CN117750956A

CN117750956A - Methods for treating depressive states

Info

Publication number: CN117750956A
Application number: CN202280047261.1A
Authority: CN
Inventors: M·德维沃; F·D·尤卡; R·瑞辛格; C·比斯利
Original assignee: Bioxcel Therapeutics Inc
Current assignee: Bioxcel Therapeutics Inc
Priority date: 2021-07-02
Filing date: 2022-07-01
Publication date: 2024-03-22

Abstract

The present disclosure relates to methods of treating or preventing depression in a human subject suffering from major depression or major depressive episode, comprising (a) an induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of a Selective Serotonin Reuptake Inhibitor (SSRI)/Serotonin Norepinephrine Reuptake Inhibitor (SNRI) for about 1 day to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of the SSRI/SNRI.

Description

Methods for treating depressive states

Cross Reference to Related Applications

The present application claims priority from U.S. patent application Ser. No. 63/218,031, 22, 2021, 7, and 22, 35U.S. C.119 (e), the disclosure of each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates to methods of treating or preventing depression in a human subject in need thereof.

Background

Major depression is characterized by discrete episodes of at least 2 weeks duration (although most episodes last significantly longer), involving significant changes in emotional, cognitive, and autonomic functions and inter-episode relief. This may also be accompanied by hypomania or manic symptoms (i.e., fewer symptoms or less duration than required for a definitive diagnosis of mania or hypomania). According to manual for diagnosis and statistics of psychotic disorders,5th edition (Diagnostic and Statistical Manual of Mental Disorders,5th edition, dsm-5), an individual must have at least one of the following symptoms: (1) depressed mood or (2) lost interest or pleasure. Investigation has shown that between 40% and 60% of patients with Major Depressive Disorder (MDD) also have anxiety symptoms and share anxiety-related features that make them difficult to distinguish in practice. In particular, both populations are characterized by agitation and internal stress that cause anxiety manifestations. Patients with anxiety disorder experience significant physiological and emotional discomfort and have elevated rates of drug abuse and medical illness. In the case of other psychotic disorders, such as Major Depressive Disorder (MDD) or bipolar disorder, the concomitant anxiety disorder is associated with a more chronic and refractory course of the disease and the risk of suicidal for these patients is increased.

The etiology of major depressive disorder is thought to be multifactorial, including biological, genetic, environmental, and psychosocial factors. MDD was previously thought to be mainly due to abnormalities in neurotransmitters, especially serotonin, norepinephrine, and dopamine. People with suicidal ideation have been found to have low levels of serotonin metabolites. This has been demonstrated by the use of different antidepressants, such as selective serotonin receptor inhibitors, serotonin-norepinephrine receptor inhibitors, dopamine-norepinephrine receptor inhibitors, for the treatment of depression. Treatment with Selective Serotonin Reuptake Inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) provides relief by increasing serotonin and norepinephrine levels in the brain. In addition, antidepressants such as SSRI and SNRI are typically administered about 4 to 6 weeks before the beneficial therapeutic effects become apparent, side effects that may lead to worse clinical outcome (including higher risk suicide) occur, or the treatment is terminated before the beneficial therapeutic effects occur.

In addition, not all patients are treated with sufficient doses of SSRI or SNRI for a sufficient period of time to achieve clinically significant benefits.

Thus, there is a need to accelerate the time to response and reduce the burden of anxiety and/or agitation symptoms that may be caused by the primary antidepressant (SSRI or SNRI) when patients are treated with SSRI or SNRI.

There is also a need to potentiate/enhance the therapeutic response to SSRI or SNRI in patients who, despite adequate therapeutic trials, still fail to achieve clinically significant improvement in depression symptoms.

Disclosure of Invention

The present disclosure provides methods for administering dexmedetomidine (dexmedetomidine) or a pharmaceutically acceptable salt thereof, alone or in combination with one or more SSRI/SNRI, to accelerate therapeutically beneficial results in subjects with major depressive episodes in cases of diagnosis of major depressive disorder or to enhance (i.e., improve) response in patients failing to exhibit a sufficient therapeutic response to a sufficient course of SSRI or SNRI treatment.

The present disclosure also provides a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject as monotherapy, wherein the subject is non-agitation. In embodiments, major depressive disorder is associated with anxiety pain. In embodiments, major depressive disorder is associated or not associated with a medical condition. In embodiments, the subject suffers from additional co-occurrence disorders or conditions such as obsessive compulsive disorder, anxiety, social anxiety, PTSD, panic disorder, or generalized anxiety disorder. In embodiments, major depressive disorder is mild or moderate. In embodiments, major depressive disorder is severe.

In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via oral mucosa (including buccal, sublingual, gingival). In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

The present disclosure also provides a method of treating Major Depressive Episode (MDE) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject as monotherapy, wherein the subject is non-agitation.

In embodiments, major depressive episodes are associated with anxiety distress. In embodiments, the major depressive episode is associated or not associated with a medical disorder. In embodiments, the subject suffers from additional co-occurrence disorders or conditions such as obsessive compulsive disorder, anxiety, social anxiety, PTSD, panic disorder, or generalized anxiety disorder. In embodiments, the subject suffers from bipolar disorder. In embodiments, the subject suffers from major depressive disorder. In embodiments, the subject does not suffer from bipolar disorder. In embodiments, the major depressive episode is mild or moderate. In embodiments, major depressive episodes are severe.

In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (including buccal, sublingual, gingival). In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a tablet, wafer, patch, film, gel or spray or droplet. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a film.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered over an extended period of time or over a prolonged period of time (e.g., over a period of weeks or months).

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides the use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in a subject suffering from Major Depressive Disorder (MDD).

In embodiments, the present disclosure provides the use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in a subject with Major Depressive Episode (MDE).

In embodiments, the present disclosure provides the use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in subjects suffering from anxiety.

In embodiments, the present disclosure provides methods of accelerating an antidepressant response in a subject suffering from Major Depressive Disorder (MDD), comprising administering to the subject dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with one or more conventional antidepressants (e.g., SSRI/SNRI).

In embodiments, the present disclosure provides methods of accelerating an antidepressant response in a subject with Major Depressive Episode (MDE) comprising administering to the subject dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with one or more conventional antidepressants (e.g., SSRI/SNRI).

The present disclosure also provides a method of treating major depressive episode in a patient in need thereof in the event of diagnosis of major depressive disorder or bipolar disorder to enhance (i.e., improve) the therapeutic response to SSRI or SNRI, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as a co-therapy to the patient and an uninterrupted and sustained therapeutic agent SSRI or SNRI, whether the patient experiences anxiety and/or agitation-related symptoms at the time of initial treatment.

The present disclosure also provides a method of treating major depressive episode in a patient in need thereof in the event of diagnosis of major depressive disorder or bipolar disorder to accelerate the therapeutic response to SSRI, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as a co-therapy to the patient and SSRI or SNRI, whether or not the patient experiences anxiety and/or agitation-related symptoms at the time of initiating treatment in the patient in need thereof.

In embodiments, the conventional antidepressant is selected from the group consisting of (but not limited to): selective Serotonin Reuptake Inhibitors (SSRI); selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI); early tricyclic antidepressants (TCAs); monoamine oxidase inhibitors (MAO-inhibitors), monoamine oxidase Reversible Inhibitors (RIMA), atypical antidepressants; tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants. In embodiments, the conventional antidepressant is an SSRI or an SNRI. In embodiments, the subject fails to respond to or does not respond adequately to current antidepressant therapy. In embodiments, the subject has not previously been exposed to any conventional anti-depressant therapy.

In embodiments, the subject also has anxiety pain.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately after the subject begins to use conventional antidepressant therapy to provide acceleration of the antidepressant response and intermittent treatment for a period of about 1 to 4 weeks, while conventional antidepressants become effective and side effects subside. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a "first aid" drug form in a subject who may suffer from a symptomatic episode of major depression (e.g., a depressed mood episode) even when conventional antidepressant therapy is used, to alleviate and mitigate symptoms of the episode as desired. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a predetermined manner with conventional antidepressant therapy as part of a complete antidepressant regimen.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder comprising administering an oral transmucosal therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an oral therapeutic amount of SSRI/SNRI.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising administering a transmucosal therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an oral therapeutic amount of SSRI/SNRI.

Patients typically present with different baseline HAM-D scores, and higher scores are associated with more severe depression. HAM-D scores below 7 indicate no depression. Mild depression is in the range of 7-17 minutes, moderate depression is in the range of 18-24 minutes and major depression exceeds 25 minutes.

In embodiments, the subject has a total HAM-D-17 score of > 18 at the beginning of treatment (or baseline). In embodiments, the subject has a total HAM-D-17 score of > 14 at the beginning of treatment.

In embodiments, the methods described herein reduce HAM-D score by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or more, compared to baseline score observed prior to treatment.

In aspects, HAM-D score may be reduced to 5, 6, 7, 8, or 9 points; preferably, the HAM-D score is reduced to below 7 or to 7. Advantageously, administration of dexmedetomidine and an antidepressant as disclosed herein achieves a decrease in HAM-D score faster than antidepressant alone, thereby providing a substantially improved therapeutic adoption and reducing therapy cessation. The reduced HAM-D score may be achieved within 4 weeks of the initial therapy, preferably within 1 to 2 weeks. This is in contrast to patients taking antidepressants alone, who typically take a longer time to achieve a HAM-D score in the range of 5 to 9 or find a 50% decrease in their HAM-D score. Patients with moderate or major depression may not achieve such low scores after treatment, but may achieve a reduction in scores that provide significant relief from their depression; for example, the reduction may be from about 4 minutes to about 8 minutes. In embodiments, the subject has a MADRS score of ≡20 at the beginning of treatment (or baseline score). In embodiments, the subject has a MADRS score of ≡10 at the beginning of treatment.

In embodiments, the present disclosure provides a method of reducing MADRS scale scores in a human subject suffering from major depressive disorder comprising administering an oral transmucosal therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an oral therapeutic amount of SSRI/SNRI. In embodiments, the present disclosure provides a method of reducing MADRS scale scores in a human subject suffering from major depressive episode, the method comprising administering an oral transmucosal therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an oral therapeutic amount of SSRI/SNRI.

In embodiments, the methods described herein provide a reduction in MADRS score of about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or more, compared to a baseline score observed prior to treatment.

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a human subject, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNR for about 1 day to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

In embodiments, the induction period comprises a treatment period of at least about 1 to 4 weeks.

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a human subject caused by starting treatment with an SSRI or an SNRI, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

In embodiments, the SSRI/SNRI is administered as monotherapy during the maintenance phase. In embodiments, the SSRI/SNRI is administered with another SSRI/SNRI during the maintenance period. In embodiments, the maintenance period continues until the underlying disease (e.g., major depressive disorder) subsides. In embodiments, the maintenance period continues until no further treatment is needed (as determined by a clinician or physician). In embodiments, the maintenance period continues until the subject experiences a recurrence of anxiety pain. In embodiments, the subject is in the manic phase, the depressive phase, or both. In embodiments, the subject has undergone prior treatment (e.g., for at least one week) with the SSRI/SNRI prior to the induction period. In embodiments, the subject has undergone prior treatment (e.g., for at least two or three weeks) with SSRI/SNRI prior to the induction period.

In embodiments, when the subject experiences a recurrence of anxiety disorder, then it may begin a second induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 day to about 28 days, followed by a maintenance period comprising administering a therapeutic amount of SSRI/SNRI to the subject. In embodiments, the maintenance period lasts at least 4 weeks. In embodiments, the maintenance period lasts at least 6 weeks. In embodiments, the maintenance period lasts at least 8 weeks. In embodiments, the maintenance period is continued for as long as the treatment is desired.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof and SSRI/SNRI are administered in separate unit dosage forms. In embodiments, the co-administration unit dosage form lasts for about 28 days, about 27 days, about 26 days, about 25 days, about 24 days, about 23 days, about 22 days, about 21 days, about 20 days, about 19 days, about 18 days, about 17 days, about 16 days, about 15 days, about 14 days, about 13 days, about 12 days, about 11 days, about 10 days, about 9 days, about 8 days, about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. In embodiments, the co-administration unit dosage form lasts about 28 days. In embodiments, the co-administration unit dosage form lasts about 21 days. In embodiments, the co-administration unit dosage form lasts about 14 days. In embodiments, the co-administration unit dosage form lasts about 7 days. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof and SSRI/SNRI are administered sequentially or simultaneously.

In embodiments, the two unit dosage forms are administered by the same or different routes, respectively, selected from the group consisting of: oral mucosa (e.g., sublingual or buccal or gingival), oral, topical, transdermal, intranasal, parenteral (e.g., intravenous, intramuscular, subcutaneous), and the like. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof and/or SS/SNRI is administered in a dosage form selected from the group comprising: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches or lozenges, films, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered transmucosally in a dosage form selected from the group consisting of tablets, films, sprays, gels, or drops. In embodiments, the oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is a film. In embodiments, the SSRI/SNRI is administered orally in the form of a tablet. In embodiments, the SSRI/SNRI is administered orally in capsule form. In embodiments, the SSRI/SNRI is administered orally in the form of a delayed release capsule.

In embodiments, the SSRI/SNRI and dexmedetomidine or pharmaceutically acceptable salts are administered orally transmucosally in a dosage form selected from the group consisting of tablets, films, sprays, gels or drops (preferably films). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and SSRI/SNRI are administered together in a single unit dosage form (e.g., film). In embodiments, dexmedetomidine and SSRI/SNRI are present together in a single oral dosage form. Such unit dosage forms may contain dexmedetomidine and SSRI/SNRI as a homogeneous mixture or in separate compartments of the unit dosage form.

In embodiments, the oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice a day; for example, once in the morning and another time in the evening; preferably at the same time of day. The evening dose may be taken within 1 to 2 hours, optionally 1 hour, of the subject's bedtime.

inembodiments,thesubjecthasatotalscoreofHamiltoniananxietyscale(HamiltonAnxietyScale,HAM-A)of>14atthebeginningoftreatment(orbaseline).

In embodiments, the present disclosure relates to a single unit dosage form provided in the form of a kit comprising a composition as described herein in a container, with or without instructions for administration to a subject in need thereof. In embodiments, the present disclosure relates to a dual unit dosage form provided in the form of a kit comprising a composition as described herein in one or more containers, with or without instructions for simultaneous, sequential or separate administration to a subject in need thereof.

Drawings

Fig. 1a: depicted is the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluoxetine (32 mg/kg; i.p.) and dexmedetomidine (10 μg/kg; i.p.) in combination with Fluoxetine (32 mg/kg; i.p.) on the time spent in the open arms of the elevated plus maze in rats (data representing mean ± SEM, one-way ANOVA), followed by Tukey multiple comparison test, ^**** p<0.0001 (relative to vehicle), n=10 rats. CLZ: clobazam (clobazam); DEX: dexmedetomidine; FLX: fluoxetine; i.p.: intraperitoneal).

Fig. 1b: depicted are effects of treatment of dexmedetomidine (10 μg/kg; i.p.), fluoxetine (32 mg/kg; i.p.) and a combination of dexmedetomidine (10 μg/kg; i.p.) and fluoxetine (32 mg/kg; i.p.) on the percentage of open arms entering the elevated plus maze in rats (data representing mean ± SEM, one-way anova followed by Tukey multiple comparison test, ^*** p<0.001 (relative to vehicle), n=10 rats. CLZ: chlorbazaar; DEX: dexmedetomidine; FLX: fluoxetine; i.p.: intraperitoneal).

Fig. 2: depicts the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluoxetine (32 mg/kg; i.p.) and a combination of dexmedetomidine (10 μg/kg; i.p.) and fluoxetine (32 mg/kg; i.p.) on the time spent in the open arms of the elevated plus maze in rats (data representing mean ± SEM, one-way anova followed by Tukey multiple comparison test, ^**** p<0.0001 (relative to vehicle), n=10 rats. CLZ: chlorbazaar; DEX: dexmedetomidine; FLX: fluoxetine; i.p.: intraperitoneal).

Fig. 3: treatment of dexmedetomidine (10 μg/kg; i.p.), fluoxetine (32 mg/kg; i.p.) and a combination of dexmedetomidine (10 μg/kg; i.p.) and fluoxetine (32 mg/kg; i.p.) was depicted in rats as an effect on the total number of four arms entering the elevated plus maze (data representing mean ± SEM, one-way anova followed by Tukey multiple comparison test, < p <0.05 (relative to vehicle), n=10 rats · CLZ: clobazam; DEX: DEX dexmedetomidine; FLX: fluoxetine; i.p.: intraperitoneal) according to example 1.

Fig. 4: the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluoxetine (32 mg/kg; i.p.) and dexmedetomidine (10 μg/kg; i.p.) in combination with fluoxetine (32 mg/kg; i.p.) on total distance travelled in the four arms of the elevated plus maze in rats is depicted according to example 1 (data representing mean ± SEM, one-way anova followed by Tukey multiple comparison test with p <0.05 (relative to vehicle), p <0.01 (relative to vehicle), n=10 rats CLZ: clobazam; DEX: dexmedetomidine; FLX: fluoxetine; i.p.

Fig. 5: depicted is the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluvoxamine (Fluvoxamine) (3 mg/kg and 10mg/kg; i.p.) and dexmedetomidine (10 μg/kg; i.p.) in combination with Fluvoxamine (3 mg/kg and 10mg/kg; i.p.) on the number of open arms entering the elevated plus maze in rats with Yohimbine (Yohimbine) -induced anxiety (data representing mean ± SEM, one-way anova, followed by Tukey multiple comparison test, ^$$$$ p<0.0001 (relative to YOH (2.5 mg/kg, i.p.)))/p<0.05 (relative to YOH (2.5 mg/kg; i.p.) + DEX (10 μg/kg; i.p.)),<0.01 (relative to YOH (2.5 mg/kg; i.p.) + DEX (10. Mu.g/kg; i.p.)),. Times. Times.p.)<0.01 (n=12 rats relative to YOH (2.5 mg/kg; i.p.) + FLUVO (3 mg/kg; i.p.)). DEX: dexmedetomidine; FLUVO: fluvoxamine; i.p.: intraperitoneal administration; YOH: yohimbine).

Fig. 6: depicts the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluvoxamine (3 mg/kg and 10mg/kg; i.p.) and dexmedetomidine (10 μg/kg; i.p.) in combination with fluvoxamine (3 mg/kg and 10mg/kg; i.p.) on the time spent in the open arms of the elevated plus maze in rats with yohimbine-induced anxiety (data representing mean ± SEM, one-way variance analysis followed by Tukey multiple comparison test, ^$$$$ p<0.0001 (relative to YOH (2.5 mg/kg, i.p.)), ^$$ p<0.01 (relative to YOH (2.5 mg/kg, i.p.))) p<0.01 (relative to YOH (2.5 mg/kg; i.p.) + DEX (10 μg/kg; i.p.)),/p.<0.001 (relative to YOH (2.5 mg/kg; i.p.) +DEX (10 μg/kg; i.p.), ≡p-<0.0001 (n=12 rats relative to YOH (2.5 mg/kg; i.p.) + FLUVO (3 mg/kg; i.p.)). DEX: dexmedetomidine; FLUVO: fluvoxamine; i.p.: intraperitoneal administration; YOH: yohimbine).

Detailed Description

In the following paragraphs, different aspects of the disclosure are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Abbreviations:

as used herein, the following abbreviations have the following meanings:

AE: adverse events

ACES: agitation-calm evaluation scale

ADS: anxiety pain specifier

BOLD: blood oxygen level dependence

CGI: clinical global impression scale

CGI-I: clinical global impression scale-improvement

CGI-S: clinical global impression scale-severity

DSM-5: manual for diagnosis and statistics of mental disorders, fifth edition

DEX: dexmedetomidine

CMAI: cohen-Mansfield agitation emotional behavior scale (Cohen-Mansfield Agitation Inventory)

C-SSRS: columbia (Columbia) -suicide severity rating scale

DASS: depression and anxiety pressure scale

ECG: electrocardiography

HAM-a: hamilton anxiety rating scale

HDRS or (HAM-D): hamilton depression rating scale

HPMC: hydroxypropyl methylcellulose

ICF: informed consent form

P.: intraperitoneal administration

MAO: monoamine oxidase

MADRS: montgomery-Eyessenberg depression rating scale

MED DRA-supervision active medical dictionary

MDD: major depressive disorder

MDE: major depressive episode

MINI: mini international neuropsychiatric meeting questionnaire

mg: mg of (milligram)

NPI-C: neuropsychiatric scale-clinician rating scale

NS: is not remarkable

PANSS or PEC: positive and negative symptom scale

PBS: phosphate buffered saline

PK: pharmacokinetics of drugs

QIDS-SR: quick self-evaluation scale for depression symptoms

SL: sublingual tongue

SNRI: serotonin-norepinephrine reuptake inhibitors

SSRI: selective serotonin reuptake inhibitors

STAI: state scale for state-trait anxiety scale

TEAE: adverse effects induced by treatment

UDS: urine drug screening

UTI: urinary tract infection

μg: micrograms of

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 in this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "about" or "approximately" when used in connection with a numerical variable generally refers to the value of the variable and all values of the variable that are within experimental error (e.g., within 95% confidence interval of the average) or within ±10% of the specified value (whichever is greater).

The terms "formulation" and "composition" are used interchangeably unless otherwise specifically defined to have a different meaning.

Throughout this specification, certain amounts of numerical ranges are provided. It is to be understood that these ranges are inclusive of all subranges therein. Thus, a range of "50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Moreover, all values within a given range may be endpoints of the range encompassed thereby (e.g., ranges 50 to 80 include ranges having endpoints such as 55 to 80, 50 to 75, etc.).

The terms "include", "having" and "with" mean "including but not limited to".

As used herein, the term "patient" or "subject" refers to a living organism suffering from or susceptible to a disorder treatable by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, and other non-mammals.

As used herein, the term "therapeutic amount" or "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect or to cause an improvement in a clinically significant condition in a subject.

As used herein, "pharmaceutically acceptable salts" refers to salts that are known to be non-toxic and commonly used in the medical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid, and the like. Salts derived from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic, hydroxyalkanoic and hydroxyalkanoic diacids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used.

The term "treating" with respect to a particular disease or disorder includes alleviating, ameliorating, alleviating or eliminating symptoms and/or lesions of the disease or disorder. Treatment may be measured in terms of a reduced level of at least 10% or more, preferably 20% or more, more preferably 40% or more, even more preferably 60%.

The term "preventing" means preventing the occurrence of a disease, disorder or related symptom, or preventing its recurrence after, for example, an improvement period.

The term "adjuvant therapy" as used herein means an additive therapy or combination of dexmedetomidine with one or more conventional antidepressants in order to enhance the efficacy of conventional antidepressants and/or to allow lower doses of conventional antidepressants, thus reducing the side effects of treating or preventing major depressive disorder or recurrence of major depressive episode or anxiety pain.

The term "selective serotonin reuptake inhibitor" or "SSRI" means an inhibitor of monoamine transporter that has a greater inhibitory effect on serotonin transporter than on dopamine and norepinephrine transporter.

The term "selective norepinephrine reuptake inhibitor" or "SNRI" means a monoamine reuptake inhibitor that inhibits serotonin and norepinephrine reuptake, both neurotransmission agents (serotonin and norepinephrine) are thought to play an important role in mood regulation.

According to DSM-5, the term "major depressive episode" or "MDE" refers to a problem when a person experiences depressed mood or loses interest in daily activities or is happy for a period of at least two weeks, and has most of the specified symptoms, such as sleep, eating, vitality, concentration or self-value. During these episodes, deterioration of the patient's functional or symptomatic level must result in the patient experiencing considerable pain. Attacks may be isolated or recurrent. To diagnose major depressive episodes, the medical care provider must ensure that:

Symptoms do not meet the criteria for mixed attacks.

Symptoms must cause considerable pain or impairment of function at work, in a social environment or in other important areas to be considered as attacks.

Symptoms are not due to direct physiological effects of a substance (e.g., drug or drug abuse) or a general medical condition (e.g., hypothyroidism).

The term "MDD" or "major depressive disorder" refers to the presence of two major depressive symptoms: depressed mood, and loss of active interest/pleasure (aphasia) and five of nine more specific symptoms (listed below), and must cause the patient to suffer considerable pain or cause significant deterioration in the patient's level of function, must frequently occur for more than two weeks (to the extent of impaired function) for diagnosis. 1) Most of the day almost every day has depressed mood as indicated by subjective reports (e.g., perceived sadness, empty, destinated) or observations of others (e.g., appearing to contain tears). 2) Most of the day almost every day, interest or pleasure is significantly diminished in all or almost all activities. 3) Significant weight loss or weight gain (e.g., weight changes of more than 5% in one month) or almost daily loss or increase in appetite when not fed. 4) Insomnia or somnolence occurs almost every day. 5) Psychological motor agitation or retardation occurs almost every day. 6) There is fatigue or loss of vitality almost every day. 7) There is no sense of value or excessive or inappropriate feelings of guilt almost every day. 8) Weakening the ability to think or concentrate, or hesitation, almost every day. 9) Repeated thinking of death (not just fear of death), repeated suicidal ideation or suicide attempts without a specific plan, or a specific plan for suicide. Major depressive episodes are characteristic of diagnosing major depressive disorder and bipolar disorder. Diagnostic criteria should depend on the characteristics, i.e. whether there is manic or hypomanic episodes-to distinguish between the two diagnoses. However, in some cases, patients rarely reported a history of mood swings; in other cases, patients who appear to be in a depressive episode have not experienced a manic episode at all.

The term "bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in emotion, vitality, activity level, and ability to perform daily tasks. The bipolar disorder includes bipolar disorder type I, bipolar disorder type II and circulatory mood disorder. Manic-depressive disorder type I is defined by a manic episode lasting at least 7 days or by a severe manic symptom requiring hospitalization. Subjects with bipolar I may also experience depressive episodes that generally last for at least 2 weeks. Depressive episodes with mixed features (i.e., depressive and manic symptoms) may also occur. Type II manic depression is characterized by a pattern of depressive and hypomanic episodes, but not by severe manic episodes characteristic of type I manic depression. Circulatory mood disorders (also known as affective gyres) are characterized by periodic hypomanic symptoms (mood swings and euphoria) and depressive symptoms that persist for a period of at least 2 years.

The term "anxiety" refers to an unpleasant state involving a complex emotional combination including fear, concern, and anxiety. It is often accompanied by physiological sensations such as palpitations, nausea, chest pain, shortness of breath, or tension headache.

The term "anxiety disorder" or "ADS" means high levels of anxiety or co-morbid/co-anxiety in a subject suffering from major depressive disorder, major depressive episode or bipolar disorder. To meet the criteria of the DSM-5 anxiety disorder specifier, the subject must exhibit two or more of the following symptoms: (1) sensory agitation or tension; (2) paresthesia; (3) difficult to concentrate due to concerns; (4) fear that something terrible may occur; and (5) feel that the individual may lose control of himself.

As used herein, the term "agitation" means a condition characterized by symptoms of irritability, emotional bursts, impaired thinking, or excessive motor and language activity that may occur due to dysfunction of a specific brain region, such as the forehead lobe, or due to dysfunction of the neurotransmitter system, such as the norepinephrine system. In embodiments, agitation may be caused by norepinephrine overdose. In the present disclosure, a irritated subject may also exhibit aggressiveness. Agitation may be acute or chronic. Agitation can be severe.

As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate administration of an active agent to a subject and absorption by the subject. It also refers to excipients that may be included in the compositions or formulations of the present disclosure and that do not cause significant adverse toxicological effects to the patient.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals (e.g., dogs), each unit containing a predetermined quantity of calculated active material in association with a suitable pharmaceutical excipient (e.g., ampoule) to produce the desired effect, tolerance and/or therapeutic effect.

The term "oral mucosa" means an application to the oral mucosa, in particular, the oral cavity and/or the pharynx. Oral transmucosal administration includes sublingual, buccal, or gingival routes.

The term "sublingual" means "under the tongue" and refers to a method of administering a substance via the blood vessels under the tongue, not via the digestive tract. Sublingual absorption occurs via the highly vascularized sublingual mucosa, which allows the substance to enter the blood circulation directly, providing direct systemic administration independent of gastrointestinal effects and avoiding unwanted first-pass liver metabolism (first-pass hepatic metabolism).

The term "buccal" means the administration of a dosage form directed to the gums, the inner lips, or the cheeks.

The term "gum" means a dosage form that is applied to the gums (gums) found in the oral cavity around a portion of the teeth of a human.

The term "film" herein includes films comprising polymers in any shape, including rectangular, square, or other desired shape. The film may have any desired thickness and size so that it can be conveniently placed on the oral mucosa of a patient. For example, the film agent may be a thin film having a thickness of about 20 microns to about 200 microns, or may be a thick film having a thickness of about 201 microns to about 1000 microns. In embodiments, the film may have a thickness of greater than about 30 microns. In embodiments, the film is self-supporting. The term "self-supporting" means that the films herein maintain structural integrity upon handling without the need for a backing layer. Some flexibility in the film is contemplated and may be desirable.

The term "mucoadhesive" is used herein to refer to adhesion to a mucous membrane, such as a mucous membrane in the oral cavity.

The term "mucoadhesion" refers to the property of adhering to mucosal tissue surfaces in vivo. Such adhesion adhesively locates the dosage form to the mucosa and requires the application of force to separate the mucoadhesive material from the mucosa.

As used herein, "Therapeutic" may mean treatment and/or prevention depending on the context.

The term "intranasal administration" means administration by the nasal route. The drug delivered may have a local or systemic effect.

The term "parenteral" refers to administration of a drug by injection through one or more layers of skin or submucosa and may include, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular injection.

In the meaning of the present disclosure, the term "co-administration" is used to refer to the simultaneous or sequential administration of dexmedetomidine or a pharmaceutically acceptable salt thereof and SSRI/SNRI or a pharmaceutically acceptable salt or ester or enantiomer thereof.

As used herein, "sequentially administered" means that the two compositions administered to a subject are administered separately by a time interval sufficient to allow the resulting beneficial effect obtained when each composition exerts its effect.

The term "sequentially administered" means that the composition is administered at intervals of more than about 60 minutes; for example, 2 hours apart, 3 hours apart, 4 hours apart, 5 hours apart, 6 hours apart, 7 hours apart, 8 hours apart, 9 hours apart, 10 hours apart, 11 hours apart or 12 hours apart. In embodiments, the compositions may be administered from about 1 hour to about 24 hours apart.

As used herein, "simultaneous administration" means simultaneous or within a short period of time, for example less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 5 minutes.

Active agent:

dexmedetomidine:

dexmedetomidine has the IUPAC name (+) 4- (S) - [1- (2, 3-dimethylphenyl) ethyl]-1H-imidazole. As monohydrochloride, it is mainly used as a drug for patient sedation during treatment in intensive care environments or for patient sedation before and/or during surgery and other procedures. Such drugs are currently known under the registered trade nameAnd (5) selling.

Pharmaceutically acceptable salts of dexmedetomidine that may be used herein generally include any suitable salt that has been approved by the US FDA or by other suitable foreign or domestic authorities for administration to humans. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrogenphosphoric, sulfuric, hydrosulfuric and hydroiodic acids. Other examples include salts derived from non-toxic organic acids including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, or combinations of these salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, and the like. In embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

Selective Serotonin Reuptake Inhibitor (SSRI):

selective Serotonin Reuptake Inhibitors (SSRIs) are a class of drugs that enhance serotonin levels and are commonly used as antidepressants in the treatment of major depressive disorders, anxiety disorders and other psychological disorders. These drugs are effective, have good tolerability and have a favorable safety profile with varying degrees of selectivity for other monoamine transporters and minimal binding affinity for norepinephrine and dopamine transporters. Exemplary Selective Serotonin Reuptake Inhibitors (SSRI) include, but are not limited to, sertraline (sertraline), fluoxetine (fluoxetine), norfluoxetine (norfluxoxetine), fluvoxamine (fluvoxamine), citalopram (citalopram), escitalopram (escitalopram), dapoxetine (dapoxetine), paroxetine (paroxetine), amoxetine (femoxetine), vortioxetine (voratile), alaprorate (alaroclate), and vilazone (vilazodone) or pharmaceutically acceptable salts or esters or enantiomers thereof. In embodiments, the SSRI of the present disclosure has no effect on norepinephrine levels.

In embodiments, the SSRI is sertraline. Sertraline has the IUPAC name (1S, 4S) -4- (3, 4-dichlorophenyl) -N-methyl-1, 2,3, 4-tetrahydronaphthalen-1-amine. The housing Qu Linke is prepared as described in U.S. Pat. No. 4,536,518 and in particular in example 2 of said patent. In embodiments, sertraline is present in a pharmaceutically acceptable salt form. For example, in embodiments, sertraline exists in the form of acid addition salts of various inorganic and organic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, acetic, lactic, maleic, fumaric, citric, tartaric, succinic, gluconic, and the like. In embodiments, the pharmaceutically acceptable salt of sertraline is the hydrochloride salt.

In embodiments, the SSRI is citalopram. Citalopram is (RS) -1- [3- (dimethylamino) propyl ] -1- (p-fluorophenyl) -5-phthalonitrile; which is first described in U.S. patent No. 4,136,193. This patent publication describes the preparation of citalopram by one process and outlines other processes for the preparation of citalopram. Citalopram is disclosed in european patent publication EP 1 169 314 B2 to show the effect of treating dementia and cerebrovascular disorders. In embodiments, citalopram is present in the form of citalopram hydrobromide.

In embodiments, the SSRI is escitalopram. Escitalopram is the S enantiomer of citalopram and is a selective, central acting serotonin reuptake inhibitor. The preparation thereof is disclosed in U.S. Pat. No. 4,943,590. It shows potent effects such as anxiolytic effects in models of neurological disorders and significant effects in the treatment of panic attacks and obsessive-compulsive disorders. In view of the stereoselectivity, escitalopram is expected to be twice as potent as the racemate in the treatment of depression, and is found to produce a faster response than the citalopram racemate in animal models (Willner p., psychropharmaceutical 1997,134,319-329). Pharmaceutically acceptable acids that can be used to prepare salts of escitalopram include (but are not limited to): inorganic acids such as, for example, hydrochloric acid, hydrobromic acid; and organic acids such as, for example, acetic acid, nitric acid, sulfuric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. In an embodiment, the pharmaceutically acceptable salt of escitalopram is an oxalate salt.

In embodiments, the SSRI is fluoxetine. Fluoxetine, N-methyl-3- (p-trifluoromethylphenoxy) -3-amphetamine, is commercially available as the hydrochloride and as a racemic mixture of its two enantiomers. U.S. Pat. No. 4,314,081 is an early reference to compounds. Robertson et al, J.Med. Chem,31,1412 (1988) teach the isolation of the R and S enantiomers of fluoxetine and show similar activity as serotonin uptake inhibitors to each other. In the present disclosure, the term "fluoxetine" is used to mean any acid addition salt or free base, and includes a racemic mixture or any of the R and S enantiomers.

In embodiments, the SSRI is fluvoxamine. Fluvoxamine, 5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentanone O- (2-aminoethyl) oxime, is taught by U.S. Pat. No. 4,085,225. Scientific papers on pharmaceuticals have been described by Claassen et al, brit.j. Pharmacol.60,505 (1977); and De Wilde et al, J.active dis.4, 249 (1982); and Benfield et al, drugs 32,313 (1986).

In embodiments, the SSRI is paroxetine. Paroxetine, trans- (-) -3- [ (1, 3-benzodioxol-5-yloxy) methyl ] -4- (4-fluorophenyl) piperidine, is found in U.S. Pat. No. 3,912,743 and 4,007,196. The report of pharmaceutical activity is found in Lassen, eur.j. Pharmacol.47,351 (1978); hassan et al, brit J.Clin.Pharmacol.19,705 (1985); laussen et al, acta Psychiat. Scand.71,249 (1985); and Battergay et al, neuropchrobiligy 13,31 (1985).

"selective norepinephrine reuptake inhibitor" or "SNRI":

serotonin-norepinephrine reuptake inhibitors (SNRI) are a class of antidepressant drugs that treat Major Depressive Disorder (MDD), anxiety disorder, obsessive Compulsive Disorder (OCD), social phobia, attention Deficit Hyperactivity Disorder (ADHD), chronic neuralgia, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRI is a monoamine reuptake inhibitor; in particular, it inhibits the reabsorption of serotonin and norepinephrine, both of which are neurotransmitters for mood regulation. Like most antidepressants, SNRI acts by ultimately effecting changes in brain chemistry and communication in the brain nerve cell circuit known to regulate emotion to help alleviate depression. Exemplary selective norepinephrine reuptake inhibitors (SSRI) include, but are not limited to, desvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof.

In embodiments, the SNRI is desmethylvenlafaxine Xin Huowen Lafaxine. Venlafaxine is known in the literature and U.S. patent No. 4,761,501 teaches methods for its synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake. Compound a was identified in venlafaxine Xin Zaisuo.

In embodiments, the SNRI is milnacipran. Milnacipran (N, N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught by U.S. Pat. No. 4,478,836, which prepares milnacipran as example 4 thereof. Said patent describes its compounds as antidepressants. Moret al, neuropharmacology 24,1211-19 (1985) describe their pharmacological activity as serotonin and norepinephrine reuptake inhibitors.

In embodiments, the SNRI is duloxetine or a salt thereof. In embodiments, the SNRI is duloxetine hydrochloride. Duloxetine, N-methyl-3- (1-naphthoxy) -3- (2-thienyl) propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It is taught first by U.S. Pat. No. 4,956,388, which shows its high efficacy.

The active agents of the present disclosure may be used in the form of the free base or a pharmaceutically acceptable acid addition salt, ester or enantiomer thereof.

Dosage is as follows:

in embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is in the range of about 0.5 micrograms to about 300 micrograms. Examples of suitable dosages include: about 0.5 to about 280 microgram, about 1 to about 270 microgram, about 1 to about 260 microgram, about 1 to about 250 microgram, about 1 to about 240 microgram, about 1 to about 230 microgram, about 1 to about 220 microgram, about 1 to about 210 microgram, about 1 to about 200 microgram, about 1 to about 190 microgram, about 1 to about 180 microgram, about 1 to about 170 microgram, about 1 to about 160 microgram, about 1 to about 150 microgram, about 1 to about 140 microgram, about 1 to about 130 microgram, about 1 to about 120 microgram, about 1 to about 110 microgram, about 1 to about 100 microgram, about 3 to about 90 microgram, about 3 to about 80 microgram, about 3 to about 70 microgram, about 3 to about 60 microgram, about 3 to about 50 microgram, about 3 to about 40 microgram, about 3 to about 35 microgram, about 5 to about 35 microgram, about 10 to about 50 microgram, about 10 to about 40 microgram, about 10 to about 35, or about 15 to about 15. The dose may be administered one or more times a day, including twice, three times, four times, five times, or six times a day.

In embodiments, the unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is 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 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, 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, or about 300 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 120 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 180 micrograms.

In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice a day. In embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 micrograms to about 90 micrograms (e.g., 30 micrograms, 45 micrograms, 60 micrograms, or 90 micrograms) during the day and at a dose of about 90 micrograms to about 180 micrograms (e.g., 120 micrograms or 180 micrograms) during the night. In embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 micrograms to about 90 micrograms during the daytime and at a dose of about 30 micrograms to about 90 micrograms during the nighttime. In embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice a day during the daytime at a dose of about 90 micrograms to about 180 micrograms and during the nighttime at a dose of 30 micrograms to about 90 micrograms. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 micrograms during the day and about 90 micrograms during the night. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 40 micrograms during the day and about 80 micrograms during the night. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 60 micrograms during the day and about 120 micrograms during the night. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 80 micrograms during the day and about 180 micrograms during the night.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 180 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 30 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 40 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 60 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 90 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice a day at a total dose of 60 micrograms/unit dose to 120 micrograms. For example, 60 microgram unit doses are taken in the morning and another 60 microgram unit doses are taken in the evening or night.

The dosage of SSRI/SNRI or other conventional antidepressant used in the present disclosure depends on the nature of the SSRI/SNRI or other antidepressant because of the difference in both molecular weight and activity. In embodiments, the SSRI/SNRI is administered at a lower dose than is normally required. In embodiments, the SSRI/SNRI is administered at a normal dose. In embodiments, the dosage of SSRI/SNRI administered is in the range between about 1mg to about 500 mg. Examples of suitable dosages include: about 1mg to about 300mg, about 5mg to about 250mg, about 5mg to about 200mg, about 1mg to about 190mg, about 1mg to about 180mg, about 1mg to about 170mg, about 1mg to about 160mg, about 1mg to about 150mg, about 1mg to about 140mg, about 1mg to about 130mg, about 1mg to about 120mg, about 1mg to about 110mg, about 1mg to about 100mg, about 1mg to about 90mg, about 1mg to about 80mg, about 1mg to about 70mg, about 1mg to about 60mg, about 1mg to about 50mg, about 1mg to about 40mg, about 1mg to about 30mg, about 1mg to about 20mg, about 1mg to about 10mg per day. In embodiments, each unit dose is about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, or about 200mg of SSRI/SNRI.

In embodiments, the dosage of sertraline or a pharmaceutically acceptable salt thereof administered is in the range of about 1mg to about 500mg per day, although variations may be made depending on the subject's condition being treated and the particular route of administration selected. Examples of suitable dosages of sertraline include: about 10mg to about 500mg, about 20mg to about 450mg, about 25mg to about 400mg, about 30mg to about 350mg, about 35mg to about 300mg, about 40mg to about 250mg, about 45mg to about 200mg, about 50mg to about 180mg, about 55mg to about 150mg, about 60mg to about 100mg. In the context of an embodiment of the present invention, the daily dose of sertraline or a pharmaceutically acceptable salt thereof is about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 125mg about 245mg, about 250mg, about 255mg, about 260mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 495mg, or about 500mg.

In embodiments, the dosage of escitalopram or a pharmaceutically acceptable salt thereof administered is in the range of about 1mg to about 100mg per day. Examples of suitable dosages include: about 5mg to about 100mg, about 5mg to about 95mg, about 10mg to about 90mg, about 15mg to about 85mg, about 20mg to about 80mg, about 25mg to about 75mg, about 30mg to about 70mg, about 35mg to about 65mg, about 40mg to about 60mg. In embodiments, the daily dose of escitalopram or a pharmaceutically acceptable salt thereof is about 2mg, about 5mg, about 7.5mg, about 9.5mg, about 10mg, about 12mg, about 15mg, about 18mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg or about 100mg. In embodiments, the dosage of escitalopram or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 20mg per day.

In embodiments, the administered citalopram or a pharmaceutically acceptable salt thereof is in a dosage ranging from about 1mg to about 100mg per day. Examples of suitable dosages include: about 5mg to about 100mg, about 5mg to about 95mg, about 10mg to about 90mg, about 15mg to about 85mg, about 20mg to about 80mg, about 25mg to about 75mg, about 30mg to about 70mg, about 35mg to about 65mg, about 40mg to about 60mg. In embodiments, the daily dose of citalopram or a pharmaceutically acceptable salt thereof is about 2mg, about 5mg, about 7.5mg, about 9.5mg, about 10mg, about 12mg, about 15mg, about 18mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg or about 100mg. In embodiments, the administered citalopram or a pharmaceutically acceptable salt thereof is in a dosage ranging from about 20mg to about 40mg per day.

In embodiments, the dosage of fluoxetine or pharmaceutically acceptable salt thereof administered is in the range of about 1 to about 80mg per day. Examples of suitable daily dosages include: about 5mg to about 80mg, about 5mg to about 75mg, about 10mg to about 65mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 20mg to about 60mg, about 25mg to about 65mg, about 30mg to about 60mg, about 35mg to about 65mg, about 40mg to about 60mg. In embodiments, the dosage of fluoxetine or pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 80mg per day.

In embodiments, the dose of norfluoxetine or pharmaceutically acceptable salt thereof administered is in the range of about 0.01 to about 20mg/kg once a day; preferably about 0.05-10mg/kg once a day, most preferably about 0.1-5mg/kg once a day. In embodiments, the dose of paroxetine or pharmaceutically acceptable salts thereof administered ranges from about 10mg to about 80mg once a day (e.g., 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80 mg) once a day; preferably, about 20 to about 30mg once daily. In embodiments, the dose of fluvoxamine or pharmaceutically acceptable salt thereof administered is in the range of about 25mg to about 150mg (e.g., 25mg, 50mg, 75mg, 100mg, 125mg, 150 mg) twice daily.

In embodiments, the dose of duloxetine or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 200 mg. Examples of suitable dosages include: about 10mg to about 180mg, about 10mg to about 170mg, about 10mg to about 160mg, about 15mg to about 200mg, about 15mg to about 180mg, about 15mg to about 160mg, about 15mg to about 150mg, about 20mg to about 120mg, about 20mg to about 110mg, about 30mg to about 100mg, about 30mg to about 90mg, about 40mg to about 80mg, about 40mg to about 70mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, or about 100mg. In embodiments, the dose of duloxetine or a pharmaceutically acceptable salt thereof administered is in the range of about 60mg to about 120mg per day.

In embodiments, the SNRI administered as atomoxetine or a pharmaceutically acceptable salt thereof is in the range of about 5 mg/day to about 200 mg/day; about 10mg to about 190mg, about 20mg to about 180mg, about 30mg to about 170mg, about 40mg to about 160mg, about 50mg to about 150mg, preferably in the range of about 60mg to about 150 mg/day; more preferably from about 60mg to about 130mg per day; and even more preferably from about 60mg to about 120mg per day.

In embodiments, the dose of venlafaxine or a pharmaceutically acceptable salt thereof administered is in the range of about 30mg to about 300mg (e.g., 37.5mg, 75mg, 150 mg) per day. In embodiments, the dose of venlafaxine or a pharmaceutically acceptable salt thereof administered is in the range of about 75mg to about 225mg per day. The dose may be administered twice or three times a day. In embodiments, the dose of desmethylvenlafaxine or a pharmaceutically acceptable salt thereof administered is in the range of about 25mg to about 100mg per day.

In embodiments, the dose of levomilnacipran, or a pharmaceutically acceptable salt thereof, administered is in the range of about 20mg to about 200mg (e.g., 20mg, 40mg, 80mg, 120 mg) per day. In embodiments, the dosage of levomilnacipran, or a pharmaceutically acceptable salt thereof, administered is in the range of about 20mg to about 120mg per day. In embodiments, the dose of the Mi Quti forest (amitriptyline) or a pharmaceutically acceptable salt thereof administered is in the range of about 50mg to about 150mg per day. In embodiments, the dose of amitriptyline, or a pharmaceutically acceptable salt thereof, administered is in the range of about 150mg to about 300mg per day. In embodiments, the dose of doxepin or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 300mg per day (e.g., 10mg, 25mg, 50mg, 75mg, 100mg, 150mg per day).

In embodiments, the dose of trimipramine (trimipramine) or a pharmaceutically acceptable salt thereof administered is in the range of about 25mg to about 150mg per day (e.g., 25mg, 50mg, 100mg per day). In embodiments, the dose of trimipramine, pharmaceutically acceptable salts thereof administered is in the range of about 100mg to about 200mg per day. In embodiments, the dose of imipramine (imipramine) or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 300mg per day (e.g., 10mg, 20mg, 25mg, 30mg, 50mg, 75mg, 100mg, 150mg, 200mg per day). In embodiments, the dose of desipramine (desipramine) or pharmaceutically acceptable salt thereof administered is in the range of about 100mg to about 300mg per day. In embodiments, the dose of desipramine or pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 300mg per unit (e.g., 10mg, 25mg, 50mg, 75mg, 100mg, 150 mg).

In embodiments, the dose of protiline (protriptyline) or a pharmaceutically acceptable salt thereof administered is in the range of about 5mg to about 10mg three times or four times a day, up to a maximum of about 60mg per day. In embodiments, the dosage of nortriptyline (nortriptyline) or a pharmaceutically acceptable salt thereof administered is in the range of 50mg to about 150mg per day. In embodiments, the dosage of nortriptyline, or a pharmaceutically acceptable salt thereof, administered is in the range of 10mg to about 150mg (e.g., about 10mg, about 25mg, about 50mg, about 75 mg) per unit.

In embodiments, the amoxapine (amoxapine) or pharmaceutically acceptable salt thereof is administered at a dose in the range of about 200mg to about 400mg per day.

In embodiments, the dose of tranylcypromine or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 20mg three times a day. In embodiments, the dosage of tranylcypromine or a pharmaceutically acceptable salt thereof administered is in the range of about 10mg to about 60mg per day. In embodiments, the dosage of the administered phenelzine or pharmaceutically acceptable salt thereof is in the range of about 30mg to about 90mg per day. In embodiments, the dosage of the administered phenelzine or pharmaceutically acceptable salt thereof is in the range of about 15mg to about 90mg per unit (e.g., 15mg, 30mg, 45mg, 60mg, 75mg, 90mg per unit). In embodiments, the dose of the administered procarbazine or a pharmaceutically acceptable salt thereof is in the range of about 10mg to about 60mg per day. In embodiments, the dose of the administered isocarboxazid or pharmaceutically acceptable salt thereof is in the range of about 10mg to about 60mg per unit (e.g., 10mg, 20mg, 30mg, 40mg, 50mg, 60mg per unit).

In embodiments, the dose of trazodone or a pharmaceutically acceptable salt thereof administered is in the range of about 50mg to about 600mg per day. In embodiments, the dose of trazodone or a pharmaceutically acceptable salt thereof administered is in the range of about 50mg to about 600mg per unit (e.g., 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg per unit). In embodiments, the dosage of nefazodone (nefazodone) or a pharmaceutically acceptable salt thereof administered is in the range of about 150mg to about 300mg twice daily. In embodiments, the dosage of nefazodone or a pharmaceutically acceptable salt thereof administered ranges from about 150mg to about 300mg twice per unit (e.g., 50mg, 100mg, 150mg, 200mg, 250mg, 300mg per unit).

In embodiments, the dose of bupropion (bupropion) or a pharmaceutically acceptable salt thereof administered is in the range of about 100mg to about 450mg twice or three times a day. In embodiments, the dose of bupropion or pharmaceutically acceptable salt thereof administered is in the range of about 50mg to about 300mg per unit (e.g., about 50mg, about 75mg, about 100mg, about 200mg, about 300mg per unit).

Each unit may be administered to the subject multiple times per day, including once, twice, three times, four times, five times, or six times per day. In embodiments, each unit may be administered at appropriate dosing intervals (e.g., about 1 hour between doses), or may be administered simultaneously.

The dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) and SSRI or a pharmaceutically acceptable salt, ester or enantiomer thereof (e.g., escitalopram or sertraline, etc.), SNRI and other conventional antidepressants to be administered to a particular patient may depend on a variety of factors such as the type and extent of the disorder, the general health of the particular patient, the particular form of dexmedetomidine and SSRI/SNRI/other antidepressant administered, and the particular formulation used to treat the patient.

Methods and applications:

in embodiments, there is provided a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as monotherapy to the subject, wherein the subject is non-agitation. In embodiments, major depressive disorder is associated with anxiety pain.

In embodiments, major depressive disorder is associated or not associated with a medical condition. In embodiments, the subject suffers from additional co-occurrence disorders or conditions such as obsessive compulsive disorder, anxiety, social anxiety, PTSD, panic disorder, or generalized anxiety disorder. In embodiments, the subject does not suffer from bipolar disorder. In embodiments, major depressive disorder is mild or moderate. In embodiments, major depressive disorder is severe.

In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via oral mucosa (including buccal, sublingual, gingival).

In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 20 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

In embodiments, the present disclosure provides a method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

In embodiments, there is provided a method of treating Major Depressive Episode (MDE) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject as monotherapy, wherein the subject is non-agitation. In embodiments, major depressive episodes are associated with anxiety distress.

In embodiments, the major depressive episode is associated or not associated with a medical disorder. In embodiments, the subject suffers from additional co-occurrence disorders or conditions such as obsessive compulsive disorder, anxiety, social anxiety, PTSD, panic disorder, or generalized anxiety disorder.

In embodiments, the subject suffers from bipolar disorder. In embodiments, the subject does not suffer from bipolar disorder. The benefits of the methods disclosed herein are particularly valuable when the subject suffers from bipolar disorder. Antidepressants are disabled for manic-depressed subjects due to their propensity to induce mania or hypomania in the patient population. This phenomenon is called "switch" and is associated with poor results.

Advantageously, co-treatment with dexmedetomidine during the induction period reduces or eliminates mania and hypomania triggering effects of antidepressants. Treatment is made more effective by avoiding the shift in potential depression, at least in part because subjects tend to better adhere to the treatment regimen. Thus, in embodiments, the present disclosure provides methods of reducing turnover in a subject suffering from bipolar disorder (e.g., bipolar I or bipolar II) by administering dexmedetomidine to the subject. Dexmedetomidine may be administered after initiation of anti-depressant therapy, but preferably, dexmedetomidine and an antidepressant are co-administered. Optionally, dexmedetomidine may stop after the induction period.

In embodiments, the subject is diagnosed with bipolar disorder with anxiety disorder specifiers (DSM-5). In embodiments, the subject is in a manic phase. In embodiments, the subject is in a depressive phase. In embodiments, the subject is in both the manic and depressive phases. In embodiments, the major depressive episode is mild or moderate. In embodiments, major depressive episodes are severe.

In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (including buccal, sublingual, gingival). In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 20 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 150 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising oromucosal administration of about 30 micrograms to about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered via a route including oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular), topical (including transdermal), inhalation (e.g., via aerosol), rectal (e.g., via suppository), oral mucosa (e.g., buccal, sublingual, gingival), intranasal, vaginal, intrathecal, or intraocular.

In embodiments, dexmedetomidine or a salt thereof is administered orally.

In embodiments, dexmedetomidine or a salt thereof is administered via the oral mucosal route (including sublingual, buccal or gingival).

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a tablet. In embodiments, the tablet is lyophilized.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in a sheet form. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally mucosally in the form of a patch. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered transmucosally in the form of a gel or spray or droplet. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally mucosally in the form of a film. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by a subject.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered over an extended period of time or over a prolonged period of time (e.g., over a period of weeks or months). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for a period of at least 7 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.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising administering about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa during the daytime and about 60 micrograms of dexmedetomidine via the oral mucosa during the nighttime, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising administering about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa during the daytime and about 90 micrograms of dexmedetomidine via the oral mucosa during the nighttime, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 80 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 120 micrograms of dexmedetomidine during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 180 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 60 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 90 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 80 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 120 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 60 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 90 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 80 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 120 micrograms of dexmedetomidine during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 180 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 60 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 90 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 80 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 120 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and about 180 micrograms during the night, wherein the subject is non-agitation.

In embodiments, the present disclosure provides methods for inhibiting serotonin and norepinephrine reuptake and reducing norepinephrine signaling in a human subject, the methods comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI. In embodiments, dexmedetomidine and SSRI/SNRI are administered in a combination of about 1 day to about 28 days. In embodiments, the method comprises (i) an induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 day to about 28 days followed by (ii) a maintenance period comprising administering a therapeutic amount of SSRI/SNRI to the subject.

In embodiments, the combination of dexmedetomidine and SSRI/SNRI produces a synergistic effect such that lower doses of SSRI/SNRI may be administered to patients, thereby minimizing the risk of related side effects at higher doses of SSRI/SNRI.

Some subjects were either completely unresponsive to antidepressants or were under-responsive after initial treatment. Thus, in aspects, dexmedetomidine induction may be used in patients who have previously been treated with antidepressants alone and found to be unresponsive or poorly responsive.

In embodiments, the present disclosure provides a method of treating major depressive disorder in a subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant for at least 1 to 28 days (e.g., 7 days), followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of an antidepressant.

In embodiments, the present disclosure provides a method of treating major depressive episode in a subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant for at least 1 to 28 days (e.g., 7 days), followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of an antidepressant.

In embodiments, the present disclosure provides a method of treating major depressive disorder in a subject in need thereof, the method comprising: (a) An induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant to the subject via the oral mucosa for at least 14 days, followed by (b) a maintenance period comprising administering a therapeutic amount of an antidepressant to the subject orally.

In embodiments, the present disclosure provides a method of treating major depressive episode in a subject in need thereof, the method comprising: (a) An induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant to the subject via the oral mucosa for at least 14 days, followed by (b) a maintenance period comprising administering a therapeutic amount of an antidepressant to the subject orally.

In embodiments, the induction period comprises a treatment period of at least about 1 week. In embodiments, the induction period comprises a treatment period of about 2 weeks. In embodiments, the induction period comprises a treatment period of about 3 weeks. In embodiments, the induction period comprises a treatment period of about 4 weeks or more.

Although the induction period may stop at 1, 2, 3 or 4 weeks, some patients may benefit from continued administration of dexmedetomidine. Thus, the induction period may be 1 month, 2 months, 3 months, 4 months, or 6 months.

In embodiments, the antidepressant comprises a Selective Serotonin Reuptake Inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant, or a monoamine oxidase inhibitor. In embodiments, the antidepressant is an SSRI. In embodiments, the antidepressant is an SNRI. In embodiments, the subject does not respond adequately or fails to respond to current antidepressant therapy. In embodiments, the subject is non-agitation. In embodiments, the subject is irritated. In embodiments, the subject also has anxiety pain.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily. In embodiments, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is divided into a first dose and a second dose. In embodiments, the first dose of dexmedetomidine is administered in the morning and the second dose is administered in the evening. In embodiments, the first dose is lower than the second dose of dexmedetomidine.

In embodiments, the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 micrograms and the second dose of dexmedetomidine is about 60 micrograms. In embodiments, the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 micrograms and the second dose of dexmedetomidine is about 90 micrograms. In embodiments, the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 40 micrograms and the second dose of dexmedetomidine is about 80 micrograms. In embodiments, the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 60 micrograms and the second dose of dexmedetomidine is about 120 micrograms. In embodiments, the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 80 micrograms and the second dose of dexmedetomidine is about 180 micrograms.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject suffering from major depressive disorder, comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 5mg to about 250mg SSRI/SNRI or a pharmaceutically acceptable salt thereof. In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject suffering from major depressive disorder, comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof (e.g., sertraline hydrochloride). In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject suffering from major depressive disorder, comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 5mg to about 50mg of escitalopram or a pharmaceutically acceptable salt thereof (escitalopram oxalate). In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject suffering from major depressive disorder, comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 20mg to about 160mg of duloxetine, a pharmaceutically acceptable salt thereof. In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of treating major depressive disorder in a non-agitation subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

In embodiments, the present disclosure provides a method of treating major depressive disorder in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating major depressive disorder in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 80mg of citalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 10mg to 80mg of citalopram or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating major depressive disorder in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 5mg to about 60mg escitalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 5mg to about 60mg escitalopram or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating major depressive disorder in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 120mg of duloxetine or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject having a major depressive episode, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 5mg to about 250mg of SSRI/SNRI or a pharmaceutically acceptable salt thereof. In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject having a major depressive episode, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof (e.g., sertraline hydrochloride). In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject having a major depressive episode, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 5mg to about 50mg of escitalopram or a pharmaceutically acceptable salt thereof (escitalopram oxalate). In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of accelerating an antidepressant response in a subject having a major depressive episode, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 20mg to about 160mg of duloxetine, a pharmaceutically acceptable salt thereof. In embodiments, the subject is non-agitation.

In embodiments, the present disclosure provides a method of treating major depressive episode in a non-agitation subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

In embodiments, the present disclosure provides a method of treating major depressive episode in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating major depressive episode in a non-agitation subject in need thereof, the method comprising i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 80mg of citalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 10mg to about 80mg of citalopram or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating major depressive episode in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 5mg to about 60mg escitalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 5mg to about 60mg escitalopram or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating major depressive episode in a non-agitation subject in need thereof, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 120mg of duloxetine or a pharmaceutically acceptable salt thereof.

In embodiments, the methods described herein reduce at least one sign or symptom of Major Depressive Disorder (MDD). In embodiments, the methods described herein provide relief from major depressive disorder within 24 hours, 1 week, 1 month, 2 months, 3 months, or 12 months after administration.

In embodiments, the methods described herein reduce at least one sign or symptom of Major Depressive Episode (MDE). In embodiments, the methods described herein provide a reduction in major depressive episode within 24 hours, 1 week, 1 month, 2 months, 3 months, or 12 months after administration.

In embodiments, the sign or symptom is depressed mood, reduced interest in activity, weight loss or weight gain, reduced or increased appetite, insomnia or somnolence, mental agitation or retardation, fatigue or loss of vigor, worthless or excessive or inappropriate feelings of guilt, reduced ability to concentrate or hesitation, or suicidal ideation or behavior.

In embodiments, the improvement in the subject is measured based on diary evaluations, clinician or carer evaluations, clinical rating scales, or by functional MRI. In embodiments, functional MRI measures amygdala Blood Oxygen Level Dependent (BOLD) responses in a subject.

In embodiments, the improvement in a subject is measured using a clinical depression rating scale, wherein the clinical depression rating scale is a rapid self-rating for symptoms of depression (Quick Inventory of Depressive Symptomatology, QIDS) -16 scale, a QIDS-16 daily scale, a hamilton depression rating scale (Hamilton Depression Rating scale, HDRS or HAM-D), a becker depression self-rating scale (Beck Depression Inventory scale), a Montgomery-Asberg Depression Rating Scale, MADRS, a clinical global impression scale, a Zung self-rating depression scale, a Raskin depression rating scale, and/or a Young mania rating scale.

In embodiments, the sign or symptom of major depressive disorder in a subject is measured using the becker depression self-score scale (BDI). In embodiments, the signs or symptoms of major depressive episode in a subject are measured using the beck depression self-score scale (BDI). BDI is a 21-term, self-reporting rating scale that measures the characteristic attitudes and symptoms of depression. The projects were scored on a 0-3 continuum (continuum) scale, where 0 = no anomaly and 3 = severe anomaly. 17-20 points indicated critical clinical depression, 21-30 points indicated moderate depression, 31-40 points indicated major depression, and more than 40 points indicated extreme depression. In embodiments, the BDI score of a subject is reduced by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more after treatment with the methods herein compared to before treatment.

In embodiments, the sign or symptom of major depression in a subject is measured using the Zung self-rating depression scale. In embodiments, the sign or symptom of major depressive episode in a subject is measured using the Zung self-rating depression scale. The Zung self-rating depression scale is a 20-item, self-reporting questionnaire that measures psychological and physical symptoms associated with depression. The questionnaire takes about 10 minutes to complete and boxes the item for positive and negative statements. Each item was scored on a Likert scale in the range of 1 to 4. The total score is derived by summing the individual item scores and is in the range of 20 to 80. Most people have a depression score between 50 and 69, while scores of 70 and above indicate major depression. In embodiments, the subject's Zung self-assessment depression score is reduced by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, after treatment with the methods herein, as compared to before treatment.

In embodiments, the sign or symptom of major depressive disorder in a subject is measured using a Raskin depression rating scale. In embodiments, the signs or symptoms of major depressive episode in a subject are measured using a Raskin depression rating scale. The Raskin depression rating scale measures the baseline level of depression and the change in severity of depression over time. Each item is scored on a scale ranging from 1 to 5, where 1 = no at all and 5 = very much. The total score is derived by summing the scores of the individual items, and a score of 9 or higher indicates moderate depression. In embodiments, the subject's Raskin depression rating scale score is reduced by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, after treatment with the methods herein, as compared to before treatment.

In embodiments, the sign or symptom of major depressive disorder in a subject is measured using a depressive symptom self-assessment scale (IDS). In embodiments, the sign or symptom of major depressive episode in a subject is measured using a depressive symptom self-assessment scale (IDS). IDS is a 30-item self-assessment for measuring signs and symptoms of depression. Each item was scored on a scale of 0 to 3, where 0 = no lesions present and 3 = severe lesions. The total score is derived by summing the individual item scores; scores between 26-38 indicate mild depression, scores between 39-48 indicate moderate depression, and scores of 49 or higher indicate severe depression. In embodiments, the IDS score of a subject is reduced by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, after treatment with the methods described herein, as compared to before treatment.

In embodiments, the signs or symptoms of major depressive disorder in a subject are measured using the rapid self-assessment of depressive symptoms (QIDS). In embodiments, the sign or symptom of major depressive episode in a subject is measured using the rapid self-assessment of depressive symptoms (QIDS). QIDS is a 16-item self-assessment for measuring signs and symptoms of depression. Each item was scored on a scale of 0 to 3, where 0 = no lesions present and 3 = severe lesions. The total score is derived by summing the individual item scores; a score between 1-15 indicates moderate depression, a score between 16-20 indicates major depression, and a score of 21 or higher indicates major depression. In embodiments, the subject's QIDS score is reduced by about 5% and about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, after treatment with the methods herein, as compared to before treatment.

In embodiments, dexmedetomidine reduces stress (as measured as PEC program) when administered to depressed subjects, reduces anxiety and promotes restitution. Notably, the promotion of restitution is not the same as the induction of sleep or sedation. Conversely, the methods herein provide relief from sleep inhibition caused by potentially depressive disorders.

In embodiments, the present disclosure provides a method of treatment comprising administering to the subject dexmedetomidine or a pharmaceutically acceptable salt thereof in an oral mucosal dosage form that provides rapid relief of anxiety pain, and then continuing treatment with SSRI/SNRI or a pharmaceutically acceptable salt for an effective period of time.

In embodiments, initial administration of dexmedetomidine and SSRI/SNRI treats anxiety in a patient for an induction period of at least about 1 to 28 days, which facilitates long term administration of SSRI/SNRI to improve clinical outcome. In embodiments, the combination of dexmedetomidine and SSRI/SNRI results in an improvement in one or more symptoms of major depressive disorder and a rapid stabilization of anxiety and agitation symptoms as compared to treatment with SSRI/SNRI alone. In embodiments, the combination of dexmedetomidine and SSRI/SNRI results in an improvement in one or more symptoms of major depressive episodes as compared to treatment with SSRI/SNRI alone. The administration of dexmedetomidine is effective in the treatment of agitation and anxiety during the manic and depressive phases. Advantageously, the combination of dexmedetomidine with SSRI/SNRI helps to reduce the dosage of SSRI/SNRI and thus reduces the risk of related side effects at higher doses of SSRI/SNRI.

In embodiments, the present disclosure provides compositions and methods for treating anxiety disorder (referred to as anxiety disorder specifiers or ADS) of Major Depressive Disorder (MDD). In embodiments, the present disclosure provides compositions and methods for treating anxiety disorder (referred to as anxiety disorder specifiers or ADS) in Major Depressive Episode (MDE). In embodiments, the present disclosure provides compositions and methods for treating anxiety disorders associated with bipolar disorder. In embodiments, the subject is non-agitation. In embodiments, anxiety pain in a subject is measured according to the DSM-5 standard.

The fifth edition of the handbook for diagnosis and statistics of mental disorders (DSM-5) is a classification and diagnosis tool disclosed by the american society for mental disorders (American Psychiatric Association, APA), i.e., the update edition of handbook for diagnosis and statistics of mental disorders 2013. It is a manual widely used in the united states by clinicians and psychiatrists to diagnose mental disorders and encompasses all classes of mental health disorders in adults and children. Anxiety pain specifiers (ADS) consist of 5 building blocks (constructs): 1. sensory agitation or tension 2. Paresthesia 3. Difficulty concentrating due to anxiety 4. Fear that something afraid may occur 5. Sensory individuals may lose control of themselves. Severity is indicated by the number and type of symptoms: a) Light: 2 symptoms; b) And (3) moderately: 3 symptoms; c) Moderate-severe: 4 or 5 symptoms; d) Severe: 4 or 5 symptoms are accompanied by actionable agitation. It helps check whether anxiety and depression symptoms co-occur in a single major depressive episode. Major Depressive Disorder (MDD) patients with anxiety features typically have: age of early onset; longer duration of disease; more severe Major Depressive Episode (MDE); increased suicidal ideation and risk of behavior; poor quality of life, greater dysfunction; higher personal and socioeconomic costs; and higher treatment failure rates.

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a human subject, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 to about 28 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

In embodiments, the SSRI/SNRI or pharmaceutically acceptable salt, ester or enantiomer thereof is administered at an initial dose that is considered to be half the recommended dose 2 weeks before the induction period, and the dose increases to full dose within additional weeks depending on tolerance. In embodiments, the antidepressant effect of SSRI/SNRI treatment is accelerated by co-administration with dexmedetomidine according to the present disclosure.

In embodiments, the subject has Major Depressive Disorder (MDD). In embodiments, the subject has bipolar I disorder. In embodiments, the subject has bipolar II. In embodiments, the subject does not suffer from bipolar disorder. In embodiments, the subject was previously exposed to an SSRI/SNRI. In embodiments, the subject has not previously been exposed to an SSRI/SNRI. In embodiments, no additional treatment is administered to the subject after administration of dexmedetomidine and SSRI/SNRI. In embodiments, the subject suffers from an additional commensal disorder or condition.

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a human subject caused by starting treatment with an SSRI or an SNRI, the method comprising: (a) An induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the subject and orally administering a therapeutic amount of SSRI/SNRI for about 1 to about 28 days, followed by (b) a maintenance period comprising orally administering a therapeutic amount of SSRI/SNRI to the subject.

In embodiments, anxiety pain is significantly reduced within about 1 week of administration. In embodiments, anxiety pain is significantly reduced within about 2 weeks of administration. In embodiments, the SSRI/SNRI is administered as monotherapy during the maintenance phase.

In embodiments, the SSRI/SNRI is administered with another SSRI/SNRI during the maintenance period. In embodiments, the SSRI/SNRI is administered in combination with another therapeutic agent during the maintenance period. In embodiments, the SSRI/SNRI can be switched to a different SSRI/SNRI in the maintenance period to achieve improved results in the event of a null or intolerance after about 2 weeks of administration. In embodiments, the maintenance period continues until the underlying disease (e.g., major depressive disorder) subsides. In embodiments, the maintenance period continues until the underlying disease (e.g., major depressive episode) subsides. In embodiments, the maintenance period continues until no further treatment is needed (as determined by a clinician or physician). In embodiments, the maintenance period continues until the subject experiences a recurrence of anxiety pain. In embodiments, the subject is in the manic phase, the depressive phase, or both. In embodiments, the subject has undergone prior treatment (e.g., for at least one week) with the SSRI/SNRI prior to the induction period. For example, the patient has undergone prior treatment for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days prior to the induction period. In embodiments, the subject has undergone prior treatment with SSRI/SNRI for more than 14 days prior to the induction period. In embodiments, the subject has undergone prior treatment (e.g., for at least two or three weeks) with SSRI/SNRI prior to the induction period. In embodiments, the subject has undergone prior treatment with SSRI/SNRI for more than 14 days prior to the induction period. In embodiments, the subject is not undergoing any prior treatment (i.e., untreated) with SSRI/SNRI. In embodiments, the subject is not concurrently treated with any other antidepressant. In embodiments, the subject is an adult 18 years old or older.

In embodiments, the SSRI is selected from the group consisting of: sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, escitalopram, dapoxetine, paroxetine, fexidectin, vortioxetine, alapropyl and vilazodone, or pharmaceutically acceptable salts or esters or enantiomers thereof. In embodiments, the SSRI is sertraline. In embodiments, the SSRI is escitalopram.

In embodiments, the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof. In embodiments, the SNRI is desmethylvenlafaxine Xin Huowen Lafaxine. In embodiments, the SNRI is duloxetine or a salt thereof. In embodiments, the SNRI is duloxetine hydrochloride. In embodiments, the SNRI is atomoxetine.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof and SSRI/SNRI are administered in separate unit dosage forms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof and SSRI/SNRI are administered sequentially or simultaneously.

In embodiments, dexmedetomidine and SSRI/SNRI are administered sequentially via two separate dosage forms separated by a period of time. The term specific period of time means any time within 24 hours of administration of another agent, e.g. 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours or 1 hour from each other.

In embodiments, the co-administration unit dosage form lasts for about 28 days, about 27 days, about 26 days, about 25 days, about 24 days, about 23 days, about 22 days, about 21 days, about 20 days, about 19 days, about 18 days, about 17 days, about 16 days, about 15 days, about 14 days, about 13 days, about 12 days, about 11 days, about 10 days, about 9 days, about 8 days, about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. In embodiments, the co-administration unit dosage form lasts about 28 days. In embodiments, the co-administration unit dosage form lasts about 21 days. In embodiments, the co-administration unit dosage form lasts about 14 days. In embodiments, the co-administration unit dosage form lasts about 7 days.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dosage range of about 0.5 micrograms to about 300 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dosage range of about 0.5 micrograms to about 240 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dosage of about 120 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dosage of about 180 micrograms.

In embodiments, the SSRI is administered orally at a dosage ranging from about 5mg to about 250 mg. In embodiments, the SNRI is administered orally at a dosage ranging from about 10mg to about 500 mg. In embodiments, the SSRI/SNRI is administered once, twice daily, three times daily or more, preferably once, twice or three times daily, for a period of at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or more until the major depressive disorder subsides.

In embodiments, the two unit dosage forms are administered by the same or different routes, respectively, selected from the group consisting of: oral mucosa (e.g., sublingual or buccal or gingival), oral, topical, transdermal, intranasal, parenteral (e.g., intravenous, intramuscular, subcutaneous), and the like.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a subject, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 5mg to about 250mg of SSRI/SNRI or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating anxiety in a subject, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 10mg to about 500mg of SSRI/SNRI or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides methods of treating or preventing anxiety pain in a subject comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof (e.g., sertraline hydrochloride).

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a subject, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 5mg to about 50mg of escitalopram or a pharmaceutically acceptable salt thereof (e.g., escitalopram oxalate).

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a subject, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 10mg to about 500mg of SNRI.

In embodiments, the present disclosure provides a method of treating or preventing anxiety pain in a subject, the method comprising administering to the subject a pharmaceutical composition comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof.

In embodiments, anxiety pain is significantly reduced within about 3 days. In embodiments, anxiety pain is significantly reduced within about 1 week. In embodiments, anxiety pain is significantly reduced within about 2 weeks.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof. In embodiments, the oral mucosal dosage form of dexmedetomidine or a pharmaceutically acceptable salt thereof is a sublingual or buccal or gingival film. In an embodiment, the oral dosage form of sertraline or a pharmaceutically acceptable salt thereof is a tablet.

In an embodiment, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 80mg of citalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 10mg to about 80mg of citalopram or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 40mg of citalopram (e.g., 10mg, 20mg, 30mg, and 40 mg) or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 5mg to about 40mg of citalopram (e.g., 5mg, 10mg, 20mg, 30mg, 40 mg) or a pharmaceutically acceptable salt thereof. In embodiments, the oral mucosal dosage form of dexmedetomidine or a pharmaceutically acceptable salt thereof is a sublingual or buccal or gingival film. In an embodiment, the oral dosage form of citalopram or a pharmaceutically acceptable salt thereof is a tablet.

In an embodiment, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 5mg to about 60mg of escitalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 5mg to about 60mg of escitalopram or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 20mg of escitalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 10mg to about 20mg of escitalopram or a pharmaceutically acceptable salt thereof. In embodiments, the oral mucosal dosage form of dexmedetomidine or a pharmaceutically acceptable salt thereof is a sublingual or buccal or gingival film. In an embodiment, the oral dosage form of escitalopram or a pharmaceutically acceptable salt thereof is a tablet.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 150mg of duloxetine or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 120mg of duloxetine or a pharmaceutically acceptable salt thereof. In embodiments, the oral mucosal dosage form of dexmedetomidine or a pharmaceutically acceptable salt thereof is a sublingual or buccal or gingival film. In an embodiment, the oral dosage form of duloxetine or a pharmaceutically acceptable salt thereof is a tablet. In an embodiment, the oral dosage form of duloxetine or a pharmaceutically acceptable salt thereof is a capsule. In an embodiment, the oral dosage form of duloxetine or a pharmaceutically acceptable salt thereof is a delayed release capsule.

In embodiments, the methods described herein provide an improvement or alleviation of anxiety pain within 1 week after administration. In embodiments, the methods described herein provide an improvement or alleviation of anxiety pain within 1 month, 2 months, 3 months, or 12 months after administration. In embodiments, anxiety pain is associated with major depressive disorder. In embodiments, anxiety pain is associated with major depressive episode.

inembodiments,themethodsofthepresentdisclosureresultinadecreaseinHAM-ascoreinahumansubjectsufferingfromanxietydistress. theHAM-ascalemeasurestheseverityofanxietysymptomsandiswidelyusedinclinicalandresearchsettings. The scale is composed of 14 items (described below), each defined by a series of symptoms, and measures mental anxiety (agitation and psychological distress) and physical anxiety (anxiety-related physical discomfort). inembodiments,thesubjecthasatotalHAM-ascoreof≡14duringtheinitialtreatmentperiod. inembodiments,thesubjectexperiencesadecreaseof1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,or56minutesasmeasuredbytheHAM-ascale. In embodiments, the decrease is experienced in less than one day. In embodiments, the decrease is experienced within 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, or 28 days. In embodiments, a decrease is experienced after 28 days.

1. Anxiety emotion: anxiety, worst expectations, fear expectations, irritability.

2. Tension: stress, fatigue, a feeling of surprise reaction, susceptibility to tearing, trembling, restlessness, and inability to relax.

3. Fear of: darkness, strangers, autism, animals, traffic, and crowd.

4. Insomnia: difficulty falling asleep, sleep interruption, sleep insufficiency, and fatigue, dreaminess, nightmare, night fright upon waking up.

5. Intelligence: attention is not focused and memory is poor.

6. Depression emotion: losing interest, lack of hobby fun, depression, early wakefulness, and daytime mood changes.

7. Body (muscle): pain and pain, tics, stiffness, myoclonus, twitch, bruxism, unstable sound, and increased muscle tone.

8. Somatic (feel): tinnitus, blurred vision, hot and cold flushes, weakness and tingling pain.

9. Cardiovascular symptoms: tachycardia, palpitations, chest pain, vascular pulsation, fainting sensation, and beat.

10. Respiratory symptoms: chest produces sense of compression or sense of tightness, sense of asphyxia, sigh and dyspnea.

11. Gastrointestinal symptoms: difficulty in swallowing, flatulence and abdominal pain (wind abdominal pain), burning, abdominal fullness, nausea, vomiting, borborygmus, loose bowel, weight loss, constipation.

12. Urogenital symptoms: frequent urination, urgent urination, amenorrhea, menorrhagia, frigidity, premature ejaculation, loss of libido, and impotence.

13. Autonomic nerve symptoms: dry mouth, flushed face, pale, easy sweating, dizziness, tension headache, and hair erection.

14. Interview behavior: dysphoria, restlessness or pacing, hand tremors, frowning, facial tension, sighing or shortness of breath, pale face, swallowing, etc.

Each item was scored in a 5-component table ranging from 0 = absent to 4 = severe. A score of 0 indicates that sensation is not present in the patient. Score 1 indicates a mild onset of the patient. Score 2 indicates moderate morbidity in the patient. Score 3 indicates severe morbidity in the patient. Score 4 indicates a very severe morbidity in the patient.

In embodiments, the methods of the present disclosure result in a decrease in HAM-D score in a human subject suffering from anxiety distress. HAM-D (or HDRS) is used as an instrument for assessing symptoms of depression (Hamilton M.A rating scale for depression.J Neurol Neurosurg Psychiatry 1960:56-62). The instrument is administered by a clinician after a structured or unstructured interview of the patient to determine its symptoms. The total score is calculated by summing the individual scores from each question. Scores below 7 generally indicate the absence or alleviation of depression. Scores between 7-17 represent mild depression. A score between 18-24 indicates moderate depression. A score of 25 and higher indicates major depressive disorder. Most depression studies consider that if the score decreases by more than 50%, the patient has experienced a 'response to treatment'. 'alleviation' is generally understood to mean a score below 7. In embodiments, the subject experiences a decrease of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 minutes as measured by the HAM-D scale. In embodiments, the HAM-D score of the subject experiences a decrease of greater than 50%. In embodiments, the decrease is experienced in less than one day. In embodiments, the decrease is experienced within 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, or 28 days. In embodiments, a decrease is experienced after 28 days. In embodiments, an improvement in symptoms of major depression is observed as measured by the HAM-D-17 depression score scale. In embodiments, an improvement in anxiety and restlessness is observed as measured by the HAM-D-17 depression total score and anxiety score scale. In embodiments, the sleep improvement is assessed using a HAM-D-17 sleep component table. In embodiments, the subject has a total HAM-D-17 score of > 18 during the initial treatment period.

In embodiments, the methods of the present disclosure result in a reduction in Montgomery-Emblica depression rating scale (MADRS) score in a human subject suffering from anxiety. MADRS is a ten-item diagnostic questionnaire that is used by psychiatry to measure the severity of major depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression and each item produces a score of 0 to 6. The total score ranges from 0 to 60. The questionnaire includes questions about the following symptoms: 1. obvious sadness 2. Reported sadness 3. Internal tension 4. Sleep reduction 5. Appetite reduction 6. Concentration difficulties 7. Tiredness 8. Sensory disability 9. Pessimistic idea 10. Suicidal idea. In embodiments, the subject experiences a decrease of 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 points as measured by the MADRS scale. In embodiments, the decrease is experienced in less than one day. In embodiments, the decrease is experienced within 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, or 28 days. In embodiments, a decrease is experienced after 28 days. In embodiments, the subject has a MADRS score of ≡20 at the beginning of treatment (or baseline score).

In embodiments, the methods of the present disclosure result in a decrease in the agitation-calm assessment scale (ACES) in human subjects suffering from anxiety distress. ACES is a single measure of assessing overall agitation and sedation, where 1 indicates significant agitation; 2-moderate agitation; 3-mild agitation; 4-normal state; 5-slightly calm; 6-moderately calm; 7-significantly calm; 8-deep sleep; and 9-not wakeable. In embodiments, the present disclosure provides methods of reducing agitation associated with depression to 3 points (hypoagitation) or 4 points (normal behavior), as measured by the agitation-calm assessment scale (ACES). In embodiments, the decrease is experienced in less than one day. In embodiments, the decrease is experienced within 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, or 28 days. In embodiments, a decrease is experienced after 28 days.

In embodiments, the methods of the present disclosure reduce the Clinical Global Impression (CGI) rating scale. The CGI scale is a common measure of symptom severity, therapeutic response, and therapeutic efficacy in the treatment study of patients with psychotic disorders.

In embodiments, the methods of the present disclosure result in a decrease in the CGI-severity scale (CGI-S) of a human subject suffering from anxiety distress. CGI-S is a 7-point scale for use by clinicians to score the severity of a patient 'S disease at the time of evaluation relative to the clinician' S past experience with patients with the same diagnosis. In embodiments, the methods of the present disclosure result in a decrease in the CGI-improvement scale (CGI-I) in human subjects suffering from anxiety distress. CGI-I measures changes in agitation in response to treatment. CGI-I scores ranged from 1 to 7: 0=unevaluated (missing), 1=greatly improved, 2=greatly improved, 3=minimally improved, 4=unchanged, 5=minimally deteriorated, 6=very deteriorated, 7=extremely deteriorated. In embodiments, the subject has a clinical global impression-severity (CGI-S) score of ≡4 during the initial treatment period. In embodiments, the subject experiences a 1, 2, 3, 4, 5, 6, or 7 point decrease as measured by the CGI-S or CGI-I scale. In embodiments, the decrease is experienced in less than one day. In embodiments, the decrease is experienced within 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, or 28 days. In embodiments, a decrease is experienced after 28 days. In embodiments, the CGI-I score is improved to about 1 (greatly improved) or about 2 (greatly improved).

Pharmaceutical composition:

in an embodiment, the present disclosure provides a pharmaceutical composition comprising:

(i) About 0.5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) About 5mg to about 250mg SSRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients.

(ii) About 10mg to about 500mg of SNRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients.

In embodiments, the SSRI is selected from the group consisting of (but not limited to): sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, paroxetine, fexixetine, and escitalopram, or pharmaceutically acceptable salts or esters or enantiomers thereof.

In embodiments, the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof.

In embodiments, the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

In embodiments, the composition is formulated as a dosage form selected from the group comprising: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches or lozenges, films, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like. In embodiments, the composition is formulated as an oral mucosal composition. The oral mucosal compositions of the present disclosure can include tablets, capsules, patches or films, cachets, wafers, powders, minitablets, pellets, pastes, gels, ointments, creams, drops, liquids (solutions, suspensions or emulsions), sprays, microspheres or nanospheres, which can be formulated according to methods standard in the art. In embodiments, the oral mucosal composition is a film (e.g., a thin film). In embodiments, the film is for sublingual use. In embodiments, the film is for buccal use. In embodiments, the film is for gingival use.

Film/patch:

in embodiments, the oral mucosal dosage form is in the form of a patch or film (e.g., a film). The patch or film may have adhesive properties to prevent the patch or film from moving or swallowing. Suitable film compositions comprising dexmedetomidine are disclosed in U.S. patent nos. 10,792,246, 9,441,142, 9,662,297, 9,585,961, 9,937,123, 9,814,674, 9,248,146, 9,545,376 and 9,662,301; U.S. patent application publication Nos. 2020/0000708, 2020/0172768 and 2021/0077188; and WIPO patent application publication No. 2021/016112A2, the disclosures of each of which are incorporated herein by reference in their entirety.

In embodiments, dexmedetomidine and SSRI/SNRI or pharmaceutically acceptable salts thereof are formulated together as a single film product. In embodiments, the film dosage form comprises SSRI/SNRI and dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within the polymer matrix or (ii) deposited on a surface of the polymer matrix, such as a surface of a "placebo" film. Furthermore, SSRI/SNRI and dexmedetomidine or pharmaceutically acceptable salts thereof may be incorporated as part of a film dosage form into taste masked forms. In embodiments, the drug particles may be coated or granulated with a taste masking agent, such as a polymer, oil, or wax. The film dosage forms of the present disclosure may comprise at least one water-soluble polymer that produces a film of sufficient film strength (i.e., self-supporting) and fast-disintegrating character.

The SSRI/SNRI and dexmedetomidine may be present as one or more droplets on the surface of the polymer matrix. The polymer component may for example consist of the water-soluble polymer hydroxypropyl cellulose, but also different water-soluble polymers are contemplated. Examples of the one or more water-soluble polymers are selected from the group consisting of: hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, and mixtures thereof, including mixtures of the same polymers having different molecular weights. Polyethylene oxide (PEO) may also be present herein as a water-soluble polymer in a pharmaceutical film composition as an example of a pharmaceutically acceptable carrier, or more particularly as a mucoadhesive.

In embodiments, the polymer component is comprised of a single water-soluble polymer. In some embodiments, the polymer component is composed of two or more water-soluble polymers, including two or more identical water-soluble polymers having different molecular weights.

In embodiments, the water-soluble polymer comprises hydroxypropyl cellulose. In embodiments, the polymer component may be composed of one, two, or three hydroxypropyl celluloses having different molecular weights. The molecular weight of the different hydroxypropyl celluloses may suitably be in the range of (i) less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), (ii) about 90,000 daltons to about 200,000 daltons, and (iii) about 200,000 daltons to about 500,000 daltons.

In an embodiment, the present disclosure provides a pharmaceutical film composition comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) A polymer component consisting of a first water-soluble polymer having a molecular weight of less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight of greater than about 60,000 daltons; and optionally (iii) one or more pharmaceutically acceptable carriers.

In embodiments, the weight ratio of the first water-soluble polymer to the second water-soluble polymer (including PEO when present in the film) in the overall film composition is from about 2:1 to about 1:50, such as from about 1:1 to about 1:40, including about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32, about 1:33, about 1:34, about 1:35, about 1:36, about 1:37, about 1:38, or about 1:38.

In embodiments, the weight ratio of the first water-soluble polymer to the second water-soluble polymer (including PEO when present in the film) in the complete film composition is from about 1:10 to about 1:30, from about 1:15 to about 1:25, or from about 1:15 to about 1:20. In some embodiments, a ratio of about 1:15 to about 1:20 provides a beneficial functional effect.

Examples of other water-soluble polymers that may be included in the film with the first/second water-soluble polymer or in place of such polymers include povidone (polyvinylpyrrolidone), copovidone (a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, polydextrose, pullulan, carboxymethyl cellulose, sodium alginate, chitosan, xanthan gum, tragacanth, guar gum, gum arabic, acacia, starch, carrageenan, gelatin, and mixtures thereof. The water-soluble polymer component, including the water-soluble polymer carrier (when present), may suitably comprise from about 40% to about 99.8%, from about 50% to about 99.7%, from about 60% to about 99.6% of the film composition, based on the weight of the film on dry weight.

In embodiments, the polyethylene oxide may be present in the film from about 50% to about 60% w/w of the total film weight.

In embodiments, the present disclosure provides a film composition comprising (e.g., consisting essentially of) the following:

(i) A therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) A polymer component consisting of one or more water-soluble polymers; and

(iii) One or more pharmaceutically acceptable carriers.

The viscosity of the deposition solution/suspension may be in the range of about 6cps to about 3700cps as measured using a brookfield viscometer with a small sample adapter at 25 ℃. For example, it may be in the range of about 5cps to about 500cps, about 6cps to about 200cps, about 6cps to about 100cps, or about 6cps to about 50 cps. In one aspect of the present disclosure, the dexmedetomidine composition has a viscosity of about 6cps to about 20cps at 25 ℃ and a shear rate of about 7 (1/s). The deposition composition may be in any form, including a solution, emulsion, suspension or dispersion. The oral mucosal film dosage forms as disclosed herein have several functional advantages to promote rapid onset of drug action. In embodiments, the film dosage forms of the present disclosure have a Disintegration Time (DT) of about 15 seconds to about 180 seconds when applied sublingually. The disintegration time in this time frame provides the best onset of drug action.

In embodiments, the film dosage form has mucoadhesive properties that provide the practical benefit of positioning the film to a sublingual (or buccal or gingival) location and reducing or preventing effective removal prior to dissolution.

A pharmaceutically acceptable carrier:

the film composition may also comprise one or more pharmaceutically acceptable carriers including, but not limited to, liquid carriers, flavoring agents, sweeteners, fresheners, antioxidants, pH adjusters, permeation enhancers, mucoadhesives, plasticizers, bulking agents, surfactant/nonionic solubilizing agents, stabilizers, defoamers, colorants, and the like. In certain embodiments, the film composition is substantially free of acidic buffers or other acidic agents.

According to one aspect, the pharmaceutically acceptable carrier in a film dosage form comprises a liquid carrier. The liquid carrier comprises one or more solvents for preparing the polymer matrix (containing the drug or placebo) and a deposition composition in a film composition.

In embodiments, the solvent may be water. In embodiments, the solvent may be a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol, and mixtures thereof. In embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride, toluene, ethyl acetate, and mixtures thereof. Some solvents are alcohols, especially ethanol, water and mixtures thereof.

In embodiments, the dosage form is an oral mucosal sheet. In embodiments, the flakes are lyophilized. In embodiments, the flakes disintegrate in less than about 1 minute after contact with the oral mucosa. In embodiments, the flakes disintegrate in not less than about 1 minute after contact with the oral mucosa. In embodiments, the flakes comprise excipients such as hydroxypropyl cellulose, lactose, mannitol, glycine, and the like.

Suitable carriers for inclusion in other oral mucosal formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifying agents, isotonic saline, pyrogen-free water and combinations thereof. Carriers that readily dissolve in saliva may be preferred.

The oral mucosal formulation may also include other pharmaceutically acceptable carriers and/or excipients, such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, dissolving agents, suspending agents, and mixtures thereof. Specific excipients that may be used in accordance with the present disclosure are known in the art, for example as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005, mcgraw Hill, edited by Rowe et al.

Sprays, drops or gels:

in embodiments, dexmedetomidine and SSRI/SNRI or pharmaceutically acceptable salts thereof are formulated as spray compositions or drop compositions suitable for sublingual or buccal or gingival administration and comprise one or more pharmaceutically acceptable liquids (about 1% to about 99.995% by weight). Such liquids may be solvents, co-solvents or non-solvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerol, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.), and the like. In addition to these ingredients, spray or drop formulations may include one or more excipients, such as viscosity modifying materials (e.g., polymers, sugars, sugar alcohols, gums, clays, silica, etc., such as polyvinylpyrrolidone (PVP)); preservatives (e.g., ethanol, benzyl alcohol, propyl parahydroxybenzoate, and methyl parahydroxybenzoate); flavoring agents (e.g., peppermint oil), sweetening agents (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, and the like), artificial sweeteners (e.g., saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (e.g., mannitol, xylitol, lactitol, maltitol syrup); buffers and pH adjusters (e.g., sodium hydroxide, citrate, and citric acid); a colorant; fragrances, chelating agents (e.g., EDTA); UV absorbers and defoamers (e.g., low molecular weight alcohols, dimethicones). In addition to one or more of the foregoing ingredients suitable for sublingual or buccal sprays or drops, the gel formulation may include one or more excipients, for example, a viscosity modifying material (e.g., a water-soluble or water-swellable polymer such as carbopol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose).

The spray dosage forms of the present disclosure for oral mucosal administration can include one or more pharmaceutically acceptable liquids (e.g., present in an amount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, co-solvents or non-solvents for dexmedetomidine and SSRI/SNRI or pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, peppermint, and the like), and the like. The pharmaceutically acceptable liquid is selected to solubilize the active pharmaceutical ingredient to produce a stable homogeneous suspension or solution thereof, or to form any combination of suspensions or solutions.

Sprays, drops and gels can be prepared by mixing the appropriate equivalent amounts of the foregoing ingredients according to standard good manufacturing practices. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, improve bioavailability, increase shelf life, reduce manufacturing and packaging costs, meet government regulatory 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.

In embodiments, the oral mucosal dosage form is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment may be adjusted to allow residence under the tongue or near the gums or cheeks or upper lips.

Tablet/minitablet:

in embodiments, the present disclosure provides a tablet formulation suitable for oral mucosal administration (e.g., sublingual or buccal or gingival administration) comprising, or consisting essentially of, a therapeutic amount of dexmedetomidine, SSRI/SNRI, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (about 1% to about 99.995% by weight). Such carriers may be taste masking agents, diluents, disintegrants, binders, lubricants, glidants, flavoring agents or liquid solvents.

Pharmaceutically acceptable liquidExamples include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerol, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.), and the like. Taste masking agents include, for example, amberlite (amberlite),Ambtan, polymethacrylate (especially +.>L100), sodium starch glycolate (Primojel), carbopol polymer, PEG-5M, sodium acetate, ethylcellulose, beta-cyclodextrin. Flavoring agents may be, for example, peppermint powder, menthol, vanilla extract, aspartame, acesulfame potassium, saccharin. Disintegrants include, for example, sodium starch glycolate, low-substituted hydroxypropyl cellulose, alginic acid, carbon dioxide, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, guar gum, methylcellulose, polacrilin potassium, poloxamer, sodium alginate. The diluent may be, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol. The binder may be, for example, alginic acid, carbomer, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate.

At least one lubricant may be suitably incorporated into the formulation to prevent the powder from adhering to the tablet die during the compression procedure. The lubricant may be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate. Slip agents are used to promote powder flow by reducing inter-particle friction and cohesion. These slip agents are used in combination with lubricants because they do not have the ability to reduce mold wall friction. The slip agent may be, for example, colloidal silica, calcium silicate, tricalcium phosphate.

In embodiments, the oral mucosal dosage form is in the form of a tablet or disc or a filling powder.

In embodiments, the dosage form is a hard or compressed powdered sublingual or buccal tablet having a low coarse particle component for a organoleptically pleasing mouthfeel. The tablet (or active agent-containing particles thereof, which may be compressed to form a tablet) may comprise a protective outer coating, such as any polymer conventionally used to form microparticles and microcapsules.

In embodiments, the dosage form is a sublingual (or buccal or gingival) tablet containing a foaming agent. Sublingual compositions comprising foaming agents are disclosed in U.S. patent No. 6,200,604, the disclosure of which is incorporated herein by reference in its entirety.

In embodiments, the oral mucosal tablet dosage form is prepared by lyophilization (or freeze drying). Suspensions containing the active agents may be prepared with suitable excipients and the active agent (SSRI/SNRI/dexmedetomidine) suspension may be dispensed into blister packs and freeze dried. Exemplary freeze-dried formulation platforms useful for Orally Disintegrating Tablets (ODT) of SSRI/SNRI and/or dexmedetomidine are(Catalyt, somerset, NJ, USA) formulation.

In embodiments, the dosage form is an oral mucosal mini-tablet. In embodiments, the miniature tablets disintegrate in less than about 1 minute after contact with the oral mucosa. In embodiments, the microtablets disintegrate in not less than about 1 minute after contact with the oral mucosa. In an embodiment, the minitablets comprise excipients based on co-processed mannitol. In embodiments, the miniature tablets contain a directly compressible excipient.

Liquid:

in embodiments, the oral mucosal dosage form is in liquid form (e.g., in solution, suspension, or emulsion form), and may be presented, for example, as a spray or as drops. In embodiments of the present disclosure, SSRI/SNRI and/or dexmedetomidine or pharmaceutically acceptable salts thereof are administered orally mucosally in liquid form, for example in the form of an odorous (flavored) or odorless physiological saline solution. The liquid dosage forms may be suitably applied as drops or sprays under the tongue or near the gums or cheeks or upper lips. The solution includes the active ingredient and a diluent such as water, physiological saline (normal saline), sodium chloride solution or any other suitable solvent such as propylene glycol, glycerol, ethanol, etc. The diluent of the solution may be, inter alia, physiological saline solution or water.

The non-solid dosage forms of the present disclosure may be suitably applied by spraying, instilling, brushing or spraying the composition under the tongue or near the gums or cheeks or upper lips.

Intranasal formulation:

the compositions of the present disclosure may be administered to the nasal cavity in any suitable form. For example, the composition may be applied to the nasal cavity in the form of a spray emulsion, suspension or solution, in the form of drops or in the form of a powder.

In embodiments, the intranasal compositions of the present disclosure comprise an aqueous suspension, solution or emulsion containing, in addition to the active ingredient, a substance such as a suitable dispersing and/or wetting agent, for example propylene glycol or polyethylene glycol, an emulsifier, a suspending agent, a surfactant, a solubilizing agent, a vehicle, and the like.

The pharmaceutical compositions may also be formulated as liposomes, microcapsules or centerbodies, with one or more suitable pharmaceutically acceptable carriers.

Any device suitable for intranasal administration may be used. In an embodiment, the device is a dosing device. The dosing device may deliver a specific dose of the composition. The dosing device may be a unit dose, a double dose or a multi-dose device. The therapeutic amount that can be administered using a dosing device can be a unit dose device. The dosing may be a device that can deliver the pharmaceutical composition intranasally.

Parenteral formulation:

liquid pharmaceutical compositions for parenteral administration may be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion may include, but are not limited to, intravenous, intraperitoneal, intramuscular, intrathecal, and subcutaneous. In embodiments, the parenteral formulation may include prefilled syringes, vials, powders for reconstitution infusion, concentrates or solutions for infusion that are diluted (ready to be diluted) prior to delivery (ready to be used).

The injectable pharmaceutical composition may be an aqueous isotonic solution or suspension, and the suppositories may be prepared from fatty emulsions or suspensions.

The pharmaceutical compositions may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, dissolution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are generally employed, and the pH of the solution should be appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the formulation isotonic.

The parenteral formulations of the present disclosure may be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating.

Oral preparation:

the present disclosure includes oral formulations useful for delivering dexmedetomidine and/or SSRI/SNRI or pharmaceutically acceptable salts, esters or enantiomers thereof. Exemplary oral formulations include tablets, orally disintegrating tablets, orally dissolving tablets, flakes, solutions, suspensions, emulsions, and capsules.

In embodiments, the present disclosure relates to an oral solid pharmaceutical composition, e.g., in the form of a tablet, comprising a therapeutic amount of SSRI/SNRI or dexmedetomidine or both and at least one pharmaceutically acceptable excipient. Tableting aids commonly used in tablet formulations may be used and reference is made to the broad literature on the subject matter, see in particular Fiedler, "Lexikon der Hilfsstoffe", 4 th edition, ECV Aulendorf,1996, incorporated herein by reference. These include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, fillers or diluents, surfactants, and the like.

Disintegrants suitable for use in the compositions of the present disclosure include, but are not limited to, crosslinked PVP, crosslinked povidone, guar gum, alginic acid, sodium alginate, and crospovidoneCo-CMCIn embodiments, the disintegrant is crospovidone.

Binders suitable for the compositions of the present disclosure include, but are not limited to, starches such as potato starch, wheat starch, corn starch, celluloses such as microcrystalline cellulose (e.g., under the registered trademark Or (b)Known products), hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, for example hydroxypropyl cellulose having a hydroxypropyl content of 5 to 16% by weight and a molecular weight of 80,000 to 1,150 000, more particularly 140 000 to 850 000.

Slip aids suitable for use in the compositions of the present disclosure include, but are not limited to, colloidal silica, e.gMagnesium trisilicate, powdered cellulose, starch, talc and tricalcium phosphate.

Fillers or diluents suitable for use in the compositions of the present disclosure include, but are not limited to, powdered sugar, compressible sugar, dextrates, dextrins, dextrose, lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose (particularly having a density of about 0.45g/cm3, for example)) Or powdered cellulose and talc. In an embodiment, the filler is +.>

Lubricants suitable for use in the compositions of the present disclosure include, but are not limited to, magnesium, aluminum or calcium stearate, polyethylene glycol (PEG) having a molecular weight of 4,000 to 8,000, and talc.

One or more of these additives may be selected and used by those skilled in the art with respect to the particular desired characteristics of the solid oral dosage form, by routine experimentation and without any undue burden. The amount of each type of additive employed, such as glidants, binders, disintegrants, fillers or diluents and lubricants, may vary within the limits conventional in the art. For example, the amount of slip agent may vary from 0.1 to 10 wt%, particularly from 0.1 to 5 wt%, such as from 0.1 to 0.5 wt%; the amount of binder may vary from about 10 wt% to 65.3 wt%, such as 10 wt% to 45 wt%, such as 20 wt% to 30 wt%; the amount of disintegrant may vary in the range of 5 to 60 wt%, such as 13 to 50%, such as 15 to 40%, such as 20 to 30%, such as 25%; the amount of filler or diluent may vary from 15 to 65 wt%, such as 20 to 50%, such as 25 to 40%, such as 30%, and the amount of lubricant may vary from 0.1 to 5.0 wt%.

The tablets may be coated by methods well known in the art. The compositions of the present disclosure may also be incorporated into microspheres, for example, microspheres made from polyglycolic acid/lactic acid (PGLA).

Liquid formulations for oral administration may be in the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product (e.g., a powder) for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may be formulated so as to provide controlled or delayed release of the active compound. Controlling or deferring release may be applicable to one or more of the APIs within the composition and may also be applicable to portions of one or more of the APIs within the composition.

The API may also be administered in the form of a liposome delivery system. It is well known that liposomes can be formed from a variety of lipids and phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Transdermal preparation:

the present disclosure includes transdermal formulations useful for delivering dexmedetomidine and/or SSRI/SNRI or pharmaceutically acceptable salts thereof. The formulation may be delivered percutaneously for systemic absorption into the blood stream.

Examples of suitable transdermal forms include, but are not limited to, creams, ointments, pastes, gels, and lotions. Creams and ointments may be viscous liquid or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes containing absorbable powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. The pharmaceutical compositions may also be formulated as liposomes, microcapsules, or hubs with one or more suitable pharmaceutically acceptable carriers.

Medical kit:

in embodiments, the present disclosure provides individual unit dosage forms provided in the form of a kit comprising a composition in a container as described herein, with or without instructions for administration to a subject in need thereof. In embodiments, the present disclosure provides a dual unit dosage form provided in the form of a kit comprising the composition in one or more containers as described herein, with or without instructions for simultaneous, sequential or separate administration to a subject in need thereof. In embodiments, the kit comprises a pharmaceutical instruction comprising instructions for using the compositions described herein for treating anxiety pain in a subject.

In embodiments, the kit comprises a pharmaceutical instruction comprising instructions for treating major depressive disorder in a subject using a composition described herein. In embodiments, the kit comprises a pharmaceutical instruction comprising instructions for treating major depressive episode in a subject using a composition described herein. In embodiments, the dexmedetomidine or pharmaceutically acceptable salt thereof and the SSRI/SNRI are each provided in a form suitable for administration in combination with the other. In embodiments, the dexmedetomidine and the SSRI/SNRI or pharmaceutically acceptable salts thereof are provided as part of the same or single dosage form.

In embodiments, the dexmedetomidine and the SSRI/SNRI or pharmaceutically acceptable salts thereof are provided in two separate dosage forms for administration of one dosage form before, after and/or simultaneously with administration of the other dosage form. When administered sequentially, the sequential administration may be proximate in time or distant in time.

This may include situations where the two dosage forms are administered (optionally repeated) close enough in time that the beneficial effect of the patient is greater during treatment of the relevant disorder than when either of the two compositions is administered (optionally repeated) alone during the same treatment.

When dexmedetomidine and SSRI/SNRI or pharmaceutically acceptable salts thereof are provided in separate dosage forms, each dosage form may be packaged separately for use in combination with the other in combination therapy. Alternatively, the two dosage forms may be encapsulated and presented together as separate components of a "combination package" for use in combination therapy in combination with one another.

In embodiments, the kit comprises a container including, but not limited to, a bottle, a vial (e.g., a dual chamber vial), a syringe (e.g., a single chamber or dual chamber syringe), and a test tube. The container may be formed of various materials, such as glass or plastic. In embodiments, the kit may comprise a label (e.g., on or associated with the container) or a pharmaceutical instruction. The label or pharmaceutical instructions may indicate that the compounds contained therein are applicable or intended for use in the treatment of major depressive disorder. The label or pharmaceutical instructions may indicate that the compounds contained therein are applicable or intended for use in the treatment of major depressive episodes. The label or pharmaceutical instructions may indicate that the compounds contained therein may be suitable for or intended for use in the treatment or prevention of anxiety pain.

The kit may also contain other materials, including other buffers, diluents, filters, needles and syringes, as desired from a commercial and user standpoint.

Detailed description of the disclosure

Embodiment 1. A method of treating Major Depressive Disorder (MDD) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as monotherapy to the subject.

Embodiment 2. A method of treating Major Depressive Disorder (MDD) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa as monotherapy.

Embodiment 3. A method of treating Major Depressive Episode (MDE) in a subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof as monotherapy to the subject.

Embodiment 4. A method of treating Major Depressive Episode (MDE) in a non-agitation subject in need thereof, the method comprising administering to the subject about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa as monotherapy.

Embodiment 5. The method of embodiment 1 or 2, wherein the major depressive disorder is associated with anxiety pain.

Embodiment 6. The method of embodiment 3 or 4, wherein the major depressive episode is associated with anxiety distress.

Embodiment 7. The method of any one of embodiments 1 to 6, wherein the subject is non-agitation upon administration of dexmedetomidine.

Embodiment 8. The method of embodiment 1 or 2, wherein the subject does not suffer from bipolar disorder.

Embodiment 9. The method of embodiment 3 or 4, wherein the subject has bipolar disorder.

Embodiment 10. The method of any one of embodiments 1 to 4, wherein the subject has additional co-occurrence disorders or conditions such as obsessive compulsive disorder, anxiety disorder, social anxiety disorder, PTSD, panic disorder, or generalized anxiety disorder.

Embodiment 11. The method of embodiment 2 or 4, wherein dexmedetomidine is administered in an amount of about 30 micrograms to about 180 micrograms.

Embodiment 12. The method of embodiment 2 or 4, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 micrograms, about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 120 micrograms, about 180 micrograms, or about 200 micrograms.

Embodiment 13 the method of any one of embodiments 2, 4, 11 or 12, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily in one or more divided doses.

Embodiment 14. The method of any one of embodiments 2, 4, 11 or 12, wherein the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is divided into a first dose and a second dose.

Embodiment 15 the method of embodiment 14, wherein the first dose is administered in the morning or daytime and the second dose is administered in the evening or nighttime.

Embodiment 16. The method of embodiment 14 or 15, wherein the first dose is lower than the second dose of dexmedetomidine.

Embodiment 17 the method of any one of embodiments 14 to 16, wherein the first dose of dexmedetomidine is about 30 micrograms and the second dose is about 90 micrograms.

Embodiment 18. The method of any one of embodiments 14 to 16, wherein the first dose of dexmedetomidine is about 40 micrograms and the second dose is about 80 micrograms.

Embodiment 19 the method of any one of embodiments 1 to 18, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered via a route including oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular), topical (including transdermal administration), inhalation (e.g., via aerosol), rectal (e.g., via suppository), oral mucosa, intranasal, (buccal, sublingual, gingival), vaginal, intrathecal, or intraocular.

Embodiment 20. The method of embodiment 19, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered transmucosally (including sublingually, bucally, or gingivally).

Embodiment 21. The method of embodiment 20, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a tablet.

Embodiment 22. The method of embodiment 21, wherein the tablet is lyophilized.

Embodiment 23. The method of embodiment 20, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a wafer form across the oral mucosa.

Embodiment 24. The method of embodiment 20, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered transmucosally in the form of a patch, gel, drop or spray.

Embodiment 25 the method of embodiment 20 wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a film.

Embodiment 26. The method of any of the preceding embodiments, wherein dexmedetomidine is self-administered.

Embodiment 27. The method of any of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for an extended period of time.

Embodiment 28 the method of embodiment 27, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for a period of at least 7 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.

Embodiment 29. A method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day time period and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night time period, wherein the subject is non-agitation.

Embodiment 30 a method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day time period and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night time period, wherein the subject is non-agitation.

Embodiment 31 a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day time period and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night time period, wherein the subject is non-agitation.

Embodiment 32 a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of about 30 micrograms to about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the day and oromucosal administration of about 90 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof during the night, wherein the subject is non-agitation.

Embodiment 33 use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in subjects suffering from Major Depressive Disorder (MDD).

Embodiment 34 use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in subjects with Major Depressive Episode (MDE).

Embodiment 35 use of dexmedetomidine or a pharmaceutically acceptable salt thereof as an adjunct therapy to one or more conventional antidepressants in subjects suffering from anxiety.

Embodiment 36. A method of accelerating an antidepressant response in a subject suffering from Major Depressive Disorder (MDD), said method comprising administering to said subject dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with one or more conventional antidepressants.

Embodiment 37 a method of accelerating an antidepressant response in a subject having a Major Depressive Episode (MDE), the method comprising administering to the subject dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with one or more conventional antidepressants.

Embodiment 38 the method of embodiment 36 or 37, wherein the subject fails treatment with conventional anti-depressant therapy.

Embodiment 39 the method of embodiment 36 or 37, wherein the subject is insufficiently responsive to conventional antidepressant therapy.

Embodiment 40. The method of embodiment 36 or 37, wherein the subject has not been previously exposed to any conventional anti-depressant therapy.

Embodiment 41. The method of embodiment 36 or 37, wherein the subject has anxiety pain.

Embodiment 42 the use or method of embodiments 33-41, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately after the subject begins to use conventional antidepressant therapy for a period of about 1 to 4 weeks.

Embodiment 43 the use or method of embodiments 33-41 wherein said conventional antidepressant is selected from the group consisting of (but not limited to): selective Serotonin Reuptake Inhibitors (SSRI); selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI); early tricyclic antidepressants (TCAs); monoamine oxidase inhibitors (MAO-inhibitors), monoamine oxidase Reversible Inhibitors (RIMA), atypical antidepressants; tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants.

Embodiment 44. A method of treating major depressive disorder in a subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant for at least 7 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of the antidepressant.

Embodiment 45. A method of treating major depressive episode in a subject in need thereof, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of an antidepressant for at least 7 days, followed by (b) a maintenance period comprising administering to the subject a therapeutic amount of the antidepressant.

Embodiment 46. A method of treating major depressive disorder in a subject in need thereof, the method comprising: (a) An induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the subject in combination with a therapeutic amount of an antidepressant administered orally for at least 14 days, followed by (b) a maintenance period comprising administering a therapeutic amount of an antidepressant orally to the subject.

Embodiment 47. A method of treating major depressive episode in a subject in need thereof, the method comprising: (a) An induction period comprising administering a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the subject in combination with a therapeutic amount of an antidepressant administered orally for at least 14 days, followed by (b) a maintenance period comprising administering a therapeutic amount of an antidepressant orally to the subject.

The method of embodiments 44-47, wherein said antidepressant comprises a Selective Serotonin Reuptake Inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant, or a monoamine oxidase inhibitor.

Embodiment 49 the method of any one of embodiments 44-48, wherein the subject has insufficient or no response to current anti-depressive therapy.

Embodiment 50. The method of any one of embodiments 44 to 49, wherein the subject is non-irritative.

Embodiment 51 the method of any one of embodiments 44-49, wherein the subject is irritated.

Embodiment 52 the method of any one of embodiments 44-51, wherein said subject is also suffering from anxiety.

Embodiment 53 the method of any one of embodiments 44 to 52, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily.

Embodiment 54 the method of any one of embodiments 44 to 53, wherein the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is delivered in a first dose and a second dose.

Embodiment 55 the method of embodiment 54, wherein the first dose of dexmedetomidine is administered in the morning/daytime and the second dose is administered in the evening/nighttime.

Embodiment 56 the method of embodiment 54 or 55, wherein said first dose is lower than said second dose of dexmedetomidine.

Embodiment 57 the method of any one of embodiments 54-56, wherein the first dose of dexmedetomidine or pharmaceutically acceptable salt thereof is about 30 micrograms and the second dose of dexmedetomidine is about 60 micrograms.

Embodiment 58 the method of any one of embodiments 54 to 56, wherein the first dose of dexmedetomidine or pharmaceutically acceptable salt thereof is about 30 micrograms and the second dose is about 90 micrograms.

Embodiment 59 the method of any one of embodiments 54 to 56, wherein the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 40 micrograms and the second dose is about 80 micrograms.

Embodiment 60 the method of any one of embodiments 54 to 56, wherein the first dose of dexmedetomidine or pharmaceutically acceptable salt thereof is about 60 micrograms and the second dose is about 120 micrograms.

Embodiment 61 the method of any one of embodiments 54 to 56, wherein the first dose of dexmedetomidine or pharmaceutically acceptable salt thereof is about 60 micrograms and the second dose is about 180 micrograms.

Embodiment 62. The method of any one of embodiments 44 to 47, wherein the induction period comprises a treatment period of at least about 1 or 2 weeks.

Embodiment 63 the method of any one of embodiments 44 to 47, wherein the induction period comprises a treatment period of at least about 3 weeks.

Embodiment 64 the method of any one of embodiments 44-47, wherein the induction period comprises a treatment period of at least about 4 weeks.

Embodiment 65 the method of any one of embodiments 44, 46, 48 to 64, alleviating at least one sign or symptom of major depressive disorder.

Embodiment 66 the method of any one of embodiments 45 and 47-64, alleviating at least one sign or symptom of major depressive episode.

Embodiment 67 the method of embodiment 65, wherein the method provides a reduction in major depressive disorder within 24 hours, 1 week, 1 month, 2 months, 3 months, or 12 months after administration.

Embodiment 68. The method of embodiment 66, wherein the method provides a reduction in major depressive episode within 24 hours, 1 week, 1 month, 2 months, 3 months, or 12 months after administration.

Embodiment 69 the method of embodiment 65 or 66, wherein the sign or symptom is depressed mood, reduced interest in activity, weight loss or weight gain, reduced or increased appetite, insomnia or sleepiness, mental agitation or retardation, fatigue or loss of vigor, worthless or excessive or inappropriate feelings of guilt, reduced ability or hesitation to concentrate, or suicidal ideation or behavior.

Embodiment 70 the method of any one of embodiments 44-69, wherein the improvement in the subject is measured according to diary assessment, clinician or carer assessment, clinical rating scale, or by functional MRI.

Embodiment 71. The method of any one of embodiments 44 to 69, wherein the improvement in the subject is measured using a clinical depression rating scale, wherein the clinical depression rating scale is a rapid self-rating for symptoms of depression (QIDS) -16 scale, a QIDS-16 daily scale, a hamilton depression rating scale (HDRS or HAM-D), a beck depression self-rating scale, a montgomery-einberg depression rating scale (MADRS), a clinical global impression scale, a Zung self-rating for depression scale, a Raskin depression rating scale, and/or a Young mania rating scale.

Embodiment 72 a method of reducing the HAM-D scale score of a human subject suffering from major depressive disorder comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an orally effective amount of SSRI/SNRI.

Embodiment 73. A method of reducing the HAM-D scale score of a human subject having major depressive episode, the method comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an orally effective amount of SSRI/SNRI.

Embodiment 74 the method of embodiment 72 or 73, wherein the subject has a total HAM-D-17 score of ≡18 at the beginning of treatment (or baseline).

embodiment75.themethodofembodiment72or73,whereinthesubjecthasatotalhamiltoniananxietyscale(HAM-a)scoreof≡14atthebeginningoftreatment(orbaseline).

Embodiment 76. The method of embodiment 72 or 73 provides a decrease in HAM-D score of about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or more, compared to the baseline score observed prior to treatment.

Embodiment 77 a method of reducing MADRS scale score in a human subject suffering from major depressive disorder, the method comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an orally effective amount of SSRI/SNRI.

Embodiment 78 a method of reducing MADRS scale score in a human subject having major depressive episode, the method comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with an orally effective amount of SSRI/SNRI.

Embodiment 79. The method of embodiment 77 or 78 provides a reduction in MADRS score of about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or more, compared to a baseline score of about.gtoreq.20 as observed prior to treatment.

Embodiment 80 the method of any one of embodiments 72-79, which provides for the alleviation of sleep inhibition caused by an underlying disorder.

Embodiment 81. A method of treatment comprising administering to the subject dexmedetomidine or a pharmaceutically acceptable salt thereof in an oral mucosal dosage form providing rapid relief of anxiety pain and then continuing treatment with SSRI/SNRI or a pharmaceutically acceptable salt for an effective period of time.

Embodiment 82. A method of treating or preventing anxiety disorder in a human subject, the method comprising:

(i) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 day to about 28 days, followed by

(ii) A maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

Embodiment 83 the method of embodiment 82, wherein the subject has major depressive disorder.

Embodiment 84 the method of embodiment 82, wherein the subject has bipolar disorder.

Embodiment 85 the method of embodiment 82, wherein the subject is non-irritated.

Embodiment 86 the method of embodiment 82, wherein the subject is irritated.

Embodiment 87. The method of embodiment 82, wherein the induction period comprises a treatment period of at least about 1 to 4 weeks.

Embodiment 88 the method of embodiment 82, wherein the subject was previously exposed to an SSRI/SNRI.

Embodiment 89 the method of embodiment 82, wherein the subject has not been previously exposed to an SSRI/SNRI.

Embodiment 90 the method of embodiment 82, wherein no additional treatment is administered to the subject after the administration of dexmedetomidine and SSRI/SNRI.

Embodiment 91 the method of embodiment 82, wherein the subject has an additional co-occurrence disorder or condition.

Embodiment 92. A method of treating or preventing anxiety disorder caused by initiation of treatment with an SSRI/SNRI in a human subject, the method comprising:

(a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutic amount of SSRI/SNRI for about 1 day to about 28 days, followed by

(b) A maintenance period comprising administering to the subject a therapeutic amount of SSRI/SNRI.

Embodiment 93. A method of treating or preventing anxiety disorder caused by initiation of treatment with an SSRI or an SNRI in a human subject, the method comprising: (a) An induction period comprising administering to the subject a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof orally in combination with a therapeutic amount of SSRI/SNRI orally for about 1 day to about 28 days, followed by (b) a maintenance period comprising orally administering to the subject a therapeutic amount of SSRI/SNRI.

Embodiment 94 the method of embodiment 92 or 93, wherein the anxiety pain is significantly reduced within about 1 week of administration.

Embodiment 95. The method of embodiment 92 or 93, wherein the anxiety pain is significantly reduced within about 2 weeks of administration.

Embodiment 96. The method of embodiment 92 or 93, wherein the SSRI/SNRI is administered as monotherapy during the maintenance phase.

Embodiment 97. The method of embodiment 92 or 93, wherein the SSRI/SNRI is administered with additional SSRI/SNRI during the maintenance period.

Embodiment 98 the method of embodiment 92 or 93, wherein the maintenance period continues until the underlying disease (e.g., major depressive disorder) subsides.

Embodiment 99 the method of embodiment 92 or 93, wherein the maintenance period continues until the subject experiences a recurrence of anxiety pain.

Embodiment 100. The method of embodiment 92 or 93, wherein the subject is in a manic phase, a depressive phase, or both.

Embodiment 101. The method of embodiment 92 or 93, wherein the subject has undergone prior treatment with SSRI/SNRI (e.g., for at least one week) prior to the induction period.

Embodiment 102. The method of embodiment 92 or 93, wherein the SSRI is selected from the group consisting of: sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, escitalopram, dapoxetine, paroxetine, fexidectin, vortioxetine, alapropyl and vilazodone, or pharmaceutically acceptable salts or esters or enantiomers thereof.

Embodiment 103. The method of embodiment 102, wherein the SSRI is sertraline or a pharmaceutically acceptable salt thereof.

Embodiment 104. The method of embodiment 102, wherein the SSRI is escitalopram or a pharmaceutically acceptable salt thereof.

Embodiment 105. The method of embodiment 102 wherein the SSRI is citalopram.

Embodiment 106. The method of embodiment 92 or 93, wherein the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof.

Embodiment 107. The method of embodiment 106, wherein the SNRI is desvenlafaxine or venlafaxine or a pharmaceutically acceptable salt thereof.

Embodiment 108. The method of embodiment 107, wherein the SNRI is duloxetine or a pharmaceutically acceptable salt thereof (e.g., duloxetine hydrochloride).

Embodiment 109. The method of embodiment 107 wherein the SNRI is atomoxetine or a pharmaceutically acceptable salt thereof.

Embodiment 110. A method of treating or preventing anxiety pain in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 25mg to about 200mg of sertraline or a pharmaceutically acceptable salt thereof.

Embodiment 111 a method of treating or preventing anxiety pain in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 40mg of citalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 40mg of citalopram or a pharmaceutically acceptable salt thereof.

Embodiment 112. A method of treating or preventing anxiety in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 10mg to about 20mg of escitalopram or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 10mg to about 20mg of escitalopram or a pharmaceutically acceptable salt thereof.

Embodiment 113 the method of embodiment 111 or 112, wherein the oral dosage form of citalopram or escitalopram or a pharmaceutically acceptable salt thereof is a tablet.

Embodiment 114. A method of treating or preventing anxiety pain in a human subject, the method comprising (i) an induction period comprising co-administering an oral mucosal dosage form comprising about 30 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and an oral dosage form comprising about 20mg to about 160mg of duloxetine or a pharmaceutically acceptable salt thereof for about 1 day to about 28 days, followed by (ii) a maintenance period comprising administering to the subject an oral dosage form comprising about 20mg to about 120mg of duloxetine or a pharmaceutically acceptable salt thereof.

Embodiment 115. The method of embodiment 114, wherein the oral dosage form of duloxetine is a tablet or capsule (e.g., a delayed release capsule).

Embodiment 116 the method of embodiments 110-115 wherein the oral mucosal dosage form of dexmedetomidine or a pharmaceutically acceptable salt thereof is a sublingual or buccal or gingival film.

Embodiment 117 the method of any one of embodiments 33 to 116, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are administered in separate unit dosage forms.

Embodiment 118. The method of embodiment 117, wherein the two unit dosage forms are administered to the subject by the same or different routes, respectively, selected from the group consisting of: oral mucosa (e.g., sublingual or buccal or gingival), oral, topical, transdermal, intranasal, parenteral (e.g., intravenous, intramuscular, subcutaneous), and the like.

Embodiment 119 the method of embodiment 118, wherein both unit dosage forms are administered by the oral mucosal route.

Embodiment 120 the method of embodiment 117, wherein the SSRI/SNRI is administered in a dosage form selected from the group consisting of: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches or lozenges, films, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like.

Embodiment 121. The method of embodiment 120, wherein the SSRI/SNRI is administered orally.

Embodiment 122. The method of embodiment 120 or 121, wherein the SSRI/SNRI is administered in the form of an oral tablet.

Embodiment 123 the method of embodiment 117 wherein the dexmedetomidine or pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered oromucosally in a dosage form selected from the group consisting of tablets, films, sprays, gels or drops, preferably films.

Embodiment 124 the method of any of embodiments 117-123, wherein the dosage form is co-administered for about 28 days.

Embodiment 125 the method of any one of embodiments 117 to 123, wherein the dosage form is co-administered for about 21 days.

Embodiment 127 the method of any one of embodiments 117-123, wherein said dosage form is co-administered for about 14 days.

Embodiment 128 the dosage form is co-administered for about 7 days according to the method of any one of embodiments 117 to 123.

Embodiment 129. The method of embodiments 33 to 116, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and the SSRI/SNRI are administered together in a single unit dosage form.

Embodiment 130. The method of embodiment 129, wherein the unit dosage form is administered to the subject via the oral mucosal route in the form of a tablet, film, spray, gel, or drop.

Embodiment 131. The method of embodiment 130, wherein the dosage form is a film and the film is a film.

Embodiment 132 the method of any one of embodiments 129 to 131, wherein the dosage form is administered for about 28 days.

Embodiment 133 the method of any one of embodiments 129 to 131, wherein the dosage form is administered for about 21 days.

Embodiment 134 the method of any one of embodiments 129 to 131, wherein the dosage form is administered for about 14 days.

Embodiment 135 the method of any of embodiments 129 to 131, wherein the dosage form is administered for about 7 days.

Embodiment 136 the method of any one of embodiments 33 to 135, wherein said dosage form is administered once a day or multiple times a day.

Embodiment 137 the method of any one of embodiments 1 to 136, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dosage ranging from about 0.5 micrograms to about 300 micrograms (e.g., 10 micrograms to 240 micrograms).

Embodiment 138 the method of embodiment 137, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is administered in a single dose containing about 180 micrograms of dexmedetomidine or pharmaceutically acceptable salt thereof.

Embodiment 139 the method of embodiment 137, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is administered in a single dose containing about 120 micrograms of dexmedetomidine or pharmaceutically acceptable salt thereof.

Embodiment 140 the method of any of embodiments 1 to 139, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 141 the method of any one of embodiments 1 to 136, wherein the SSRI is administered at a dose ranging from about 5mg to about 250 mg.

Embodiment 142 the method of any one of embodiments 1 to 136, wherein the SNRI is administered at a dose ranging from about 10mg to about 500 mg.

Embodiment 143 the method of any one of embodiments 44 to 114, wherein the maintenance period continues until the underlying disease (e.g., major depressive disorder) subsides or until the subject experiences a recurrence of anxiety afflictions.

Embodiment 144 the method of any one of embodiments 44 to 143, wherein the subject is in a manic phase, a depressive phase, or both.

Embodiment 145 the method of any one of embodiments 44 to 144, wherein the subject has undergone prior treatment with SSRI/SNRI for at least one week prior to the induction period.

Embodiment 146 the method of any one of embodiments 44 to 145, wherein the subject does not have bipolar disorder.

Embodiment 147 a pharmaceutical composition for treating major depressive disorder in a human subject in need thereof, the pharmaceutical composition comprising:

(i) A therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof,

(ii) A therapeutic amount of an antidepressant, and

(iii) One or more pharmaceutically acceptable carriers/excipients,

wherein the composition is administered during the induction period of the treatment cycle for about 1 day to about 28 days.

Embodiment 148 a pharmaceutical composition for treating major depressive episode in a human subject in need thereof, the pharmaceutical composition comprising:

(i) A therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) A therapeutic amount of an antidepressant; and

(iii) One or more pharmaceutically acceptable carriers/excipients,

Embodiment 149 a pharmaceutical composition for treating or preventing anxiety disorder in a human subject in need thereof, the pharmaceutical composition comprising:

(ii) A therapeutic amount of SSRI/SNRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients,

Embodiment 150. A pharmaceutical composition for treating or preventing anxiety disorder caused by initiation of treatment with an SSRI/SNRI in a human subject in need thereof, the pharmaceutical composition comprising:

(ii) A therapeutic amount of SSRI/SNRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients,

Embodiment 151 the pharmaceutical composition of embodiment 149 or 150, wherein administration of the composition is followed by a maintenance period comprising administration of a therapeutic amount of SSRI/SNRI until the underlying disease (e.g., major depressive disorder) subsides or until the subject experiences recurrence of anxiety disorder.

Embodiment 152 the pharmaceutical composition according to embodiments to 150, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 153 the pharmaceutical composition of any of embodiments 149 or 150, wherein the SSRI is selected from the group consisting of: sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, escitalopram, dapoxetine, paroxetine, fexidectin, vortioxetine, alapropyl and vilazodone, or pharmaceutically acceptable salts or esters or enantiomers thereof, preferably sertraline or escitalopram.

Embodiment 154 is the pharmaceutical composition of embodiment 149 or 150, wherein the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof.

Embodiment 155 the pharmaceutical composition according to embodiment 147 or 148, wherein said antidepressant is selected from the group consisting of: selective Serotonin Reuptake Inhibitors (SSRI); selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI); early tricyclic antidepressants (TCAs); monoamine oxidase inhibitors (MAO-inhibitors), monoamine oxidase Reversible Inhibitors (RIMA), atypical antidepressants; tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants.

Embodiment 156 the pharmaceutical composition of embodiments 147-155, wherein the subject is agitation.

Embodiment 157 the pharmaceutical composition of embodiments 147-155, wherein the subject is non-agitated.

Embodiment 158 the pharmaceutical composition according to embodiments 149 to 157, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are present in separate unit dosage forms.

Embodiment 159 the pharmaceutical composition of embodiment 158, wherein the two unit dosage forms are administered to the subject by the same or different routes selected from the group consisting of: oral mucosa (sublingual or buccal or gingival), oral, topical, transdermal, intranasal or parenteral (intravenous, intramuscular, subcutaneous) routes.

Embodiment 160 the pharmaceutical composition of embodiment 159, wherein the unit dosage form is administered to the subject orally transmucosally in the form of a tablet, film, spray, gel or drop.

Embodiment 161 the pharmaceutical composition of embodiment 160 wherein the dosage form is a film and the film is a film.

Embodiment 162 the pharmaceutical composition of embodiment 149 or 150, wherein the SSRI/SNRI is administered in a dosage form selected from the group consisting of: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches, lozenges, films, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like.

Embodiment 163. The pharmaceutical composition according to embodiment 162, wherein the SSRI/SNRI is administered orally in the form of a tablet.

Embodiment 164. The pharmaceutical composition of embodiment 162 wherein the SSRI/SNRI is administered orally in capsule form.

Embodiment 165 the pharmaceutical composition of embodiment 158, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosal administered in a dosage form selected from the group consisting of: films, sheets, patches, lozenges, gels, sprays, tablets, and drops.

Embodiment 166. The pharmaceutical composition according to embodiment 165, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oral mucosally in the form of a film.

Embodiment 167 the pharmaceutical composition of any of embodiments 160-166, wherein the dosage form is co-administered to the subject for about 28 days.

Embodiment 168 the pharmaceutical composition of any of embodiments 160-166, wherein the dosage form is co-administered to the subject for about 21 days.

The pharmaceutical composition of any one of embodiments 160-166, wherein the dosage form is co-administered to the subject for about 14 days.

Embodiment 170 the pharmaceutical composition of any one of embodiments 160-166, wherein said dosage form is co-administered to said subject for about 7 days.

Embodiment 171 the pharmaceutical composition according to embodiments 149 to 157, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are present together in a single unit dosage form.

Embodiment 172 the pharmaceutical composition of embodiment 171, wherein the unit dosage form is in the form of a tablet, film, spray, gel, or drop for administration to the subject via the oral mucosal route.

Embodiment 173 the pharmaceutical composition of embodiment 172, wherein said unit dosage form is a film and said film is a film.

Embodiment 174 the pharmaceutical composition of any of embodiments 170-173, wherein the dosage form is administered to the subject for about 28 days.

Embodiment 175 the pharmaceutical composition of any one of embodiments 170-173, wherein the dosage form is administered to the subject for about 21 days.

Embodiment 176 the pharmaceutical composition of any one of embodiments 170-173, wherein said dosage form is administered to said subject for about 14 days.

Embodiment 177 the pharmaceutical composition of any one of embodiments 170-173, wherein said dosage form is administered to said subject for about 7 days.

Embodiment 178 the pharmaceutical composition of embodiment 149 or 150, wherein the therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is in the range of about 0.5 micrograms to about 240 micrograms.

Embodiment 179 the pharmaceutical composition of embodiment 149 or 150, wherein the therapeutic amount of dexmedetomidine or pharmaceutically acceptable salt thereof is about 120 micrograms.

Embodiment 180 the pharmaceutical composition of embodiment 149 or 150, wherein the therapeutic amount of dexmedetomidine or pharmaceutically acceptable salt thereof is about 180 micrograms.

Embodiment 181 the pharmaceutical composition of embodiment 149 or 150, wherein the therapeutic amount of the SSRI is in the range of about 5mg to about 250 mg.

Embodiment 182 the pharmaceutical composition of embodiment 149 or 150, wherein the therapeutic amount of the SNRI is in the range of about 10mg to about 500 mg.

Embodiment 183 the pharmaceutical composition of any of embodiments 147 to 182, wherein the dosage form is administered once a day or multiple times a day.

embodiment184.themethodorpharmaceuticalcompositionofanyoftheprecedingembodiments,whereinthesubject'sHAM-ascoreisimprovedorreducedcomparedtothescoreobservedduringtheonsetoftreatment.

Embodiment 185 the method or pharmaceutical composition of any one of the preceding embodiments, wherein the HAM-D score of the subject is improved or reduced compared to the score observed during initiation of treatment.

Embodiment 186 the method or pharmaceutical composition of any of the preceding embodiments, wherein the subject has an improved MADRS score.

Embodiment 187 the method or pharmaceutical composition according to any one of the preceding embodiments, wherein the ACES score of said subject is improved or reduced.

The method or pharmaceutical composition of any one of embodiments 184-187, wherein the decrease in score is about 5% to about 100% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or more) compared to the baseline score observed prior to treatment.

Embodiment 189 the method or pharmaceutical composition of any one of the preceding embodiments, wherein the subject has improved CGI-I score.

Embodiment 190 the method or pharmaceutical composition of any of the preceding embodiments, wherein anxiety pain is significantly reduced within 1 week (including within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days).

Embodiment 191 the method or pharmaceutical composition of any of the preceding embodiments, wherein depression or anxiety pain is significantly reduced within 1 month, 2 months, 3 months, 6 months, or 12 months.

Embodiment 192 a single unit dosage form provided in the form of a kit comprising a composition as described herein in a container with or without instructions for administration to a subject in need thereof.

Embodiment 193 a dual unit dosage form provided in the form of a kit comprising a composition as described herein in one or more containers with or without instructions for simultaneous, sequential or separate administration to a subject in need thereof.

Embodiment 194 the kit of embodiments 192 or 193 comprising a pharmaceutical instruction comprising instructions for using a composition described herein for treating major depressive disorder in a subject.

Embodiment 195 the kit of embodiments 192 or 193 comprising a pharmaceutical instruction comprising instructions for using a composition described herein for treating major depressive episode in a subject.

Embodiment 196 the kit of embodiments 192 or 193 comprising a pharmaceutical instruction comprising instructions for using a composition described herein for treating or preventing anxiety pain in a subject.

Examples

Example 1. Use of the elevated plus maze test to evaluate the effect of dexmedetomidine hydrochloride, fluoxetine hydrochloride, and combinations thereof after acute intraperitoneal (i.p.) administration in rats.

Test, comparison, reference and control substances

Test substance I

Name and vehicle: dexmedetomidine hydrochloride in physiological phosphate buffered saline.

Test substance II

Name and vehicle: fluoxetine hydrochloride (Carbosynth reference BF 163653) dispersed in physiological saline 0.2% HPMC.

Reference substance

Name and vehicle: chlorbazaar (Carbosynth reference number C-2991) was dispersed in 0.2% hpmc in physiological saline.

Control material: vehicle for testing substances

Name: phosphate Buffered Saline (PBS).

Preparation of dosage forms

The clobazaar and fluoxetine hydrochloride were dispersed in 0.2% hpmc in physiological saline using a mortar and pestle.

Dexmedetomidine was dissolved in PBS with magnetic stirring. The amount of formulation W/V (stock) and then V/V (serial dilutions) were made on each day of the experiment.

Test system

The species used: male Wistar (Han) rats, the experiment started at 180-280g (maximum range per experiment=500 g).

Quantity: 52 males (including 2 spares). Additional animals are ordered as necessary.

The reason for the selection of the species: the characteristics of the animals used (age, strain and species) are comparable to those described in the scientific literature.

In addition, porsolt maintained historical data for tracking the biological response over time of these standard tests and positive and negative control groups of animals.

Breeder: janvier Labs,53940Le Genest-Saint-Isle, france.

Reception and adaptation period: animals were delivered to the laboratory at least 7 days prior to the experiment during which time the animals were acclimatized to laboratory conditions.

Identification: the tail is marked with a mark which cannot be wiped off.

Living and environmental conditions: rats were housed in groups on wood litter in macrolon cages (no more than 5 animals per cage) (SAFE, 89290Augy,France). The environment is enriched (e.g., channeling, biting and nesting materials). The animal house was maintained at a controlled ambient temperature of 22.+ -. 2 ℃ and a relative humidity of between 30% -70% under artificial lighting (12 hours) between 7:00 and 19:00.

Information relating to any clinical signs and mortality was archived with the study material.

Food and water: all animals were free to access food (code a04-SAFE,89290Augy,France) and water.

Analysis of contaminants: the composition and contaminant level of each batch of diet and wood litter was analyzed by the supplier. Bacterial and chemical analysis of water was performed periodically by an external laboratory. These assays involve the detection of possible contaminants (pesticides, heavy metals and nitrate byproducts).

No contaminants that could interfere with or destroy the results of the study were expected to be found in the diet, drinking water or wood bedding.

Design of experiment

Treatment of

Route and duration of administration

The test, reference, comparative or vehicle formulation is administered in a single intraperitoneal dose (i.p.) form.

Processing schedule

The 1-1 doses of dexmedetomidine, fluoxetine, and clobazaar were evaluated individually. The same dose of dexmedetomidine was evaluated in combination with the same dose of fluoxetine as described in table 1.

TABLE 1 treatment schedules

Experimental procedure

Elevated plus maze test for rats

The method of detecting anxiolytic activity followed the method described by Handley and Mithani (Naunyn. Schmied. Arch. Pharmacol.,327,1-5,1984).

Under standard artificial lighting (about 200 Lux), there is a contrast between the closed (shaded and safe) and open (brightly lit and anxious) arms of the maze. In these cases, control rats avoid open arms, while anxiolytics increase exploratory activity in open arms.

The day before the experiment, rats were randomly grouped based on their body weight.

The maze consists of 4 arms of equal length and width (50 x 10 cm) arranged in the form of a plus sign (+). The two opposite arms are closed by a 40cm high wall (closed arm). The 2 other arms have no walls (open arms). The maze was raised to about 65cm above the ground. Rats were placed in the center of the plus maze and allowed to explore for 5 minutes.

The test was recorded and the number of open and closed arms entered and the time spent in the open arms was automatically measured using a video tracking system (EthoVision, noldus). The percent open arm ingress (open arm ingress/total arm ingress x 100) was calculated. The total distance travelled is also reported.

10 rats were studied per group. The test was performed blindly within 2 days, with half of the animals in each group used daily.

The 10 μg/kg dose was i.p. administered 30 minutes prior to testing, and dexmedetomidine was evaluated and compared to the vehicle control group.

Fluoxetine (32 mg/kg i.p.) administered 30 minutes prior to testing was used as a comparison substance.

Clobazaar (16 mg/kg i.p.) administered 30 minutes prior to testing was used as a reference substance.

All animals received 2 consecutive administrations 30 minutes prior to testing. When the drug is not expired, the animals receive administration of the vehicle, as described in table 2 below:

TABLE 2 treatment given 30min before testing

Group number	30min before i.p. treatment-test	30min before i.p. treatment-test
			1	PBS	0.2% HPMC in physiological saline
2	Dexmedetomidine 10 μg/kg	0.2% HPMC in physiological saline
			3	PBS	Fluoxetine 32mg/kg
4	Dexmedetomidine 10 μg/kg	Fluoxetine 32mg/kg
			5	PBS	Chlorba accounting for 16mg/kg

The data of the test substances (for each parameter measured) were analyzed by using one-way analysis of variance and then comparing the treated group with the vehicle control group by post-hoc Dunnett's test.

Data comparing reference substances (clobazin) were analyzed separately by comparing each treatment group with vehicle control group using unpaired Student T test.

Results and discussion: the results of this study are provided in tables 3 to 6 below.

Table 3a.

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Table 3b.

Table 4.

Table 5.

Table 6.

Discussion-upon administration of dexmedetomidine: after 10 μg/kg, i.p. (group 2), there were the following increases: number of open arms entered (fig. 1a and table 3 a); the time spent entering (fig. 1b and table 3 b) or in the open arms of the elevated plus maze (fig. 2, table 4), but the results were not significant compared to the vehicle control group (group 1).

32mg/kg fluoxetine compared to the vehicle control (group 1); the i.p. treated group (group 3) reduced the number of times of entry into the open arms of the elevated plus maze (fig. 1a and table 3 a), entry (fig. 1b and table 3 b) and time spent (fig. 2; table 4), but the results were not significant. In addition, it significantly reduced the total number of entries into the four arms of the maze and the total distance traveled therein (-57%, p <0.05; fig. 3, and-65%, p <0.01; fig. 4) compared to the vehicle control group (group 1).

When fluoxetine (32 mg/kg) was co-administered with dexmedetomidine 10 μg/kg (group 4), the synergistic effect increased the number of times to open arms of the elevated plus maze (fig. 1 a), the entry% (fig. 1 b) and the time spent (fig. 2, table 4) (+150%, +431% and +102% ns, respectively) compared to fluoxetine 32mg/kg alone (group 3). There was no significant effect (+28%, NS, fig. 3, table 5) on the total number of entries compared to fluoxetine alone. However, the total distance travelled was significantly reduced (-55%, p <0.05; fig. 4, table 6) compared to vehicle control, but not (+29% NS; fig. 4, table 6) compared to fluoxetine alone.

These results indicate that there is no anxiolytic-like activity for i.p. administration of 10 μg/kg dexmedetomidine in rats in the elevated plus maze test. On the other hand, i.p. administration of 32mg/kg of fluoxetine tended to show anxiety-like effects. 10 μg/kg of dexmedetomidine tended to reverse the anxiety-like effects of fluoxetine (32 mg/kg i.p.).

Example 2. Use of the elevated plus maze test to evaluate the effects of dexmedetomidine hydrochloride, fluvoxamine maleate and combinations thereof following acute intraperitoneal (i.p.) administration in yohimbine stimulated rats.

Experimental group:

108 male Wistar rats were used. They were randomly distributed to 8 different experimental groups (12 animals per group) as given in table 7:

table 7: details of the groups

Treatment with test compounds:

-as summarized in the table

Vehicle is physiological saline

Overhead plus maze:

after compound administration, rats were placed on a platform opposite the closed arm. The number of entries into each arm and the time spent therein was recorded during a 5min period (the goal was reached). When an animal places its four soles into the arms, it is considered to enter the arms.

Series and data:

the number of rats treated per day in this model was about 20. Thus, experiments were divided into several series.

Statistical analysis:

variant Analysis (ANOVA) was performed on the result data. Fisher's PLSD for

The p values were compared in pairs and were considered significant at < 0.05.

Results and discussion: the results of this study are presented in tables 8 and 9 below.

The vehicle group (group 2) administered yohimbine (2.5 mg/kg; i.p.) showed a significant reduction in the number of open arms entered (table 8, fig. 5, -63%, p < 0.0001) and the time spent therein (table 9, fig. 6, -81%, p < 0.0001) compared to the vehicle (saline) treated group (group 1). This suggests the occurrence of yohimbine-induced anxiety-like behavior as assessed in the EPM paradigm.

The treatment with 1mg/kg of diazepam administered i.p. (group 3) reversed yohimbine-induced anxiety as shown by the significant increase in open arm entry times (table 8, fig. 5, +262%, p < 0.0001) and time spent in open arms (table 9, fig. 6, +620%, p < 0.0001) compared to the vehicle group administered yohimbine (group 2).

The group treated with dexmedetomidine (10 μg/kg; i.p.) showed no significant results compared to the vehicle group to which yohimbine was administered (group 2), although it showed an increase in the number of open arm entries (+48%, NS) and the time spent in the open arm of the elevated plus maze (+146%, NS).

Furthermore, no significant improvement in the number of open arms entered (fig. 5) was observed in groups 5 and 6 treated with 3mg/kg of i.p. administered fluvoxamine and 10mg/kg of fluvoxamine, respectively, when compared to the vehicle group to which yohimbine was administered (group 2). Furthermore, the group treated with fluvoxamine (3 mg/kg; i.p) (group 5) did not significantly increase the time spent in open arms compared to the vehicle group to which yohimbine was administered (+105%, NS) (figure 6). However, the group treated with fluvoxamine (10 mg/kg; i.p.) significantly increased the time spent in the open arms (group 6) compared to the yohimbine-administered vehicle group in group 2 (+232%, p < 0.01) (fig. 6).

Co-administration of dexmedetomidine (10 μg/kg; i.p.) with fluvoxamine (3 mg/kg; i.p.) and fluvoxamine (10 mg/kg; i.p.), respectively (groups 7 and 8), significantly increased the number of entries into the open arms (fig. 5, +152%, p <0.0001, and +133%, p < 0.0001), respectively) and the time spent therein (fig. 6, +406%, p <0.0001, and +382%, p < 0.0001), respectively) compared to the vehicle group (group 2) to which yohimbine was administered. In addition, group 7 treated with a combination of dexmedetomidine (10 μg/kg) and fluvoxamine (3 mg/kg) significantly increased the number of entries (fig. 5, +71%, p <0.01, and +66%, p < 0.01) when compared to the 10 μg/kg (group 4) and fluvoxamine 3mg/kg (group 5) individual treatments.

Group 7 (Dex 10. Mu.g/kg+Fluvoxamine 3 mg/kg) also significantly increased the time spent in the open arms of the maze (FIG. 6, +105%, p <0.001, and +146%, p < 0.0001) compared to the 10. Mu.g/kg (group 4) and Fluvoxamine 3mg/kg (group 5) treatments individually. Co-administration of 10 μg/kg of dexmedetomidine increased the number of entries significantly (FIG. 5, +58%, p < 0.05) with 10mg/kg of fluvoxamine (group 8) when compared to 10 μg/kg of dexmedetomidine (group 4) individual treatment, whereas the results were not significant (+32% relative to its NS) when compared to fluvoxamine (10 mg/kg) alone (group 6). Similar trends were observed in terms of time spent in the open arm as for combination group 8 (dexmedetomidine (10 μg/kg) and fluvoxamine (10 mg/kg) (fig. 6, +96%, p < 0.01), showing significant results compared to individual dexmedetomidine (10 μg/kg) (group 4), but not significant (+45%, NS) with respect to group 6, of 10mg/kg of fluvoxamine alone.

The above results indicate that, despite the anxiolytic-like effects of dexmedetomidine alone (10 μg/kg i.p.) and fluvoxamine alone (3 mg/kg i.p.) in yohimbine-administered rats, the observed effects were statistically insignificant (see groups 4 and 5, relative to group 2). On the other hand, i.p. administration of 10mg/kg of fluvoxad clearly showed a significant anxiolytic-like effect in terms of time spent in the open arm. The combination of 10 μg/kg dexmedetomidine with 3mg/kg fluvoxamine (group 7) showed a significant anxiolytic-like effect in the rats administered yohimbine in the elevated plus maze test, not only with respect to the group administered yohimbine but also with respect to its individual drug-treated group.

Considering that the anxiolytic-like effects of dexmedetomidine (10 μg/kg) and fluvoxamine (3 mg/kg) (in groups 4 and 5) individually were not significant in terms of the number of times of entry into the open arms and the time spent therein, the very high level of statistical significance exhibited by this combination (table 10) suggests a synergistic effect of the two drugs in this dose combination (group 7). The combined anxiolytic-like effect (group 7) was much higher than the sum of the individual effects of dexmedetomidine (10 μg/kg; group 4) and fluvoxamine (3 mg/kg, group 5) (+152% for the number of entries and +406% for the time spent in the open arm, table 10).

Table 8:

table 9.

Table 10 shows the percent change in the effect of treatment of dexmedetomidine (10 μg/kg; i.p.), fluvoxamine (3 and 10mg/kg; i.p.) and a combination of dexmedetomidine (10 μg/kg; i.p.) and fluvoxamine (3 and 10mg/kg; i.p.) on the number of times to enter the open arms of the elevated cross maze and the time spent therein in rats with yohimbine-induced anxiety compared to the group administered yohimbine.

Table 10.

Conclusion-it has been found that the combined anxiolytic effect of dexmedetomidine (10 μg/kg) and fluvoxamine (3 mg/kg) is more than the sum of the two parameters measured in the elevated plus maze, respectively.

Example 3: phase 1 study of the maximum tolerated dose discovery study of dexmedetomidine hydrochloride sublingual film with concomitant treatment of antidepressants in healthy volunteers.

Main objective

The main objective was to first determine the Maximum Tolerated Dose (MTD) of the dexmedetomidine sublingual film agent relative to placebo alone in healthy volunteers, and then determine whether this MTD of the dexmedetomidine sublingual film agent was sufficiently tolerated given together with effective doses of serotonin and norepinephrine reuptake inhibitors (SNRI; duloxetine) incorporated into the acute pharmacological effects of Selective Serotonin Reuptake Inhibitors (SSRI) and Norepinephrine Reuptake Inhibitors (NRI).

Secondary target

A key secondary objective was to evaluate the safety and tolerability of each dose studied. Specific security concerns are: sedation, resting hemodynamic vital sign values obtained at rest and under orthostatic pressure or any occurrence of a potentially clinically significant change in hemodynamic vital sign values.

Other secondary targets

The Pharmacokinetics (PK) of dexmedetomidine sublingual film agent and its metabolites after single and multiple doses in healthy volunteers were characterized.

Primary endpoint

Determining the safety profile of dexmedetomidine sublingual film formulation as measured by: vital signs, agitation-calm assessment scale (ACES) administered after each morning dose for study treatment of hemodynamic changes (at rest and under orthostatic pressure) of excessive sedation, blood pressure and heart rate (on days 1, 4 and 7), and reporting of Adverse Events (AEs) for sedation, hemodynamic changes and other events.

Overall tolerance and local site (oral/sublingual) tolerance of oral films in terms of AE reporting are described.

Secondary endpoint

Pharmacokinetics: plasma concentration-time data were analyzed by standard non-compartmental methods to estimate Pharmacokinetic (PK) parameters including maximum plasma concentration (Cmax), time to observe Cmax (Tmax), area under the curve (AUC; fraction and infinity), half-life, apparent clearance, and apparent distribution volume.

Study design

Overall study design and planning

This is a randomized, double-blind, placebo-controlled MAD study that evaluates the MTD of dexmedetomidine sublingual film in healthy volunteers and was subsequently evaluated when MTD was administered simultaneously with SNRI antidepressant in a total of 6 cohorts.

A total of 102 subjects (i.e., healthy volunteers) were scheduled to be enrolled at 1 study site in the united states. These subjects participated in one of six cohorts; the first five cohorts consisted of 18 subjects each, and the last cohort consisted of 12 subjects.

This inpatient study randomized subjects at 2:1 to receive dexmedetomidine sublingual film or matched placebo for 7 days. The dose of dexmedetomidine sublingual film dosage received depends on the cohort of the given subject as assigned:

queue 1: 30 μg or placebo (12 actives; 6 placebo) was administered daily in the morning (qAM).

Queue 2: qAM 60 μg or placebo (12 active agents; 6 placebo).

Queue 3: qAM 80 μg (12 active agents; 6 placebo).

Queue 4: qAM 30 μg and 60 μg per night (qPM) or placebo (12 active agents; 6 placebo).

Queue 5: qAM to 40. Mu.g and qPM to 80. Mu.g, or placebo (12 active agents; 6 placebo).

Queue 6: in addition to the MTD of the dexmedetomidine sublingual film formulation without duloxetine or placebo, 30 milligrams (mg) of duloxetine, twice daily (BID) has been identified (8 active agents; 4 placebo). This dose of dexmedetomidine sublingual film agent may be 30 μg qAM;60 μg of qAM, 80 μg of qAM, 30 μg of qAM and 60 μg of qPM, or 40 μg of qAM and 80 μg of qPM. Determination of MTD all possible dexmedetomidine sublingual membranes or placebo queues were determined after having been treated and safety data was reviewed. Subjects in this cohort were treated for 7 days, with similar evaluations being performed as the 3 initial cohorts above.

After each queue is completed, a review of the security data is made by the sponsor and researcher to determine if any security signals are present before the next queue begins. If such a signal is noted during the examination, dose escalation is stopped, the dose administered in the previous cohort is considered MTD, and the study moves immediately to cohort 6. If any such signals are noted during the review of queue 1, the study is terminated.

After confirmation of eligibility, the subject enters the hospitalized patient ward in the afternoon prior to the first day that they received treatment. Subjects were observed and evaluated for a further 3 days after the last dose of study treatment to the hospitalized patient ward, with the primary purpose of this observation period being to evaluate the potential retrograde/rebound effects. Subjects who discontinued early in the study were encouraged to stay in the hospitalization for 3 days post-study drug observation and evaluation.

After confirmation of eligibility, subjects were randomized to 2:1 to receive dexmedetomidine sublingual film or matching placebo, starting with cohort 1 (30 μg), and when all participants completed treatment with dexmedetomidine sublingual film in the previous cohort for 7 days and all safety data for those 7 days had been fully reviewed (including 3 days of evaluation data after the last dose of study treatment), after safety review, were moved to the subsequent dosing cohort. The treatment duration for each cohort was 7 days. During this study, subjects were admitted to the hospital patient clinical study environment/facility (added afternoon the day before they received the first dose of study treatment). The subjects were admitted to the facility after the final safety assessment the third day after the last dose of subjects receiving study treatment (and duloxetine for those in cohort 6).

Upon administration of the study treatment as described above, the subject is instructed on how to take the study product sublingually, and it should hold the study product in the sublingual cavity until dissolved. Subjects self-administered dexmedetomidine sublingual film. If the subject is unable to self-administer, the event is recorded and participation of the subject is ended.

Participants were also evaluated for local irritation around the area where the film was placed. Safety assessments were made periodically before and after dosing according to the event schedule for each possible queue (see tables 11 and 12). All efforts were made to complete all evaluations according to the protocol.

Safety and tolerability were measured at various time points during the entire treatment period as described in the time course of the events in table 11.

Dense sampling of plasma concentrations of dexmedetomidine sublingual film agent and its metabolites was performed in each cohort. Blood samples were drawn at 0.25, 0.50, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00 and 24.00 hours prior to dosing and after dosing on days 1, 2 and 7. For those cohorts receiving twice daily administration, blood samples for analysis were collected on a time course consistent with the above time course following the morning dose. Furthermore, for once daily and twice daily dosing, blood samples were drawn prior to dosing on days 3-6. These blood samples were obtained for determining the plasma concentrations of dexmedetomidine sublingual film agent and metabolites thereof.

Population of subjects

Selection of study population

A maximum of 102 subjects (i.e., healthy volunteers) were scheduled to be recruited at 1 study site in the united states. Subjects who did not complete all 7-day treatment and 3-day follow-up observations were replaced.

Inclusion criteria

A subject meets the inclusion study conditions if the subject meets all of the following criteria:

1. the subjects were healthy volunteers, 18 years of age or older.

2. The subject would like to provide informed consent.

3. Body Mass Index (BMI) is between 18.5 and 29.9.

4. As determined by a detailed medical history, physical examination, a set of three 10 second 12 lead Electrocardiographs (ECG), blood chemistry profile, hematology, urinalysis, and the opinion of the primary researcher or prescribing personnel, subjects with good general health status prior to study participation.

5. If the subject is female, she must not be pregnant or lactating. If the subject has fertility, she must agree to use clinically acceptable methods of contraception or be fasted during the study and 1 month after completion of the study.

Exclusion criteria

Subjects were excluded from the study if they met any of the following criteria:

1. benzodiazepines or other sedative hypnotics were used during the study.

2. Any antipsychotic was used within 1 week of the start of the study (6 weeks of the long acting antipsychotic) or during the study.

3. A subject with alcohol or substance use disorder in need of treatment is clinically considered.

4. Treatment with an alpha-1 norepinephrine blocker (terazosin, doxazosin, he Su Luoxin, alfuzosin, or prazosin) or other prohibitive agent.

5. Subjects with abnormal scores based on the Columbia-suicide severity rating scale (C-SSRS) must be excluded (C-SSRS. Gtoreq.4).

6. Female subjects with a positive pregnancy test or being lactated at screening or baseline (day 0).

7. Subjects with a history of water brain, seizures, or severe head trauma, stroke, transient ischemic attacks, subarachnoid hemorrhage, brain tumors, encephalopathy, meningitis, parkinson's disease, or focal neurological findings.

8. There is a history of syncope or other syncope onset, current evidence indicating hypovolemia, there is a standing hypotension at screening and baseline (at least 20mmHg decrease in Systolic Blood Pressure (SBP) or at least 10mmHg decrease in Diastolic Blood Pressure (DBP) within 3 minutes of standing), screening and baseline heart rate <60 beats/min, or screening and baseline Systolic Blood Pressure (SBP) <100mmHg or Diastolic Blood Pressure (DBP) <55mmHg.

9. Subjects with laboratory or ECG abnormalities considered clinically valuable by a investigator or qualified prescriber [ advanced heart block (secondary or higher atrioventricular block without pacemaker), diagnosis of atrial chamber imbalance syndrome ], will have a clinical impact on the participation of the subject in the study.

10. Subjects with a personal history of hereditary long QT syndrome or a known family history (if the family history is known, but the subject is genetically confirmed to have no familial genetic change, the subject may enter the study). The mean of 3 screening QTcF values for female subjects is >470 milliseconds (msec) and for male subjects >450msec.

11. A subject suffering from a severe or unstable medical condition. These conditions include current liver (moderate-severe liver injury), kidney, gastrointestinal, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrine or hematological disorders.

12. Subjects who received the study drug within 30 days prior to the first dose of study drug.

13. Subjects who are considered by the investigator as candidates unsuitable for receiving DEX (dexmedetomidine sublingual film agent) for any reason; such as subjects having a history of allergic reactions to DEX.

14. Any drug that might interfere with the activity of uridine diphosphate-glucuronosyl transferase (UGT) and cytochrome P450 2A6 (CYP 2 A6) was used within 2 weeks of starting the study until the study was completed.

15. Subjects with positive drug screening at screening or baseline (day 0).

After confirmation, subjects will be randomized at 2:1 to receive dexmedetomidine hydrochloride sublingual film (at the doses specified per cohort) or matched placebo. Subjects withdrawn from the study retain their random cohort numbers if assigned.

Therapeutic administration

Upon administration of the study treatment as described above, the subject is instructed on how to take the study product sublingually, and it should hold the study product in the sublingual cavity until dissolved. Subjects self-administered a sublingual film formulation of dexmedetomidine hydrochloride. If the subject is unable to self-administer, the event is recorded and participation of the subject is ended. The subject should be limited by food or water intake within 15 minutes after administration.

Participants were also evaluated for local stimulation around the area where the membrane was placed daily during the treatment and follow-up periods of the study.

Subjects in cohort 6 were also instructed by the on-site staff how to take their duloxetine dose.

Study evaluation

Pharmacokinetics of drugs

Blood samples (4 milliliters (mL)) were collected over the time course of the event (tables 11 and 12).

For each subject, up to 80 blood samples (up to 320mL of blood) were collected for PK analysis during the study. 40 samples were taken from subjects in cohorts 1-3. 80 samples of subjects in cohorts 4 and 5 were taken. Taking 40 or 80 samples of subjects in cohort 6; the total number depends on whether the subjects were given only mid-day afternoon or twice daily sublingual dexmedetomidine film formulation in the cohort.

Statistical method

General considerations

Statistical Analysis Planning (SAP) describing the details of the analysis to be performed is completed before the database is locked.

Statistical analysis

The data will be summarized in terms of treatment using descriptive statistics (number of subjects, mean, median, standard deviation, minimum and maximum) for continuous variables, and frequency and percentage of use in terms of treatment for class variables. Baseline is defined as the last observation available before starting the study drug.

Security analysis

All security analyses were performed using the security population. All subjects receiving at least one dose of study drug will be included in the population for safety analysis.

Adverse events are characterized by type, severity, and relationship to treatment. Adverse events were coded by the preferred terms and system organ classifications using the latest version of MedDRA. The incidence of AE will be summarized in terms of overall treatment, severity and relationship to study drug. Serious adverse events and AEs resulting in discontinuation of study drug were also presented. A list of subjects experiencing withdrawal due to AE, severe AE, and/or death is presented.

Laboratory parameters were summarized in terms of treatment by using a data list of descriptive statistical and clinically significant abnormalities. Vital signs, pulse oximetry and ECG data are summarized by changes from baseline values using descriptive statistics.

Safety assessment is based on the incidence of treatment-induced adverse events (TEAEs), incidence of discontinuing AEs, vital sign measurements, pulse oximetry, physical examination, body weight, laboratory test results, ECG findings, ACES, C-SSRS results, oral administration site findings, and concomitant medication.

Table 11: event time schedules for queues 1-3

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Annotation of event schedules for queues 1-3:

¹ if queue 6 only involved AM administration of dexmedetomidine sublingual film, this time course of queue 6 should be followed.

² And is carried out on an empty stomach.

³ For women with fertility

⁴ Resting vital signs: temperature, pulse oximetry, heart rate and blood pressure after resting in the supine position for 5 minutes

⁵ Upright vital signs: immediately after collection of resting vital signs; collected 1 minute and 3 minutes after standing.

⁶ Study drug administration: between 8:30AM and 10:00AM per day.

⁷ Local stimulation examination: is performed 2 hours after administration on days 1 to 7 and once daily on days 8 to 10.

⁸ Resting vital signs: taken 2, 4 and 6 hours after administration.

⁹ Upright vital signs: resting vital signs were collected immediately after 2, 4 and 6 hours post-dosing.

¹⁰ ECG: obtained 2 hours after administration.

¹¹ ACES: administered 4, 6 and 8 hours after day 1 dosing.

¹² Blood samples were drawn at day 1, day 2 and day 7 at 0.25, 0.50, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00 and 24.00 hours after dosing (timing chart 2. Extend the draw to the next day).

¹³ ACES: use 4, 6 and 8 hours before breakfast and after dosing on days 4 and 7

¹⁴ MMSE to be used after administration on day 7

¹⁵ Fasting glucose: obtained before administration on days 2 to 7

¹⁶ Pre-dose, rising vital signs: immediately after collection of the pre-dosing resting vital signs.

¹⁷ ECG: if ECG notices QT prolongation on the previous day, it is obtained only on days 5 and 6

¹⁸ Duloxetine administration: only for subjects in cohort 6. Twice daily. The morning dose should be taken at breakfast. The evening dose should be taken when the subject is sleeping in the lying position at night (ideally between 8:00pm and sub-night).

TABLE 12 event time course for queues 4-5 ¹

Annotation of event schedules for queues 4-5:

¹ If cohort 6 involved BID administration of dexmedetomidine sublingual film, this time course of cohort 6 should be followed.

² And is carried out on an empty stomach.

³ For women with fertility

⁶ Study drug administration: AM doses were taken between 8:30AM and 10:00 AM. PM doses were taken at 8:30PM-10:00 PM.

⁷ Local stimulation testChecking: AM dosing was performed 2 hours after day 1 to day 7 and once daily on day 8 to day 10.

⁸ Resting vital signs: taken 2, 4 and 6 hours after dosing (AM and PM doses).

⁹ Upright vital signs: resting vital signs were collected immediately after 2 hours, 4 hours and 6 hours after AM administration

¹⁰ ECG: obtained 2 hours after dosing (AM and PM dose).

¹¹ ACES: use at day 1 at 4, 6 and 8 hours after AM administration.

¹² On days 1, 2 and 7, blood samples will be drawn 0.25, 0.50, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00 and 24.00 hours after administration (AM and PM doses) (timing extends the draw to the next day).

¹³ ACES: use 4, 6 and 8 hours before breakfast and after AM administration on days 4 and 7

¹⁴ MMSE to be used after PM administration on day 7

¹⁵ Fasting glucose: obtained before administration on days 2-7

Example 4: phase 2 studies evaluating the effect of dexmedetomidine sublingual film on major depressive episodes.

The main object is: to determine if a single dose of dexmedetomidine hydrochloride sublingual film agent effectively reduced MDE-related symptoms at the end of one week treatment compared to placebo, as assessed using the hamilton depression rating scale-17 item (HAM-D-17).

Key secondary objective: to determine if a single dose of dexmedetomidine hydrochloride sublingual film agent was effective in reducing symptoms associated with anxiety-causing MDD at the end of 4 weeks treatment compared to placebo, as assessed using hamilton depression rating scale-17 item (HAM-D-17).

Other exploratory targets: to further determine the efficacy, safety, tolerability and PK of dexmedetomidine hydrochloride sublingual film dosage in patients diagnosed with MDD, comprising:

to determine the overall clinical improvement after drug administration, as measured by the clinical global impression-improvement scale (CGI-I).

To determine the effect of dexmedetomidine hydrochloride sublingual film agent on sleep disorders, as measured by the HAM-D-17 sleep score scale.

To determine the effect of dexmedetomidine hydrochloride sublingual film agent on the core symptoms of depression as measured by the HAM-D-17 depression score scale.

To determine the safety profile of dexmedetomidine hydrochloride sublingual film dosage as measured by adverse event reporting and vital signs.

To describe the overall tolerance and local site (buccal/sublingual) tolerance of oral films in terms of treatment-induced adverse event reporting.

Study design: this will be a randomized, double-blind, parallel-group, placebo-controlled phase 2 study that evaluates efficacy, safety and tolerability of dexmedetomidine hydrochloride sublingual film administration in adult (18-75 years old) men and women with MDE as defined by the DSM-5 standard.

This would be an outpatient study in which subjects were randomized 1:1 to receive dexmedetomidine hydrochloride sublingual film (120 μg dose of DEX) or matched placebo film except for one of the four SSRIs (i.e., sertraline, fluoxetine, citalopram, escitalopram). Random grouping will be layered by age; age <65 years and age > 65 years.

Eligible subjects (those diagnosed with anxiety-causing MDD) will be identified in an outpatient clinic or in mental health, mental or medical emergency services, including medical/psychiatric observation units. The subject will undergo a screening procedure based on the clinic.

After confirmation of eligibility, subjects were randomized to receive 120 μg dexmedetomidine sublingual film or matched placebo. Binding titrates one of the following SSRIs: sertraline; fluoxetine; citalopram; escitalopram was dosed with 120 μg of dexmedetomidine sublingual film agent or matched placebo for 4 weeks per night.

The treatment group will contain an appropriate number of subjects receiving 120 μg of dexmedetomidine sublingual film + SSRI or placebo + SSRI. SSRI dosing will start at half the recommended dose for weeks 1 and 2 and will increase to the recommended dose for weeks 3 and 4.

This study will include two phases: hospitalization/clinical period, which is mainly used to confirm the safety of the beginning of the administration of dexmedetomidine sublingual film agent and SSRI up to one week; and outpatient period, which evaluates the safety, efficacy and tolerability of sublingual dexmedetomidine based on the outpatient.

In cases of persistent or recurrent anxiety and restlessness, the investigator may choose to repeat the administration at half the intensity. The patient will be repeatedly dosed only when he is hemodynamically stable, not hypotensive (must be greater than 90/60 systolic/diastolic) and not bradycardia (must be greater than 60 bpm). Repeated dosing of the patient will not occur if the patient is upright (reduced contraction >20mm Hg, or reduced relaxation by 10mm Hg) or if it experiences an AE that prevents repeated dosing when assessed according to PI. The maximum number of repeat doses per subject was 1 during 12 hours after the first dose. The dose is administered no earlier than 2 hours after the previous dose.

Participants will also be evaluated for local irritation around the area where the film is placed. Efficacy and safety assessments will be made periodically before and after dosing. All efforts will be made to have the patient make all evaluations according to the protocol.

Efficacy, safety, tolerability and Pharmacokinetics (PK) will be measured at various time points throughout the treatment period.

Number of subjects (plan): about 80 subjects. This test will be performed at up to 3 sites in the united states.

The subject:

a eligible individual will include a subject diagnosed with anxiety-bearing MDE and signed an Informed Consent Form (ICF) prior to any study-related procedure. After confirmation of eligibility, subjects will be randomized to 120 μg of film of sublingual dexmedetomidine or matched placebo in a 1:1 randomized group.

Test product, dose and mode of administration: dexmedetomidine hydrochloride will be provided in a thin film formulation of DEX for Sublingual (SL) administration. Administration will deliver 60 μg or 120 μg dex sublingually. The product will be a small solid dose film formulation with an area of about 193.6mm ² And a thickness of 0.7mm, designed to dissolve completely in the sublingual space in 1-3 minutes.

Reference therapy, dose and mode of administration: the film will be administered sublingually or buccally as described above.

Duration of treatment: 4 weeks of

The foregoing examples and description of certain embodiments should be taken as illustrating, rather than limiting, the invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above may be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entirety.

Claims

1. A method of treating major depressive disorder or major depressive episode in a human subject in need thereof, the method comprising:

(i) Administering at least one daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject for a period of at least 14 days, and

(ii) Administering an antidepressant to the subject.

2. The method of claim 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject twice daily.

3. The method of claim 2, wherein the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the morning (or daytime) and the second dose is administered in the evening (or nighttime).

4. The method of claim 2 or 3, wherein the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is lower than the second dose of dexmedetomidine or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1 to 4, wherein the total daily dexmedetomidine dosage is about 30 micrograms to about 200 micrograms.

6. The method of claim 5, wherein the first dose of dexmedetomidine is about 30 micrograms and the second dose of dexmedetomidine is about 60 micrograms.

7. The method of claim 5, wherein the first dose of dexmedetomidine is about 40 micrograms and the second dose of dexmedetomidine is about 80 micrograms.

8. The method of any one of claims 1 to 7, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by a route selected from the group consisting of: oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular), topical (including transdermal), intranasal, inhalation (e.g., via aerosol), or oral mucosa (e.g., buccal, sublingual, gingival).

9. The method of claim 8, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a tablet, wafer, patch, liquid spray, gel, film or spray.

10. The method of claim 8 or 9, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally transmucosally in the form of a film.

11. The method of claim 1, wherein the subject is non-agitation upon administration.

12. The method of any one of the preceding claims, wherein the subject also has anxiety suffering.

13. The method of any of the preceding claims, wherein the antidepressant is administered orally for an extended period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months or more until the potential disease resolves.

14. The method of claim 1, wherein the antidepressant is an SSRI or an SNRI.

15. A method of treating or preventing anxiety in a human subject, the method comprising

(ii) A maintenance period comprising administering to the subject a therapeutic amount of the SSRI/SNRI.

16. A method of treating or preventing anxiety disorder caused by initiation of treatment with an SSRI/SNRI in a human subject, the method comprising

17. The method of claims 14-16, wherein the SSRI is selected from the group consisting of: sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, escitalopram, dapoxetine, paroxetine, fexidectin, vortioxetine, alapropyl and vilazodone, or pharmaceutically acceptable salts or esters or enantiomers thereof, preferably sertraline or escitalopram.

18. The method of any one of claims 14 to 17, wherein the SSRI is sertraline or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 14 to 17, wherein the SSRI is escitalopram or citalopram or a pharmaceutically acceptable salt thereof.

20. The method of claims 14-16, wherein the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol, or a pharmaceutically acceptable salt or ester or enantiomer thereof.

21. The method of claim 20, wherein the SNRI is duloxetine or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1 to 21, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are administered in separate unit dosage forms.

23. The method of claim 22, wherein the two unit dosage forms administered to the subject are administered separately by the same or different routes selected from the group consisting of: oral mucosa (e.g., sublingual or buccal), oral, topical, transdermal, intranasal, parenteral (e.g., intravenous, intramuscular, subcutaneous), and the like.

24. The method of claim 23, wherein both unit dosage forms are administered by the oral mucosal route.

25. The method of claims 12-16, wherein the SSRI/SNRI is administered in a dosage form selected from the group consisting of: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches or lozenges, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like.

26. The method of claim 25, wherein the SSRI/SNRI is administered orally in the form of a tablet or capsule.

27. The method according to claim 24, wherein the oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride) is in the form of a tablet, film, spray, gel or drop, preferably film.

28. The method of any one of claims 22-27, wherein the dosage form is co-administered for about 28 days.

29. The method of any one of claims 22-27, wherein the dosage forms are co-administered for about 21 days.

30. The method of any one of claims 22-27, wherein the dosage forms are co-administered for about 14 days.

31. The method of any one of claims 22-27, wherein the dosage forms are co-administered for about 7 days.

32. The method of any one of claims 1 to 21, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and the SSRI/SNRI are administered together in a single unit dosage form.

33. The method of claim 32, wherein the unit dosage form is administered to the subject via the oral mucosal route in the form of a tablet, film, spray, gel, or drop.

34. The method of claim 33, wherein the dosage form is a film and the film is a film.

35. The method of any one of claims 32 to 34, wherein the dosage form is administered for about 28 days.

36. The method of any one of claims 32 to 34, wherein the dosage form is administered for about 21 days.

37. The method of any one of claims 32 to 34, wherein the dosage form is administered for about 14 days.

38. The method of any one of claims 32 to 34, wherein the dosage form is administered for about 7 days.

39. The method of any one of claims 32 to 38, wherein the dosage form is administered once a day or multiple times a day.

40. The method of any one of claims 1 to 39, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dosage ranging from about 0.5 micrograms to about 240 micrograms.

41. The method of claim 40, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is administered in a single dose containing about 180 micrograms of dexmedetomidine or pharmaceutically acceptable salt thereof.

42. The method of claim 40, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is administered in a single dose containing about 120 micrograms of dexmedetomidine or pharmaceutically acceptable salt thereof.

43. The method of any one of claims 1 to 42, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

44. The method of any one of claims 1 to 43, wherein the SSRI is administered at a dose in the range of about 5mg to about 250 mg.

45. The method of any one of claims 1 to 43, wherein the SNRI is administered at a dose ranging from about 10mg to about 500 mg.

46. The method of claims 15 and 16, wherein the maintenance period continues until the underlying disease (e.g., major depression) subsides or until the subject experiences a recurrence of anxiety disorder.

47. The method of claims 15 and 16, wherein the subject is in a manic phase, a depressive phase, or both.

48. The method of claim 15, wherein the subject has undergone prior treatment with SSRI for at least one week prior to the induction period.

49. A pharmaceutical composition for treating or preventing anxiety pain in a human subject in need thereof, the pharmaceutical composition comprising:

(ii) A therapeutic amount of SSRI/SNRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients,

50. A pharmaceutical composition for treating or preventing anxiety disorder caused by initiation of treatment with an SSRI/SNRI in a human subject in need thereof, the pharmaceutical composition comprising:

(ii) A therapeutic amount of SSRI/SNRI; and

(iii) One or more pharmaceutically acceptable carriers/excipients,

51. The pharmaceutical composition of claim 49 or 50, wherein administration of the composition is followed by a maintenance period comprising administration of a therapeutic amount of SSRI/SNRI until the underlying disease (e.g., major depressive disorder) subsides or until the subject experiences recurrence of anxiety afflictions.

52. The pharmaceutical composition of claim 49 or 50, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

53. The pharmaceutical composition of any one of claims 49-52, wherein the SSRI is selected from the group consisting of: sertraline, fluoxetine, norfluoxetine, fluvoxamine, citalopram, escitalopram, dapoxetine, paroxetine, fexidectin, vortioxetine, alapropyl and vilazodone, or pharmaceutically acceptable salts or esters or enantiomers thereof, preferably sertraline or escitalopram.

54. The pharmaceutical composition of any one of claims 49-52, wherein the SNRI is selected from the group consisting of: desmethylvenlafaxine, venlafaxine, levomilnacipran, milnacipran, duloxetine, atomoxetine, sibutramine, reboxetine, tramadol or a pharmaceutically acceptable salt or ester or enantiomer thereof, preferably duloxetine.

55. The pharmaceutical composition of claim 49 or 50, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are present in separate unit dosage forms.

56. The pharmaceutical composition of claim 55, wherein two unit dosage forms are administered to the subject by the same or different routes selected from the group consisting of: oral mucosa (sublingual or buccal), oral, topical, transdermal, intranasal or parenteral (intravenous, intramuscular, subcutaneous).

57. The pharmaceutical composition according to claim 56, wherein said unit dosage form is administered to said subject orally and mucosally in the form of a tablet, film, spray, gel or drop.

58. The pharmaceutical composition of claim 57, wherein the dosage form is a film and the film is a film.

59. The pharmaceutical composition of claim 55, wherein the SSRI/SNRI is administered in a dosage form selected from the group consisting of: tablets, orally Disintegrating Tablets (ODT), effervescent tablets, capsules, pellets, pills, troches, lozenges, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions, and the like.

60. The pharmaceutical composition of claim 59, wherein the SSRI/SNRI is administered orally in tablet form.

61. The pharmaceutical composition of claim 55, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosal administered in a dosage form selected from the group consisting of: films, sheets, patches, lozenges, gels, sprays, tablets, and drops.

62. The pharmaceutical composition according to claim 61, wherein dexmedetomidine or pharmaceutically acceptable salt is administered oral transmucosally in the form of a film.

63. The pharmaceutical composition of any one of claims 55-62, wherein the dosage form is co-administered to the subject for about 28 days.

64. The pharmaceutical composition of any one of claims 55-62, wherein the dosage form is co-administered to the subject for about 21 days.

65. The pharmaceutical composition of any one of claims 55-62, wherein the dosage form is co-administered to the subject for about 14 days.

66. The pharmaceutical composition of any one of claims 55-62, wherein the dosage form is co-administered to the subject for about 7 days.

67. The pharmaceutical composition of claims 49 and 50, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and the SSRI/SNRI are present together in a single unit dosage form.

68. The pharmaceutical composition of claim 67, wherein the unit dosage form is administered to the subject by the oral mucosal route in the form of a tablet, film, spray, gel, or drop.

69. The pharmaceutical composition of claim 68, wherein the unit dosage form is a film and the film is a film.

70. The pharmaceutical composition of any one of claims 67-69, wherein the dosage form is administered to the subject for about 28 days.

71. The pharmaceutical composition of any one of claims 67-69, wherein the dosage form is administered to the subject for about 21 days.

72. The pharmaceutical composition of any one of claims 67-69, wherein the dosage form is administered to the subject for about 14 days.

73. The pharmaceutical composition of any one of claims 67-69, wherein the dosage form is administered to the subject for about 7 days.

74. The pharmaceutical composition according to claims 49 and 50, wherein the therapeutic amount of dexmedetomidine or pharmaceutically acceptable salt thereof is in the range of about 0.5 micrograms to about 240 micrograms, preferably about 180 micrograms, about 120 micrograms.

75. The pharmaceutical composition of claims 49 and 50, wherein the therapeutic amount of the SSRI is in the range of about 5mg to about 250 mg.

76. The pharmaceutical composition of claims 49 and 50, wherein the therapeutic amount of the SNRI is in the range of about 10mg to about 500 mg.

77. The pharmaceutical composition of any one of claims 49-76, wherein the dosage form is administered once a day or multiple times a day.

78. The pharmaceutical composition according to any one of the preceding claims, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.