Methods and Compositions for Treating Agitation

Abstract

The present disclosure relates to the treatment of agitation caused by noradrenergic hyperarousal in a subject who is agitated.The present disclosure provides an oral mucosal 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.Also provided are methods of using the same.The present disclosure also provides a method of treating depression by administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine via oral mucosal administration.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 154,281, filed February 26, 2021, the contents of which are incorporated herein in their entirety as if set forth herein.

[0002] The present disclosure relates to the treatment of agitation in a subject in need thereof by administering an oral mucosal 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 treating depression in a subject in need thereof, comprising oromucosally administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine.The present disclosure also relates to the treatment of other disorders associated with noradrenergic hyperarousal. [Background technology]

[0003] 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 associated 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 feelings of sadness and loss of interest due to a complex interplay of social, psychological, and biological factors. During a depressive episode, the patient experiences a 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 thus treat specific aspects of agitation. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Miller CW,Hodzic V,Weintraub E.Current Understanding of the Neurobiology of Agitation.Western Journal of Emergency Medicine.2020 Jul;21(4):841 Summary of the Invention

[0005] The present disclosure provides an oral mucosal dosage form comprising an effective amount of latrepirdine alone or in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers and / or excipients.The present disclosure provides a method for treating a disorder associated with noradrenergic-mediated hyperarousal in a subject, comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof to the subject. 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 pharma- ceutically acceptable salt thereof.

[0006] The present disclosure also provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating acute agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating acute agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating or preventing chronic agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating or preventing chronic agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0007] The present disclosure also provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the agitation is caused by noradrenergic hyperarousal. In an embodiment, the subject exhibiting agitation also exhibits aggression. In an embodiment, the agitation is treated without inducing significant sedation. The present disclosure also provides a method of treating acute agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating chronic agitation in a subject, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0008] In embodiments, the disclosure provides a method of treating agitation in an agitated subject, the method comprising administering to the subject via an oral mucosa (e.g., sublingual, buccal, or gingival) a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. In embodiments, the disclosure provides a method of treating agitation in an agitated subject, the method comprising administering to the subject via an oral mucosa (e.g., sublingual, buccal, or gingival) a dosage form comprising about 1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof. In embodiments, the disclosure provides a method of treating agitation in an agitated subject comprising administering to the subject via the oral mucosa (e.g., sublingual, buccal, or gingival) 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 ​​in between) of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0009] In an embodiment, about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered twice a day. In an embodiment, about 30 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered three times a day. In an embodiment, a total daily dose of about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered to the subject. In an embodiment, a total daily dose of about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered to the subject. In an embodiment, a total daily dose of about 30 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered to the subject. In an embodiment, a total daily dose of about 40 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered to the subject. In an embodiment, a total daily dose of about 60 mg of latrepirdine or a pharma- ceutically acceptable salt thereof is administered to the subject.

[0010] 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 pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt); oromucosal administration to the subject of a dosage form comprising: In embodiments, oromucosal administration includes sublingual, buccal, or gingival administration.

[0011] 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 pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride); and administering to the subject oromucosally a dosage form comprising:

[0012] In an embodiment, the present disclosure provides a method of treating agitation in an agitated subject, the method comprising administering to the subject about 1 mg to about 500 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.In an embodiment, the present disclosure provides a method of treating agitation in an agitated subject, the method comprising oromucosally administering to the subject about 1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating agitation in an agitated subject, the method comprising oromucosally administering to the subject about 5 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.In an embodiment, the present disclosure provides a method of treating agitation in an agitated subject, the method comprising oromucosally administering to the subject about 5 mg to about 60 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0013] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0014] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0015] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0016] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0017] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0018] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0019] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0020] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0021] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0022] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0023] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0024] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0025] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0026] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0027] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0028] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0029] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0030] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0031] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0032] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0033] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0034] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0035] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0036] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0037] In an embodiment, the disclosure provides a method of treatment comprising administering dexmedetomidine or a pharma- ceutically acceptable salt to a subject in an oral mucosal dosage form that provides rapid relief of agitation, and then continuing treatment with latrepirdine or a pharma- ceutically acceptable salt for an effective period of time. In an embodiment, latrepirdine and dexmedetomidine or a pharma- ceutically acceptable salt are administered sublingually. In an embodiment, latrepirdine and dexmedetomidine or a pharma- ceutically acceptable salt are administered buccally. In an embodiment, latrepirdine and dexmedetomidine or a pharma- ceutically acceptable salt are administered sublingually or buccally as a tablet. In an embodiment, the tablet is lyophilized. In an embodiment, latrepirdine and dexmedetomidine or a pharma- ceutically acceptable salt are administered sublingually or buccally or gingivally as a wafer. In an embodiment, latrepirdine and dexmedetomidine or a pharma- ceutically acceptable salt are administered sublingually or buccally or gingivally as a patch. In an embodiment, latrepirdine and dexmedetomidine or pharma- ceutically acceptable salts thereof are administered sublingually or buccally or gingivally as a film.

[0038] In embodiments, the present disclosure provides a method for the treatment of agitation in a subject in need thereof, comprising administering to said subject: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0039] In an embodiment, 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 an embodiment, the agitation is associated with sundowning syndrome in Alzheimer's disease / dementia. In an embodiment, the agitation is chronic and associated with dementia.

[0040] 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., MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure).

[0041] In an embodiment, the agitation is caused by noradrenergic hyperarousal.

[0042] In embodiments, agitation is treated without inducing significant sedation.

[0043] 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 as a result of administration of cocaine. In embodiments, the agitation is caused as a result of administration of lurasidone. In embodiments, the agitation is caused as a result of administration of mirtazapine. In embodiments, the agitation is caused as a result of administration of esmirtazapine. In embodiments, the agitation is caused as a result of administration of atipamezole. In embodiments, the agitation is caused as a result of administration of trazodone. In embodiments, the disclosure provides a method of treating agitation in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused due to administration of yohimbine.

[0044] 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.

[0045] In an embodiment, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0046] The present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0047] The present disclosure provides a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.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 pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0048] In an embodiment, the present disclosure provides a method of 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 pharma- ceutically acceptable salt thereof, and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically 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 has a HAM-D-17 total score of ≧18 at the start of treatment.

[0049] In an embodiment, the present disclosure provides a method for reducing a score on the HDRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.In an embodiment, the present disclosure provides a method for reducing a score on the HDRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0050] In embodiments, the present disclosure provides a method of 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 pharma- ceutically acceptable salt thereof.

[0051] In an embodiment, 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 an embodiment, 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 an embodiment, 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.

[0052] In an embodiment, the depression is moderate or severe. In an embodiment, the depression is major depression, bipolar disorder or mixed depression.

[0053] In an embodiment, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once daily, twice daily, three times daily or four, five or six times daily, preferably once, two or three times daily.

[0054] 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.

[0055] 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 pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0056] In an embodiment, 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 latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0057] In an embodiment, the disclosure provides a method of treating a psychosis in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, to the subject via the oral mucosa (e.g., sublingual, buccal, or gingival).

[0058] In an embodiment, the 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0059] In embodiments, the disclosure provides a method of treating a psychosis in a subject in need thereof, comprising oral mucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0060] In embodiments, treatment is effective without causing significant sedation.

[0061] In an embodiment, the treatment is effective without experiencing clinically significant cardiovascular effects. In an embodiment, the severity of psychosis in a subject is assessed using the PANSS scale.

[0062] In embodiments, the disclosure provides a method of 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 pharma- ceutically acceptable salt thereof.

[0063] In embodiments, the 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 pharma- ceutically acceptable salt thereof.

[0064] In embodiments, the 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 pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof.

[0065] In embodiments, the 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0066] In an embodiment, the decrease in PANSS score is at least about 20% to about 50% from the baseline score. In an embodiment, the decrease in PANSS score is about 25% from the baseline score. In an embodiment, the decrease in PANSS total score is about 30% from the baseline score. In an embodiment, the decrease in PANSS total score is about 35% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 40% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 45% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 50% points from the baseline score.

[0067] 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.

[0068] In an embodiment, 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 an embodiment, the psychosis is associated with a neurodegenerative disorder.

[0069] In embodiments, the psychosis is associated with a medical condition such as a substance abuse disorder (eg, alcohol, opioid and other substance withdrawal).

[0070] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is single episode. In embodiments, the psychosis is relapsing or comprises relapsing episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes.

[0071] In embodiments, the dosage form disintegrates within about 1 second to about 10 minutes after contacting the oral mucosa. In embodiments, the dosage form disintegrates in more than 1 minute after contacting the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 2 minutes after contacting the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 5 minutes after contacting the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 10 minutes after contacting the oral mucosa. In embodiments, the dosage form disintegrates in less than 60 seconds.

[0072] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; The dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0073] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; The dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0074] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (iii) one or more mucoadhesives, and (iv) one or more pharma- ceutically acceptable excipients or carriers; The dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0075] In embodiments, the buccal dosage form is a tablet, capsule, patch, film, sachet, cachet, 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.

[0076] 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).

[0077] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical 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 pharma- ceutically 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.

[0078] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical 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 pharma- ceutically 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.

[0079] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical 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 pharma- ceutically acceptable excipients; 4. A freeze-dried sublingual, buccal or gingival tablet comprising: (viii) the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0080] In embodiments, the dosage form comprises: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical 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 pharma- ceutically 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.

[0081] 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 pharma- ceutically acceptable salts thereof. In an embodiment, the agitation is caused by noradrenergic hyperarousal. In an embodiment, the agitation is treated without inducing significant sedation.

[0082] In an embodiment, dexmedetomidine and latrepirdine are provided in a single dosage form as a buccal tablet for treating depression comprising therapeutically effective amounts of dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof.

[0083] In an embodiment, dexmedetomidine and latrepirdine are provided in two separate dosage forms, one containing a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, as an oromucosal tablet for treating agitation. In an embodiment, the active agents dexmedetomidine and latrepirdine are co-administered 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.

[0084] In an embodiment, dexmedetomidine and latrepirdine are provided in two separate dosage forms, one containing a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof, and the other containing a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, as an oromucosal tablet for treating depression in a subject. In an embodiment, the active agents dexmedetomidine and latrepirdine are co-administered to a subject in need thereof. In an embodiment, the active agents dexmedetomidine and latrepirdine are administered sequentially to a subject in need thereof.

[0085] In an embodiment, the active agents dexmedetomidine and latrepirdine, or pharma- ceutically acceptable salts thereof, are co-administered (e.g., in a single dosage form or in 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 prior to administration of latrepirdine so that symptoms are alleviated 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.

[0086] In embodiments, the active agents dexmedetomidine and latrepirdine, or pharma- ceutically acceptable salts thereof, are administered for a particular 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 holiday 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 in two separate dosage forms) to the 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.).

[0087] In embodiments, the active agent is administered 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 , 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, etc. (including all ranges and values ​​in between). In an embodiment, the active agents are co-administered simultaneously or within a short time, usually less than about 60 minutes (i.e., about 1 hour), preferably within about 45 minutes, more preferably within about 15 minutes. In an embodiment, the active agents are co-administered simultaneously or within a short time, usually less than about 60 minutes (i.e., about 1 hour), preferably within about 45 minutes, more preferably within about 15 minutes.

[0088] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and (iii) instructions for administering (i) and (ii) to a subject in need thereof; The present invention provides an individual unit oral mucosal freeze-dried tablet form provided as a kit comprising:

[0089] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a first buccal freeze-dried tablet form comprising a therapeutic amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof; (ii) a second buccal freeze-dried tablet form comprising a therapeutic amount of latrepirdine or a pharma- ceutically 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 description of the drawings]

[0090] [Figure 1] Figure 1 illustrates 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. [Diagram 2] 1 shows the study design and administration time points of various drugs according to Example 2. [Diagram 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 in comparison with Wistar rats administered yohimbine hydrochloride (2.5 mg / kg). [Figure 4] According to Example 2, the number of entries into the open arms of an elevated plus maze by Wistar rats administered yohimbine hydrochloride (2.5 mg / kg) followed by administration of latrepirdine (3 mg / kg and 10 mg / kg) is shown in comparison with dextromethorphan hydrobromide (10 mg / kg) and fluvoxamine maleate (10 mg / kg). [Diagram 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) followed by administration of 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 (3 mg / kg + saline) itself. [Figure 6] According to Example 3, the number of entries into the open arms of the elevated plus maze by Wistar rats treated with yohimbine hydrochloride (2.5 mg / kg) followed by administration of 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 (3 mg / kg + saline) itself. [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 behavior (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 effect 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 behavior (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 effect 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 Assay is shown. [Figure 8B] According to Example 5, the effect 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 Assay is 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 Assay. [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 Assay. [Figure 10] According to Example 5, the effect 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 a combination 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 Assay. [Figure 11] According to Example 6, the SMARTCUBE signatures of dexmedetomidine hydrochloride, latrepirdine and the combination of dexmedetomidine hydrochloride and latrepirdine on antipsychotic behavior are shown. [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 a 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 (in centimeters) in Swiss albino mice in the open field test are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] Yohimbine is an alpha 2 adrenergic antagonist, useful for testing 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.

[0092] Administration of an alpha2 adrenergic receptor agonist or a pharma- ceutically 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-agitational effects when administered intravenously during surgical procedures and intensive care unit (ICU) set-up.

[0093] 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 over conventional treatments, in addition to other advantages.

[0094] As described in Example 4 below, in a rodent forced swimming model, it was discovered that administration of a combination including latrepirdine and dexmedetomidine resulted in a significant increase in swimming behavior (correlated with an antidepressant effect) compared to administration of dexmedetomidine and latrepirdine individually. Abbreviation AD: Alzheimer's disease AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA: Analysis of variance 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 MRI: Magnetic resonance imaging μg: microgram mg: milligram MADRS: Montgomery-Asberg Depression Rating Scale MW: molecular weight NE: norepinephrine NMDA: N-methyl-D-aspartic acid OPD:Outpatient Department PANSS: Positive and Negative Symptoms Scale PTSD: Post-traumatic stress disorder wt%: weight percentage

[0095] 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.

[0096] Unless otherwise indicated, reference herein to compounds such as latrepirdine, dexmedetomidine, etc., by structure, name, or any other means includes pharma- ceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, etc., tautomers, deuterium-modified compounds, e.g., deuterium-modified latrepirdine or dexmedetomidine, or any chemical species to which the compounds described herein may be rapidly converted under the conditions in which they are used as described herein.

[0097] 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.

[0098] 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 within that range (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, all values ​​within a given range may be endpoints of the range encompassed thereby (e.g., the range 50 to 80 includes ranges having endpoints of 55 to 80, 50 to 75, etc.).

[0099] 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 there is more than one agent.

[0100] As used herein, the term "comprise" and its conjugations as used in the specification and claims are used in their open-ended sense meaning to include what follows the word but not to exclude what is not specifically mentioned. The disclosure may "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims, as appropriate.

[0101] As used herein, the term "subject" preferably refers to a human patient. In embodiments, the subject may be any animal, including non-human mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates.

[0102] As used herein, the terms "dosage form," "pharmaceutical composition," "composition," "formulation," and "composition of the disclosure" are used interchangeably unless otherwise indicated. Unless otherwise indicated, the terms are meant to encompass, but are not limited to, dosage forms that contain the active pharmaceutical ingredient, i.e., dexmedetomidine or latrepirdine, or both.

[0103] 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 of a subject. An effective amount may be administered in one or more administrations, applications, or dosages.

[0104] 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.The preferred salt is the hydrochloride (or dihydrochloride).

[0105] 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 disorder, the term "treatment" can refer to alleviating or reducing agitation and any combination of its symptoms in a subject that exhibits agitation (e.g., pacing, rocking, gesturing, pointing, restlessness, performing repetitive habits, screaming, talking excessively loudly, swearing, screaming, yelling, grabbing, pushing, poking, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, 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, one skilled in the art will understand that treatment can be measured with respect to well-known agitation scales, such as 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 agitation is treated in a patient, the patient may experience a reduction in 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, treated patients may be measured on the CGI-I scale and may refer to patients 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 patients with a score of 3, 4, 5, 6, or 7.

[0106] 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.

[0107] The term "sublingual" means "under the tongue" and refers to a method of administering a substance through the oral cavity in such a manner that the substance is rapidly absorbed through the blood vessels under the tongue, rather than through 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 form of the present disclosure sublingually, the total amount of latrepirdine and / or dexmedetomidine can be reduced, thereby reducing the possibility of adverse side effects and providing cost benefits to the manufacturer.

[0108] The term "buccal" refers to administration of a dosage form to the gums and inner lips or cheeks. Oral mucosal absorption occurs via the highly vascularized mucosa, allowing a substance direct access to the blood circulation, thereby providing direct systemic administration independent of gastrointestinal action and avoiding undesirable first-pass hepatic metabolism.

[0109] 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 eventually into fine and large particles, or by the dosage form eroding from the outside until it disappears.

[0110] 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 the practice of the present disclosure, including drug formulations as described herein. Oral dosage forms are typically sublingual or buccal dosage forms, although in some cases other oral transmucosal routes may be employed. The present disclosure relies on such oral dosage forms to provide sustained delivery of the drug 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 the 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 as described in more detail herein.

[0111] 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, such as the USP <701> Disintegration can be measured using the disintegration test method. As explained in the above 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, defined in Section 701 of USP 24-NF 19 as the condition in which any residue of the 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.

[0112] The term "film" as used herein 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 more than about 30 millimeters.

[0113] 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 in terms of "mucoadhesive strength" or "mucoadhesive peak force."

[0114] The term "mucoadhesive" refers to a material that adheres to mucosal tissue surfaces in vivo such that the dosage form adheres and localizes on the mucosa, requiring the application of a force to separate the mucoadhesive material from the mucosa.

[0115] As used herein, "treatment" can mean treatment and / or prophylaxis, depending on the context.

[0116] 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 a specific brain region, such as the frontal lobe, or dysfunction of a neurotransmitter system, 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.

[0117] The term "acute agitation" refers to 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.

[0118] 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.

[0119] 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").

[0120] The term "neurodegenerative disorder" includes, but is not limited to, Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia (e.g., Lewy body dementia, vascular dementia), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular cognitive disorder, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0121] The term "neuropsychiatric disorder" includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, and delirium.

[0122] The term "sundown syndrome" generally refers to a circadian syndrome in which confusion, agitation, and / or restlessness increases later in the day in patients with some form of dementia. Some subjects suffering from sundown syndrome may have more than one disease or disorder. For example, a patient with sundown syndrome may suffer from dementia, Alzheimer's disease, or both. Approximately 20-45% of Alzheimer's patients will experience some form of sundown confusion. Sundown syndrome also refers to confusion and / or agitation that worsens in the late afternoon, evening, or as the sun sets.

[0123] 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.

[0124] The term "freeze-drying" or "lyophilization" refers 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.

[0125] The term "pharmacologically 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.

[0126] As used herein, the term "unit dosage form" refers to physically discrete units suited as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

[0127] 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.

[0128] Within the meaning of this disclosure, the terms "co-administration" or "simultaneous administration" are used to refer to the administration of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and latrepirdine, or a pharma- ceutically acceptable salt thereof, at the same time, either in separate formulations or as a combined formulation (i.e., in a single dosage form).

[0129] The term "sequential administration" refers to the administration of latrepirdine and dexmedetomidine in two or more separate dosage forms, one after the other (i.e., not simultaneously). When the disclosed drug substances are administered sequentially, typically administration of the last drug substance begins within one hour, and generally within 30 minutes, of administration of the first drug substance beginning.

[0130] 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.

[0131] The term "spray drying" refers to a process that involves breaking up a liquid mixture into small droplets (atomization) in a spray drying device 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 prior art. 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.

[0132] The term "sublimation" refers to a direct physical phase transition from a solid state 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 may be achieved by the freeze-drying process.

[0133] 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 includes 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 includes 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 compressed granules or compressed granules as disclosed herein are preferably prepared by dry granulation.

[0134] "Direct compression" refers to a process that involves mixing the ingredients and then compressing them into a tablet.

[0135] I. Activators The IUPAC name for dexmedetomidine is (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As the monohydrochloride salt, it is primarily used as a medicine for sedation of patients during treatment in intensive care settings or to sedate patients before and / or during surgery and other procedures. Such medicines are currently sold under the trademark name "PRECEDEX®".

[0136] Pharmaceutically acceptable salts of dexmedetomidine that may be used herein generally include any suitable salt that has been or may be approved by the US FDA or other appropriate domestic or international agencies for administration to humans. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, 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 acid salts thereof. 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 pharma- ceutically acceptable salt thereof may be included.

[0137] 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, which is to be understood herein to include any pharma- ceutically acceptable form. By "pharma-ceutically acceptable form" is meant any pharma-ceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, cocrystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. It may exist in the form of salts with pharma-ceutically acceptable acids, and in the form of quaternized derivatives. Pharmaceutically acceptable base addition salts may be prepared from inorganic and / or organic bases.

[0138] Pharmaceutically acceptable acid addition salts of latrepirdine are prepared in a conventional manner by treating free base solution or suspension with, for example, one or two chemical equivalents of a pharma-ceutically 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, 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.

[0139] II. Dosage In an embodiment, the dosage of dexmedetomidine or a pharma- ceutically acceptable salt thereof administered may conveniently range between about 0.5 micrograms and about 300 micrograms. Examples of suitable dosages include about 0.5 micrograms to about 280 micrograms, about 1 micrograms to about 270 micrograms, about 1 micrograms to about 260 micrograms, about 1 micrograms to about 250 micrograms, about 1 micrograms to about 240 micrograms, about 1 micrograms to about 230 micrograms, about 1 micrograms to about 220 micrograms, about 1 micrograms to about 210 micrograms, about 1 micrograms to about 200 micrograms, about 1 micrograms to about 190 micrograms, about 1 micrograms to about 180 micrograms, about 1 micrograms to about 170 micrograms, about 1 micrograms to about 160 micrograms, about 1 micrograms to about 150 micrograms, about 1 micrograms to about 140 micrograms, about 1 micrograms to about 180 micrograms, about 1 micrograms to about 190 micrograms, about 1 micrograms to about 200 micrograms, about 1 micrograms to about 220 micrograms, about 1 micrograms to about 230 micrograms, about 1 micrograms to about 220 micrograms, about 1 micrograms to about 210 micrograms, about 1 micrograms to about 200 micrograms, about 1 micrograms to about 190 micrograms, about 1 micrograms to about 180 micrograms, about 1 micrograms to about 170 micrograms, about 1 micrograms to about 160 micrograms, about 1 micrograms to about 150 micrograms, about 1 microgram Micrograms 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 about 35 micrograms. The dose may be administered once or more times per day, for example, 2, 3, 4, 5, or 6 times per day.

[0140] In embodiments, dexmedetomidine or a pharma- ceutically 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 in between).

[0141] Each unit may be administered to a subject one or more times per day, for example, 1, 2, 3, 4, 5, or 6 times per day. In embodiments, each unit may be administered with an appropriate dosing interval (e.g., about 1 hour between each administration) or may be administered simultaneously.

[0142] 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 pharma- ceutically acceptable salt thereof. In an embodiment, the total daily dose of dexmedetomidine or a pharma- ceutically acceptable salt thereof is from about 0.5 micrograms to about 500 micrograms, for example, the total daily dose is from 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, 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).

[0143] In an embodiment, the daily dose of latrepirdine or a pharma- ceutically acceptable salt thereof administered may conveniently range between about 0.5 mg and about 100 mg. Examples of suitable dosage amounts 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 3 ... 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 the amount 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, or about 5 mg to about 10 mg.In an embodiment, the daily dose of latrepirdine or a pharma- ceutically 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 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).

[0144] 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.

[0145] Exemplary dosages of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt) and latrepirdine or a pharma- ceutically acceptable salt thereof (e.g., the dihydrochloride salt) to be administered to a particular patient will depend on the type and extent of the condition, the overall health of the particular patient, the particular forms of dexmedetomidine and latrepirdine or their pharma- ceutically acceptable salts being administered, and the particular formulations used to treat the patient.

[0146] III. Dosage form In embodiments, the present disclosure provides an oral mucosal dosage form comprising latrepirdine or a pharma- ceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharma- ceutically acceptable excipients or carriers.

[0147] 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 an embodiment, the dosage form disintegrates in less than about 1 minute, 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) after contacting the oral mucosa. In an embodiment, the dosage form does not disintegrate within 1 minute after contacting the oral mucosa. In an embodiment, the dosage form disintegrates in more than 1 minute, 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 after contacting the oral mucosa. 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.

[0148] 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.

[0149] In embodiments, the 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.

[0150] 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. In embodiments, the dosage forms described herein effectively reduce noradrenergic hyperarousal.

[0151] In an embodiment, the dosage form described herein effectively treats depression in a subject. For example, the dosage form described herein effectively treats depression in a subject as measured by the HAM-D scale or the MADRS scale. In an embodiment, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., hydrochloride salt), one or more mucoadhesives, and one or more pharma- ceutically acceptable excipients or carriers for treating agitation. In an embodiment, the dosage form disintegrates in less than about 1 minute after contacting 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 ​​in between). In an embodiment, the dosage form disintegrates in more than about 1 minute after contacting 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 contacting 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 form described herein effectively treats depression in a subject.

[0152] In an embodiment, the present disclosure provides an oral mucosal dosage form for treating agitation, comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof and latrepirdine or a pharma- ceutically acceptable salt thereof, one or more mucoadhesives, and one or more pharma- ceutically acceptable excipients or carriers. In an embodiment, the dosage form disintegrates in less than about 1 minute after contacting 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 contacting the oral mucosa. In an embodiment, the dosage form disintegrates in about 1 minute or more after contacting 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 an embodiment, the dosage form effectively treats agitation in a subject. In embodiments, the dosage forms effectively treat 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.

[0153] In an embodiment, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and a second oromucosal dosage form comprising latrepirdine, or a pharma- ceutically acceptable salt thereof, for co-administration, either simultaneously or sequentially, to treat agitation.

[0154] In embodiments, the dosage form is administered for the treatment of agitation associated with neurodegenerative disorders, neuropsychiatric disorders, and substance abuse withdrawal, including alcohol withdrawal or opioid withdrawal, hi 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).

[0155] In an embodiment, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and a second oromucosal dosage form comprising latrepirdine, or a pharma- ceutically acceptable salt thereof, for co-administration, either simultaneously or sequentially, to treat depression in a subject.

[0156] 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, cachet, 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.

[0157] In an embodiment, the dosage form is an oral mucosal wafer. In an embodiment, the wafer is lyophilized. 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 comprises an excipient, such as hydroxypropylcellulose, lactose, mannitol, glycine, etc.

[0158] 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.

[0159] In an embodiment, the buccal dosage form is in the form of a tablet or round disc or in the form of a packed powder.

[0160] In an embodiment, the dosage form is a hard or compressed powder sublingual or buccal tablet with low coarse content for an organoleptically pleasant mouthfeel.In an embodiment, the tablet (or its particles containing active agents that can be compressed to form a tablet) contains a protective outer coating, such as any polymer that is 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, which is incorporated herein by reference in its entirety for all purposes.

[0161] In an embodiment, the oral mucosal tablet advantageously contains the active ingredient in a base. In an embodiment, 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 may advantageously have a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

[0162] In an embodiment, the oral mucosal dosage form is in the form of a patch or a film (e.g., a thin film).The patch can have adhesive properties to prevent the patch from moving or being swallowed.A suitable film composition comprising dexmedetomidine is disclosed in U.S. Patent No. 10,792,246, the entirety of which is incorporated herein by reference for all purposes.

[0163] 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.

[0164] In embodiments, the oral mucosal dosage form is in liquid form (e.g., as a solution, suspension or emulsion), and may be presented as, for example, a spray or drops. In certain embodiments of the present disclosure, latrepirdine and / or dexmedetomidine, or a pharma- ceutically acceptable salt thereof, is administered to the oral mucosa in liquid form, for example, a flavored or unflavored saline solution. The liquid dosage form may conveniently be administered under the tongue or near the gums or cheek or on the upper lip as drops or spray. The solution contains 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, and the like. The diluent for the solution may be, in particular, saline solution or water.

[0165] The spray dosage form of the present disclosure for oral mucosal administration may include one or more pharma- ceutically 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 their pharma- ceutically acceptable salts. Examples of pharma-ceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharma-ceutically acceptable oils (e.g., soybean, sunflower, peanut, mint, etc.), and the like. The pharma-ceutically acceptable liquid is selected to dissolve the active pharmaceutical ingredient, to produce a stable homogenous suspension or solution thereof, or to form any combination of suspensions or solutions. In addition to these components, the spray formulation may contain one or more excipients such as viscosity modifiers (e.g., polymers, sugars, sugar alcohols, gums, clays, silicas, etc., e.g., polyvinylpyrrolidone (PVP)), preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben), flavorings (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, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.).

[0166] Aerosols can be prepared by mixing the above-mentioned components in appropriate amounts according to 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.

[0167] In one embodiment, the patient may be treated by sublingual or buccal administration with one or two actuations of the spray pump. The advantage of spray delivery is that it can be easily titrated to the patient with one or two doses per single actuation, as needed.

[0168] Pump-actuated sprays are characterized in that they require the application of external pressure for actuation, e.g., pressure that is externally initiated manually, mechanically, or electrically. This is 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).

[0169] Non-solid dosage forms of the present disclosure may be conveniently administered by spraying, dropping, smearing or squirting the composition under the tongue or near the gums or cheek or onto the upper lip.

[0170] 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 suitable excipients, and the active agent (latrepirdine / dexmedetomidine) suspension may be dispensed into blister packs and freeze-dried. An exemplary freeze-drying preparation platform that may be used for latrepirdine and / or dexmedetomidine orally disintegrating tablets (ODT) is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipients are blended, and the active agent is milled and granulated separately, and then mixed with the excipients. The solution / suspension is then lyophilized by quick freezing and freeze-drying. This aqueous solution / suspension must be chemically and morphologically stable throughout the administration process. Gelatin may be used to give the dosage form sufficient strength to prevent breakage upon removal from the package, but once in the mouth, the dosage form will disintegrate immediately due to the gelatin. Other alternatives such as fish gelatin and modified starch may be used. During processing, the dosing solution / suspension is preferably frozen by passing it through a gaseous medium. This allows the solution / suspension to be rapidly immobilized, thereby improving manufacturing efficiency.Examples of buccal dosage forms include those described 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 No. 29,958, U.S. Patent No. 6,726,928, U.S. Patent No. 9,192,580, U.S. Patent No. 6,709,669, U.S. Application Publication No. 20200138721, U.S. Application Publication No. 20190276707, U.S. Application Publication No. 20190314274, U.S. Application Publication No. 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351, and U.S. Application Publication No. 20090226522 and related patents / patent applications.

[0171] Other methods of preparing oral mucosal dosage forms, such as ODTs, may be used without limitation, and detailed descriptions of such general methods can be 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, 6,471,992, 6,814,978, 6,908,626, 6,982,226, and 6,102,232, 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.

[0172] 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.

[0173] In embodiments, oral mucosal dosage forms (e.g., sublingual or buccal or gingival tablets) of the present disclosure may be prepared by sublimation, nanonization, spray drying, granulation (including wet granulation, dry granulation) or direct compression methods, etc. 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.

[0174] In embodiments, the buccal tablet form used herein may be prepared by direct compression, which involves mixing the active agents (latrepirdine and / or dexmedetomidine) with one or more pharma- ceutically acceptable excipients, lubricating the mixture, and tableting by direct compression.

[0175] In an embodiment, the method comprises the steps of: (i) preparing a mixture containing an active agent (latrepirdine and / or dexmedetomidine) and one or more pharma- ceutically 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; There is provided a process for preparing an oral mucosal tablet form by dry granulation, comprising:

[0176] In an embodiment, the compacting in step (ii) is carried out by roller compaction or slugging techniques.

[0177] In an embodiment, the method comprises the steps of: (i) preparing a mixture containing an active agent (latrepirdine and / or dexmedetomidine) and one or more pharma- ceutically acceptable excipients; (ii) granulating the mixture obtained in step (i) with a suitable granulation fluid to form a wet granulation; (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; There is provided a process for preparing an oral mucosal tablet form by wet granulation, comprising:

[0178] 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.

[0179] 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.

[0180] In an embodiment, latrepirdine, or a pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma- ceutically acceptable salt thereof, are formulated as a sublingual or buccal tablet.

[0181] In an embodiment, the dosage form comprises a mucoadhesive for adhering the active agent(s) to the oral mucosa. The mucoadhesive has the property of swelling and expanding on contact with water, thus allowing the tablet to disintegrate when wetted with saliva. In an embodiment, 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 , 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 present in an amount of about 1% w / w to about 5% 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 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 % 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).

[0182] In embodiments, the mucoadhesive dosage form has a viscosity of at least about 50 dynes / cm2 , for example, about 50 dynes / cm 2 , about 75 dynes / cm 2 , about 100 dynes / cm 2 , about 150 dynes / cm 2 , about 200 dynes / cm 2 , about 250 dynes / cm 2 , about 300 dynes / cm 2 , about 350 dynes / cm 2 , about 400 dynes / cm 2 , about 450 dynes / cm 2 , about 500 dynes / cm 2 , about 550 dynes / cm 2 , approximately 600 dynes / cm 2 , approximately 650 dynes / cm 2 , about 700 dynes / cm 2 , about 750 dynes / cm 2 , about 800 dynes / cm 2 , approximately 850 dynes / cm 2 , about 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 strength of greater than about 50g, about 100g, about 200g, about 300g, about 400g, about 500g, about 600g, about 700g, about 800g, about 900g, about 1000g, about 1100g, about 1200g, about 1300g, about 1400g, or about 1500g. In embodiments, the dosage form has a mucoadhesive peak strength of greater than about 50g, about 100g, about 200g, about 300g, about 400g, about 500g, about 600g, about 700g, about 800g, about 900g, about 1000g, about 1100g, about 1200g, about 1300g, about 1400g, or about 1500g (including all ranges and values ​​in between).

[0183] 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), ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose (e.g., HPMC-K100L or low viscosity grades such as 4000 cps), methyl cellulose, carboxymethyl cellulose, ... Examples of suitable cellulose acetate hydrochloride 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), croscarmelose, poloxamer (i.e., a non-ionic triblock copolymer consisting of a central polyoxypropylene hydrophobic chain flanked by two polyoxyethylene hydrophilic chains, e.g., Poloxamer 407), and mixtures thereof.

[0184] 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.

[0185] 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.

[0186] 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 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 2-12 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 an embodiment, the diluent / filler (or base former) is present in the range of 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).

[0187] 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 their salts, 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).

[0188] In embodiments, examples of suitable flow agents are selected from the group including calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, talc, colloidal silicon dioxide, silica gel, precipitated silica, and mixtures thereof. In embodiments, the flow agent is present in the range of about 0% to about 5% w / w of the dosage form. For example, the amount of flow 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 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).

[0189] In embodiments, examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearyl, sucrose fatty acid esters, aluminum stearate, sodium potassium tartrate, light anhydrous silicic acid, carnauba wax, carmellose calcium, carmellose sodium, silicon dioxide hydrate, hydrogenated oils, 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).

[0190] In embodiments, examples of suitable plasticizers include, but are not limited to, macrogol, triethyl citrate, acetylated monoglycerides, glycerin, monoacetin, diacetin, triacetin, phthalic acid 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).

[0191] In embodiments, examples of suitable pH adjusting agents 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 adjusting agent is present in a range of about 0% to about 2% w / w of the dosage form. For example, the amount of pH adjusting agent 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).

[0192] 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., iron oxide red, iron oxide yellow, iron oxide black), 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).

[0193] In embodiments, examples of suitable flavoring agents include, but are not limited to, strawberry, apple, pear, peach, plum, orange, pineapple, apricot, lemon, peppermint, black currant, banana, raspberry, raspberry aroma, wild berry, caramel, mint, licorice, grapefruit, caramel, vanilla, cherry, and grape flavor, flavor oils such as cinnamon oil, oil of wintergreen, 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).

[0194] In embodiments, suitable flavoring agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents, or microencapsulated actives. 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 range from about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, 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).

[0195] In embodiments, suitable viscosity enhancing agents include, but are not limited to, polymers, sugars, sugar alcohols, gums, clays, silicas, and the like. 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 range from about 0.1% w / w to about 65% w / w, about 0.1% w / w to about 50% w / w, about 0.1% w / w to about 20% w / w, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 5% w / w to about 65% w / w, about 5% w / w to about 50% w / w, and the like. 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, from about 30% w / w to about 35% w / w, from about 40% w / w to about 65% w / w, from about 40% w / w to about 50% w / w, from about 40% w / w to about 45% w / w, from about 50% w / w to about 65% w / w, from about 50% w / w to about 60% w / w, or from about 50% w / w to about 55% w / w. In embodiments, the viscosity enhancing agent is 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).

[0196] In embodiments, examples of suitable sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, sorbitol, erythritol, xylitol, aspartame, stevia extract, licorice, mogroside, sodium cyclamate, saccharin, sodium saccharin, 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).

[0197] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically 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).

[0198] In an embodiment, the mucoadhesive is sodium alginate. In an embodiment, the mucoadhesive is carbomer.

[0199] In an embodiment, there is provided an oral mucosal (e.g., sublingual or buccal or gingival) freeze-dried tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically 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 pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in more than about 1 minute after contact with the oral mucosa.

[0200] In an embodiment, an oral mucosal (e.g., sublingual or buccal or gingival) freeze-dried tablet is provided that comprises (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, (ii) sodium alginate, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) mannitol, and (vii) optionally other pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in more than about 1 minute after contact with the oral mucosa.

[0201] In an embodiment, an oral mucosal (e.g., sublingual or buccal or gingival) freeze-dried tablet is provided that comprises (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) magnesium stearate, (vi) mannitol, and (vii) optionally other pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0202] In an embodiment, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided that comprises (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) lactose monohydrate, and (vii) optionally other pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0203] In an embodiment, the mucoadhesive is xanthan gum.

[0204] In an embodiment, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided that comprises (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically 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 pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0205] In an embodiment, an oral mucosal (e.g., sublingual or buccal) freeze-dried tablet is provided that comprises (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, (ii) xanthan gum, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) silicon dioxide, (vi) mannitol, and (vii) optionally other pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0206] In an embodiment, the dosage form is a sublingual tablet and is oval or oblong. In an embodiment, the dosage form is a buccal tablet and is oblong. In an embodiment, the dosage form is used to treat agitation. In an embodiment, the dosage form is used to reduce noradrenergic hyperarousal. In an embodiment, the dosage form is used to treat depression.

[0207] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; The present invention provides an oral mucosal tablet form comprising:

[0208] In embodiments, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0209] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; The present invention provides an oral mucosal tablet form comprising:

[0210] In embodiments, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0211] In an embodiment, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (iii) one or more mucoadhesives, and (iv) one or more pharma- ceutically acceptable excipients or carriers; The present invention provides an oral mucosal tablet form comprising:

[0212] In an embodiment, the tablet disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

[0213] In embodiments, the dosage form is lyophilized (freeze-dried).

[0214] In an embodiment, the dosage form is used to treat agitation caused by noradrenergic hyperarousal. In an embodiment, the agitation is treated in a subject without causing significant sedation. In an embodiment, the dosage form is used to treat depression in a subject.

[0215] 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 pharma- ceutically acceptable salt thereof, (ii) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof, (iii) sodium alginate, xanthan gum, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 pharma- ceutically acceptable excipients. In an embodiment, the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0216] In an embodiment, the oral mucosal tablet contains about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, and about 0.1 mg to about 100 mg of latrepirdine per unit. In an embodiment, the oral mucosal tablet contains about 10 micrograms to about 240 micrograms (e.g., about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, about 180 micrograms, about 210 micrograms, or about 240 micrograms (including all intermediate ranges and values)) of dexmedetomidine or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof per unit.

[0217] 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.

[0218] IV. Methods and Administration In an embodiment, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, hi an embodiment, the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein.

[0219] In embodiments, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. In embodiments, latrepirdine or a pharma- ceutically acceptable salt thereof is administered 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 (e.g., daily).

[0220] In an embodiment, the disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In an embodiment, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In an embodiment, the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein. In an embodiment, the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein. In an embodiment, the therapeutically effective amounts of latrepirdine and dexmedetomidine or pharma- ceutically acceptable salts thereof are present in the same dosage form or in separate dosage forms as described herein.

[0221] In embodiments, the active agents dexmedetomidine and latrepirdine are administered simultaneously (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.).

[0222] The present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., hydrochloride). In an embodiment, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In an embodiment, a single administration of the combination treats agitation and maintains a sedative effect for at least 12 hours. In an embodiment, the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein. In an embodiment, the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein. In an embodiment, the therapeutically effective amounts of latrepirdine or a pharma- ceutically acceptable salt thereof and dexmedetomidine or a pharma- ceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0223] In embodiments, the agitation can be acute agitation, chronic agitation, or both.

[0224] In an embodiment, the agitation is caused by noradrenergic hyperarousal.

[0225] In embodiments, agitation is treated without causing any significant sedation.

[0226] In embodiments, the agitation is associated with a neuropsychiatric disorder selected from schizophrenia, bipolar disorder, bipolar mania, delirium, depression or other related neurodegenerative disorders.

[0227] In an embodiment, 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.

[0228] In embodiments, the agitation is associated with substance abuse withdrawal, including alcohol withdrawal or opioid withdrawal.

[0229] 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 pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In an embodiment, the subject suffers from dementia. In an embodiment, dementia includes Alzheimer's dementia (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's syndrome dementia.

[0230] In an embodiment, the present disclosure provides a method of treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof. In an embodiment, the subject suffers from dementia. In an embodiment, dementia includes Alzheimer's dementia (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's syndrome dementia.

[0231] In an embodiment, the present disclosure provides a method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the agitation is caused by noradrenergic hyperarousal. In an embodiment, the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein. In an embodiment, the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in a dosage form as described herein.

[0232] In an embodiment, the agitation is severe. In an embodiment, the agitation is mild.

[0233] 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 pharma- ceutically acceptable salt thereof, wherein the subject suffers from Alzheimer's disease.

[0234] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Alzheimer's disease.

[0235] 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 pharma- ceutically acceptable salt thereof, wherein the subject suffers from concomitant dementia.

[0236] 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from concomitant dementia.

[0237] 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 pharma- ceutically acceptable salt thereof, wherein the subject suffers from Parkinson's disease.

[0238] 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Parkinson's disease.

[0239] In embodiments, the disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from co-occurring PTSD.

[0240] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from PTSD.

[0241] 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 pharma- ceutically acceptable salt thereof, wherein the subject suffers from concurrent vascular cognitive impairment.

[0242] 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from concurrent vascular cognitive impairment.

[0243] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Huntington's disease.

[0244] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Huntington's disease.

[0245] In embodiments, the disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from schizophrenia.

[0246] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from schizophrenia.

[0247] In embodiments, the disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from a co-occurring bipolar disorder.

[0248] In embodiments, the disclosure provides a method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from a co-occurring bipolar disorder.

[0249] In embodiments, the disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from co-occurring depression.

[0250] 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from co-occurring depression.

[0251] In embodiments, the disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from delirium.

[0252] 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject is also suffering from delirium.

[0253] 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 pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride); (ii) about 0.1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof; to said subject.

[0254] 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 pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma- ceutically acceptable salt thereof, are present in the same dosage form or in separate dosage forms, as described herein.

[0255] 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 pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride); (ii) about 5 mg to about 50 mg of latrepirdine or a pharma- ceutically acceptable salt thereof; to said subject.

[0256] 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 pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma- ceutically acceptable salt thereof, are present in the same dosage form or in separate dosage forms, as described herein.

[0257] 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 pharma- ceutically acceptable salt thereof.

[0258] In embodiments, the disclosure provides a method for reducing noradrenergic hyperarousal, comprising oromucosally administering to a subject a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

[0259] 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 pharma- ceutically acceptable salts thereof are administered as a single dose, either via a single unit dosage form or 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.

[0260] In embodiments, the disclosure provides a method of treatment comprising administering dexmedetomidine or a pharma- ceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation, followed by continuing treatment with latrepirdine or a pharma- ceutically acceptable salt for an effective period of time.

[0261] In an embodiment, the disclosure provides a method of treating behavioral and psychological symptoms in a subject with a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, hi an embodiment, the behavioral and psychological symptoms include agitation or aggression.

[0262] In embodiments, the disclosure provides a method of treating behavioral and psychological symptoms in a subject with a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latrepirdine and dexmedetomidine or pharma- ceutically acceptable salts thereof, hi embodiments, the behavioral and psychological symptoms include agitation or aggression.

[0263] In an embodiment, the 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 or a pharma- ceutically acceptable salt thereof, hi an embodiment, the behavioral and psychological symptoms include agitation or aggression.

[0264] In embodiments, the 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 pharma- ceutically acceptable salts thereof, hi embodiments, the behavioral and psychological symptoms include agitation or aggression.

[0265] In embodiments, the present disclosure provides the use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0266] In embodiments, the present disclosure provides the use of therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharma- ceutically acceptable salts thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0267] In embodiments, the present disclosure provides the use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0268] In embodiments, the disclosure provides the use of therapeutically effective amounts of latrepirdine and dexmedetomidine, or pharma- ceutically acceptable salts thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0269] In an embodiment, the present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically 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.

[0270] The present disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0271] The present disclosure provides a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.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 pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0272] In an embodiment, the present disclosure provides a method of treating depression in a subject in need of such treatment, the method comprising oromucosal administration to the subject of about 1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0273] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0274] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0275] In an embodiment, the 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 pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0276] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0277] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0278] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0279] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0280] In an embodiment, the disclosure provides a method of treating depression in a subject in need thereof, comprising oromucosal administration to the subject of about 20 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0281] In an embodiment, improvement in depressive symptoms is observed as measured by the HAM-D-17 depression subscale.

[0282] In an embodiment, the subject has a HAM-D-17 total score of ≧18 at the start of treatment.

[0283] In an embodiment, there is provided 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 dexmedetomidine alone or in combination with latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0284] In an embodiment, a method is provided for reducing a 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 pharma- ceutically acceptable salt thereof.

[0285] HAM-D or HDRS is used as a measurement to evaluate symptoms of depression. The measurement is administered to determine the symptoms of a patient after a structured or unstructured interview with a clinician. A total score is calculated by summing the individual scores of each question. Generally, a score below 7 represents the absence or remission of depression. A score between 7 and 17 represents mild depression. A score between 18 and 24 represents moderate depression. A score of 25 or more represents severe depression. Most depression studies consider a patient to have "success" in treatment if the score is reduced by more than 50%. Remission is generally understood to be a score below 7.

[0286] 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. difficulty sensing mood, 9. pessimistic thoughts, and 10. suicidal thoughts.

[0287] In an embodiment, the unit dosage forms comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof and latrepirdine are co-administered at the same time or closely spaced apart, usually within a period of less than 1 hour, preferably 0.5 hours, more preferably 0.25 hours.

[0288] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof and latrepirdine are administered sequentially, separated from one another by no more than about 24 hours, e.g., 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.

[0289] In an embodiment, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once daily, twice daily, three times daily or four, five or six times daily, preferably once, two or three times daily.

[0290] 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.

[0291] In an embodiment, the depression is moderate or severe. In an embodiment, the depression is major depression, bipolar disorder or mixed depression.

[0292] 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 pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0293] In an embodiment, the disclosure provides a method of treating a psychosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically 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 10 mg. In an embodiment, latrepirdine is administered twice daily at a dosage of about 20 mg. In an embodiment, 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.

[0294] In an embodiment, the present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising oromucosal administration to the subject of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0295] 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 pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof.

[0296] The present disclosure provides a method of treating a psychosis in a subject in need thereof, comprising oral mucosal (e.g., sublingual, buccal, or gingival) administration to the subject of a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0297] In embodiments, treatment is effective without causing significant sedation.

[0298] In an embodiment, the treatment is effective without experiencing clinically significant cardiovascular effects. In an embodiment, the severity of psychosis in a subject is assessed using the PANSS scale.

[0299] 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 with the PANSS, a clinical interview of 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.

[0300] In embodiments, the disclosure provides a method of 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 pharma- ceutically acceptable salt thereof.

[0301] In embodiments, the 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 pharma- ceutically acceptable salt thereof.

[0302] In embodiments, the 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 pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof.

[0303] In embodiments, the 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0304] In an embodiment, the decrease in PANSS score is at least about 20% to about 50% from the baseline score. In an embodiment, the decrease in PANSS score is about 25% from the baseline score. In an embodiment, the decrease in PANSS total score is about 30% from the baseline score. In an embodiment, the decrease in PANSS total score is about 35% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 40% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 45% points from the baseline score. In an embodiment, the decrease in PANSS total score is about 50% points from the baseline score.

[0305] 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.

[0306] In an embodiment, 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 an embodiment, the psychosis is associated with a neurodegenerative disorder.

[0307] In embodiments, the psychosis is associated with a medical condition such as a substance abuse disorder (eg, alcohol, opioid and other substance withdrawal).

[0308] In an embodiment, the psychosis is acute. In an embodiment, the psychosis is chronic. In an embodiment, the psychosis is single episode. In an embodiment, the psychosis is recurrent or includes recurrent episodes. In an embodiment, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes. In an embodiment, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered by the buccal route. In an embodiment, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered by the sublingual route. In an embodiment, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered sublingually or bucally in the form of a tablet or a round.

[0309] The combination disclosed herein can be administered as long as necessary to treat agitation.In an embodiment, 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.

[0310] 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.

[0311] 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 said subject the following: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The present invention provides a combination comprising:

[0312] In embodiments, the present disclosure provides a method for the treatment of agitation in a subject in need thereof, comprising administering to said subject: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The present invention provides a synergistic combination comprising:

[0313] In embodiments, the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0314] In an embodiment, the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride or dihydrochloride.

[0315] In embodiments, subjects exhibiting agitation have a baseline score of about 14 or greater on the PEC scale.

[0316] In an embodiment, a subject exhibiting agitation experiences a decrease in PEC score after administering a dosage form of the present disclosure according to the methods described herein. In an embodiment, the patient achieves a change in PEC score of more than -2 relative to baseline within 2 hours of administration of 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 an embodiment, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof. In an embodiment, the dexmedetomidine or a pharma- ceutically 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 an embodiment, the dosage form comprises latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dose of about 0.5 mg to about 100 mg. In an embodiment, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof, and latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the reduction in PEC score lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, 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 after administration of the composition.

[0317] In an embodiment, a subject exhibiting agitation has a baseline ACES score of about 3 or less.

[0318] In embodiments, a subject exhibiting agitation experiences an improvement in Agitation-Calmness Evaluation Scale (ACES) score after administration of a dosage form of the present disclosure according to the methods described herein. In embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 2 hours after administration of the composition as measured by the Agitation-Calmness Evaluation Scale (ACES). For example, the ACES score is improved to about 3 (mild agitation) or 4 (normal behavior). In embodiments, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof. In embodiments, the dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in a dose of about 0.5 micrograms to about 500 micrograms (e.g., about 30, about 60, about 90, about 120, about 180 or about 240 micrograms). In embodiments, the dosage form comprises latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dose of about 0.5 mg to about 500 mg. In an embodiment, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof, and latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the improvement in ACES score lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, 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 after administration of the composition. In an embodiment, the ACES score after treatment is preferably between 3 and 7, for example, 3, 4, 5, 6, or 7. Advantageously, the improved ACES score is obtained shortly after latrepirdine (alone or, preferably, with dexmedetomidine) is administered, for example, the improved ACES score may be obtained within about 2 hours of administration of the composition.For example, an improved ACES score may be obtained within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes. An improved ACES score may be obtained within about 5 minutes to about 120 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 30 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 120 minutes, about 60 minutes to about 90 minutes, or about 90 minutes to about 120 minutes after administration of the composition.

[0319] In embodiments, subjects exhibiting agitation have a baseline score of about 3 or greater on the CGI-I.

[0320] In an embodiment, a subject exhibiting agitation experiences an improvement in CGI-I score after administering a dosage form of the present disclosure according to the methods described herein. For example, the CGI-I score is improved to about 1 (very great improvement) or about 2 (great improvement). In an embodiment, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof. In an embodiment, the dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in a dose of about 0.5 micrograms to about 500 micrograms (e.g., 30, 60, 90, 120, or 180 micrograms). In an embodiment, the dosage form comprises latrepirdine or a pharma- ceutically acceptable salt thereof. In an embodiment, the latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dose of about 0.5 mg to about 500 mg. In an embodiment, the latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dose of about 1 mg to about 100 mg. In an embodiment, latrepirdine or a pharma- ceutically acceptable salt thereof is present in a dose of about 5 mg to about 50 mg. In an embodiment, the dosage form comprises dexmedetomidine or a pharma- ceutically acceptable salt thereof, and latrepirdine and a pharma- ceutically acceptable salt thereof. In an embodiment, the improvement in CGI-I score lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, 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 after administration of the composition. In an embodiment, the CGI-I score is about 1.

[0321] V. Medical Kit: According to the present disclosure there is provided a kit-of-parts comprising two oral mucosal freeze-dried tablet forms (i) and (ii), said dosage forms comprising: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and optionally (iii) instructions for administering (i) and (ii) simultaneously, sequentially or separately to a subject in need thereof; Includes.

[0322] According to the present disclosure: (i) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and optionally (iii) instructions for administering the single dosage form to a subject in need thereof; Also provided is a kit-of-parts comprising a single oral mucosal lyophilized tablet form comprising:

[0323] Dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and latrepirdine, or a pharma- ceutically acceptable salt thereof, are each provided in a form suitable for administration in combination with the other.

[0324] In an embodiment, dexmedetomidine and latrepirdine, or pharma- ceutically acceptable salts thereof, are provided as part of the same or a single dosage form.

[0325] In an embodiment, dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are provided as two separate dosage forms for administration (optionally repeatedly) of one dosage form before, after, and / or simultaneously with administration of the other dosage form. When administered sequentially, the sequential administration may be close in time or distant in time. This may include situations where administration of the two dosage forms sufficiently close in time (optionally repeatedly) over the course of the treatment of a related condition provides a greater beneficial effect on the patient than administration of either one of the two compositions alone (optionally repeatedly) over the course of the same treatment.

[0326] As used in this context, the terms "administered simultaneously" and "administered at the same time" include individual doses of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and latrepirdine, or a pharma- ceutically acceptable salt thereof, being administered within about 24 hours, e.g., about 23 hours, about 22 hours, about 21 hours, about 20 hours, about 19 hours, about 18 hours, about 17 hours, about 16 hours, about 15 hours, about 14 hours, about 13 hours, 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, about 1 hour or less than about 1 hour (i.e., about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute) of each other.

[0327] In an embodiment, dexmedetomidine and latrepirdine or a pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, the active agents are administered together in a single dosage form. When dexmedetomidine and latrepirdine or a pharmaceutically acceptable salt thereof are provided as separate dosage forms, each dosage form may be packaged separately for use in combination with the other in a combination therapy. Alternatively, the two dosage forms may be packaged together and present as separate components of a "combination pack" for use in combination with each other in a combination therapy.

[0328] Specific embodiments Embodiment 1. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutic amount of latrepirdine, or a pharma- ceutical acceptable salt thereof, in combination with a therapeutic amount of dexmedetomidine, or a pharma-ceutical acceptable salt thereof.

[0329] Embodiment 2. A method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0330] Embodiment 3. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0331] Embodiment 4. A method of treating agitation in a subject exhibiting agitation, comprising: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; The method comprises oromucosally administering to the subject a dosage form comprising:

[0332] Embodiment 5. A method of reducing noradrenergic hyperarousal, comprising oromucosally administering to a subject a dosage form comprising a therapeutically effective amount of latrepirdine, or a pharma-ceutically acceptable salt thereof.

[0333] Embodiment 6. A method for reducing noradrenergic hyperarousal comprising oromucosal administration of a dosage form comprising a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof, and a therapeutically effective amount of dexmedetomidine, or a pharma-ceutical acceptable salt thereof.

[0334] Embodiment 7. A method of treating behavioral and psychological symptoms in a subject having a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latrepirdine, or a pharma-ceutically acceptable salt thereof.

[0335] Embodiment 8. A method of treating behavioral and psychological symptoms in a subject with a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latrepirdine and dexmedetomidine or pharma- ceutically acceptable salts thereof.

[0336] Embodiment 9. 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, or a pharma-ceutically acceptable salt thereof.

[0337] Embodiment 10. A method for treating behavioral and psychological symptoms in a subject with a neuropsychiatric disorder, comprising oromucosal administration of therapeutically effective amounts of latrepirdine, or a pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma-ceutically acceptable salt thereof.

[0338] Embodiment 11. Use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0339] Embodiment 12. Use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0340] Embodiment 13. Use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neurodegenerative disorder.

[0341] Embodiment 14. Use of a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, and dexmedetomidine, or a pharma- ceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject with a neuropsychiatric disorder.

[0342] Embodiment 15. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Alzheimer's disease.

[0343] Embodiment 16. A method for treating chronic agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from dementia.

[0344] Embodiment 17. A method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Parkinson's disease.

[0345] Embodiment 18. A method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from PTSD.

[0346] Embodiment 19. A method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from concurrent vascular cognitive impairment.

[0347] Embodiment 20. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Huntington's disease.

[0348] Embodiment 21. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from schizophrenia.

[0349] Embodiment 22. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from a bipolar disorder.

[0350] Embodiment 23. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from depression.

[0351] Embodiment 24. A method for treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from delirium.

[0352] Embodiment 25. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Alzheimer's disease.

[0353] Embodiment 26. A method for treating chronic agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from dementia.

[0354] Embodiment 27. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Parkinson's disease.

[0355] Embodiment 28. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from PTSD.

[0356] Embodiment 29. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from Huntington's disease.

[0357] Embodiment 29. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from schizophrenia.

[0358] Embodiment 30. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from a concomitant bipolar disorder.

[0359] Embodiment 31. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject also suffers from depression.

[0360] Embodiment 32. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject suffers from vascular cognitive impairment.

[0361] Embodiment 33. A method for treating agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof, in combination with dexmedetomidine, or a pharma- ceutically acceptable salt thereof, wherein the subject is also suffering from delirium.

[0362] Embodiment 34. The method of any preceding embodiment, wherein the agitation is severe.

[0363] Embodiment 35. The method of any of the preceding embodiments, wherein the agitation is mild or moderate.

[0364] Embodiment 36 The method of any of the preceding embodiments, wherein latrepirdine is administered once a day at a dosage of about 10 mg.

[0365] Embodiment 37. The method of any of the preceding embodiments, wherein latrepirdine is administered once a day at a dosage of about 20 mg.

[0366] Embodiment 38. The method of any of the preceding embodiments, wherein latrepirdine is administered at a dosage of about 10 mg twice a day.

[0367] Embodiment 39. The method of any of the preceding embodiments, wherein latrepirdine is administered at a dosage of about 10 mg three times a day.

[0368] Embodiment 40. The method of any of the preceding embodiments, wherein latrepirdine is administered at a dosage of about 20 mg twice a day.

[0369] Embodiment 41 The method of any of the preceding embodiments, wherein latrepirdine is administered to the subject in a total daily dose of about 60 mg.

[0370] Embodiment 42. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 0.1 mg to about 500 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 0.5 micrograms to about 300 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0371] Embodiment 42. A method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject from about 0.1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and from about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0372] Embodiment 43. A method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject about 5 mg to about 60 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0373] Embodiment 44. A method of treating agitation in a subject exhibiting agitation, comprising oromucosally administering to the subject from about 1 mg to about 40 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and from about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0374] Embodiment 45. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine, or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine, or a pharma- ceutically acceptable salt thereof.

[0375] Embodiment 46. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0376] Embodiment 47. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0377] Embodiment 48. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0378] Embodiment 49. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0379] Embodiment 50. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0380] Embodiment 51. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0381] Embodiment 52. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0382] Embodiment 53. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0383] Embodiment 54. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0384] Embodiment 55. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0385] Embodiment 56. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0386] Embodiment 57. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0387] Embodiment 58. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0388] Embodiment 59. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0389] Embodiment 60. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 120 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0390] Embodiment 61. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0391] Embodiment 62. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0392] Embodiment 63. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0393] Embodiment 64. A method of treating agitation in a subject exhibiting agitation, comprising administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 180 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof, wherein the agitation is caused by noradrenergic hyperarousal.

[0394] Embodiment 65. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0395] Embodiment 66. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0396] Embodiment 67. A method for treating depression in a subject in need thereof, comprising administering to the subject a dosage form comprising a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0397] Embodiment 68. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of dexmedetomidine, or a pharma-ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma-ceutically acceptable salt thereof.

[0398] Embodiment 69. A method for treating depression in a subject in need of such treatment, comprising oromucosally administering to the subject about 5 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0399] Embodiment 70. The method of embodiments 65-69, wherein the depression is moderate or severe.

[0400] Embodiment 71. The method of embodiments 65-69, wherein the depression is major depression.

[0401] Embodiment 72. The method of embodiments 65-69, wherein the depression is mixed depression.

[0402] Embodiment 73. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0403] Embodiment 74. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0404] Embodiment 75. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharma-ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0405] Embodiment 76. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 30 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0406] Embodiment 77. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharma-ceutically acceptable salt thereof, and about 40 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0407] Embodiment 78. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharma-ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0408] Embodiment 79. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharma-ceutically acceptable salt thereof, and about 60 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0409] Embodiment 80. A method of treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 10 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0410] Embodiment 81. A method for treating depression in a subject in need thereof, comprising oromucosally administering to the subject about 20 mg of latrepirdine or a pharma-ceutically acceptable salt thereof, and about 80 micrograms of dexmedetomidine or a pharma-ceutically acceptable salt thereof.

[0411] Embodiment 82. A method for reducing a score on the HDRS scale in a human subject suffering from depression, comprising oromucosally administering an effective amount of dexmedetomidine alone or in combination with latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0412] Embodiment 83. 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 alone or in combination with latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0413] Embodiment 84. The method of any of embodiments 1, 4, 6, 8, 10, 13, 14, 25-33, 42-64, 66-69, 73-78, wherein dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt) and latrepirdine are administered simultaneously or sequentially in two separate dosage forms.

[0414] Embodiment 85. The method of any one of embodiments 1, 4, 6, 8, 10, 13, 14, 25-33, 42-64, 66-69, 73-78, wherein dexmedetomidine or a pharma- ceutically acceptable salt thereof and latrepirdine are administered simultaneously in a single unit dosage form.

[0415] Embodiment 86. The method of embodiment 85, wherein the two separate dosage forms are administered sequentially separated by a specific time, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.

[0416] Embodiment 87. The method of any preceding embodiment, wherein the dosage form is lyophilized.

[0417] Embodiment 88. The method of any of the preceding embodiments, wherein the dosage form is administered sublingually or bucally.

[0418] Embodiment 89. The method of any preceding embodiment, wherein the dosage form disintegrates in about 1 minute or more after contact with the oral mucosa.

[0419] Embodiment 90. The method of any of the preceding embodiments, wherein the dosage form is mucoadhesive.

[0420] Embodiment 91. The method of embodiment 88, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are oromucosally administered in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop.

[0421] Embodiment 92. The method of embodiment 91, wherein the dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered sublingually or buccally in the form of a tablet.

[0422] Embodiment 93. The method of any of the preceding embodiments, wherein said 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, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0423] Embodiment 94. The method of any of the preceding embodiments, wherein the agitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression.

[0424] Embodiment 95. The method of any of the preceding embodiments, wherein the agitation is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal, and substance abuse withdrawal.

[0425] Embodiment 96. The method of any of the preceding embodiments, wherein 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).

[0426] Embodiment 97. The method of any preceding embodiment, wherein the agitation is acute.

[0427] Embodiment 98. The method of any preceding embodiment, wherein the agitation is chronic.

[0428] Embodiment 99. The method of any of the preceding embodiments, wherein the agitation is caused by noradrenergic hyperarousal.

[0429] Embodiment 100. The method of any of the preceding embodiments, wherein the agitation is treated without causing significant sedation.

[0430] Embodiment 101. The method of any of the preceding embodiments, wherein latrepirdine or a pharma- ceutically acceptable salt thereof is administered in an amount of about 0.5 mg to about 500 mg.

[0431] Embodiment 102. The method of embodiment 101, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0432] Embodiment 103. The method of any of the preceding embodiments, wherein the dexmedetomidine is present in an amount of about 0.5 micrograms to about 300 micrograms.

[0433] Embodiment 104. The method of embodiment 103, wherein the dexmedetomidine is present in an amount of about 10 micrograms to about 300 micrograms.

[0434] Embodiment 105. The method of any of the preceding embodiments, wherein the dosage form(s) is administered multiple times daily.

[0435] Embodiment 106. The method of any of the preceding embodiments, wherein the dosage form(s) is administered once daily.

[0436] Embodiment 107. The method of any of the preceding embodiments, wherein the dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0437] Embodiment 108. The method of any of the preceding embodiments, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride (or dihydrochloride).

[0438] Embodiment 109. The following: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; 1. An oral mucosal dosage form comprising:

[0439] Embodiment 110. The following: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; 1. An oral mucosal dosage form comprising:

[0440] Embodiment 111. The following: (iv) a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof; (v) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof; (vi)(iii) one or more mucoadhesives, and (vii) one or more pharma- ceutically acceptable excipients or carriers; 1. An oral mucosal dosage form comprising:

[0441] Embodiment 112. The oral mucosal dosage form of embodiment 109 or 110, wherein the dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0442] Embodiment 113. The oromucosal dosage form of any of embodiments 109-111, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride or dihydrochloride.

[0443] Embodiment 114. The oral mucosal dosage form of embodiment 110 or 111, wherein the therapeutic amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof (e.g., hydrochloride) is from about 5 micrograms to about 300 micrograms per unit dose, e.g., from about 20 micrograms to about 200 micrograms per unit dose, from about 30 micrograms to about 100 micrograms per unit dose, or from about 10 micrograms to about 50 micrograms per unit dose.

[0444] Embodiment 115. The oral mucosal dosage form of embodiment 114, wherein the therapeutic amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, or about 180 micrograms.

[0445] Embodiment 116. The oromucosal dosage form according to embodiments 109-111, wherein the therapeutic amount of latrepirdine or a pharma- ceutically acceptable salt thereof is from about 0.5 mg to about 100 mg per unit dose.

[0446] Embodiment 117. The oromucosal dosage form according to embodiments 109-111, wherein the therapeutic amount of latrepirdine or a pharma- ceutically acceptable salt thereof is from about 10 mg to about 100 mg per unit dose.

[0447] Embodiment 118. The oral mucosal dosage form according to embodiments 109 to 111, wherein the one or more mucoadhesives are selected from the group consisting of polyacrylic acid polymers, methacrylic acid polymers, cellulose derivatives, such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, thiolated carboxymethylcellulose, polysaccharides, xanthan gum, karaya gum, tragacanth gum, propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide, microcrystalline cellulose (Avicel), croscarmellose, and mixtures thereof.

[0448] Embodiment 119. The oral mucosal dosage form of embodiment 118, wherein the one or more mucoadhesives are present in an amount of about 0.5% to about 20% w / w.

[0449] Embodiment 120. The oral mucosal dosage form of embodiment 118, wherein the polyacrylic acid polymer is a carbomer, a polycarbophil, or a combination thereof.

[0450] Embodiment 121. The oral mucosal dosage form of embodiment 118, wherein the polysaccharide is pectin, chitosan, or a combination thereof.

[0451] Embodiment 122. The oral mucosal dosage form of embodiments 109-111, wherein one or more of the pharma- ceutically acceptable excipients or carriers are selected from the group consisting of disintegrants, fillers / diluents (base formers), binders, flow agents, lubricants, plasticizers, pH adjusters, colorants, flavorings, taste masking agents, viscosity enhancers, sweeteners, and combinations thereof.

[0452] Embodiment 123. The oral mucosal dosage form of any of the preceding embodiments, wherein the dosage form has a mucoadhesive peak strength of greater than about 50 g (e.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).

[0453] Embodiment 124. An oral mucosal dosage form according to any of the preceding embodiments, wherein the dosage form is prepared by spray drying, sublimation, nanonization, granulation, direct compression or lyophilization, preferably by lyophilization.

[0454] Embodiment 125. An oral mucosal dosage form according to any of the preceding embodiments, wherein the dosage form is a sublingual tablet.

[0455] Embodiment 126. An oral mucosal dosage form according to any of the preceding embodiments, wherein the dosage form is a buccal tablet.

[0456] Embodiment 127. An oral mucosal (e.g., sublingual or buccal) freeze-dried tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharma-ceutically acceptable salt thereof, (ii) xanthan gum, (iii) croscarmellose sodium (or) sodium starch glycolate, (iv) sucralose, (v) magnesium stearate and / or silicon dioxide, (vi) lactose monohydrate (or) mannitol and optionally other pharma-ceutically acceptable excipients, wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0457] Embodiment 128. An oral mucosal (e.g., sublingual or buccal) freeze-dried tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharma-ceutically acceptable salt thereof, (ii) sodium alginate, (iii) croscarmellose sodium (or) sodium starch glycolate, (iv) sucralose, (v) magnesium stearate and / or silicon dioxide, (vi) lactose monohydrate or mannitol and optionally other pharma-ceutically acceptable excipients, wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0458] Embodiment 129. An oral mucosal (e.g., sublingual or buccal) freeze-dried tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharma-ceutically acceptable salt thereof, (ii) carbomer, (iii) croscarmellose sodium or sodium starch glycolate, (iv) sucralose, (v) magnesium stearate and / or silicon dioxide, (vi) lactose monohydrate or mannitol and optionally other pharma-ceutically acceptable excipients, wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0459] Embodiment 130. An oral mucosal (e.g., sublingual or buccal) freeze-dried tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharma-ceutically acceptable salt thereof; (iii) carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 pharma-ceutically acceptable excipients; wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0460] Embodiment 131. An oral mucosal (e.g., sublingual or buccal) freeze-dried tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharma-ceutically acceptable salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 pharma-ceutically acceptable excipients; wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0461] Embodiment 132. The oral mucosal freeze-dried tablet according to embodiments 127 to 131, wherein the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is from about 10 micrograms to about 300 micrograms.

[0462] Embodiment 133. The oral mucosal freeze-dried tablet of embodiment 132, wherein the therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof is about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, about 180 micrograms or about 240 micrograms.

[0463] Embodiment 134. The oral mucosal freeze-dried tablet according to embodiments 127-131, wherein the therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof is from about 10 mg to about 100 mg.

[0464] Embodiment 135. The oral mucosal freeze-dried tablet according to embodiment 133, wherein the therapeutically effective amount of latrepirdine or a pharma-ceutically acceptable salt thereof is about 30 mg.

[0465] Embodiment 136. The oromucosal dosage form of any one of the preceding embodiments, administered for the treatment of agitation caused by noradrenergic hyperarousal.

[0466] Embodiment 137. The oral mucosal dosage form of embodiment 136, wherein the agitation caused by noradrenergic hyperarousal is associated with a neurodegenerative disorder selected from the group consisting of dementia, Alzheimer's disease, frontotemporal dementia, Parkinsonism, sundowning syndrome in Alzheimer's disease / dementia, or other neurodegenerative disorders.

[0467] Embodiment 138. The oromucosal dosage form of embodiment 136, wherein the agitation caused by noradrenergic hyperarousal is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related neuropsychiatric disorder.

[0468] Embodiment 139. The oromucosal dosage form of embodiment 136, wherein the agitation caused by noradrenergic hyperarousal is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal and substance abuse withdrawal.

[0469] Embodiment 140. The oromucosal dosage form of any of the preceding embodiments, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are provided as a single unit dosage form or in separate dosage forms.

[0470] Embodiment 141. A pharmaceutical combination for treating agitation caused by noradrenergic hyperarousal, comprising a therapeutic amount of dexmedetomidine or a pharma- ceutical acceptable salt thereof (e.g., the hydrochloride salt) and a therapeutic amount of latrepirdine or a pharma- ceutical acceptable salt thereof.

[0471] Embodiment 142. The combination according to embodiment 141, wherein the dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0472] Embodiment 143. The combination according to embodiment 141, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride.

[0473] Embodiment 144. The combination of embodiment 141, wherein the therapeutic amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof includes from about 5 micrograms to about 300 micrograms per unit dose.

[0474] Embodiment 145. The combination of embodiment 141, wherein the therapeutic amount of latrepirdine or a pharma- ceutically acceptable salt thereof includes from about 10 mg to about 100 mg per unit dose.

[0475] Embodiment 146. The combination of embodiment 141, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered sublingually or buccally in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop.

[0476] Embodiment 147. A combination according to embodiment 146, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered sublingually in the form of a tablet.

[0477] Embodiment 148. A combination according to embodiment 146, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered bucally in the form of a tablet.

[0478] Embodiment 149. The combination of embodiment 147 or 148, wherein the tablet disintegrates in 1 minute or more after contact with the oral mucosa.

[0479] Embodiment 150. The combination according to embodiment 141, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered simultaneously in a single dosage form.

[0480] Embodiment 151. A combination according to embodiment 141, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered simultaneously or sequentially in separate dosage forms.

[0481] Embodiment 152. The combination according to embodiment 141, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered once a day, twice a day, three times a day, four times a day, five times a day, or six times a day.

[0482] Embodiment 153. A kit-of-parts comprising at least two separate oral mucosal freeze-dried tablet forms (a) and (b), said dosage forms comprising: (a) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (b) a therapeutically effective amount of latrepirdine or a pharma- ceutical acceptable salt thereof, and optionally (c) instructions for administering (a) and (b) simultaneously, sequentially or separately to a subject in need thereof; the kit-of-parts comprising:

[0483] Embodiment 154. A kit-of-parts comprising a single oral mucosal freeze-dried tablet form, comprising: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof, and optionally (iii) instructions for administering the single dosage form to a subject in need thereof; the kit-of-parts comprising:

[0484] Embodiment 155. The kit according to embodiment 153 or 154, wherein the dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0485] Embodiment 156. The kit according to embodiment 153 or 154, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride.

[0486] Embodiment 157. The kit of embodiment 153 or 154, wherein latrepirdine or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 mg to about 100 mg.

[0487] Embodiment 158. The kit of embodiment 154, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered in a single unit dose once a day, twice a day, three times a day, four times a day, five times a day, or six times a day.

[0488] Embodiment 159. The kit according to any one of embodiments 153 to 158, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered together or separately as sublingual or buccal tablets.

[0489] Embodiment 160. The kit of embodiment 159, wherein the tablet disintegrates in about 1 minute or more after contact with the oral mucosa.

[0490] Embodiment 161. A kit according to any one of embodiments 153 to 160, wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered for the treatment of agitation caused by noradrenergic hyperarousal.

[0491] Embodiment 162. The kit of embodiment 161, wherein the agitation is acute or chronic.

[0492] Embodiment 163. The kit of embodiment 161, wherein the agitation caused by noradrenergic hyperarousal is associated with a neurodegenerative disorder selected from the group consisting of agitation / symptoms of dementia, Alzheimer's disease, frontotemporal dementia, Parkinsonism, agitation associated with sundowning syndrome in Alzheimer's disease / dementia, or agitation associated with other neurodegenerative disorders.

[0493] Embodiment 164. The kit of embodiment 161, wherein the agitation caused by noradrenergic hyperarousal is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related neuropsychiatric disorder.

[0494] Embodiment 165. The kit of embodiment 161, wherein the agitation caused by noradrenergic hyperarousal is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal, substance abuse withdrawal or an OPD / IPD procedure (e.g., MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure).

[0495] Embodiment 166. The kit of embodiment 155, wherein dexmedetomidine or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 micrograms to 300 micrograms (including about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, about 180 micrograms, about 240 micrograms).

[0496] Embodiment 167. A method / formulation / combination or kit according to any of the preceding embodiments, wherein said agitation is treated in said subject without causing significant sedation.

[0497] Embodiment 168. A method / formulation / combination or kit according to any of the preceding embodiments, wherein the agitation is treated in the subject without causing cardiovascular effects.

[0498] Embodiment 169. A method for treating a psychosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0499] Embodiment 170. The method of treatment of embodiment 169, wherein the latrepirdine is administered at a dosage of about 1 mg to about 100 mg once a day, about 10 mg once a day, about 20 mg once a day, about 30 mg once a day, about 20 mg twice a day, about 20 mg three times a day, about 30 mg once a day, about 30 mg twice a day, or about 60 mg once a day.

[0500] Embodiment 171. A method for treating a psychosis in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof.

[0501] Embodiment 172. A method for treating a psychosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0502] Embodiment 173. A method for treating a psychosis in a subject in need thereof, comprising oromucosally administering to the subject a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof.

[0503] Embodiment 174. A method for treating depression in a subject in need of such treatment, comprising oromucosally administering to the subject from about 1 mg to about 100 mg of latrepirdine or a pharma- ceutically acceptable salt thereof, and from about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharma- ceutically acceptable salt thereof.

[0504] Embodiment 175. The method of embodiments 169 to 174, wherein the treatment is effective without causing significant sedation.

[0505] Embodiment 176. The method of embodiments 169-174, wherein the treatment is effective without experiencing clinically significant cardiovascular effects.

[0506] Embodiment 177. The method of embodiments 169-174, wherein the severity of psychosis in the subject is assessed using the PANSS scale.

[0507] Embodiment 178. The method of embodiments 169-174, wherein the psychosis is acute.

[0508] Embodiment 179. The method of embodiments 169-174, wherein the psychosis is chronic.

[0509] Embodiment 180. The method of embodiments 169-174, wherein the subject is experiencing agitation.

[0510] Embodiment 181. The method of embodiments 169-174, wherein the subject is not experiencing agitation.

[0511] Embodiment 182. 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 latrepirdine or a pharma- ceutical acceptable salt thereof.

[0512] Embodiment 183. 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of latrepirdine, or a pharma- ceutical acceptable salt thereof.

[0513] Embodiment 184. The method of embodiment 182 or 183, wherein the reduction in the PANSS score is at least about 20% to about 50% from the baseline score.

[0514] Embodiment 185. The method of embodiment 184, wherein the reduction in the PANSS score is about 25% from the baseline score.

[0515] Embodiment 186. The method of embodiment 184, wherein the reduction in the PANSS score is about 50 percentage points from the baseline score.

[0516] Embodiment 187. The method of any of embodiments 169-186, wherein 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.

[0517] Embodiment 188. The method of any one of embodiments 169 to 186, wherein the psychosis is associated with a neurodegenerative disorder.

[0518] Embodiment 189. The method of any of embodiments 169-186, wherein the psychosis is associated with a medical condition such as a substance abuse disorder (e.g., alcohol, opioid and other substance withdrawal).

[0519] Embodiment 190. The method of any of embodiments 169-189, wherein the psychosis is a single, recurrent or mixed episode. EXAMPLES

[0520] The details of the present disclosure, its objects and advantages are explained in more detail below with reference to non-limiting exemplary examples. Example 1. Latrepirdine dihydrochloride hydrate and dexmedetomidine hydrochloride Sublingual / buccal / gingival tablets with mucoadhesive properties: [Table 1] [Table 2] [Table 3] [Table 4]

[0521] The tablets described in this example (see Tables 1-4) can be manufactured according to the processes described herein. A representative process is illustrated below. 1. Disperse the drug substance (latrepirdine and / or dexmedetomidine), binder, and sweetener in water. 2. Prepare a mixture of remaining ingredients except magnesium stearate / silicon dioxide and sift. 3. Granulate the mixture with the solution from step 1 in a suitable high speed agitator granulator. 4. Dry the granules in a suitable fluid bed dryer. 5. The dried granules are sized appropriately using a Quadrocomill or Multimill and then placed into a suitable blender such as a V-blender. 6. Lubricate with magnesium stearate / silicon dioxide and compress the final lubricated blend into tablets of specified size using appropriate machinery.

[0522] Example 2. Effect of latrepirdine dihydrochloride hydrate on yohimbine-induced noradrenaline-mediated hyperarousal in Wistar rats Background: Yohimbine is an alpha2-adrenergic receptor antagonist that has been reported to induce panic attacks in healthy volunteers and to exacerbate symptoms in patients with panic disorder (Charney et al., 1992 Acta Psychiatr Scand., Vol. 86(4):273-282). Peripheral administration of yohimbine produces noradrenaline-mediated hyperarousal in rats as assessed by the EPM paradigm.

[0523] Theory: The drug yohimbine is a natural substance used to test a specific pathway of noradrenaline-mediated hyperarousal. Yohimbine is an alpha2-adrenergic receptor antagonist and is well established to activate the locus coeruleus (LC) and increase noradrenergic signaling (opposite alpha2-adrenergic agonists such as dexmedetomidine and clonidine). Increased LC activity and noradrenergic signaling produces anxiety and agitation in animals, which can be measured using the elevated plus maze. In the elevated plus maze, rodents are placed in closed arms and explore the open arms in response to their anxiety and agitation (rats and mice normally explore their environment extensively when calm). Administration of yohimbine caused animals to generally stay in the closed arms and not explore the open arms.

[0524] Animal Groups: Male: Wistar rats were used in this study and were randomly divided into different experimental groups (12 animals per group).

[0525] Acclimatization: Animals were numbered and allowed to acclimate for 5-7 days before the start of the experiment. During the acclimatization period, male Wistar rats were regularly inspected, handled, and weighed to ensure proper health and suitability.

[0526] Food and water: Ad libitum access to normal rodent chow was maintained and autoclaved fresh drinking water was provided ad libitum.

[0527] All animal experiments were performed in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, and the Association for Assessment and Accreditation of Laboratory Animal Care international (AAALAC).

[0528] Test drugs: To find drugs that are effective in reducing yohimbine-induced agitation, four test drugs with different mechanisms of action related to agitation were selected: (1) fluvoxamine (selective serotonin reuptake inhibitor), (2) dextromethorphan (NMDA signal modulator), (3) diazepam (gamma-aminobutyric acid (GABA) modulator as a positive control), and (4) latrepirdine (complex pharmacological action).

[0529] [Table 5]

[0530] Study drugs were sourced from Sigma or Tocris, dextromethorphan was sourced from Sigma Aldrich, Cat No. D9684, latrepirdine was sourced from Sigma Aldrich, Cat No. D6196 or Tocris Cat No. 3201, and diazepam and fluvoxamine were sourced from Sigma Aldrich, Cat No. F2802 or Tocris, Cat No. 1033. All of these study drugs were formulated in sufficient quantities in 0.9% saline except for fluvoxamine, which was formulated in 30% ethanol in 0.9% saline.

[0531] Apparatus: An elevated plus maze (EPM) was used (Figure 1). The maze consisted of two closed and two open arms forming a cross with a square platform in the center. All visible surfaces were black acrylic. Each arm of the maze was placed on a post on the floor. An enclosure was created around the EPM using antistatic black vinyl curtains.

[0532] Test design and dosing: Yohimbine was administered intraperitoneally (ip) at a dose of 2.5 mg / kg (30 min before testing) to induce agitation, and the effect was evaluated by measuring the number of open arm entries and exploration time in the EPM 30 min after yohimbine injection. The test drugs fluvoxamine, dextromethorphan and latrepirdine dihydrochloride hydrate were administered intramuscularly into the hind thigh muscle of rats (60 min before testing, 30 min before yohimbine administration), and diazepam was administered intraperitoneally. Diazepam was injected intraperitoneally 30 min before the assay, i.e., together with yohimbine administration. The test design is shown in Figure 2 and Table 5.

[0533] After administration of the test drug, the rat was placed on the platform facing the closed arm. The number of entries and the time spent in each arm were recorded for 5 minutes. When the animal had four paws in the arm, the animal was considered to have entered the arm.

[0534] Statistical analysis: Analysis of variance (ANOVA) was performed on the obtained data, using Fisher's PLSD for pairwise comparisons, and a p value ≤ 0.05 was considered significant.

[0535] Results: Unexpectedly, it was found that pretreatment of animals with latrepirdine dihydrochloride hydrate (3 mg / kg and 10 mg / kg, im) for 1 h reduced noradrenaline-mediated hyperarousal, as indicated by a significant increase in the number of entries into the open arms and a significant increase in the exploration time. In other words, latrepirdine dihydrochloride hydrate reversed yohimbine-induced noradrenaline-mediated hyperarousal. The effect of latrepirdine dihydrochloride hydrate on reducing noradrenaline-mediated hyperarousal was specific, since pretreatment of animals with dextromethorphan (10 mg / kg, im) or fluvoxamine (10 mg / kg, im) had no effect. Pretreatment with diazepam (1 mg / kg, ip) served as a positive control.

[0536] Figures 3 and 4 show that latrepirdine dihydrochloride hydrate significantly increased the number of open arm entries and the time spent in the open arms (seconds) comparable to diazepam (1 mg / kg, ip). The other test drugs, dextromethorphan (10 mg / kg, im) and fluvoxamine (10 mg / kg, im), showed no effect.

[0537] Conclusion: Latrepirdine dihydrochloride hydrate is able to reduce behaviors associated with high noradrenergic signaling, and its pretreatment reverses anxiety behaviors in rats induced by selective alpha2-adrenergic receptor antagonism. This supports a putative multifaceted pharmacological approach in disorders associated with hyperarousal with compounds acting via alpha2-adrenergic receptor agonism. Thus, latrepirdine dihydrochloride hydrate should be effective in patients associated with high noradrenergic-mediated hyperarousal.

[0538] Example 3. Evaluation of the effect of latrepirdine dihydrochloride hydrate at various doses on yohimbine-induced noradrenergic hyperarousal in Wistar rats. Materials and Methods:

[0539] Drug Preparation: All compounds / drugs were prepared in saline (0.9% NaCl).

[0540] Yohimbine was prepared in a 2.5 mg / mL solution and injected ip at 1 mL / kg to give a dose of 2.5 mg / kg. Diazepam was prepared in a 1 mg / mL solution and injected ip at 1 mL / kg to give a dose of 1 mg / kg. Latrepirdine dihydrochloride hydrate was prepared in 7.5, 2.5, 0.75, and 0.25 mg / mL solutions and injected im in 100 μL volumes into a 250 g rat to give doses of 3, 1, 0.3, and 0.1 mg / kg, respectively. Latrepirdine dihydrochloride hydrate was prepared in a 0.3 mg / mL solution and injected ip at 1 mL / kg to give a dose of 3 mg / kg.

[0541] Test animals:

[0542] Male Wistar rats (Janvier; Le Genest St Isle-France) were used for the study. They weighed 150 g at the time of purchase and reached a body weight of approximately 220 g at the time of use. They were group-housed (3-4 rats per cage) and kept in a room with controlled temperature (21-22°C) and reversed light / dark cycle (12 h / 12 ​​h, lights on: 17:30-05:30, lights off: 05:30-17:30) and had free access to food and water.

[0543] Processing Schedule:

[0544] Rats were assigned to 9 different experimental groups with 12 rats in each group, as shown in Table 6. Each experimental group was also coded so that the experimenter would be blinded to the true experimental group during the EPM test. The dose, route and pretreatment time are also shown in Table 6.

[0545] [Table 6]

[0546] * Weights are calculated on a free base basis.

[0547] Testing Procedure:

[0548] Rats were randomly assigned to one of the various experimental groups. Each animal was identified by group name, cage number, experimental system (day), and number (1-9) written in permanent ink on its tail. They were handled by the experimenter for approximately 3 min each day starting one week before the EPM test day. The apparatus was a PVC maze covered with Plexiglas, subdivided into four equal exploration arms (40 x 10 cm), all of which were interconnected by a small platform (10 x 10 cm). The apparatus was placed 65 cm above the floor. Two arms were open and the other two arms were closed with walls (height: 10 cm). After compound administration, the rat was placed on the platform facing the closed arm. The number of entries and the time spent in each arm were recorded for 5 min. An animal was considered to have entered an arm when all four paws of the animal were in the arm. Between each animal, the apparatus was washed with alcohol (70%). Urine and feces were removed from the maze. During the study, animal handling and operator visibility was minimized as much as possible.

[0549] Calculations and statistical analysis:

[0550] Analysis of variance (ANOVA) was performed on the obtained data. Fisher's PLSD was used for pairwise comparisons, and a p-value ≦0.05 was considered significant. For comparison, changes in EPM performance of yohimbine rats were expressed as a percentage increase / decrease relative to the levels recorded in the vehicle (set as 0% change). Thus, for each of the EPM parameters, the following formula was used: [performance of a given group−performance of the vehicle group] / [performance of the vehicle group]×100.

[0551] result

[0552] Health Status: There were no signs of macroscopic side effects related to compound treatment.

[0553] Actions in EPM

[0554] Figures 5 and 6 show the average performance of each experimental group in terms of the number of entries and the time spent in the open arms, respectively. Table 7 shows the percentage change (decrease or increase) in EPM parameters relative to the vehicle performance level (set as 0% change). As shown in Figures 5 and 6, vehicle-treated yohimbine-administered rats showed a markedly significant decrease in the number of visits and the time spent in the open arms compared to vehicle-treated saline rats. This suggests the development of yohimbine-induced noradrenaline-mediated hyperarousal as assessed by the EPM paradigm. Yohimbine-induced noradrenaline-mediated hyperarousal was reversed by 1 mg / kg diazepam treatment, as shown by a significant increase in the number of visits and the time spent in the open arms (294% and 642% increase, respectively) (Table 7). Furthermore, latrepirdine dihydrochloride hydrate dose-dependently increased the number of visits and time spent in the open arms of yohimbine-treated rats, and the effect was significant at doses of 1 and 3 mg / kg, as shown in Table 7 and Figures 5 and 6. It was also observed that the EPM performance of yohimbine rats treated with latrepirdine dihydrochloride hydrate (3 mg / kg im) was comparable to that of intraperitoneally treated subjects, suggesting that intramuscular (im) administration of latrepirdine dihydrochloride hydrate is as effective as administration by the intraperitoneal (ip) route (see Table 7 and Figures 5 and 6). Of note, latrepirdine dihydrochloride hydrate (3 mg / kg im) did not significantly alter the EPM performance of saline-treated rats (rats not treated with yohimbine), suggesting that latrepirdine dihydrochloride hydrate did not induce any significant anti-agitation behavior in rats not treated with yohimbine (see Table 7 and Figures 5 and 6).

[0555] [Table 7] Conclusion: The results showed that latrepirdine dihydrochloride hydrate (1 and 3 mg / kg) significantly reduced noradrenaline-mediated hyperarousal in yohimbine-treated rats in a dose-dependent manner (see Table 7 and Figures 5 and 6).

[0556] Example 4. Evaluation of the antidepressant effect of a combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate in the dark phase rat forced swimming test model. Materials and Methods Test system Species: Rattus norvegicus Lineage: Sprague Dawley (SD) Sex and age: Male, 8-10 weeks old Source: Hylasco Biotechnology Pvt.Ltd.4B,MNPark,Turkaplly(Vil),Shameerpet(Mdl),Medchal Dist,-500078 Number of groups: 7, total number of animals: 78 Number of animals in each group: 9-12 [Table 8] [Table 9]

[0557] environmental conditions Animals were housed in an environmentally controlled room at 22 ± 3°C and 30-70% relative humidity. A 12 / 12 light / dark cycle was maintained throughout the study. Lights in the acclimation area were turned off at 06:00 PM. All experiments were performed under dark lighting (06:00 PM to 06:00 AM) at ambient temperature. An adequate supply of fresh air was maintained in the laboratory with 12-15 air changes per hour. Maximum and minimum laboratory temperatures and relative humidity were recorded daily. Laboratory relative humidity was calculated daily from dry-bulb and wet-bulb temperature records.

[0558] Accommodation The animals were group-housed in standard animal cages with provision for pelleted food and drinking water in polycarbonate bottles with stainless steel tips, two per cage. Animals were housed in a single laboratory during the experimental period.

[0559] Diet

[0560] All animals were fed a standard rodent diet ad libitum.

[0561] water

[0562] The animals had free access to water that had been passed through a porous activated charcoal filter in an Aquaguard water filter-cum-purifier manufactured by Eureka Forbes Ltd., Mumbai-400 001, India and exposed to UV light.

[0563] Randomization Animals were assigned to different groups based on body weight data.

[0564] Protocol:

[0565] A. Acclimatization period

[0566] After the quarantine period, animals were allowed to acclimate for 7 days. We ensured that the weight differences between groups were minimal and did not exceed ±10% of the mean weight across groups.

[0567] The study was conducted as a staggered treatment with each treatment group divided into Cohort 1, Cohort 2, and Cohort 3.

[0568] Swimming 1 took place between 18:30 and 21:30.

[0569] Swimming 2 was performed between 19:30 and 21:30. After 18:30, 60 min before FST 2, the test compound was administered to the animals in a staggered manner.

[0570] After intramuscular injection, the animals were observed for any abnormal effects due to the intramuscular injection.

[0571] During the Swim 1 and Swim 2 procedures, the experimental chamber was equipped with a 50 watt red light bulb.

[0572] B. Forced swim test

[0573] The forced swimming test was performed during the dark period.

[0574] On day 1, animals were subjected to a 15 min forced swim test training (Swim 1), and on day 2, Swim 2 was performed after treatment.

[0575] On the second day, animals were administered each treatment 60 min before performing the FST.

[0576] The forced swim test (Swim 2) was not video recorded and was scored manually.

[0577] The forced swimming test (FST) was used to study depressive-like behavior in rodents. The test was performed in a transparent cylindrical glass container with dimensions 46 cm height and 20 cm diameter.

[0578] The container was filled with water (23–25°C) to a depth of 30 cm.

[0579] To avoid hypothermia, clean dry cages, heat lamps and heat pads were used for animals completing the procedure.

[0580] All animals were handled for approximately 2 min each day for 5 days prior to the start of the experimental procedures.

[0581] Two swimming sessions were performed 24 h apart: the first session, Swim 1, was the pre-test / training phase (15 min), and the second session, Swim 2, was the testing phase (8 min).

[0582] For swim 2, the first minute of data was excluded from the analysis and the remaining 7 minutes of data was considered, which was then split into 5 minutes and 2 minutes.

[0583] Swimming 1

[0584] Rats were placed in a cylinder filled with water for 15 min (swim 1).

[0585] After 15 minutes, the rats were removed from the cylinder and placed in a temporary dry cage with a heat lamp above and a heating pad below for 15 minutes.

[0586] After the pre-test swim 1 and a 15 minute dry period, the animals were returned to their home cages.

[0587] Water was replaced after each session to avoid any effects on the next rat.

[0588] Swimming 2

[0589] The test swim (swim 2) was performed 24 hours after the start of swim 1.

[0590] Rats were placed in a cylinder filled with water for 8 min (swim 2).

[0591] After 8 minutes, the rats were removed from the container and placed in a temporary dry cage with a heat lamp above and a heating pad below for 15 minutes. The rats were allowed to recover in the cage while being closely and continuously monitored.

[0592] Water was replaced after each session to avoid any effects on the next rat.

[0593] During swim 2, animals were observed for floating without any movement (amokinesia), climbing, and swimming.

[0594] The duration of time spent immobile, swimming, and climbing was observed by an observer blinded to the treatment groups.

[0595] Observation criteria

[0596] Immobility time

[0597] Rats were considered immobile if they remained floating in the water without struggling, making only those movements necessary to keep their head above the water surface.

[0598] Swimming behavior

[0599] Rats were judged to be swimming if they demonstrated more active horizontal (swimming) movements (e.g., moving around in the cylinder) than those required simply to keep the head above the water surface.

[0600] Climbing behavior

[0601] Rats were considered to be climbing if they showed active vertical movements of the forepaws, usually towards the wall, both in and out of the water.

[0602] statistical analysis

[0603] Using GraphPad Prism version 9 software, one-way ANOVA, Dunnett's multiple comparison test was applied for vehicle saline, and Tukey's multiple comparison test was applied for data comparison between groups.

[0604] result

[0605] The effects of the therapeutic agents (desipramine hydrochloride, dexmedetomidine hydrochloride, and latrepirdine dihydrochloride hydrate) on immobility, swimming, and climbing are shown in Figures 7A-D.

[0606] A standard antidepressant, i.e., desipramine hydrochloride (30 mg / kg, po), significantly decreased immobility time and increased climbing time compared to the vehicle saline group during the 5-min observation on the FST test day. However, treatment with desipramine hydrochloride (30 mg / kg, po) did not show any significant effect on swimming time, suggesting the involvement of noradrenergic mechanisms in the desipramine-mediated antidepressant effect in the FST rat model (Detke et al., 1995) (see Figure 7A-D).

[0607] Treatment with dexmedetomidine hydrochloride (1 and 5 μg / kg, im) significantly decreased immobility time compared to the vehicle saline group. Furthermore, dexmedetomidine hydrochloride (1 μg / kg, im) significantly increased climbing time compared to the vehicle saline group. In addition, dexmedetomidine hydrochloride (5 μg / kg, im) significantly increased swimming time, indicating that it exerts an antidepressant effect (see FIG. 7C).

[0608] Treatment with the combination of dexmedetomidine hydrochloride (1 μg / kg, im) and latrepirdine dihydrochloride hydrate (1 mg / kg, im) significantly increased swimming time (about 64.3%) compared to the vehicle saline group, but the increase in swimming time for each individual drug was about 1.6% for dexmedetomidine hydrochloride (1 μg / kg, im) and 9.8% for latrepirdine dihydrochloride hydrate (1 mg / kg, im) compared to the vehicle saline group, suggesting a synergistic interaction between these two drugs at that particular dose combination. The effect of drug combination treatment on swimming behavior may be due to an increase in brain levels of the neurotransmitter serotonin, which is known to have mood-elevating effects (see Figure 7B).

[0609] Conclusion: It can be concluded that the synergy observed between dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate at certain doses (1 μg / kg and 1 mg / kg, respectively) results from the specific norepinephrine (NE) and serotonin brain levels produced by the drugs at those doses.

[0610] The study evaluated the antidepressant-like effects of dexmedetomidine hydrochloride alone (1 and 5 μg / kg, im) or in combination with latrepirdine dihydrochloride hydrate (1 mg / kg, im) in a dark forced swimming test rat model. The combination significantly increased swimming behavior more than dexmedetomidine hydrochloride at 5 μg / kg, im, indicating a synergistic effect of the two suboptimal individual doses of dexmedetomidine hydrochloride and latrepirdine dihydrochloride.

[0611] Example 5. Evaluation of the effects of dexmedetomidine hydrochloride, latrepirdine dihydrochloride hydrate and their combination on aggressive behavior in male Swiss albino mice in a resident intruder test. Materials and Methods

[0612] Test system: Mouse

[0613] Lineage / Gender: Swiss Albino / Male

[0614] Source: Vivo Bio Tech Ltd.Hyderabad,Telangana,India

[0615] Group assignment

[0616] [Table 10]

[0617] Total number of animals: 280 males and 140 females.

[0618] Age at time of study: 3-6 weeks

[0619] Weight range: approx. 25-40g (140 male residents) / approx. 10-20g (140 male intruders) / 15-25g (140 females)

[0620] Veterinary Examination: Prior to final allocation to the study, the selected mice were subjected to a veterinary examination to ensure that they were in good health.

[0621] Identification: Marked on tail with permanent marker.

[0622] Acclimatization: After health examination, animals were allowed to acclimate to test conditions for one week. Only animals without visible signs of disease were used in the study.

[0623] Breeding

[0624] Conditions: Standard laboratory conditions maintained at 21±3°C and relative humidity 30-70% with a 12-hour light / dark cycle (lights on between 07:00 and 19:00).

[0625] Housing: All resident mice were individually housed (1 animal / cage) and intruder mice were group housed (5 animals / cage) in sterile solid-bottom polycarbonate cages (dimensions 17 in. (L) x 10 in. (W) x 8 in. (H) with stainless steel trellis tops, provisions for food and water bottles, and clean corncob bedding). Cages were mounted on stainless steel racks.

[0626] Diet: SAFE® Laboratory diet for rodents, manufactured by SAFE, France, was provided in pellet form.

[0627] Water: Drinking water was provided ad libitum in polycarbonate bottles with stainless steel tips that had been passed through a water filtration system.

[0628] Animal handling: Experiments were performed by qualified and trained scientists (trained in animal handling, drug administration and experimentation).

[0629] Safety precautions: Routine hygiene measures (apron, gloves, goggles, face mask and head cap) were followed.

[0630] Dose preparation: Test substances were dissolved in 0.9% saline, which served as the vehicle.

[0631] Compound vehicles: dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate * :0.9% saline.

[0632] Formulation preparation of sodium valproate: Sodium valproate was dissolved in 0.9% saline.

[0633] Formulation preparation of β-estradiol: β-estradiol was dissolved in 0.9% saline.

[0634] Formulation appearance: Dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (clear solution), sodium valproate (clear solution), β-estradiol (clear solution). * Note regarding Latrepirdine: Vortexing and sonication can be applied for 5 minutes to obtain a clear solution.

[0635] Formulation stability:

[0636] All formulations were prepared fresh on the day of treatment. Dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate formulations were stored at 4°C protected from light until administration.

[0637] Processing method: IP

[0638] Acclimatization period: At least 1 week

[0639] Dosage frequency: once

[0640] Dosage: 10 mL / kg

[0641] Testing Procedure:

[0642] Bilateral ovariectomy was performed in 3-4 week old female Swiss albino mice according to standard methods (Alagwu and Nneli, 2005). Animals were anesthetized with Avertin (2,2,2-tribromoethanol) 250 mg / kg, ip, and placed on the operating table and immobilized with adhesive tape. A midline incision was made below the ribs on the dorsal side, and small incisions were made in the fascia 1 cm on both sides lateral to the midline to isolate the fat supporting the ovaries. The ovaries were identified by gently pulling out the fat tissue, and the uterine horns were ligated with silk sutures, after which the ovaries were removed. The fascia was covered with sutures, and the same procedure was repeated on the other side. The epidermal layer was sutured, and gentamicin (80 mg / kg, sc) was administered as an antibiotic and meloxicam (4 mg / kg, sc) as an analgesic, and then povidone-iodine was applied to the epidermal layer. Polyethylene glycol (PEG) was applied to prevent dryness of the eyes and a recovery period of 3 weeks was ensured (surgery was performed by a single experimenter). Male Swiss albino mice (25-40 grams, resident animals) were housed individually, i.e., 1 animal / cage, together with ovariectomized female Swiss albino mice for 3 weeks (isolation acclimation). During this acclimation period, β-estradiol was administered sc to female mice at a dose of 0.2 mg / kg. Male Swiss albino mice (10-20 grams, intruder animals) were housed 5 animals / cage for 5 days (social acclimation). On the day of exposure, the animals were placed in the experimental room 60 min before the start of the experiment to allow them to become accustomed to the experimental conditions. On days 1 and 2, the intruders were placed in the housing cages of the resident animals for 10 min and then returned to their original housing cages. During this 10-min exposure, aggressive behaviors of resident animals (tail-wagging, chasing, biting, flanking, clinching) were recorded as attack duration in addition to attack latency, during which female mice were removed from the resident cage (choice phase was performed by three experimenters between 9AM and 1PM).

[0643] Animals were selected for treatment if they met the following criteria:

[0644] The average duration of aggression (days 1 and 2) for resident animals must be greater than 30 seconds. The selected animals were randomized into different groups based on their challenge duration.

[0645] On the fourth day after the first exposure, the test substance / vehicle / sodium valproate was administered to the resident animals and the same resident animals were exposed to the same intruder 60 minutes prior to testing. Sodium valproate was administered to the resident animals 30 minutes prior to testing.

[0646] Statistical analysis:

[0647] The data obtained were compared with baseline scores by using Student's paired two-tailed t-test. Attack duration and attack latency between groups were analyzed using One-Way ANOVA followed by Bonferroni's post-hoc test. All statistical analyses were performed using the Graph pad prism software package (Version 7 or higher), and p values ​​below 0.05 were considered significant. Observations: Mortality and clinical signs were monitored and reported.

[0648] result: It was found that latrepirdine dihydrochloride hydrate reduced the agitation / aggression of resident mice. In Figure 8A & 8B, latrepirdine dihydrochloride hydrate (1 mg / kg, 3 mg / kg, and 10 mg / kg, ip) significantly reduced the duration of the attack. Similarly, several combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (dexmedetomidine 4 mcg / kg (ip) + latrepirdine 3 mg / kg (ip), dexmedetomidine 4 mcg / kg (ip) + latrepirdine 10 mg / kg (ip), and dexmedetomidine 10 mcg / kg (ip) + latrepirdine 1 mg / kg (ip)) were found to have a significant effect on reducing the duration of the attack compared to vehicle (Figure 9A & 9B). Two combinations of dexmedetomidine and latrepirdine, namely dexmedetomidine 4 μg / kg (ip) + latrepirdine 3 mg / kg (ip) and dexmedetomidine 10 μg / kg (ip) + latrepirdine 1 mg / kg (ip), showed an almost equivalent effect to that of latrepirdine 10 mg / kg (ip) in reducing the duration of attacks, with the mean duration of attacks being 42.58 seconds, 40.73 seconds, and 36.87 seconds, respectively (Figure 10). These two combinations may be useful from the viewpoint of drug safety, and instead of using a high dose of a single compound alone, a combination of lower doses of each individual component can be used to achieve a similar effect.

[0649] Example 6: Antipsychotic effects of dexmedetomidine hydrochloride and latrepirdine in mice using the Smart-cube system. Dexmedetomidine and latrepirdine have antipsychotic effects when tested with the SmartCube® system (Psychogenics, Inc., Paramus, NJ, see also U.S. Patent No. 7,580,798, which is incorporated herein by reference in its entirety). The system uses features derived from mouse behavioral data to first classify mice into compound-treated vs. vehicle-treated. This criterion reveals how well the system can distinguish between compound-treated and vehicle-treated mice. Secondly, SmartCube® assigns a signature to the behavior by comparing the features against a unique reference database of behavioral feature sets linked to classes of marketed drugs known to treat neuropsychiatric conditions. Thus, the system can be used as a model to identify both the activity and psychotherapeutic effects of compounds by comparing their effects against drugs with known and verified effects.

[0650] By comparing the animals' responses to known drugs, the test drugs can be classified according to their function, e.g., hallucinogens, anxiolytics, analgesics, nootropics, psychostimulants, mood stabilizers, high-dose antipsychotics, antipsychotics, sedatives / hypnotics, anxiolytics, high-dose antidepressants, antidepressants.

[0651] Once all features are extracted from the raw data through an automated pipeline, proprietary bioinformatics algorithms are used to decorrelate the features and find the combination of values ​​that best separates the different groups of interest. For each compound, at each dose, the system provides the probability that the drug is active and classifies such putative activity into the different classes of interest.

[0652] The SmartCube reference data used herein includes antipsychotics and antidepressants tested at several dose ranges. The "antipsychotic" vs. "high dose antipsychotic" in the legend reflects the notion that the antipsychotic reference data is dose-dependent. Antipsychotics may engage additional receptor systems when administered at high doses, thus affecting mouse behavior differently. The same applies to different doses of antidepressants.

[0653] Materials and Methods:

[0654] Animals: Male C57 / Bl6 mice (N=12 per group) from Taconic Laboratories were used. Upon receipt, mice were housed in groups of 4 per cage in OPTI ventilated mouse cages. Mice were acclimated to the colony room for at least 1 week prior to testing and then tested at approximately 8-9 weeks of age. All animals were examined, handled, and weighed prior to the start of the study to ensure adequate health and suitability, and to minimize non-specific stress associated with the manipulations.

[0655] During the study, the light / dark cycle was maintained at 12 / 12. The room temperature was maintained between 20 and 23°C, and the relative humidity was maintained between approximately 30 and 70%. Chow and water were available ad libitum throughout the study.

[0656] Animals were acclimatized to the vivarium up to 1 week before the start of the study. Room temperature and humidity were continuously recorded. The experimenter(s) were blinded to treatment allocation. Behavioral testing was performed according to established protocols approved by the IACUC committee and PGI Standard Operation Procedures (SOPs). Standard safety precautions were applied in all studies. Personnel working in the animal and laboratory rooms wore protective clothing.

[0657] Treatment: 8 groups (N=12 per group)

[0658] All test compounds were formulated in NP3 (vehicle solution): 5% Pharmasolve, 30% P3 (1:1:1 PEG200:PEG400:propylene glycol), 65% saline, pH 5.1-6. All SmartCube runs were performed under identical settings using NP3 as the vehicle. Study Group: Vehicle: NP3 Dexmedetomidine at 0.005 and 0.010 mg / kg 1 and 10 mg / kg latrepirdine Dexmedetomidine and latrepirdine combination (mg / kg): 0.005 / 1.0, 0.005 / 10, 0.010 / 1.0, 0.010 / 10 Test compounds were injected intraperitoneally (IP) for 15 min before the animals were placed in the SmartCube for evaluation.

[0659] SmartCube Legend Explanation:

[0660] Vehicle: Activity profile of mice injected intraperitoneally (IP) with vehicle (NPS).

[0661] Antipsychotics: The SmartCube classifies the behavior of mice with test compounds as being similar to treatment with commercially available antipsychotics at therapeutically relevant doses.

[0662] High-dose antipsychotics: SmartCube classifies the behavior of mice with test compounds as similar to treatment with commercially available antipsychotics at doses considered to be high therapeutic doses, which often cause sedation.

[0663] Antidepressants: The SmartCube classifies the behavior of mice with test compounds as being similar to treatment with commercially available antidepressants at therapeutically relevant doses.

[0664] High Dose Antidepressants: The SmartCube classifies the behavior of mice with test compounds as being similar to treatment with commercially available antidepressants at doses considered to be high therapeutic doses.

[0665] Mood stabilizers: The SmartCube classifies the behavior of mice with test compounds as being similar to treatment with commercially available mood stabilizers at doses considered to be therapeutically high.

[0666] result:

[0667] The results of the class analysis are shown as standardized bar graphs with percentages summing to 100 for each dose. The percentages indicate the likelihood that the classifier can distinguish between the vehicle and test groups. The patterns indicate which class signatures were assigned.

[0668] The signature of dexmedetomidine in SmartCube is an antipsychotic.

[0669] Smart-Cube signatures (Figure 11) of mice (IP mg / kg, N=12 per group) administered dexmedetomidine, an alpha2 adrenergic receptor agonist, at two doses (0.005 and 0.010 mg / kg). The Smart-Cube deep learning classifier assigns activity signatures by comparing the phenotypic behavior of dexmedetomidine-injected mice to a reference data library obtained with known compounds. At 0.005 and 0.010 mg / kg, the Smart-Cube classifies the dexmedetomidine group (vs. vehicle) with high accuracy and assigns an antipsychotic signature.

[0670] The signature of latrepirdine in the SmartCube is an antipsychotic.

[0671] Smart-Cube signatures of mice (IP mg / kg, N=12 per group) administered latrepirdine at two doses (1.0 and 10 mg / kg) (Figure 11). The Smart-Cube deep learning classifier assigns activity signatures by comparing the phenotypic behavior of mice injected with latrepirdine to a reference data library obtained with known compounds. At 1 and 10 mg / kg, the Smart-Cube classifies the latrepirdine group (vs. vehicle) with high accuracy and assigns an antipsychotic signature.

[0672] Synergistic effect of dexmedetomidine 0.010 mg / kg and latrepirdine 1 mg / kg.

[0673] Smart-Cube signatures of mice (IP mg / kg, N=12 per group) injected with dexmedetomidine and latrepirdine combinations: 0.005 / 1.0, 0.005 / 10, 0.010 / 1.0, 0.010 / 10 (dexmedetomidine / latrepirdine, mg / kg, Figure 11). The Smart-Cube deep learning classifier assigns activity signatures by comparing the phenotypic behavior of mice injected with dexmedetomidine and latrepirdine combinations to a reference data library obtained with known compounds. Dose 0.005 / 1.0 (dexmedetomidine / latrepirdine, mg / kg): Smart-Cube assigns an antipsychotic signature and a total activity that is the approximate sum (25%) of each dose separately (9% and 20% for individual dexmedetomidine and latrepirdine doses, respectively). Dose 0.005 / 10 (dexmedetomidine / latrepirdine, mg / kg): Smart-Cube assigns a high dose antipsychotic signature and assigns a total activity that is approximately the sum (90%) of each dose separately (9% and 80% for individual dexmedetomidine and latrepirdine doses, respectively). Dose 0.010 / 1.0 (dexmedetomidine / latrepirdine, mg / kg): Smart-Cube assigns an antipsychotic signature plus some high dose antipsychotic signature and assigns a total activity that is higher than the sum of each dose separately (40% and 20% for individual dexmedetomidine and latrepirdine doses, respectively). The sum is 60%, but the combined dose effect is 76%. Dose 0.01 / 10 (dexmedetomidine / latrepirdine, mg / kg): The Smart-Cube assigns a high dose antipsychotic signature and assigns a total activity that is up to 95%.

[0674] These data indicate that dexmedetomidine (0.010 mg / kg) and latrepirdine (1 mg / kg) at suboptimal doses act synergistically while retaining a primarily antipsychotic signature.

[0675] Example 7. Evaluation of the effects of dexmedetomidine hydrochloride, latrepirdine dihydrochloride hydrate and their combination on motor activity (locomotor activity) and sedated behavior of male Swiss albino mice in the open field test. Materials and Methods Test system Test system: Mouse Lineage / Gender: Swiss Albino / Male Research: Open field test

[0676] Open field test: In the open field test, spontaneous locomotor activity is measured in terms of total distance traveled. Comparatively, less distance traveled indicates less or sedated locomotor activity.

[0677] Group Assignment: [Table 11] Total number of animals: 120 males Age at time of study: 6-7 weeks Weight range: approx. 25-40g

[0678] Acclimatization: After health examination, animals were allowed to acclimate to test conditions for one week. Only animals without visible signs of disease were used in the study.

[0679] Breeding

[0680] Conditions: Standard laboratory conditions maintained at 21±3°C and relative humidity 30-70% with a 12-hour light / dark cycle (lights on between 07:00 and 19:00).

[0681] Housing: All mice were housed in groups of 4 (dimensions 17" (L) x 10" (W) x 8" (H) with stainless steel grid tops, facilities for food and water bottles, and clean corncob bedding). Cages were mounted on stainless steel racks.

[0682] Diet: SAFE® Laboratory diet for rodents, manufactured by SAFE, France, was provided in pellet form.

[0683] Water: Drinking water was provided ad libitum in polycarbonate bottles with stainless steel tips that had been passed through a water filtration system.

[0684] Animal handling: Experiments were performed by qualified and trained scientists (trained in animal handling, drug administration and experimentation).

[0685] Safety precautions: Routine hygiene measures (apron, gloves, goggles, face mask and head cap) were followed.

[0686] Dose preparation

[0687] Test substances were dissolved in 0.9% saline, which served as the vehicle.

[0688] Dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate vehicle * :0.9% saline.

[0689] Product appearance: Dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (clear solution).

[0690] * Note for Latrepirdine dihydrochloride hydrate: Vortexing and sonication can be applied for 5 min to obtain a clear solution.

[0691] Stability of the formulation

[0692] All formulations were prepared fresh on the day of treatment. Dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate formulations were stored at 4°C protected from light until administration.

[0693] Experimental procedure

[0694] Mice were placed in the laboratory and allowed to acclimate for at least 7 days. The open field test was performed under 40 lux lighting conditions. Mice were dosed according to allocation. After a 60-minute interval after dosing, groups of four mice were placed in the open field and their movements were tracked for 30 minutes. Immediately after completing the test, the mice were removed from the open field and the arena was cleaned. Following this, the next set of four mice was placed in the arena and tracked.

[0695] statistical analysis

[0696] Distance traveled during 30 min was analyzed in 5-min increments and compared with that of the vehicle group using one-way ANOVA followed by Dunnett's test. All statistical analyses were performed using the Graph pad prism software package (Version 7 or higher), and p values ​​below 0.05 were considered significant.

[0697] result:

[0698] Dexmedetomidine hydrochloride (4 μg / kg, 10 μg / kg and 20 μg / kg) did not show any significant decrease in the distance traveled (FIG. 12). In addition, latrepirdine dihydrochloride hydrate tested at 1 mg / kg, 3 mg / kg and 10 mg / kg also did not show any significant decrease in the distance traveled. Furthermore, the combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg+10 mg / kg and 10 μg / kg+1 mg / kg, respectively) also did not show any significant decrease in the distance traveled. Meanwhile, only dexmedetomidine hydrochloride at 30 μg / kg showed a significant decrease in the distance traveled.

Claims

1. A combination for treating agitation in a subject exhibiting agitation, the combination comprising dexmedetomidine or a pharma- ceutical acceptable salt thereof and latrepirdine or a pharma-ceutical acceptable salt thereof, characterized in that the dexmedetomidine or a pharma-ceutical acceptable salt thereof and the latrepirdine or a pharma-ceutical acceptable salt thereof are administered oromucosally to the subject in combination.

2. 1. A dosage form for treating agitation in a subject exhibiting agitation, said dosage form comprising latrepirdine or a pharma- ceutically acceptable salt thereof, said dosage form being oromucosally administered to said subject.

3. A combination for the treatment of depression in a subject in need of such treatment, comprising dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and latrepirdine, or a pharma- ceutically acceptable salt thereof, characterized in that the dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and the latrepirdine, or a pharma- ceutically acceptable salt thereof, are administered in combination to the subject.

4. 1. A dosage form for the treatment of depression in a subject in need thereof, said dosage form comprising latrepirdine or a pharma- ceutically acceptable salt thereof, said dosage form being characterized in that said dosage form is administered oromucosally to said subject.

5. A combination for the treatment of a psychosis in a subject in need of such treatment, comprising dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and latrepirdine, or a pharma- ceutically acceptable salt thereof, characterized in that the dexmedetomidine, or a pharma- ceutically acceptable salt thereof, and the latrepirdine, or a pharma- ceutically acceptable salt thereof, are administered in combination to the subject.

6. 1. A dosage form for treating a psychosis in a subject, said dosage form comprising latrepirdine or a pharma- ceutically acceptable salt thereof, said dosage form being characterized in that said dosage form is administered oromucosally to said subject.

7. The combination according to claim 1, characterized in that dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are administered sequentially in separate dosage forms.

8. The combination according to claim 1 , wherein dexmedetomidine and latrepirdine or pharma- ceutically acceptable salts thereof are formulated in a single dosage form.

9. 9. The dosage form according to any one of claims 2, 4 and 6 or the combination according to claim 7 or 8, characterized in that the dosage form is administered once a day.

10. 9. The dosage form according to any one of claims 2, 4 and 6 or the combination according to claim 7 or 8, characterized in that the dosage form is administered multiple times daily.

11. The dosage form according to claims 2, 4, 6, 9 and 10 or the combination according to any of claims 7 to 10, characterized in that the dosage form is a freeze-dried oromucosal tablet, preferably for sublingual or buccal administration.

12. 3. The combination of claims 1-2, wherein 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, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

13. The combination according to claims 1 to 2, wherein the agitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression.

14. The combination of claims 1-2, wherein the agitation is associated with alcohol, opioid use disorder, opioid withdrawal and substance use withdrawal.

15. The combination according to claims 1 to 2, wherein the agitation is caused by noradrenaline-mediated hyperarousal.

16. The combination of claims 1-2, wherein the treatment is effective in suppressing agitation in an agitated subject without causing significant sedation.

17. The combination according to claims 1 to 2, wherein the agitation is acute or chronic.

18. below: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof; (ii) one or more mucoadhesives, and (iii) one or more pharma- ceutically acceptable excipients or carriers; The oral mucosal dosage form comprises:

19. below: (i) a therapeutically effective amount of latrepirdine, or a pharma- ceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharma- ceutically acceptable salt thereof; (iii) one or more mucoadhesives, and (iv) one or more pharma- ceutically acceptable excipients or carriers; The oral mucosal dosage form comprises:

20. The oral mucosal dosage form according to claims 18-19, wherein the one or more mucoadhesives are present in an amount of about 0.5% to about 30% w / w.

21. The oromucosal dosage form according to claims 18 to 20, wherein the dosage form is prepared by spray drying, sublimation, nanonization, granulation, direct compression or freeze drying, preferably by freeze drying.

22. 22. The oral mucosal dosage form of claims 18-21, wherein the dosage form has a mucoadhesive peak force of greater than about 50g, greater than about 100g, greater than about 200g, greater than about 300g, greater than about 400g, greater than about 500g, greater than about 600g, greater than about 700g, greater than about 800g, greater than about 900g, greater than about 1000g, greater than about 1100g, greater than about 1200g, greater than about 1300g, greater than about 1400g or greater than about 1500g.

23. The oral mucosal dosage form according to any one of claims 18 to 22, wherein the dosage form is a sublingual tablet.

24. 23. The oral mucosal dosage form according to any one of claims 18 to 22, wherein the dosage form is a buccal or gingival tablet.

25. The dosage form comprises:

19. The oral mucosal dosage form of claim 18, which is a freeze-dried tablet comprising: (i) sodium alginate, (ii) croscarmellose sodium or sodium starch glycolate, (iii) sucralose, (iv) magnesium stearate and / or silicon dioxide, (v) lactose or mannitol, and (vi) optionally other pharma-ceutically acceptable excipients.

26. The dosage form comprises:

19. The oral mucosal dosage form of claim 18, which is a freeze-dried tablet comprising: (i) carbomer; (ii) croscarmellose sodium or sodium starch glycolate; (iii) sucralose; (iv) magnesium stearate and / or silicon dioxide; (v) lactose or mannitol; and (vi) optionally other pharmaceutically acceptable excipients.

27. The dosage form comprises:

20. The oral mucosal dosage form of claim 18, which is a freeze-dried tablet comprising: (i) xanthan gum, (ii) croscarmellose sodium or sodium starch glycolate, (iii) sucralose, (iv) magnesium stearate and / or silicon dioxide, (v) lactose or mannitol, and (vi) optionally other pharma- ceutically acceptable excipients.

28. The dosage form comprises:

20. The oral mucosal dosage form of claim 18, which is a freeze-dried tablet comprising: (i) carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyethylene oxide; (ii) croscarmellose sodium, or sodium starch glycolate; (iii) sucralose; (iv) magnesium stearate and / or silicon dioxide; (v) lactose or mannitol; and (vi) optionally other pharmaceutically acceptable excipients.

29. The dosage form comprises:

20. The oral mucosal dosage form of claim 18, which is a freeze-dried tablet comprising: (i) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyethylene oxide, (ii) croscarmellose sodium or sodium starch glycolate, (iii) sucralose, (iv) magnesium stearate and / or silicon dioxide, (v) lactose or mannitol, and (vi) optionally other pharmaceutically acceptable excipients.

30. 1. A kit comprising an oral mucosal freeze-dried tablet form comprising: (i) a therapeutically effective amount of dexmedetomidine, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) a therapeutically effective amount of latrepirdine or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt), and optionally (iii) instructions for administering the dosage form to a subject in need thereof; The kit comprising:

31. 10. The oromucosal dosage form / combination / kit according to any of the preceding claims, wherein the latrepirdine or a pharma- ceutically acceptable salt thereof is latrepirdine hydrochloride or latrepirdine dihydrochloride.

32. 10. The oromucosal dosage form / combination / kit according to any of the preceding claims, wherein the dexmedetomidine or a pharma- ceutically acceptable salt thereof is dexmedetomidine hydrochloride.

33. An oral mucosal dosage form / combination / kit described in any of the preceding claims, wherein dexmedetomidine or a pharma- ceutically acceptable salt thereof is administered in a therapeutically effective amount, said therapeutically effective amount being in the range of about 10 micrograms to about 300 micrograms.

34. An oral mucosal dosage form / combination / kit described in any of the preceding claims, wherein latrepirdine or a pharma- ceutically acceptable salt thereof is administered in a therapeutically effective amount, said therapeutically effective amount being in the range of about 10 mg to about 100 mg.

35. 28. The oral mucosal dosage form of any one of claims 20 to 27, wherein the one or more mucoadhesives are selected from the group consisting of polyacrylic acid polymers, methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, thiolated carboxymethylcellulose, polysaccharides, xanthan gum, karaya gum, tragacanth gum, propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide, microcrystalline cellulose (Avicel), croscarmellose and mixtures thereof.

36. 36. The oral mucosal dosage form of claim 35, wherein the polyacrylic acid polymer is a carbomer, a polycarbophil, or a combination thereof.

37. 36. The oral mucosal dosage form of claim 35, wherein the polysaccharide is pectin, chitosan, or a combination thereof.

38. 28. The oral mucosal dosage form of any one of claims 20 to 27, wherein the one or more pharma- ceutically acceptable excipients or carriers are selected from the group consisting of disintegrants, fillers / diluents, binders, flow agents, lubricants, plasticizers, pH adjusters, colorants, flavoring agents, sweetening agents, and combinations thereof.

39. 10. The oral mucosal dosage form of any preceding claim, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes of contact with the oral mucosa.

40. A composition for treating agitation in a subject exhibiting agitation, the composition comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof, the composition being administered orally to the subject in combination with latrepirdine or a pharma- ceutically acceptable salt thereof.

41. A composition for treating agitation in a subject exhibiting agitation, the composition comprising latrepirdine or a pharma- ceutically acceptable salt thereof, the composition being administered orally to the subject in combination with dexmedetomidine or a pharma- ceutically acceptable salt thereof.

42. A composition for treating depression in a subject in need of such treatment, the composition comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof, the composition being administered to the subject in combination with latrepirdine or a pharma- ceutically acceptable salt thereof.

43. A composition for treating depression in a subject in need of such treatment, the composition comprising latrepirdine or a pharma- ceutically acceptable salt thereof, the composition being administered to the subject in combination with dexmedetomidine or a pharma- ceutically acceptable salt thereof.

44. A composition for treating a psychosis in a subject in need of such treatment, the composition comprising dexmedetomidine or a pharma- ceutically acceptable salt thereof, the composition being administered to the subject in combination with latrepirdine or a pharma- ceutically acceptable salt thereof.

45. A composition for treating a psychosis in a subject in need of such treatment, the composition comprising latrepirdine or a pharma- ceutically acceptable salt thereof, the composition being administered to the subject in combination with dexmedetomidine or a pharma- ceutically acceptable salt thereof.

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