Piromelatine for the treatment of parasomnia associated with loss of muscle relaxation during REM sleep

Abstract

A method for treating a patient with a parasomnia associated with rapid eye movement (REM) sleep and slowing the progression of the disease to synucleinopathy and Parkinson's disease by administering to the patient a formulation containing an effective amount of piromelatine, and a method for treating a patient with a parasomnia associated with rapid eye movement (REM) sleep and slowing the progression of the disease from the parasomnia to chronic post-traumatic stress disorder (PTSD) by administering to the patient a formulation containing an effective amount of piromelatine.

Description

[Technical Field]

[0001] [Incorporation of Related Applications] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 479,781, filed January 13, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] [Field] Provided herein is the melatonin MT1 / MT2 / MT3 and serotonin 5-HT1A and 5-HT1D receptor agonist N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide (piromelatine), for the manufacture of a medicament for treating parasomnias associated with loss of muscle relaxation during REM sleep, such as REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA), thereby delaying or preventing phenoconversion to synucleinopathy and chronic post-traumatic stress disorder. [Background technology]

[0003] Rapid eye movement (REM) sleep (or REMS) is a specific phase of sleep characterized by rapid, low-voltage, asynchronous brain waves similar to those observed during wakefulness, rapid eye movements, a high tendency to dream, and low muscle tone (atonia), which prevents humans from acting out the contents of their dreams. It is physiologically distinct from other sleep phases, collectively known as non-rapid eye movement (NREM) sleep (synchronous sleep). REM and non-rapid eye movement (REMS) sleep alternate throughout the night, with the REM sleep stage becoming longer as the night progresses, especially toward the last third of the night.

[0004] REM sleep behavior disorder (RBD) is a parasomnia characterized by the actinization of dreams during loss of REM relaxation (DSM-5 327.42 and ICSD-3 classification). RBD is considered idiopathic (isolated; iRBD) or can occur in the context of other disorders (e.g., traumatic brain injury, pesticide exposure, posttraumatic stress disorder (PTSD), or antidepressant medication). Patients with RBD, particularly during the last third of the night, experience impaired voluntary muscle relaxation characteristic of REM sleep, leading them to act out their dreams. Early on, patients begin vocalizing, speaking, and performing complex movements. As the disorder progresses, patients may scream, fight, or jump out of bed, often injuring themselves or their partners. The disorder affects 0.5% of the population, primarily men over the age of 50.

[0005] Abnormally high RSWA may predict progression to chronic PTSD, and patients generally show a high prevalence of both RSWA and RBD (Feemster JC et al., J Clin Sleep Med. 2019, 15;15(2):345-349; Elliott JE et al., Sleep J, 2020, 1-10; Feemster JC et al., Sleep J, 2022, Vol. 45, No. 3). Furthermore, patients with PTSD exhibit a significant decrease in slow oscillation power below 1 Hz during non-REM sleep and an increase in power in the high-frequency range, and an increase in slow oscillation power in the occipital region during REM sleep. The latter effect is positively correlated with nightmare activity (Boer et al., SLEEP J, 2020, 1-9).

[0006] In recent years, iRBD has been recognized as the most reliable prodromal biomarker for synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA) (Iranzo, Fernandez-Arcos et al. 2014; Postuma, Iranzo et al. 2019; Li and Le 2020). A decrease in spectral power in the alpha band during REM sleep is an early marker of phenotypic conversion from RBD to synucleinopathies (Gong SY et al., Nature and Science of Sleep 2022: 14 407-418). Patients with RBD have a 45% 5-year and 76% 10-year risk of developing Parkinson's disease (PD) (Tianbai L and Weidong L, Neurosci. Bull. 2020, 36(2): 183-194; Fereshtehnejad SM et al., Mov Disord. 2017, 32: 865-873; Postuma RB et al., Brain. 2019, 1;142(3):744-759). Therefore, RBD offers an opportunity for early intervention to prevent phenotypic transformation to synucleinopathy.

[0007] High levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and C-reactive protein (CRP) in serum may also predict phenotypic transformation in RBD patients (Kim, Lee et al. 2020; Wang, Liu et al. 2022).

[0008] Currently, there are no approved medications for REM sleep-related parasomnias (RSWA and RBD). Most reported treatment outcomes are based on clinical experience or case reports (Jimenez-Jimenez J. Pers. Med. 2021, 11, 1204). Clonazepam (a benzodiazepine) and melatonin are the most commonly used treatment options. However, the use of clonazepam in elderly patients raises numerous concerns, including the worsening of obstructive sleep apnea and cognitive impairment, and more tolerable treatments are needed (Jimenez-Jimenez, Alonso-Navarro et al. 2021). Reports on the effects of melatonin on RBD are relatively few and mostly inconsistent, leading to general doubt about its efficacy (Kunz D and Mahlberg R. J Sleep Res. 2010 Dec;19(4):591-6; Jun JS et al., Ann Clin Transl Neurol. 2019 Apr;6(4):716-722; Kim et al. 2019; Gilat M et al., Movement Disorders, Vol. 35, No. 2, 2020; Gilat M et al., Journal of Neurology 2022, 269:125-148). It has been suggested that timed melatonin treatment may delay the phenotypic transformation to parkinsonism, but evidence remains lacking (Kunz D and Bes F. Neuropsychobiology. 2017;76(2):100-104). In PTSD, the use of benzodiazepines or other sedative-hypnotics should be avoided because they cause a slow worsening of depressing dissociative symptoms, thus limiting their use in cases of PTSD-associated RBD (Guina J et al., J Psychiatr Pract. 2015, 21:281-303).

[0009] Isolated case reports provide conflicting data suggesting that 5-HT1A receptor agonists (e.g., buspirone, SEP-363856) may induce or eliminate sleepwalking by affecting relaxation during REM sleep (Moses TEH and Javanbakht A. J Clin Psychopharmacol. 2022; 42(1): 96-98; Hopkins et al., Translational Psychiatry 2021; 11:228), and tandospirone (a 5-HT1A partial agonist) has also been reported to exacerbate RBD symptoms (Takahashi et al., Sleep Med. 2008, 9, 317-319). Serotonergic drugs (selective serotonin reuptake inhibitors (SSRIs)) can induce, worsen, or improve RBD symptoms and restless REM sleep (Winkelman & James Sleep. 2004;27:317-321; Takahashi et al., Sleep Med. 2008, 9, 317-319).

[0010] There is little or no evidence in the published literature that administration of melatonin receptor agonists or serotonin 5HT-1A receptor agonists affects sleep architecture in the embodiments disclosed herein (Arbon et al. J Psychopharmacol. 2015 Jul;29(7):764-76; Biard et al. J Psychopharmacol. 2015 Oct;29(10):1106-11).

[0011] Piromelatine is a dual agonist that acts on both serotonergic 5HT-1A and melatonin receptors and has been tested for the treatment of insomnia and Alzheimer's disease (Patents US7635710B2, US9101613, Schneider et al. J Prev Alz Dis 2021, which are incorporated herein by reference for all purposes), but has not been tested for RBD or its phenotypic transformation to Parkinson's disease. Summary of the Invention

[0012] Surprisingly, the present inventors have found that, in contrast to the results of the above-mentioned known literature, the test compound N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide (piromelatine), an agonist for MT1 / MT2 / MT3-type melatonin receptors and serotonin 5-HT1A and 5-HT1D receptors, increases spectral power in the alpha band during REM sleep in insomnia patients aged 20 to 80 years, with little or no fluctuations in other frequencies (see Examples 1 and 2). Because delayed alpha waves during REM sleep is a biomarker for phenotypic conversion from RBD to synucleinopathy (e.g., Parkinson's disease) (Gong SY et al., Nature and Science of Sleep 2022: 14 407-418), the use of piromelatine is disclosed herein to improve RBD symptoms while inhibiting or delaying phenotypic conversion to synucleinopathy, such as Parkinson's disease. The present invention provides an unexpected method for using piromelatine in patients with RBD and RBD to inhibit or reduce the risk of phenotypic conversion to synucleinopathy.

[0013] Provided herein is a method for treating a patient with REM sleep-related parasomnia, comprising administering to the patient a formulation containing an effective amount of piromelatine, and a formulation containing an effective amount of parasomnia for use in treating a patient with REM sleep-related parasomnia.In some embodiments, the patient has REM sleep behavior disorder (RBD).In another embodiment, the patient has restless REM sleep (RSWA).

[0014] According to one embodiment described herein, there is provided a method of delivering piromelatine to a patient for disease modification, such as prevention, slowing the progression of, or reducing the risk of phenotypic conversion to a synucleinopathy, comprising administering to the patient a formulation comprising an effective amount of piromelatine. The present disclosure also includes formulations comprising an effective amount of piromelatine for use in disease modification, such as prevention, slowing the progression of, or reducing the risk of phenotypic conversion to a synucleinopathy.

[0015] Provided herein are methods for delivering piromelatine to a patient to treat REM sleep behavior disorder (RBD) or slow its progression to a synucleinopathy or Parkinson's disease, comprising administering to the subject a formulation comprising an effective amount of piromelatine. The disclosure also includes formulations comprising an effective amount of piromelatine for use in treating RBD or slowing its progression to a synucleinopathy or Parkinson's disease.

[0016] Provided herein is a method for delivering piromelatine to a patient to reduce the progression of REM sleep-related parasomnias to chronic PTSD, the method comprising administering to the patient a formulation comprising an effective amount of piromelatine. The present disclosure also includes a formulation comprising an effective amount of piromelatine for use in reducing the progression of REM sleep-related parasomnias to chronic PTSD.

[0017] In any of the embodiments described herein, formulations comprising an effective amount of piromelatine include the use of piromelatine in unit dosage form, wherein a single dosage contains 2 to 100 mg of piromelatine, in the manufacture of a medicament for treating parasomnias associated with REM sleep relaxation (e.g., RSWA, RBD, and their associated conditions).

[0018] Provided herein are methods for delivering piromelatine to patients for the purpose of inhibiting progression to RBD-associated synuclein-specific neurodegenerative (synucleinopathy) diseases.

[0019] Provided herein are methods for improving RBD and RSWA in PTSD patients and reducing the risk of these disorders progressing to chronic PTSD.

[0020] In any embodiment herein, a pharmaceutical composition comprising a therapeutically effective amount of piromelatine or a pharmaceutically acceptable salt thereof, and any stereoisomer thereof, as an active ingredient may be used together with one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers conventionally used in the formulation of pharmaceutical and veterinary medicines. The pharmaceutical formulations are applicable for administration to humans and / or animals.

[0021] These and other aspects of the present invention will become evident upon reference to the following detailed description, claims, embodiments, procedures, compounds and / or compositions, and related background art and references, all of which are hereby incorporated herein in their entirety. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the effect of 4 weeks of piromelatine (Neu-P11) 20 mg and 50 mg compared to placebo on alpha power % during REM sleep in three nightly halves.

[0023] [Figure 2] FIG. 2 shows the effect of piromelatine (Neu-P11) 20 mg and 50 mg for 4 weeks compared to placebo on spectral power density (% of baseline) during non-REM sleep. DETAILED DESCRIPTION OF THE INVENTION

[0024] Although various aspects of the technical subject matter of the present disclosure can be embodied in various forms, the following description is intended to disclose only some of these forms as examples of the subject matter encompassed by the present disclosure, and therefore the technical subject matter of the present disclosure is not limited to the described forms or embodiments.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; however, other suitable methods and materials known in the art can also be used. These materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of any conflict with the present specification, the present specification (including definitions) will control.

[0026] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

[0027] The singular forms "a," "an," and "the" are intended to include the plural unless the context clearly dictates otherwise.

[0028] The terms "treat" or "treatment," as used herein and as well understood in the art, refer to an approach for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results include alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the disease state, reduction in recurrences, partial or complete remission (whether detectable or undetectable), and the like. "Treat" and "treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. In addition to being useful as therapeutic methods, the methods described herein can also be useful as prophylaxis or preventative treatments for disease.

[0029] Concentrations, amounts, and other numerical data may be described or presented in a range format herein. This range format is used for convenience and brevity, and should be interpreted flexibly as if each individual value or subrange within the range, as well as the numerical values ​​explicitly stated as the upper and lower limits of the range, were expressly set forth. For example, a numerical range of "about 0.01 to 2.0" includes not only the explicitly stated values ​​"about 0.01" and "about 2.0," but also individual values ​​such as 0.5, 0.7, and 1.5, and subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5. This interpretation applies regardless of the breadth of the range or the nature of the subject matter described. Furthermore, all percentages are by weight unless otherwise specified.

[0030] In understanding the scope of the present disclosure, the terms "including" and "comprising" and their derivatives are intended to be open-ended terms specifying the presence of stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, or steps. The same applies to the terms "including" and "having" and their derivatives. The term "consisting" and its derivatives are closed-ended terms specifying the presence of stated features, elements, components, groups, integers, or steps, but excluding the presence of other unstated items. The term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, steps, and / or steps, as well as other things that do not materially affect the basic and novel characteristics of the stated elements, components, groups, integers, steps, and / or steps. Additionally, reference to any of these transitional phrases ("including," "comprising," "essentially consisting") is intended to provide direct support in this specification for substitution with any other transitional phrase not specifically used. For example, amending the transitional phrase from "comprising" to "consisting essentially of" is directly supported under this definition.

[0031] The term "about" is used herein to provide flexibility to the endpoints of a range, by allowing for the assumption that the numerical value may be slightly above or below the endpoints. The flexibility of the term will vary depending on the variable in question, but is within the knowledge of a skilled artisan based on experience and the relevant explanations herein. For example, in one embodiment, the flexibility may be within about ±10% of the numerical value, in another embodiment, within about ±5%, and in further embodiments, within about ±2%, ±1%, or ±0.05%.

[0032] Generally, in this specification, the term "or" includes "and / or."

[0033] Although a plurality of compounds, elements, or procedures may be presented in a single list for convenience herein, the list is constructed so that each item in the list is identified as a separate and independent component, and therefore, each item contained in such a list should not be construed as an interchangeable equivalent of other items in the same list merely by virtue of their presence in the same list without any specific statement that they are not interchangeable equivalents of other items in the same list.

[0034] Additionally, this disclosure may describe certain compositions, elements, excipients, ingredients, diseases, conditions, properties, steps, etc., in the context of a particular embodiment or aspect, or in a separate paragraph or section. It is understood that this is for convenience and brevity only, and any such description is intended to apply equally to and be combined with any portion of any other embodiment or aspect found in any of the present disclosures and claims, all of which form the application and claimed invention as of the filing date. For example, a list of method steps, active ingredients, kits, or compositions described with respect to piromelatine or a method of treating a patient is intended, and does, provide direct support for embodiments relating to compositions, formulations of piromelatine, or methods of treating a patient described elsewhere in this disclosure, even if the relevant method steps, active ingredients, kits, or compositions are not relisted in the context or section of that embodiment or aspect.

[0035] The term "overnight" as used herein can mean a period of about 6 to 18 hours, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 hours, or any range or time between about 6 hours and about 18 hours.

[0036] "Ratio" as used herein means the measured value divided by the baseline value multiplied by 100.

[0037] Provided herein are novel uses and methods of treatment with piromelatine.

[0038] Also, as used herein, the term "compound of piromelatine," its salt, or its stereoisomer is intended to include one or more of the compound, its salt, or its stereoisomer. Furthermore, the term "compound" is intended to include a salt or stereoisomer of the compound with respect to pharmaceutical formulations discussed below.

[0039] Provided herein is the preparation of a piromelatine-containing composition useful as a pharmaceutical. The pharmaceutical composition contains an effective amount of piromelatine or a pharmaceutically acceptable salt thereof, and its stereoisomers, as an active ingredient, in combination with one or more diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, and carriers commonly used in pharmaceutical and veterinary drug formulations. The formulation is applicable for administration to humans and / or animals.

[0040] In certain embodiments, the pharmaceutical formulation preferably has at least one of the following characteristics: (i) Suitable for oral, parenteral (i.e., intramuscular, intraperitoneal, intravenous, subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical administration, and can be prepared in a dosage form appropriate for each administration method; (ii) a single-dose dosage form, the dosage form containing about 2 mg to 100 mg of piromelatine; or (iii) Both (i) and (ii) are satisfied.

[0041] The formulations may be characterized as being able to be administered alone, as well as in combination or co-administration with other compounds known in the art to be useful in the treatment of RBD or RSWA disorders or in the prevention of related conditions, such as PTSD, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA).

[0042] In some embodiments, the methods comprise administering to a patient a formulation comprising an effective amount of piromelatine to treat RBD and RSWA, where "treating" as used herein means alleviating or curing the disease, disorder, or condition, or alleviating at least one symptom of the disease, disorder, or condition.

[0043] In some embodiments, the method comprises administering to a patient an effective amount of a formulation comprising piromelatine to inhibit the progression of phenotypic transformation to pathologies associated with RBD and RSWA, such as transformation from PTSD to synucleinopathy, Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy (MSA). RBD- and RSWA-associated pathologies refer to diseases that directly or indirectly result in RBD and RSWA, diseases that result from RBD and RSWA, or diseases that correlate with the prevalence of RBD or RSWA, even in the absence of a clear causal relationship.

[0044] In a preferred embodiment, the disease or disorder occurs in a human and a formulation comprising an effective amount of piromelatine is administered to the human.

[0045] Provided herein is a method for treating a patient with a parasomnia associated with rapid eye movement (REM) sleep, comprising administering to the patient an effective amount of a formulation comprising piromelatine. In some embodiments, the patient has REM sleep behavior disorder (RBD). In some embodiments, the patient has restless REM sleep (RSWA).

[0046] Provided herein is a method for suppressing disease phenotype conversion from RBD-associated parasomnia to synucleinopathy, comprising administering to a patient a formulation containing an effective amount of piromelatine.

[0047] Provided herein is a method for treating or inhibiting disease progression of RBD-associated parasomnia to Parkinson's disease, comprising administering to a patient a formulation containing an effective amount of piromelatine.

[0048] Provided herein is a method for inhibiting the progression of REM sleep-related parasomnia to chronic PTSD, comprising administering to a patient a formulation containing an effective amount of piromelatine.

[0049] In some embodiments, after administering piromelatine to a patient for about four weeks, the proportion of alpha power band during REM sleep measured at night may be increased compared to baseline. In some embodiments, after administering piromelatine to a patient for about four weeks, the proportion of alpha power band during REM sleep measured at night may be about 101% to about 110%, about 102% to about 108%, about 103% to about 107%, about 104% to about 106%, or about 105% compared to baseline. In some embodiments, after administering piromelatine to a patient for about four weeks, the proportion of alpha power band during REM sleep measured at night may be increased by about 106% compared to baseline.

[0050] In some embodiments, after administering piromelatine to a patient for about 4 weeks, the ratios of delta power, theta power, sigma power, beta power, beta 1 power, beta 2 power, and beta 3 power during REM sleep measured nightly may independently be about 97% to about 105%, about 98% to about 104%, about 99% to about 103%, about 100% to about 102%, or about 101% compared to baseline.

[0051] In some embodiments, after administering piromelatine to a patient for about four weeks, the percentage of non-rapid eye movement (NREM) sleep in the low frequency band of 0.5-1.5 Hz measured nightly may be increased compared to baseline. In some embodiments, after administering piromelatine to a patient for about four weeks, the percentage of NREM sleep in the low frequency band of 0.5-1.5 Hz measured nightly may be greater than 100% to about 120%, about 105% to about 115%, about 107% to about 112%, or about 110% compared to baseline.

[0052] In some embodiments, a formulation comprising an effective amount of piromelatine may be administered alone or in combination with other agents known to be beneficial in treating the disease, disorder, or condition being treated, e.g., as a combination therapy. As used herein, the terms "in combination" or "combination therapy" refer to piromelatine and other agents administered together, i.e., as concomitant therapy, or as a fixed physical combination, or administered at different times but acting in a complementary manner. In some embodiments, a formulation comprising an effective amount of piromelatine may be administered in combination with one or more additional therapeutic agents.

[0053] In treating or preventing such conditions (broadly defined as REM sleep disorders), the compounds can be administered alone or in combination with other compounds having therapeutic properties, such as anti-inflammatory agents, antioxidants, hypnotics, anxiolytics, antipsychotics, antianxiety agents, mild sedatives, melatonin agonists and antagonists, melatonin, benzodiazepines, barbiturates, 5-HT2 receptor antagonists, and the like.For example, adinazolam, allobarbital, alonimide, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbochloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, chloretate, clozapine , ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, eszopiclone, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, imipramine, indiplon, lithium, lorazepam Pam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, Midaflu, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclase

[0049] The compound may be administered in combination with the group consisting of benzodiazepine, benzodiazepine, benzocaine, benzodiazepine, benzophenone, benzocaine, benzodiazepine ...

[0054] Combining piromelatine with one or more of these known therapeutic agents provides additive, complementary, and often synergistic effects that may enhance the desirable properties of the known therapeutic agents.

[0055] In some embodiments, a formulation comprising an effective amount of piromelatine can be administered as a combination therapy with other compounds having therapeutic properties (e.g., compounds described above). In some embodiments, the combination therapy can be administered simultaneously. In some embodiments, the combination therapy can include separately administering a formulation comprising an effective amount of piromelatine and one or more additional therapeutic agents. In some embodiments, the combination therapy can be administered as a mixed formulation.

[0056] In some embodiments, the combination therapy includes an anti-inflammatory agent, an antioxidant, a hypnotic, an anxiolytic, an antipsychotic, an anxiety agent, a mild sedative, a melatonin agonist, a melatonin antagonist, melatonin, a benzodiazepine, a barbiturate, a 5-HT2 antagonist, or a combination thereof.

[0057] Piromelatine alone or a combination of piromelatine with any of the known therapeutic agents may further be administered in combination with a physical therapy, such as phototherapy, psychotherapy, etc. In some embodiments, a formulation containing an effective amount of piromelatine may be administered in conjunction with a physical therapy. In some embodiments, the combination therapy may be administered together with a physical therapy. In some embodiments, the physical therapy may include phototherapy, psychotherapy, or a combination thereof.

[0058] Piromelatine can be formulated as a pharmaceutical composition suitable for oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical administration. The composition may include one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, and / or carriers. In some embodiments, a formulation comprising an effective amount of piromelatine can be administered orally, parenterally, nasally, vaginally, rectally, sublingually, or topically. In some embodiments, a formulation comprising an effective amount of piromelatine can be administered in a unit dosage form.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, minitablets, pellets, powders, and granules. In such solid single-dose dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as magnesium stearate as a lubricant. Examples of additives that may be incorporated into tablets, capsules, pills, etc. include: binders such as tragacanth gum, acacia, cornstarch, or gelatin; excipients such as microcrystalline cellulose; disintegrants such as cornstarch, pregelatinized starch, alginic acid, etc.; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; and flavors such as peppermint, oil of wintergreen, or cherry. In addition, capsules, tablets, and pills may contain buffering agents. Capsules may also contain a liquid carrier, such as fatty oil, in addition to the above ingredients. Various other materials may be present as coatings or may be used to modify the physical form of the dosage unit. Tablets and pills may be prepared with enteric coatings; tablets may be coated with shellac, sugar, or both.

[0060] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, self-microemulsifying drug delivery systems (SMEDDS), liposomes, syrups, and elixirs containing inert diluents commonly used in the art, such as water. In addition to these inert diluents, compositions may contain additives such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, aroma enhancers, oils, surfactants, and co-surfactants. Syrups or elixirs may contain the active compound, sucrose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavor.

[0061] Oral SMEDDS formulations increase the bioavailability of piromelatine and / or other therapeutic agents. These formulations typically contain emulsions containing oil or lipid materials, surfactants, and hydrophilic cosurfactants. Poorly water-soluble drugs or formulations are emulsified in self-microemulsifying carrier formulations, improving the bioavailability of the drug or formulation in the body. Furthermore, poorly water-soluble drugs can be used in combination with piromelatine.

[0062] In some embodiments, the SMEDDS pharmaceutical composition can be prepared as a formulation for piromelatine suitable for oral administration, such as an emulsion, aqueous or oily suspension, hard or soft capsule, syrup, powder or granules, troche, tablet or lozenge, etc. Pharmaceutically acceptable carriers or additives for the formulation include lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin as a binder, dicalcium phosphate as an excipient, corn starch or sweet potato starch as a disintegrant, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. as a lubricant.

[0063] In some embodiments, parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Sterile compositions for injection may be prepared according to conventional pharmaceutical practice by dissolving or suspending the active ingredient in water for injection, natural vegetable oils such as sesame oil, coconut oil, peanut oil, or cottonseed oil, or synthetic fatty carriers such as ethyl oleate. Buffers, preservatives, antioxidants, and the like may be incorporated as needed. Examples of non-aqueous solvents or carriers include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These preparations may be sterilized, for example, by filtration through a bacteria-removing filter, adding a sterilizing agent to the composition, irradiating the composition, or heating the composition. Alternatively, sterile solid compositions may be prepared and dissolved in sterile water or other sterile injectable medium immediately before use.

[0064] Compositions for rectal or vaginal administration are preferably presented as suppositories and may contain, in addition to the active ingredient, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration may also be prepared using standard excipients well known to those skilled in the art.

[0065] In any of the above-described embodiments, the dosage of the active therapeutic agent in the composition can vary as long as an effective amount is administered to achieve a therapeutic effect. Desirably, the active therapeutic agent is administered to a patient (human or veterinary) in need of such treatment at a dosage that provides optimal pharmaceutical efficacy. The selected dosage will depend on the nature and severity of the disease or disorder being treated, the desired therapeutic effect, the route of administration, and the duration of treatment. The dosage can also vary depending on the patient's weight and other factors. For example, the dosage of piromelatine induced to alter the RBD may differ from the dosage required to prevent synucleinopathy. The dosage can vary from patient to patient depending on the nature and severity of the disease, the patient's weight, any special diet the patient is currently following, any concurrent medications, the bioavailability of the administered compound, and other factors recognized by those skilled in the art.

[0066] In treating the conditions according to the embodiments described herein, a suitable daily dosage is generally about 2 to 100 mg. The daily dosage can be administered in one or more divided doses. Preferably, the dosage is about 5 to 50 mg, more preferably about 20 to 40 mg. According to one or more embodiments described herein, an effective amount of piromelatine can be about 2 mg to about 100 mg, about 5 mg to about 50 mg, or about 20 mg to about 40 mg, or about 30 mg. In some embodiments, an effective amount of piromelatine can be about 50 mg.

[0067] The formulations according to the embodiments described herein may be in immediate-release form, or, if desired, in sustained-release form, e.g., as solid formulations for oral administration. Sustained-release formulations include delayed-release, sustained-release, pulsed-release, or controlled-release formulations. Sustained-release formulations applicable to certain embodiments described herein include those described in U.S. Patent Nos. 6,106,864, 7,053,122, and 7,118,762, which are incorporated herein by reference in their entireties. Details of other suitable release technologies, such as high-energy dispersions and osmotic or coated particles, are described, for example, in Verma, R. and S. Garg, Pharmaceutical Technology On-Line, 25(2), 1-14 (2001), which is incorporated herein by reference.

[0068] In some embodiments, a formulation containing an effective amount of piromelatine may be administered to a patient from about 10 minutes to about 60 minutes, or from about 20 minutes to about 40 minutes, or about 30 minutes before bedtime.

[0069] The period over which a sustained-release formulation releases the compound varies based on the indication and the desired therapeutic level. For example, in the case of RBD, it is desirable to limit the pharmacological effect of the administered compound to nighttime, i.e., approximately 8 hours.

[0070] The methods described herein are methods for treating a patient with a parasomnia associated with RBD, comprising administering to the patient a formulation comprising about 2 mg to about 100 mg, about 5 mg to about 50 mg, or about 20 to about 40 mg of piromelatine. In some embodiments, the patient is diagnosed with RBD by video polysomnography (vPSG). In some embodiments, vPSG measurements are quantified using the RBD Severity Scale (RBDSS). In some embodiments, the patient does not have untreated obstructive sleep apnea (OSA). In some embodiments, the patient is not taking selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, Cp3A inhibitors, melatonin, beta-blockers, or combinations thereof.

[0071] In some embodiments, the patient is evaluated using dopamine transporter imaging (DaT scan), a blood test, or a combination thereof. In some embodiments, the blood test includes measuring TNF-α and CRP levels in a serum sample of the patient.

[0072] In some embodiments, the patient is assessed using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), or a combination thereof.

[0073] In some embodiments, the formulation is a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients and / or carriers. In some embodiments, the formulation is administered orally, parenterally, nasally, vaginally, rectally, sublingually, or topically. [Example]

[0074] The following examples are intended to be illustrative of the present disclosure and not limiting of the claimed invention. All molecules, compositions, methods, assays, and results shown in the examples form a non-limiting part of the present disclosure.

[0075] Example 1: Effects of 4-week treatment with piromelatine 20 mg and 50 mg compared to placebo on REM sleep spectral power

[0076] REM sleep EEG (electroencephalogram) power was calculated to assess the effect of continuous (4-week) treatment with piromelatine 20 mg and 50 mg compared with placebo in patients with primary insomnia. Sleep EEG was recorded at nine different centers in a three-arm parallel study in which patients were randomly assigned to three groups: placebo, piromelatine 20 mg, and piromelatine 50 mg. (Of 121 patients with available sleep EEG data, 42 received placebo, 39 received piromelatine 20 mg, and 40 received piromelatine 50 mg.) REM EEG spectral profiles of the three groups were comparable at baseline (measured on two consecutive nights before treatment), and treatment effects could be reliably compared as a ratio to baseline values.

[0077] Spectral power was calculated for the entire EEG spectrum (0.5; 32) Hz throughout the night and during REM sleep, and in the following frequency bands: delta (0.5; 4) Hz, theta (4; 8) Hz, alpha (8; 13) Hz, sigma (11.5; 15.5) Hz, beta (15.5; 32) Hz, beta 1 (15.5; 20.5) Hz, beta 2 (20.5; 25.5) Hz, and beta 3 (25.5; 32) Hz. [Table 1]

[0078] Figure 1 shows the effect of 20 mg and 50 mg piromelatine (Neu-P11) on REM alpha power during each of three equal nighttime periods, compared with placebo, for 4 weeks. REM sleep is longest during the third nighttime period.

[0079] The results show that treatment with piromelatine enhanced the REM sleep alpha power band compared with baseline and placebo, particularly during the longest REM sleep period in nighttime stage 3 (Table 1, Figure 1).

[0080] Example 2: Effects of 4-week treatment with piromelatine 20 mg and 50 mg compared to placebo on non-REM sleep spectral power Non-REM sleep EEG power was calculated to assess the effect of continuous (4-week) treatment with piromelatine 20 mg and 50 mg compared with placebo in patients with primary insomnia. Sleep EEG was recorded at nine different centers in a three-arm parallel study in which patients were randomly assigned to three groups: placebo, piromelatine 20 mg, and piromelatine 50 mg. (Of 121 patients with available sleep EEG data, 42 received placebo, 39 received piromelatine 20 mg, and 40 received piromelatine 50 mg.) The NREM EEG spectral profiles of the three groups were comparable at baseline, and treatment effects could be reliably compared as a ratio of baseline values.

[0081] Spectral power was calculated for the entire EEG spectrum during all night and non-REM sleep at [0.5;32] Hz and in the following frequency bands: delta [0.5;4] Hz, theta [4;8] Hz, alpha [8;13] Hz, sigma [11.5;15.5] Hz, beta [15.5;32] Hz, beta 1 [15.5;20.5] Hz, beta 2 [20.5;25.5] Hz, and beta 3 [25.5;32] Hz.

[0082] Figure 2 shows the effect of 4 weeks of piromelatine (NEU-P11) 20 mg and 50 mg on the power spectrum of non-REM sleep (as a percentage of baseline spectral power density) compared to placebo. The results show that piromelatine administration increased the non-REM low-frequency band (0.5-1.5 Hz) compared to baseline and placebo.

[0083] Example 3: Protocol for an open-label sleep study to evaluate the efficacy and safety of piromelatine in a well-defined population with idiopathic RBD

[0084] Study medication:

[0085] Piromelatine, 2 x 20 mg tablets, orally, once daily at the same time (set 30 minutes before the patient's usual bedtime), after meals, preferably between 21:00 and 23:00.

[0086] Test purpose:

[0087] A) To evaluate the effects of short-term (1 month) treatment with pyromelatine compared to baseline measures on sleep and RBD symptom severity.

[0088] B) If the treatment is deemed effective in the short term, evaluate the effects of long-term treatment (up to 1 year) compared with baseline measurements.

[0089] Study design:

[0090] This is a proof-of-concept, open-label study in line with recent recommendations for RBD drug research (Videnovic, Ju et al. 2020). The study protocol will be approved by the Ethics Committee of the Free University of Berlin, and all participants will provide written informed consent.

[0091] Participants in clinical trials for RBD must be diagnosed with RBD according to the International Classification of Sleep Disorders-3 (ICSD-3) (ICSD-3 and Medicine 2014) or the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (DSM-5 and Association 2013). The diagnosis of RBD, in particular, requires confirmation by video polysomnography (vPSG), as many similar disorders exist.

[0092] Adult patients with RBD, male and female, aged 50-70 years, who meet the criteria for RBD as determined by the RBD single-question screening (Postuma, Iranzo et al. 2019) and vPSG, will be eligible. Approximately 12 eligible patients with iRBD (idiopathic RBD) confirmed by vPSG will be recruited within 6 months.

[0093] Patients with untreated or suboptimally treated obstructive sleep apnea (OSA) or other sleep disorders should be excluded. Given that treatment with antidepressants (SSRIs) may exacerbate or precipitate RBD symptoms, these medications and benzodiazepine-based hypnotics should be discontinued prior to participation. Use of Cyp3A inhibitors (Table 1), melatonin, and beta-blockers is prohibited in this study. Other medications must be on stable doses for at least 3 months.

[0094] All eligible patients will undergo baseline (night 3) vPSG recording of RBD severity. Because RBD symptom severity varies significantly from night to night, vPSG will be performed on two nights (nights -2 and -1) to reduce this variability. The first night (night -3) will be used as a habituation night to reduce the impact of sleeping in an unfamiliar environment on RBD behavior and will not be analyzed. vPSG measurements will be quantified using the RBD Severity Scale (RBDSS), an established method for assessing the frequency and severity of motor and vocal events during REM sleep.

[0095] Before starting drug treatment, all patients in this study will undergo dopamine transporter imaging (DaTscan), blood tests for general safety assessment, and serum TNF-α and CRP levels. In addition, patients will complete the PSQI and ESS.

[0096] Patients are administered pyrometabolite once daily at the same time for 30 days. This time should be 30 minutes before the patient's usual bedtime, preferably between 9:00 PM and 11:00 PM, after meals. vPSG recordings are performed on the evenings of nights 29 and 30, after which patients are released for evaluation of the treatment effect on iRBD severity. If improvement is observed, patients are permitted to continue into the long-term extension phase (1 year), during which vPSG measurements, DaTscan, serum TNF-α and CRP levels, and clinical assessments are performed. Monthly interim visits or phone calls are conducted to monitor safety and clinical status (Table 2). Patients who do not achieve a response by month 1 will not be continued into the long-term phase.

[0097] Statistical analysis:

[0098] Demographic data and medical and surgical history will be summarized using descriptive statistics; no formal statistical tests will be performed on these data.

[0099] Baseline and end-of-treatment scores will be summarized using descriptive statistics (sample size, mean, standard deviation, median, minimum, and maximum), including actual values ​​and changes from baseline, at baseline (mean of nights -2 and -1) and by the end of short-term 6-week treatment (mean of nights 29 and 30) or long-term 1-year treatment (days 364 and 365). At each visit, the mean PSG value from the two nights will be used in the summary. Baseline and end-of-treatment scores (short-term and long-term) will be compared using paired t-tests. Due to the exploratory nature of this study, Bonferroni corrections for multiple comparisons will not be performed.

[0100] Descriptive statistics will be provided for adverse events (AEs), physical examination parameters, laboratory parameters, and vital signs. The number of patients taking concomitant medications during the treatment period will be summarized by WHO classification code for each treatment group.

[0101] The number of patients reporting adverse events will be summarized by system organ class (SOC) and preferred term by treatment group.

[0102] Changes in laboratory parameters from baseline to the end of one year of treatment will be summarized using shift tables showing the number of patients with values ​​below, within, and above the normal range at each assessment time point. Data will not be carried forward for patients who discontinue due to treatment failure.

[0103] Changes in physical examination parameters from baseline to the end of the short-term and long-term treatment periods will be summarized as the number of patients with normal or abnormal findings at each assessment time point. Data will not be repeated (carried forward) for patients who discontinued treatment due to treatment failure.

[0104] Vital signs will be summarized (as actual values ​​and change from baseline) using descriptive statistics (number of patients, mean, standard deviation, median, minimum, maximum) at baseline and at the end of each treatment period.

[0105] The number of patients who discontinued during each treatment period will be summarized by primary reason for discontinuation. Protocol amendments will be introduced in accordance with ethical and regulatory requirements and are subject to approval by appropriate health authorities.

[0106] The following numbered aspects also form part of this disclosure: [Other embodiments] [1] A method, use, or composition for use in treating a patient with a parasomnia associated with REM sleep, comprising administering to the patient a formulation comprising an effective amount of piromelatine. [2] A method, use, or composition for use according to [1], wherein the patient has REM sleep behavior disorder (RBD). [3] A method, use, or composition for use according to [1], wherein the patient has rapid eye movement (RSWA) sleep-inspiring disorder. [4] A method, use, or composition for use in treating a patient to inhibit disease progression to a synucleinopathy, the method, use, or composition comprising administering to the patient a formulation comprising an effective amount of piromelatine. [5] A method, use, or composition for use in treating a patient to inhibit disease progression to Parkinson's disease, the method, use, or composition comprising administering to the patient a formulation comprising an effective amount of piromelatine. [6] A method, use, or composition for use in inhibiting disease progression from REM sleep-related parasomnia to chronic post-traumatic stress disorder (PTSD) in a patient, comprising administering to the patient an effective amount of a formulation comprising piromelatine. [7] A method, use, or composition for use according to any one of the embodiments [1] to [6], wherein the patient is administered piromelatine for about 4 weeks, after which the non-rapid eye movement (NREM) low frequency band of 0.5 to 1.5 Hz is enhanced compared to baseline. [8] A method, use, or composition for use according to the embodiment of [7], wherein after about 4 weeks of administration, the ratio of the non-REM low frequency band of 0.5 to 1.5 Hz is greater than 100% and less than or equal to about 120% of baseline. [9] A method, use, or composition for use according to any one of the embodiments [1] to [8], wherein the effective amount of piromelatine is about 2 to 100 mg, about 5 to 50 mg, or about 20 to 40 mg per day.

[10] A method, use, or composition for use according to any one of the embodiments of [1] to [9], wherein the effective amount of piromelatine is about 50 mg per day.

[11] A method, use, or composition for use according to any one of the embodiments of [1] to

[10] , wherein the formulation containing the effective amount of piromelatine is administered orally, parenterally, nasally, intravaginally, intrarectally, sublingually, or topically.

[12] A method, use, or composition for use according to any one of the embodiments of [1] to

[11] , wherein a formulation comprising an effective amount of piromelatine is administered in a self-microemulsifying drug delivery system (SMEDDS).

[13] A method, use, or composition for use according to any one of the embodiments of [1] to

[12] , wherein the formulation containing the effective amount of piromelatine is administered in a single-dose dosage form.

[14] A method, use, or composition for use according to any one of the embodiments of [1] to

[13] , wherein the formulation containing the effective amount of piromelatine is administered once a day.

[15] A method, use, or composition for use according to any one of the embodiments of [1] to

[14] , wherein the formulation containing the effective amount of piromelatine is administered from about 10 minutes to about 60 minutes or about 30 minutes before bedtime.

[16] A method, use, or composition for use according to any one of the embodiments of [1] to

[15] , wherein the formulation containing the effective amount of piromelatine is administered orally.

[17] A method, use, or composition for use according to any one of the embodiments of [1] to

[16] , wherein the formulation comprising the effective amount of piromelatine is administered as a combination therapy with a second therapeutic agent.

[18] A method, use, or composition for use according to the embodiment of

[17] , wherein the combination therapy is administered simultaneously with the second therapeutic agent.

[19] A method, use, or composition for use according to the embodiment of

[17] , wherein the combination therapy is administered as a mixed formulation with the second therapeutic agent.

[20] A method, use, or composition for use according to the embodiment of

[17] , wherein the formulation containing the effective amount of piromelatine and one or more additional therapeutic agents are administered separately.

[21] The method, use, or composition for use according to any one of the embodiments

[17] to

[20] , wherein the combination therapy comprises an anti-inflammatory agent, an antioxidant, a hypnotic, an anxiolytic, an antipsychotic, an anxiolytic agent, a mild sedative, a melatonin agonist, a melatonin antagonist, melatonin, a benzodiazepine, a barbiturate, a 5-HT2 antagonist, a dopamine agonist, or a combination thereof.

[22] The method, use, or composition for use according to any one of the embodiments

[17] to

[20] , wherein the second therapeutic agent is adinazolam, allobarbital, alonimide, alprazolam, amantadine, amitriptyline, amobarbital, amoxapine, apomorphine, bentazepam, benzoctamine, benzhexol, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbochloral, chloral betaine, chloral hydrate, chlordiazepine, oxidized, clomipramine, cloperidone, clorazepate, chloretate, clozapine, co-beneldopa, co-careldopa, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, entacapone, estazolam, eszopiclone, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxam Dhol, glutethimide, halazepam, hydroxyzine, imipramine, indiplon, levodopa, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, opicapone, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, pramipexole, prazepam, prochloridine, promethazine , propofol, protriptyline, quazepam, ramelteon, rasagiline, reclazepam, loretamide, ropinirole, rotigotine, safinamide, secobarbital, selegiline, sertraline, suproclon, temazepam, thioridazine, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, triexyphenidyl, trifluoperazine, trimetozine, trimipramine, urdazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, zopiclone,and salts thereof, or combinations thereof.

[23] A method, use, or composition for use according to any one of the embodiments of [1] to

[22] , wherein the formulation containing the effective amount of piromelatine is administered in combination with a physical therapy.

[24] A method, use, or composition for use according to the embodiment of

[23] , wherein the physical therapy comprises light therapy, psychotherapy, or a combination thereof.

[25] A method, use, or composition for use according to any one of the embodiments [1] to

[24] , wherein the patient is a human.

[26] A method, use, or composition for treating a patient with RBD-related parasomnia, comprising administering to the patient a formulation containing about 2 to about 100 mg, about 5 to about 50 mg, or about 20 to about 40 mg of piromelatine per day.

[27] A method, use, or composition for use according to the embodiments of

[26] , wherein the patient has been diagnosed with RBD by video polysomnography (vPSG).

[28] A method, use, or composition for use according to the embodiments of

[27] , wherein the vPSG assessment is quantified using the RBD Severity Scale (RBDSS).

[29] A method, use, or composition for use according to the embodiment of

[28] , wherein the patient is diagnosed by the Clinical Global Improvement Scale (CGI-I) scale.

[30] A method, use, or composition for use according to any one of the embodiments

[26] to

[29] , wherein the patient is diagnosed by dopamine transporter imaging DaTscan, a blood test, or a combination thereof.

[31] A method, use, or composition for use according to the embodiments of

[30] , wherein the blood test comprises measuring tumor necrosis factor alpha (TNF-α) and / or C-reactive protein (CRP) levels in a serum sample from the patient.

[32]

[26] to

[31] . A method, use, or composition for use according to any one of the embodiments, wherein the patient is assessed using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleep Scale (ESS), or a combination thereof.

[33] A method for the use of any one of the embodiments

[26] to

[32] , wherein the formulation comprises one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients and / or carriers.

[34]

[26] to

[33] . A method, use, or composition for use according to any one of the embodiments, wherein the formulation is administered orally, parenterally, nasally, vaginally, rectally, sublingually, or topically.

[0107] While the subject matter of the present disclosure has been described and illustrated in detail with reference to exemplary embodiments incorporating various combinations and subcombinations of features, those skilled in the art will readily recognize other embodiments, variations, and modifications thereof that are within the scope of the present disclosure. Furthermore, the description of such embodiments, combinations, and subcombinations is not intended to convey that the claimed subject matter necessarily requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present disclosure is intended to include all modifications and variations that are within the spirit and scope of the claims appended below. The section headings, materials, methods, and examples are illustrative only and not limiting.

[0108] Other aspects, advantages, and modifications of the present disclosure are within the scope of the following claims.

Claims

1. 1. A method for treating a patient having a parasomnia associated with REM sleep, comprising administering to said patient a formulation comprising an effective amount of piromelatine.

2. 10. The method of claim 1, wherein the patient has REM sleep behavior disorder (RBD).

3. 10. The method of claim 1, wherein the patient has rapid eye movement (RSWA) sleep-free.

4. 1. A method of treating a patient to inhibit disease progression to a synucleinopathy, comprising administering to the patient a formulation comprising an effective amount of piromelatine.

5. 1. A method of treating a patient to inhibit disease progression to Parkinson's disease, comprising administering to said patient a formulation comprising an effective amount of piromelatine.

6. 1. A method for inhibiting disease progression from REM sleep-related parasomnia to chronic post-traumatic stress disorder (PTSD) in a patient, comprising administering to the patient a formulation comprising an effective amount of piromelatine.

7. 7. The method of any one of claims 1 to 6, wherein after about 4 weeks of administering piromelatine to the patient, the non-rapid eye movement (NREM) low frequency band between 0.5 and 1.5 Hz is enhanced compared to baseline.

8. 8. The method of claim 7, wherein after about 4 weeks of administration, the proportion of non-REM low frequency band between 0.5 and 1.5 Hz is greater than 100% and less than or equal to about 120% of baseline.

9. 9. The method of any one of claims 1 to 8, wherein the effective amount of piromelatine is about 2 to 100 mg, about 5 to 50 mg, or about 20 to 40 mg per day.

10. 10. The method according to any one of claims 1 to 9, wherein the effective amount of piromelatine is about 50 mg per day.

11. The method according to any one of claims 1 to 10, wherein the formulation containing the effective amount of piromelatine is administered orally, parenterally, nasally, vaginally, rectally, sublingually or topically.

12. The method according to any one of claims 1 to 11, wherein the formulation containing an effective amount of piromelatine is administered in a self-microemulsifying drug delivery system (SMEDDS).

13. The method according to any one of claims 1 to 12, wherein the formulation containing the effective amount of piromelatine is administered in a single dose dosage form.

14. The method according to any one of claims 1 to 13, wherein the formulation containing the effective amount of piromelatine is administered once a day.

15. The method according to any one of claims 1 to 14, wherein the formulation containing the effective amount of piromelatine is administered about 10 minutes to about 60 minutes or about 30 minutes before bedtime.

16. The method according to any one of claims 1 to 15, wherein the formulation containing the effective amount of piromelatine is administered orally.

17. 17. The method of any one of claims 1 to 16, wherein the formulation containing the effective amount of piromelatine is administered as a combination therapy with a second therapeutic agent.

18. 18. The method of claim 17, wherein the combination therapy is administered simultaneously with the second therapeutic agent.

19. 18. The method of claim 17, wherein the combination therapy is administered as a co-formulation with the second therapeutic agent.

20. 18. The method of claim 17, wherein the formulation containing the effective amount of piromelatine and one or more additional therapeutic agents are administered separately.

21. 21. The method of any one of claims 17-20, wherein the combination therapy comprises an anti-inflammatory agent, an antioxidant, a hypnotic, an anxiety agent, an antipsychotic, an antianxiety agent, a mild sedative, a melatonin agonist, a melatonin antagonist, melatonin, a benzodiazepine, a barbiturate, a 5-HT2 antagonist, a dopamine agonist, or a combination thereof.

22. 21. The method of any one of claims 17 to 20, wherein the second therapeutic agent is selected from the group consisting of adinazolam, allobarbital, alonimide, alprazolam, amantadine, amitriptyline, amobarbital, amoxapine, apomorphine, bentazepam, benzoctamine, benzhexol, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbochloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, chloramphenicol ... Zepate, chloretate, clozapine, co-beneldopa, co-careldopa, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, entacapone, estazolam, eszopiclone, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxydiazepam imipramine, indiplon, levodopa, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, opicapone, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, pramipexole, prazepam, prochloridine, promethazine, propofol, protriptyline, quazepam, Ramelteon, rasagiline, levazepam, loretamide, ropinirole, rotigotine, safinamide, secobarbital, selegiline, sertraline, suproclon, temazepam, thioridazine, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, triexyphenidyl, trifluoperazine, trimetozine, trimipramine, urdazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, zopiclone, and salts thereof, or combinations thereof;method.,

23. The method according to any one of claims 1 to 22, wherein the formulation containing the effective amount of piromelatine is administered in combination with a physical therapy.

24. 24. The method of claim 23, wherein the physical treatment comprises light therapy, psychotherapy, or a combination thereof.

25. 25. The method of any one of claims 1 to 24, wherein the patient is a human.

26. 1. A method of treating a patient with RBD-related parasomnia, comprising administering to the patient a formulation comprising about 2 to about 100 mg, about 5 to about 50 mg, or about 20 to about 40 mg of piromelatine per day.

27. 27. The method of claim 26, wherein the patient has been diagnosed with RBD by video polysomnography (vPSG).

28. 28. The method of claim 27, wherein the vPSG assessment is quantified using the RBD Severity Scale (RBDSS).

29. 29. The method of claim 28, wherein the patient is diagnosed by the Clinical Global Improvement Scale (CGI-I) scale.

30. 30. The method of any one of claims 26 to 29, wherein the patient is diagnosed by dopamine transporter imaging DaTscan, a blood test, or a combination thereof.

31. 31. The method of claim 30, wherein the blood test comprises measuring tumor necrosis factor alpha (TNF-α) and / or C-reactive protein (CRP) levels in a serum sample from the patient.

32. 32. The method of any one of claims 26 to 31, wherein the patient is assessed with the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleep Scale (ESS), or a combination thereof.

33. 33. The method of any one of claims 26 to 32, wherein the formulation comprises one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients and / or carriers.

34. 34. The method of any one of claims 26 to 33, wherein the formulation is administered orally, parenterally, nasally, vaginally, rectally, sublingually or topically.

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