Methods and compositions for treating acute stress disorder

Abstract

The present disclosure relates to the treatment of disorders associated with noradrenergic hyperarousal in human subjects. The present disclosure also provides a method for treating acute stress disorder (ASD), comprising administering a therapeutically effective amount of latrepirdine or dexmedetomidine, or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating autism spectrum disorder in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or dexmedetomidine alone, or a combination thereof, to the subject. The present disclosure provides an oral mucosal dosage form comprising an effective amount of latrepirdine alone, or a combination thereof with dexmedetomidine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. Methods for using the same are also provided. The present disclosure also provides a method for treating depression by oromucosally administering a therapeutically effective amount of dexmedetomidine alone, or a combination thereof with latrepirdine.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 402,855, filed August 31, 2022, the contents of which are incorporated herein in their entirety to the same extent as if set forth herein. Incorporation by Reference

[0002] The contents of PCT / US2022 / 017963, filed February 25, 2022, and PCT / US2019 / 039268, filed June 26, 2019, are incorporated herein in their entireties as if set forth herein.

[0003] The present disclosure also relates to the treatment of agitation in a subject in need thereof by administering an oromucosal dosage form comprising an effective amount of latrepirdine alone or in combination with an effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. The present disclosure also provides a method for the treatment of depression in a subject in need thereof, comprising oromucosal administration of a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine. [Background technology]

[0004] Noradrenergic hyperarousal is a subclinical state in which there is excessive noradrenergic signaling that causes hemodynamic and motility changes. Excessive noradrenergic signaling, which is norepinephrine-dependent, can further increase sympathetic tone and lead to other stress-related psychiatric symptoms.

[0005] Acute stress disorder (ASD) is a mental health condition resulting from the experience of a traumatic event. According to DSM IV (class of disorders: anxiety disorders) and DSM V (class of disorders: trauma- and stressor-related disorders), symptoms of ASD can include a) increased anxiety, b) sleep disturbances, c) exaggerated startle response, d) lack of motivation, e) irritability, and f) inability to stop moving or sit still. ASD symptoms typically begin at least three days and within four weeks after the traumatic event. ASD can also be a precursor to the development of posttraumatic stress disorder (PTSD). For example, ASD symptoms, such as anxiety, irritability, and inability to stop moving, are related to stress-mediated sympathetic hyperarousal and therefore should be treatable with pharmacological agents suitable for treating agitation. Similarly, another symptom of ASD is lack of motivation or helplessness.

[0006] Therefore, to effectively treat ASD, it is necessary to develop pharmacological treatments that are effective against both depression and agitation. Many existing pharmacological treatments (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors) are available and have shown uncertain efficacy rates, but these treatments require multiple administrations or are accompanied by adverse effects such as memory impairment due to traumatic events. Therefore, there is a great need to develop strategies that provide adequate solutions for patients with ASD.

[0007] Autism spectrum disorders are neurological and developmental disorders that affect how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is referred to as a "developmental disorder" because symptoms typically appear during the first two years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide developed by the American Psychiatric Association and used by healthcare providers to diagnose mental disorders, people with autism often have the following: difficulty communicating and interacting with others, restricted interests and repetitive behaviors, and symptoms that affect their ability to function at school, work, and other areas of life. Autism is known as a "spectrum disorder" because there is wide variation in the type and severity of symptoms people experience. Currently, there are few treatment options for children and adults with autism, so more effective therapies are needed to treat people with autism.

[0008] The pathology of ASD is not fully understood but may be related to genetic disorders that cause changes in neural circuitry in newborns. Children with ASD have difficulty establishing and maintaining social relationships. As a result, they often suffer from panic disorder and exhibit aggressive behavior. Children with ASD often experience hyperarousal or heightened noradrenergic signaling, which may contribute to panic and aggressive behavior (Patriquin MA, Hartwig EM, Friedman BH, Porges SW, Scarpa A. Autonomic response in autism spectrum disorder: Relationship to social and cognitive functioning. Biol Psychol. 2019 Jul;145:185-197).

[0009] Agitation is a complex biological phenomenon that represents a loss of behavioral control. No single drug is effective against all types of agitation. Many neural pathways and associated receptors mediate aspects of agitation. These neural pathways include the amygdala, frontal cortex, nucleus accumbens, and locus coeruleus. Drugs and related drug targets acting on these brain regions to treat agitation include antipsychotics and dopamine D2 receptors, benzodiazepines and GABA receptors, ketamine and glutamate receptors, and serotonin uptake inhibitors (Miller CW, Hodzic V, Weintraub E. Current Understanding of the Neurobiology of Agitation. Western Journal of Emergency Medicine. 2020 Jul;21(4):841). Depression is a mood disorder that causes persistent sadness and loss of interest due to a complex interplay of social, psychological, and biological factors. During a depressive episode, patients experience depressed mood (e.g., sadness, irritability, or emptiness) or loss of pleasure or interest in activities almost every day for at least two weeks.Depressive episodes can be classified as mild, moderate, or severe depending on the number and severity of symptoms and their impact on individual functioning.Increasingly, extensive scientific and medical efforts are being made to develop drugs that target specific pathways and therefore treat specific aspects of depression. Summary of the Invention

[0010] Trauma induces changes in brain neurochemistry that can lead to ASD, which can ultimately become PTSD. Fear memory consolidation occurs 12 to 24 hours after experiencing a traumatic event. During this time, new connections are made between neurons in the brain, which associates the traumatic memory with an emotional response.

[0011] Without being bound by theory, it is believed that the composition may be more effective if administered soon after a traumatic event, ideally as soon as practicable, rather than later. For example, the composition may be administered within about 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 1 day, or 2 days. In embodiments, the composition is administered within about 1 hour to 1 day after the trauma. Long-term treatment is usually not required. Typically, administration may be once or more times daily for a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, or up to 6 weeks.

[0012] The present disclosure provides an oromucosal dosage form comprising an effective amount of latrepirdine alone or in combination with dexmedetomidine, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In an embodiment, the present disclosure provides a method for treating a stress-mediated neuropsychiatric disorder, such as ASD, mediated by noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine, an alpha2-adrenergic receptor agonist, wherein the therapeutic intervention has a therapeutic effect on the stress-mediated neuropsychiatric disorder, such as ASD, mediated by noradrenergic hyperarousal.

[0013] The present disclosure provides a method for treating a disorder associated with noradrenergic-mediated hyperarousal in a human subject, comprising administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating a disorder associated with noradrenergic-mediated hyperarousal in a human subject, comprising orally administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating a disorder associated with noradrenergic-mediated hyperarousal in a human subject, comprising oromucosally administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0014] The present disclosure provides a method for treating acute stress disorder (ASD) in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating ASD in a subject in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0015] The present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also relates to a method for treating autism spectrum disorder in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure further relates to a method for treating autism spectrum disorder in a subject in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0016] In an embodiment, the disorder is acute stress disorder.

[0017] In embodiments, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, exaggerated startle response, irritability, inability to stop moving or sit still, lack of motivation, and agitation.

[0018] In an embodiment, the symptom is anxiety.

[0019] In an embodiment, the symptom is a sleep disorder.

[0020] In an embodiment, the symptom is an exaggerated startle response.

[0021] In an embodiment, the symptom is irritability.

[0022] In an embodiment, the symptom is an inability to stop moving or sit still.

[0023] In an embodiment, the symptom is lack of motivation. In an embodiment, the symptom is agitation.

[0024] In an embodiment, the disorder in a human subject is an autism spectrum disorder.

[0025] In an embodiment, the method prevents the disorder from developing into post-traumatic stress disorder, hi an embodiment, the disorder is caused by a traumatic event experienced by the human subject.

[0026] In embodiments, latrepirdine is administered within 1 week, 2 weeks, or 4 weeks after the traumatic event.

[0027] In embodiments, latrepirdine is administered within 3 days of the traumatic event. In embodiments, latrepirdine is administered within 1 day of the traumatic event. In embodiments, latrepirdine is administered within 4 hours of the traumatic event. In embodiments, latrepirdine is administered within 6 hours of the traumatic event. In embodiments, latrepirdine is administered within 12 hours of the traumatic event. In embodiments, latrepirdine is administered once daily, twice daily, or three times daily.

[0028] In embodiments, the present disclosure provides a method of treating a stress-mediated neuropsychiatric disorder mediated by noradrenergic hyperarousal in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0029] In embodiments, the present disclosure provides a method of treating a stress-mediated neuropsychiatric disorder mediated by noradrenergic hyperarousal in a human subject in need thereof, comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0030] In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 5 mg to about 300 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 200 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 100 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 80 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 15 mg to about 60 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 30 mg to about 45 mg per day.

[0031] In embodiments, the therapeutically effective amount of latrepirdine is evenly divided for administration either twice daily or three times daily.

[0032] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially, or intermittently in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0033] In embodiments, the present disclosure provides preclinical animal models established to link noradrenergic signaling to psychiatric conditions such as acute stress disorder, PTSD, depression, substance withdrawal, substance use dependence, agitation, panic disorder, and anxiety.

[0034] In embodiments, preclinical animal models include the resident intruder assay, the forced swim test, the yohimbine-induced anxiety model, and the CCK-induced panic model.

[0035] In embodiments, preclinical animal models have surprisingly and unexpectedly demonstrated that latrepirdine reduces the severity of symptoms in stress-related psychiatric conditions, including acute stress disorder, PTSD, depression, substance withdrawal, substance use dependence, agitation, panic disorder, and anxiety.

[0036] In embodiments, noradrenergic signaling is associated with ADHD in preclinical models.

[0037] In embodiments, the methods of the present disclosure reduce the severity of symptoms experienced by a patient and improve the patient's clinical outcome due to improved compliance with the underlying therapeutic treatment, including adherence to medication regimens and participation in treatment.

[0038] In embodiments, clinical outcomes may improve as patients with reduced symptoms interact more effectively in social settings, reducing aggressive and panicky symptoms that may result from a lack of social interaction, such as those seen in conditions such as autism spectrum disorder.

[0039] In embodiments, the present disclosure provides effective symptom management that prevents worsening of the condition, as may be the case when acute stress disorder evolves into PTSD.

[0040] In embodiments, the present disclosure provides that the deterioration over time of disorders such as acute stress disorder and autism spectrum disorder is treated and prevented by latrepirdine.

[0041] In embodiments, the present disclosure provides a method of treating noradrenergic-mediated hyperarousal in a subject, comprising administering to a subject: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); oromucosally administering to the subject a dosage form comprising:

[0042] In embodiments, oromucosal administration includes sublingual, buccal, or gingival administration.

[0043] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0044] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, the method comprising administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0045] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, the method comprising orally administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0046] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, the method comprising orally administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0047] In embodiments, the present disclosure provides a method for treating an ASD in a subject in need thereof, the method comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0048] In embodiments, the present disclosure provides a method for treating an ASD in a subject in need thereof, the method comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating an ASD in a subject in need thereof, the method comprising administering to the subject a dosage form comprising about 20 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0049] In embodiments, the present disclosure provides a method for treating worsening of ASD in a subject following a traumatic event, the method comprising administering to the subject about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof, for a period of about 2 to about 4 weeks.

[0050] In embodiments, the present disclosure provides a method for treating worsening of ASD in a subject following a traumatic event, the method comprising administering to the subject about 20 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof, for a period of about 2 to about 4 weeks.

[0051] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally as a tablet.

[0052] In embodiments, the present disclosure provides a method for increasing resilience to the development of PTSD in a subject following a traumatic event, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0053] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0054] In one embodiment, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In one embodiment, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In one embodiment, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In one embodiment, the target plasma concentration of latrepirdine is about 1 to 5 ng / ml.

[0055] In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered immediately after the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values ​​in between) after the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, the traumatic event is directly and personally experienced by the subject. In embodiments, the traumatic event is witnessed by the subject. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered in single or multiple units.

[0056] In embodiments, the present disclosure provides a method for treating an ASD in a subject in need thereof, the method comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof within 24 hours of a traumatic event, and continuing for a period of about 2 to about 4 weeks after the traumatic event.

[0057] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof within 24 hours of a traumatic event, up to 4 weeks after the traumatic event.

[0058] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, the method comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0059] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered as a tablet, capsule, solution, suspension, or the like.

[0060] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered bucally. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or bucally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

[0061] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally (sublingually or bucally or gingivally) as a wafer, patch or film.

[0062] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0063] In embodiments, the present disclosure provides a method of treating an ASD in a subject in need thereof, comprising oral mucosal (e.g., sublingual, buccal, or gingival) administration of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0064] In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately after the traumatic event. In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values ​​in between) after the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the event. In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in single or multiple units.

[0065] In embodiments, about 10 micrograms to about 300 micrograms (including all ranges and values ​​therebetween) of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms, or more. In embodiments, about 60 micrograms to about 80 micrograms (including all ranges and values ​​therebetween) of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, the target plasma concentration of dexmedetomidine is about 50 to 200 pg / ml.

[0066] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0067] In embodiments, the present disclosure provides a method of treating an ASD in a subject in need thereof, comprising orally administering to the subject a dosage form comprising about 20 micrograms to about 180 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof, within 24 hours of a traumatic event, up to four weeks after the traumatic event.

[0068] In embodiments, the present disclosure provides a method of treating an ASD in a subject in need thereof, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a dosage form comprising about 20 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of a traumatic event, up to four weeks after the traumatic event.

[0069] In embodiments, the present disclosure provides a method of treating an ASD in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or gingival) a dosage form comprising about 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of a traumatic event, up to four weeks after the traumatic event.

[0070] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, the method comprising orally administering to the subject a dosage form comprising 20 micrograms to about 180 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a dosage form comprising 20 micrograms to about 180 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0072] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a dosage form comprising 60 micrograms to about 80 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0073] In embodiments, the present disclosure provides a method of increasing resilience to the development of PTSD in a subject following a traumatic event, the method comprising orally administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0074] In embodiments, the present disclosure provides a method of increasing resilience to the development of PTSD in a subject following a traumatic event, the method comprising oromucosal (e.g., sublingual, buccal, or gingival) administration of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0075] In an embodiment, the subject has been experiencing aggressive, reckless, or self-destructive behavior, sleep disturbances, hypervigilance, or related problems for more than one month.

[0076] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered bucally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried). In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, or gingivally as a wafer, patch, or film.

[0077] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, the method comprising administering to the subject therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, in an embodiment. In embodiments, the present disclosure provides a therapeutically effective amount of about 20 mg to 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0078] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, the method comprising administering to the subject therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof.

[0079] In embodiments, the dosage form is administered immediately prior to an anticipated event that may lead to the onset of PTSD, hi embodiments, the dosage form is continued during and / or for a period of time after the PTSD-inducing event.

[0080] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0081] In embodiments, the present disclosure provides a method for treating an autism spectrum disorder in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0082] In embodiments, the disclosure provides a method of treating autism spectrum disorder in a subject, comprising administering to the subject a dosage form comprising about 10 mg to about 60 mg, e.g., about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg (including all ranges and values ​​intermediate).

[0083] In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject.

[0084] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0085] In embodiments, the present disclosure provides a method of treating autism spectrum disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0086] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally as a tablet. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

[0087] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally (sublingually or bucally or gingivally) as a wafer, patch or film.

[0088] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually / buccally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried). In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, or gingivally as a wafer, patch, or film.

[0089] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dosage forms.

[0090] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dosage forms.

[0091] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0092] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0093] In an embodiment, dexmedetomidine and latrepirdine are provided as two separate dosage forms for treating autism spectrum disorder in a subject, one containing a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine or a pharmaceutically acceptable salt thereof are administered simultaneously to a subject in need thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine or a pharmaceutically acceptable salt thereof are administered sequentially to a subject in need thereof.

[0094] In embodiments, dexmedetomidine and latrepirdine are provided as a single dosage form for treating autism spectrum disorder, comprising therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0095] In embodiments, the combination comprising latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days, or longer.

[0096] In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children (CARS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - Standard Edition (CARS2-ST). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - High Functioning Edition (CARS2-HF). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Vineland II Adaptive Behavior Scales (VABS-II).

[0097] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0098] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0099] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0100] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0105] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0106] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0107] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale 2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0108] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0109] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0110] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0111] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale 2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0112] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0113] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0114] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0115] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0116] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0117] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0118] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0119] In embodiments, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0120] In embodiments, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0121] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0122] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0123] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0124] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0125] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0126] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0127] In embodiments, treatment results in a score reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the pre-treatment score, where the severity of autism spectrum symptoms is assessed based on the CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the score reduction is achieved after at least 4, 8, 12, 16, 24, or more weeks of treatment.

[0128] In embodiments, treatment inhibits the progression of or reduces the severity of one or more symptoms of autistic disorder. In embodiments, treatment inhibits the progression of or reduces the severity of one or more symptoms of Asperger's disorder. In embodiments, treatment inhibits the progression of or reduces the severity of one or more symptoms of childhood disintegrative disorder. In embodiments, treatment inhibits the progression of or reduces the severity of one or more symptoms of Rett's disorder. In embodiments, treatment inhibits the progression of or reduces the severity of one or more symptoms of pervasive developmental disorder not otherwise specified (PDD-NOS).

[0129] The present disclosure provides a method of treating agitation in a subject, the method comprising administering to the subject a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0130] The present disclosure also provides a method for treating agitation in a subject experiencing agitation, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. The present disclosure also provides a method for treating acute agitation in a subject experiencing agitation, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. The present disclosure also provides a method for treating acute agitation in a subject experiencing agitation, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. The present disclosure also provides a method for treating or preventing chronic agitation in a subject experiencing agitation, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. The present disclosure also provides a method for treating or preventing chronic agitation in a subject experiencing agitation, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject.

[0131] The present disclosure also provides a method for treating agitation in a subject experiencing agitation, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the agitated subject also exhibits aggression. In embodiments, the agitation is treated without inducing significant sedation. The present disclosure also provides a method for treating acute agitation in a subject experiencing agitation, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating chronic agitation in a subject, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0132] In embodiments, the present disclosure provides a method for treating agitation in an agitated subject, the method comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating agitation in an agitated subject, the method comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof via an oral mucosa (e.g., sublingually, buccally, or gingivally) of the subject. In embodiments, the present disclosure provides a method for treating agitation in an agitated subject, the method comprising orally administering to the subject a dosage form comprising about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof via an oral mucosa (e.g., sublingually, buccally, or gingivally) of the subject. In embodiments, the disclosure provides a method of treating agitation in a subject experiencing agitation, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a dosage form containing about 10 mg to about 60 mg, e.g., about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg (including all ranges and values ​​therebetween) of latrepirdine or a pharmaceutically acceptable salt thereof.

[0133] In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject.

[0134] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride); oromucosally administering to the subject a dosage form comprising:

[0135] In embodiments, the present disclosure provides a method for treating agitation in a subject experiencing agitation, the method comprising administering to the subject about 1 mg to about 500 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.In embodiments, the present disclosure provides a method for treating agitation in a subject experiencing agitation, the method comprising oromucosally administering to the subject about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating agitation in a subject experiencing agitation, the method comprising oromucosal administration to the subject of about 5 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.In embodiments, the present disclosure provides a method for treating agitation in a subject experiencing agitation, the method comprising oromucosal administration to the subject of about 5 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0136] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0137] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0138] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0139] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0140] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0141] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0142] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0143] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0144] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0145] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0146] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0147] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0148] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0149] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0150] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0151] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0152] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0153] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0154] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0155] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0156] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0157] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0158] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0159] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0160] In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oral dosage form that provides rapid relief of agitation, followed by continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation, followed by continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered bucally. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually or buccally as a tablet. In embodiments, the tablet is freeze-dried. In an embodiment, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually, buccally, or gingivally as an oblate. In an embodiment, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually, buccally, or gingivally as a patch. In an embodiment, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually, buccally, or gingivally as a film.

[0161] In embodiments, the present disclosure provides a method for treating agitation in a subject in need thereof, comprising administering to said subject a composition comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0162] In embodiments, the agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy, and other related neurodegenerative disorders. In embodiments, the agitation is associated with sundowning syndrome in Alzheimer's disease or dementia. In embodiments, the agitation is chronic and associated with dementia.

[0163] In embodiments, the agitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression. In embodiments, the agitation is associated with alcohol and substance abuse withdrawal, including opioid withdrawal. In embodiments, the agitation is associated with an OPD / IPD procedure (e.g., an MRI, CT, or CAT scan, a lumbar puncture, a bone marrow aspiration / biopsy, a tooth extraction or other dental procedure).

[0164] In an embodiment, the agitation is caused by noradrenergic hyperarousal.

[0165] In embodiments, agitation is treated without inducing significant sedation.

[0166] In embodiments, the agitation is the result of administration of an alpha-2 adrenergic receptor antagonist, such as yohimbine. In embodiments, the agitation is caused by administration of cocaine. In embodiments, the agitation is caused by administration of lurasidone. In embodiments, the agitation is caused by administration of mirtazapine. In embodiments, the agitation is caused by administration of esmirtazapine. In embodiments, the agitation is caused by administration of atipamezole. In embodiments, the agitation is caused by administration of trazodone. In embodiments, the present disclosure provides a method of treating agitation in a subject in need thereof, the method comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by administration of yohimbine.

[0167] In embodiments, the agitation may be acute or chronic. In embodiments, the agitation may be severe or mild. In embodiments, the agitation may be acute or chronic. In embodiments, the agitation may be severe or mild.

[0168] In embodiments, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0169] The present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0170] The present disclosure provides a method for treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.The present disclosure provides a method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0171] In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, improvement in depressive symptoms is observed as measured by the HAM-D-17 depression subscale. In an embodiment, the subject's HAM-D-17 total score at the start of treatment is ≧18.

[0172] In embodiments, the present disclosure provides a method for reducing the score on the HDRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for reducing the score on the HDRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0173] In embodiments, the present disclosure provides a method for reducing a score on the HDRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0174] In embodiments, the present disclosure provides a method for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of a combination of dexmedetomidine and latrepirdine or a pharmaceutically acceptable salt thereof.

[0175] In embodiments, the depression is moderate or severe. In embodiments, the depression is major depression, bipolar disorder, or mixed depression.

[0176] In an embodiment, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once, twice, three or four, five or six times daily, preferably once, twice or three times daily.

[0177] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0178] In embodiments, the present disclosure provides a method for the treatment of depression in a subject in need thereof, comprising administering to said subject: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0179] In embodiments, the present disclosure provides a method of treating a psychosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0180] In embodiments, the present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0181] In embodiments, the present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0182] In embodiments, treatment is effective without causing significant sedation.

[0183] In embodiments, treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of psychosis in a subject is assessed using the PANSS scale.

[0184] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0185] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising oromucosal administration to the subject of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0186] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0187] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0188] In embodiments, the reduction in PANSS score is at least about 20% to about 50% from the baseline score. In embodiments, the reduction in PANSS score is about 25% from the baseline score. In embodiments, the reduction in PANSS total score is about 30% from the baseline score. In embodiments, the reduction in PANSS total score is about 35 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 40 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 45 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 50 percentage points from the baseline score.

[0189] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the subject is experiencing agitation. In embodiments, the subject is not experiencing agitation.

[0190] In embodiments, the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia, and bipolar disorder, or another related neuropsychiatric disorder, hi embodiments, the psychosis is associated with a neurodegenerative disorder.

[0191] In embodiments, the psychosis is associated with a pathological condition such as a substance abuse disorder (eg, alcohol, opioid and other substance withdrawal).

[0192] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is single-episode. In embodiments, the psychosis is recurrent or comprises recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes.

[0193] In embodiments, the dosage form disintegrates within about 1 second to about 10 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within more than 1 minute after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 2 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 5 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates in less than 60 seconds.

[0194] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable excipients or carriers; an oral dosage form comprising:

[0195] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form comprises the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0196] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable excipients or carriers; an oral dosage form comprising:

[0197] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form comprises the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0198] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) one or more mucoadhesives, and (iv) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form comprises the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0199] In embodiments, the buccal dosage form is a tablet, capsule, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension, or emulsion), spray, microsphere, or nanoparticle, which can be formulated according to standard methods in the art.

[0200] In an embodiment, the dosage form is an oromucosal tablet for sublingual or buccal or gingival administration. In an embodiment, the dosage form is lyophilized (or freeze-dried).

[0201] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate, (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose, (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol, and (vii) optionally other pharmaceutically acceptable excipients; and a freeze-dried sublingual, buccal, or gingival tablet comprising the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0202] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose, (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol, and (vii) optionally other pharmaceutically acceptable excipients; and a freeze-dried sublingual, buccal, or gingival tablet comprising the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0203] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum, (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose, (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol, and (vii) optionally other pharmaceutically acceptable excipients; and a freeze-dried sublingual, buccal, or gingival tablet comprising the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0204] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide; (iv) croscarmellose sodium or sodium starch glycolate; (v) sucralose, (vi) magnesium stearate and / or silicon dioxide; (vii) lactose or mannitol, and (viii) optionally other pharmaceutically acceptable excipients; and a freeze-dried sublingual, buccal, or gingival tablet comprising the compound, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0205] In an embodiment, dexmedetomidine and latrepirdine are provided in a single dosage form as an oromucosal tablet for treating agitation, comprising a therapeutically effective amount of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof. In an embodiment, the agitation is caused by noradrenergic hyperarousal. In an embodiment, the agitation is treated without inducing significant sedation.

[0206] In an embodiment, dexmedetomidine and latrepirdine are provided in a single dosage form as an oromucosal tablet for treating depression, comprising therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0207] In an embodiment, dexmedetomidine and latrepirdine are provided in two separate dosage forms as buccal tablets for treating agitation, one containing a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered simultaneously to a subject in need thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered sequentially to a subject in need thereof. In an embodiment, the agitation is caused by noradrenergic hyperarousal. In an embodiment, the agitation is treated without inducing significant sedation.

[0208] In an embodiment, dexmedetomidine and latrepirdine are provided in two separate dosage forms as buccal tablets for treating depression in a subject, one containing a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered simultaneously to a subject in need thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered sequentially to a subject in need thereof.

[0209] In an embodiment, the active agents dexmedetomidine and latrepirdine, or pharmaceutically acceptable salts thereof, are co-administered (e.g., in a single dosage form or two separate dosage forms) to a subject for a specific period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, etc.), followed by administration of latrepirdine alone to the subject for a specific period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, etc.). In an embodiment, dexmedetomidine or a salt thereof is administered at least 1 hour before latrepirdine administration to ensure symptom relief as soon as possible. In an embodiment, dexmedetomidine is administered at least 0.5 hours before latrepirdine administration so that symptoms are alleviated as soon as possible. In an embodiment, dexmedetomidine is administered at least 0.25 hours before latrepirdine administration so that symptoms are alleviated as soon as possible. In an embodiment, dexmedetomidine is administered simultaneously with latrepirdine so that symptoms are alleviated as soon as possible.

[0210] In embodiments, the active agents dexmedetomidine and latrepirdine, or pharmaceutically acceptable salts thereof, are administered for a specified period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 month, 2 months, 3 months, etc.), followed by a drug-free period (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, etc.), and then administered intermittently (e.g., in a single dosage form or two separate dosage forms) to a subject for an administration period (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 month, 2 months, 3 months, etc.).

[0211] In embodiments, the active agent is lysed for about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes (1 hour), about 2 hours, about 3 hours, about 4 hours, about 5 hours The active agents may be administered sequentially, separated by a suitable time, such as about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours, including all ranges and values ​​therebetween. In embodiments, the active agents are co-administered simultaneously or within a short time, typically less than about 60 minutes (i.e., about 1 hour), preferably about 45 minutes, and more preferably about 15 minutes. In embodiments, the active agents are co-administered simultaneously or within a short time, typically less than about 60 minutes (i.e., about 1 hour), preferably about 45 minutes, and more preferably about 15 minutes.

[0212] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (iii) instructions for administering (i) and (ii) to a subject in need thereof; and a single unit oral tablet form provided as a kit comprising:

[0213] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (iii) instructions for administering (i) and (ii) to a subject in need thereof; The present invention provides a single unit oral mucosal freeze-dried tablet formulation provided as a kit comprising:

[0214] In embodiments, the present disclosure provides: (i) a first oral tablet form comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a second oral tablet form comprising a therapeutic amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for administering (i) and (ii) simultaneously, sequentially, or separately to a subject in need thereof; and a two-unit oral dosage form provided as a kit comprising:

[0215] In embodiments, the present disclosure provides: (i) a first buccal freeze-dried tablet form comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a second buccal lyophilized tablet form comprising a therapeutic amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for administering (i) and (ii) simultaneously, sequentially, or separately to a subject in need thereof; The present invention provides a two-unit dosage form provided as a kit comprising: [Brief explanation of the drawings]

[0216] [Figure 1] Figure 1 depicts an elevated plus maze apparatus. According to Example 2, the maze consists of two closed arms and two open arms forming a cross, with a square platform in the middle. [Figure 2] 1 shows the study design and administration time points of various drugs according to Example 2. [Figure 3] According to Example 2, the time (seconds) spent in the open arms of an elevated plus maze by Wistar rats administered latrepirdine dihydrochloride hydrate (3 mg / kg and 10 mg / kg) in comparison with dextromethorphan (10 mg / kg) and fluvoxamine maleate (10 mg / kg) is shown. [Figure 4]According to Example 2, the number of times rats entered the open arms of an elevated plus maze after administration of latrepirdine (3 mg / kg and 10 mg / kg) to Wistar rats administered yohimbine hydrochloride (2.5 mg / kg) is shown in comparison with dextromethorphan hydrobromide (10 mg / kg) and fluvoxamine maleate (10 mg / kg). [Figure 5] According to Example 3, the time (seconds) spent in the open arms of the elevated plus maze by Wistar rats treated with yohimbine hydrochloride (2.5 mg / kg) and then latrepirdine dihydrochloride hydrate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg and 3 mg / kg) is shown, along with those treated with latrepirdine dihydrochloride hydrate itself (3 mg / kg + saline). [Figure 6] According to Example 3, the number of times rats entered the open arms of the elevated plus maze after administration of latrepirdine dihydrochloride hydrate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg and 3 mg / kg) to Wistar rats administered yohimbine hydrochloride (2.5 mg / kg) is shown, along with those treated with latrepirdine dihydrochloride hydrate itself (3 mg / kg + saline). [Figure 7A] FIG. 1 shows the effects of administration of dexmedetomidine hydrochloride (1 μg / kg and 5 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg), and a combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (1 μg / kg + 1 mg / kg and 5 μg / kg + 1 mg / kg, respectively) on immobility (seconds) during a 5-minute dark-phase FST test in Sprague-Dawley (SD) rats according to Example 4. [Figure 7B] FIG. 1 shows the effects of administration of dexmedetomidine hydrochloride (1 μg / kg and 5 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg), and a combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (1 μg / kg+1 mg / kg and 5 μg / kg+1 mg / kg, respectively) on swimming behavior (seconds) during a 5-minute dark-phase FST test in Sprague-Dawley (SD) rats according to Example 4. [Figure 7C] FIG. 1 shows the effects of administration of dexmedetomidine hydrochloride (1 μg / kg and 5 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg), and a combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (1 μg / kg+1 mg / kg and 5 μg / kg+1 mg / kg, respectively) on climbing activity (seconds) during a 5-minute dark-phase FST test in Sprague-Dawley (SD) rats according to Example 4. [Figure 7D] FIG. 1 shows the effects of administration of dexmedetomidine hydrochloride (1 μg / kg and 5 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg), and a combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (1 μg / kg + 1 mg / kg and 5 μg / kg + 1 mg / kg, respectively) on total activity (seconds) during a 5-minute dark-phase FST test in Sprague-Dawley (SD) rats according to Example 4. [Figure 8A] According to Example 5, the effects of dexmedetomidine hydrochloride (4 μg / kg and 10 μg / kg) and latrepirdine dihydrochloride hydrate (0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg) on ​​the duration of aggression (seconds) in Swiss albino mice in the Resident Intruder Task are shown. [Figure 8B] According to Example 5, the effects of dexmedetomidine hydrochloride (4 μg / kg and 10 μg / kg) and latrepirdine dihydrochloride hydrate (0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg) on ​​the duration of aggression (seconds) in Swiss albino mice in the Resident Intruder Task are shown. [Figure 9A] According to Example 5, the effect of combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 0.3 mg / kg, 4 μg / kg + 1 mg / kg, 4 μg / kg + 3 mg / kg, 4 μg / kg + 10 mg / kg, and 10 μg / kg + 1 mg / kg, respectively) on the duration of aggression (seconds) in Swiss albino mice in the Resident Intruder Task is shown. [Figure 9B] According to Example 5, the effect of combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 0.3 mg / kg, 4 μg / kg + 1 mg / kg, 4 μg / kg + 3 mg / kg, 4 μg / kg + 10 mg / kg, and 10 μg / kg + 1 mg / kg, respectively) on the duration of aggression (seconds) in Swiss albino mice in the Resident Intruder Task is shown. [Figure 10] According to Example 5, the effects of dexmedetomidine hydrochloride (4 μg / kg and 10 μg / kg), latrepirdine dihydrochloride hydrate (0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg), and combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 0.3 mg / kg, 4 μg / kg + 1 mg / kg, 4 μg / kg + 3 mg / kg, 4 μg / kg + 10 mg / kg, and 10 μg / kg + 1 mg / kg, respectively) on the duration of aggression (seconds) in Swiss albino mice in the Resident Intruder Task are shown. [Figure 11] 1 shows the SMARTCUBE signatures of dexmedetomidine hydrochloride, latrepirdine, and the combination of dexmedetomidine hydrochloride and latrepirdine on antipsychotic behavior according to Example 6. [Figure 12] According to Example 7, the effects of dexmedetomidine hydrochloride (4 μg / kg, 10 μg / kg, 20 μg / kg and 30 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg, 3 mg / kg and 10 mg / kg) and the combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 10 mg / kg and 10 μg / kg + 1 mg / kg, respectively) on the distance traveled (centimeters) in Swiss albino mice in the open field test are shown. [Figure 13] 1 shows the number of entries into the open arms after administration of latrepirdine dihydrochloride hydrate (1, 3, 10 and 15 mg / kg) to CCK-4-treated rats according to Example 8. [Figure 14]1 shows the time spent in the open arms after administration of latrepirdine dihydrochloride hydrate (1, 3, 10 and 15 mg / kg) to CCK-4 treated rats according to Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0217] Yohimbine is an alpha-2 adrenergic antagonist and is useful for studying norepinephrine-mediated hyperarousal pathways. As described herein, yohimbine was used to induce sympathetic hyperarousal in rodents, and three different classes of drugs were tested to determine their ability to reduce hyperarousal. Surprisingly, only latrepirdine (Dimebon), a drug with complex pharmacological actions, was able to reduce hyperarousal. Latrepirdine is an orally active small molecule compound that acts through multiple mechanisms of action and functions through complex mechanisms.

[0218] Administration of an alpha2 adrenergic receptor agonist or a pharmaceutically acceptable salt thereof is a particularly effective and safe intervention for the treatment of agitation. Dexmedetomidine is an alpha2 adrenergic agonist that has been reported to have anti-agitation effects when administered intravenously during surgical procedures and intensive care unit (ICU) setup.

[0219] The inventors of the present application have discovered that administration of latrepirdine alone or in combination with dexmedetomidine provides significantly improved outcomes in anti-agitation responses, in addition to other benefits, over conventional treatments.

[0220] As described in Example 4 below, in a rodent forced swimming model, we found that administration of a combination containing latrepirdine and dexmedetomidine resulted in a significant increase in swimming behavior (correlated with an improvement in lack of motivation or helplessness behavior, which is a symptom of ASD as well as depression) compared to administration of dexmedetomidine and latrepirdine individually.

[0221] The inventors of the present application have discovered that administration of latrepirdine and / or dexmedetomidine, individually or in combination, has a beneficial role in reducing symptoms of stress-mediated sympathetic hyperarousal (e.g., anxiety, agitation, irritability, etc.), thus treating symptoms associated with ASD as well as preventing the potential onset of PTSD.

[0222] These symptoms are present in psychiatric disorders, including acute stress disorder, PTSD, depression, withdrawal, substance use dependence, agitation, panic, anxiety, ADHD, and panic disorder. The inventors of the present application have discovered that the active agent (i.e., latrepirdine and / or dexmedetomidine or a pharmaceutically acceptable salt thereof) reduces the severity of symptoms in norepinephrine-dependent, stress-induced psychiatric indications. Treating these symptoms can improve patients' clinical outcomes by (1) enabling them to better adhere to underlying therapeutic treatments, including taking prescribed medications and participating in treatment; (2) enabling them to interact socially better, thereby reducing the aggressive and panicky symptoms that result from a lack of social interaction, such as those experienced in autism spectrum disorder; and (3) enabling patients to better manage their symptoms and prevent the worsening of symptoms that occurs when acute stress disorder develops into PTSD. It has also been found that latrepirdine can not only treat the symptoms of disorders such as acute stress disorder or autism spectrum disorder, but can also prevent the disorders from worsening over time.

[0223] The inventors of the present application have also discovered that the administration of latrepirdine and / or dexmedetomidine, either individually or in combination, has a beneficial role in treating autism spectrum disorders. Abbreviation AD: Alzheimer's disease AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA: Analysis of variance ASD: Acute Stress Disorder CNS: central nervous system CT / CAT scan: Computed tomography scan EPM: Elevated plus maze FTD: Frontotemporal dementia GABA: gamma-aminobutyric acid 5-HT: 5-hydroxytryptamine HDRS or (HAM-D): Hamilton Depression Rating Scale ICU: intensive care unit IPD: Inpatient department IM: intramuscular IP: intraperitoneal LC: locus coeruleus MRI: Magnetic Resonance Imaging μg: microgram mg: milligram MADRS: Montgomery-Asberg Depression Rating Scale MW: molecular weight NE: norepinephrine NMDA: N-methyl-D-aspartate OPD:Outpatient Department PANSS: Positive and Negative Symptom Scale PTSD: Post-traumatic stress disorder wt%: weight percentage

[0224] definition It is to be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0225] Unless otherwise indicated, reference herein to compounds such as latrepirdine, dexmedetomidine, etc., by structure, name, or any other means includes pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, etc., tautomers, deuterium-modified compounds such as deuterium-modified latrepirdine or dexmedetomidine, or any chemical species to which the compounds described herein may be rapidly converted under the conditions in which the compounds described herein are used as described herein.

[0226] As used herein, "about" or "approximately," when used in connection with a numerical variable, generally refers to the value of that variable and all values ​​of that variable that fall within experimental error (e.g., a 95% confidence interval of the mean) or within ±10% of the indicated value, whichever is greater.

[0227] Throughout this specification, numerical ranges are provided for specific quantities. It is to be understood that these ranges include all subranges within that range. Thus, a range of "50 to 80" includes all possible ranges thereof (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, every value within a given range may be an endpoint of the range encompassed thereby (e.g., the range 50 to 80 includes ranges having endpoints of 55 to 80, 50 to 75, etc.).

[0228] The terms "a" or "an" refer to one or more of that entity. In addition, reference to "an agent" by the indefinite article "a" or "an" does not necessarily exclude the possibility that more than one agent may be present.

[0229] As used herein, the term "comprise" and its conjugations as used in the specification and claims are used in their open-ended sense, meaning that the items that follow the word are included, but items not specifically mentioned are not excluded. The disclosure may, as appropriate, "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0230] As used herein, the term "subject" preferably refers to a human patient. In embodiments, the subject can be any animal, including non-human mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates.

[0231] As used herein, the terms "dosage form," "pharmaceutical composition," "composition," "formulation," and "composition of the disclosure" are used interchangeably unless otherwise specified. Unless otherwise specified, the terms are meant to encompass, but are not limited to, dosage forms containing the active pharmaceutical ingredient, i.e., dexmedetomidine or latrepirdine, or both.

[0232] As used herein, the term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect. An effective amount is an amount sufficient to improve a clinically significant condition in a subject. An effective amount can be administered in one or more administrations, applications, or dosages.

[0233] As used herein, "pharmaceutically acceptable salts" refers to salts that are known to be non-toxic and are commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, etc. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxylalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. may also be used. A preferred salt is the hydrochloride (or dihydrochloride).

[0234] As used herein, the term "treatment" refers to alleviating or reducing at least one symptom of disease in a subject.For example, with respect to behavioral disorders, the term "treatment" can refer to alleviating or reducing agitation and any combination of its symptoms in the subject who is agitated (for example, pacing, shaking, gesturing, pointing, restlessness, performing repetitive habits, screaming, speaking excessively loudly, swearing, screaming, yelling, grabbing, pushing, poking, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting themselves, slamming doors, tearing objects, destroying property, etc.).Treatment can be measured as a reduction in level of at least 10% or more, preferably 20% or more, more preferably 40% or more, even more preferably 60% or more, even more preferably 80% or more, and 90% or more compared to control. For example, with respect to agitation, those skilled in the art will understand that treatment can be measured in terms of well-known agitation scales, such as the PEC score, CGI-I, and ACES (each of which is described in detail in WO / 2020 / 006119, which is incorporated by reference in its entirety for all purposes). By way of example, when a patient is treated for agitation, the patient may experience a reduction in the PEC total score (e.g., measured 2 hours after administration) of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more from baseline. Similarly, a treated patient may be measured on the CGI-I scale and may refer to a patient with a score of 1 or 2 (e.g., measured 1, 2, or 4 hours after administration), or may be measured on the Agitation-Calmness Evaluation Scale (ACES) scale and may refer to a patient with a score of 3, 4, 5, 6, or 7.

[0235] The term "prophylaxis" means preventing the onset of a disease, condition, or associated symptoms, or preventing their recurrence, for example, after a period of improvement.

[0236] The terms "oral mucosal delivery" or "oral mucosal administration" and the like refer to administration to the oral mucosa, including delivery across any tissue of the oral cavity, pharynx, larynx, trachea, or upper gastrointestinal tract, and particularly including delivery across sublingual, buccal, gingival, and palatal mucosal tissues.

[0237] The term "sublingual" means "under the tongue" and refers to a method of administering a substance via the oral cavity in such a manner that the substance is rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, allowing the substance direct access to the blood circulation, thereby providing direct systemic administration independent of digestive tract action and avoiding undesirable first-pass hepatic metabolism. Thus, by administering the dosage forms of the present disclosure sublingually, the total amount of latrepirdine and / or dexmedetomidine can be reduced, thereby reducing the potential for adverse side effects and providing cost benefits to manufacturers.

[0238] The term "buccal" refers to administration of a dosage form to the gums and inner lip or cheek. Oral mucosal absorption occurs through the highly vascularized mucosa, allowing substances direct access to the blood circulation, thereby providing direct systemic administration independent of gastrointestinal action and avoiding undesirable first-pass hepatic metabolism.

[0239] The term "disintegration" refers to the breakdown or loss of structural cohesion of the constituent particles that comprise a solid dosage form. This can occur in many different ways, including breaking down into smaller pieces, and ultimately into fine and large particles, or by eroding from the outside in until the dosage form disappears.

[0240] The terms "oral dosage form," "oral mucosal dosage form," and "oral transmucosal dosage form" may be used interchangeably herein and refer to dosage forms for use in practicing the present disclosure, including drug formulations as described herein. Oral dosage forms are typically sublingual or buccal dosage forms, although other oral transmucosal routes may be employed in some cases. The present disclosure relies on such oral dosage forms for sustained drug delivery across the oral mucosa, and by adjusting the formulation design, as described below, immediate, intermediate, and sustained release of the drug can be achieved. The dosage form includes an active ingredient (dexmedetomidine and / or latrepirdine) and one or more mucoadhesives that adhere to the patient's oral mucosa, as well as other carriers and excipients described in more detail herein.

[0241] The term "orally disintegrating tablet" (ODT) refers to an oral dosage form consisting of a tablet designed to disintegrate in the oral cavity without the need for chewing or swallowing with liquid. Orally disintegrating tablets may have the characteristics set forth by the US Food and Drug Administration in Guidance for Industry: Orally Disintegrating Tablets (Dept. of Health and Human Services, USFDA Center for Drug Evaluation and Research, December 2008). The disintegration rate of the solid pharmaceutical composition of the present disclosure can be measured by various in vitro test methods, for example, USP <701> Disintegration can be measured using a disintegration test method. As explained in the aforementioned section of the United States Pharmacopoeia, the USP disintegration test method is performed by placing the dosage form to be tested in a basket rack assembly, immersing the assembly in a specified fluid at a temperature between 35°C and 39°C for a given time, and raising and lowering the basket in the immersion fluid a distance of about 5.5 cm at a frequency of about 30 cycles per minute. The dosage form is visually inspected at the specified time for complete disintegration, as defined in Section 701 of USP 24-NF 19 as a state in which any residue of dosage form remaining on the basket rack of the testing apparatus is "a soft mass with no palpable hard core." Thus, it can be seen that the dosage form is optimal for disintegration in the oral cavity without the need for additional water intake. Adsorption can be through the oral mucosa.

[0242] As used herein, the term "film" includes thin membranes, sheets, and flakes of any shape, including rectangular, square, or other desired shapes. The film can be of any desired thickness and size so that it can be conveniently placed under the patient's tongue. For example, the film can be a relatively thin film having a thickness of about 20 micrometers to about 200 micrometers, or a somewhat thicker film having a thickness of about 20 micrometers to about 1000 micrometers. In embodiments, the film can be even thicker, for example, having a thickness of greater than about 30 millimeters.

[0243] The term "mucoadhesion" is used herein to refer to adhesion to a mucosa, such as the mucosa in the oral cavity. Mucoadhesion can be measured by "mucoadhesion strength" or "mucoadhesion peak force." The term "mucoadhesive" refers to a substance that adheres to a mucosal tissue surface in vivo. Such adhesion is such that a dosage form adheres and localizes on the mucosa, requiring the application of force to separate the mucoadhesive substance from the mucosa.

[0244] As used herein, "treatment" can mean treatment and / or prophylaxis, depending on the context.

[0245] The term "hyperarousal" as used herein refers to a subclinical state in which there is excessive noradrenergic signaling that causes hemodynamic and motility changes. Stress-related psychiatric symptoms can result from increased sympathetic tone (excessive noradrenergic signaling).

[0246] The term "acute stress disorder" or "ASD" refers to a mental health condition that results from experiencing a traumatic event. Symptoms of ASD typically begin no sooner than three days and no later than four weeks after the traumatic event.

[0247] The term "trauma" or "traumatic events" that can lead to ASD include, but are not limited to, spontaneous abortion, military combat, violent personal attack (sexual assault, physical assault, robbery, snatching), kidnapping, hostage taking, terrorist attack, torture, incarceration as a prisoner of war or incarceration in a concentration camp, natural or man-made disaster, automobile accident (including, but not limited to, a serious automobile accident), or being diagnosed with a life-threatening illness. For children, sexual traumatic events can include developmentally inappropriate sexual experiences that do not involve threatened or actual violence or harm. Witnessing events include, but are not limited to, witnessing the severe injury or unnatural death of another person resulting from a violent assault, accident, war, or disaster, or the unexpected sighting of a dead body or body parts. Learning about events experienced by others includes, but is not limited to, learning about a violent personal attack, serious accident, or severe injury experienced by a family member or close friend, learning about the sudden and unexpected death of a family member or close friend, or learning that one's child has a life-threatening illness.

[0248] The term "posttraumatic stress disorder" is also referred to as PTSD. According to the DSM-5, behavioral symptoms associated with PTSD include four distinct diagnostic clusters. These are described as reexperiencing, avoidance, negative cognitions and mood, and arousal. Reexperiencing includes spontaneous recollections of the traumatic event and associated recurrent dreams, flashbacks, or other intense or persistent mental distress. Avoidance refers to the exogenous recall of distressing memories, thoughts, emotions, or events. Negative cognitions and moods represent a myriad of emotions, ranging from persistent and distorted feelings of self-blame or blame to feelings of discord with others, markedly reduced interest in activities, and an inability to remember important aspects of the event. The arousal aspect of PTSD is characterized by aggressive, reckless, or self-destructive behavior, sleep disturbances, hypervigilance, or related problems. According to the DSM-5, PTSD is characterized by a disturbance(s) lasting for more than one month (excluding the distinction between acute and chronic phases of PTSD). With regard to PTSD-related arousal and reactivity, there must be significant changes in two (or more) of the following aspects: a) agitated behavior and angry outbursts (with little or no provocation), usually expressed as verbal or physical aggression toward people or objects; b) reckless or self-destructive behavior; c) hypervigilance; d) exaggerated startle response; e) problems concentrating; f) sleep disturbances (e.g., difficulty falling asleep or waking up or difficulty staying asleep).

[0249] The term "autism spectrum disorder" is used interchangeably with "autism" and refers to a complex developmental condition involving persistent social-communicative challenges, restricted interests, and repetitive behaviors. As used herein, the term "spectrum" refers to a wide range of symptoms and severity. Symptoms may include behavioral symptoms including: (i) persistence in sameness or resistance to change, (ii) difficulty expressing needs, (iii) repeating words or phrases instead of usual responsive language, (iv) laughing, crying, or showing signs of distress for reasons not apparent to others, (v) preference for solitude or distance, (vi) epilepsy, (vii) difficulty interacting with others, (viii) possible unwillingness to cuddle or be cuddled, (ix) little or no eye contact, (x) failure to respond to usual teaching methods, (xi) persistent bizarre movements, (xii) apparent hypersensitivity or hyposensitivity to pain, (xiii) little or no realistic fear of danger, (xiv) marked physical hyperactivity or hypoactivity, (xv) gross motor / fine motor skill imbalance, and / or (xvi) unresponsiveness to verbal cues. In some embodiments, the behavioral symptoms are selected from the group consisting of obsessive-compulsive behaviors, ritualistic behaviors, restricted behaviors, stereotypies, identity preoccupation, or self-injury. Autism spectrum disorders include autistic disorder (classic autism), Asperger's syndrome, childhood disintegrative disorder (CDD), Rett's syndrome, and pervasive developmental disorder not otherwise specified (commonly referred to as PDD-NOS). These disorders begin in early childhood and ultimately cause problems with social functioning (e.g., socially, at school, and at work). The term "Asperger's syndrome" refers to autism spectrum disorders that are milder than autism but share some of the symptoms of autism, such as language and communication problems and repetitive or restricted thought and behavior patterns. Obsessive-compulsive attention in a single subject is one of the primary symptoms of Asperger's syndrome. The term "pervasive developmental disorder" refers to a group of disorders characterized by delayed development of socialization and communication skills.Symptoms may include problems with using and understanding language, difficulties with people or objects, difficulties with changes in everyday or familiar environments, and repetitive body movements or patterns of behavior. As used herein, the term "Rett's Disorder" refers to a neurodevelopmental disorder classified as an autism spectrum disorder by DSM-IV. Rett's Disorder mostly affects girls, and its clinical features include slowed head growth (including microcephaly in some cases) and small hands and feet. Behavioral symptoms include stereotyped and repetitive hand movements, such as putting hands in the mouth or hand wringing.

[0250] As used herein, the term "agitation" refers to a disorder characterized by symptoms of irritability, emotional outbursts, disordered thinking, or excessive motor and verbal behavior, which may result from either dysfunction of specific brain regions, such as the frontal lobe, or dysfunction of neurotransmitter systems, such as the noradrenergic system. In embodiments, agitation may be caused by noradrenergic hyperarousal. In the present disclosure, a subject exhibiting agitation may also exhibit aggression. Agitation may be acute or chronic. Agitation may be severe.

[0251] The term "acute agitation" means agitation that occurs rapidly and is severe and sudden in onset. Acute agitation can be associated with, for example, neurodegenerative and neuropsychiatric disorders, but it can be particularly present in neuropsychiatric conditions. If acute agitation is left untreated, it can lead to chronic agitation.

[0252] The term "chronic agitation" refers to agitation that develops over a long period of time and is less severe than acute agitation. Chronic agitation can be associated with, for example, neurodegenerative and neuropsychiatric disorders, but it can be particularly present in neurodegenerative disorders.

[0253] Terms such as "without significant sedation" or "without inducing significant sedation" mean that the patient experiences a level of sedation equal to or less than Level 3 on the Ramsay Sedation Scale, meaning sedated but responsive to commands. In embodiments, dexmedetomidine may be dosed to achieve a Richmond Agitation Sedation Scale (RASS)-1 ("mild sedation").

[0254] The term "neurodegenerative disorder" includes, but is not limited to, Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia (e.g., dementia with Lewy bodies, vascular dementia), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0255] The term "neuropsychiatric disorders" includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, and delirium.

[0256] The term "sunset syndrome" generally refers to a circadian syndrome in which confusion, agitation, and / or restlessness increase later in the day in patients with some form of dementia. Some subjects with sunset syndrome may have more than one disease or disorder. For example, patients with sunset syndrome may have dementia, Alzheimer's disease, or both. Approximately 20-45% of Alzheimer's patients will experience some form of sunset confusion. Sunset syndrome also refers to confusion and / or agitation that worsens in the late afternoon, evening, or as the sun sets.

[0257] The term "behavioral and psychological symptoms" refers to agitation / aggression, delusions and / or hallucinations, abnormal motor behavior, abnormal vocalizations, anxiety, euphoria / elation, irritability, depression / dysphoria, lethargy, disinhibition, changes in sleep and nocturnal behavior, and changes in appetite and feeding.

[0258] The terms "freeze-drying" or "lyophilization" refer to a process used to create a stable preparation of a substance by freezing a liquid formulation containing the substance and subsequently removing the freezing liquid under vacuum. The term "lyophilization" refers to the conventional, art-recognized technique of freeze-drying a composition. "Lyophilized" and "freeze-dried" are used synonymously herein.

[0259] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inactive substance to be used as a carrier. As used herein, the words "carrier" and "excipient" are used interchangeably unless otherwise clearly intended to have a different meaning.

[0260] As used herein, the term "unit dosage form" refers to physically discrete units suited as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect, in association with the required pharmaceutical carrier.

[0261] It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0262] Within the meaning of the present disclosure, the terms "co-administration" or "simultaneous administration" are used to refer to the simultaneous administration of dexmedetomidine, or a pharmaceutically acceptable salt thereof, and latrepirdine, or a pharmaceutically acceptable salt thereof, either in separate formulations or as a combined formulation (i.e., in a single dosage form).

[0263] The term "sequential administration" refers to the administration of latrepirdine and dexmedetomidine in two or more separate dosage forms, administered sequentially (i.e., not simultaneously). When the disclosed drug substances are administered sequentially, administration of the last drug substance typically begins within one hour, and generally within 30 minutes, of administration of the first drug substance.

[0264] As used herein, "nanonization" refers to the process of reducing particles so that the average particle size is in a range such as less than 1000 nanometers in size, preferably less than 100 nanometers in size.

[0265] The term "spray drying" refers to a process involving breaking up a liquid mixture into small droplets (atomization) in a spray drying apparatus where there is a strong driving force to evaporate the solvent from the droplets, and rapidly removing the solvent from the mixture. The term spray drying is widely used in the past. The spray drying process and spray dryers are generally described in Perry, Robert H., and Don W. Green (eds.), Perry's Chemical Engineers' Handbook, New York: McGraw-Hill, 2007 (8 th It is described in the edition.

[0266] The term "sublimation" refers to a direct physical phase transition from a solid to a vapor state. More specifically, sublimation is the process by which a substance goes from a solid to a gas without passing through a liquid phase. Sublimation of a solution can sometimes be achieved by the freeze-drying process.

[0267] As used herein, the term "granulation" refers to the process of agglomerating powder particles into larger aggregates (i.e., granules) containing the active agent. The term "granulation" includes dry granulation and wet granulation techniques. The term "wet granulation" refers to any process that involves adding a liquid, preferably water, including water to a powder starting material, preferably kneading, and drying to obtain a solid dosage form. The term "dry granulation" refers to any process that involves compressing a powder, usually by slugging or using a roller compactor, and preferably milling the compressed powder to obtain granules. No liquid is used in dry granulation. The compacted granules or compacted granules as disclosed herein are preferably prepared by dry granulation.

[0268] "Direct compression" refers to a process that involves blending the ingredients and then compressing them into a tablet.

[0269] I. Activators The IUPAC name for dexmedetomidine is (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Dexmedetomidine as the monohydrochloride salt is primarily used as a medication to sedate patients during treatment in intensive care settings or before and / or during surgical and other procedures. Such medications are currently sold under the trademark name "PRECEDEX®."

[0270] Pharmaceutically acceptable salts of dexmedetomidine that can be used herein generally include any suitable salt that has been or can be approved for human administration by the U.S. FDA or other appropriate foreign or domestic agency. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrosulfic acid, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, etc. In embodiments, a deuterated form of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

[0271] Latrepirdine (also known as Dimebon) has the IUPAC name 2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole, and is understood herein to include any pharmaceutically acceptable form. By "pharmaceutically acceptable form," we mean any pharmaceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, cocrystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. It can exist in the form of a salt with a pharmaceutically acceptable acid and in the form of a quaternized derivative. Pharmaceutically acceptable base addition salts can be prepared from inorganic and / or organic bases.

[0272] Pharmaceutically acceptable acid addition salts of latrepirdine are prepared in a conventional manner by treating a free base solution or suspension with, for example, one or two chemical equivalents of a pharmaceutically acceptable acid.Exemplary suitable acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, mesylic acid, tosylic acid, benzoic acid, cinnamic acid, fumaric acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, dihydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and related acids.In an embodiment, latrepirdine is present as a free base.In an embodiment, latrepirdine is present as latrepirdine dihydrochloride.In an embodiment, latrepirdine is present as latrepirdine hydrochloride.In an embodiment, latrepirdine is present as latrepirdine dihydrochloride dihydrate. In an embodiment, latrepirdine is present as latrepirdine dihydrochloride hydrate.

[0273] II. Dosage In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof administered may conveniently range from about 0.5 micrograms to about 300 micrograms. Examples of suitable dosages include about 0.5 micrograms to about 280 micrograms, about 1 microgram to about 270 micrograms, about 1 microgram to about 260 micrograms, about 1 microgram to about 250 micrograms, about 1 microgram to about 240 micrograms, about 1 microgram to about 230 micrograms, about 1 microgram to about 220 micrograms, about 1 microgram to about 210 micrograms, about 1 microgram to about 200 micrograms, about 1 microgram to about 190 micrograms, about 1 microgram to about 180 micrograms, about 1 microgram to about 170 micrograms, about 1 microgram to about 160 micrograms, about 1 microgram to about 150 micrograms, about 1 microgram to about 140 micrograms, and about 1 microgram to about 280 micrograms. Examples of such doses include about 1 microgram to about 130 micrograms, about 1 microgram to about 120 micrograms, about 1 microgram to about 110 micrograms, about 1 microgram to about 100 micrograms, about 3 micrograms to about 90 micrograms, about 3 micrograms to about 80 micrograms, about 3 micrograms to about 70 micrograms, about 3 micrograms to about 60 micrograms, about 3 micrograms to about 50 micrograms, about 3 micrograms to about 40 micrograms, about 3 micrograms to about 35 micrograms, about 5 micrograms to about 35 micrograms, about 10 micrograms to about 50 micrograms, about 10 micrograms to about 40 micrograms, about 10 micrograms to about 35 micrograms, or about 15 micrograms to 35 micrograms. The dose may be administered once or more times per day, for example, two, three, four, five, or six times per day.

[0274] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 105 micrograms, about 110 micrograms, about 115 micrograms, about 120 micrograms, about 125 micrograms, about 130 micrograms, about 135 micrograms, about 140 micrograms, about 145 micrograms, about 150 micrograms, about 155 micrograms, or about 160 micrograms per unit dose. micrograms, about 160 micrograms, about 165 micrograms, about 170 micrograms, about 175 micrograms, about 180 micrograms, about 185 micrograms, about 190 micrograms, about 195 micrograms, about 200 micrograms, about 205 micrograms, about 210 micrograms, about 215 micrograms, about 220 micrograms, about 225 micrograms, about 230 micrograms, about 235 micrograms, about 240 micrograms, about 245 micrograms, about 250 micrograms, about 255 micrograms, about 260 micrograms, about 265 micrograms, about 270 micrograms, about 275 micrograms, about 280 micrograms, about 285 micrograms, about 290 micrograms, about 295 micrograms, or about 300 micrograms (including all values ​​and ranges therebetween).

[0275] Each unit can be administered to a subject one or more times daily, for example, 1, 2, 3, 4, 5, or 6 times daily. In embodiments, each unit can be administered with an appropriate dosing interval (e.g., about 1 hour between each administration) or can be administered simultaneously.

[0276] An effective total daily dose may include one or more unit doses, for example, up to about a 1 mg total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is from about 0.5 micrograms to about 500 micrograms, for example, the total daily dose may be about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, about 180 micrograms, about 190 micrograms, or about 200 micrograms. ram, about 210 micrograms, about 220 micrograms, about 230 micrograms, about 240 micrograms, about 250 micrograms, about 260 micrograms, about 270 micrograms, about 280 micrograms, about 290 micrograms, about 300 micrograms, about 310 micrograms, about 320 micrograms, about 330 micrograms, about 340 micrograms, about 350 micrograms, about 360 micrograms, about 370 micrograms, about 380 micrograms, about 390 micrograms, about 400 micrograms, about 410 micrograms, about 420 micrograms, about 430 micrograms, about 440 micrograms, about 450 micrograms, about 460 micrograms, about 470 micrograms, about 480 micrograms, about 490 micrograms or about 500 micrograms (including all ranges and values ​​in between).

[0277] In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently range from about 0.5 mg to about 500 mg. Examples of suitable dosages include about 0.5 mg to about 450 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 350 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 250 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 100 mg, about 1 mg to about 500 mg, about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, and about 1 mg to about 500 mg. Approximately 200mg, approximately 1mg to approximately 150mg, approximately 1mg to approximately 100mg, approximately 2mg to approximately 500mg, approximately 2mg to approximately 450mg, approximately 2mg to approximately 400mg, approximately 2mg to approximately 350mg, approximately 2mg to approximately 300mg, approximately 2mg ~250mg, 2mg~200mg, 2mg~150mg, 2mg~100mg, 3mg~500mg, 3mg~450mg, 3mg~400mg, 3mg~350mg, 3m g ~ about 300mg, about 3mg - about 250mg, about 3mg - about 200mg, about 3mg - about 150mg, about 3mg - about 100mg, about 4mg - about 500mg, about 4mg - about 450mg, about 4mg - about 400mg, about 4 mg ~ approx. 350 mg, approx. 4 mg ~ approx. 300 mg, approx. 4 mg ~ approx. 250 mg, approx. 4 mg ~ approx. 200 mg, approx. 4 mg ~ approx. 150 mg, approx. Examples of such a dose include 5 mg to about 400 mg, about 5 mg to about 350 mg, about 5 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, and about 5 mg to about 10 mg. In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 200 mg. In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 100 mg.In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 80 mg. In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 15 mg to about 60 mg. In an embodiment, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 15 mg to about 45 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 5 mg to about 60 mg, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, 9 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, or about 60 mg (including all values ​​and ranges in between).

[0278] In embodiments, latrepirdine is about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, about 0.5 mg or about 0.1 mg (including all ranges and values ​​in between) per unit dose.

[0279] In embodiments, the therapeutically effective amount of latrepirdine is evenly divided for administration either twice daily or three times daily.

[0280] Exemplary dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) and latrepirdine or a pharmaceutically acceptable salt thereof (e.g., the dihydrochloride salt) to be administered to a particular patient will depend on the type and severity of the condition, the overall health of the particular patient, the particular forms of dexmedetomidine and latrepirdine or their pharmaceutically acceptable salts being administered, and the particular formulation used to treat the patient.

[0281] III. Dosage form Oral dosage form:

[0282] In embodiments, the present disclosure provides an oral dosage form comprising an effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral dosage form comprising an effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. @@Remove@@

[0283] In embodiments, the oral dosage form comprising latrepirdine or dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a tablet, orally disintegrating tablet (ODT), effervescent tablet, capsule, pellet, pill, lozenge or troche, powder, dispersible granules, cachet, aqueous solution, syrup, emulsion, suspension, solution, soft gel, dispersion, or the like.

[0284] tablet In embodiments, the present disclosure provides an oral tablet form comprising an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral tablet form comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The dosage form of the present disclosure comprises conventional additives in the dosage form. Tableting aids commonly used in tablet formulations may be used, and reference is made to the extensive literature on this subject. See, in particular, Fiedler's "Lexikon der Hilfsstoffe", 4th Edition, ECV Aulendorf, 1996, which is incorporated herein by reference. These include, but are not limited to, diluents, binders, disintegrants, flow agents, lubricants, pH adjusters, and combinations thereof.

[0285] Diluents: The one or more diluents include, but are not limited to, dicalcium phosphate, pullulan, maltodextrin, isomalt, sugar pellets, mannitol, spray-dried mannitol, microcrystalline cellulose, dicalcium phosphate dihydrate, lactose, sugars, sorbitol, a mixture of microcrystalline cellulose and guar gum (Avicel CE-15), a mixture of mannitol, polyplasdone, and syloid (Pharmaburst), a mixture of mannitol, crospovidone, and polyvinyl acetate (Ludiflash), isomalt, Panexcea, F-Melt, sucrose, calcium salts and similar inorganic salts, ground magnesium carbonate, and the like, and mixtures thereof.

[0286] Binders: The one or more binders include, but are not limited to, low-substituted hydroxypropyl cellulose, xanthan gum, polyvinylpyrrolidone (povidone), gelatin, sugars, glucose, natural gums, gums, synthetic cellulose, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, and other cellulose derivatives, and the like, and mixtures thereof.

[0287] Disintegrants: The one or more binders include, but are not limited to, at least one of sodium starch glycolate, croscarmellose sodium, crospovidone, sodium alginate, gum, starch, and magnesium aluminum silicate, or mixtures thereof.

[0288] Lubricants: One or more lubricants include, but are not limited to, sodium stearyl fumarate, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, metallic stearates, hydrogenated castor oil, and the like, and mixtures thereof.

[0289] Glidants: The one or more glidants include, but are not limited to, stearic acid, colloidal silicon dioxide, talc, aluminum silicate, and the like, and mixtures thereof.

[0290] pH Adjusting Agents: The one or more pH adjusting agents include, but are not limited to, organic acids or salts thereof, such as phosphoric acid, citric acid, and the like.

[0291] Oral suspension:

[0292] In embodiments, the present disclosure provides an oral fluid suspension comprising an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral fluid suspension comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0293] The fluid pharmaceutical suspension of the present disclosure for oral administration contains at least one particulate drug as an active ingredient, which is latrepirdine or dexmedetomidine or a pharmaceutically acceptable salt thereof. The particulate drug (latrepirdine or dexmedetomidine) may be partially dissolved in the liquid phase, but preferably should be greater than about 50 percent particulate. The suspension of the present disclosure contains at least one suspension polymer exhibiting plastic flow, imparting a yield value of about 0.2 to about 15 Pa, preferably about 0.5 to about 10 Pa, with polymers exhibiting Bingham plastic flow and shear-thinning plastic flow being preferred. Polymers exhibiting thixotropic plastic flow can be used only if the time required to recover to 50% of the yield value is short (less than about 1 hour, preferably less than about 5 minutes, most preferably less than about 1 minute). The polymer exhibiting plastic flow may be selected from, but is not limited to, xanthan gum, carbomer, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and combinations thereof. The final yield value of the suspension should be less than about 15 Pa, preferably less than about 10 Pa, to ensure that the product can be poured without shaking.

[0294] In addition to the yield value, the rheology of the final suspension should have an apparent viscosity of at least about 50 cps, preferably at least about 100 cps, and most preferably at least about 200 cps at a shear rate of 100 sec-1 to retard particle migration when the shear rate exceeds the yield value, such as during shaking or pouring. In thixotropic plastic flow, high viscosity retards particle migration while the yield value is restored after shear is applied. The suspension polymer(s) added to impart the yield value should have an apparent viscosity of at least about 50 cps, preferably at least about 100 cps, and most preferably at least about 200 cps at a shear rate of 100 sec-1. -1 If the shear rate is not sufficient to achieve the desired apparent viscosity of at least about 50 cps at a shear rate of 100 rpm, a thickener without a yield value can be added. Such thickeners may be selected from, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, guar gum, locust bean gum, and combinations thereof.

[0295] The fluid suspensions of the present disclosure may contain additional ingredients (herein referred to as excipients) used in the pharmaceutical industry, including well-known components such as, but not limited to, sweeteners, flavoring agents, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH adjusters, acidifying agents, preservatives, cosolvents, and mixtures thereof.

[0296] Oral solution:

[0297] The present disclosure relates to a homogeneous and stable pharmaceutical solution of latrepirdine or a pharmaceutically acceptable salt thereof suitable for oral administration. The present disclosure also relates to a homogeneous and stable pharmaceutical solution of dexmedetomidine or a pharmaceutically acceptable salt thereof suitable for oral administration.

[0298] The oral fluid pharmaceutical solution of the present disclosure comprises one or more pharmaceutically acceptable excipients selected from the group comprising co-solvents, solvents, antioxidants, microbial preservatives, buffers, flavoring agents, sweeteners and diluents.

[0299] Co-solvents and solvents may include, but are not limited to, glycerin, alcohol, propylene glycol, polyethylene glycol, benzyl alcohol, water, ethanol, isopropyl alcohol, or mixtures thereof.

[0300] Suitable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycerol, cysteine, sodium thioglycolate, acetone sodium bisulfite, ascorbate (sodium / acid), sodium bisulfite, cysteine / cysteic acid HCl, sodium dithionite (sodium hydrosulfite, sodium sulfoxylate), gentisic acid, gentisic acid ethanolamine, monosodium glutamate, formaldehyde sodium sulfoxylate, potassium metabisulfite, sodium metabisulfite, monothioglycerol (thioglycerol), propyl gallate, sodium sulfite, alpha-tocopherol, sodium thioglycolate, calcium and sodium EDTA compounds, or mixtures thereof.

[0301] Buffering agents can include, but are not limited to, ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate anhydrous, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, calcium carbonate phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide, or mixtures thereof.

[0302] Diluents can include, but are not limited to, maltitol solution, glucose syrup, glycerin, sorbitol and mannitol solution, sucrose, sorbitol, xylitol, dextrose, fructose, potassium saccharin, aspartame, saccharin sodium, spray dried or anhydrous lactose, mannitol, starch, or mixtures thereof.

[0303] Sweetening agents may include, but are not limited to, sucralose, aspartame, acesulfame-K, thaumatin, mogrosides, saccharin and its salts, sodium cyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol, lactitol, xylitol, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoammonium glycyrrhizinate, isomalt, glycerin, dextrose, or mixtures thereof.

[0304] Fragrances may include, but are not limited to, fruit fragrances such as orange, banana, strawberry, cherry, wild cherry, lemon, and other fragrances such as cardamom, anise, mint, menthol, vanillin, or mixtures thereof.

[0305] Microbial preservatives may include, but are not limited to, sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acid and its alkyl esters, methyl and propyl paraben, or mixtures thereof.

[0306] Oral mucosal agent

[0307] In embodiments, the present disclosure provides an oral mucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers. In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers. In embodiments, the dosage forms described herein disintegrate within about 5 seconds to about 10 minutes after contact with the oral mucosa, e.g., about 5 seconds to about 10 minutes, about 5 seconds to about 5 minutes, about 5 seconds to about 1 minute, about 5 seconds to about 30 seconds, about 5 seconds to about 10 seconds, about 30 seconds to about 10 minutes, about 30 seconds to about 5 minutes, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes, about 1 minute to about 5 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 10 minutes, about 2 minutes to about 5 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 5 minutes, about 4 minutes to about 10 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 7 minutes, or about 7 minutes to about 10 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa, e.g., about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds (including all ranges and values ​​in between). In embodiments, the dosage form does not disintegrate within 1 minute after contact with the oral mucosa. In embodiments, the dosage form disintegrates in more than 1 minute after contact with the oral mucosa, e.g., about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. Thus, a dosage form produced according to one of the embodiments of the present disclosure may: <701> When tested by the Disintegration Test Method (see Guidance to Industry, incorporated herein by reference), it meets the disintegration time criteria of disintegrating within about 5 seconds to about 10 minutes.

[0308] In embodiments, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the drug in a dosage form comprising a formulation of the present disclosure is absorbed through the oral mucosa.

[0309] In embodiments, dosage forms of the present disclosure have sufficient mechanical strength to withstand abrasion / chips during packaging in blisters and bottles, storage and shipping for commercial distribution, and end use.

[0310] In embodiments, the dosage forms described herein effectively treat disorders associated with noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively reduce noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treat acute stress disorder (ASD). In embodiments, the dosage forms described herein effectively prevent post-traumatic stress disorder (PTSD). In embodiments, the dosage forms described herein effectively treat autism spectrum disorder.

[0311] In embodiments, the dosage forms described herein effectively treat agitation in a subject exhibiting agitation. For example, the dosage forms described herein effectively treat agitation in a subject as measured by PEC, CGI-I, and / or ACES. In embodiments, the dosage forms effectively treat agitation in a subject without inducing significant sedation. In embodiments, the subject is treated without experiencing clinically significant cardiovascular effects. In embodiments, the agitation is caused by noradrenergic hyperarousal.

[0312] In embodiments, the dosage forms described herein effectively treat depression in a subject. For example, the dosage forms described herein effectively treat depression in a subject as measured by the HAM-D scale or the MADRS scale. In embodiments, the present disclosure provides an oral mucosal dosage form for treating agitation, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt), one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers. In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds (including all ranges and values ​​therebetween). In embodiments, the dosage form disintegrates in more than about 1 minute after contact with the oral mucosa. In embodiments, the dosage form disintegrates in about 1 minute or more, for example, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes, after contact with the oral mucosa. In embodiments, the dosage form effectively treats agitation in a subject. In embodiments, the dosage form effectively treats agitation in a subject without inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treat depression in a subject.

[0313] In an embodiment, the present disclosure provides a dosage form for treating a disorder associated with noradrenergic hyperarousal, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially, or intermittently in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0314] In embodiments, the present disclosure provides an oral mucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for treating ASD in a subject. In embodiments, the present disclosure provides an oral mucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for preventing PTSD in a subject.

[0315] In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for treating autism spectrum disorder in a subject. In embodiments, the present disclosure provides an oral mucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for treating autism spectrum disorder in a subject.

[0316] In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for treating ASD in a subject. In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for preventing PTSD in a subject. In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharmaceutically acceptable excipients or carriers for treating agitation. In embodiments, the dosage form disintegrates in less than about 1 minute upon contact with the oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds after contact with the oral mucosa. In embodiments, the dosage form disintegrates in about 1 minute or more after contact with the oral mucosa. For example, the dosage form may disintegrate in about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In embodiments, the dosage form effectively treats agitation in a subject. In embodiments, the dosage form effectively treats agitation in a subject without inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treat depression in a subject.

[0317] In embodiments, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, and a second oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, for co-administration, either simultaneously or sequentially, to treat agitation.

[0318] In embodiments, the dosage form is administered for the treatment of agitation associated with neurodegenerative disorders, neuropsychiatric disorders, and substance abuse withdrawal, including alcohol or opioid withdrawal. In embodiments, the dosage form is administered for the treatment of agitation associated with an OPD / IPD procedure (e.g., MRI, CT, or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure).

[0319] In embodiments, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, and a second oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, for co-administration, either simultaneously or sequentially, to treat depression in a subject.

[0320] In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa. For example, the dosage form can disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds after contact with the oral mucosa. In embodiments, the dosage form disintegrates in about 1 minute or more after contact with the oral mucosa. For example, the dosage form can disintegrate in about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

[0321] In embodiments, the oral mucosal (e.g., sublingual or buccal) dosage form of the present disclosure is a tablet, capsule, disc, patch or film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (solution, suspension, or emulsion), spray, microsphere, or nanoparticle, which can be formulated according to standard methods in the art.

[0322] In an embodiment, the dosage form is an oral mucosal wafer. In an embodiment, the wafer is freeze-dried. In an embodiment, the wafer disintegrates in less than about 1 minute after contact with the oral mucosa. In an embodiment, the wafer disintegrates in more than about 1 minute after contact with the oral mucosa. In an embodiment, the wafer includes an excipient such as hydroxypropyl cellulose, lactose, mannitol, glycine, etc.

[0323] In an embodiment, the dosage form is an oral mucosal minitablet. In an embodiment, the minitablet disintegrates in less than about 1 minute after contact with the oral mucosa. In an embodiment, the minitablet disintegrates in more than about 1 minute after contact with the oral mucosa. In an embodiment, the minitablet comprises a mixed-extract mannitol-based excipient. In an embodiment, the minitablet contains a directly compressible excipient. In an embodiment, the compressible excipient is in hydrate form and may be selected from organic compounds such as dextrose monohydrate, maltodextrin, lactose monohydrate, and dextrin, and inorganic compounds including dibasic calcium phosphate dihydrate, dibasic sodium phosphate dihydrate, dibasic sodium phosphate heptahydrate, dibasic sodium phosphate dodecahydrate, monobasic sodium phosphate monohydrate, and monobasic sodium phosphate dihydrate. In an embodiment, the rapidly disintegrating tablet portion comprises a compressible excipient selected from the group consisting of isomalt, dextrose monohydrate, hydrogenated starch hydrolysates, maltodextrin, lactose monohydrate, dextrin, mannitol, lactitol, sorbitol, xylitol, erythritol, sucrose, and lactose.

[0324] In embodiments, the buccal dosage form is in the form of a tablet or round disc or a packed powder.

[0325] In an embodiment, the dosage form is a hard or compressed powder sublingual or buccal tablet with a low coarse content for an organoleptically pleasant mouthfeel. In an embodiment, the tablet (or its particles containing an active agent that can be compressed to form a tablet) includes a protective outer coating, such as any polymer conventionally used in the formation of microparticles and microcapsules. In an embodiment, the dosage form is a sublingual (or buccal) tablet containing an effervescent agent. Sublingual compositions containing effervescent agents are disclosed in U.S. Patent No. 6,200,604, the entire contents of which are incorporated herein by reference for all purposes.

[0326] In embodiments, the buccal tablet advantageously contains the active ingredient in a base. In embodiments, the base is, for example, composed of at least one filler and / or lubricant. Fillers include, for example, lactose or mannitol, and suitable lubricants include, but are not limited to, magnesium stearate, silicon dioxide, and talc. The base may also include one or more of a binder (e.g., povidone, sugar, or carboxymethylcellulose), a disintegrant (e.g., croscarmellose sodium, crospovidone, or sodium starch glycolate), a sweetener (e.g., sucralose), and the like. The tablet advantageously has a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

[0327] In embodiments, the oral mucosal dosage form is in the form of a patch or a film (e.g., a thin film).The patch may have adhesive properties to prevent the patch from moving or being swallowed.Suitable film compositions containing dexmedetomidine are disclosed in U.S. Patent No. 10,792,246, the entire contents of which are incorporated herein by reference for all purposes.

[0328] In embodiments, the buccal dosage form is in the form of a paste, gel, or ointment. The viscosity of the paste, gel, or ointment can be adjusted so that it can be held under the tongue or near the gums or cheek, or on the upper lip.

[0329] In embodiments, the oral mucosal dosage form is in liquid form (e.g., as a solution, suspension, or emulsion), and can be presented, for example, as a spray or drops. In certain embodiments of the present disclosure, latrepirdine and / or dexmedetomidine, or a pharmaceutically acceptable salt thereof, is administered orally in liquid form, for example, in a flavored or unflavored saline solution. The liquid dosage form can conveniently be administered sublingually or near the gums or cheeks or onto the upper lip as drops or a spray. A solution comprises the active ingredient together with a diluent, for example, water, saline, sodium chloride solution, or any other suitable solvent, for example, propylene glycol, glycerol, ethyl alcohol, etc. The diluent for the solution can be, in particular, saline solution or water.

[0330] Spray dosage forms of the present disclosure for oral mucosal administration may contain one or more pharmaceutically acceptable liquids (e.g., present in an amount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, cosolvents, or nonsolvents for dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, mint, etc.), and the like. The pharmaceutically acceptable liquid is selected to dissolve the active pharmaceutical ingredient or to form a stable, homogeneous suspension or solution thereof, or to form any combination of suspensions or solutions. In addition to these ingredients, the spray formulation may contain one or more excipients such as viscosity adjusting substances (e.g., polymers, sugars, sugar alcohols, gums, clays, silicas, etc., e.g., polyvinylpyrrolidone (PVP)), preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben), flavoring agents (e.g., peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g., saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (mannitol, xylitol, lactitol, maltitol syrup), buffers and pH adjusters (e.g., sodium hydroxide, citrate, and citric acid), colorants, fragrances, chelating agents (e.g., EDTA), UV absorbers, and antifoaming agents (e.g., low molecular weight alcohols, dimethicone). In addition to one or more of the aforementioned ingredients suitable for sublingual or buccal administration, the spray may contain one or more excipients such as viscosity adjusting substances (e.g., water-soluble or water-swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, etc.).

[0331] Aerosols can be prepared by mixing the aforementioned ingredients in appropriate amounts in accordance with standard manufacturing practices. Such excipients can be included in the formulation to improve patient or subject acceptance or taste, improve bioavailability, enhance shelf life, reduce manufacturing and packaging costs, comply with government regulatory agency requirements, and for other purposes. The relative amounts of each component should not interfere with the desired pharmacological and pharmacokinetic properties of the resulting formulation.

[0332] In one embodiment, a patient may be treated by sublingual or buccal administration with one to two actuations of the spray pump. The advantage of spray delivery is that it can be easily titrated to the patient in one or two doses per single actuation, as needed.

[0333] Pump-action sprays are characterized in that they require the application of external pressure, e.g., externally induced manual, mechanical, or electrical pressure, for actuation, in contrast to pressurized systems, e.g., propellant-driven aerosol sprays, where actuation is typically achieved by pressure-controlled release (e.g., by controlling the opening of a valve).

[0334] The non-solid dosage forms of the present disclosure may be conveniently administered by spraying, dropping, smearing or spraying the composition under the tongue or near the gums or cheek or onto the upper lip.

[0335] In an embodiment, the oral mucosal tablet form is prepared by lyophilization (or freeze-drying). A suspension containing the active agent(s) may be prepared with appropriate excipients, and the active agent (latrepirdine / dexmedetomidine) suspension may be dispensed into blister packs and freeze-dried. An exemplary freeze-drying preparation platform that can be used for latrepirdine and / or dexmedetomidine orally disintegrating tablets (ODTs) is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. Specifically, the excipients are blended, and the active agent is separately milled and granulated, then mixed with the excipients. The solution / suspension is then lyophilized by rapid freezing and freeze-drying. This aqueous solution / suspension must be chemically and morphologically stable throughout the administration process. Gelatin may be used to provide the dosage form with sufficient strength to prevent breakage upon removal from the package, but the gelatin will cause the dosage form to quickly disintegrate once placed in the mouth. Other alternatives such as fish gelatin and modified starch may also be used. During processing, the dosing solution / suspension is preferably frozen by passing it through a gaseous medium. This rapidly immobilizes the solution / suspension, thereby improving manufacturing efficiency.Examples of oromucosal dosage forms include those disclosed in U.S. Pat. No. 6,509,040, U.S. Pat. No. 7,972,621, U.S. Pat. No. 1,054,8839, U.S. Pat. No. 9,775,819, U.S. Pat. No. 5,188,825, U.S. Pat. No. 5,631,023, U.S. Pat. No. 6,297,240, U.S. Pat. No. 6,413,549, U.S. Pat. No. 5,976,577, U.S. Pat. No. 6,156,339, U.S. Pat. No. 5,827,541, U.S. Pat. No. 5,7 ...776,577, U.S. Pat. No. 5,776,577, U.S Nos. 29,958, 6,726,928, 9,192,580, 6,709,669, U.S. Patent Application Publication No. 20200138721, 20190276707, 20190314274, 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351, and U.S. Patent Application Publication No. 20090226522 and related patents / patent applications.

[0336] Other methods of preparing oromucosal dosage forms, such as ODTs, may be used without limitation, and detailed descriptions of such general methods are found in, for example, U.S. Pat. Nos. 5,837,287, 6,149,938, 6,212,791, 6,284,270, 6,316,029, 6,465,010, 6,471,992, 6,814,978, 6,908,626, 6,982,222, and 6,149,938, which are incorporated herein by reference in their entireties for all purposes. No. 51, U.S. Pat. No. 7,282,217, U.S. Pat. No. 7,425,341, U.S. Pat. No. 7,939,105, U.S. Pat. No. 7,993,674, U.S. Pat. No. 8,048,449, U.S. Pat. No. 8,127,516, U.S. Pat. No. 8,158,152, U.S. Pat. No. 8,221,480, U.S. Pat. No. 8,256,233, U.S. Pat. No. 8,313,768, U.S. Pat. No. 5,039,540, U.S. Pat. No. 5,120,549, U.S. Pat. No. 5,330,763, U.S. Pat. No. 4,760,093, U.S. Pat. No. 4,760,094, and U.S. Pat. No. 4,767,789.

[0337] Various technologies that may be used to prepare the oramucosal dosage forms of the present disclosure include, but are not limited to, Flash Dose, Orasolv, durasolv, wowtab technology, Flash Tab Technology, Oraquick Technology, Quick-Dis Technology, Nanocrystal Technology, Shearform Technology, Ceform Technology, Pharmaburst technology, Frosta technology, Ziplet technology, Humidity processing, Sintering, Lyoc Technology, Quicksolv Technology, Nanocrystal technology, Pharmafreeze, AdvaTab Technology, cotton candy technology, and the like.

[0338] In embodiments, oral mucosal dosage forms (e.g., sublingual or buccal or gingival tablets) of the present disclosure may be prepared by methods such as sublimation, nanonization, spray drying, granulation (including wet granulation, dry granulation), or direct compression. U.S. Patent Nos. 5,178,878, 6,269,615, and 6,221,392, which are incorporated herein by reference in their entireties for all purposes, disclose the production of friable, orally disintegrating tablets by direct compression and packaging into specially designed dome-shaped blister packages using a robotically controlled integrated tablet forming and packaging system.

[0339] In embodiments, the buccal tablet form used herein may be prepared by a direct compression method, which involves mixing the active agent (latrepirdine and / or dexmedetomidine) with one or more pharmaceutically acceptable excipients, lubricating the mixture, and tableting by direct compression.

[0340] In an embodiment, the following steps: (i) preparing a mixture containing an active agent (latrepirdine and / or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii) compressing the mixture obtained in step (i) to form granules; (iii) optionally blending the granules obtained in step (ii) with the remaining excipients; and (iv) subjecting the granules to compression to obtain tablets; A process for preparing an oral mucosal tablet form by dry granulation is provided, comprising:

[0341] In an embodiment, the compacting in step (ii) is carried out by roller compaction or slugging techniques.

[0342] In an embodiment, the following steps: (i) preparing a mixture containing an active agent (latrepirdine and / or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii) granulating the mixture obtained in step (i) with a suitable granulation fluid to form wet granules; (iii) drying the wet granules obtained in step (ii); (iv) optionally blending the dried granules obtained in step (iii) with one or more excipients; and (v) subjecting the granules obtained in step (iii) or the mixture obtained in step (iv) to compression to obtain tablets; A process for preparing an oral mucosal tablet form by wet granulation is provided, comprising:

[0343] In embodiments, the mixture of step (i) is granulated with any suitable solvent, including, but not limited to, water, an alcohol such as ethanol or isopropyl alcohol, or mixtures thereof.

[0344] The dosage forms of the present disclosure can be administered to mammals, including humans, as well as non-mammals (eg, rats, cats, and dogs) in need thereof.

[0345] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are formulated as a sublingual or buccal tablet.

[0346] In embodiments, the dosage form comprises a mucoadhesive agent for adhering the active agent(s) to the oral mucosa. The mucoadhesive has the property of swelling and expanding upon contact with water, thus allowing the tablet to disintegrate when wetted with saliva. In embodiments, the dosage form comprises one or more mucoadhesives in an amount of about 0.5% to about 30% w / w. For example, the one or more mucoadhesives may be from about 0.5% w / w to about 30% w / w, from about 0.5% w / w to about 25% w / w, from about 0.5% w / w to about 20% w / w, from about 0.5% w / w to about 10% w / w, from about 0.5% w / w to about 5% w / w, from about 1% w / w to about 30% w / w, from about 1% w / w to about 20% w / w, from about 1% w / w to about 10% w / w, from about 1% w / w to about 5% w / w, from about 1% w / w to about 3% w / w, from about 1% w / w to about 2% w / w, from about 3% w / w to about 30% w / w, from about 3% w / w to about 20% w / w In embodiments, the mucoadhesive is present in an amount ranging from about 1% w / w to about 5% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 15% w / w to about 30% w / w, about 15% w / w to about 20% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, or about 25% w / w to about 30% w / w. In embodiments, the mucoadhesive is about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about % w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, or about 30% w / w (including all ranges and values ​​therebetween).

[0347] In embodiments, the mucoadhesive dosage form has a viscosity of at least about 50 dynes / cm2 , for example, about 50 dynes / cm 2 , approximately 75 dynes / cm 2 , approximately 100 dynes / cm 2 , approximately 150 dynes / cm 2 , approximately 200 dynes / cm 2 , approximately 250 dynes / cm 2 , approximately 300 dynes / cm 2 , approximately 350 dynes / cm 2 , approximately 400 dynes / cm 2 , approximately 450 dynes / cm 2 , approximately 500 dynes / cm 2 , approximately 550 dynes / cm 2 , approximately 600 dynes / cm 2 , approximately 650 dynes / cm 2 , approximately 700 dynes / cm 2 , approximately 750 dynes / cm 2 , approximately 800 dynes / cm 2 , approximately 850 dynes / cm 2 , approximately 900 dynes / cm 2 , approximately 950 dynes / cm 2 , or approximately 1000 dynes / cm 2 (including all ranges and values ​​in between). In embodiments, the mucoadhesive dosage form has a mucoadhesive strength of about 1000 dynes / cm 2 In embodiments, the dosage form has a mucoadhesive peak force of greater than about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g, or about 1500 g. In embodiments, the dosage form has a mucoadhesive peak force of greater than about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g, or about 1500 g (including all ranges and values ​​in between).

[0348] In embodiments, suitable mucoadhesives for use in the present disclosure include, but are not limited to, polyacrylic acid polymers (e.g., carbomers (e.g., low viscosity), polycarbophil, etc.), methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (e.g., HPC - low viscosity grades with MW<150K Daltons), ethylhydroxyethyl cellulose, hydroxypropyl methylcellulose (e.g., HPMC-K100L or low viscosity grades such as 4000 cps), methylcellulose, carboxymethylcellulose, Examples of suitable cellulose acetate preparations include sodium cellulose, thiolated carboxymethylcellulose, polysaccharides (e.g., chitosan, pectin, etc.), xanthan gum, karaya gum, tragacanth gum, propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide (PEO), microcrystalline cellulose (Avicel), croscarmellose, poloxamer (i.e., a nonionic triblock copolymer consisting of a central polyoxypropylene hydrophobic chain flanked by two polyoxyethylene hydrophilic chains, e.g., Poloxamer 407), and mixtures thereof.

[0349] In embodiments, excipients or carriers for inclusion in the buccal dosage form are selected from the group consisting of disintegrants, fillers / diluents (base formers), binders, flow agents, lubricants, plasticizers, pH adjusters, colorants, flavoring agents, taste masking agents, viscosity enhancers, sweeteners, and combinations thereof. Preferably, the carrier is readily soluble in saliva.

[0350] In embodiments, examples of suitable disintegrants for use in the present disclosure include, but are not limited to, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch, native starch, carboxymethyl starch, sodium starch glycolate, pregelatinized starch, dextrin, and other modified starches (starch in which the hydroxyl groups are esterified, hydroxypropyl distarch phosphate, enzymatically modified starch, pregelatinized distarch phosphate, hydroxyethyl starch, hydroxypropyl starch, pregelatinized acetylated distarch phosphate, and pregelatinized refined starch), carboxymethylcellulose calcium, carboxymethylcellulose sodium (or croscarmellose sodium), microcrystalline cellulose, cellulose gum, and mixtures thereof. In embodiments, the amount of disintegrant present in the dosage form may range from about 1% w / w to about 5% w / w. For example, the amount of disintegrant present in the dosage form can range from about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, or about 4% w / w to about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w. In embodiments, the disintegrant is present in an amount of about 2% w / w. In embodiments, the disintegrant is present in an amount of about 3% w / w. In an embodiment, the disintegrant is present in an amount of about 4% w / w. In an embodiment, the disintegrant is present in an amount of about 5% w / w.

[0351] In embodiments, examples of suitable diluents / fillers (also referred to as base formers) include, but are not limited to, materials derived from animal or vegetable proteins, such as mammalian gelatin, non-mammalian gelatin, fish gelatin (e.g., high molecular weight gelatin, where more than 50%, more than 60%, or more than 70% of the molecular weight distribution of the gelatin is greater than 30,000 daltons, standard molecular weight gelatin, where substantially more than 50%, preferably more than 60%, and most preferably more than 70% of the molecular weight distribution of the gelatin is below 30,000 daltons, and combinations that can be formed with ratios of high molecular weight gelatin to standard molecular weight gelatin (HMW:SMW) ranging from substantially 1:1 to 1:9), dextrin, and soy, wheat, and psyllium seed proteins; acacia, guar, agar, and xanthan. Examples of suitable diluents / fillers include gums such as polysaccharides, alginates, carboxymethylcellulose, carrageenan, dextran, pectin, synthetic polymers such as polyvinylpyrrolidone, and polypeptide / protein or polysaccharide complexes such as gelatin-acacia complex, starch, mannitol, dicalcium phosphate, potassium sulfate, microcrystalline cellulose, dextrose, lactose, galactose, and trehalose, cyclic sugars such as cyclodextrins, inorganic salts such as sodium phosphate, sodium chloride, and aluminum silicate, and amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine, and mixtures thereof. In embodiments, the diluent / filler (or base-forming agent) is present in an amount ranging from about 1% to about 50% w / w of the dosage form.For example, the amount of diluent / filler present in the dosage form may be from about 1% w / w to about 50% w / w, from about 1% w / w to about 20% w / w, from about 1% w / w to about 10% w / w, from about 1% w / w to about 5% w / w, from about 5% w / w to about 50% w / w, from about 5% w / w to about 25% w / w, from about 5% w / w to about 15% w / w, from about 5% w / w to about 10% w / w, from about 10% w / w to about 50% w / w, from about 10% w / w to about 40% w / w, from about 10% w / w to about 30% w / w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 50% w / w, or about 40% w / w to about 45% w / w. In embodiments, the diluent / filler is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w (including all ranges and values ​​in between).

[0352] In embodiments, examples of suitable binders include, but are not limited to, starch, pregelatinized starch, PVP (polyvinylpyrrolidone), polyethylene oxide, polyethylene glycol, acacia, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and carboxymethylcellulose (CMC) and salts thereof, and mixtures thereof. In embodiments, the binder is present in the range of about 0% to about 20% w / w of the dosage form. For example, the amount of binder present in the dosage form can range from about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 20% w / w, or about 10% w / w to about 15% w / w. In embodiments, the binder is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, or about 20% w / w (including all ranges and values ​​in between).

[0353] In embodiments, examples of suitable fluidizing agents are selected from the group consisting of calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, talc, colloidal silicon dioxide, silica gel, precipitated silica, and mixtures thereof. In embodiments, the fluidizing agent is present in the dosage form in an amount ranging from about 0% to about 5% w / w. For example, the amount of fluidizing agent present in the dosage form may be from about 0.1% w / w to about 5% w / w, from about 0.1% w / w to about 3% w / w, from about 0.1% w / w to about 1% w / w, from about 0.5% w / w to about 5% w / w, from about 0.5% w / w to about 3% w / w, from about 0.5% w / w to about 1% w / w, from about 1% w / w to about 5% w / w, or from about 1% w / w to about 5% w / w. % w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, or about 4% w / w to about 5% w / w. In embodiments, the fluidizing agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w (including all ranges and values ​​in between).

[0354] In embodiments, examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, sodium potassium tartrate, light anhydrous silicic acid, carnauba wax, carmellose calcium, carmellose sodium, silicon dioxide hydrate, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the lubricant is present in the range of about 0% to about 3% w / w of the dosage form. For example, the amount of lubricant present in the dosage form can range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the lubricant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w (including all ranges and values ​​in between).

[0355] In embodiments, examples of suitable plasticizers include, but are not limited to, macrogol, triethyl citrate, acetylated monoglycerides, glycerin, monoacetin, diacetin, triacetin, phthalate derivatives such as dimethyl, diethyl, and dibutyl phthalate, polysorbate 80, and propylene glycol, 1,2,3-propanetriol triacetate, hydrogenated starch hydrolysates, corn syrup, distilled acetylated monoglycerides, castor oil and its derivatives, sucrose acetate isobutyrate, and mixtures thereof. In embodiments, the plasticizer is present in the range of about 0% to about 10% w / w of the dosage form. For example, the amount of fluidizing agent present in the dosage form may be from about 0.1% w / w to about 10% w / w, from about 0.1% w / w to about 5% w / w, from about 0.1% w / w to about 3% w / w, from about 0.1% w / w to about 1% w / w, from about 0.5% w / w to about 10% w / w, from about 0.5% w / w to about 5% w / w, from about 0.5% w / w to about 3% w / w, from about 0.5% w / w to about 1% w / w, from about 1% w / w to about 10% w / w, from about 1% w / w to about 5% w / w, from about 1% w / w to about The concentration may range from about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the plasticizer is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w (including all ranges and values ​​in between).

[0356] In embodiments, examples of suitable pH adjusters include, but are not limited to, inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide), organic acids (e.g., citric acid, acetic acid, tartaric acid, succinic acid, boric acid, edetic acid, glucuronic acid, glutaric acid, malic acid, formic acid, gluconic acid, ascorbic acid, or fatty acids), and / or organic bases (e.g., ethanolamine, triethanolamine), or mixtures thereof. In embodiments, the pH adjuster is present in a range of about 0% to about 2% w / w of the dosage form. For example, the amount of pH adjuster present in the dosage form can range from about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 1% w / w to about 2% w / w. In embodiments, the pH adjuster is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w (including all ranges and values ​​in between).

[0357] In embodiments, examples of suitable colorants include, but are not limited to, Food, Drug, and Cosmetic (FD&C) dyes (FD&C Blue, FD&C Green, FD&C Red, FD&C Yellow, FD&C Lake), Ponceau, indigo Drug and Cosmetic (D&C) Blue, indigo carmine, iron oxides (e.g., red iron oxide, yellow iron oxide, black iron oxide), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow, and mixtures thereof. In embodiments, the amount of colorant used ranges from about 0% to about 3% w / w of the dosage form. For example, the amount of colorant present in the dosage form can range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the colorant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w (including all ranges and values ​​in between).

[0358] In embodiments, examples of suitable flavoring agents include, but are not limited to, strawberry, apple, pear, peach, plum, orange, pineapple, apricot, lemon, peppermint, blackcurrant, banana, raspberry, raspberry aroma, wild berry, caramel, mint, licorice, grapefruit, caramel, vanilla, cherry, and grape flavor, flavor oils such as cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil, and mixtures thereof. In embodiments, the amount of flavoring agent used ranges from about 0% to about 3% w / w of the dosage form. For example, the amount of flavoring agent present in the dosage form can range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the flavoring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w (including all ranges and values ​​in between).

[0359] In embodiments, suitable flavoring agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents, or microencapsulated active agents. In embodiments, the amount of flavoring agent used ranges from about 0% to about 10% w / w of the dosage form. For example, the amount of flavoring agent present in the dosage form may be from about 0.1% w / w to about 10% w / w, from about 0.1% w / w to about 5% w / w, from about 0.1% w / w to about 3% w / w, from about 0.1% w / w to about 1% w / w, from about 0.5% w / w to about 10% w / w, from about 0.5% w / w to about 5% w / w, from about 0.5% w / w to about 3% w / w, from about 0.5% w / w to about 1% w / w, from about 1% w / w to about 10% w / w, from about 1% w / w to about 5% w / w, or from about 1% w / w to about The concentration may range from about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the flavoring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w (including all ranges and values ​​in between).

[0360] In embodiments, suitable viscosity enhancing agents include, but are not limited to, polymers, sugars, sugar alcohols, gums, clays, silica, etc. In embodiments, the amount of viscosity enhancing agent used ranges from about 0% to about 65% w / w of the dosage form. For example, the amount of viscosity enhancing agent present in the dosage form may be from about 0.1% w / w to about 65% w / w, from about 0.1% w / w to about 50% w / w, from about 0.1% w / w to about 20% w / w, from about 0.1% w / w to about 10% w / w, from about 0.1% w / w to about 5% w / w, from about 5% w / w to about 65% w / w, or from about 5% w / w to about 50% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 65% w / w, about 10% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 1 0% w / w to about 15% w / w, about 20% w / w to about 65% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 65% w / w, about 30% w / w to about 50% w / w, about 30% w / w The range may be from about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 65% w / w, about 40% w / w to about 50% w / w, about 40% w / w to about 45% w / w, about 50% w / w to about 65% w / w, about 50% w / w to about 60% w / w, or about 50% w / w to about 55% w / w. In embodiments, the viscosity enhancing agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w , about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, or about 65% w / w (including all ranges and values ​​therebetween).

[0361] In embodiments, examples of suitable sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, sorbitol, erythritol, xylitol, aspartame, stevia extract, licorice, mogrosides, sodium cyclamate, saccharin, saccharin sodium, acesulfame, dextrose, sucralose, monosodium glycyrrhizinate, monoammonium glycyrrhizinate, isomalt, glycerin, dipotassium glycyrrhizinate, thaumatin, and mixtures thereof. In embodiments, the amount of sweetener ranges from about 0.5 to about 2% w / w of the dosage form. For example, the amount of sweetener present in the dosage form can range from about 0.5% w / w to about 2% w / w, from about 0.5% w / w to about 1% w / w, or from about 1% w / w to about 2% w / w. In embodiments, the sweetener is present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w (including all ranges and values ​​therebetween).

[0362] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates in about 1 minute or more upon contact with the oral mucosa. In embodiments, the dosage form is lyophilized (freeze-dried).

[0363] In an embodiment, the mucoadhesive is sodium alginate. In an embodiment, the mucoadhesive is carbomer.

[0364] In embodiments, an oral mucosal (e.g., sublingual, buccal, or gingival) freeze-dried tablet is provided, comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) sodium alginate, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) magnesium stearate, (vi) lactose monohydrate, and (vii) optionally other pharmaceutically acceptable excipients. In embodiments, the tablet disintegrates in more than about 1 minute after contact with the oral mucosa.

[0365] In an embodiment, an oral mucosal (e.g., sublingual, buccal, or gingival) freeze-dried tablet is provided, comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) sodium alginate, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) mannitol, and (vii) optionally other pharmaceutically acceptable excipients. In an embodiment, the tablet disintegrates in more than about 1 minute after contact with the oral mucosa.

[0366] In an embodiment, an oral mucosal (e.g., sublingual, buccal, or gingival) freeze-dried tablet is provided, comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) magnesium stearate, (vi) mannitol, and (vii) optionally other pharmaceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0367] In one embodiment, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided, comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) lactose monohydrate, and (vii) optionally other pharmaceutically acceptable excipients. In one embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0368] In an embodiment, the mucoadhesive is xanthan gum.

[0369] In embodiments, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided, comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) xanthan gum, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) magnesium stearate, (vi) lactose monohydrate, and (vii) optionally other pharmaceutically acceptable excipients. In embodiments, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0370] In an embodiment, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided, comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) xanthan gum, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) mannitol, and (vii) optionally other pharmaceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0371] In embodiments, the dosage form is a sublingual tablet and is oval or oblong. In embodiments, the dosage form is a buccal tablet and is oblong. In embodiments, the dosage form is used to treat agitation. In embodiments, the dosage form is used to reduce noradrenergic hyperarousal. In embodiments, the dosage form is used to treat depression.

[0372] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharmaceutically acceptable excipients or carriers; an oral dosage form comprising:

[0373] In embodiments, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0374] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharmaceutically acceptable excipients or carriers; an oral dosage form comprising:

[0375] In embodiments, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0376] In embodiments, the present disclosure provides: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) one or more mucoadhesives, and (iv) one or more pharmaceutically acceptable excipients or carriers; an oral dosage form comprising:

[0377] In an embodiment, the tablet comprises: It disintegrates within about 5 seconds to 10 minutes after coming into contact with the oral mucosa.

[0378] In embodiments, the dosage form is lyophilized (freeze-dried).

[0379] In embodiments, the dosage form is used to treat a disorder associated with noradrenergic hyperarousal. In embodiments, the dosage form is used to treat ASD. In embodiments, the dosage form is used to prevent PTSD. In embodiments, the dosage form is used to treat autism spectrum disorder. In embodiments, the dosage form is used to treat agitation caused by noradrenergic hyperarousal. In embodiments, the agitation is treated in a subject without causing significant sedation. In embodiments, the dosage form is used to treat depression in a subject. In an embodiment, the present disclosure provides an oral mucosal (sublingual or buccal) freeze-dried tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyethylene oxide, (iv) croscarmellose sodium or sodium starch glycolate, (v) sucralose, (vi) magnesium stearate and / or silicon dioxide, (vii) lactose or mannitol, and (viii) optionally other pharmaceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0380] In one embodiment, the oral mucosal tablet contains, per unit, about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, and about 0.1 mg to about 100 mg of latrepirdine. In another embodiment, the oral mucosal tablet contains, per unit, about 10 micrograms to about 240 micrograms (e.g., about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, 180 micrograms, about 210 micrograms, or about 240 micrograms (including all intermediate ranges and values)) of dexmedetomidine or a pharmaceutically acceptable salt thereof, and about 1 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg (including all intermediate ranges and values)) of latrepirdine or a pharmaceutically acceptable salt thereof.

[0381] In embodiments, the tablet is administered sublingually, buccally, or gingivally. In embodiments, the dosage form is administered via a single dosage form or via multiple dosage forms.

[0382] IV. Methods and Administration In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal in a human subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0383] In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal in a human subject, comprising orally administering to the subject a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0384] In embodiments, the present disclosure provides a method of treating a disorder associated with noradrenergic hyperarousal in a human subject, comprising administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0385] In an embodiment, the disorder is acute stress disorder.

[0386] In embodiments, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, exaggerated startle response, irritability, inability to stop moving or sit still, lack of motivation, or agitation.

[0387] In an embodiment, the symptom is anxiety.

[0388] In an embodiment, the symptom is a sleep disorder.

[0389] In an embodiment, the symptom is an exaggerated startle response.

[0390] In an embodiment, the symptom is irritability.

[0391] In an embodiment, the symptom is an inability to stop moving or sit still.

[0392] In an embodiment, the symptom is lack of motivation.

[0393] In an embodiment, the symptom is agitation.

[0394] In an embodiment, the disorder in a human subject is an autism spectrum disorder.

[0395] In an embodiment, the method prevents the disorder from developing into post-traumatic stress disorder.

[0396] In an embodiment, the disorder is caused by a traumatic event experienced by the human subject.

[0397] In embodiments, latrepirdine is administered within 1 week, 2 weeks, or 4 weeks after the traumatic event.

[0398] In embodiments, latrepirdine is administered within 3 days of the traumatic event. In embodiments, latrepirdine is administered within 1 day of the traumatic event. In embodiments, latrepirdine is administered within 4 hours of the traumatic event. In embodiments, latrepirdine is administered within 6 hours of the traumatic event. In embodiments, latrepirdine is administered within 12 hours of the traumatic event.

[0399] In embodiments, latrepirdine is administered once daily, twice daily, or three times daily.

[0400] In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 5 mg to about 300 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 200 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 100 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 10 mg to about 80 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 15 mg to about 60 mg per day. In an embodiment, the therapeutically effective amount of latrepirdine is in the range of about 30 mg to about 45 mg per day.

[0401] In embodiments, the therapeutically effective amount of latrepirdine is evenly divided for administration either twice daily or three times daily.

[0402] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially, or intermittently in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0403] In embodiments, the present disclosure provides preclinical animal models established to link noradrenergic signaling to psychiatric conditions such as acute stress disorder, PTSD, depression, substance withdrawal, substance use dependence, agitation, panic disorder, and anxiety.

[0404] In embodiments, preclinical animal models include the resident intruder assay, the forced swim test, the yohimbine-induced anxiety model, and the CCK-induced panic model.

[0405] In an embodiment, the preclinical animal model is a resident intruder assay, and latrepirdine treatment reduces aggression in response to social intrusion.

[0406] In an embodiment, the preclinical animal model is a CCK-induced panic model, in which rodents are administered CCK and become panicky or anxious, avoiding leaving the closed arms of a maze. In an embodiment, when latrepirdine is administered, the rodents leave the closed arms and explore the open arms, indicating that the rodents are less anxious. In an embodiment, CCK also induces panic in healthy human volunteers, indicating that this is a translatable model.

[0407] In embodiments, preclinical animal models have surprisingly and unexpectedly demonstrated that latrepirdine reduces the severity of symptoms in stress-related psychiatric conditions, including acute stress disorder, PTSD, depression, substance withdrawal, substance use dependence, agitation, panic disorder, and anxiety.

[0408] In embodiments, noradrenergic signaling is associated with ADHD in preclinical models.

[0409] In embodiments, the methods described herein reduce the severity of symptoms experienced by a patient and improve the patient's clinical outcome due to improved compliance with the underlying therapeutic treatment, including adherence to medication regimens and participation in treatment.

[0410] In embodiments, clinical outcomes improve as patients with reduced symptoms interact more effectively in social settings, reducing aggressive and panicky symptoms that can result from lack of social interaction, such as those seen in conditions such as autism spectrum disorder.

[0411] In embodiments, the methods described herein provide effective symptom management to prevent worsening of the condition, as may be the case when acute stress disorder evolves into PTSD.

[0412] In embodiments, the present disclosure provides that the deterioration over time of disorders such as acute stress disorder and autism spectrum disorder is treated and prevented by latrepirdine.

[0413] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0414] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, the method comprising administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0415] In embodiments, the present disclosure provides a method for treating ASD in a subject in need thereof, the method comprising orally administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0416] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0417] In embodiments, the present disclosure provides a method for treating ASD after a traumatic event in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0418] In embodiments, the present disclosure provides a method for treating an ASD in a subject in need thereof, the method comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0419] In embodiments, the present disclosure provides a method for increasing resilience to the development of PTSD in a subject following a traumatic event, the method comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0420] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg (including all ranges and values ​​therebetween) of latrepirdine or a pharmaceutically acceptable salt thereof.

[0421] In one embodiment, about 10 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once, twice, or three times daily. In another embodiment, about 20 mg to about 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once, twice, or three times daily.

[0422] In an embodiment, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject.

[0423] In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered immediately after the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values ​​in between) after the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, administration of latrepirdine is continued for up to 4 weeks. In embodiments, the dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered in single or multiple units.

[0424] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0425] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0426] In embodiments, the present disclosure provides a method of treating an ASD in a subject in need thereof, comprising oral mucosal (e.g., sublingual, buccal, or gingival) administration of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0427] In embodiments, the present disclosure provides a method of treating ASD following a traumatic event in a subject in need thereof, the method comprising oral mucosal (e.g., sublingual, buccal, or gingival) administration of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0428] In embodiments, the present disclosure provides a method of increasing resilience to the development of PTSD in a subject following a traumatic event, the method comprising oromucosal (e.g., sublingual, buccal, or gingival) administration of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0429] In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately after a traumatic event. In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values ​​in between) after the traumatic event. In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event (or prior to the onset of ASD). In embodiments, administration of dexmedetomidine is continued for up to 4 weeks. In embodiments, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in single or multiple units.

[0430] In embodiments, about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (including all ranges and values ​​therebetween) are administered to a subject. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms, or more.

[0431] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0432] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered bucally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried). In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, or gingivally as a wafer, patch, or film.

[0433] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, within 24 hours of a traumatic event and continuing for a period of up to 4 weeks.

[0434] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, within 24 hours of a traumatic event and continuing for a period of up to 4 weeks.

[0435] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, within 24 hours of a traumatic event and continuing for a period of up to four weeks.

[0436] In embodiments, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising orally administering a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, within 24 hours of a traumatic event and continuing for a period of up to 4 weeks.

[0437] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0438] In embodiments, the present disclosure provides a method for treating an autism spectrum disorder in a subject in need thereof, the method comprising administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0439] In embodiments, the present disclosure provides a method for treating an autism spectrum disorder in a subject in need thereof, the method comprising orally administering to the subject as monotherapy a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0440] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject, the method comprising administering to the subject a dosage form comprising about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0441] In embodiments, the dosage form contains about 10 mg to about 60 mg, e.g., about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg (including all ranges and values ​​in between) of latrepirdine or a pharmaceutically acceptable salt thereof.

[0442] In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to a subject.

[0443] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally. In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

[0444] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally (sublingually or bucally or gingivally) as a wafer, patch or film.

[0445] In an embodiment, latrepirdine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dosage forms.

[0446] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0447] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0448] In embodiments, the present disclosure provides a method of treating an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0449] In embodiments, the present disclosure provides a method of treating autism spectrum disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0450] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually / buccally. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried). In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, or gingivally as a wafer, patch, or film.

[0451] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dosage forms.

[0452] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times daily (e.g., once daily, twice daily, three times daily, or four, five, six times daily), preferably once, twice, or three times daily.

[0453] In an embodiment, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are co-administered simultaneously or within a short period of time, typically within less than 1 hour, preferably 0.5 hours, more preferably 0.25 hours.

[0454] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered sequentially within about 24 hours, for example, separated from each other by any of about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour.

[0455] In an embodiment, dexmedetomidine and latrepirdine are provided as two separate dosage forms for treating autism spectrum disorder in a subject, one containing a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered simultaneously to a subject in need thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered sequentially to a subject in need thereof.

[0456] In embodiments, dexmedetomidine and latrepirdine are provided as a single dosage form for treating autism spectrum disorder, comprising therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0457] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days, or longer.

[0458] In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children (CARS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - Standard Edition (CARS2-ST). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - High Functioning Edition (CARS2-HF). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Vineland II Adaptive Behavior Scales (VABS-II).

[0459] In embodiments, the improvement in score is measured at least 8, 16, 24, 32, 40, 50, 60, or 80 weeks after treatment and compared to the score before treatment.

[0460] In embodiments, improvement in symptoms is measured after treatment has ceased for at least 2, 4, 6, 8, 10 or more weeks and compared to pre-treatment measurements.

[0461] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0462] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0463] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0464] In embodiments, the present disclosure provides a method for reducing a Childhood Autism Rating Scale (CARS) score in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0465] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0466] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0467] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0468] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2 - Standard Version (CARS2-ST) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0469] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale 2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0470] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0471] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0472] In embodiments, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale-2-High Functioning Version (CARS2-HF) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0473] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0474] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0475] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0476] In embodiments, the present disclosure provides a method for reducing an Aberrant Behavior Checklist (ABC) score in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0477] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0478] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0479] In embodiments, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0480] In embodiments, the present disclosure provides a method for reducing a score on the Social Responsiveness Scale (SRS) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0481] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0482] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising orally administering an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0483] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0484] In embodiments, the present disclosure provides a method for reducing a score on the Vineland II Adaptive Behavior Scale (VABS-II) in a human subject suffering from an autism spectrum disorder, comprising administering an effective amount of a combination of dexmedetomidine and latrepirdine, or a pharmaceutically acceptable salt thereof.

[0485] In embodiments, treatment results in a score reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the pre-treatment score, where the severity of autism spectrum symptoms is assessed based on the CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the score reduction is achieved after at least 4, 8, 12, 16, 24, or more weeks of treatment.

[0486] In an embodiment, the treatment reduces the severity of autism symptoms by 10% to 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, 50% to 90%, 60% to 70%, 60% to 80%, 60% to 90%, 70% to 80%, 70% to 90%, 80% to 90%, 80% to 90%, 90% to 100%, 1 ... % to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90% reduction in autism symptom severity, wherein the severity of autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment results in a 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 60% reduction in the severity of autistic symptoms 8 weeks or more after treatment compared to before treatment began, where the severity of autistic symptoms is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment results in a 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 60% reduction in the severity of autistic symptoms 12 weeks or more after treatment compared to before treatment began, where the severity of autistic symptoms is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, the treatment reduces the severity of ASD symptoms by 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 60% after 18 weeks or more of treatment compared to before treatment began, where the severity of autism symptoms is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II.In embodiments, the treatment reduces the severity of autistic symptoms by 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 60% 24 weeks or more after treatment compared to before treatment began, where the severity of autistic symptoms is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II.

[0487] In embodiments, the subject is an infant, adolescent, pediatric patient or geriatric patient. In embodiments, the subject is a child under about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In embodiments, the subject is an adult patient. In embodiments, the subject is an elderly patient. In embodiments, the subject is over about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old.

[0488] In embodiments, treatment inhibits the progression or reduces the severity of one or more symptoms of autistic disorder. In embodiments, treatment inhibits the progression or reduces the severity of one or more symptoms of Asperger's disorder. In embodiments, treatment inhibits the progression or reduces the severity of one or more symptoms of childhood disintegrative disorder. In embodiments, treatment inhibits the progression or reduces the severity of one or more symptoms of Rett's disorder.

[0489] In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children (CARS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - Standard Edition (CARS2-ST). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Autism Rating Scale for Children 2 - High Functioning Edition (CARS2-HF). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of symptoms of autism spectrum disorder is assessed by the Vineland II Adaptive Behavior Scales (VABS-II).

[0490] The Childhood Autism Rating Scale (CARS) is a 15-item scale covering: Interactions, Imitation, Emotional Reactivity, Body Use, Manipulation, Adaptation to Change, Visual Reactivity, Auditory Reactivity, Taste, Smell, and Touch Reactivity and Use, Fear and Anxiety, Verbal Communication, Nonverbal Communication, Activity Level, Level and Balance of Intellectual Functioning, and Overall Impression. The CARS can be used to assess the diagnosis of both autism and ASD, as well as the severity of overall symptoms. The CARS assessment is administered by the same assessor after the ADIR assessment.

[0491] The second edition of the CARS, known as the Childhood Autism Rating Scale-2 or CARS-2, was developed by Schopler et al. (Childhood Autism Rating Scale-Second edition (CARS2): Manual. Los Angeles: Western Psychological Services, 2010). The original CARS was developed primarily for individuals with comorbid intellectual functioning and was criticized for not accurately distinguishing high-functioning individuals with ASD. The CARS-2 retains the format of the original CARS for use with younger or lower-functioning individuals (the "standard version" has now been renamed CARS2-ST), but also includes a separate rating scale for use with higher-functioning individuals (the "high-functioning version" is named CARS2-HF), as well as a non-scoring information-gathering scale (the "Parent or Caregiver Questionnaire" or CARS2-QPC) that can be used to develop the CARS2-ST and CARS2-HF assessments.

[0492] The Aberrant Behavior Checklist (ABC) is a symptom assessment checklist used to assess and classify problem behaviors in children and adults in a variety of settings. The ABC contains 58 items divided into five subscales: (1) Irritability / Agitation, (2) Lethargy / Social Withdrawal, (3) Stereotypic Behaviors, (4) Hyperactivity / Insubordination, and (5) Inappropriate Language.

[0493] The Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairments that are core problems in autism, including social awareness, social information processing, reciprocal social communication skills, social anxiety / avoidance, and autistic perseverations and traits. See Constantino et al., Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord. 2003 August;33(4):427-33.

[0494] The Repetitive Behavior Scale-Revised (RBS-R) (Bodfish et al., The Repetitive Behavior Scale: A test manual (1998)) is an observational clinical rating scale for measuring the presence and severity of various forms of restrictive repetitive behaviors characteristic of individuals with autism. The RBS-R consists of six subscales: stereotyped behaviors, self-injurious behaviors, obsessive-compulsive behaviors, ritualistic behaviors, identity-preserving behaviors, and restricted behaviors. The scale provides an overall raw score for the severity of repetitive behaviors and separate measures of severity for each subtype of repetitive behavior. Higher scores indicate more severe behavioral symptoms.

[0495] The Vineland II Adaptive Behavior Scales (VABS-II) is a measure of functioning level in four different domains: communication, daily living skills, social skills, and motor skills, as well as 11 subdomains. Raw scores are converted to age equivalents. This scale complements the ABCs in assessing problem behaviors. See Sara et al., Vineland Adaptive Behavior Scales, Second Edition (Vineland™-II), Pearson Publishing, 2005.

[0496] Other scales that may be used to assess improvement in autism spectrum disorders include the Clinical Global Impression (CGI), Pervasive Developmental Disorders Behavior Inventory (PDDBI), Expressive One-Word Picture Vocabulary Test-4 (EOWPVT-4), Childhood Behavioral Assessment-Social Competence Subscale, Sensory Experience Questionnaire, Intelligence Scale (Mullen Early Learning Scales or Stanford-Binet), Language Environment Analysis, Early Childhood Mental Assessment, Preverbal Autism Diagnostic Observation Schedule (PL-ADOS), Autism Diagnostic Interview-Revised (ADI-R), ATN GI Symptom Inventory, and Parenting Stress Index.

[0497] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, hi embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein.

[0498] In embodiments, the present disclosure provides a method for treating agitation in a subject experiencing agitation, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the latrepirdine or a pharmaceutically acceptable salt thereof is administered (e.g., daily) for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 1 year.

[0499] In embodiments, the present disclosure provides a method of treating agitation in a subject experiencing agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In embodiments, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are present in the same dosage form or in separate dosage forms as described herein.

[0500] In embodiments, the active agents dexmedetomidine and latrepirdine are co-administered (in the same dosage form or in separate dosage forms) to a subject for a specified period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, etc.), followed by administration of latrepirdine alone to the subject for a specified period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, etc.).

[0501] The present disclosure provides a method for treating agitation in a subject experiencing agitation, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In embodiments, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In embodiments, a single administration of the combination treats agitation and maintains sedation for at least 12 hours. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amounts of latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0502] In embodiments, the agitation can be acute agitation, chronic agitation, or both.

[0503] In an embodiment, the agitation is caused by noradrenergic hyperarousal.

[0504] In embodiments, agitation is treated without causing any significant sedation.

[0505] In embodiments, the agitation is associated with a neuropsychiatric disorder selected from schizophrenia, bipolar disorder, bipolar mania, delirium, depression or other related neurodegenerative disorders.

[0506] In embodiments, the agitation is associated with a neurodegenerative disorder selected from Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia, dementia with Lewy bodies, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy, or other related neurodegenerative disorders.

[0507] In embodiments, the agitation is associated with substance abuse withdrawal, including alcohol withdrawal or opioid withdrawal.

[0508] The present disclosure provides a method for treating chronic agitation in a subject, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In embodiments, the subject suffers from dementia. In embodiments, dementia includes Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's syndrome dementia.

[0509] In embodiments, the present disclosure provides a method for treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the subject is suffering from dementia. In embodiments, dementia includes Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's syndrome dementia.

[0510] In embodiments, the present disclosure provides a method for treating agitation in a subject exhibiting agitation, the method comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein.

[0511] In embodiments, the agitation is severe. In embodiments, the agitation is mild.

[0512] In embodiments, the present disclosure provides a method for treating agitation in a subject, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has Alzheimer's disease.

[0513] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject has Alzheimer's disease.

[0514] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from concomitant dementia.

[0515] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from dementia.

[0516] In embodiments, the present disclosure provides a method for treating agitation in a subject, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from Parkinson's disease.

[0517] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from Parkinson's disease.

[0518] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from PTSD.

[0519] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from PTSD.

[0520] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from concurrent vascular cognitive impairment.

[0521] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject suffers from concurrent vascular cognitive impairment.

[0522] In embodiments, the present disclosure provides a method for treating agitation in a subject, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from Huntington's disease.

[0523] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from Huntington's disease.

[0524] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from schizophrenia.

[0525] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from schizophrenia.

[0526] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from a co-occurring bipolar disorder.

[0527] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from bipolar disorder.

[0528] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from depression.

[0529] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject also suffers from depression.

[0530] In embodiments, the present disclosure provides a method for treating agitation in a subject, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject is also suffering from delirium.

[0531] In embodiments, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, wherein the subject is also suffering from delirium.

[0532] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising: (i) about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), and (ii) about 0.1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof; to the subject via oral mucosal administration.

[0533] In embodiments, agitation is treated without inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amounts of latrepirdine, or a pharmaceutically acceptable salt thereof, and dexmedetomidine, or a pharmaceutically acceptable salt thereof, are present in the same dosage form or in separate dosage forms, as described herein.

[0534] In embodiments, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising: (i) about 5 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), and (ii) about 5 mg to about 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof; to the subject via oral mucosal administration.

[0535] In embodiments, agitation is treated without inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amounts of latrepirdine, or a pharmaceutically acceptable salt thereof, and dexmedetomidine, or a pharmaceutically acceptable salt thereof, are present in the same dosage form or in separate dosage forms, as described herein.

[0536] In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal, comprising orally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to a subject. In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal, comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to a subject.

[0537] In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal, comprising orally administering to a subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

[0538] In embodiments, the present disclosure provides a method for reducing noradrenergic hyperarousal, comprising oromucosally administering to a subject a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

[0539] In an embodiment, dexmedetomidine and latrepirdine are administered together in a single dosage form. In an embodiment, dexmedetomidine and latrepirdine are co-administered in separate dosage forms. In an embodiment, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered as a single dose, either via a single unit dosage form or via multiple unit dosage forms administered simultaneously. In an embodiment, dexmedetomidine or a salt thereof is administered in one or more unit doses for a total daily dose of about 0.5 micrograms to about 500 micrograms. In an embodiment, latrepirdine or a salt thereof is administered in one or more unit doses for a total daily dose of about 1 mg to about 100 mg.

[0540] In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oral dosage form that provides rapid relief of agitation, followed by continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period. In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation, followed by continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period.

[0541] In embodiments, the present disclosure provides a method for treating behavioral and psychological symptoms in a subject with a neurodegenerative disorder, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, hi embodiments, the behavioral and psychological symptoms include agitation or aggression.

[0542] In embodiments, the present disclosure provides a method of treating behavioral and psychological symptoms in a subject with a neurodegenerative disorder, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, in which the behavioral and psychological symptoms include agitation or aggression.

[0543] In embodiments, the present disclosure provides a method for treating behavioral and psychological symptoms in a subject with a neuropsychiatric disorder, the method comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, in embodiments, the behavioral and psychological symptoms include agitation or aggression.

[0544] In embodiments, the present disclosure provides a method of treating behavioral and psychological symptoms in a subject with a neuropsychiatric disorder, comprising oromucosal administration of a therapeutically effective amount of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, in which the behavioral and psychological symptoms include agitation or aggression.

[0545] In embodiments, the present disclosure provides the use of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0546] In embodiments, the present disclosure provides the use of therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0547] In embodiments, the present disclosure provides the use of a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0548] In embodiments, the present disclosure provides the use of therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharmaceutically acceptable salts thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0549] In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising oromucosally administering to the subject a dosage form containing a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In an embodiment, latrepirdine is administered once daily at a dosage of about 1 mg to about 100 mg. In an embodiment, latrepirdine is administered once daily at a dosage of about 10 mg. In an embodiment, latrepirdine is administered once daily at a dosage of about 20 mg. In an embodiment, latrepirdine is administered once daily at a dosage of about 30 mg. In an embodiment, latrepirdine is administered twice daily at a dosage of about 20 mg. In an embodiment, latrepirdine is administered three times daily at a dosage of about 20 mg. In an embodiment, latrepirdine is administered once daily at a dosage of about 30 mg. In an embodiment, latrepirdine is administered at a dosage of about 30 mg twice daily. In an embodiment, latrepirdine is administered to a subject at a total daily dose of about 60 mg.

[0550] The present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0551] The present disclosure provides a method for treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.The present disclosure provides a method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0552] In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising oromucosal administration to the subject of about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0553] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0554] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0555] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0556] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0557] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0558] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0559] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0560] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0561] In an embodiment, improvement in depressive symptoms is observed as measured by the HAM-D-17 depression subscale.

[0562] In an embodiment, the subject's HAM-D-17 total score is ≧18 at the start of treatment.

[0563] In embodiments, there is provided a method for reducing the score on the HDRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0564] In embodiments, there is provided a method for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharmaceutically acceptable salt thereof.

[0565] The HAM-D or HDRS is used as a measuring instrument to assess symptoms of depression. The measuring instrument is administered to determine a patient's symptoms after a structured or unstructured interview with a clinician. The total score is calculated by adding up the individual scores for each question. A score of less than 7 generally indicates the absence of depression or its remission. A score of 7 to 17 indicates mild depression. A score of 18 to 24 indicates moderate depression. A score of 25 or higher indicates severe depression. Most depression studies consider a patient to have "successful" treatment if their score decreases by more than 50%. Remission is generally understood to be a score below 7.

[0566] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression, and each item is given a score from 0 to 6. The total score ranges from 0 to 60. The questionnaire includes questions about the following symptoms: 1. outward sadness, 2. verbal sadness, 3. inner tension, 4. decreased sleep, 5. decreased appetite, 6. difficulty concentrating, 7. fatigue, 8. mood perception, 9. pessimistic thoughts, and 10. suicidal thoughts.

[0567] In an embodiment, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are co-administered simultaneously or within a short period of time, typically within less than 1 hour, preferably 0.5 hours, more preferably 0.25 hours.

[0568] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered sequentially within about 24 hours, for example, separated from each other by any of about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour.

[0569] In an embodiment, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once, twice, three or four, five or six times daily, preferably once, twice or three times daily.

[0570] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0571] In embodiments, the depression is moderate or severe. In embodiments, the depression is major depression, bipolar disorder, or mixed depression.

[0572] In embodiments, the present disclosure provides a method for the treatment of depression in a subject in need thereof, comprising administering to a subject: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0573] In embodiments, the present disclosure provides a method for treating a psychosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, latrepirdine is administered once daily at a dosage of about 1 mg to about 100 mg. In embodiments, latrepirdine is administered once daily at a dosage of about 10 mg. In embodiments, latrepirdine is administered once daily at a dosage of about 20 mg. In embodiments, latrepirdine is administered once daily at a dosage of about 30 mg. In embodiments, latrepirdine is administered twice daily at a dosage of about 10 mg. In embodiments, latrepirdine is administered twice daily at a dosage of about 20 mg. In embodiments, latrepirdine is administered twice daily at a dosage of about 30 mg. In an embodiment, latrepirdine is administered at a dosage of about 10 mg three times a day. In an embodiment, latrepirdine is administered at a dosage of about 20 mg three times a day. In an embodiment, latrepirdine is administered at a dosage of about 30 mg three times a day. In an embodiment, latrepirdine is administered to a subject at a total daily dose of about 60 mg.

[0574] In embodiments, the present disclosure provides a method for treating a psychosis in a subject in need thereof, the method comprising oromucosal administration to the subject of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0575] The present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0576] The present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising oromucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0577] In embodiments, treatment is effective without causing significant sedation.

[0578] In embodiments, treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of psychosis in a subject is assessed using the PANSS scale.

[0579] The Positive and Negative Symptoms Scale (PANSS) scale is widely used in clinical trials and is considered the "gold standard" for evaluating the therapeutic effects of antipsychotics. To assess patients using the PANSS, a clinical interview lasting approximately 45 minutes is conducted. Based on the interview as well as reports from family members or primary care providers at the hospital, patients are rated on a scale of 1 to 7 for 30 symptoms. Scores are often given separately for positive items, negative items, and overall psychopathology.

[0580] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0581] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising oromucosal administration to the subject of a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0582] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0583] In embodiments, the present disclosure provides a method for achieving a sustained reduction in PANSS score for psychosis in a subject over a period of time, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharmaceutically acceptable salt thereof.

[0584] In embodiments, the reduction in PANSS score is at least about 20% to about 50% from the baseline score. In embodiments, the reduction in PANSS score is about 25% from the baseline score. In embodiments, the reduction in PANSS total score is about 30% from the baseline score. In embodiments, the reduction in PANSS total score is about 35 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 40 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 45 percentage points from the baseline score. In embodiments, the reduction in PANSS total score is about 50 percentage points from the baseline score.

[0585] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the subject is experiencing agitation. In embodiments, the subject is not experiencing agitation.

[0586] In embodiments, the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia, and bipolar disorder, or another related neuropsychiatric disorder, hi embodiments, the psychosis is associated with a neurodegenerative disorder.

[0587] In embodiments, the psychosis is associated with a pathological condition such as a substance abuse disorder (eg, alcohol, opioid and other substance withdrawal).

[0588] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is single-episode. In embodiments, the psychosis is recurrent or includes recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered buccally. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered sublingually. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered sublingually or buccally in the form of a tablet or round disc.

[0589] The combination disclosed herein can be administered as long as necessary to treat agitation.In embodiments, the combination is administered at least once a day, for example, once a day or twice a day, for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days or more.The combination disclosed herein can be administered as long as necessary to treat depression.

[0590] The unit dose can be administered once, twice, three or four, five or six times a day, preferably once, twice or three times a day. The daily dose depends on the frequency of administration, preferably once or twice a day, or three or five times a day. The daily dose can be divided into two, three, four, five or six doses.

[0591] In embodiments, the present disclosure provides a method for the treatment of behavioral and psychological symptoms in a subject in need thereof, comprising administering to a subject: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The present invention provides a combination comprising:

[0592] In embodiments, the present disclosure provides a method for the treatment of depression in a subject in need thereof, comprising administering to a subject: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0593] In an embodiment, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0594] In an embodiment, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride or dihydrochloride.

[0595] In an embodiment, a subject exhibiting agitation has a baseline score of about 14 or greater on the PEC scale.

[0596] In embodiments, a subject experiencing agitation experiences a decrease in PEC score after administering a dosage form of the present disclosure according to the methods described herein. In embodiments, the patient achieves a change in PEC score of greater than -2 relative to baseline within two hours of administering the composition. For example, the decrease in PEC score is about -1, about -2, about -3, about -4, about -5, about -6, about -7, about -8, about -9, or about -10 relative to baseline. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dose of about 0.5 micrograms to about 500 micrograms (e.g., about 30, about 60, about 80, about 90, about 120, about 180, or about 240 micrograms). In embodiments, the dosage form comprises latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is present in a do...

Claims

1. A pharmaceutical composition for use in treating disorders associated with noradrenergic hyperarousal in human subjects, comprising, optionally, a therapeutically effective amount of latrepyridine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition for use according to claim 1, wherein the disorder is acute stress disorder.

3. The pharmaceutical composition for use according to claim 2, wherein the human subject has one or more symptoms associated with acute stress disorder, selected from the group consisting of anxiety, sleep disturbance, excitability, inability to stop moving or sit still, lack of motivation, and agitation.

4. The method relates to a pharmaceutical composition for use according to any one of claims 1 to 3, which prevents the disorder from developing into post-traumatic stress disorder.

5. The pharmaceutical composition for use according to claim 1, wherein the disorder is autism spectrum disorder.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the disorder is caused by a traumatic event experienced by the human subject.

7. The latrepiridine is administered once, twice, or three times a day in the pharmaceutical composition for use according to any one of claims 1 to 6.

8. The pharmaceutical composition for use according to claim 6, wherein the latrepiridine is administered within four weeks, two weeks, or one week from the traumatic event.

9. The pharmaceutical composition for use according to claim 6, wherein the latrepiridine is administered within three days or within one day of the traumatic event.

10. The pharmaceutical composition for use according to claim 6, wherein the latrepiridine is administered within 12 hours, 6 hours, or 4 hours from the traumatic event.

11. The pharmaceutical composition for use according to any of the prior claims, wherein the therapeutically effective dose of latrepiridine is in the range of about 5 mg to about 300 mg per day.

12. The therapeutically effective dose of latrepiridine is in the range of approximately 10 mg to approximately 200 mg per day, optionally approximately 10 mg to approximately 100 mg per day, optionally approximately 10 mg to approximately 80 mg per day, optionally approximately 15 mg to approximately 60 mg per day, or optionally approximately 30 mg to approximately 45 mg per day, according to any of the prior claims, for use in the pharmaceutical composition according to any of the prior claims.

13. The therapeutically effective amount of latrepiridine is equally divided for administration twice or three times a day, according to any of the prior claims, in the pharmaceutical composition for use according to any of the prior claims.

14. The pharmaceutical composition for use according to any of the prior claims, wherein the latrepiridine or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially, or intermittently in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Images