the template material comprises heating to a temperature of 840°C to 1200°C.

[0140] Conditions can be optimized to avoid interparticle agglomeration during the heating step, which may lead to redispersibility issues. Although in some embodiments, it is not necessary to add other agents to avoid interparticle agglomeration, in other embodiments, agents to avoid interparticle agglomeration (e.g., anti-sintering agents) are added during and / or before the heating step described herein. Such anti-sintering agents are described, for example, in Okada, M., et al., 2014, Journal of nanoparticle research, 16(7), 1-9.

[0141] The conversion of the template material described herein can be carried out at any suitable temperature or any suitable temperature range. In order to enable the template material described herein to be converted, the minimum suitable temperature for the conversion is set to a certain temperature, such as about 210°C (for example, for carbonates of silver and gold as template materials), about 840°C (for example, for using calcium carbonate as template material), about 900°C, about 1000°C or about 1200°C (for example, for using potassium carbonate and / or sodium carbonate as template material). Those skilled in the art can determine the appropriate minimum suitable temperature from the decomposition temperature of the template material. Temperature increase can shorten the conversion time, however, the melting of the carrier material may have an undesirable effect on the carrier particles, such as incomplete formation of the carrier particles or reduced hardness of the carrier particles. In order to avoid melting of the carrier material, the maximum suitable temperature for the conversion of the template material described herein is set to below the melting temperature of the carrier material. At temperatures below the melting temperature of the carrier material, the desired structure that increases the surface area of ​​the carrier particles (for example, petals on the surface of the carrier particles) may have been deformed and / or lost. Thus, in certain embodiments, the maximum suitable temperature for conversion of the template material described herein is set at about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C below the melting temperature of the support material.

[0142] In certain embodiments, converting the template material comprises heating to a temperature from about the decomposition temperature of the template material to about the melting temperature of the support material, preferably, from about the decomposition temperature of the template material to about 400°C below the melting temperature of the support material, and more preferably, from about the decomposition temperature of the template material to about 500°C below the melting temperature of the support material.

[0143] In certain embodiments, converting the template material comprises heating to a temperature of from 840°C to 1600°C, preferably, from 840°C to 1200°C, more preferably, about 1100°C.

[0144] The duration of heating used to convert the template material described herein depends on various factors, such as the template material, support material, temperature range, particle size, and / or desired support particle surface area.

[0145] The heating duration for converting the template material described herein can be, for example, about 1 hour. In certain embodiments, the heating duration for converting the template material described herein is about 5 min to about 24 h, about 10 min to about 12 h, 20 min to about 4 h.

[0146] The heating described herein for converting the template material (e.g., to a temperature in a range such as 840°C to 1200°C or 600°C to 900°C) can be achieved by any heating mode (e.g., a linear increase in temperature or with one or more preheating steps). The preheating step described herein may include maintaining the temperature at a certain temperature level for a period of time before heating the template material to a temperature in a range such as 840°C to 1200°C or 600°C to 900°C. Preheating can, for example, remove undesirable volatile components, such as solvents.

[0147] In some embodiments, the pressure is reduced during the heating process, thereby serving to transform the template material to a temperature in a range, for example, 840°C to 1200°C.

[0148] In some embodiments, pressure is added during the heating process, thereby serving to transform the template material to a temperature in a range, for example, 840°C to 1200°C.

[0149] In some embodiments, the heating used to convert the template material induces an endothermic chemical reaction.

[0150] In some embodiments, an inert substance (eg, an inert gas) is provided to avoid side reactions during the heating process used to convert the template material to a temperature in a range, for example, 840°C to 1200°C.

[0151] In some embodiments, the heating used to convert the template material induces evaporation of a volatile portion of the template material.

[0152] Heating to a temperature in a range, for example, 840°C to 1200°C can induce transformation of the template material without changing the support material or without changing the support material to the same extent. This enables removal of the transformed template material based on the altered properties. Lower temperatures (e.g., about 600°C to about 839°C or 600°C to about 900°C) can be used to maintain the petal structure to a greater extent, which can increase the hardness of the resulting tablet.

[0153] If the temperature is higher than the recommended range, the fine petal structure of the granules melts and decreases, and the flexibility of the petals decreases; therefore, the hardness of tablets made with such overheated materials is greatly reduced. Pharmaceutical tablets made with overheated materials show capping and delamination and cannot be used equally well in pharmaceutical preparations.

[0154] Thus, the heating step used to transform the template material can produce carrier particles having a secondary internal structure that facilitates enhancing one or more desired drug delivery properties.

[0155] In certain embodiments, the step of converting the template material comprises calcining.

[0156] As used herein, the term "calcining" refers to heating a solid or a mixture comprising a solid to a high temperature (eg, a temperature of 840 to 1200°C or 600 to 900°C) with air or oxygen provided to the solid or mixture.

[0157] In some embodiments, calcination described herein induces decomposition of a template material comprising a carbonate (eg, a carbonate, such as a calcium carbonate) into carbon dioxide.

[0158] In some embodiments, calcination as described herein induces decomposition of the template material comprising a metal carbonate into a metal oxide, preferably, a basic oxide.

[0159] In some embodiments, calcination as described herein induces decomposition of the hydrated template material by removing water.

[0160] In some embodiments, calcination as described herein induces decomposition of volatile species in the template material.

[0161] Accordingly, the calcination step used to transform the template material can produce carrier particles having a secondary internal structure that facilitates enhancing one or more desired drug delivery properties.

[0162] In certain embodiments, converting the template material comprises subsequently adding water.

[0163] The water subsequently added converts the template material in a chemical reaction, but does not change the support material or does not substantially change the support material. This enables the removal of the converted template material based on the changed properties.

[0164] In some embodiments, the subsequently added water reacts with the metal oxide as described herein.

[0165] Accordingly, the conversion step process includes the addition of water, allowing for the production of carrier particles having a secondary internal structure that facilitates enhanced one or more desired drug delivery properties.

[0166] In certain embodiments, the addition of water allows an exothermic reaction to occur.

[0167] As used herein, the term "exothermic reaction" refers to a reaction in which the total standard enthalpy change is negative.

[0168] As described herein, the subsequently added water transforms the template material in an exothermic chemical reaction, but does not change the support material or does not substantially change the support material. This enables removal of the transformed template material based on the altered properties.

[0169] The basic oxides described herein are non-toxic or substantially non-toxic at the dosages used as described herein. In some embodiments, the water subsequently added reacts with the basic oxide as described herein. In some embodiments, the water subsequently added 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 as described herein. In some embodiments, the water subsequently added reacts with magnesium oxide and / or calcium oxide as described herein.

[0170] The exothermic reaction described herein can facilitate the subsequent removal of the template material. The forces released during the exothermic reaction and / or the properties of the exothermic reaction products can reduce 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 density of 2.21 g / cm 3 of calcium hydroxide.

[0171] Therefore, the added water supports the secondary structure formation through an exothermic reaction and promotes the subsequent removal of the template material.

[0172] In certain embodiments, removing the template material includes dissolving the transformed template material to form a secondary internal structure.

[0173] The secondary internal structure may be formed by removing the converted template material by dissolution in a solvent that dissolves the converted template material but does not dissolve the support material.

[0174] In some embodiments, removing the template material comprises dissolving the converted template material with water or an aqueous solution. In some embodiments, the pH of the aqueous solution is changed before dissolving the converted template material to increase the solubility of the converted template material or reduce the solubility of the support material in the aqueous solution.

[0175] In some embodiments, removing the template material comprises dissolving the converted template with an organic solvent.

[0176] Removal of the template material by dissolution is particularly gentle on the support material. Thus, this gentle removal helps to preserve the primary support material structure and enables the formation of a secondary internal structure that is particularly conducive to crystallization during drug loading.

[0177] Therefore, removing the template material includes dissolving the transformed template material, which helps to form the secondary internal structure.

[0178] In certain embodiments, the template material comprises a metal carbonate.

[0179] In certain embodiments, the template material comprises at least one metal carbonate selected from the group consisting of Li2CO3, LiHCO3, Na2CO3, NaHCO3, Na3H(CO3)2, MgCO3, 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.

[0180] 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.

[0181] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% metal carbonate.

[0182] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% of at least one metal carbonate selected from the group consisting of Li2CO3, LiHCO3, Na2CO3, NaHCO3, Na3H(CO3)2, MgCO3, 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.

[0183] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% magnesium carbonate.

[0184] In certain embodiments, the template material comprises calcium carbonate.

[0185] In certain embodiments, the template material comprises greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% calcium carbonate.

[0186] In some embodiments, the calcium carbonate described herein includes anhydrous calcium carbonate, a complex comprising calcium carbonate and / or a hydrated calcium carbonate, such as CaCO 3 ·H 2 O and / or calcium carbonate hexahydrate.

[0187] In some embodiments, the calcium carbonate described herein is an anhydrous calcium carbonate.

[0188] The metal carbonates described herein can be used as primary ingredients to produce support materials with different properties on the surface of the template material (e.g., to produce insoluble metal phosphates by reaction of the metal carbonate with H3PO4), and can be converted as described herein.

[0189] In certain embodiments, the support material comprises at least one salt and / or complex selected from calcium phosphates and magnesium phosphates.

[0190] In certain embodiments, the support material comprises at least one salt and / or complex of magnesium phosphate.

[0191] In certain embodiments, the support material comprises at least one salt and / or complex of calcium phosphate.

[0192] Calcium phosphate and magnesium phosphate have particularly low solubility in water and exhibit suitable heat resistance. In addition, calcium phosphate and magnesium phosphate are generally pharmacologically inert and non-toxic. Therefore, calcium phosphate and magnesium phosphate are stable and non-toxic and can be transformed into template materials as described herein without decomposition.

[0193] Therefore, production of the support particles described herein is particularly efficient when the support material comprises at least one salt and / or complex selected from calcium phosphates and magnesium phosphates.

[0194] Preferably, the carrier particles encompassed by the present invention comprise calcium phosphate and / or magnesium phosphate. More preferably, the carrier particles encompassed by the present invention comprise calcium phosphate.

[0195] Preferably, the calcium phosphate is in the form of hydroxyapatite. As described herein, hydroxyapatite is a substance having the formula Ca5(OH)(PO4)3.

[0196] Accordingly and preferably, the carrier particles encompassed by the present invention comprise hydroxyapatite. Further preferably, the carrier particles encompassed by the present invention further comprise calcium hydroxide.

[0197] Therefore, preferably, the present invention relates to an embodiment, wherein dexmedetomidine (or an orally disintegrating tablet comprising dexmedetomidine) is formulated by using carrier particles having a secondary internal structure, wherein the carrier particles comprise 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, even more preferably, about 100% w / w.

[0198] The template material can have a variety of structures, such as powders (e.g., powders with 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 with particle sizes ranging from approximately 1 μm to 100 μm, 100 μm to 300 μm, or 300 μm to 600 μm) or nanoparticles.

[0199] In certain embodiments, the template material comprises particles having a diameter of 1 μm to 300 μm. In certain embodiments, the template material consists of particles, wherein about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% of the particles have a diameter of 1 μm to 300 μm. In certain embodiments, the template material comprises particles having a median diameter of about 1 μm to 300 μm, about 1 μm to 250 μm, about 1 μm to 200 μm, about 1 μm to 150 μm, about 1 μm to 100 μm, about 1 μm to 90 μm, about 1 μm to 80 μm, about 1 μm to 70 μm, about 1 μm to 60 μm, about 1 μm to 50 μm, about 1 μm to 40 μm, about 1 μm to 30 μm, or about 1 μm to 20 μm.

[0200] The particle size of the template material affects the diameter of the carrier particles. In certain embodiments, the particles of the template material have a median diameter that is about the same as the median diameter of the carrier particles. In embodiments where the template material and the carrier material are combined by delamination and / or crystallization as described herein, the carrier particles have a similar or larger median diameter than the template material.

[0201] 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 diameter than the template material.

[0202] One skilled in the art can predict support materials based on the template materials, support materials, and techniques for combining the template materials and support materials described herein.

[0203] In certain embodiments, the carrier particles have a diameter of 1 μm to 300 μm.

[0204] Particles of a certain 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; US5376347A). Particle size and particle shape measurement can be performed using any method known in the art (e.g., 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).

[0205] In some applications, a specific low carrier particle diameter is desired. In certain embodiments, the diameter of the carrier particles for intrapulmonary administration and / or nasal administration is about 1 μm to 20 μm, about 1 μm to 15 μm, about 1 μm to 10 μm, or about 1 μm to 5 μm. In some applications, a specific low carrier particle diameter is desired to increase the diffusion surface and accelerate the release of the loaded agent.

[0206] In some applications, a larger carrier particle diameter is desired to enhance the flowability of the carrier particles and facilitate further processing. In certain embodiments, the diameter of the carrier particles is about 5 μm to 300 μm, about 10 μm to 250 μm, about 15 μm to 200 μm, or about 20 μm to 150 μm.

[0207] Therefore, methods for producing carrier particles described herein, wherein the diameter of the carrier particles is within a certain range, may be particularly useful for further processing (e.g., flowability) and / or application (e.g., diffusion surface) of the carrier particles produced according to the method.

[0208] In certain embodiments, the surface area of ​​the carrier particles is 15 m 2 / g to 400m 2 / g or 30m 2 / g to 400m 2 / g.

[0209] In certain embodiments, the surface area of ​​the support particles is about 15 m 2 / g to 400m 2 / g, about 30m 2 / g to 400m 2 / g, about 50m 2 / g to 350m 2 / g, about 70m 2 / g to 320m 2 / g, about 90m 2 / g to 300m 2 / g, or about 100m 2 / g to 280m 2 / g.

[0210] 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).

[0211] The surface area of ​​the support particles can be varied, for example, by varying the particle size of the support material, the support material, and / or by varying the surface structure via the parameters described herein (eg, heat, duration of heating).

[0212] In certain embodiments, the support particles are used as adsorbents.

[0213] The carrier particles described herein have a large specific surface area, resulting in strong van der Waals interactions once the particles come into contact. This effect results in a higher tensile strength of the final dosage form. These van der Waals interactions can be weakened by the addition of water and support the disintegration of the particle clusters.

[0214] Accordingly, if the surface area of ​​the carrier particles is 15 m 2 / g to 400m 2 / g, preferably 30m 2 / g to 400m 2 / g, the method for producing the carrier particles described herein provides them with mechanical stability and disintegration ability.

[0215] In certain embodiments, the secondary internal structure comprises pores having diameter sizes ranging from ≥ 0.2 μm and ≤ 1.5 μm.

[0216] 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.

[0217] 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 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.

[0218] 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).

[0219] The porous structure that can be formed by the method for producing carrier particles described herein allows the pores to have a particularly large size. Such a large pore size is conducive to loading the drug on the carrier particles and accelerating the release of the drug from the carrier particles.

[0220] Pore ​​sizes larger than 90% of the particle diameter of the template material will result in unstable support particles. Therefore, the maximum pore size depends on the particle size of the template material.

[0221] In certain embodiments, the secondary internal structure comprises pores having a diameter size 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. Accordingly, the method described herein for producing carrier particles, wherein the secondary internal structure comprises pores having a specific diameter size, is particularly useful for subsequent drug loading and drug release of the carrier particles produced as described herein.

[0222] In certain embodiments, the total volume of the secondary internal structure of the obtained support particles having a secondary internal structure is ≥10% to ≤90% of the volume of the particle, as determined by image analysis of cross-sectional images of the resin-embedded particles by SEM-FIB and SEM. Another analytical method to measure the volume ratio of the internal structure to the particle includes calculating the porosity, which is the ratio of the tapped bulk of the support material to the density of the true crystals of the support material.

[0223] The total volume of the secondary internal structure refers to the volume of the interior of the particle created by removing the template material. In certain embodiments, the total volume of the secondary internal structure described herein is the average internal volume of the support particles obtained as described herein.

[0224] In certain embodiments, the total volume of the secondary internal structure described herein is the median internal volume of a carrier particle obtained as described herein.

[0225] In certain embodiments, the total volume of the secondary internal structure of the obtained carrier particles having a secondary internal structure 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 volume of the particles.

[0226] In certain embodiments, the total volume of the secondary internal structure of the obtained carrier particles having a secondary internal structure 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 volume of the particles.

[0227] In certain embodiments, the total volume of the secondary internal structure of the obtained carrier particles having a secondary internal structure ranges from 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 volume of the particles. %, about ≥65% to ≤90%, about ≥70% to ≤90%, about ≥10% to ≤80%, about ≥15% to ≤80%, about ≥20% to ≤80%, about ≥25% to ≤80%, about ≥30% to ≤80%, about ≥35% to ≤80%, about ≥40% to ≤80%, about ≥45% to ≤80%, about ≥50% to ≤80%, about ≥55% to ≤80%, about ≥60% to ≤80%, about ≥65% to ≤80%, about ≥70% to ≤80% , about ≥10% to ≤70%, about ≥15% to ≤70%, about ≥20% to ≤70%, about ≥25% to ≤70%, about ≥30% to ≤70%, about ≥35% to ≤70%, about ≥40% to ≤70%, about ≥45% to ≤70%, about ≥50% to ≤70%, about ≥55% to ≤70%, about ≥60% to ≤70%, about ≥65% to ≤70%, about ≥10% to ≤60%, about ≥15% to ≤60%, about ≥20% to ≤60% , about ≥25% to ≤60%, about ≥30% to ≤60%, about ≥35% to ≤60%, about ≥40% to ≤60%, about ≥45% to ≤60%, about ≥50% to ≤60%, about ≥55% to ≤60%, about ≥10% to ≤50%, about ≥15% to ≤50%, about ≥20% to ≤50%, about ≥25% to ≤50%, about ≥30% to ≤50%, about ≥35% to ≤50%, about ≥40% to ≤50%, or about ≥45% to ≤50%.

[0228] In certain embodiments of the carrier particles described herein and obtained as described above, the loading capacity of the carrier particles is ≥72% v / v, ≥70% v / v, ≥68% v / v, ≥66% v / v, ≥64% v / v, ≥62% v / v or ≥60% v / v.

[0229] In certain embodiments of the carrier particles described herein, the loading capacity of the carrier particles is ≥ 60% v / v.

[0230] As used herein, the term "loading capacity" refers to the volume of a carrier particle that can be used to load an agent compared to the volume of the entire carrier particle. Accordingly, a carrier particle with a loading capacity of 60% v / v can load an agent that is 60% of the volume of the carrier particle. The volume of the carrier particle is calculated from the diameter of the carrier particle. Therefore, in this calculation, the volume of the internal structure is a portion of the volume of the carrier particle.

[0231] In some embodiments, the agent loaded on the carrier particle includes a loading solvent, and removal of the loading solvent completes the loading.

[0232] The agent to be loaded is dissolved in the loading solvent and contacted with the carrier particles to ensure that the carrier particles are fully wetted. 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: evaporation, vacuum assisted evaporation, atmospheric drying, vacuum freeze drying, freeze drying under atmospheric pressure, spray drying, spray drying in a fluidized bed apparatus, microwave assisted drying, electrospray assisted drying, dielectric drying, fluidized bed assisted drug loading and solvent adsorption methods.

[0233] In the present invention, the agent to be loaded into the carrier particles is dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the solvent adsorption process comprises high shear granulation.

[0235] Selection of an appropriate loading solvent depends on solvent toxicity, solvent partial vapor pressure, the nature of the agent to be loaded (eg, pH stability and / or solubility of the agent to be loaded), and / or the nature of the carrier material.

[0236] In some embodiments, the load 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, olefins, dienes, fatty acids, glycerol, silicone oil, γ-butyrolactone and tetrahydrofuran. In some embodiments, the load solvent described herein is water.

[0237] Some loading solvents, such as water, have high surface tension, so despite extremely large pore sizes, additional measures may still be needed to support their entry into the pores of the carrier particles described herein. In some embodiments, the loading solvent described herein includes at least one surfactant, such as a tenside. In some embodiments, the addition of the loading solvent is performed under pressure to support the loading solvent entering the interior of the carrier particles.

[0238] In some embodiments, loading on and into carrier particles as described herein includes adding an antisolvent that reduces the solubility of the agent to be loaded in the loading solvent. In some embodiments, the antisolvent is at least one 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, olefins, dienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran.

[0239] In some embodiments, the loading solvent is removed by evaporation, for example, by increasing the temperature and / or reducing the pressure. The maximum temperature for removing the loading solvent depends on the thermal stability of the loaded agent.

[0240] As described herein, support particles having a secondary internal structure may be compacted to obtain compacted support particles.

[0241] As used herein, the term "compacted carrier material" refers to a cluster of more than one carrier particle with adhesive forces acting between the carrier particles.

[0242] As used herein, the term "compacting" refers to applying pressure to more than one particle (e.g., carrier particles) to form a compacted carrier material, wherein the carrier particles remain at least partially adhered to each other after the pressure is released. Techniques for compacting are known to those skilled in the art (see, e.g., Odeku, OA et al., 2007, Pharmaceutical Reviews, 5 (2)). Examples of compacting techniques include, but are not limited to, tableting, roller pressing, slugging, briquetting and / or centrifugation.

[0243] The compacted carrier materials described herein are particularly stable and can be used to obtain particularly stable pharmaceutical compositions. During the compaction process, the large surface area of ​​the carrier particles described herein forms strong inter-particle van der Waals adhesion forces, thereby achieving mechanical stability. After ingestion, water enters between the particles (e.g., through capillary forces), the distance-dependent van der Waals adhesion forces weaken, and the compacted carrier material disintegrates.

[0244] Accordingly, the compacted carrier materials described herein exhibit a particular mechanical stability and / or a fast disintegration time.

[0245] The present inventors surprisingly found that dexmedetomidine formulations formulated using carrier particles exhibit improved bioavailability and / or reduced bitter taste, resulting in increased patient compliance.

[0246] Accordingly and preferably, the carrier particles according to the invention are compacted.

[0247] Thus, preferably, the present invention relates to an embodiment wherein dexmedetomidine (or an orally disintegrating tablet comprising dexmedetomidine) is formulated by using carrier particles having a secondary internal structure, wherein the carrier particles are compacted, wherein the carrier particles comprise 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, even more preferably, about 100% w / w.

[0248] The sleep disorder that can be treated with dexmedetomidine according to the present invention is not particularly limited, and any sleep disorder known to the skilled person according to the present invention can be treated with dexmedetomidine for use according to the present invention. Preferably, the sleep disorder is selected from insomnia disorder, excessive sleepiness disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep arousal disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance or drug-induced sleep disorder. Therefore, accordingly, the present invention relates in one embodiment to dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to the present invention, wherein the sleep disorder is selected from insomnia disorder, excessive sleepiness disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep arousal disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance or drug-induced sleep disorder.

[0249] It is known to the technician that sleep disorders usually coexist with other conditions that the subject may suffer from. These conditions may be life-threatening, or may not be life-threatening. It is obvious to the technician that sleep disorders are usually accompanied by depression, anxiety and cognitive changes, which must be addressed in treatment plans and management. Sleep disorders are also the definite risk factors for the subsequent development of common mental illnesses, and may represent the prodromal symptoms of mental illness onset, thereby providing possibilities for early intervention, to prevent or alleviate comprehensive onset. In addition, sleep disorders provide clinically useful signs of medical disorders and neurological disorders, which usually coexist with depression and other common mental disorders. Sleep-wake complaints can provide clinically actionable clues for breathing-related sleep disorders, heart and lung disorders (such as congestive heart failure and chronic obstructive pulmonary disease), neurodegenerative disorders (Alzheimer's disease or Parkinson's disease) and musculoskeletal system disorders. The characteristics of each of these are significant sleep-wake complaints, and each is often accompanied by depression and anxiety disorders.

[0250] Conversely, mental health clinicians should also understand that some medical disorders not only interfere with sleep (such as the examples above), but they themselves may be exacerbated during sleep. Thus, some patients may experience apnea or ECG arrhythmias during REM sleep, confusional arousals in dementia, excessive sleepiness disorders associated with anxiety disorders and insomnia, or REM sleep behavior disorder in alpha synucleinopathies such as Parkinson's disease.

[0251] Accordingly, as disclosed herein and as 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.

[0252] Further accordingly, as disclosed herein and as encompassed by the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof can be used to treat subjects suffering from disorders of the heart and lungs (e.g., congestive heart failure or chronic obstructive pulmonary disease), neurodegenerative disorders (e.g., Alzheimer's disease or Parkinson's disease), or disorders of the musculoskeletal system.

[0253] Preferably, within the scope of the present invention, the sleep disorder is insomnia disorder.

[0254] Insomnia is one of the most common complaints in the general population (Mahowald & Schenck, 2005). Ohayon reviewed more than 50 epidemiological studies on insomnia and found that about one-third of the general population meets at least one DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) insomnia criteria. In addition, 6% of the general population is 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). At the same time, the DSM sleep-wake disorder classification has been updated to the fifth edition (DSM-V).

[0255] Insomnia can be an isolated disorder or can be comorbid with another psychiatric disorder (depression), a medical condition (pain), or another sleep disorder (American Psychiatric Association, 2013, p. 362). Based on DSM-V (2013, p. 362), the diagnostic criteria for insomnia disorder are:

[0256] Dissatisfaction with sleep quality due to difficulty falling asleep or staying asleep and early awakening and inability to fall asleep again Disturbance in sleep leading to impairment in social, occupational, educational, academic, behavioral, or other areas of functioning

[0257] Occurs at least three nights a week

[0258] Has been in existence for at least three months

[0259] Despite normal sleep conditions,

[0260] It does not occur only during another sleep disorder

[0261] It is not due to the physiological effects of a substance such as a drug

[0262] · The complaint is not explained by a coexisting medical or psychiatric condition

[0263] Another method for diagnosing insomnia is a questionnaire. An example is the Insomnia Severity Index (ISI). It measures the severity of insomnia and allows us to understand the course of insomnia disorders. The ISI consists of 7 items using a 5-point Likert-type rating scale (0 to 4 points), which assesses the severity of insomnia complaints in the past two weeks (Stuck et al., 2021, pp. 26-28). These points add up to a score of 0 to 28 points. According to the final score, the following interpretations are made: no insomnia (0 to 7), subthreshold insomnia (8 to 14), moderate insomnia (15 to 21) and severe insomnia (22 to 28) (Morin, CM, Belleville, G., Bélanger, L., & Ivers, H. (2011). The Insomnia Severity Index: Psychometric Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep, 34 (5), 601-608).

[0264] As discussed above, insomnia may coexist with other conditions. Accordingly, as disclosed herein and as encompassed by the present invention, the insomnia disorder to be treated according to the present invention is selected from insomnia associated with depression, insomnia associated with anxiety disorders, 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.

[0265] In a specific embodiment, insomnia is insomnia associated with PTSD. Although current PTSD treatment is effective, the results of prevention strategies are not satisfactory. Therefore, there is an urgent need for effective prevention strategies to target this debilitating mental disorder. Painful intrusive memories are the main symptoms of trauma-related disorders, which are characterized by repeated re-experiencing of traumatic memories after exposure to traumatic events. The formation of the invasion may depend on the failure of traumatic memories to be fully integrated into the hippocampus-cortical memory network during slow-wave sleep (SWS)-dependent encoding, due to the huge negative emotional intensity of the traumatic event. In addition, the immune response associated with post-traumatic stress mainly involves an increase in cytokines, but may also involve metabolites of the kynurenine pathway, which is a pathogenic factor of PTSD, and also impairs sleep physiology and memory consolidation. In fact, recent studies have revealed a close relationship between sleep physiology and the severity of intrusion, and found that insufficient sleep quality immediately after a traumatic event increases the vulnerability to developing intrusive memories. In addition, it is known to technicians that poor sleep can affect physical and cognitive performance and emotions during the day. Similarly, it is known that sleep has a huge impact on memory consolidation. Accordingly, since PTSD is characterized by severe insomnia symptoms (including nightmares) and a lack of traumatic memory consolidation (which occurs particularly during deep sleep), it has been reasonably suggested that treatment with dexmedetomidine, as disclosed herein, to treat (or prevent) insomnia or its mnemonic symptoms may be effective in the treatment or prevention of PTSD.

[0266] Accordingly, in one embodiment of the invention, the treatment or prevention of a sleep disorder in a subject, in particular the treatment or prevention of insomnia as defined herein, constitutes the treatment or prevention of post-traumatic stress disorder.

[0267] The inventors have shown that, when administered according to the present invention, dexmedetomidine shortens sleep latency, increases REM latency, and increases time spent in NREM sleep (N2+N3). Furthermore, dexmedetomidine has been shown to increase slow wave activity. Accordingly, dexmedetomidine at doses according to the present invention has been shown to facilitate deeper sleep. It has further been shown that administration of dexmedetomidine according to the present invention will result in reproducible plasma levels in different subjects, thereby minimizing inter-subject variability and potentially leading to reproducible therapeutic effects.

[0268] In addition, the inventors have found that sublingual bedtime doses of dexmedetomidine that result in plasma concentrations above 0.15 ng / mL upon awakening may lead to hangover effects upon awakening, particularly orthostatic dysregulation and dizziness. Based on these findings, the inventors suggest that sublingual bedtime doses above 120 μg to 150 μg may lead to next-day residual effects. Therefore, the inventors have found that the therapeutic window for sublingual dexmedetomidine in the treatment of sleep disorders is 10 μg to 120 μg.

[0269] Accordingly, the inventors reasonably believe that dexmedetomidine used in accordance with the present invention may be used to treat sleep disorders other than insomnia.

[0270] Accordingly, encompassed by the present invention are embodiments wherein the sleep disorder is hypersomnia and narcolepsy.It is to be understood that dexmedetomidine or a salt thereof is to be administered according to the present invention, ie as described herein.

[0271] Excessive sleepiness is defined as the inability to stay awake and alert during the day despite adequate sleep at night. Excessive sleepiness creates challenges in work life, social life and family life.

[0272] Narcolepsy is understood herein as a chronic sleep disorder that results in extreme daytime sleepiness. Narcolepsy results in sudden attacks of drowsiness. Sudden loss of muscle tone and hallucinations may occur. The extended REM sleep latency demonstrated by the inventors may be particularly useful for treating disorders associated with a pathological shortening of REM sleep latency (also known as sleep onset REM period), which is very common in narcolepsy, but also in affective disorders such as major depressive disorder.

[0273] Narcolepsy is characterized by fragmented NREM / REM sleep and shortened REM sleep latency. In addition, REM density is higher in narcolepsy than in healthy individuals. In addition, narcolepsy is characterized by excessive daytime sleepiness due to non-restorative sleep and nighttime awakenings / nightmares. Interestingly, DEX 1) consolidates NREM and REM sleep, 2) significantly shortens REM sleep latency, 3) increases NREM sleep at the expense of REM sleep, and 4) is able to reduce daytime sleepiness. In addition, DEX has anxiolytic properties and is effective in reducing nocturnal anxiety (nightmares, abnormal thoughts). Therefore, DEX appears to actively address multiple key pathological features of narcolepsy and may therefore be a promising therapy for this disorder.

[0274] The present invention also provides the use of dexmedetomidine or a pharmaceutically acceptable salt thereof in the treatment of a sleep disorder, wherein the sleep disorder is a circadian rhythm sleep disorder. Circadian rhythm sleep disorders include difficulty falling asleep, awakening during the sleep cycle or waking up early and being unable to fall asleep again. Particularly preferred embodiments of the present invention relate to circadian rhythm sleep disorders characterized by delayed sleep-wake phases, shift work, non-24-hour sleep-wake rhythms or irregular sleep-wake rhythms. It should be understood that dexmedetomidine or a salt thereof will be administered according to the present invention, i.e. as described herein.

[0275] The present invention also provides the use of dexmedetomidine in treating REM sleep behavior disorder. Rapid eye movement (REM) sleep behavior disorder is a sleep disorder in which during REM sleep you physically act out vivid, often unpleasant dreams, accompanied by vocalizations and sudden, often violent arm and leg movements, sometimes referred to as dream enactment behavior. As shown in the Examples, and in particular Table 1, administration of dexmedetomidine according to the present invention can reduce the time a subject spends in the REM phase, thereby demonstrating the potential for administering dexmedetomidine according to the present invention to treat REM disorders. It should be understood that dexmedetomidine or a salt thereof will be administered according to the present invention, i.e., as described herein.

[0276] Also provided is dexmedetomidine for use according to the invention for treating restless legs syndrome. Restless legs syndrome (RLS) is a condition that causes an uncontrollable urge to move the legs, usually due to a feeling of discomfort. It usually occurs in the evening or at night when you sit or lie down. Moving the legs temporarily relieves the feeling of discomfort. It will be understood that dexmedetomidine or a salt thereof will be administered according to the invention, i.e. as described herein.

[0277] In addition, the ability of dexmedetomidine to increase REM sleep latency indicates its effectiveness in treating conditions associated with pathological shortening of REM sleep latency. Such conditions include narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin syndrome (KLS) and brainstem injury. Accordingly, in one embodiment, the present invention relates to the use of dexmedetomidine for the present invention, wherein the sleep disorder is characterized by pathological shortening of REM sleep latency. Pathological shortening of REM sleep latency is understood herein as being characterized by an increase in the occurrence of the sleep onset REM phase (SOREM). This means that the patient enters REM sleep instead of NREM sleep at the onset of sleep, which is a non-physiological sleep structure feature. Technicians are able to measure REM sleep latency and accordingly select a group of patients for dexmedetomidine treatment according to the present invention, while these patients cannot be selected in other cases.

[0278] In addition, the ability of dexmedetomidine to improve sleep quality by reducing noradrenergic signaling indicates the effectiveness of dexmedetomidine in treating disorders characterized by overactive noradrenergic signaling. Such disorders include anxiety, PTSD, depression and ADHD. In the case of ADHD, patients often suffer from insomnia caused by stimulants (e.g., D-amphetamine, methylphenidate, atomoxetine, dislexamphetamine). Dexmedetomidine is believed to counteract the overactive noradrenergic signaling caused by these stimulants, thereby reducing their negative effects on sleep. Accordingly, in one embodiment, the present invention relates to the use of dexmedetomidine for the present invention, wherein the sleep disorder is characterized by overactive noradrenergic signaling.

[0279] An overactive noradrenergic system, also known as noradrenergic overactivity, refers to a state of excessive release and / or overactivity of the neurotransmitter norepinephrine (also known as noradrenaline) in the central nervous system. Norepinephrine is a chemical messenger that plays a vital role in regulating a variety of physiological functions and behaviors, including the "fight or flight" response, attention, mood, and arousal. In neurological or psychiatric conditions, an overactive noradrenaline system may be associated with a variety of disorders and symptoms:

[0280] 1. Anxiety disorders: Excessive release of norepinephrine in certain brain areas may lead to increased alertness, vigilance, and anxiety responses.

[0281] 2. Post-traumatic stress disorder (PTSD): In individuals with PTSD, the norepinephrine system may become dysregulated, leading to a persistent state of hypervigilance and intrusive memories.

[0282] 3. Panic disorder: Noradrenergic overactivity is associated with the sudden and intense panic attacks experienced by patients with panic disorder.

[0283] 4. Attention Deficit Hyperactivity Disorder (ADHD): An imbalance in noradrenergic activity is thought to cause the symptoms of impulsivity, hyperactivity, and inattention in ADHD.

[0284] 5. Bipolar disorder: During a manic episode of bipolar disorder, norepinephrine levels increase, which can lead to elevated moods, increased energy, and anxiety.

[0285] 6. Major depressive disorder: Some studies suggest that dysregulation of the noradrenergic system may play a role in depressive symptoms.

[0286] 7. Schizophrenia: Noradrenergic abnormalities are associated with schizophrenia and may lead to cognitive deficits and confusion.

[0287] 8. Autonomic Dysregulation: An overactive norepinephrine system can affect the autonomic nervous system, leading to symptoms such as increased heart rate, sweating, and increased blood pressure.

[0288] A skilled artisan is able to measure noradrenergic signaling and accordingly select a group of patients for treatment with dexmedetomidine according to the present invention who would not otherwise be selected.

[0289] In a first specific embodiment, dexmedetomidine or a salt thereof is administered at a dose of 60 meg to 80 meg.

[0290] In a second specific embodiment, dexmedetomidine or a salt thereof is administered at a dose of 20 meg to 40 meg.

[0291] In a third specific embodiment, the subject suffers from depression and / or anxiety.

[0292] In a fourth specific embodiment, the subject suffers from a disorder of the heart and lungs (eg, congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (eg, Alzheimer's disease or Parkinson's disease), or a disorder of the musculoskeletal system.

[0293] Further examples and / or embodiments of the present invention are disclosed in the following numbered items: 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 salt thereof is administered to the subject at a dose of 10mcg to 120mcg via a transmucosal administration route.

[0294] 2. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to Item 1, wherein the dexmedetomidine or the salt thereof is administered at a dose of 40mcg to 120mcg, preferably at a dose of 40mcg to 80mcg.

[0295] 3. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to Item 1 or 2, wherein the dexmedetomidine or the salt thereof is administered at a dose of 60 mcg to 80 mcg.

[0296] 4. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the dexmedetomidine or the salt thereof is administered at a dose of 20 mcg to 40 mcg.

[0297] 5. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 4, wherein the dexmedetomidine or the salt thereof is administered to the subject sublingually or buccally.

[0298] 6. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to Item 5, wherein the dexmedetomidine or the salt thereof is administered to the subject buccally.

[0299] 7. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 6, wherein the dexmedetomidine or the salt thereof is administered to the subject in the form of an orally disintegrating tablet.

[0300] 8. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 7, wherein the orally disintegrating tablet is formulated by using templated carrier particles, preferably templated reverse phase particles, preferably comprising calcium phosphate and / or magnesium phosphate.

[0301] 9. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 8, wherein the sleep disorder is selected from insomnia disorder, excessive sleepiness disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep arousal disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance or drug-induced sleep disorder.

[0302] 10. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 9, wherein the subject suffers from depression and / or anxiety.

[0303] 11. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 10, wherein the subject suffers from a cardiac and 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 disorder of the musculoskeletal system.

[0304] 12. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 11, wherein the sleep disorder is insomnia disorder.

[0305] 13. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 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.

[0306] 14. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 11, wherein the sleep disorder is excessive sleepiness disorder or narcolepsy.

[0307] 15. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the sleep disorder is a circadian rhythm sleep disorder, preferably characterized by delayed sleep-wake phase, shift work, a non-24-hour sleep-wake rhythm or an irregular sleep-wake rhythm,

[0308] or

[0309] The sleep disorder is REM sleep behavior disorder.

[0310] or

[0311] One of the sleep disorders is restless legs syndrome.

[0312] The present invention is illustrated by the following examples. However, they should not be construed as limiting, since the scope of the present invention is characterized by the appended claims.

[0313] Example

[0314] In the following five studies, the pharmacokinetics of dexmedetomidine at different doses and formulations and its effects on sleep physiology and next-day cardiovascular effects were investigated in healthy young volunteers. Therefore, the following experiments were performed as summarized in Table 1:

[0315] Table 1. Research overview

[0316]

[0317] Preparation of formulations:

[0318] Study 1 - ODT Preparation

[0319] Dexmedetomidine dissolving tablets are obtained by freeze drying. Therefore, Dextran FP40 is used as a filler and dissolved in Dexdor TM The solution was then 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 tablets were obtained accordingly, but Dexdor was replaced with 0.9% saline (B. Braun Medical AG, Sempach, Switzerland). TM , to simulate Dexdor TM Slightly salty taste of the solution. On each study day, placebo and test (verum) tablets were combined so that the total dose was 40 μg (2×20 μg), 20 μg (1×20 μg+placebo) or 0 μg (2×placebo). All tablets were stored under dry conditions (desiccant bags) at room temperature.

[0320] Study on the preparation of 2-TIP tablets (20 μg / tablet)

[0321] The steps for preparing the formulations used in Study 2 are summarized in Table 2 below. At 20mcg, 1 tablet of 20mcg dexmedetomidine and 1 tablet of placebo were administered, and at 40mcg, 2 tablets of 20mcg dexmedetomidine were administered. All tablets were stored in dry conditions (desiccant bags) at room temperature.

[0322] Table 2. Preparation of Dexmedetomidine-Loaded G-TIP 210821 Tablets for Study 2

[0323]

[0324]

[0325] Study 3 to 5-TIP tablet preparation (50 μg / tablet)

[0326] The preparation steps of the formulations used in Studies 3 to 5 were the same as summarized in the table above, with the only difference being that tablets with a potency of 50mcg instead of 20mcg were prepared by adjusting the amount of powder blend filled into the 7mm die. In Studies 3 and 4, one tablet was administered. In Study 5, three tablets were administered. All tablets were stored under dry conditions (desiccant bags) at room temperature.

[0327] Inclusion criteria for studies 1 to 5

[0328] To investigate the effects of dexmedetomidine on sleep architecture and subjective sleep quality, a double-blind, placebo-controlled, randomized and balanced crossover study was conducted. 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:

[0329] ·male

[0330] 18 to 35 years old

[0331] Body mass index (BMI) of 18.5 kg / m 2 Up to 24.9kg / m 2

[0332] Moderate alcohol (<5 drinks per week) and caffeine (<3 drinks per day) intake

[0333] Not taking medication

[0334] ·Don’t smoke

[0335] Normal or corrected-to-normal vision

[0336] ISI score ranges from 0 to 8

[0337] No sleep disturbance

[0338] No neurological, psychological or clinical illnesses or regular medications that could interfere with the measurements No known strong allergies or hypersensitivities

[0339] No night shift work

[0340] · Has not crossed more than two time zones in the past 30 days

[0341] ·Not participated in other clinical trials in the past 30 days

[0342] Subjects are invited to participate in a one-night screening to check for possible sleep disorders, assess whether their sleep efficiency is sufficient for participation in the study, and whether all criteria are met. In addition, this allows the subjects to acclimate to the experimental environment.

[0343] Experimental Procedure - Study 1 + Study 2

[0344] The subjects attended three experimental nights, each separated by a week. Before the subjects went to bed, they received one of three treatments. Treatments included placebo, a 20 μg dose of dexmedetomidine, or a 40 μg dose of dexmedetomidine. During sleep, ECGs and polysomnograms were recorded. The study used a double-blind, randomized, crossover design. Manually scored polysomnograms allowed us to see if dexmedetomidine affected sleep architecture.

[0345] Blood drawing and analysis

[0346] To determine the pharmacokinetic profile of the administered dexmedetomidine formulation, blood samples were collected during the study. In the evening prior to the experimental night, a Venflon intravenous indwelling catheter was placed in the median cubital vein of the non-dominant arm of the study participants. Blood was collected during sleep at 0.25 hours, 0.5 hours, 0.75 hours, 1.0 hours, 1.25 hours, 1.5 hours, 1.75 hours, 2.0 hours, 2.5 hours, 3.0 hours, 4.0 hours, 5.0 hours, 6.0 hours, 7.0 hours, and 8.0 hours after the administration of dexmedetomidine. Throughout the experimental night, the indwelling catheter was connected to an adjacent room with a Heidelberg plastic tubing extension to avoid disturbing the subject's sleep. The vein was kept open by slowly dripping (10 mL / h) heparinized saline (1000 IU heparin in 0.9 g NaCl / dl; HEPARIN Bichsel, Bichsel AG, 3800 Unterseen, Switzerland) between each blood draw. Immediately after collection, each 5.5 mL blood sample was centrifuged at 4700 RCF for 5 min, and each 600 μL plasma sample was stored in a freezer at -28°C. The dexmedetomidine concentration in plasma was analyzed and quantified by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0347] EEG setup - Study 1 and Study 2

[0348] Polysomnography consists of different physiological monitoring methods that can be used to assess the quality and quantity of a patient's sleep. In our study, polysomnography was performed during an 8-hour sleep period from 24.00h to 8.00h. The SIENNAULTIMATE system (EMS Biomedical, Korneuburg, Austria) was used for this purpose. Before installing the electrodes, the head circumference was determined to ensure accurate placement of the electrodes using a suitable EEG electrode cap. The skin was treated with a frosted skin pretreatment gel (NuPrep) to increase skin conductivity and reduce impedance. The electrodes were then fixed with Grass EC2 Plus electrode paste and a cut gauze dressing from DermaPlast. 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) according to the 10-20 system, and the electrooculogram (EOG) of both eyes was used to track eye movements. On the face, a three-part electromyogram (EMG) on two recording tracks was used to track muscle activity, and the PGND electrode was used as ground. Heart rate was determined using a 2-channel electrocardiogram (ECG) with a sampling rate of 512Hz, which was recorded on two independent channels using two electrodes attached to the sternum and the lower left chest. In addition, pulse oximetry was performed during sleep. Nasal breathing, thoracic and abdominal respiratory movements, and body position were not measured in this study.

[0349] Visual Sleep Stage Scoring - Study 1 and Study 2

[0350] Sleep variables were scored visually based on 30-s epochs according to the criteria of the American Academy of Sleep Medicine (American Academy of Sleep Medicine Berry, 2020, p. 17; Berry, RB et al. AASM Scoring Manual Updates for 2017 (Version 2.4) J. Clin. Sleep Med. 13, 665–6 (2017)). For sleep scoring, C3-A2 leads were used. Artifacts related to movement and arousal were visually determined and excluded from the analysis.

[0351] Figure 8The specific characteristics of EEG, EOG, and EMG during the wakefulness stage and different sleep stages are shown. If the subject is still awake, the EEG shows alpha waves (8Hz to 13Hz) in the occipital area, the EOG shows frequent eye movements, and high muscle tone is visible in the EMG (Berry, 2020). During N1, the EEG shows waves in the theta range (4Hz to 7Hz), the EOG shows slow and rolling eye movements, and the muscle tone is lower than when awake (Berry, 2020). N1 is also called the light sleep stage because slight stimulation can quickly wake up the subject (Kandel, ER, Koester, JD, Mack, SH, & Siegelbaum, SA (2021). Principles of neural science (6 th ed.). McGraw Hill, p. 1082). For N2, two important markers in the EEG are K-complexes (frontal leads) and spindles (central leads). There are no or low eye movements, and muscle tone is reduced compared to N1. N3, also known as the deep sleep stage, is characterized by slow wave (0.5Hz to 2Hz and >75μV) activity in the frontal leads (hence the name SWS). Typically, there are no eye movements, and muscle tone is lower than N2 (Berry, 2020). As the name suggests, during REM sleep, the EOG shows rapid eye movements, the EEG shows a pattern similar to that of wakefulness, and muscle tone is at its lowest level. During REM sleep, dreams are often vivid, unrealistic, and strange. Motor neurons are inhibited to prevent dreams from replaying. This inhibition leads to atonia (extremely low muscle tone) (Berry, 2020; Kandel et al., 2021, p. 1082).

[0352] Shellong Test - Studies 1 to 5

[0353] The validated Shellong test is performed directly after awakening. In the two-part Shellong test, blood pressure and heart rate are first measured in the supine position for 3 minutes, with a 1-minute interval between each measurement. Subsequently, the subject stands and 5 measurements are taken at 1-minute intervals. Based on the values ​​measured in the test, it can be inferred whether an orthostatic response occurs and to what extent. Physiologically, when the body position changes, the systolic blood pressure of a healthy person decreases by 10 mmHg and the diastolic blood pressure increases by about 5 mmHg. The heart rate of a healthy person is expected to increase by 5 to 20 BPM (Moya, Angel, et al. Guidelines for the diagnosis and management of syncope (version 2009). European Heart Journal, Bd. 30, Nr. 21, November 2009, S. 2631–2671. Pub-Med Central).

[0354] Questionnaires - Study 1 and Study 2

[0355] The following three questionnaires were then assessed: PANAS (Positive-Negative Affect Scale) upon awakening, SIQ-Acute (Sleep Inertia Questionnaire-Acute), and the Morningness Questionnaire (MQ). The questionnaires are explained in detail below:

[0356] Positive and Negative Affect Scale (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, which are rated on a 5-point Likert-type scale according to the subject's feelings at the time (1 = not at all or very slightly, 2 = slightly, 3 = some degree, 4 = quite, 5 = extremely). Adjectives are divided into positive affect (PA) and negative affect (NA). Positive affect includes positive, interested, excited, intense, motivated, proud, enthusiastic, awake, determined, and alert. Negative affect includes distressed, annoyed, guilty, afraid, hostile, irritated, ashamed, nervous, confused, and anxious. The ratings given for these adjectives are then summed. Therefore, there is one rating for PA and one rating for 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). PA adjectives and NA adjectives are listed in the table PANAS. A high PA score indicates that the subject has a high energy level, can concentrate completely, and is in a good mood. On the other hand, a low PA score is characterized by sadness and listlessness. A high NA score is associated with the subject feeling angry, contemptuous, disgusted, guilty, fearful, and nervous, while a high NA score indicates that the subject is in a calm and serene mood (Watson et al., 1988).

[0357] Sleep Inertia Questionnaire (SIQ)(Appendix pp. 101-102) was developed by Kanady and Harvey in 2015. Sleep inertia is a state immediately following sleep characterized by reduced arousal and impaired performance. The SIQ assesses 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 rated on a 5-point Likert-type scale. The Landolt group added two more questions, changed the rating scale to a 7-point Likert-type scale for questions 1 to 22 (-3 = very little, -2 = quite a little, -1 = slightly less, 0 = the same, 1 = slightly more, 2 = quite a lot, 3 = very much), and a visual analog scale (VSA) of 0 (no effort) to 100 (extreme effort) for question 23, and called it SIQ-Acute. For analysis, questions 22 and 23 were treated separately, while questions 1 to 21 were classified into one of four factors (physiological, inertial, cognitive, and affective). An overview of the characteristics of each factor as well as questions 22 and 23 is seen in Table 2.

[0358] Morning Questionnaire

[0359] The Morning Questionnaire is a short questionnaire that is filled out by the study participants 30 minutes after awakening. The questionnaire can be divided into two parts. In the first part, the study participants indicate the estimated duration of falling asleep (in minutes), how often they think they wake up during the night, and how long they think they wake up during the night (in minutes, excluding the duration of falling asleep). In the second part, comparisons with a usual night and normal mental state are recorded on seven visual scales. Study participants are asked, for example, how tired, calm, or focused they are at the moment, and how deep or light their sleep is compared to normal sleep.

[0360] Cortisol awakening response

[0361] Cortisone-D7 was purchased from Sigma Aldrich (Buchs, Switzerland), and 13C3-cortisol was purchased from Isoscience (Ambler, USA). Saliva was collected from each subject at 08:00 (immediately after awakening), 08:15, 08:30, 08:45, and 09:00. Participants were instructed to chew the swab for 60 seconds and then place it back in the Tubes (Sarstedt, Germany). After sampling, the tubes were immediately stored on ice until final storage at -80 °C. For cortisol detection, the tubes were thawed and centrifuged at 5000 rpm for 5 min to obtain clear saliva in conical tubes. The swabs were then removed and 50 μL of IS (0.1 ng / μL cortisone-d7) was added to the resulting saliva for further analysis. 265 μL of saliva was transferred to a tube from The samples were placed in a column holder (24 × 6 mL) of Extrahera (Biotage, Uppsala, Sweden) and 300 μL of water was added to the sample for fully automated supported liquid extraction (SLE). After mixing, the extract was automatically loaded onto the Isolute SLE+ column and absorbed for 5 min. The analytes were then eluted twice with 1.5 mL of ethyl acetate with a waiting time of 5 min in between. The extract was then (Biotage, Uppsala, Sweden) and dried at 35°C. 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 using 13C3-labeled cortisol as a surrogate analyte for calibration according to a recently published method40. Saliva samples were analyzed on a LC-MS / MS system consisting of a Shimadzu Prominence UFLC (Shimadzu, Kyoto, Japan) high pressure liquid chromatography (HPLC) system coupled to a Sciex 6500+ linear ion trap quadrupole mass spectrometer (Sciex, Darmstadt, Germany). 10 μL of sample was injected into C18 column (2.6 μm, 50 × 2.10 mm). The mobile phase consisted of 10 mL of ammonium formate (1 M) and 2 mL of formic acid in 2 L of water (A), 10 mL of ammonium formate (1 M) in 2 L of methanol (B). The flow rate was 0.3 mL / min, and the column oven temperature was set to 40 °C. Quantification was achieved by using a mass spectrometer under multiple reaction monitoring (MRM) with an ion spray voltage of -4500 V. Cortisol was measured as formic acid adduct [(MH)+46]- in negative electrospray ionization mode. The method was validated according to the guidelines of the German Society of Toxicology and Forensic Chemistry (GTFCh). Calibrators were prepared by spiking saliva with 13C3-cortisol in a concentration range of 0.55 nmol / mL to 55 nmol / mL. QC samples were prepared at a low concentration (1.5 nmol / L). The detection limit of cortisol was 0.55 nmol / L, and the quantification limit was 1.1 nmol / L.

[0362] result

[0363] Pharmacokinetic Results: Study 1

[0364] The results are shown in Table 3 and Part 1 of Figure 1 It is worth noting that Part 1 of Figure 1 As shown, the standard errors seen in the PK curves are very small, especially when compared to the plasma curves following oral administration of 300 / 500 / 700mcg DEX ( Fig.11 ; as reported in Akeju et al., 2018, Neurophysiology - https: / / pubmed.ncbi.nlm.nih.gov / 29154132 / ). It is also evident that the bioavailability of DEX is greatly increased after sublingual administration compared to oral administration, such that similar mean plasma values ​​were achieved with sublingual administration of 40mcg DEX and oral administration of 300 / 500mcg DEX. Thus, the sublingual approach not only improves the predictability of systemic exposure levels after a dose of DEX, but also significantly reduces the risk of overdosing in low metabolizers when high oral doses of DEX are administered.

[0365] Table 3. PK parameters of dexmedetomidine administration (Study 1).

[0366]

[0367] Pharmacokinetic Results: Study 3 and Study 4

[0368] The results are shown in Figure 2. Of note, as shown in Figure 2, the inter-subject variability seen in the PK profiles was very small, especially when compared to the plasma profiles following oral administration of 300 / 500 / 700mcg DEX ( Fig.11; as reported in Akeju et al., 2018, Neurophysiology). Interestingly, the formulations used in Studies 2 and 3 produced a mildly sustained release profile compared to the ODT formulation used in Study 1, with slightly lower Cmax values ​​(mean: 0.16 ng / mL) but a clear plateau. This was particularly surprising, as sustained release profiles are not typically observed with sublingual formulations. The development of a plateau may be particularly valuable for use in therapy, where sustained levels of dexmedetomidine throughout the night are of interest. Even more interesting is that despite the clear plateau, plasma levels fell to the same level observed in Study 1 at 40 mcg (approximately 0.6 ng / mL).

[0369] Pharmacokinetic Results: Study 5

[0370] The results are as follows Figure 1, part 2 The Cmax observed after administration of 150 mcg was approximately 0.5 ng / mL, thus approximately 3 times that of studies 3 and 4 where 50 mcg of the same formulation was administered. This demonstrates the ability of this formulation to accurately deliver dexmedetomidine via the sublingual route.

[0371] Relationship between morning plasma levels and side effects

[0372] Figure 1, part 2 Described are DEX plasma profiles following sublingual administration of 50mcg DEX at 24:00 and 50mcg / 150mcg sublingually at 4:30. The Shellong task was performed immediately after awakening at 8:00. When 50mcg was administered at 24:00, no one (0 of 4) experienced orthostatic dysregulation or dizziness. In contrast, when 50mcg was administered at 4:30, 3 of 4 participants experienced dizziness, orthostatic problems, and nausea at 8:00. Similarly, participants who took 150mcg at 4:30 experienced severe side effects after awakening at 8:00, including syncope, nausea, hypotonia, bradycardia, and cognitive impairment. Based on this data, we believe that morning plasma levels of 0.18ng / mL are associated with side effects that should be avoided in insomnia therapy. This can be achieved by selecting a bedtime dose of sublingual DEX that produces post-awakening concentrations (after 8h of sleep) below 0.15ng / mL. Based on our data, this dose is estimated to be 100mcg to 150mcg.

[0373] Sleep Physiological Outcomes - Study 1

[0374] The effects of 20mcg and 40mcg dexmedetomidine ODT (Study 1) on visual rating sleep variables are shown in Table 4 below. As highlighted in orange, both doses can shorten sleep latency, prolong REM sleep latency, and increase the time spent in stage N2+N3 (deep sleep). In particular, shortened sleep latency and prolonged deep sleep represent two clinically significant features, because both sleep latency and deep sleep are impaired in most patients with insomnia. It is worth noting that dexmedetomidine can significantly shorten sleep latency, even if it is not pre-administered (e.g., 30min to 60min before going to bed), but administered immediately before turning off the lights. This shows that the effect on sleep latency is very fast and effective. Extended REM sleep latency is particularly useful for treating disorders associated with pathological shortening of REM sleep latency (also known as sleep onset REM period), which is very common in narcolepsy and also very common in affective disorders such as MDD. It should be noted that the effect of 40mcg is more pronounced than that of the 20mcg condition, and therefore, the 20mcg condition often only reaches the statistical trend level. Therefore, based on these data, we believe that the therapeutic window may start at a value between 20mcg and 40mcg, and the lower the value, the worse the clinical effect obtained. In any case, very sensitive individuals or people with low body weight may also respond to 10mcg. Therefore, based on this data, the inventors have determined the lower limit of the therapeutic window for sublingual dexmedetomidine for the treatment of insomnia.

[0375] Table 4. Visually Rated Sleep Variables Following Administration of Placebo, 20mcg DEX, and 40mcg DEX (Study 1)

[0376]

[0377] Effects of DEX on slow wave activity - Study 1

[0378] This study investigated the effects of 40 mcg of sublingual DEX on slow wave activity compared with placebo (see Fig. 9 ), slow wave activity is a recognized marker of sleep depth and sleep regeneration potential. Higher levels of SWA are associated with increased sleep depth and regeneration. As described, 40mcg sublingual DEX significantly increased slow wave activity, most pronounced in the first half of the night, while these effects gradually disappeared shortly before awakening at 7:00. Therefore, this dose of dexmedetomidine may be particularly suitable for improving sleep at night without causing any hangover in the morning. Interestingly, most known hypnotic drugs instead reduce SWA and therefore fail to restore physiological sleep and wake function. In contrast, dexmedetomidine may provide an innovative way to improve sleep quality and wake quality by increasing restorative SWA.

[0379] Sleep Physiology Outcomes - Study 2

[0380] Study 2 included only 8 subjects, a relatively small sample size. Based on the observed data, the "G*Power" program estimated the minimum sample size required to obtain a significant result of n≥19. Therefore, in the table below, the effects of 20mcg dexmedetomidine TIP and 40mcg dexmedetomidine TIP (Study 2) on visual rating sleep variables are shown in a descriptive manner. As observed in Study 1, both doses administered in this study shortened sleep latency, prolonged REM sleep latency, and increased the time spent in stage N2+N3 (deep sleep). Similarly, shortened sleep latency and prolonged deep sleep represent two clinically significant features, because both sleep latency and deep sleep are impaired in most patients with insomnia. It is worth noting that the dexmedetomidine formulation used in this study was able to significantly shorten sleep latency, even if it was not pre-administered (e.g., 30min to 60min before going to bed), but administered immediately before turning off the lights. This shows that the effect on sleep latency is very fast and effective. REM sleep latency prolongation is particularly useful in treating disorders associated with pathologically shortened REM sleep latency (also known as sleep onset REM period), which is very common in narcolepsy and also very common in affective disorders such as MDD. It should be noted that the effect was more pronounced in the 40mcg condition compared to the 20mcg condition.

[0381] Table 5. Descriptive statistics of sleep latency.

[0382]

[0383] Table 6. Descriptive statistics of REM latency.

[0384]

[0385] Table 7. Descriptive statistics of time spent in the wakefulness phase.

[0386]

[0387] Table 8. Descriptive statistics of time spent in the N1 phase.

[0388]

[0389] Table 9. Descriptive statistics of time spent in the N2 phase.

[0390]

[0391] Table 10. Descriptive statistics of time spent in stage N3 throughout the night.

[0392]

[0393] Table 11. Descriptive statistics of time spent in REM phase.

[0394]

[0395] Table 12. Descriptive statistics of time spent in stage N3 in the first half of the night.

[0396]

[0397] Table 13. Descriptive statistics of time spent in stage N3 in the second half of the night.

[0398]

[0399] Morning Questionnaire - Study 2

[0400] Study 2 included only 10 subjects, a relatively small sample size. Based on the observed data, the "G*Power" procedure estimated the minimum sample size required to obtain a significant result of n≥19. Therefore, in the following tables (14 to 23), the effects of 20mcg dexmedetomidine TIP and 40mcg dexmedetomidine TIP (Study 2) on the morning questionnaire are shown in a descriptive manner. Although no statistical analysis was performed on the current data, the mean differences between placebo and the two dexmedetomidine conditions suggest that dexmedetomidine has a restorative effect, as reflected by better ratings of perceived sleep quality, improved mood, excitement, and focus.

[0401] Table 14. Descriptive statistics of estimated sleep latencies.

[0402]

[0403] Table 15. Descriptive statistics of estimated number of awakenings.

[0404]

[0405] Table 16. Descriptive statistics for estimated time spent awake.

[0406]

[0407] Table 17. Descriptive statistics of perceived sleep quality.

[0408]

[0409] Table 18. Descriptive statistics of perceived sleep depth.

[0410]

[0411] Table 19. Descriptive statistics of subjects' fatigue.

[0412]

[0413] Table 20. Descriptive statistics of subjects' emotions.

[0414]

[0415] Table 21. Descriptive statistics of energy by subject.

[0416]

[0417] Table 22. Descriptive statistics of subjects' arousal.

[0418]

[0419] Table 23. Descriptive statistics of subjects’ concentration levels.

[0420]

[0421] Next-day residual effects after bedtime administration of dexmedetomidine

[0422] The most common adverse reactions associated with the administration of DEX are cardiovascular dysregulation and sedation. This is due to the antagonistic effect of DEX on the adrenergic system, which is able to reduce the activity of the sympathetic nervous system. This can lead to hypotonia, bradycardia and, at higher doses, orthostatic dysregulation and syncope. In our study, we used the so-called Shellong test to study orthostatic regulation immediately after awakening (8:00), because we believe that (as with other sleep drugs) the occurrence of residual effects after awakening (hangover effect) such as dizziness and hypotonia limits the maximum dose that can be given before bedtime (the upper limit of the therapeutic window).

[0423] Shellong Test Results: Study 1

[0424] Table 24 below shows the changes in diastolic blood pressure during the Shellong test. Comparison with reference measurement 3 shows that diastolic blood pressure significantly increased by 13 mmHg to 18 mmHg after standing (measurements 6 to 10), which is also expected for a physiological orthostatic response. For 20 μg DMTN and 40 μg DMTN, no significant differences were detected compared to placebo.

[0425] Table 24. Comparison of mean diastolic blood pressure values ​​during Shellong test

[0426]

[0427] Table 25 below shows the changes in systolic blood pressure during the Shellong test. Comparison with reference measurement 3 shows that a significant increase in systolic blood pressure of about 7 mmHg was observed only at baseline (measurement 6) after standing. For 20 μg DMTN and 40 μg DMTN, no significant differences were detected compared to placebo.

[0428] Table 25. Comparison of mean systolic blood pressure values ​​during Shellong test

[0429] Compare Mean Mean change Standard Deviation p-value Reference measurement value 3 108.06 PI 3 (lying flat) vs. PI 4 (lying flat) 0.76 2.70 0.792 PI3 (lying flat) vs. PI 5 (lying flat) -0.94 2.70 0.745 PI3 (lying flat) and PI6 (standing) 6.96 2.74 0.019 P13 (lying flat) and PI7 (standing) 1.59 2.70 0.584 P13 (lying flat) and PI8 (standing) 0.08 2.74 0.979 PI3 (lying flat) and PI9 (standing) 2.97 2.74 0.314 PI3 (lying flat) and PI10 (standing) 0.94 2.70 0.745 Placebo versus 20 mcg dexmedetomidine -0.38 2.74 0.896 Placebo versus 40 mcg dexmedetomidine -2.06 2.70 0.478

[0430] Adverse Reactions During Shellong Testing - Studies 1 to 5

[0431] As shown in Table 26 below, after administration before bedtime (24:00), the 20mcg condition (1 of 17), the 40mcg condition (2 of 17), and the 50mcg condition (0 of 4) reported orthostatic dysregulation during the Shellong test after awakening (8:00), which was comparable to the number of orthostatic problems that occurred in the placebo condition (1 of 17). DEX plasma levels at the Shellong test time points were 0.03ng / mL (20mcg), 0.06ng / mL (40mcg), and 0.06ng / mL (50mcg). Therefore, the range of plasma levels after awakening was 0.03ng / mL (20mcg) to 0.06ng / mL (40 / 50mcg), which appears to be quite tolerable and therefore suitable for clinical use. Additionally, it was noted that if 50mcg was administered at 4:30am, 3 of the 4 volunteers reported moderate orthostatic problems on the 4:30am Shellong test. The mean plasma value for these subjects was 0.18ng / mL. Another subject received 150mcg at 4:30am and reported severe orthostatic dysregulation (bradycardia, hypotonia, syncope, cognitive impairment) that gradually resolved within 2 to 3 hours after awakening (5 to 6 hours after administration). Upon awakening, this subject had a plasma level of 0.45ng / mL. Based on this data, we believe that higher post-awakening plasma levels of more than about 0.15ng / mL to 0.18ng / mL produced by bedtime dosing may produce excessive hangover effects and therefore be clinically useless. Therefore, based on our data, we estimate that the upper limit of the therapeutic window in the study sample studied (healthy young volunteers) is about 80mcg to 100mcg.

[0432] Table 26.

[0433]

[0434] Cortisol Awakening Response - Study 1

[0435] Fig.10 The difference in cortisol awakening response (CAR) between placebo, 20mcg dexmedetomidine and 40mcg dexmedetomidine is shown. CAR reflects the activation of the HPA axis after awakening and is thought to play an important role in mobilizing psychological and physical resources to cope with the challenges of the day. Since the HPA axis is tightly regulated by the noradrenergic system, it is a good biomarker for the residual effect of dexmedetomidine on the HPA axis. As shown in the figure, there is no difference between placebo, 20mcg and 40mcg, indicating that dexmedetomidine generally has no relevant residual effect on the adrenergic system or HPA axis.

[0436] in conclusion

[0437] In summary, the inventors surprisingly found that sublingual bedtime administration of 20mcg and 40mcg dexmedetomidine had significant effects on sleep physiology, including a dramatic shortening of sleep latency, an increase in REM latency, and an increase in time spent in NREM sleep (N2+N3). These effects suggest that dexmedetomidine has a reinforcing and consolidating effect on the sleep process, and therefore represents a promising treatment option for patients suffering from sleep disorders such as insomnia. Although the inventors believe that higher doses may further amplify the observed effects, the inventors also surprisingly found that bedtime doses above 120mcg to 150mcg may be associated with next-day residual effects, including orthostatic dysregulation and dizziness, which greatly limits the use of such doses in treating patients.

[0438] Furthermore, the present inventors have surprisingly found that administration of dexmedetomidine via the sublingual route produces a superior pharmacokinetic profile than oral administration of dexmedetomidine, such that use of the sublingual route increases bioavailability and reduces inter-subject variability in plasma levels compared to oral delivery. This effect was found using both lyophilized tablets (ODT) and carrier particles.

[0439] Further data: summary and clinical implications

[0440] DEX ODTs were prepared by freeze drying, 20 μg each. Each ODT contained:

[0441] ·DEX 20 μg

[0442] ·Glucan FP40 30mg

[0443] ·dH2O ad 0.2mL

[0444] DEX and dextran FP40 were dissolved in dH2O, and the solutions were filled into aluminum molds by volume and freeze-dried for 30 hours.

[0445] Dexmedetomidine shortens sleep onset latency (see Fig.12 ), prolonging REM latency (see Fig.13 ), added N2+N3 deep sleep (such as Fig.14 As shown by the shortening of REM phase length, Fig.15 As shown by the N2 stage increase, and as Fig.16 The latter is also characterized by increased slow wave activity and SWE, especially in the first half of the night. In addition, dexmedetomidine reduces sleep fragmentation during NREM and REM sleep (see Fig.17 and Fig.23 ). Considering the sleep pharmacology characteristics of dexmedetomidine shown in this article, it is proposed that dexmedetomidine is a treatment option suitable for the conditions associated with inability to fall asleep, inability to maintain sleep, and inability to produce restorative slow-wave deep sleep. These symptoms are very common in the following conditions: psychiatric conditions include depression, anxiety, PTSD, ADHD, schizophrenia, psychosis, etc., and neurological conditions include neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, etc.) and sleep-related neurological disorders such as restless legs syndrome, REM sleep behavior disorder, narcolepsy, etc. and pain-induced insomnia. In addition, the ability of dexmedetomidine to increase REM sleep latency indicates its efficacy in treating conditions associated with pathological shortening of REM sleep latency (including narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Klein-Levin syndrome (KLS), brainstem injury).

[0446] In addition, the ability of dexmedetomidine to improve sleep quality by reducing noradrenergic signaling (as described in the results) suggests that dexmedetomidine has clinical efficacy in treating conditions associated with overactive noradrenergic signaling, including anxiety, PTSD, depression, and ADHD. In the case of ADHD, patients often suffer from insomnia caused by stimulants (e.g., D-amphetamine, methylphenidate, atomoxetine, dextroamphetamine). Dexmedetomidine is thought to counteract the overactive noradrenergic signaling caused by these stimulants, thereby reducing their negative effects on sleep. Similarly, dexmedetomidine is proposed to reduce the negative effects of SSRIs and SNRIs on sleep by counteracting the sleep disturbances caused by noradrenaline.

[0447] Furthermore, the ability of dexmedetomidine to reduce NREM and REM sleep fragmentation suggests that it has clinical efficacy in treating conditions associated with NREM and REM sleep fragmentation.

Claims

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

2. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the dexmedetomidine or the salt thereof is administered at a dose of 40mcg to 120mcg.

3. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the dexmedetomidine or the salt thereof is administered at a dose of 40mcg to 80mcg.

4. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein dexmedetomidine or a salt thereof is administered at a dose of 60mcg to 80mcg.

5. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the dexmedetomidine or the salt thereof is administered at a dose of 20mcg to 40mcg.

6. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein the dexmedetomidine or the salt thereof is administered to the subject sublingually or buccally.

7. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 6, wherein the dexmedetomidine or the salt thereof is administered to the subject buccally.

8. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the dexmedetomidine or the salt thereof is administered to the subject in the form of an orally disintegrating tablet.

9. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 8, wherein the orally disintegrating tablet is formulated by using templated carrier particles.

10. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the templated carrier particles are templated reverse phase particles.

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

12. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 9 to 11, wherein the templated carrier particles comprise a porous hydroxyapatite shell, at least one cavity and calcium hydroxide.

13. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein the sleep disorder is selected from insomnia disorder, excessive sleepiness disorder, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, non-REM (NREM) sleep arousal disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance or drug-induced sleep disorder.

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

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

16. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 13, wherein the subject suffers from a neurodegenerative disorder, preferably such as Alzheimer's disease or Parkinson's disease.

17. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 13, wherein the subject suffers from a disorder of the musculoskeletal system.

18. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 13, wherein the subject suffers from PTSD.

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

20. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to 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. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 18, wherein the sleep disorder is excessive sleepiness disorder or narcolepsy.

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

23. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 18, wherein the sleep disorder is REM sleep behavior disorder.

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

25. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 13, wherein the sleep disorder is characterized by a pathological shortening of REM sleep latency.

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

27. Dexmedetomidine or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 13, wherein the sleep disorder is characterized by overactive noradrenergic signaling.

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

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