WO2024023261A1 - Dexmédétomidine pour le traitement de troubles du sommeil - Google Patents
Dexmédétomidine pour le traitement de troubles du sommeil Download PDFInfo
- Publication number
- WO2024023261A1 WO2024023261A1 PCT/EP2023/070918 EP2023070918W WO2024023261A1 WO 2024023261 A1 WO2024023261 A1 WO 2024023261A1 EP 2023070918 W EP2023070918 W EP 2023070918W WO 2024023261 A1 WO2024023261 A1 WO 2024023261A1
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- WO
- WIPO (PCT)
- Prior art keywords
- dexmedetomidine
- sleep
- disorder
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Definitions
- Present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a sleep disorder in a subject, wherein dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg.
- Said dexmedetomidine or a pharmaceutically acceptable salt thereof is preferably formulated as an orodispersible tablet and is particularly useful in the treatment of insomnia
- insomnia Sleep takes up a third of our lives, and there is evidence that sleep has multiple essential functions, such as detoxification, development, memory consolidation, and synaptic plasticity.
- sleep problems are the second most common reason patients seek medical help, and current treatments for insomnia have several side effects.
- Dexmedetomidine is a sedative drug used during surgery. In addition, it can act anxiolytic, sympatholytic, and analgesic. Furthermore, it was shown that dexmedetomidine attenuates overactive wake-promoting pathways. Hence, dexmedetomidine comes into consideration as a potential drug to treat sleep disorders, in particular insomnia.
- Sleep problems are the second most common reason patients seek medical help after pain (Mahowald & Schenck, (2005). Insights from studying human sleep disorders. Nature, 437(7063), 1279-1285.). Patients who suffer from sleep problems complain about dissatisfaction with sleep quality and how it negatively affects their social, educational, or professional life. In addition, insufficient sleep has been shown to increase the probability of developing other diseases, such as diabetes mellitus and impaired glucose tolerance (Gott Kunststoff, D. J., Punjabi, N. M., Newman, A. B., Resnick, H. E., Redline, S., Baldwin, C. M., & Nieto, F.J. (2005).
- Sleep problems can also be caused by other diseases such as cancer (Savard, J., & Savard, M.-H. (2013). Insomnia and cancer: prevalence, nature, and nonpharmacologic treatment. Sleep Medicine Clinics, 8(3), 373-387) and HIV (human immunodeficiency virus) (Norman, S. E., Chediak, A. D., Kiel, M., & Cohn, M. A. (1990). Sleep disturbances in HIV-infected homosexual men. AIDS, 4(8), 775-782). There is also a clear association between sleep loss- associated sleepiness and accidents, such that patients with sleep problems have a higher chance of committing errors and causing accidents, which can be lethal (Dinges, D. F. (1995).
- the American Academy of Sleep Medicine (AASM) publishes the International Classification of Sleep Disorders (ICSD). Based on the ICSD-3 (third edition of the ICSD), there are six major groups of sleep disorders.
- the first group is insomnia, which contains problems related to sleep initiation, duration, 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 abnormalities in respiration during sleep (Sateia, 2014, p. 49).
- the third group are central disorders of hypersomnolence, also referred to as hypersomnolence disorder or excessive daytime somnolence (EDS) (Chokroverty, S. (2010). Overview of sleep & sleep disorders. The Indian Journal of Medical Research,131(2), 126-140; Sateia, 2014, p.143).
- the fourth group is circadian rhythm sleep-wake disorders, characterized by the inability to sleep at the desired time (Sateia, 2014, p.189).
- the fifth group is parasomnias, which are undesirable physical events or experiences during sleep (Sateia, 2014, p. 225).
- the last group is sleep- related movement disorders, characterized by simple movements that disturb sleep or its onset (Sateia, 2014, p.281).
- Insomnia is considered to be the most common sleep disorder. Insomnia treatments can be grouped into non-pharmacological and pharmacological treatments (Cunnington et al., 2013). Non-pharmacological treatments include establishing good sleep hygiene and cognitive-behavioral therapy (CBT-i) (Cunnington et al., 2013, pp. 90-93; Stuck et al., 2021). The main pharmacological treatments include benzodiazepines, melatonin, and variants of antidepressants, antipsychotics, and antihistamines (Cunnington, D., Junge, M. F., & Fernando, A. T. (2013). Insomnia: prevalence, consequences and effective treatment.
- Good sleep hygiene aims to reduce sleep-incompatible behaviors and introduce sleep- promoting behaviors. Examples of what can be done are: creating a comfortable atmosphere in the bedroom, reducing alcohol and caffeine consumption, or reducing stimulating activities such as working, sports, or watching TV late 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. Its targets are maladaptive behavior and thoughts the patients may have developed because of insomnia (Cunnington et al., 2013; Stuck et al., 2021, p.93). Morin et al.
- De Wit and Griffiths reviewed the abuse liability of anxiolytic and hypnotic drugs in humans. They found that especially individuals with histories of drug abuse are more likely to develop a dependency on these kinds of drugs (de Wit, H., & Griffiths, R. R. (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 an abrupt termination of benzodiazepines causes rebound insomnia, which encourages a drug-taking behavior and increases the potential for a drug dependence (Kales, A., Manfredi, R. L., Vgontzas, A. N., Bixler, E.
- 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.
- antipsychotics e.g., quetiapine
- antihistamines e.g., diphenhydramine
- Dexmedetomidine has not only a sedative effect but is also anxiolytic, sympatholytic, and analgesic (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 roused, allowing them to cooperate during procedures (Venn, R. M., & Grounds, R. M. (2001). Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions.
- Document WO 2018/126182 discloses certain use of sublingual dexmedetomidine for the treatment of agitation.
- Document WO 2020/006092 discloses film formulations containing dexmedetomidine and methods of producing them. The document teaches that sublingual tablets have a tendency to be swallowed before complete dissolution and trans-mucosal delivery, leading to wastage of active substance due to hepatic first pass metabolism. As a result, sublingual tablets may not achieve therapeutic levels of dexmedetomidine in the blood plasma.
- Document WO 2016/061413 discloses prevention or treatment of sleep disorders using dexmedetomidine formulation. Therein dexmedetomidine is to be administered in a therapeutically effective amount of about 0.1 mg to about 5 mg.
- Document US 2017/239221 provides a composition suitable for oral transmucosal administration (sublingual) comprising dexmedetomidine.
- the composition is useful for the treatment of sleep disorders such as insomnia and capable of providing sleep on demand.
- the composition comprises an effective amount of dexmedetomidine or pharmaceutically acceptable salts thereof, solvates thereof, or derivatives thereof, formulated for delivery of dexmedetomidine across a subject's oral mucosa.
- Document US 2022/226288 discloses methods of administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject.
- the disclosed methods are particularly suitable for the treatment of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases or disorders such as dementia and delirium.
- Document US 2010/196286 discloses devices and kits for treating sleep disorders, anxiety disorders, and developmental disorders, and/or for inducing an arousable state of sedation in a subject.
- Document US 2005/025807 provides a cured porous calcium phosphate material, an alternative living body tissue material, a tissue engineering scaffold and a drug support medium for DDS using the same. Summary of the invention It was an objective technical problem to provide a treatment for sleep disorders with reduced side effects. Said problem is solved by the embodiments described herein and as characterized in the claims. The present inventors have studied sleep of 17 healthy subjects that was recorded for three nights. They received either a placebo, 20 ⁇ g dexmedetomidine, or 40 ⁇ g dexmedetomidine.
- the present inventors have accordingly demonstrated that dexmedetomidine decreased the sleep latency, increased the REM latency and increased the time spent in NREM sleep (N2 + N3), whereas the effects were more pronounced in the 40 ⁇ g compared to the 20 ⁇ g condition.
- dexmedetomidine at the dosages according to the invention contributes to deeper sleep without causing next-day residual effects such as sedation or cardiovascular effects.
- the effects of dexmedetomidine on sleep architecture are summarized in Table 4.
- Figure 9 shows the slow wave sleep enhancing effect of dexmedetomidine in a representative subject.
- the present inventors have further shown that the proposed dosing scheme allows for achieving of plasma concentration of dexmedetomidine sufficient for achieving efficacy, i.e., about 0.2 ng/ml after 1-2 hours of administering buccally an orodispersible tablet with 40 ⁇ g dexmedetomidine, and about 0.1 ng/ml after 1-2 hours of administering buccally an orodispersible tablet with 20 ⁇ g dexmedetomidine.
- the present inventors have further shown that, surprisingly, the so obtained plasma concentration is very similar among different subjects.
- transmucosal administration of dexmedetomidine according to the invention may minimize inter-subject differences in bioavailability of dexmedetomidine compared to orally administered dexmedetomidine.
- the pharmacokinetic profiles following the sublingual administration of 20/40 ⁇ g ( Figure 1 part 1), 50 ⁇ g ( Figure 1 part 2 and Figure 2 part 1/2) and 150 ⁇ g ( Figure 1 part 2) of dexmedetomidine are shown.
- the present inventors have also found in the present study that, surprisingly, sublingual bedtime doses of dexmedetomidine leading to plasma concentrations higher than 0.15ng/ml are likely to cause hangover effects upon awakening, most of all orthostatic dysregulation and dizziness.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a sleep disorder in a subject, wherein dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg.
- the present invention relates to a method of treatment or prevention of a sleep disorder in a subject in need thereof, comprising administering dexmedetomidine or its pharmaceutically acceptable salt to said subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg.
- the present invention relates to use of dexmedetomidine or a pharmaceutically acceptable salt thereof in manufacture of a medicament for the treatment or prevention of a sleep disorder in a subject, wherein dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered in a dose of between 40 mcg and 120 mcg, preferably in a dose of between 40 mcg and 80 mcg.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered in a dose of between 60 mcg and 80 mcg.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered in a dose of between 10 mcg and 40 mcg, preferably 20 mcg and 40 mcg.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered to a subject sublingually or buccally.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered to a subject buccally.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein dexmedetomidine or its salt is to be administered to a subject in a form of an orodispersible tablet.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein said dexmedetomidine (in particular said orodispersible tablet) is formulated by using templated carrier particles, preferably templated inverted particles, preferably comprising calcium phosphate and/or magnesium phosphate.
- templated carrier particles preferably templated inverted particles, preferably comprising calcium phosphate and/or magnesium phosphate.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is selected from insomnia disorder, hypersomnolence 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 medication-induced sleep disorder.
- the sleep disorder is selected from insomnia disorder, hypersomnolence 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 medication-induced sleep disorder.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the subject is suffering from depression and/or anxiety.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the subject is suffering from a disorder of the heart and lungs (for example congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (for example Alzheimer’s disease or Parkinson’s disease) or a disorder of the musculoskeletal system.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is insomnia disorder.
- the insomnia disorder is selected from insomnia related to depression, insomnia related to anxiety, insomnia related to post-traumatic stress disorder (PTSD), insomnia related to schizophrenia, insomnia related to Parkinson’s disease, insomnia related to Alzheimer’s disease, insomnia related to multiple sclerosis and insomnia related to stroke.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is hypersomnolence disorder or narcolepsy.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is circadian rhythm sleep disorder, preferably characterized by delayed sleep–wake phase, shift work, non-24 hour sleep–wake rhythm, or irregular sleep- wake rhythm.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is REM sleep behaviour disorder.
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, to a method of the present invention or to the use of the present invention, wherein the sleep disorder is restless leg syndrome.
- the term "preferably” is used to describe features or embodiments which are not required in the present invention but may lead to improved technical effects and are thus desirable but not essential.
- Figure 1 shows a plot of plasma concentration of dexmedetomidine with time upon transmucosal administration of 20 mcg and 40 mcg dexmedetomidine as orodispersible tablet to the subject (an average of values measured for 17 subjects in each case is shown).
- Part 2 shows the plasma profiles of DEX following the sublingual administration of 50mcg DEX at 24:00 and 50mcg/150mcg at 4:30.
- Figure 2 part 1 shows a plot of plasma concentration of dexmedetomidine with time upon transmucosal administration of 50 mcg dexmedetomidine as orodispersible tablet to the subject given once at 24:00 (“long”-labels) and once at 4:30 (“short”-labels). an average of values measured for 4 subjects in each case is shown in part 2.
- Figure 3 shows electrode positions for EEG (Klem et al., 1999).
- Figure 4 shows electrode positions for EOG (Berry, 2020, p.18).
- Figure 5 shows electrode positions for the EMG (Berry, 2020, p.19).
- Figure 6 shows Electrode positions for the ECG (Caples et al., 2007).
- Figure 7 shows a screenshot from the program “Embla Rembrandt Manager”.
- Figure 8 shows exemplary EEG, EOG and EMG signal traces for the different sleep stages and wake phase (Kandel et al., 2021, p.1080).
- Figure 9 shows the deep sleep promoting properties of dexmedetomidine, indicated by an increase in slow wave activity following the administration of 40mcg of dexmedetomidine (lower panel) compared to placebo (upper panel)
- Figure 10 shows the difference in cortison awakening response (CAR) between placebo, 20 mg and 40 mg DEX.
- Figure 11 shows the PK profile following the oral administration of 300 (lower curve), 500 (middle curve) and 700mcg (top curve) of dexmedetomidine.
- FIG. 12 shows the effect of 20 and 40 mcg dexmedetomidine on sleep onset latency. Both 20 and 40 ⁇ g of Dexmedetomidine (DEX) significantly reduce sleep onset latency compared to placebo. This is remarkable, considering that the drug was administered exactly at scheduled bedtime (no premedication). Thus, Dexmedetomidine shows a very rapid onset of action and can be taken immediately at bedtime and does not require any premedication.
- Figure 13 shows the effect of 20 and 40 mcg dexmedetomidine on REM latency. Both 20 and 40 ⁇ g of Dexmedetomidine (DEX) significantly increase REM sleep latency compared to placebo.
- FIG 15 shows the effect of 20 and 40 mcg dexmedetomidine on percentage of stage N2. Both 20 and 40 ⁇ g of Dexmedetomidine (DEX) significantly increased percentage of time spent in stage N2. This supports the view of overall sleep improvement via Dexmedetomidine.
- Figure 16 shows accumulation plot for NREM sleep stages. The plot shows the percentage of deep sleep (N2+N3) of total sleep time for each hour of the night (1-8).
- Figure 17 shows a hypnogram and spectral plots following the administration of placebo (top) and Dexmedetomidine (40 ⁇ g; bottom) in a representative individual. As displayed, Dexmedetomidine consolidates NREM sleep during the first half of the night and REM sleep in the second half of the night, indicated by less fragmentation (lower number of grey columns) of NREM and REM sleep episodes.
- Dexmedetomidine could be particularly suited for the treatment of conditions associated with strong REM sleep fragmentation, including psychiatric and neurological conditions, such as depression, anxiety, PTSD, schizophrenia, psychosis, ADHD, periodic limb movement disorder, restless leg syndrome, Morbus Parkinson, Morbus Alzheimer, REM sleep behavior disorder.
- Figure 18 shows a time course of slow wave activity (SWA) following placebo (upper figure) and Dexmedetomidine (40 ⁇ g; below figure) administration in a representative individual. Dexmedetomidine consolidates NREM sleep epochs and increases overall SWA.
- Figure 19 shows slow wave energy (SWE) during stages N1, N2, N3 following the administration of placebo and Dexmedetomidine at 20 ⁇ g and 40 ⁇ g.
- SWA slow wave activity
- SWE slow wave energy
- FIG. 20 shows an increase in SWE activity, most pronounced during N3 sleep, indicating an augmentation of restorative sleep functions.
- Figure 20 shows drug effects on SWE during the 1st (A) and 2nd (B) half of the night. The plot indicates a highly significant increase in SWE in the 1st half of the night, whereas the effects were not stronger in the 40 ⁇ g compared to the 20 ⁇ g condition. SWE in the 2nd half of the night was not affected by the drug.
- Figure 22 shows blood Plasma Melatonin Release Profiles: No effect on melatonin release profiles upon drug administration.
- Figure 23 shows the number of arousals during REM sleep. As indicated by the asterisks, both 20 ⁇ g and 40 ⁇ g of DEX significantly reduced the number of arousal during REM sleep, indicating a consolidation of REM sleep. This indicates DEXs’ ability to reduce REM sleep fragmentation (also referred to as restless REM sleep) – which is typically caused by phasic bursts of noradrenergic activity – by blocking the locus coeruleus.
- REM sleep fragmentation also referred to as restless REM sleep
- the present invention relates to dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a sleep disorder in a subject.
- Dexmedetomidine refers to a compound according to formula: Dexmedetomidine is also known as Precedex, Dexdor, Igalmi.
- the configuration of stereogenic carbon atom is as shown in the formula hereinabove. Accordingly, preferably the invention encompasses only an enantiomer as depicted in the formula hereinabove.
- Dexmedetomidine may also be referred to herein according to abbreviation Dex., dex. or DEX.
- dexmedetomidine may exist in the form of different isomers, in particular prototropic tautomers. All such tautomers are contemplated as being encompassed by the invention. It is to be understood that dexmedetomidine may exhibit tautomerism. Accordingly, the formula provided hereinabove expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.
- dexmedetomidine is present in a form of two tautomers, namely (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole and (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole, which differ by the position of H on the imidazole ring. Accordingly, when reference is made to dexmedetomidine, none of these tautomeric forms is excluded; it is to be understood that both forms remain in equilibrium.
- pharmaceutically acceptable indicates that the compound or composition, typically and preferably the salt or carrier, must be compatible chemically or toxicologically with the other ingredient(s), typically and preferably with the inventive composition or with the parts of the inventive kit of parts, when typically and preferably used in a formulation or when typically and preferably used for treating the animal, preferably the human, therewith.
- pharmaceutically acceptable indicates that the compound or composition, typically and preferably the salt or carrier, must be compatible chemically and toxicologically with the other ingredient(s), typically and preferably with the inventive composition or with the parts of the inventive kit of parts, when typically and preferably used in a formulation or when typically and preferably used for treating the animal, preferably the human, therewith.
- compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22nd edition. Accordingly, the scope of the invention embraces all pharmaceutically acceptable salt forms of dexmetedomidine which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
- Exemplary base addition salts comprise, 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; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylam
- Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
- Preferred pharmaceutically acceptable salts of dexmedetomidine include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt.
- a particularly preferred pharmaceutically acceptable salt of dexmedetomidine is a hydrochloride salt.
- the present invention also specifically relates to dexmedetomidine, in non-salt form.
- the scope of the invention embraces dexmedetomidine in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of dexmedetomidine are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of dexmedetomidine are likewise embraced by the invention.
- the scope of the invention also preferably embraces analogues of dexmedetomidine, in which one or more atoms are replaced by a specific isotope of the corresponding atom.
- the invention encompasses compounds according to formula hereinabove, in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as “D”).
- the invention also embraces corresponding compounds which are enriched in deuterium.
- Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol % hydrogen 1 (1H) and about 0.0156 mol % deuterium (2H or D).
- the content of deuterium in one or more hydrogen positions in the corresponding compounds can be increased using deuteration techniques known in the art.
- the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
- it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1H hydrogen atoms in the compound according to formula hereinabove is preferred.
- treatment of a disorder or disease, as used herein, is well known in the art. “Treatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a subject.
- a subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
- the “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
- the “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease.
- the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described hereinabove).
- the treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
- prevention of a disorder or disease, as used herein, is also well known in the art.
- a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease.
- the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
- a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the subject (for example, the subject does not show any clinical or pathological symptoms).
- prevention comprises the use of dexmedetomidine or its salt according to the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
- treatment or prevention of a sleep disorder in a subject according to the present invention is treatment of a sleep disorder in a subject.
- the subject preferably refers to a human subject. It is to be understood that dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg.
- the doses of dexmedetomidine refer to amount of pure dexmedetomidine, for example pure dexmedetomidine in dexmedetomidine salt or solvate. By way of example, such amount may be different from the amount of dexmedetomidine salt, if in a particular case dexmedetomidine is present in a form of pharmaceutically acceptable salt.
- mcg stands for microgram, also referred to as ⁇ g or 10 -6 g.
- dexmedetomidine or its salt is to be administered in a dose of between 20 mcg and 120 mcg, more preferably in a dose of between 40 and 120 mcg.
- the doses of dexmedetomidine as described herein refer to a single bolus doses to be administered before sleep, i.e. before going to bed (e.g. at midnight). Accordingly, said doses may be considered to be daily doses, wherein the daily dose is to be administered before the subject goes to sleep. Accordingly and preferably, in the present invention, dexmedetomidine is to be administered as a single bolus dose before going to sleep. More preferably, dexmedetomidine or its salt is to be administered in a dose of between 40 mcg and 80 mcg.
- dexmedetomidine or its salt is to be administered in a dose of between 60 mcg and 80 mcg.
- dexmedetomidine or its salt is to be administered to the subject via transmucosal administration route.
- dexmedetomidine is to be directly placed in contact with mucosa and allow to be absorbed into the subject’s bloodstream therethrough.
- a mucosa (or a mucous membrane) is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue.
- transmucosal routes include intranasal, buccal, sublingual, vaginal and rectal routes of administration. They are non-invasive routes for systemic drug delivery with the possibility of self-administration, or administration by family caregivers. These methods of administration are known to the skilled person.
- transmucosal routes of administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication is absorbed directly into the bloodstream and does not pass through the digestive system, thereby avoiding first pass metabolism.
- dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route, selected from intranasal, buccal, sublingual vaginal and rectal route of administration.
- transmucosal administration through the oral cavity is particularly preferred.
- dexmedetomidine or its salt is to be administered to a subject sublingually or buccally.
- administering a medication sublingually preferably refers to placing it under the subject’s tongue so that it can dissolve and be absorbed through the mucosa at this location.
- administering a medication buccally preferably refers to placing said medication between gums and cheek of the subject and allow it to dissolve and absorb through mucosa at this location. More preferably, dexmedetomidine or its salt is to be administered to a subject buccally. Buccal administration, in comparison to sublingual administration, reduces the chances of accidental oral administration, through swallowing of the saliva including dissolved medication by the subject.
- Suitable pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, hydroxy-propyl-methyl- cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter.
- Pharmaceutically acceptable carriers of the invention can be solid, semi-solid or liquid.
- dexmedetomidine or its pharmaceutically acceptable salt may be formulated according to the present invention as a tablet, orodispersible tablet, mucoadhesive film, lyophilizates, sachets, powder, granule, pellet, suppository, ointment, cream, lotion, gel, or paste.
- the formulation may contain liposomes, micelles and/or microspheres.
- Dexmedetomidine may also be formulated in a form of films or patches, e.g. buccal film, buccal patch, sublingual film, in a form of droplets, e.g. droplets for sublingual administration, or in a form of buccal spray.
- the film or patch formulations are so prepared that they are adhesive to the mucus and at the same time soluble, so that they solubilize and disappear from, e.g. the oral cavity, having had released the medicament, herein dexmedetomidine, through the mucosa.
- Tablets, or sachets are usually supplied in dosage units and may contain conventional excipients, such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, colorants, flavors and wetting agents. Tablets may be coated in accordance 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.
- the liquid compositions can contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non aqueous carriers (which can include edible oil), for example almond oil, fractionated coconut oil, oily esters, such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; penetration enhancer, for example dimethylsulfoxide (DMSO); pH buffer systems, for example phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer and other pharmaceutically acceptable buffer systems; solubilizers, for example beta-cyclodextrin, and if desired, conventional flavors or colorants.
- suspending agents for example sorbi
- Formulations for administration into the oral cavity may optionally further include taste- masking components to optimize the taste perception.
- taste- masking components may be citrus-, licorice-, mint-, grape-, black currant- or eucalyptus-based flavorants known to those well-skilled in the art.
- the form of dosage for intranasal administration may include solutions, suspensions or emulsions of the active compound in a liquid carrier in the form of nose drops. Suitable liquid carriers include water, propylene glycol and other pharmaceutically acceptable alcohols.
- For administration in drop form formulations may suitably be put in a container provided, e.g. with a conventional dropper/closure device, e.g.
- the dosage forms may be sterilized, as required.
- the dosage forms may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying the osmotic pressure or buffers, as required.
- Buffer systems may include for example phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer and other pharmaceutically acceptable buffer systems.
- Intranasal formulations may optionally further include smell-masking components to optimize the smell.
- dexmedetomidine or its salt is to be administered to a subject in a form of an orodispersible tablet.
- Orodispersible tablet which may also be referred to as orally disintegrating tablet (ODT) is herein preferably understood as a tablet that is configured to disintegrate (e.g. through effervescence or through dissolution, preferably through dissolution) once placed in an oral cavity, e.g. on the tongue, under the tongue or between the gums and cheek, and liberate the medicament to the oral cavity accordingly.
- ODT orally disintegrating tablet
- a tablet may be obtained by freeze- drying (lyophilization) of a solution comprising dexmedetomidine or its pharmaceutically acceptable salt, and an excipient.
- mannitol which is known to the skilled person as increasing binding and/or decreasing dissolution rate.
- Mannitol which can be replaced with another sugar typically serves as the major diluent of the orodispersible tablet and is also the primary contributor to their smooth and creamy mouth feel.
- Other processes known to the skilled person for the preparation of orodispersible tablets include loose compression tabletting, wherein said tablets are compressed at much lower forces (4 - 20 kN) than traditional tablets due to the need to them to be soft enough to disintegrate rapidly in the mouth.
- Lubricants such as magnesium stearate are added to the blend to reduce the amount of material that may stick to the die wall.
- disintegrating aids such as crospovidone, and binding agents that aid in mouth feel, such as microcrystalline cellulose, are typically used in the formulation of orodispersible tablets.
- dexmedetomidine or an orodispersible tablet comprising the same
- dexmedetomidine is formulated by using templated carrier particles, preferably templated inverted particles, preferably comprising calcium phosphate and/or magnesium phosphate.
- dexmedetomidine is formulated by using carrier particles.
- the carrier particles are not to be particularly limited and any carrier particles known to the skilled person can be used within the invention.
- carrier particle refers to a material that is nontoxic or not substantially toxic to a subject, which can be used to improve a desired drug delivery property of a solid pharmaceutical composition.
- the carrier particle described herein has no or no substantial therapeutic effect upon administration to a subject unless it is loaded with a therapeutic agent.
- the carrier particle described herein is pharmacologically inert unless it is loaded with a therapeutic agent.
- the carrier particle described herein does not or not substantially dissolve in water.
- the desired drug delivery properties described herein of the solid pharmaceutical composition include, without limitation, effectiveness, safety, pharmacokinetic properties (e.g., bioavailability), physical stability, chemical stability, drug loading capacity, and/or disintegration time.
- the desired drug delivery properties of a solid pharmaceutical composition are physical stability, drug loading capacity, and disintegration time.
- the desired drug delivery properties of a solid pharmaceutical composition are high drug loading capacity of the solid pharmaceutical composition (e.g., the drug loading capacity of v/v ⁇ 50%, ⁇ 55%, ⁇ 60%, ⁇ 65%, ⁇ 70%, ⁇ 75%, ⁇ 80%, preferably ⁇ 60%, more preferably between 60%, and 85%), low disintegration time of the solid pharmaceutical composition (e.g., ⁇ 15s, ⁇ 14s, ⁇ 13s, ⁇ 12s, ⁇ 11s, ⁇ 10s, preferably ⁇ 10s) and/or physical stability (e.g., tablet hardness of ⁇ 200N, ⁇ 210N ⁇ 220N, ⁇ 230N, ⁇ 240N, or ⁇ 250N, for an 11mm tablet or ⁇ 40N, ⁇ 50N, ⁇ 60N for a 6mm tablet, preferably ⁇ 50N for an
- a carrier particle according as described herein can have any shape, preferably a carrier particle as described herein has a shape similar to that of a sphere, a spheroid, and/or a bead. Removal of the template material can result in at least one pore in the otherwise largely uniform structure.
- the carrier particle preferably can form a hollow structure in a dry environment. As such, the carrier particle described herein does not or not substantially collapse upon drying.
- dexmedetomidine that is formulated as carrier particles may be formulated as orodispersible tablet. Accordingly, said carrier particles loaded with dexmedetomidine may be compacted together to form a tablet. Depending on the disintegration properties of the tablet, said tablet may be orodispersible.
- the carrier particles are templated carrier particles, preferably templated inverted particles, which also may be referred to as TIP particles.
- TIP particles templated carrier particles
- the technology of manufacturing and using TIP particles is described in detail in patent application PCT/EP2022/051799, which is incorporated herein by reference in its entirety. Said technology of manufacturing and using TIP particles is also described in the following.
- Said templated inverted particles may also be referred to as carrier particles with secondary internal structure.
- the method for the production of carrier particles with secondary internal structures comprises the steps of 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 secondary internal structures.
- carrier particles exhibit the desired drug delivery properties when produced with a template material that undergoes a transformation as described herein. Accordingly, whenever reference is made to carrier particles as described hereinabove, preferably the particles obtainable according to the method of production of carrier particles with secondary internal structure, as described hereinabove, are meant.
- carrier material refers to a material or a mixture that comprises the raw material for the carrier particle as described herein. In some embodiments, the carrier material described herein is an inorganic salt or comprises an inorganic salt to a substantial degree.
- the carrier material described herein is insoluble or poorly soluble in water. In some embodiments, the carrier material is dissolved in a solvent. In some embodiments, the carrier material or a precursor of the carrier material is a liquid. In some embodiments, the carrier material described herein is a non-polymer or comprises a non-polymer to a substantial degree.
- template material refers to a solid material comprising particles suitable to serve as a template to enable the formation of the primary structure of the carrier particles. The particles in the template material preferably have the shape of a sphere, a spheroid, and/or a bead.
- the template material described herein is a non-polymer or comprises a non-polymer to a substantial degree. In some embodiments, the template material described herein has a uniform or almost uniform particle size distribution. In some embodiments, the template material described herein has 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.
- 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,
- the template material is any material that is transformable and has sufficient stability to hold the carrier material.
- a template material poorly soluble in a combining liquid should be used.
- the template material described herein is poorly soluble in at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO 2 , dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma- Butyrolactone, and tetrahydrofuran.
- the template material described herein is poorly soluble in water.
- the template material described herein is poorly soluble in an aqueous solution comprising solubility altering agents (e.g.
- the term “poorly soluble” as described herein refers to a solubility at 25°C of about ⁇ 100mg/L, ⁇ 80mg/L, ⁇ 60mg/L, ⁇ 40mg/L, ⁇ 20mg/L, ⁇ 10mg/L, ⁇ 9mg/L, ⁇ 8mg/L, ⁇ 7mg/L, ⁇ 6mg/L, ⁇ 5mg/L, ⁇ 4mg/L, ⁇ 3mg/L, ⁇ 2mg/L, ⁇ 1mg/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, ⁇ 100 ⁇ g/L, ⁇ 90 ⁇ g/L, ⁇ 80 ⁇ g/L, ⁇ 70 ⁇ g/L, ⁇ 60 ⁇
- the template material described herein comprises a salt. In some embodiments, the template material described herein comprises an organic salt. In some embodiments, the template material described herein is a carbonate salt or comprises a carbonate salt to a substantial degree. In some embodiments, the template material described herein comprises a basic oxide.
- the term “transforming”, as used herein, refers to changing the properties of the template material by at least one physical step and at least one chemical step that in combination enable removal of the template material.
- the physical step of “transforming” comprises providing energy to the material. In some embodiments, the energy is applied in form of a rise in temperature, and/or alteration of pressure. In some embodiments, the physical step of “transforming” induces an endothermic chemical reaction in the template material.
- the chemical step of “transforming” comprises providing a chemical reactant to the template material.
- the reactant provided in the chemical step of “transforming” reacts with the template material but not or not substantially with the carrier material.
- the chemical reactant provided in the chemical step of “transforming” is provided in liquid, dissolved, and/or gaseous form.
- the carrier particles as described herein are carrier particles with secondary internal structures. In some embodiments, these secondary internal structures enable high drug loading, because, without being bound by theory, the carrier particles can be loaded with the drug inside the secondary internal structures and not only on the surface of the carrier particles. The loaded agent or drug can leave the carrier by diffusion through the porous carrier wall.
- the carrier particles have certain stability at a target site (e.g., on the mucosa of a patient). Therefore, these carrier particles can remain at a target site (e.g., by adhesion to the mucosa) and enable specific drug delivery.
- the carrier particles mask the unpleasant taste of a loaded agent, because the loaded agent is continuously released at the site of absorption.
- the release rate of the loaded agent can be controlled by geometry of the template material and/or by diffusion rate modifiers such as disintegrants. Therefore, the unpleasant taste diffuses to a lesser extent to the locations of perceptions (e.g., the tongue).
- the secondary internal structure described herein enables efficient drug loading on the inside of the carrier particle.
- the secondary internal structure is accessible via pores e.g., for loading solvents.
- the carrier particle can be loaded with less effort and/or has a particularly high loading capacity.
- the carrier particle has a particularly large surface area that is beneficial for interparticle forces. These interparticle forces act between the carrier particles in absence of water and increase the mechanical stability of carrier particle clusters. This increased mechanical stability reduces the need for additional stabilization material in the use of the carrier particles in pharmaceutical compositions such as solid pharmaceutical compositions, e.g., tablets.
- the interparticle forces acting between the carrier particles can be diminished by water enabling a low disintegration time of pharmaceutical compositions such as solid pharmaceutical compositions, e.g., tablets, comprising the carrier particle as described herein.
- the carrier material is an inorganic material or consists primarily of inorganic material.
- the term “consists primarily of”, as used herein, in the context of a material refers to consisting of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the material.
- the carrier material and the template material are inorganic salts or consist primarily of inorganic salts.
- the template material is preferably suspended in a liquid before combining a carrier material with a template material.
- the template material can be suspended in a combining liquid (e.g., water) under stirring in a reaction vessel.
- a combining liquid e.g., water
- the set agitation speed ensures stable turbulent mixing to impede particle agglomeration, which enables the treatment of the particles individually.
- combining a carrier material with a template material comprises adding the template material described herein and the carrier material described herein to a combining liquid.
- the combining liquid described herein is at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO 2 , dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran.
- the combining liquid described herein is water.
- the combining liquid described herein is an aqueous solution comprising solubility altering agents (e.g. salt water).
- an appropriate ratio of the amount of template material compared to the amount of the combining liquid should be used. This appropriate ratio depends on the solubility of the template material in the combining liquid.
- amount of the template material and combining liquid is chosen such that less than about 0.05%(w/w), less than about 0.04%(w/w), less than about 0.03%(w/w), less than about 0.02%(w/w), less than about 0.01%(w/w), less than about 0.0095%(w/w), less than about 0.009%(w/w), less than about 0.0085%(w/w), less than about 0.0008%(w/w), less than about 0.0075%(w/w), less than about 0.007%(w/w), less than about 0.0065%(w/w), less than about 0.06%(w/w), less than about 0.0055%(w/w), or less than about 0.005%(w/w) of the template material are dissolved in the combining liquid.
- combining a carrier material with a template material comprises chemical precipitation, layering, and/or crystallization of the carrier material on the template material.
- chemical precipitation refers to the process of conversion of a chemical substance from a solution into a solid by converting the substance into an insoluble form.
- combining a precursor of the carrier material forms the carrier material in a chemical reaction with the surface of the template material.
- the soluble precursor of the carrier material described herein is phosphoric acid.
- the conversion grade is relevant in embodiments wherein combining a precursor of the carrier material forms the carrier material in a chemical reaction with the surface of the template material.
- a too low conversion grade can cause particles with holes or broken shells, whereas a too high conversion can reduce the size of the inner cavity and produces more external crystals for example of dicalcium phosphate, which further converts to hydroxyapatite slabs.
- the conversion grade described herein is between about 30% and about 60%, between about 35% and 55%, or between about 40% and about 50%.
- the temperature during the chemical precipitation described herein can have a substantial influence on the material. For example, dicalcium phosphate as it is a less thermodynamically stable form than the hydroxyapatite. Therefore, too low temperatures and fast or uncontrolled orthophosphoric acid addition to calcium carbonate will trigger its precipitation and yield more dicalcium phosphate resulting in separate crystals that are more difficult to process.
- the temperature during the chemical precipitation is about 60°C or higher, preferably between about 60°C and about 100°C, more preferably between about 70°C and about 95°C, more preferably between about 80°C and about 95°C.
- a soluble precursor of the carrier material is added in a solution to the template material and distributed on the template material by the addition of a reactant that converts the soluble precursor of the carrier material to the insoluble carrier material.
- the soluble precursor of the carrier material described herein is sodium phosphate or calcium chloride (e.g., as Despotovi ⁇ , R., et al., 1975, Calc. Tis Res.18, 13–26).
- layering refers to a technique for adding at least one layer of the carrier on the template material. Any layering technique known in the art may be used (see, e.g., Decher, G. H. J. D., 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, G. H. J.
- ⁇ refers to the process of conversion of a chemical substance from a super-saturated solution.
- the carrier material is added in a super-saturated solution to the template material and distributed on the template material by the initiation of chemical precipitation.
- combining a carrier material with a template material comprises chemical precipitation and crystallization of the carrier material on the template material.
- combining a carrier material with a template material comprises chemical layering and crystallization of the carrier material on the template material.
- combining a carrier material with a template material comprises chemical precipitation and layering of the carrier material on the template material.
- the chemical precipitation process can be carried out by pumping a solution of a precursor of the template material onto the carrier material or into the liquid comprising the carrier material. During this process, the carrier material can start growing (e.g., in the form of a crystalline lamellae structure) on the surface of template material and thus forming the stratum layer.
- the template material as described herein is converted to the carrier material.
- the template material as described herein is converted to at least about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% to the carrier material.
- Chemical precipitation, layering, and/or crystallization enable fine and/or uniform distribution of the carrier material on the template material. This fine and/or uniform distribution affects the formation of the secondary internal structures. Accordingly, the carrier particles produced as described herein exhibit particularly fine and/or uniform secondary internal structures by using chemical precipitation, layering, and/or crystallization of the carrier material on the template material.
- transforming the template material comprises heating to a temperature from about 600 °C to about 1200 °C, preferably about 600 to about 900°C, preferably about 600”C to 839°C, preferably about 650°C to about 700°C. In certain embodiments, transforming the template material comprises heating to a temperature from 840 °C to 1200 °C.
- the conditions can be optimized to avoid interparticle condensation during the heating step, which can result in redispersability problems. While in some embodiments no further agents to avoid interparticle condensation need to be added, in other embodiments agents to avoid interparticle condensation (e.g., anti-sintering agents) are added during and/or before the heating step described herein.
- the transformation of the template material described herein can be done at any suitable temperature or any suitable temperature range.
- the minimal suitable temperature for transformation is set at a certain temperature e.g., about 210°C (e.g., for silver and gold carbonate as the template material), about 840°C (e.g., for calcium carbonate as the template material), about 900°C, about 1000°C, or about 1200°C (e.g., for potassium and/or sodium carbonates as template material).
- the person skilled in the art can identify the appropriate minimal suitable temperature from the decomposition temperature of the template material.
- An increased temperature can shorten the transformation time, however, melting of the carrier material may have an undesired effect on the carrier particles such as incomplete carrier particle formation or reduced carrier particle hardness.
- the maximal suitable temperature for the transformation of the template material described herein is set below the melting temperature of the carrier material. Deformation and/or loss of desired structures (e.g., petals on the surface of the carrier particles) that enhance the surface area of the carrier particles can already occur at temperatures below the melting temperature of the carrier material.
- the maximal suitable temperature for the transformation of the template material described herein is set about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C below the melting temperature of the carrier material.
- transforming the template material comprises heating to a temperature from about the decomposition temperature of the template material to about the melting temperature of the carrier material, preferably from about the decomposition temperature of the template material to about 400°C below the melting temperature of the carrier material, more preferably about the decomposition temperature of the template material to about 500°C below the melting temperature of the carrier material.
- transforming the template material comprises heating to a temperature from 840°C to 1600°C, preferably from 840°C to 1200°C, more preferably around 1100°C.
- the duration of the heating for transforming the template material described herein depends on various factors such as the template material, the carrier material, the temperature range, particle size, and/or the desired carrier particle surface area.
- the duration of the heating for transforming the template material described herein may for example be about 1 hour. In certain embodiments, the duration of the heating for transforming the template material described herein is between about 5 min and about 24 h, about 10 min and about 12 h, 20 min and about 4 h.
- the heating for transforming the template material described herein can be achieved by any heating pattern such as a linear increase of temperature or with one or more preheating steps.
- the preheating steps described herein may comprise keeping the temperature at a certain temperature level for a certain time before heating the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C or 600°C to 900°C. Preheating allows for example removal of undesired volatile components such as solvents.
- the pressure is reduced during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C. In some embodiments, the pressure is increased during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C. In some embodiments, the heating for transforming the template material induces an endothermic chemical reaction. In some embodiments, an inert substance (e.g., noble gas) is supplied to avoid side reactions during the heating for the transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C.
- an inert substance e.g., noble gas
- the heating for transforming the template material induces the evaporation of volatile fractions of the template material.
- the heating to a temperature in a certain range, e.g., from 840 °C to 1200 °C, may initiate the transformation of the template material but does not or not to the same extent alter the carrier material. This enables the removal of the transformed template material based on the altered properties.
- Lower temperature e.g. about 600°C to about 839°C or 600°C to about 900°C
- a heating step for the transformation of the template material enables the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.
- the step of transforming the template material comprises calcination.
- calcination refers to heating a solid or a mixture comprising a solid to high temperatures (e.g., a temperature from 840 °C to 1200 °C or 600°C to 900°C) under the supply of air or oxygen to the solid or the mixture.
- the calcination as described herein induces decomposition of template material comprising a carbonate (e.g., carbonate salts such as calcium carbonate) to carbon dioxide.
- the calcination as described herein induces decomposition of template material comprising a metallic carbonate to a metallic oxide, preferably to a basic oxide.
- the calcination as described herein induces the decomposition of hydrated template material by the removal of water. In some embodiments, the calcination as described herein induces the decomposition of volatile matter in the template material. Accordingly, the calcination step for the transformation of the template material enables the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.
- transforming the template material comprises a subsequent addition of water. The subsequent addition of water transforms the template material in a chemical reaction but does not alter or unsubstantially alter the carrier material. This enables the removal of the transformed template material based on the altered properties. In some embodiments, the subsequent addition of water as described herein reacts with a metallic oxide.
- the transformation step method comprises the addition of water enables the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.
- the addition of water enables an exothermic reaction.
- the subsequent addition of water as described herein transforms the template material in an exothermic chemical reaction but does not alter or unsubstantially alter the carrier material. This enables the removal of the transformed template material based on the altered properties.
- the basic oxide described herein is not toxic or unsubstantially toxic at the dose used as described herein.
- the subsequent addition of water as described herein reacts with a basic oxide.
- the subsequent addition of water as described herein reacts with at least one basic oxide selected from the group of lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide, barium oxide, and bismuth(III) oxide.
- the subsequent addition of water as described herein reacts with magnesium oxide and/or calcium oxide.
- the exothermic reaction as described herein can facilitate subsequent removal of the template material. The forces released during the exothermic reaction and/or the properties of the products of the exothermic reaction can decrease density and/or increase solubility. For example, the exothermic reaction of calcium oxide with a density of 3.34g/cm 3 with water results in calcium hydroxide with a density of 2.21g/cm 3 .
- removing the template material comprises dissolution of the transformed template material to form secondary internal structures.
- the secondary internal structures can be formed by the removal of the transformed template material by dissolution in a solvent that dissolved the transformed template material but not the carrier material.
- removing the template material comprises dissolution of the transformed template material with water or an aqueous solution.
- the pH of the aqueous solution is altered before the dissolution of the transformed template material to increase the solubility of the transformed template material or decrease the solubility of the carrier material in the aqueous solution.
- removing the template material comprises the dissolution of the transformed template with an organic solvent.
- removing the template material comprises dissolution of the transformed template material supports the formation of the secondary internal structures.
- the template material comprises a metal carbonate.
- the template material comprises at least one metal carbonate selected from the group of Li 2 CO 3 , LiHCO 3 , Na 2 CO 3 , NaHCO 3 , Na 3 H(CO 3 ) 2 , MgCO 3 , Mg(HCO 3 ) 2 , Al 2 (CO 3 ) 3 , K 2 CO 3 , KHCO 3 , CaCO 3 , Ca(HCO 3 ) 2 , MnCO 3 , FeCO 3 ,NiCO 3 , Cu 2 CO 3 , CuCO 3 , ZnCO 3 , Rb 2 CO 3 , PdCO 3 , Ag 2 CO 3 , Cs 2 CO 3 , CsHCO 3 , BaCO 3 , and (BiO) 2 CO 3 .
- Li 2 CO 3 LiHCO 3 , Na 2 CO 3 , NaHCO 3 , Na 3 H(CO 3 ) 2 , MgCO 3 , Mg(HCO 3 ) 2 , Al 2 (CO 3 ) 3 , K 2 CO 3
- the template material comprises at least one metal selected from the group of Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt and Sn.
- the template material comprises at least one non-metal selected from the group of Si, S, Sb, I, and C.
- the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% metal carbonate.
- the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% of at least one metal carbonate selected from the group of Li 2 CO 3 , LiHCO 3 , Na 2 CO 3 , NaHCO 3 , Na3H(CO 3 ) 2 , MgCO 3 , Mg(HCO 3 ) 2 , Al 2 (CO 3 ) 3 , K 2 CO 3 , KHCO 3 , CaCO 3 , Ca(HCO 3 ) 2 , MnCO 3 , FeCO 3 ,NiCO 3 , Cu 2 CO 3 , CuCO 3 , ZnCO 3 , Rb 2 CO 3 , PdCO 3 , Ag 2 CO 3 , Cs 2 CO 3 , CsHCO 3 , BaCO 3 , and (BiO) 2 CO 3 .
- Li 2 CO 3 LiHCO 3 , Na 2 CO 3 , NaHCO 3 , Na3H(CO 3 ) 2 , MgCO 3
- the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% magnesium carbonate.
- the template material comprises calcium carbonate.
- the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% calcium carbonate.
- the calcium carbonate as described herein comprises anhydrous calcium carbonate, complexes comprising calcium carbonate and/or hydrated calcium carbonate such as CaCO 3 ⁇ H 2 O and/or calcium carbonate hexahydrate.
- the calcium carbonate as described herein is anhydrous calcium carbonate.
- the metal carbonates described herein can be used as a basis to produce a carrier material with distinct properties (e.g., an insoluble metal phosphate by a reaction of the metal carbonate with H3PO4) on the surface of the template material and can be transformed as described herein.
- the carrier material comprises at least one salt and/or complex selected from the group of calcium phosphate and magnesium phosphate.
- the carrier material comprises at least one salt and/or complex of magnesium phosphate.
- the carrier material comprises at least one salt and/or complex of calcium phosphate. Calcium phosphate and magnesium phosphate have a particularly low solubility in water and show a reasonable heat resistance.
- the carrier particles as described herein are particularly efficient when the carrier material comprises at least one salt and/or complex selected from the group of calcium phosphate and magnesium phosphate.
- the carrier particles as encompassed by the present invention comprise calcium phosphate and/or magnesium phosphate. More preferably, the carrier particles as encompassed by the present invention comprise calcium phosphate.
- the calcium phosphate is present in the form of hydroxyapatite.
- hydroxyapatite is a substance according to formula Ca 5 (OH)(PO 4 ) 3
- the carrier particles as encompassed by the present invention comprise hydroxyapatite.
- the carrier particles as encompassed by the present invention further comprise calcium hydroxide.
- the present invention relates to an embodiment, wherein dexmedetomidine (or an orodispersible tablet comprising dexmedetomidine) is formulated by using carrier particles with secondary internal structures, wherein said carrier particles comprise hydroxyapatite and optionally comprise calcium chloride.
- the content of the hydroxyapatite in said particle 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.
- the template material can have various structures, e.g., powder (e.g., a powder with D50 of about: 1.9 ⁇ m, 2.3 ⁇ m, 3.2 ⁇ m, 4.5 ⁇ m, 5.5 ⁇ m, 6.5 ⁇ mo or 14 ⁇ m; a powder with a particle size range of about: 1 to 100 ⁇ m, 100 ⁇ m to 300 ⁇ m or 300 ⁇ m to 600 ⁇ m) or nanoparticles.
- the template material comprises particles that have a diameter of 1 to 300 ⁇ m. 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 that have a diameter of 1 to 300 ⁇ m.
- the template material comprises particles that have a median diameter of about 1 to 300 ⁇ m, about 1 to 250 ⁇ m, about 1 to 200 ⁇ m, about 1 to 150 ⁇ m, about 1 to 100 ⁇ m, about 1 to 90 ⁇ m, about 1 to 80 ⁇ m, about 1 to 70 ⁇ m, about 1 to 60 ⁇ m, about 1 to 50 ⁇ m, about 1 to 40 ⁇ m, about 1 to 30 ⁇ m or about 1 to 20 ⁇ m.
- the particle size of the template material influences the diameter of the carrier particle.
- the particles of the template material have about the same median diameter as the median diameter of the carrier particles.
- the carrier particle has a similar or larger median diameter compared to the template material. In embodiments wherein the template material and the carrier material are combined by chemical precipitation as described herein, the carrier particle has a similar or smaller median diameter compared to the template material.
- the person skilled in the art can predict the carrier material from the template material, carrier material, and the techniques used for combining the template material with the carrier material as described herein.
- the carrier particles have a diameter of 1 to 300 ⁇ m. Particles of a certain size can be obtained by methods known in the art, including milling, sieving (see, e.g., Patel, R.
- Particle size and shape measurements can be made using any method known in the art, such as laser diffraction or in situ microscopy (Kempkes, M., Eggers, J., & Mazzotti, M., 2008, Chemical Engineering Science, 63(19), 4656-4675; Allen, T. (2013). Particle size measurement. Springer). In some applications, a particular low carrier particle diameter is desired.
- the carrier particles have a diameter of about 1 to 20 ⁇ m, about 1 to 15 ⁇ m, about 1 to 10 ⁇ m, or about 1 to 5 ⁇ m for use in intrapulmonary administration and/or nasal administration.
- a particular low carrier particle diameter is desired to increase the diffusion surface and accelerate the release of the loaded agent.
- a larger carrier particle diameter is desired to enhance the flowability of the carrier particles and to facilitate further processing.
- the carrier particles have a diameter of about 5 to 300 ⁇ m, about 10 to 250 ⁇ m, about 15 to 200 ⁇ m, or about 20 to 150 ⁇ m.
- the method for the production of the carrier particles as described herein wherein the carrier particles have a diameter in a certain range can be particularly useful for further processing (e.g., flowability) and/or application (e.g., diffusion surface) of the carrier particle produced according to said method.
- the carrier particles have a surface area between 15m 2 /g to 400 m 2 /g or 30m 2 /g to 400m 2 /g.
- the carrier particles have a surface area between about 15m 2 /g to 400 m 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 as measured by 5- point BET (Brunnauer-Emmet-Teller) surface area analysis with nitrogen as a gas.
- 5- point BET Brunauer-Emmet-Teller
- the surface area of carrier particles can be measured by any method known in the art (see, e.g., Akashkina, L.V., Ezerskii, M.L., 2000, Pharm Chem J 34, 324–326; Bauer, J. F., 2009, Journal of Validation Technology, 15(1), 37-45).
- the surface area of the carrier particles can be altered e.g., by the particle size of the carrier material, the carrier material, and/or changing the surface structure by the parameters as described herein (e.g., heat, duration of heating).
- the carrier particle is used as an adsorber. A greater specific surface of carrier particles described herein allows strong Van der Waals interactions once the particles are brought in contact.
- the method for the production of carrier particles as described herein enables mechanical stability and disintegration capabilities if the carrier particles have a surface area between 15m 2 /g to 400 m 2 /g, preferably 30m 2 /g to 400m 2 /g.
- the secondary internal structure comprises pores having a diameter size in the range of ⁇ 0.2 ⁇ m and ⁇ 1.5 ⁇ m.
- the secondary internal structure comprises pores having a diameter size of about ⁇ 0.2 ⁇ m, about ⁇ 0.3 ⁇ m, about ⁇ 0.4 ⁇ m, about ⁇ 0.5 ⁇ m, about ⁇ 0.6 ⁇ m, about ⁇ 0.7 ⁇ m, about ⁇ 0.8 ⁇ m, about ⁇ 0.9 ⁇ m, about ⁇ 1 ⁇ m, about ⁇ 1.1 ⁇ m, about ⁇ 1.2 ⁇ m, about ⁇ 1.3 ⁇ m, or about 1.5 ⁇ m.
- the secondary internal structure comprises pores having a diameter size in the range of about ⁇ 0.2 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.3 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.4 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.5 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.6 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.7 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.8 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 0.9 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 1 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 1.1 ⁇ m to ⁇ 1.5 ⁇ m, about ⁇ 1.2 ⁇ m to ⁇ 1.5 ⁇ m or about ⁇ 1.3 ⁇ m to ⁇ 1.5 ⁇ m.
- the pore size of carrier particles can be measured by any method known in the art (see, e.g. Markl, D. et al., 2018, International Journal of Pharmaceutics, 538(1-2), 188- 214).
- the porous structure that can be formed by the method for the production of the carrier particles as described herein enables pores of a, particularly, large size. This large pore size facilitates drug loading on the carrier particle and accelerates drug release from the carrier particle.
- a pore size diameter greater than 90% of the diameter of the particles of the template material results in unstable carrier particles. Therefore, the maximal pore size depends on the size particles of the template material.
- the secondary internal structure comprises pores having a diameter size of about ⁇ 270 ⁇ m, about ⁇ 225 ⁇ m, about ⁇ 180 ⁇ m, about ⁇ 135 ⁇ m, about ⁇ 90 ⁇ m, about ⁇ 81 ⁇ m, about ⁇ 72 ⁇ m, about ⁇ 63 ⁇ m, about ⁇ 54 ⁇ m, about ⁇ 45 ⁇ m, about ⁇ 36 ⁇ m, about ⁇ 27 ⁇ m, or about ⁇ 18 ⁇ m diameter. Accordingly, the method for the production of the carrier particles as described herein, wherein the secondary internal structure comprises pores that have a certain diameter size is particularly useful for the subsequent drug loading and drug release of the carrier particles produced as described herein.
- the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is in the range of ⁇ 10% to ⁇ 90% of the particle volume as determined by image analysis of SEM-FIB and SEM of resin-embedded particles’ cross-section images.
- Alternative analytical methods to measure the volume ratio of the internal structure and particle include porosity calculation as a ratio of tapped bulk of the carrier material to the true crystalline density of the carrier material.
- the total volume of the secondary internal structures refers to the volume inside the particle inside that results from the removal of the template material.
- the total volume of the secondary internal structures described herein is the average internal volume of the carrier particles obtained as described herein.
- the total volume of the secondary internal structures described herein is the median internal volume of the carrier particles obtained as described herein. In certain embodiments, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume. In certain embodiments, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume.
- the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is in the range of about ⁇ 10% - ⁇ 90%, about ⁇ 15% - ⁇ 90%, about ⁇ 20%- ⁇ 90%, about ⁇ 25%- ⁇ 90%, about ⁇ 30%- ⁇ 90%, about ⁇ 35% - ⁇ 90%, about ⁇ 40% - ⁇ 90%, about ⁇ 45% - ⁇ 90%, about ⁇ 50% - ⁇ 90%, about ⁇ 55% - ⁇ 90%, about ⁇ 60% - ⁇ 90%, about ⁇ 65% - ⁇ 90%, about ⁇ 70% - ⁇ 90%, about ⁇ 10% - ⁇ 80%, about ⁇ 15% - ⁇ 80%, about ⁇ 20%- ⁇ 80%, about ⁇ 25%- ⁇ 80%, about ⁇ 30%- ⁇ 80%, about ⁇ 35% - ⁇ 80%, about ⁇ 40% - ⁇ 80%, about ⁇ 45% - 80%, about ⁇ 50% - ⁇ 80%, about ⁇ 40%
- the carrier particle has a loading capacity of ⁇ 72% v/v, ⁇ 70% v/v, ⁇ 68% v/v, ⁇ 66% v/v, ⁇ 64% v/v, ⁇ 62% v/v, or ⁇ 60% v/v. In certain embodiments of the carrier particle as described herein, the carrier particle has a loading capacity of ⁇ 60% v/v.
- loading capacity refers to the volume of the carrier particle that can be used for loading of an agent compared to the volume of the whole carrier particle.
- a carrier particle with a loading capacity of 60% v/v can load an agent having 60% of the volume of the carrier particle.
- the volume of the carrier particle is calculated from the diameter of the carrier particle. Therefore, the volume of the internal structure is part of the volume of the carrier particle for this calculation.
- an agent that is loaded on the carrier particle is comprised of a loading solvent and the loading solvent is removed to complete loading.
- the agent to be loaded is dissolved in the loading solvent and put in contact with the carrier particle ensuring complete wetting of the latter.
- the loading solvent can be removed by method any solvent removal method known to the person skilled in the art.
- the loading solvent is removed by a method selected from the group of evaporation, vacuum-assisted evaporation, atmospheric drying, vacuum- freeze drying, freeze drying at atmospheric pressure, spray drying, spray drying in fluidized bed apparatus, microwave assisted drying, electrospray-assisted drying, dielectric drying, fluidized-bed assisted drug loading, and solvent-sorption method.
- the agent to be loaded in the carrier particle is dexmedetomidine, or a pharmaceutically acceptable salt thereof.
- the solvent-sorption method comprises high shear granulation.
- the loading solvent described herein comprises at least one organic solvent, preferably at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO 2 , dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran.
- the loading solvent described herein is water. Some loading solvents such as water have high surface tension and may therefore require additional measures to support entering the pore(s) of the carrier particle as described herein despite the exceptionally large pore size.
- the loading solvent described herein comprises at least one surface-active agent such as a tenside.
- the addition of the loading solvent occurs under increased pressure, to support the loading solvent by entering into the inside of the carrier particle.
- loading on and into the carrier particle as described herein comprises the addition of an antisolvent that reduces the solubility of the agent to be loaded in the loading solvent.
- the antisolvent is at least one antisolvent selected from the group of water, dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO 2 , dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran.
- the loading solvent is removed by evaporation, e.g., by increased temperature and/or decreased pressure. The maximal temperature for the removal of the loading solvent depends on the heat stability of the loaded agent.
- the carrier particles with secondary internal structures, as described herein, can be compacted to obtain compacted carrier particles.
- compacted carrier matter refers to clusters of more than one carrier particle with adhesive forces acting between the carrier particles.
- compacting refers to applying pressure to more than one particle (e.g., carrier particle) to form compacted carrier matter, wherein the carrier particle at least partially remains adherent to each other upon release of the pressure. Techniques for compacting are known to the person skilled in the art (see, e.g., Odeku, O. A. et al., 2007, Pharmaceutical Reviews, 5(2)).
- Examples of techniques for compaction include, without limitation tableting, roller compaction, slugging, briquetting and/or centrifugation.
- the compacted carrier matter described herein is particularly stable and can be used for the obtainment of a particularly stable pharmaceutical composition.
- the large surface areas of the carrier particles as described herein form strong interparticle Van Der Waals adhesion forces that enable mechanical stability.
- water enters between the particles e.g., by capillary forces
- the distance- dependent Van Der Waals adhesion forces diminish, and the compacted carrier matter disintegrates. Accordingly, the compacted carrier matter described herein show particular mechanical stability and/or fast disintegration time.
- the formulations of dexmedetomidine formulated using carrier particles show improved bioavailability and/or reduced bitter taste, thereby leading to increased compliance with the patients.
- the carrier particles as described in the present invention are compacted.
- the present invention relates to an embodiment, wherein dexmedetomidine (or an orodispersible tablet comprising dexmedetomidine) is formulated by using carrier particles with secondary internal structures, wherein the carrier particles are compacted, wherein said carrier particles comprise hydroxyapatite and optionally comprise calcium chloride.
- the content of the hydroxyapatite in said particle 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.
- the sleep disorder that can be treated with dexmedetomidine according to the present invention is not particularly limited and according to the present inventors any sleep disorder known to the skilled person can be treated with dexmedetomidine for use according to the present invention.
- the sleep disorder is selected from insomnia disorder, hypersomnolence 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 medication-induced sleep disorder.
- the present invention relates in one embodiment to dexmedetomidine or a pharmaceutically acceptable salt thereof for use of the present invention, wherein the sleep disorder is selected from insomnia disorder, hypersomnolence 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 medication-induced sleep disorder.
- sleep disorders commonly coexist with other conditions that the subject may be suffering from. These conditions may be life- threatening or not. It is apparent to the skilled person that sleep disorders are often accompanied by depression, anxiety, and cognitive changes that must be addressed in treatment planning and management. Sleep disorders are also established risk factors for the subsequent development of common mental illnesses and may represent the prodromal expression of an episode of mental illness, allowing the possibility of early intervention to preempt or attenuate a full-blown episode. In addition, sleep disturbances furnish a clinically useful indicator of medical and neurological disorders that often coexist with depression and other common mental disorders.
- Sleep-wake complaints can provide clinically actionable clues in breathing-related sleep disorders, disorders of the heart and lungs (e.g., congestive heart failure and chronic obstructive pulmonary disease), neurodegenerative disorders (Alzheimer’s disease or Parkinson’s disease), and disorders of the musculoskeletal system. Each of these is characterized by prominent sleep-wake complaints and each is frequently accompanied by depression and anxiety disorders. Conversely, mental health clinicians should also understand that some medical disorders may not only disturb sleep (as in the examples above) but may themselves be worsened during sleep.
- dexmedetomidine or its pharmaceutically acceptable salt may be used for the treatment of subject suffering from depression and/or anxiety.
- dexmedetomidine or its pharmaceutically acceptable salt may be used for the treatment of subject suffering from a disorder of the heart and lungs (for example congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (for example Alzheimer’s disease or Parkinson’s disease) or a disorder of the musculoskeletal system.
- a disorder of the heart and lungs for example congestive heart failure or chronic obstructive pulmonary disease
- a neurodegenerative disorder for example Alzheimer’s disease or Parkinson’s disease
- a disorder of the musculoskeletal system preferably, within the scope of the present invention, the sleep disorder is insomnia disorder. Insomnia is amongst the most common complaints in the general population (Mahowald & Schenck, 2005).
- insomnia Ohayon reviewed more than 50 epidemiological studies about insomnia and found that about a third of the general population presents at least one criterion for insomnia as defined by the DSM-IV (Diagnostic and statistical manual of mental disorders, fourth edition). Furthermore, 6% of the general population is diagnosed with insomnia based on these criteria (Ohayon, M. M. (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews, 6(2), 97-111). In the meantime, the DSM Sleep Wake Disorders Classification has been updated to the fifth edition (DSM-V). Insomnia can be an independent condition, or it can be comorbid with another mental disorder (depression), medical condition (pain), or other sleep disorders (American Psychiatric Association, 2013, p. 362).
- the diagnostic criteria for insomnia disorders are: • Dissatisfaction with the sleep quality caused by difficulties initiating or maintaining sleep and early-morning awakening with the inability to return to sleep •
- the sleep disturbance causes impairments in social, occupational, educational, academic, behavioral, or other areas of functioning • It occurs at least three nights per week • It has been present for at least three months • It occurs despite having normal sleep conditions • It does not occur exclusively during another sleep disorder • It is not caused by a physiological effect of a substance such as drugs • Coexisting medical or mental conditions do not explain the complaint
- Another method to diagnose insomnia is questionnaires.
- One example is the Insomnia Severity Index (ISI). It measures the insomnia severity and allows us to understand the disorder’s course.
- ISI Insomnia Severity Index
- the ISI consists of seven items with a five-point Likert-type rating scale (0-4 points), which assesses the severity of insomnia complaints over the last two weeks (Stuck et al., 2021, pp.26-28). The points are added together to a score between 0 and 28 points. Based on the end score, the following interpretation is made: absence of insomnia (0-7), sub-threshold insomnia (8-14), moderate insomnia (15-21), and severe insomnia (22-28) (Morin, C. M., 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).
- the insomnia disorder to be treated according to the invention is selected from insomnia related to depression, insomnia related to anxiety, insomnia related to PTSD, insomnia related to schizophrenia, insomnia related to Parkinson’s disease, insomnia related to Alzheimer’s disease, insomnia related to multiple sclerosis and insomnia related to stroke.
- the insomnia is insomnia related to PTSD.
- contemporary PTSD treatments are effective, prevention strategies yield unsatisfactory results.
- prevention strategies yield unsatisfactory results.
- Distressing intrusive memories represent a cardinal symptom of trauma-related disorders, characterized by a recurrent re- experiencing of traumatic memories after exposure to a traumatic event.
- the formation of said intrusions may rely on an insufficient integration of the trauma memory into hippocampal-cortical memory networks during slow-wave sleep (SWS) dependent encoding because of the overwhelming negative emotional intensity of the traumatic event.
- SWS slow-wave sleep
- the post-traumatic stress-related immune reaction involving mainly increased cytokines, but potentially also kynurenine pathway metabolites, is a pathogenetic factor of PTSD, additionally impairing sleep physiology and memory consolidation.
- recent studies revealed a tight relationship between sleep physiology and the severity of intrusions, whereas insufficient sleep quality in the immediate aftermath of a traumatic event was found to increase the vulnerability to develop intrusive memories.
- treatment or prevention of a sleep disorder in a subject as defined herein constitutes treatment or prevention of a post-traumatic stress disorder.
- dexmedetomidine when dosed according to the present invention decreased the sleep latency, increased the REM latency and increased time spent in NREM sleep (N2+N3). Moreover, it was shown that dexmedetomidine increases slow wave activity. Accordingly, it has been shown that dexmedetomidine at the dosages according to the invention contributes to deeper sleep. It has further been shown that dosing dexmedetomidine according to the present invention would allow achieving reproducibly plasma levels in different subjects, thus minimizing inter-subject differences and likely leading to reproducible therapeutic effect.
- sublingual bedtime doses of dexmedetomidine leading to plasma concentrations higher than 0.15ng/ml at wake-up time are likely to cause hangover effects upon awakening, most of all orthostatic dysregulation and dizziness.
- the present inventors have suggested that sublingual bedtime doses higher then 120-150 ⁇ g are likely to cause next-day residual effects.
- the therapeutic window of sublingual dexmedetomidine for the treatment of sleep disorders is between 10 to 120 ⁇ g. Accordingly, it has been made plausible by the present inventors that dexmedetomidine to be used according to the present invention can be used in the treatment of sleep disorders beyond insomnia.
- the sleep disorder is hypersomnolence disorder or narcolepsy.
- dexmedetomidine or its salt is to be dosed according to the present invention, i.e. as described herein.
- Hypersomnolence is understood as the inability to stay awake and alert during the day despite having more than an adequate amount of nighttime sleep. Hypersomnia challenges work life, social life and home life. Narcolepsy is herein understood as a chronic sleep disorder that causes overwhelming daytime drowsiness. Narcolepsy causes sudden attacks of sleep. Sudden loss of muscle tone and hallucinations may occur.
- REM sleep latency The prolongation of the REM sleep latency demonstrated by the present inventors could be particularly interesting for the treatment of disorders that are associated with pathologically shortened REM sleep latency (also called sleep onset REM episodes), which is very common in narcolepsy but also in affective disorders like major depressive disorder.
- Narcolepsy is characterized by fragmented NREM/REM sleep and shortened REM sleep latency.
- narcoleptics display higher REM density compared to healthy individuals.
- narcolepsy is characterized by excessive daytime sleepiness due to non-restorative sleep and nighttime arousals/nightmares.
- DEX 1 consolidates NREM and REM sleep, 2) massively reduces REM sleep latency, 3) increases NREM sleep at costs of REM sleep and 4) is able to reduce daytime sleepiness.
- DEX has anxiolytic features and is likely to effectively reduce night-time anxiety (nightmares, abnormal thoughts).
- the present invention further provides dexmedetomidine or a pharmaceutically acceptable salt thereof for use in the treatment of the sleep disorder, wherein said sleep disorder is circadian rhythm sleep disorder.
- Circadian rhythm sleep disorders involve either difficulty falling asleep, waking up during the sleep cycle or waking up too early and being unable to fall back to sleep.
- Particularly preferred embodiments of the present invention involve the circadian rhythm sleep disorder characterized by delayed sleep–wake phase, shift work, non-24-hour sleep–wake rhythm, or irregular sleep-wake rhythm.
- dexmedetomidine or its salt is to be dosed according to the present invention, i.e., as described herein.
- the present invention further provides dexmedetomidine for use in the treatment of REM sleep behaviour disorder.
- Rapid eye movement (REM) sleep behavior disorder is a sleep disorder in which you physically act out vivid, often unpleasant dreams with vocal sounds and sudden, often violent arm and leg movements during REM sleep ⁇ sometimes called dream-enacting behavior.
- dexmedetomidine according to the invention may lead to reduction of time spent by the subject in REM phase, thus substantiating the possibilities of treatment of REM disorders dosing dexmedetomidine according to the invention.
- dexmedetomidine or its salt is to be dosed according to the present invention, i.e., as described herein.
- Dexmedetomidine for use of the present invention is further provided for the treatment of restless leg syndrome.
- Restless legs syndrome is a condition that causes an uncontrollable urge to move the legs, usually because of an uncomfortable sensation. It typically happens in the evening or nighttime hours when you're sitting or lying down.
- the present invention relates to Dexmedetomidine for use of the present invention, wherein the sleep disorder is characterized by pathologically reduced REM sleep latency.
- Pathologically reduced REM sleep latency is herein to be understood as characterized by increased prevalence of sleep onset REM episodes (SOREM). This means, that upon sleep onset patients go into REM sleep instead of NREM sleep, which is an non-physiological sleep architectural feature
- SOREM sleep onset REM episodes
- the skilled person is capable of measuring the REM sleep latency and accordingly selecting a group of patients for the treatment with Dexmedetomidine, according to the present invention, which otherwise could not be selected.
- the ability of Dexmedetomidine to improve sleep quality by a reduction of noradrenergic signalling plausibilises efficacy of Dexmedetomidine in the treatment of conditions characterized by overactive noradrenergic signalling.
- Such disorders include anxiety, PTSD, depression and ADHD
- patients often suffer from stimulant-induced (e.g. D-amphetamine, methylphenidate, atomoxetine, dislexamphetamine) insomnia.
- Dexmedetomidine is supposed to antagonize the overactive noradrenergic signaling induced by these stimulants and thus reduce their negative impact on sleep.
- the present invention relates to Dexmedetomidine for use of the present invention, wherein the sleep disorder is characterized by overactive noradrenergic signalling.
- An overactive noradrenaline system also known as noradrenergic overactivity, refers to a state in which there is excessive release and/or activity of the neurotransmitter noradrenaline (also called norepinephrine) within the central nervous system.
- Noradrenaline is a chemical messenger that plays a crucial role in the regulation of various physiological functions and behaviors, including the "fight or flight" response, attention, mood, and arousal.
- an overactive noradrenaline system can be associated with several disorders and symptoms: 1.
- Anxiety disorders Excessive noradrenaline release in certain brain regions can lead to increased alertness, vigilance, and heightened anxiety responses. 2.
- Post-Traumatic Stress Disorder PTSD: In individuals with PTSD, the noradrenaline system can become dysregulated, contributing to the persistent state of hypervigilance and intrusive memories. 3.
- Panic disorder Noradrenergic overactivity has been linked to the sudden and intense panic attacks experienced by individuals with panic disorder. 4. Attention Deficit Hyperactivity Disorder (ADHD): An imbalance in noradrenergic activity is believed to contribute to the symptoms of impulsivity, hyperactivity, and inattention seen in ADHD. 5.
- Bipolar disorder During manic episodes in bipolar disorder, there is an increase in noradrenaline levels, which may contribute to the elevated mood, increased energy, and agitation. 6.
- Major depressive disorder Some research suggests that dysregulation of the noradrenergic system may play a role in depressive symptoms. 7.
- Schizophrenia Noradrenergic abnormalities have been implicated in schizophrenia, possibly contributing to cognitive deficits and disorganized thinking. 8. Autonomic dysregulation: An overactive noradrenaline system can affect the autonomic nervous system, leading to symptoms such as increased heart rate, sweating, and elevated blood pressure. The skilled person is capable of measuring the noradrenergic signalling and accordingly selecting a group of patients for the treatment with Dexmedetomidine, according to the present invention, which otherwise could not be selected. In a first specific embodiment, dexmedetomidine or its salt is to be administered in a dose of between 60 mcg and 80 mcg.
- dexmedetomidine or its salt is to be administered in a dose of between 20 mcg and 40 mcg.
- the subject is suffering from depression and/or anxiety.
- the subject is suffering from a disorder of the heart and lungs (for example congestive heart failure or chronic obstructive pulmonary disease), a neurodegenerative disorder (for example Alzheimer’s disease or Parkinson’s disease) or a disorder of the musculoskeletal system. 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 the treatment or prevention of a sleep disorder in a subject wherein dexmedetomidine or its salt is to be administered to a subject via transmucosal administration route in a dose of between 10 mcg and 120 mcg. 2.
- Dexmedetomidine or a pharmaceutically acceptable salt thereof for use of item 1 wherein dexmedetomidine or its salt is to be administered in a dose of between 40 mcg and 120 mcg, preferably in a dose of between 40 mcg and 80 mcg. 3.
- the sleep disorder is selected from insomnia disorder, hypersomnolence 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 medication-induced sleep disorder.
- NREM non-REM
- the sleep disorder is circadian rhythm sleep disorder, preferably characterized by delayed sleep-wake phase, shift work, non-24 hour sleep-wake rhythm, or irregular sleep-wake rhythm, or wherein the sleep disorder is REM sleep behaviour disorder, or wherein the sleep disorder is restless leg syndrome.
- the invention is illustrated by the following examples. They are however not to be construed as limiting, as the scope of the invention is characterized by the claims appended hereto. Examples In the following 5 studies, pharmacokinetics of different doses and formulations of dexmedetomidine and their effects on sleep physiology, next-day cardiovascular effects were investigated in healthy young volunteers. Therefore, the following experiments summarized
- Study 1 - ODT manufacturing Dexmedetomidine melting tablets were obtained by freeze-drying. Therefore, Dextran FP40 was used as bulking agent and dissolved in Dexdor TM injectable solution (100 ⁇ g/ml; Orion Pharm AG, Switzerland). The solution was then volumetrically filled into aluminum blister molds (0.2ml/cavity) using an Eppendorf Micropipette and finally freeze-dried for 30 hours, to yield lyophilized tablets with a strength of 20 ⁇ g each. The placebo melting tablets, were obtained accordingly, but Dexdor TM was replaced by saline 0.9% (B.Braun Medical AG, Sempach, Switzerland) to mimic the slight salty taste of the Dexdor TM solution.
- Study 2 - TIP Tablet manufacturing (20 ⁇ g/tbl.) The manufacturing procedure of the formulation used in study 2 is outlined in table 2 below. In the 20 mcg condition 1 tablet à 20 mcg dexmedetomidine plus 1 placebo tablet was administered, in the 40 mcg condition 2 tablets à 20 mcg dexmedetomidine were administered. All tablets were stored at room temperature under dry conditions (desiccator bag). Table 2. Manufacturing of dexmedetomidine loaded G-TIP 210821 tablets for study 2
- Study 3-5 TIP Tablet manufacturing (50 ⁇ g/tbl.)
- the manufacturing procedure of the formulation used in study 3-5 is the same as outlined in the tables above, with the only difference that tablets with a strength of 50mcg instead of 20mcg were manufactured, by adjusting the amount of powder blend filled into the 7mm dye.
- study 3 and 4 one tablet was administered.
- study 5 3 tablets were administered. All tablets were stored at room temperature under dry conditions (desiccator bag).
- Inclusion criteria for studies 1-5 To study the influence of dexmedetomidine on sleep structure and subjective sleep quality, a double-blinded, placebo-controlled, randomized, and balanced cross-over study has been conducted. This report focuses on the second part of the main study, which includes ten healthy subjects.
- the first step was to recruit ten subjects based on the following criteria: • Male • 18-35 years old • Body mass index (BMI) between 18.5 and 24.9 kg/m2 • Moderate alcohol ( ⁇ 5 drinks/week) and caffein ( ⁇ 3 drinks/day) consumption • No drug consumption • Non-smoker • Normal or normal corrected eyesight • ISI score of 0-8 • No sleep disorders • No neurological, psychological, and clinical diseases or regular intake of medication that could interfere with the measurements • No known strong allergies or hypersensitivities • No night shift work • Not having crossed more than two time zones in the last 30 days • No participation in another clinical trial in the previous 30 days The subjects were invited for one screening night, allowing them to check for possible sleep disorders, assess if their sleep efficiency is sufficient to participate, and if all the criteria are fulfilled.
- the intravenous line was kept open between each blood sampling with a slow drip (10ml/h) of heparinized saline (1000 IU heparin in 0.9g NaCl/dl; HEPARIN Bichsel, Bichsel AG, 3800 Unterseen, Switzerland).
- the blood samples of 5.5ml volume each were centrifuged immediately after collection, for 5min at 4700 RCF, and the plasma samples of 600 ⁇ l volume each were kept in the freezer at -28°C.
- Analysis and quantification of the dexmedetomidine concentration in the blood plasma was performed by liquid chromatography-tandem mass spectroscopy (LC-MS/MS).
- EEG setup – Study 1 and 2 Polysomnography consists of different physiological monitoring methods, which can be used to assess the quality and quantity of a patient's sleep. In our study polysomnography was performed during 8 hours of sleep, from 24.00h - 8.00h.
- the SIENNA ULTIMATE system (EMS Biomedical, Korneuburg, Austria) was used for this purpose. Before mounting the electrodes, the head circumference was determined to ensure precise placement of the electrodes with an appropriate EEG electrode cap.
- the skin was prepared with an abrasive skin preparation gel (NuPrep) to improve skin conductivity and to reduce impedances. The electrodes were then fixed with Grass EC2 Plus electrode cream and cut gauze dressings 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 a REF between Fz and Cz) according to the 10-20 system, a binocular electrooculogram (EOG) for tracking eye movements.
- EEG electrooculogram
- EMG electromyogram
- Heart rate was determined using a 2-channel electrocardiogram (ECG) with a sample rate of 512Hz, which was recorded on two separate channels using two electrodes attached to the sternum and the left lower ribcage.
- Figure 8 shows the specific hallmarks of the EEG, EOG, and EMG during the wake phase and the different sleep stages.
- the EEG shows alpha waves (8-13 Hz) in the occipital region, frequent eye movement in the EOG, and a high muscle tone is visible in the EMG (Berry, 2020).
- the EEG shows waves in the theta range (4-7 Hz), there is slow and rolling eye movement in the EOG, and the muscle tone is lower than the one while awake (Berry, 2020).
- N1 is also known as the light sleep stage since light stimulation can quickly awaken the subject (Kandel, E. R., Koester, J. D., Mack, S. H., & Siegelbaum, S. A. (2021).
- N2 The two important markers for N2 are the K-complex (frontal derivation) and spindle (central derivation) in the EEG.
- K-complex frontal derivation
- spindle central derivation
- N3, also known as the deep sleep stage, is characterized by the slow wave (0.5-2 Hz and >75 ⁇ V) activity (hence the name SWS) in the frontal derivation.
- SWS slow wave
- the EOG shows rapid eye movements
- the EEG shows a similar pattern to the one of being awake, and the muscle tone is at its lowest.
- Shellong Test Studies 1-5 Directly after waking up, the validated Shellong test was performed. In the two-part Shellong test, blood pressure and heart rate are first measured in the supine position for 3 minutes, with 1 minute between each measurement. Subsequently, the subjects stand up and 5 measurements are taken at intervals of 1 minute each. From the values determined in the test, it can be deduced whether and to what extent an orthostatic reaction takes place.
- the systolic blood pressure of a healthy person decreases by 10 mmHg and the diastolic blood pressure increases by approx.5mmHg when the position is changed.
- An increase in heart rate of 5-20 BPM can be expected in a healthy person (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).
- Questionnaires – Study 1 and 2 Following three questionnaires were assessed post-awakening PANAS (Positive and negative affect schedule), SIQ-Acute (Sleep Inertia Questionnaire Acute), and Morning questionnaire (MQ).
- PANAS Positive and Negative Affect Schedule
- a high NA score is associated with the subject feeling anger, contempt, disgust, sadness, fear, and nervousness, while a high NA score shows that the subject is in a calm and serene mood (Watson et al., 1988).
- the Sleep Inertia Questionnaire (SIQ) (appendix pages 101-102) was developed in 2015 by Kanady and Harvey. Sleep inertia is the state right after sleep, characterized by a lowered arousal and an impaired performance. The SIQ allows assessing the level of sleep inertia (Kanady, J. C., & Harvey, A. G. (2015). Development and Validation of the Sleep Inertia Questionnaire (SIQ) and Assessment of Sleep Inertia in Analogue and Clinical Depression.
- the original SIQ consists of 21 questions rated on a 5-point Likert-type scale.
- questions 22 and 23 are treated individually, while questions 1 to 21 are grouped into one of the four factors (physiological, inertia, cognitive, and emotional).
- Morning questionnaire The Morning Questionnaire is a short questionnaire which was filled out by the study participants 30 minutes after awakening. The questionnaire can be divided into two parts. In the first, the study participants indicated how long the estimated duration of falling asleep was in minutes, how often they thought they had woken up during the night and how long they thought they had been awake during the night (in minutes, not including the duration of falling asleep). In a second part, the comparison with usual nights and the normal state of mind were recorded on seven visual scales. The study participants were asked, for instance, how tired, calm, or concentrated they were at the moment or how deeply or superficially they have slept compared to normal sleep.
- Cortisol Awakening Response Cortisone-D7 was purchased from Sigma Aldrich (Buchs, Switzerland) and 13C3- cortisol was purchased from Isoscience (Ambler, USA). Saliva of each subject was sampled at time points 08:00 (immediately after awakening), 08:15, 08:30, 08:45, and 09:00. Participants were instructed to chew the swab for 60 s and then return it into the Salivette® tube (Sarstedt, Germany). After sampling, tubes were immediately stored on ice until final storage at ⁇ 80 °C. For cortisol detection, tubes were defrosted and centrifuged for 5 min at 5000 rpm to yield clear saliva in the conical tube.
- swab was removed and the yielded saliva was spiked with 50 ⁇ l IS (0.1 ng/ ⁇ l Cortison- d7) for further analysis.
- a fully automated supported liquid extraction (SLE) was carried out by transferring 265 ⁇ l saliva into a column rack (24 ⁇ 6 ml) from Biotage® Extrahera (Biotage, Uppsala, Sweden) and adding 300 ⁇ l water to the sample. After mixing the extracts were automatically loaded onto Isolute SLE + columns and allowed to absorb for 5 min. Analytes were then eluted two times with 1.5 ml ethyl acetate with a waiting time of 5 min in-between.
- the extracts were dried in a Turbovap® (Biotage, Uppsala, Sweden) at 35 °C.
- the dry residues were resuspended using 150 ⁇ l methanol and 350 ⁇ l ammonium formate (5 mM) solution, which was used for liquid chromatography- tandem mass spectrometry (LC–MS/MS) analysis following a recently published method using 13C3-labeled cortisol as surrogate analyte for calibration40.
- the saliva samples were analyzed on an LC–MS/MS system that consisted of a Shimadzu Prominence UFLC (Shimadzu, Kyoto, Japan) high pressure liquid-chromatography (HPLC) system coupled to a Sciex QTRAP® 6500+linear ion trap quadrupole mass spectrometer (Sciex, Darmstadt, Germany).10 ⁇ l of the samples were injected onto a Phenomenex® Kinetex® C18 column (2.6 ⁇ m, 50 ⁇ 2.10 mm).
- the mobile phase consisted of 10 ml ammonium formate (1 M) and 2 ml formic acid in 2 l water (A) and 10 ml ammonium formate (1 M) in 2 l methanol (B).
- the flow rate was 0.3 ml/min and the temperature of the column oven was set to 40 °C.
- the quantification was achieved by using the mass spectrometer in multiple reaction monitoring (MRM) with an ion spray voltage of ⁇ 4500 V.
- Cortisol was measured as formic acid adduct [(M–H) + 46] ⁇ in negative electrospray ionization mode.
- the method was validated according to the guidelines of the German Society of Toxicology and Forensic Chemistry (GTFCh).
- the calibration was prepared by adding 13C3-cortisol to saliva in the concentration range of 0.55 nmol/ml up to 55 nmol/ml. QC samples were prepared in low concentrations (1.5 nmol/l).
- the Shellong Task was conducted at 8:00, immediately after awakening.
- 50mcg were administered at 24:00, nobody (0 out of 4) experienced orthostatic dysregulation or dizziness.
- 50mcg were administered at 4:30, 3 out of 4 participants experienced dizziness, orthostatic problems and nausea at 8:00.
- the participant that received 150mcg at 4:30 experienced severe side effects post-awakening at 8:00, including fainting, nausea, hypotonia, bradycardia and cognitive disturbances. Based on this data we suggest that morning plasma levels of 0.18ng/ml are associated with side effects that should be avoided in the therapy of insomnia.
- dexmedetomidine was able to dramatically shorten the sleep latency, even though it was not pre-dosed (e.g.30-60 min before going to bed), but was given immediately before lights were switched off. This implicates a very quick and efficient onset of action on sleep latency.
- the prolongation of the REM sleep latency could be particularly interesting for the treatment of disorders that are associated with pathologically shortened REM sleep latency (also called sleep onset REM episodes), which are very common in narcolepsy but also in affective disorders like MDD. It should be noted that the effects are more pronounced in the 40mcg compared to the 20mcg condition, such that the 20mcg condition often only reaches statistical trend levels.
- the therapeutic window might start somewhere between 20-40mcg and going lower is likely to yield less clinical effects. Anyhow, very sensitive individuals or persons with a low body weight may also respond to 10 mcg. Thus, with this data the present inventors have identified the lower end of the therapeutic window of sublingual dexmedetomidine for the treatment of insomnia. Table 4. Visually scored sleep variables following the administration of placebo, 20 and 40 mcg of DEX (Study 1)
- dexmedetomidine may provide an innovative way to improve both sleeping and waking quality by the augmentation of restorative SWA.
- Sleep physiological results - Study 2 With only 8 subjects included in study 2, the sample size is relatively small. Based on the observed data, the program “G*Power” estimated the minimal sample size needed to obtain significant results of n ⁇ 19.
- the effects of 20 and 40mcg of dexmedetomidine TIP (study 2) on visually scored sleep variables are presented in a descriptive manner.
- both doses administered in this study shortened sleep latency, prolonged REM sleep latency and increased the time spent in stages N2+N3 (deep sleep).
- the shortening of the sleep latency and the prolongation of deep sleep represent two clinically meaningful features, since both sleep latency and deep sleep are compromised in most insomnia patients. It has to be noted, that again the dexmedetomidine formulation used in this study was able to dramatically shorten the sleep latency, even though it was not pre-dosed (e.g.30- 60min before going to bed), but was given immediately before lights were switched off. This implicates a very quick and efficient onset of action on sleep latency.
- the prolongation of the REM sleep latency could be particularly interesting for the treatment of disorders that are associated with pathologically shortened REM sleep latency (also called sleep onset REM episodes), which are very common in narcolepsy but also in affective disorders like MDD.
- Table 5 Descriptive statistics for the sleep latency. Table 6. Descriptive statistics for the REM latency Table 7. Descriptive statistics for the time spent in the wake stage Table 8. Descriptive statistics for the time spent in the N1 stage Table 9. Descriptive statistics for the time spent in the N2 stage Table 10. Descriptive statistics for the time spent in the N3 stage during the whole night Table 11. Descriptive statistics for the time spent in the REM stage Table 12. Descriptive statistics for the time spent in the N3 stage during the first night half. Table 13. Descriptive statistics for the time spent in the N3 stage during the second night half.
- the HPA axis is tightly regulated by the noradrenergic system, it is a good biomarker for carry-over dexmedetomidine effects on the HPA axis.
- the present inventors have surprisingly found that sublingual bedtime administration of 20 and 40 mcg of dexmedetomidine leads to significant effects on sleep physiology, including a drastic shortening of sleep latency, a prolongation of REM latency and a prolongation of the time spent in NREM sleep (N2+N3).
- the present inventors have surprisingly found, that the administration of dexmedetomidine via the sublingual route yields substantially superior pharmacokinetic profiles over orally administered dexmedetomidine, such that the bioavailability was increased and intersubject plasma level variability was decreased by the use of the sublingual route compared to oral delivery.
- This effect was found using both freeze-dried melting tablets (ODT) and carrier particles.
- ODT freeze-dried melting tablets
- Further Data Summary and clinical Meaning DEX ODTs, each of 20 ⁇ g, were manufactured by freeze-drying.
- Each ODT contained: ⁇ DEX 20 ⁇ g ⁇ Dextran FP4030mg ⁇ dH2O ad 0.2ml DEX and Dextran FP40 were dissolved in dH 2 O and the solution was volumetrically filled into aluminum molds and freeze-dried for 30 hours.
- Dexmedetomidine shows a reduction in sleep onset latency (see Figure 12), a prolongation of REM latency (see Figure 13) and an increase in N2+N3 deep sleep (as seen in Figure 14 through reduced length of REM stage, in Figure 15 through increase in stage N2, as well as in Figure 16 through increased length of non-REM stage).
- the latter is further characterized by an increase in slow wave activity and SWE, particularly in the 1 st half of the night.
- Dexmedetomidine reduces sleep fragmentation during both NREM and REM sleep (see Figure 17 and Figure 23). Given its sleep pharmacological profile presented herein, Dexmedetomidine is proposed to be a suitable treatment option for conditions associated with the inability to fall asleep, stay asleep and generate restorative slow wave deep sleep. These symptoms are highly prevalent in psychiatric conditions, including depression, anxiety, PTSD, ADHD, schizophrenia, psychosis, etc. and neurological conditions, including neurodegenerative disorders (Parkinson’s, Alzheimer’s, etc.) and sleep related neurological disorders, such as restless leg syndrome, REM sleep behavioral disorder, narcolepsy, etc. and pain-induced insomnia.
- psychiatric conditions including depression, anxiety, PTSD, ADHD, schizophrenia, psychosis, etc.
- neurological conditions including neurodegenerative disorders (Parkinson’s, Alzheimer’s, etc.) and sleep related neurological disorders, such as restless leg syndrome, REM sleep behavioral disorder, narcolepsy, etc. and pain-induced insomnia.
- the ability to increase REM sleep latency suggests efficacy of Dexmedetomidine in treating conditions associated with pathologically reduces REM sleep latency, including narcolepsy, idiopathic hypersomnia, REM sleep behavior disorder, depression, PTSD, Kleine-Levin Syndrom (KLS), Brainstem Lesions.
- the ability of Dexmedetomidine to improve sleep quality (as outlined in the results) by a reduction of noradrenergic signaling suggests clinical efficacy of Dexmedetomidine in the treatment of conditions associated with overactive noradrenergic signaling, including anxiety, PTSD, depression and ADHD. In the case of ADHD, patients often suffer from stimulant-induced (e.g.
- D-amphetamine, methylphenidate, atomoxetine, dislexamphetamine) insomnia D-amphetamine, methylphenidate, atomoxetine, dislexamphetamine) insomnia.
- Dexmedetomidine is supposed to antagonize the overactive noradrenergic signaling induced by these stimulants and thus reduce their negative impact on sleep.
- Dexmedetomidine is proposed to reduce the negative impact of SSRI and SNRIs on sleep, by antagonizing the noradrenaline induced sleep disturbances.
- the ability of Dexmedetomidine to reduce NREM and REM sleep fragmentation implies clinical efficacy in treating conditions associated with NREM and REM sleep fragmentation.
Abstract
La présente invention concerne de la dexmédétomidine ou un sel pharmaceutiquement acceptable de celle-ci pour une utilisation dans le traitement ou la prévention d'un trouble du sommeil chez un sujet, la dexmédétomidine ou son sel devant être administré à un sujet par voie d'administration transmucosale à une dose comprise entre 10 mcg et 120 mcg. Ladite dexmédétomidine ou un sel pharmaceutiquement acceptable de celle-ci est de préférence formulé sous la forme d'un comprimé orodispersible et est particulièrement utile dans le traitement de l'insomnie.
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5376347A (en) | 1991-07-22 | 1994-12-27 | Osaka Gas Company, Limited | Uniform inorganic micropheres and production thereof |
US20050025807A1 (en) | 2003-07-31 | 2005-02-03 | National Institute Of Advanced Industrial Science And Technology | Cured porous calcium phosphate material and uses thereof |
KR20080013907A (ko) * | 2005-05-18 | 2008-02-13 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | 드록시도파를 함유하는 안정한 정제 |
US20100196286A1 (en) | 2008-12-01 | 2010-08-05 | Armer Thomas A | Inhalation delivery methods and devices |
US20110248417A1 (en) * | 2010-04-07 | 2011-10-13 | Kaohsiung Medical University | Method for preparing composition comprising porous ceramic with thermo-response hydrogel |
WO2016061413A1 (fr) | 2014-10-15 | 2016-04-21 | Bioxcel Corporation | Prévention ou traitement de troubles du sommeil au moyen d'une formulation de dexmédétomidine |
WO2018126182A1 (fr) | 2016-12-31 | 2018-07-05 | Bioxcel Therapeutics, Inc. | Utilisation de dexmédétomidine sublinguale permettant le traitement de l'agitation |
WO2020006092A1 (fr) | 2018-06-27 | 2020-01-02 | Bioxcel Therapeutics, Inc. | Formulations de film contenant de la dexmédétomidine et leurs procédés de production |
US20220226288A1 (en) | 2021-01-04 | 2022-07-21 | Bioxcel Therapeutics, Inc. | Dexmedetomidine treatment regimens |
-
2023
- 2023-07-27 WO PCT/EP2023/070918 patent/WO2024023261A1/fr unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5376347A (en) | 1991-07-22 | 1994-12-27 | Osaka Gas Company, Limited | Uniform inorganic micropheres and production thereof |
US20050025807A1 (en) | 2003-07-31 | 2005-02-03 | National Institute Of Advanced Industrial Science And Technology | Cured porous calcium phosphate material and uses thereof |
KR20080013907A (ko) * | 2005-05-18 | 2008-02-13 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | 드록시도파를 함유하는 안정한 정제 |
US20100196286A1 (en) | 2008-12-01 | 2010-08-05 | Armer Thomas A | Inhalation delivery methods and devices |
US20110248417A1 (en) * | 2010-04-07 | 2011-10-13 | Kaohsiung Medical University | Method for preparing composition comprising porous ceramic with thermo-response hydrogel |
WO2016061413A1 (fr) | 2014-10-15 | 2016-04-21 | Bioxcel Corporation | Prévention ou traitement de troubles du sommeil au moyen d'une formulation de dexmédétomidine |
US20170239221A1 (en) | 2014-10-15 | 2017-08-24 | Bioxcel Corporation | Prevention or treatment of sleep disorders using dexmedetomidine formulation |
WO2018126182A1 (fr) | 2016-12-31 | 2018-07-05 | Bioxcel Therapeutics, Inc. | Utilisation de dexmédétomidine sublinguale permettant le traitement de l'agitation |
WO2020006092A1 (fr) | 2018-06-27 | 2020-01-02 | Bioxcel Therapeutics, Inc. | Formulations de film contenant de la dexmédétomidine et leurs procédés de production |
US20220226288A1 (en) | 2021-01-04 | 2022-07-21 | Bioxcel Therapeutics, Inc. | Dexmedetomidine treatment regimens |
Non-Patent Citations (55)
Title |
---|
AKASHKINA, L.V.EZERSKII, M.L., PHARM CHEM J, vol. 34, 2000, pages 324 - 326 |
AKEJU ET AL., NEUROPHYSIOLOGY, 2018 |
ALLEN, T: "Particle size measurement", 2013, SPRINGER |
AMERICAN ACADEMY OF SLEEP MEDICINE BERRY, 2020, pages 17 |
AYAS, N. T.WHITE, D. P.MANSON, J. E.STAMPFER, M. J.SPEIZER, F. E.MALHOTRA, AHU, F. B.: "A Prospective Study of Sleep Duration and Coronary Heart Disease in Women", ARCHIVES OF INTERNAL MEDICINE, vol. 163, no. 2, 2003, pages 205 - 209 |
BAUER, J. F., JOURNAL OF VALIDATION TECHNOLOGY, vol. 15, no. 1, 2009, pages 37 - 45 |
BERRY, R. B. ET AL.: "AASM Scoring Manual Updates for 2017", J. CLIN. SLEEP MED., vol. 13, 2017, pages 665 - 6 |
BLOOR, BYRON C., WARD, DENHAM S., BELLEVILLE, JON P., & MAZE, M.: "Effects of Intravenous Dexmedetomidine in Humans: II. Hemodynamic Changes", ANESTHESIOLOGY, vol. 77, no. 6, 1992, pages 1134 - 1142 |
CAGNACCI, AARANGINO, SANGIOLUCCI, MMASCHIO, EMELIS, G. B.: "Influences of melatonin administration on the circulation of women", AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY, INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, vol. 274, no. 2, 1998, pages 335 - 338 |
CARUSO, F ET AL., SCIENCE, vol. 282, no. 5391, 1998, pages 1111 - 1114 |
CHANDRAN, RPANDA, S.K.MALLIK, A: "A short review on the advancements in electroplating of CulnGaSe2 thin films", MATER RENEW SUSTAIN ENERGY, vol. 7, 2018, pages 6 |
CHOKROVERTY, S.: "Overview of sleep & sleep disorders", THE INDIAN JOURNAL OF MEDICAL RESEARCH, vol. 131, no. 2, 2014, pages 126 - 140 |
CUNNINGTON, DJUNGE, M. F.FERNANDO, A. T.: "Insomnia: prevalence, consequences and effective treatment", MEDICAL JOURNAL OF AUSTRALIA, vol. 199, no. 8, 2013, pages 36 - 40 |
CURRAN, H. V.COLLINS, RFLETCHER, SKEE, S. C. Y.WOODS, BILIFFE, S: "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life", PSYCHOLOGICAL MEDICINE, vol. 33, no. 7, 2003, pages 1223 - 1237 |
DAVID, JPETER, R, FUNDAMENTALS OF EARLY CLINICAL DRUG DEVELOPMENT: FROM SYNTHESIS DESIGN TO FORMULATION, vol. 247, 2006 |
DE WIT, HGRIFFITHS, R. R.: "Testing the abuse liability of anxiolytic and hypnotic drugs in humans", DRUG AND ALCOHOL DEPENDENCE, vol. 28, no. 1, 1991, pages 83 - 111, XP023165317, DOI: 10.1016/0376-8716(91)90054-3 |
DECHER, G. H. J. D. ET AL., THIN SOLID FILMS, vol. 210, 1992, pages 831 - 835 |
DESPOTOVIC, R ET AL., CALC. TIS RES., vol. 18, 1975, pages 13 - 26 |
DINGES, D. F.: "An overview of sleepiness and accidents", J SLEEP RES, vol. 4, no. 2, 1995, pages 4 - 14 |
DONATH, E ET AL., ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 37, no. 16, 1998, pages 2201 - 2205 |
FORD, D. E.KAMEROW, D. B.: "Epidemiologic Study of Sleep Disturbances and Psychiatric Disorders: An Opportunity for Prevention?", JAMA, vol. 262, no. 11, 1989, pages 1479 - 1484, XP008076346, DOI: 10.1001/jama.262.11.1479 |
GOTTLIEB, D. J.PUNJABI, N. M.NEWMAN, A. B.RESNICK, H. E.REDLINE, SBALDWIN, C. M.NIETO, F.J.: "Association of Sleep Time With Diabetes Mellitus and Impaired Glucose Tolerance", ARCHIVES OF INTERNAL MEDICINE, vol. 165, no. 8, 2005, pages 863 - 867 |
HAJAK, GRODENBECK, AVODERHOLZER, URIEMANN, DCOHRS, SHOHAGEN, FBERGER, MRUTHER, E: "Doxepin in the treatment of primary insomnia - A placebo-controlled, double-blind, polysomnographic study", NEUROPSYCHOPHARMACOLOGY, vol. 10, 2000, pages 248 - 249, XP027389371 |
HALL, J. E., UHRICH, T. D., BARNEY, J. A., ARAIN, S. R., & EBERT, T. J.: "Sedative, Amnestic, and Analgesic Properties of Small-Dose Dexmedetomidine Infusions", ANESTHESIA AND ANALGESIA, vol. 90, no. 3, 2000, pages 699 - 705, XP008154643, DOI: 10.1097/00000539-200003000-00035 |
JOHNSON, H. E.DOTSON, J. M.ELLIS, C. S.HILL, K. K.: "Severe Hypotension in an Adolescent After a Melatonin Overdose", JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY, vol. 29, no. 9, 2019, pages 726 - 727 |
KALES, AMANFREDI, R. L.VGONTZAS, A. N.BIXLER, E. O.VELA-BUENO, AFEE, E. C.: "Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines", CLINICAL PHARMACOLOGY & THERAPEUTICS, vol. 49, no. 4, 1991, pages 468 - 476 |
KANADY, J. C.HARVEY, A. G.: "Development and Validation of the Sleep Inertia Questionnaire (SIQ) and Assessment of Sleep Inertia in Analogue and Clinical Depression", COGNITIVE THERAPY AND RESEARCH, vol. 39, no. 5, 2015, pages 601 - 612, XP035545160, DOI: 10.1007/s10608-015-9686-4 |
KANDEL, E. R.KOESTER, J. D.MACK, S. H.SIEGELBAUM, S. A.: "Practice of Sleep Medicine: Sleep Disorders in Children and Adults", 2021, SPRINGER INTERNATIONAL PUBLISHING AG, pages: 1082 - 92 |
KARSTEN, JHAGENAUW, L. A.KAMPHUIS, JLANCEL, M: "Low doses of mirtazapine or quetiapine for transient insomnia: A randomised, double-blind, cross-over, placebo-controlled trial", JOURNAL OF PSYCHOPHARMACOLOGY, vol. 31, no. 3, 2017, pages 327 - 337 |
KAY, G. G.: "The effects of antihistamines on cognition and performance", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 105, 2000, pages 622 - 627, XP004542125, DOI: 10.1067/mai.2000.106153 |
KEMPKES, MEGGERS, JMAZZOTTI, M, CHEMICAL ENGINEERING SCIENCE, vol. 63, no. 19, 2008, pages 4656 - 4675 |
KENNAWAY, D. J.: "What do we really know about the safety and efficacy of melatonin for sleep disorders?", CURRENT MEDICAL RESEARCH AND OPINION, vol. 38, no. 2, 2022, pages 211 - 227 |
KHAWAM, E. A.LAURENCIC, GMALONE, D. A., JR: "Side effects of antidepressants: an overview", CLEVELAND CLINICAL JOURNAL OF MEDICINE, vol. 73, no. 4, 2006, pages 351 - 353,356-361 |
LEE, S: "Dexmedetomidine: present and future directions", KOREAN JOURNAL OF ANESTHESIOLOGY, vol. 72, no. 4, 2019, pages 323 - 330 |
MAHOWALDSCHENCK: "Insights from studying human sleep disorders", NATURE, vol. 437, no. 7063, 2005, pages 1279 - 1285 |
MARKL, D ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 538, no. 1-2, 2018, pages 188 - 214 |
MORIN, C. M., BELLEVILLE, G., BELANGER, L., & IVERS, H.: "The Insomnia Severity Index: Psychometric Indicators to Detect Insomnia Cases and Evaluate Treatment Response", SLEEP, vol. 34, no. 5, 2011, pages 601 - 608 |
MORIN, C. M.KOETTER, UBASTIEN, CWARE, J. C.WOOTEN, V: "Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial", SLEEP, vol. 28, no. 11, 2005, pages 1465 - 1471 |
MOYA, ANGEL ET AL.: "European Heart Journal", vol. 30, November 2009, PUB- MED CENTRAL, article "Guidelines for the diagnosis and management of syncope (version 2009)", pages: 2631 - 2671 |
NORMAN, S. E., CHEDIAK, A.D., KIEL, M., & COHN, M. A.: "Sleep disturbances in HIV-infected homosexual men", AIDS, vol. 4, no. 8, 1990, pages 775 - 782 |
ODEKU, O. A. ET AL., PHARMACEUTICAL REVIEWS, vol. 5, no. 2, 2007 |
OHAYON, M. M.: "Epidemiology of insomnia: what we know and what we still need to learn", SLEEP MEDICINE REVIEWS, vol. 6, no. 2, 2002, pages 97 - 111 |
OKADA, M ET AL., JOURNAL OF NANOPARTICLE RESEARCH, vol. 16, no. 7, 2014, pages 1 - 9 |
PARIS, ATONNER, P. H.: "Dexmedetomidine in anaesthesia", CURRENT OPINION IN ANESTHESIOLOGY, vol. 18, no. 4, 2005 |
PATEL, R. P. ET AL., ASIAN JOURNAL OF PHARMACEUTICS (AJP, vol. 2, no. 4, 2014 |
SAVARD, JSAVARD, M.-H.: "Insomnia and cancer: prevalence, nature, and nonpharmacologic treatment", SLEEP MEDICINE CLINICS, vol. 8, no. 3, 2013, pages 373 - 387 |
SERIZAWA, TKAMIMURA, S ET AL., LANGMUIR, vol. 18, no. 22, 2002, pages 8381 - 8385 |
SIM, J. H.YU, H. J.KIM, S. T.: "The effects of different loading doses of dexmedetomidine on sedation", KOREAN JOURNAL OF ANESTHESIOLOGY, vol. 67, no. 1, 2014, pages 8 - 12 |
SUCH, G. K. ET AL., CHEMICAL SOCIETY REVIEWS, vol. 40, no. 1, 2010, pages 19 - 29 |
SUN RUI ET AL: "Highly Porous Amorphous Calcium Phosphate for Drug Delivery and Bio-Medical Applications", NANOMATERIALS, vol. 10, no. 1, 19 December 2019 (2019-12-19), pages 20, XP055908492, DOI: 10.3390/nano10010020 * |
UGOK, AGAEBEL, W: "Side effects of atypical antipsychotics: a brief overview", WORLD PSYCHIATRY: OFFICIAL JOURNAL OF THE WORLD PSYCHIATRIC ASSOCIATION (WPA, vol. 7, no. 1, 2008, pages 58 - 62 |
VENN, R. M.GROUNDS, R. M.: "Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions", BRITISH JOURNAL OF ANAESTHESIA, vol. 87, no. 5, 2001, pages 684 - 690 |
WATSON, D., CLARK, L. A., & TELLEGEN, A.: "Development and validation of brief measures of positive and negative affect: The PANAS scales", JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY, vol. 54, no. 6, 1988, pages 1063 - 1070 |
WATSON, THE SLEEP INERTIA QUESTIONNAIRE (SIQ), 1988, pages 101 - 102 |
ZHANG, Y ET AL., MACROMOLECULES, vol. 36, no. 11, 2003, pages 4238 - 4240 |
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