Non-sedating dexmedetomidine treatment regimens

Abstract

To provide methods of administering relatively high doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, without inducing significant sedation.SOLUTION: The disclosed methods are particularly suitable for treatment of agitation, especially when associated with neurodegenerative and / or neuropsychiatric diseases such as schizophrenia, bipolar illness such as bipolar disorder or mania, dementia, depression, or delirium. Disclosed herein are methods of treating a human subject having a condition (e.g. agitation) which can be improved using an alpha-2 adrenergic receptor agonist.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 876,371, filed July 19, 2019, U.S. Provisional Patent Application No. 62 / 877,056, filed July 22, 2019, U.S. Provisional Patent Application No. 62 / 963,769, filed January 21, 2020, U.S. Provisional Patent Application No. 62 / 970,411, filed February 5, 2020, U.S. Provisional Patent Application No. 62 / 977,554, filed February 17, 2020, U.S. Provisional Patent Application No. 63 / 037,759, filed June 11, 2020, and U.S. Provisional Patent Application No. 62 / 943,022, filed December 3, 2019, the disclosures of each of which are incorporated herein by reference in their entirety.

[0002] Disclosed herein is a method for treating a human subject having a condition (e.g., agitation) that can be improved using an alpha-2 adrenergic receptor agonist. The method involves administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a suitable dose and via an appropriate route of administration to achieve a plasma concentration profile that results in rapid improvement in the subject's condition without inducing significant sedation. The dosing regimen is also selected to provide maximum therapeutic benefit to the subject without causing any significant side effects, such as undesirable cardiovascular events. Suitable routes of administration include sublingual, buccal, oral, intranasal, and parenteral. The disclosed method is particularly suitable for treating agitation or symptoms of agitation, especially when associated with neurodegenerative and / or neuropsychiatric disorders, such as schizophrenia, bipolar disorders, e.g., bipolar disorder, or mania, dementia, depression, and delirium. [Background technology]

[0003] On December 17, 1999, the U.S. Food and Drug Administration approved PRECEDEX®, a dexmedetomidine product formulated as an intravenous solution for continuous infusion and indicated as a sedative for patients who are initially intubated and receiving mechanical ventilation during treatment in an intensive care setting. PRECEDEX® was subsequently approved as a sedative for non-intubated patients before and / or during surgical and other procedures.

[0004] Dexmedetomidine has also been administered intravenously and via other routes to treat a variety of conditions, often perioperative or postoperative, including the treatment of pain, anxiety, delirium, withdrawal symptoms, sleep disorders, and agitation. However, administering dexmedetomidine appropriately to provide effective and rapid relief to subjects without inducing significant sedation presents a challenge. Furthermore, the use of dexmedetomidine has been limited in clinical practice due to common side effects of dexmedetomidine, such as hypotension and bradycardia. For example, significant cardiovascular side effects have occurred at therapeutic doses after administration of dexmedetomidine hydrochloride via sublingual spray or tablet or intravenous administration. Thus, there exists a continuing unmet need for effective dexmedetomidine products that are desirably effective without causing significant sedation and without causing significant adverse effects, such as cardiovascular events. The unmet need is particularly acute for non-addictive agents that can effectively treat agitation or symptoms of agitation without causing the aforementioned adverse effects and sedation.

[0005] The inventors of the present application have surprisingly found that, when administered via certain treatment regimens, human subjects may be able to tolerate relatively high doses of dexmedetomidine hydrochloride without inducing significant associated sedation. For example, in accordance with the present disclosure, sublingual administration of dexmedetomidine hydrochloride at doses of at least 180 μg is herein shown to be safe, well-tolerated, and effective in treating agitation without inducing significant sedation. Surprisingly, it has also been found that sublingual administration of dexmedetomidine hydrochloride at doses of 120 μg and 180 μg, e.g., via a film, results in a superior pharmacokinetic profile and causes fewer cardiovascular adverse effects than PRECEDEX®. Furthermore, the inventors have found that when dexmedetomidine hydrochloride is administered at a dose of at least 180 μg, subjects respond well, showing significant improvement in agitation as early as 45 minutes after administration, and the calming effect is maintained for an extended period of time, e.g., up to at least 24 hours. Summary of the Invention

[0006] In some embodiments, the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder (e.g., bipolar disorder Type I) without inducing significant sedation, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that results in a mean total dexmedetomidine exposure of about 3800 ng·h / L, as measured by plasma AUC T0-T∞.

[0007] In some embodiments, the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that results in a mean total dexmedetomidine exposure of about 1800 ng·h / L, as measured by plasma AUC T0-T∞.

[0008] In some embodiments, the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that results in a total dexmedetomidine exposure of about 600 ng·h / L to about 12,600 ng·h / L, as measured by plasma AUC T0-T∞.

[0009] In some embodiments, the disclosure provides a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that results in a total dexmedetomidine exposure of about 590 ng·h / L to about 8750 ng·h / L, as measured by plasma AUC T0-T∞.

[0010] The present disclosure also provides a method of treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, a booster dose of 90 μg or 60 μg may be taken two hours after the initial dose.

[0011] The present disclosure further provides a method of treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In another embodiment, a booster dose of 90 μg or 60 μg may be taken 2 hours after the initial dose.

[0012] In some embodiments, the present disclosure provides for sublingual administration of about 180 μg of dexmedetomidine hydrochloride as a single dose to a human subject, which administration results in a substantially lower systemic exposure level of dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

[0013] In some embodiments, the present disclosure provides for sublingual administration of about 120 μg of dexmedetomidine hydrochloride as a single dose to a human subject, which administration results in substantially lower systemic exposure levels of dexmedetomidine than administration of PRECEDEX® at its highest approved dose, as measured by comparative Cmax and AUC values.

[0014] Lower systemic exposure reduces the risk of hypotension and / or respiratory depression commonly encountered when administering effective doses of PRECEDEX®.

[0015] In some embodiments, sublingual administration of about 180 μg of dexmedetomidine hydrochloride as a single dose results in an approximately 3-fold decrease in Cmax compared to administration of PRECEDEX®. In some embodiments, such sublingual administration results in an approximately 7.5-fold decrease in AUC compared to administration of PRECEDEX®. In one particular embodiment, administration of a sublingual film containing about 180 μg of dexmedetomidine hydrochloride to a human subject results in an approximately 3-fold decrease in Cmax and an approximately 7.5-fold decrease in AUC compared to administration of PRECEDEX®.

[0016] In some embodiments, the disclosure provides for sublingual or buccal administration of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, which administration results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 400 ng / L and AUC T0-T∞ of about 2900 ng·h / L.

[0017] In some embodiments, the disclosure provides for sublingual or buccal administration of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, which administration results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 220 ng / L and AUC T0-T∞ of about 1420 ng·h / L.

[0018] In some embodiments, the disclosure provides for sublingual or buccal administration of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, which administration results in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L.

[0019] In some embodiments, the disclosure provides for sublingual or buccal administration of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, which administration results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L.

[0020] The present disclosure also provides a method of treating agitation or symptoms of agitation in a human subject with dementia without inducing significant sedation, the method comprising administering about 30 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject with dementia without inducing significant sedation, the method comprising administering 30 μg, 60 μg, or 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single daily dose. In some embodiments, the present disclosure provides a method for treating agitation or symptoms of agitation in a human subject with dementia without inducing significant sedation, the method comprising oromucosal administration of a unit dose containing about 30 μg to about 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof 1 to 6 times daily at intervals of at least 2 hours (e.g., 2, 4, 6, 8, or 12 hours) upon the onset of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) is administered oromucosally (e.g., sublingually or bucally) as a film.

[0021] The present disclosure provides a method for shortening opioid withdrawal in a human subject in need of opioid withdrawal, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily to the subject, wherein the withdrawal period is up to 14 days. In some embodiments, the withdrawal period can be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In another embodiment, the human subject is an adult (at least 18 years of age). In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (i.e., sublingually, buccally), orally, intranasally, or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally at a dose range of about 30 μg to about 200 μg. In specific embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered twice daily in a unit dose containing about 30 μg, about 60 μg, about 90 μg, 120 μg, or 180 μg. In some embodiments, the opioid may be selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil / carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil / butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene), thebaine, sufentanil, or pentazocine.

[0022] The present disclosure also provides a method for managing or treating agitation in a delirious subject without inducing significant sedation, comprising administering about 20 μg to about 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized in an intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered in a unit dose containing about 20 μg or 60 μg as a single dose. In some embodiments, each dosage unit can be administered one to four times with an appropriate dosing interval (e.g., at least 0.5 hours) to produce the desired effect, for example, four 20 μg units administered at 0.5 hour dosing intervals within six hours of the first dose to produce the effect of an 80 μg dose, or four 60 μg units administered at 0.5 hour dosing intervals within six hours of the first dose to produce the effect of a 240 μg dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g., sublingually or bucally) as a film.

[0023] The present disclosure also provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder Type I), and in some embodiments, the patient has both schizophrenia and a bipolar disorder (e.g., bipolar disorder Type I).

[0024] In some embodiments, the disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 180 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder I), and in some embodiments, the patient has both schizophrenia and a bipolar disorder (e.g., bipolar disorder I).

[0025] The present disclosure also provides methods for treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder I), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar disorder I).

[0026] The present disclosure also provides a method for treating or ameliorating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years of age and the withdrawal period is up to 14 days. "Opioid withdrawal" refers to a variety of symptoms and complaints that occur with the sudden removal or rapid reduction of a normal opioid dosage. Physical symptoms may include sweating, nausea, yawning, chills, diarrhea, nipple swelling, piloerection, tachycardia, elevated blood pressure, hyperalgesia, stomach cramps, and muscle spasms. Observed psychological symptoms of opioid withdrawal may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. Onset often begins within 6 to 24 hours of the last opioid use. In some embodiments, treatment or amelioration of opioid withdrawal refers to treatment or reduction of one or more of the aforementioned symptoms. Treatment or amelioration may be measured by various means known in the art, including, but not limited to, the Clinical Opiate Withdrawal Scale (COWS) and / or the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) score.

[0027] The present disclosure also provides pharmaceutical compositions comprising about 20 μg to about 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 μg. In some embodiments, the dose of dexmedetomidine is about 180 μg.

[0028] The present disclosure also provides methods for achieving a 40% or greater reduction in agitation within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, agitation is reduced within about 20 minutes to about 1 hour, e.g., within about 20 minutes, about 30 minutes, or about 40 minutes. In some embodiments, agitation is reduced by 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, or 100% or greater. In some embodiments, agitation reduction is maintained for more than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0029] The present disclosure also provides a method for achieving a sustained reduction in PEC score of agitation in a subject with bipolar disorder or schizophrenia, comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg, wherein the PEC score reduction is about -8 to about -10 and lasts for about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the duration is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the PEC score reduction is about -8, about -9, or about -10.

[0030] The present disclosure also provides a method for achieving an improvement in ACES score over a sustained period in a subject with bipolar disorder or schizophrenia, comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg, wherein the improvement in ACES score is about 3 to about 4 and lasts for about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the duration is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the ACES score is about 4.

[0031] The present disclosure also provides a method for achieving a sustained improvement in CGI-I score in a subject with bipolar disorder or schizophrenia, comprising administering to the subject a pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 120 mcg to about 180 mcg, wherein the CGI-I score improvement is about 1 (very improved) or about 2 (much improved), and the duration of the improvement is about 2 hours to about 6 hours. In some embodiments, the composition comprises dexmedetomidine hydrochloride. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 mcg. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 mcg. In some embodiments, the duration is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the CGI-I score is about 1. [Brief explanation of the drawings]

[0032] [Figure 1] 1 shows the mean change from baseline in PEC total score in patients with schizophrenia (intent-to-treat population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 2]1 shows the percentage of responders in PEC total score over time in patients with schizophrenia (intent-to-treat population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 3] Figure 1 shows the resolution of agitation, as measured by achieving an ACES score of at least 4, over time in schizophrenia patients (intention-to-treat population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. Error bars in the figure represent "standard error." The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 4] Figure 1 shows the percentage of responders in CGI-I scores over time in patients with schizophrenia (intent-to-treat population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. Error bars in the figure represent "standard error." The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1, and the preparation of dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 5A] 1 shows mean plasma dexmedetomidine concentrations (semi-logarithmic scale) versus nominal time sorted by dosing and re-dosing in patients with schizophrenia (pharmacokinetic population) treated with sublingual films containing dexmedetomidine hydrochloride (20 μg, 20 μg (re-dosing), 60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 5B]1 shows mean plasma dexmedetomidine concentrations versus nominal time sorted by dosing and re-dosing (linear scale) in schizophrenia patients (pharmacokinetic population) treated with sublingual films containing dexmedetomidine hydrochloride (20 μg, 20 μg (re-dosing), 60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (20 μg and 60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 6A] 1 shows mean resting systolic blood pressure (SBP) values ​​over time in schizophrenia patients (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 6B] 1 shows mean resting diastolic blood pressure (DBP) values ​​over time in schizophrenia patients (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 6C] 1 shows mean resting heart rate (HR) values ​​over time in schizophrenia patients (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 7A]1 shows the mean change from baseline in resting systolic blood pressure (SBP) over time in patients with schizophrenia (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 7B] 1 shows the mean change from baseline over time in resting diastolic blood pressure (DBP) in patients with schizophrenia (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual films (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 7C] 1 shows the mean change from baseline in resting heart rate (HR) over time in patients with schizophrenia (safety population) treated with sublingual films containing dexmedetomidine hydrochloride (60 μg, 80 μg, 120 μg, and 180 μg) compared to a placebo group. The preparation of dexmedetomidine hydrochloride sublingual film (60 μg) is exemplified in Example 1, and dexmedetomidine hydrochloride sublingual films (80 μg, 120 μg, and 180 μg) is exemplified in Example 2. [Figure 8] 1 shows the mean plasma dexmedetomidine log concentration (semi-log scale) over time for 10 μg, 20 μg, and 40 μg dose levels of dexmedetomidine sublingual films. Error bars represent 1 standard deviation. [Figure 9A] 1 shows individual dexmedetomidine concentration-time profiles (semi-logarithmic scale) for all subjects by dose following administration of dexmedetomidine sublingual film (10 μg), as exemplified in Example 1. [Figure 9B]1 shows individual dexmedetomidine concentration-time profiles (semi-logarithmic scale) for all subjects by dose following administration of dexmedetomidine sublingual film (20 μg), which is exemplified in Example 1. [Figure 9C] 1 shows individual dexmedetomidine concentration-time profiles (semi-logarithmic scale) for all subjects by dose following administration of dexmedetomidine sublingual film (40 μg). The preparation of dexmedetomidine sublingual film is exemplified in Example 1. [Figure 10] 1 shows the mean VAS / S scores versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, 40 μg) and placebo. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 11] 1 shows standing systolic blood pressure versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, 40 μg) and placebo. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 12] Figure 1 shows supine systolic blood pressure versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, and 40 μg) and placebo. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 13] 1 shows standing diastolic blood pressure versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, and 40 μg) and placebo. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 14] Figure 1 shows supine diastolic blood pressure versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, and 40 μg) and placebo. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 15] Pulse rate versus nominal time after administration of dexmedetomidine sublingual films (10 μg, 20 μg, and 40 μg) and placebo is shown. The preparation of dexmedetomidine sublingual films (10 μg and 20 μg) and dexmedetomidine sublingual film (40 μg) is exemplified in Example 1. [Figure 16] The proportion (percentage) of schizophrenic patients who achieved a RASS of −1 in the treatment group (intravenous dexmedetomidine hydrochloride treatment group) compared to the placebo group is shown. [Figure 17] 1 shows the mean PEC score reduction over time in patients with schizophrenia in the treatment group (intravenous dexmedetomidine hydrochloride treatment group) compared to the placebo group. [Figure 18] 1 shows the maximum dose of intravenous dexmedetomidine hydrochloride administered to patients with schizophrenia for the treatment of agitation. [Figure 19] 1 shows the total intravenous dose of dexmedetomidine hydrochloride administered to patients with schizophrenia for the treatment of agitation. [Figure 20] 1 shows mean plasma concentrations (pg / ml) over time in schizophrenic patients treated with dexmedetomidine hydrochloride. [Figure 21A] 1 shows the change from baseline in PEC score in patients with schizophrenia up to 2 hours after administration of 120 μg and 180 μg dexmedetomidine sublingual thin film (as exemplified in Example 2) compared to placebo. [Figure 21B] 1 shows the change from baseline in PEC scores in patients with schizophrenia up to 6 hours after administration of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo. [Figure 22] FIG. 1 shows improvement in calmness in patients with schizophrenia at 2 and 4 hours after administration of 120 μg dexmedetomidine (center bar) and 180 μg dexmedetomidine (right bar) sublingual films (as exemplified in Example 2) compared to placebo (left bar), as measured by the Agitation and Calmness Evaluation Scale (ACES). [Figure 23] FIG. 1 shows the percent response in schizophrenia patients at 30, 60, 120, and 240 minutes after administration of 120 μg dexmedetomidine (center bar) and 180 μg dexmedetomidine (right bar) sublingual films (as exemplified in Example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI). [Figure 24A] 1 shows the change from baseline in PEC scores in bipolar patients up to 2 hours after administration of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo. [Figure 24B] 1 shows the change from baseline in PEC scores in bipolar patients up to 6 hours after administration of 120 μg and 180 μg dexmedetomidine sublingual film (as exemplified in Example 2) compared to placebo. [Figure 25] FIG. 1 shows improvement in calming in bipolar patients at 2 and 4 hours after administration of 120 μg dexmedetomidine (center bar) and 180 μg dexmedetomidine (right bar) sublingual films (as exemplified in Example 2) compared to placebo (left bar), as measured by the Agitation-Calmness Scale (ACES). [Figure 26] FIG. 1 shows the percent response in bipolar patients at 30, 60, 120, and 240 minutes after administration of 120 μg dexmedetomidine (center bar) and 180 μg dexmedetomidine (right bar) sublingual films (as exemplified in Example 2) compared to placebo (left bar), as measured by Clinical Global Impression-Improvement (CGI). DETAILED DESCRIPTION OF THE INVENTION

[0033] Abbreviation: ACES: Agitation-Sedation Scale AD: Alzheimer's disease AE: adverse event AUC: Area under the curve AUClast: area under the curve calculated up to the last observable time point AUC0-Inf: Area under the plasma concentration-time curve from the time of administration to infinity BID: Twice a day BMI: Body Mass Index CGI-I: Clinical Global Impression-Improvement CGI-S: Clinical Global Impression-Severity Cmax: maximum plasma concentration COWS: Clinical Opiate Withdrawal Scale CMAI: Cohen-Mansfield Agitation Inventory CMC: Carboxymethyl cellulose C-SSRS: Columbia-Suicide Severity Rating Scale CT: Computed tomography CTCAE: Common Terminology Criteria for Adverse Events DBP: diastolic blood pressure Dex or DEX: dexmedetomidine DLB: Dementia with Lewy bodies DLT: Dose-limiting toxicity DSM: Diagnostic and Statistical Manual of Mental Disorders DT: Disintegration Time ECG: electrocardiogram FTD: Frontotemporal disease HPC: Hydroxypropyl cellulose HPMC: Hydroxypropyl methylcellulose HR: Heart rate ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICU-Intensive Care Unit IUD: Intrauterine device IPD: Inpatient Department ITT: Intention-to-treat population LAR: Legally Authorized Representative LSM: least squares means LS: least squares MedDRA: Drug Regulatory Information MMRM: Repeated Measures Mixed Models MMSE: Mini-Mental State Examination MRI: Magnetic Resonance Imaging MW: molecular weight mm: millimeters mcg: microgram mg: milligram μg: microgram ml: milliliter mmHG: millimeters of mercury msec: milliseconds ng: nanogram OPD:Outpatient Department PANSS: Positive and Negative Symptom Scale PAS: Pittsburgh Agitation Scale PCRS: Placebo-Controlled Reminder Script PEC:PANSS excitement items PEO: Polyethylene oxide PD: Pharmacodynamic PK: Pharmacokinetics PVA: Polyvinyl alcohol QTcF: QT interval corrected for heart rate using Fridericia's formula QID: 4 times a day RASS: Richmond Agitation-Sedation Scale SAE: Serious Adverse Event, SOWS-Gossop: Gossop Short-Term Opiate Withdrawal Scale SAP: Statistical Analysis Plan SBP: systolic blood pressure SD=standard deviation SE=standard error SL: sublingual T 1 / 2 :Elimination half-life TEAE: Treatment-emergent adverse event Tmax: Time to reach maximum plasma concentration Wt%: weight percent ULN: upper limit of normality VAS: Visual Analogue Scale YMRS: Young Mania Rating Scale

[0034] Definition: As used herein, "about" means ±10% of the indicated numerical value.

[0035] The terms "formulation" and "composition" are used interchangeably unless different meanings are expressly intended.

[0036] Throughout this specification, numerical ranges are provided for certain specific quantities. These ranges should be understood to include all subranges within that range. Thus, a range of "50 to 80" includes all possible ranges within that range (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, all values ​​within a given range may be endpoints of the ranges included within that range (e.g., a range of 50 to 80 includes ranges with endpoints such as 55 to 80, 50 to 75, etc.).

[0037] The term "a" or "an" refers to one or more of that entity. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. In addition, a reference to "an agent" with the indefinite article "a" or "an" does not exclude the possibility that more than one agent is present, unless the context clearly dictates that only one agent is present.

[0038] As used herein, the verb "comprise" and variations thereof as used in the description and claims are used in their open-ended sense, meaning that the items following the word are included, but not the exclusion of items not expressly mentioned. The present disclosure may suitably "comprise," "consist of," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0039] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inactive substance used as a carrier. As used herein, the terms "carrier" and "excipient" are used interchangeably unless a different meaning is clearly intended otherwise.

[0040] The term "agitation" as used herein refers to irritability, emotional outbursts, disordered thinking, or excessive motor and verbal activity that can result from either dysfunction of certain areas of the brain, such as the frontal lobe, or dysfunction of neurotransmitter systems, such as dopamine and norepinephrine. In the present invention, agitation also includes aggression and hyperarousal in post-traumatic stress disorder. Agitation can be acute or chronic.

[0041] The term "signs of agitation" includes excessive motor activity (e.g., pacing, rocking, gesturing, pointing, restlessness, repetitive speech and behavior), verbal aggression (e.g., yelling, speaking excessively loudly, using profanity, screaming, yelling, threatening others), physical aggression (e.g., grabbing, shoving, shoving, clenching hands into fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things), and destruction of property.

[0042] Terms such as "without significant sedation" mean that the patient experiences a level of sedation not exceeding level 3 on the Ramsay Sedation Scale, meaning sedated but responsive to commands. In some embodiments, dexmedetomidine may be administered to achieve a Richmond Agitation-Sedation Scale (RASS) of -1 ("mild sedation").

[0043] The term "soluble" as used herein refers to a film that readily disintegrates within at least about 20 minutes after administration to, for example, the cavity mucosa. Disintegration is accomplished by saliva and / or other aqueous substances on the mucosal surface.

[0044] The term "neuropsychiatric condition" includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium, or other related neuropsychiatric conditions.

[0045] The term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect. An effective amount is sufficient to cause improvement in a subject's condition (e.g., agitation).

[0046] As used herein, the terms "treating" and "treatment" refer to curative therapy, prophylactic therapy, and / or preventative therapy, and can be used interchangeably.

[0047] The term "significantly reduced" refers to a reduction level of at least 10% or more, preferably 20% or more, more preferably 40% or more, even more preferably 60% or more, still more preferably 80% or more, and even more preferably 90% or more compared to a control. For example, in the context of agitation, one skilled in the art will readily understand that the reduction can be measured in terms of well-known agitation scales, such as the PEC score and CGI-I (described in more detail in the Examples). As an example, when a patient's agitation is significantly reduced, the reduction can be interpreted as one who achieves at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more reduction in the PEC total score from baseline (e.g., measured 2 hours after administration). In some embodiments, significantly reduced agitation refers to a reduction in the PEC total score from baseline of at least 40%. Similarly, a significant reduction in agitation may be measured on the CGI-I scale and may refer to patients having a score of 1 or 2 on the CGI-I scale (e.g., measured at 1, 2, or 4 hours after administration), or may be measured on the Agitation Calming Scale (ACES) scale and may refer to patients having a score of 3 or greater.

[0048] The term "pharmaceutically acceptable salt" refers to salts that are known to be non-toxic and are commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid, and the like. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxylalkanedioc acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like may also be used. A preferred salt is the hydrochloride salt.

[0049] The term "film" as used herein includes thin films, sheets, and wafers of any shape, including rectangular, square, or other desirable shapes. The film may be of any desired thickness and size so that it can be conveniently placed under the patient's tongue. For example, the film may be a relatively thin film having a thickness of about 20 micrometers to about 200 micrometers, or a somewhat thicker film having a thickness of about 20 micrometers to about 1000 micrometers. In certain embodiments, the film may be even thicker, for example, having a thickness of greater than about 30 millimeters.

[0050] As used herein, the phrase "water-soluble polymer" refers to (i) a polymer that is at least partially soluble in water, and desirably completely or predominantly soluble in water, and / or (ii) a polymer that absorbs water. Polymers that absorb water are referred to herein as water-swellable polymers.

[0051] The term "self-supporting" is used herein to mean a film that maintains its structural integrity during handling without the need for a support layer. Some flexibility in the film is contemplated, and may be desirable.

[0052] As used herein, the phrase "disposed in a polymer matrix" means that the dexmedetomidine or a pharmaceutically acceptable salt thereof is incorporated directly into the polymer solution prior to forming the solid polymer matrix film composition.

[0053] As used herein, the phrase "deposited on the surface of a polymer matrix" means that, separate from the preparation of a solid polymer matrix, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a liquid composition and deposited, for example, as one or more microdeposits, on the solid polymer, where it dries. This dried product is sometimes referred to herein as a "microdeposited matrix film." The drug liquid formulation may be in any form, including a solution, emulsion, suspension, or dispersion.

[0054] The term "intranasal administration" refers to administration by the nasal route, whereby the drug is inhaled through the nose. This administration can be either local or systemic, meaning that locally delivered drugs can act to exert either a purely local effect or a systemic effect.

[0055] The term "parenteral" refers to the administration of a drug by injection beneath one or more layers of the skin or mucus, and can include, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular injection.

[0056] The term "percentage of treatment responders" is defined as subjects who exhibit a PEC score reduction of approximately 40% at 2 hours.

[0057] The term "clinically significant cardiovascular effect" as used herein means a decrease in blood pressure (hypotension) and / or a decrease in heart rate (bradycardia) to an extent that medical intervention is required to address the cardiovascular side effect, where "medical intervention" means an intervention more significant than administering a fluid such as an energy drink.

[0058] I. Active Agent Dexmedetomidine has the IUPAC name (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As the hydrochloride salt, dexmedetomidine is primarily used as a drug to sedate patients during treatment in intensive care settings or to sedate patients before and / or during surgical and other procedures. The drug is currently sold under the trademark name "PRECEDEX."

[0059] Pharmaceutically acceptable salts of dexmedetomidine that may be used herein generally include any suitable salt that has been or may be approved for human administration by the U.S. FDA or other appropriate agency within or outside the United States. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrogensulfuric acid, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, etc. In another embodiment, a deuterated form of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

[0060] II. Dosage In some embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be conveniently within the range of about 0.5 μg to about 1200 μg, depending on factors such as the route of administration. Examples of suitable dosages include about 0.5 μg to about 1200 μg, about 0.5 μg to about 500 μg, about 0.5 μg to about 450 μg, about 0.5 μg to about 405 μg, about 0.5 μg to about 360 μg, about 0.5 μg to about 270 μg, about 0.5 μg to about 180 μg, and about 0.5 μg to about 120 μg. This dose may be administered to a subject one or more times daily (including two, three, four, five, or six times daily).

[0061] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered in a unit dose of about 10 μg to about 300 μg of the total pharmaceutical composition weight, e.g., about 10 μg to about 270 μg, about 20 μg to about 240 μg, about 30 μg to about 180 μg, about 40 μg to about 140 μg, about 60 μg to about 120 μg, about 70 μg to about 100 μg, or about 80 μg to about 100 μg. These doses may be provided in one or more units to deliver the total dose. Examples of suitable doses include 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, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, and about 250 μg.

[0062] In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered to the oral mucosa (e.g., sublingually or bucally) in a unit dose of about 10 μg to about 300 μg of the total sublingual film composition weight, e.g., about 10 μg to about 270 μg, about 20 μg to about 240 μg, about 30 μg to about 180 μg, about 40 μg to about 140 μg, about 50 μg to about 120 μg, about 60 μg to about 120 μg, about 70 μg to about 100 μg, or about 80 μg to about 100 μg. These doses may be provided in one or more units to deliver the total dose. Examples of suitable doses include 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, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, and about 250 μg.

[0063] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered in a unit dose of about 120 μg to about 405 μg, e.g., about 120 μg to about 270 μg (including about 120 μg and about 180 μg) of total pharmaceutical composition weight. These doses can be provided in one or more units to deliver the total dose. Examples of suitable doses include about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 300, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 455, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about Examples include about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, and about 405 μg.

[0064] In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to the oral mucosa (e.g., sublingually or bucally) in a unit dose of about 120 μg to about 405 μg, for example, about 120 μg to about 270 μg, inclusive, of the total sublingual film composition weight. These doses can be provided in one or more units to deliver the total dose. Examples of suitable doses include about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, Examples include about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, and about 405 μg.

[0065] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be orally administered in a dose of about 500 μg to about 1500 μg, e.g., about 900 μg to about 1200 μg, based on the total oral composition weight. These doses may be provided in one or more units to deliver the total dose. Examples of suitable doses include about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, and about 760. , about 770, about 780, about 790, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, about 900, about 910, about 920, about 930, about 940, about 950, about 960, about 970, about 980, about 990, about 1000, about 1010, about 1020, about 1030, about 1040, About 1050, about 1060, about 1070, about 1080, about 1090, about 1100, about 1110, about 1120, about 1130, about 1140, about 1150, about 1160, about 1170, about 1180, about 1190, about 1200, about 1210, about 1220, about 1230, about 1240, about 1250, about 1260, about 1270, about 1280, about 1 about 1400, about 1410, about 1410, about 1420, about 1430, about 1440, about 1450, about 1460, about 1470, about 1480, about 1490, and about 1500 μg.

[0066] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered intramuscularly at a dose of about 100 μg to about 200 μg, e.g., about 120 μg to about 190 μg, based on the total intramuscular injection weight. Examples of suitable doses include about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, and about 200 μg.

[0067] Exemplary dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof administered to a particular patient will depend on the type and severity of the condition, the general health of the particular patient, the particular form of dexmedetomidine or a pharmaceutically acceptable salt thereof being administered, and the particular formulation used to treat the patient.

[0068] III. Pharmaceutical Compositions According to the present disclosure, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to a human subject via a variety of routes, including oromucosal (e.g., sublingual, buccal), oral, parenteral, etc. Suitable formulations for use according to the present disclosure are outlined below. Additional formulations suitable for use according to the present disclosure are described in US2020 / 0000717, which is incorporated herein by reference in its entirety for all purposes.

[0069] Oromucosal preparations (sublingual and / or buccal preparations) According to the present disclosure, dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated into dosage forms suitable for sublingual or buccal administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, etc. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.

[0070] Carriers suitable for inclusion in sublingual or buccal 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, emulsifiers, isotonic saline, pyrogen-free water, and combinations thereof. Carriers that are readily soluble in saliva may be preferred.

[0071] Sublingual or buccal formulations may also include other pharmaceutically acceptable carriers and / or excipients, such as binders, lubricants, diluents, coating agents, disintegrants, barrier layer components, glidants, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, and mixtures thereof. Certain excipients that may be used in accordance with the present disclosure are known in the art and are described, for example, in Handbook of Pharmaceutical Excipients (2005, 5th ed., edited by Rowe et al., McGraw Hill).

[0072] film Films suitable for sublingual or buccal administration (i.e., oromucosal administration) according to the present disclosure comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within a polymer matrix or (ii) deposited on the surface of a polymer matrix, e.g., on the surface of a "placebo" film.

[0073] Polymer components of the film The polymer component consists of one or more water-soluble polymers in the film matrix and / or as part of a drug-containing deposit (e.g., one or more droplets) on the surface of the polymer. In some embodiments of the present disclosure, the polymer component consists of a single water-soluble polymer. In some embodiments, the polymer component consists of two or more water-soluble polymers, including two or more of the same water-soluble polymers with different molecular weights.

[0074] The polymer component in the film matrix is ​​of suitable composition and present in an amount sufficient to ensure rapid disintegration of the film matrix in the oral mucosa. For example, the presence of the polymer component may enable the film matrix to completely disintegrate in the oral mucosa in about 15 seconds to about 180 seconds, e.g., about 30 seconds to about 180 seconds (including about 120 seconds). The polymer component in the film matrix also provides sufficient strength to the film (i.e., the film is self-supporting).

[0075] When present in one or more droplets of the dexmedetomidine composition deposited on the surface of a polymer matrix / substrate, the polymer component may comprise, for example, the water-soluble polymer hydroxypropyl cellulose; however, different water-soluble polymers are also contemplated, as described in the definitions of "first water-soluble polymer" and "second water-soluble polymer" herein below. For example, the polymer component may comprise one, two, or three hydroxypropyl celluloses having different molecular weights. The molecular weights of the different hydroxypropyl celluloses can conveniently range from (i) less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons), (ii) from about 90,000 daltons to about 200,000 daltons, and (iii) from about 200,000 daltons to about 500,000 daltons. Two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve a desired droplet viscosity. The viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer equipped with a small sample adapter at a temperature of 25°C and can range from about 5 cps to about 3700 cps. For example, the viscosity can range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps, or about 6 cps to about 50 cps. In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition solution or suspension is about 6 cps to about 20 cps at 25°C and a shear rate of about 7 (1 / s).

[0076] When present in a monolithic (i.e., placebo or drug-containing) film, the polymer component may consist of, for example, one water-soluble polymer or two different water-soluble polymers. When two different water-soluble polymers are present, one of the water-soluble polymers may comprise the same polymer but with different molecular weights present in the polymer component. For example, the polymer component may consist of one, two, or three hydroxypropyl celluloses having different molecular weights, although different water-soluble polymers are also contemplated, as described in the definitions of "first water-soluble polymer" and "second water-soluble polymer" herein below, such as polyethylene oxide. The molecular weights of the different hydroxypropyl celluloses can conveniently range from (i) less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons), (ii) from about 90,000 daltons to about 200,000 daltons, and (iii) from about 200,000 daltons to about 500,000 daltons (e.g., from about 300,000 daltons to about 450,000 daltons). Two or more hydroxypropyl celluloses (e.g., low molecular weight hydroxypropyl cellulose and high molecular weight hydroxypropyl cellulose) can be mixed in any suitable ratio to achieve the desired film properties. When present in a monolithic (i.e., placebo- or drug-containing) film or microdeposited film matrix composition, the polymer component can advantageously consist of one or more water-soluble polymers having a molecular weight of less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), and / or about 90,000 daltons to about 200,000 daltons, and / or about 200,000 daltons to about 500,000 daltons (e.g., about 300,000 daltons to about 450,000 daltons). When a structurally different water-soluble polymer is also present, that polymer can advantageously have a higher molecular weight, e.g., a molecular weight greater than about 500,000 daltons.

[0077] In some embodiments, the present disclosure provides pharmaceutical film compositions 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., from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0078] In some embodiments, the present disclosure provides pharmaceutical film compositions consisting essentially of (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., from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0079] In some embodiments, the present disclosure provides pharmaceutical film compositions comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component comprising a first water-soluble polymer having a molecular weight of less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight greater than about 60,000 daltons; and, optionally, (iii) one or more pharmaceutically acceptable carriers.

[0080] Examples of the one or more first water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, methyl cellulose, and mixtures thereof (including mixtures of the same polymer with different molecular weights).

[0081] Exemplary one or more second water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof (including mixtures of the same polymer with different molecular weights). Polyethylene oxide (PEO) may also be present herein as a second water-soluble polymer, or may be present in the pharmaceutical film composition as an example of a pharmaceutically acceptable carrier, or more specifically, as a mucoadhesive, as described separately herein below.

[0082] In one embodiment, the weight ratio of the first water-soluble polymer to the second water-soluble polymer(s) (including PEO, if present in the film) in the total film composition is from about 2:1 to about 1:50, e.g., from about 1:1 to about 1:40 (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 1:1 about 1:3, 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, about 1:39, and about 1:40).

[0083] In further embodiments, the weight ratio of the first water-soluble polymer to the second water-soluble polymer(s) (including PEO, if present in the film) in the total 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 from about 1:15 to about 1:20 provides beneficial functional effects.

[0084] Examples of other water-soluble polymers that can be included in the film along with the first / second water-soluble polymer or can replace such polymer(s) 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, carboxymethylcellulose, sodium alginate, chitosan, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, starch, carrageenan, gelatin, and mixtures thereof. The water-soluble polymer component (including the water-soluble polymer carrier, if present) can conveniently comprise from about 40% to about 99.8%, from about 50% to about 99.7%, or from about 60% to about 99.6% of the film composition, based on the weight of the film on a dry weight basis.

[0085] In some embodiments, the polymer component of the film composition may include a first water-soluble polymer present in an amount of about 2% to about 15% by dry weight of the polymer component (e.g., about 3% to about 8% by weight of the total film). The water-soluble polymer may conveniently have a molecular weight of about 5,000 Daltons to about 49,000 Daltons. Examples of suitable such water-soluble polymers include polymers selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

[0086] In some embodiments, the low molecular weight hydroxypropyl cellulose may be present in the film at about 3 w / w% to about 8 w / w% of the total film weight.

[0087] In some embodiments, the one or more second water-soluble polymers (including water-soluble polymer carriers such as polyethylene oxide) can be present in an amount of, for example, about 50 to about 98 weight percent based on the dry weight of the polymer component. The one or more second water-soluble polymers each have a molecular weight greater than 60,000 daltons, for example, about 90,000 daltons to about 1,500,000 daltons, particularly when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

[0088] In some embodiments, when the one or more second water-soluble polymers each have a molecular weight of about 90,000 Daltons to about 200,000 Daltons and / or about 200,000 Daltons to about 500,000 Daltons, and the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof, the one or more second water-soluble polymers may collectively be present in the film at about 25 wt% to about 40 wt% of the total film weight.

[0089] In some embodiments, polyethylene oxide may be present in the film from about 50 w / w% to about 60 w / w% of the total film weight.

[0090] In one embodiment, the polymer component of the film composition comprises a low molecular weight water-soluble polymer (e.g., having a molecular weight less than about 60,000 daltons) and one or more high molecular weight polymers (e.g., having a molecular weight greater than about 60,000 daltons, up to about 1,500,000 daltons if polyethylene oxide is included in the polymer mixture, or up to about 500,000 daltons if polyethylene oxide is not included in the polymer mixture). This polymer combination, particularly when the polymer is a combination of hydroxypropyl cellulose and polyethylene oxide, provides certain advantages in the tensile strength and pharmacokinetics of the film composition.

[0091] In some embodiments, the present disclosure provides: (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; (iii) one or more pharmaceutically acceptable carriers.

[0092] In one embodiment, the present disclosure provides: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a polymer component consisting of: (a) one or more first water-soluble polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof) having a molecular weight of about 5,000 daltons to about 49,000 daltons, e.g., about 2 to about 15 weight percent of the total polymer component on a dry weight basis; and (b) one or more second water-soluble polymers (e.g., polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and mixtures thereof) having a molecular weight of greater than 60,000 daltons, e.g., greater than 100,000 daltons, e.g., about 50 to about 98 weight percent of the total polymer component on a dry weight basis; (iii) one or more pharmaceutically acceptable carriers.

[0093] When hydroxypropyl cellulose is present in the films of the present disclosure, its molecular weight may vary and it may be present as both a low molecular weight water-soluble polymer and one or more high molecular weight water-soluble polymers. In some embodiments, its molecular weight may be less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons). In other embodiments, its molecular weight may be in the range of from about 90,000 daltons to about 200,000 daltons. In still other embodiments, its molecular weight may be in the range of from about 200,000 daltons to about 500,000 daltons.

[0094] When hydroxypropyl cellulose is part of a film composition that includes polyethylene oxide, it may conveniently be present in a range of from about 10% to about 90% by weight based on the dry weight of the polymer component, such as from about 20% to about 80% by weight based on the dry weight of the polymer component, such as from about 20% to about 50% by weight based on the dry weight of the polymer component, for example, from about 25% to about 45% by weight based on the dry weight of the polymer component.

[0095] When polyethylene oxide is present in the films of the present disclosure, its molecular weight may also vary. In some embodiments, high molecular weight water-soluble polyethylene oxide may be used, for example, to improve the mucoadhesiveness of the film. In certain embodiments, the molecular weight may range from about 100,000 daltons to about 1,500,000 daltons, including about 100,000, 200,000, 300,000, 600,000, 900,000, or 1,000,000 daltons. In some embodiments, it may be desirable to use a combination of polyethylene oxide having a molecular weight of about 600,000 daltons to about 900,000 daltons and polyethylene oxide having a molecular weight of about 100,000 daltons to about 300,000 daltons in the polymer component.

[0096] When polyethylene oxide is part of the film composition, it may conveniently be present in a range of from about 30% to about 90% by weight based on the dry weight of the total polymer components, e.g., from about 40% to about 85% by weight based on the dry weight of the polymer components, e.g., from about 55% to about 80% by weight based on the dry weight of the polymer components.

[0097] Such film compositions may include a drug dispersed throughout the film or microdeposited on the surface of the film, which, when microdeposited on the surface of a "placebo" film, may conveniently be added as part of a dexmedetomidine composition as one or more droplets in a liquid carrier, e.g., a solvent (e.g., an alcohol such as ethanol), optionally together with one or more (e.g., two) water-soluble polymers and / or a pharmaceutically acceptable carrier. Suitable water-soluble polymers include (1) low molecular weight water-soluble polymers, e.g., low molecular weight water-soluble polymers having a molecular weight of less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons), and, optionally, (2) one or more (e.g., one or two) high molecular weight water-soluble polymers, e.g., high molecular weight water-soluble polymers having a molecular weight of greater than about 60,000 daltons (e.g., from about 60,000 daltons to about 150,000 daltons, e.g., hydroxypropyl cellulose (77,000 MW), hydroxypropyl cellulose (80,000 MW), hydroxypropyl cellulose (90,000 MW), or hydroxypropyl cellulose (140,000 MW)), and / or about Included are high molecular weight water-soluble polymers having a molecular weight of greater than 60,000 daltons (e.g., a molecular weight of about 200,000 daltons to about 900,000 daltons, e.g., hydroxypropyl cellulose (340,000 MW), hydroxypropyl cellulose (370,000 MW), polyethylene oxide (200,000 MW), or polyethylene oxide (600,000 MW)). Each water-soluble polymer can be independently selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide, and methyl cellulose (e.g., hydroxypropyl cellulose and / or polyethylene oxide).

[0098] In some embodiments, the dexmedetomidine composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer that is hydroxypropyl cellulose, and one or two high molecular weight polymers, each hydroxypropyl cellulose, in an ethanol solvent.

[0099] In one embodiment, the dexmedetomidine composition includes dexmedetomidine or a pharmaceutically acceptable salt (e.g., dexmedetomidine hydrochloride), hydroxypropyl cellulose (40,000 MW), and one or both of hydroxypropyl cellulose (140,000 MW) and hydroxypropyl cellulose (370,000 MW).

[0100] In another embodiment, the dexmedetomidine composition includes dexmedetomidine or a pharmaceutically acceptable salt (e.g., dexmedetomidine hydrochloride) and only two hydroxypropyl celluloses: hydroxypropyl cellulose (40,000 MW) and hydroxypropyl cellulose (140,000 MW).

[0101] In some embodiments, the deposition composition may be in any form, including a solution, emulsion, suspension, or dispersion. For example, the dexmedetomidine composition may be applied as one or more droplets in an ethanol-based solution, optionally containing a pH neutralizer such as sodium hydroxide. In some embodiments, the film substrate surface comprises two or more microdeposition spots (e.g., two microdeposition spots) in a polymer matrix. The viscosity of the deposition solution / suspension may range from about 6 cps to about 3700 cps, measured at 25°C using a Brookfield viscometer equipped with a small sample adapter. By way of example, the viscosity may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps, or about 6 cps to about 50 cps.

[0102] In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition is about 6 cps to about 20 cps at 25° C. and a shear rate of about 7 (1 / s).

[0103] After drying to remove the solvent, the film comprises a film substrate (e.g., placebo) having deposited (e.g., microdeposited) on the surface of the film substrate the dexmedetomidine composition described above, but without the solvent. The dry composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) can cover the entire film substrate surface or only a portion of the film substrate surface.

[0104] In some embodiments, the dried dexmedetomidine composition appears as one or more discrete drug-containing droplets on the surface of the film substrate. Alternatively, stenciling can be used to obtain one or more defined, discrete regions having the drug-containing composition on the surface of the film substrate.

[0105] In some embodiments, the present disclosure provides a dry film product comprising a film substrate having one or more discrete drug-containing droplets on the film substrate surface, wherein each of the drug-containing droplets comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and two molecular weights of hydroxypropyl cellulose: hydroxypropyl cellulose (40,000 MW) available as HPC-SSL and hydroxypropyl cellulose (140,000 MW) commercially available under the trade name Klucel™ Type JF NF; and the film substrate comprises three molecular weights of hydroxypropyl cellulose: hydroxypropyl cellulose (40,000 MW) commercially available under the trade name Klucel™ Type GF NF, hydroxypropyl cellulose (140,000 MW), and hydroxypropyl cellulose (370,000 MW). In some embodiments, the film substrate also comprises polyethylene oxide (600,000 MW) available under the trade name Sentry Polyox WSR 205 LEO NF.

[0106] In some embodiments, the dry film product comprises a deposition composition (also referred to herein as a “dexmedetomidine composition”) comprising: (i) dexmedetomidine hydrochloride present at about 9% to about 50% w / w of the deposition composition, e.g., about 15% to about 25% w / w of the deposition composition; (ii) hydroxypropyl cellulose (40,000 MW) present at about 5% to about 85% w / w of the deposition composition; (iii) hydroxypropyl cellulose (140,000 MW) present at about 5% to 85% w / w of the deposition composition; and (iv) hydroxypropyl cellulose (370,000 MW) present at about 0% to about 65% w / w of the deposition composition. The film also includes a polymer matrix comprising: (i) hydroxypropyl cellulose (40,000 MW) present at about 3% to about 40% w / w of the polymer matrix; (ii) hydroxypropyl cellulose (140,000 MW) present at about 3% to about 40% w / w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 MW) present at about 0% to about 30% w / w of the polymer matrix; and (iv) polyethylene oxide (600,000 MW) present at about 55% to about 75% w / w of the polymer matrix.

[0107] In some embodiments, the dry film product (e.g., a microdeposited film product) comprises: (i) dexmedetomidine hydrochloride present at about 1% to about 50% w / w of the total film weight; (ii) hydroxypropyl cellulose (40,000 MW) present at about 2% to about 30% w / w of the total film weight; (iii) hydroxypropyl cellulose (140,000 MW) present at about 2% to about 30% w / w of the total film weight; (iv) hydroxypropyl cellulose (370,000 MW) present at about 10% to about 50% w / w of the total film weight; (v) polyethylene oxide (600,000 MW) present at about 40% to about 75% w / w of the total film weight; and (vi) optionally, other pharmaceutically acceptable carriers.

[0108] In some embodiments, the films disclosed herein combine several types of hydroxypropyl cellulose (HPC) to provide the film with beneficial properties. For example, a film composition may include a combination of two or three of hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000 MW), and hydroxypropyl cellulose (370,000 MW). In certain embodiments, polyethylene oxide (600,000 MW) is included with these types of HPC when part of a monolithic film.

[0109] In certain film compositions of the present disclosure, low molecular weight hydroxypropyl cellulose (e.g., 40,000 MW) is present at about 3% to about 8% (e.g., about 5%) of the total film weight, high molecular weight hydroxypropyl cellulose (e.g., 140,000 MW) is present at about 3% to about 8% (e.g., about 5%) of the total film weight, high molecular weight hydroxypropyl cellulose (e.g., 370,000 MW) is present at about 20% to about 40% (e.g., about 5%) of the total film weight, and polyethylene oxide (e.g., 600,000 MW) is present at about 40% to about 70% (e.g., about 50% to about 60%) of the total film weight. In some embodiments, these two high molecular weight water-soluble polymers are present together at about 25% to about 40% (e.g., about 5%) of the total film weight.

[0110] The selection and ratio of water-soluble polymers can be determined so that the film composition completely dissolves in oral mucus within a few seconds to a few minutes, for example, about 0.25 to about 15 minutes, thereby ensuring delivery of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa. For example, the film composition may remain in the sublingual or buccal region of the oral cavity for up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes, including from about 30 seconds to about 15 minutes, from about 1 minute to about 10 minutes, or from about 1 minute to about 5 minutes.

[0111] Standard basket or paddle apparatus as described in any pharmacopoeia can be used for in vitro dissolution testing. The choice of dissolution medium will essentially depend on the sinking conditions and maximum dose of the drug. The dissolution medium should be maintained at a temperature of 37±0.5°C and 50 rpm (see Bala et al., Int J Pharm Investigation, vol. 3(2), pages 67-76).

[0112] The films disclosed herein have several functional advantages that promote rapid onset of drug effect. In some embodiments, the thin film compositions of the present disclosure, when applied sublingually or bucally, have a disintegration time (DT) of about 15 seconds to about 180 seconds, about 15 seconds to about 160 seconds, about 25 seconds to about 150 seconds, about 15 seconds to about 140 seconds, about 15 seconds to about 120 seconds, about 40 seconds to about 120 seconds, about 50 seconds to about 120 seconds, e.g., about 120 seconds. A disintegration time within this time frame provides optimal onset of drug effect.

[0113] In some embodiments, the thin film compositions of the present invention possess mucoadhesive properties that provide the practical benefit of localizing the film in a sublingual location and effectively reducing or preventing pre-dissolution peeling. This property is particularly beneficial in clinical settings involving agitated subjects. Thus, in some embodiments, the thin film compositions have a mucoadhesion (mucoadhesive strength or shear strength) of about 50 g or greater, about 100 g or greater, about 200 g or greater, about 300 g or greater, about 400 g or greater, about 500 g or greater, about 600 g or greater, about 700 g or greater, about 800 g or greater, about 900 g or greater, or about 1000 g or greater. In some embodiments, the mucoadhesion is within the range of about 300 g to about 4000 g, about 500 g to about 3000 g, or about 1000 g to about 2000 g.

[0114] The burst strength of the film also contributes to drug delivery. Certain thin film compositions of the present invention have a burst strength of 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800 g, 1900 g, 2000 g, 2100 g, 2200 g, 2300 g, 2400 g, 2500 g, 2600 g, 2700 g, 2800 g, 2900 g, 3000 g, 3100 g, 3200 g, 3300 g, 3400 g, 3500 g, 3600 g, 3700 g, 3800 g, 3900 g, 4000 g, 4100 g, 4200 g, 4300 g, 4400 g, 4500 g, 4600 g, 4700 g, 4800 g, 4900 g, 5000 g, 5100 g, 5200 g, 5300 g, 5400 g, 5500 g, 5600 g, 5700 g, 5800 g, 5900 g, 6000 g, 6100 g, 6200 g, 6300 g, 6400 g, 6500 g, 6600 g, 6700 g, 6800 g, 6900 g, 7000 g The burst strength may be 2,500 g, 3,000 g, 3,500 g, 4,000 g, 4,500 g, 5,000 g, 5,500 g, 6,000 g, 6,500 g, 7,000 g, 7,500 g, 8,000 g, 8,500 g, 9,000 g, 9,500 g, 10,000 g, or 15,000 g or more. For example, the burst strength may be within the range of about 200 g to about 15,000 g, about 300 g to about 10,000 g, or 400 g to about 5,000 g.

[0115] Pharmaceutically acceptable carrier The film composition may further comprise one or more pharmaceutically acceptable carriers, including, but not limited to, liquid carriers, flavoring agents, sweeteners, cooling agents, antioxidants, pH adjusters, permeation enhancers, mucoadhesives, plasticizers, bulking agents, surfactants / nonionic solubilizers, stabilizers, antifoaming agents, colorants, etc. In certain embodiments, the film composition is substantially free of acidic buffers or other acidic agents.

[0116] Liquid Carrier According to some embodiments, the pharmaceutically acceptable carrier includes a liquid carrier. The liquid carrier includes a polymer matrix (drug-containing or placebo) and one or more solvents useful in preparing a deposition composition on the polymer matrix. In some embodiments, the solvent can be water. In some embodiments, the solvent can be a polar organic solvent, including, but not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol, and mixtures thereof. In some embodiments, the solvent can be a nonpolar organic solvent, such as methylene chloride, toluene, ethyl acetate, and mixtures thereof. Particular solvents are alcohols, particularly ethanol, water, and mixtures thereof. Desirably, the solvent content in the wet polymer matrix is ​​at least about 30% by weight of the total wet weight of the total film composition before drying. The subsequently dried film composition will desirably contain less than about 10% by weight of solvent, more desirably less than about 8% by weight of solvent, even more desirably less than about 6% by weight of solvent, and most desirably less than about 2% by weight of solvent.

[0117] Flavorings / Sweeteners / Cooling Agents It may be beneficial to add sweeteners, flavoring agents, cooling agents, taste-masking agents, or combinations thereof to the film composition to improve the taste of the film composition. The flavoring agent may be selected from natural flavor liquids and synthetic flavor liquids. An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavor fragrances, flavor oils, flavor liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. Non-limiting flavor oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedarwood oil, nutmeg oil, sage oil, and almond oil. In one embodiment, the flavoring agent is peppermint oil flavoring, available as peppermint oil (NF).

[0118] The amount may be varied to achieve the desired result in the final product. Such variations are within the ability of one skilled in the art without undue experimentation. Generally, an amount of about 0.1% to about 30% by weight of the film may be used to provide flavor. Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, for example, water-soluble sweeteners, such as monosaccharides, disaccharides, and polysaccharides, such as xylose, ribulose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and dihydrochalcones; water-soluble artificial sweeteners, such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamates; and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as chlorinated derivatives of sugar (sucrose), such as those known as sucralose. In one embodiment, the sweetener is sucralose.

[0119] Flavoring agents, sweeteners, and cooling agents may be added in conventional amounts, generally in a maximum total amount of from about 0.01% to about 10% of the film weight on a dry weight basis, e.g., from about 0.1% to about 7% of the film weight on a dry weight basis, e.g., from about 0.1% to about 5% of the film weight on a dry weight basis.

[0120] Other taste-masking agents include, for example, polymers, oils, or waxes. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is coated with a taste-masking agent before the film composition is formulated. In some embodiments, when a taste-masking agent is used to coat the active ingredient, the taste-masking agent may be present in an amount of about 5% to about 80% by weight of the particles or granules containing the active ingredient. In another embodiment, the taste-masking agent is present in an amount of about 25% to about 35% by weight of the particles or granules containing the active ingredient.

[0121] antioxidants Examples of oxygen scavengers or antioxidants that substantially improve the long-term stability of the film composition against oxidative degradation include sulfites, such as sodium sulfite, sodium bisulfite, sodium metabisulfite, and similar salts of potassium and calcium. A suitable amount of sulfite (e.g., sodium sulfite) is up to about 5% by weight of the film composition on a dry weight basis, e.g., from about 0.001% to about 2%.

[0122] pH adjuster / pH neutralizer Absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa may be increased in an alkaline microenvironment. For example, this absorption may be achieved when the film composition is maintained at a pH greater than 6, between about 6 and about 9, or between about 6.5 and about 8. In some embodiments, the film may contain an alkaline substance that increases the pH of the film product. Non-limiting examples of pH adjusters / pH neutralizers include bicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassium citrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodium lactate), acetates (e.g., calcium acetate), alkaline buffers (e.g., glycine), sodium hydroxide, sodium chloride, and the like. An alkaline buffer such as glycine is an example of a pH neutralizer. Suitable amounts of pH adjusters / pH neutralizers present in the film composition include, for example, up to about 10% by weight of the film composition on a dry weight basis, e.g., between about 1% and about 5%.

[0123] Permeation enhancers Certain effective permeation enhancers for facilitating the absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa include alcohols. An alcohol permeation enhancer, such as butanol, can be conveniently added to the film composition in an amount of up to about 10%, e.g., about 0.1% to about 5%, e.g., about 1% to about 3%, based on the weight of the film composition on a dry weight basis.

[0124] Mucoadhesive Examples of mucoadhesives that can be added to the film composition include, but are not limited to, sodium alginate, sodium carboxymethylcellulose, guar gum, polyethylene oxide, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, karaya gum, methylcellulose, retene, tragacanth, etc. One mucoadhesive is polyethylene oxide, which can be conveniently added to the film composition in an amount of about 20% to about 90%, e.g., about 40% to about 70%, based on the total film composition weight on a dry weight basis.

[0125] plasticizer Plasticizers that can be effectively used herein include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate, and glycerol. Depending on the film-forming polymer(s) selected and other components of the film formulation, a suitable amount of plasticizer included in the film composition can typically be up to about 10% by weight of the film on a dry weight basis, e.g., about 0.1% to about 5%, e.g., about 0.5% to about 5%. For certain applications, higher molecular weight polyethylene glycols, including polyethylene oxide, can be utilized.

[0126] Filler: Suitable fillers that can be added to the film composition include starch, calcium salts such as calcium carbonate, sugars such as lactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose, trehalose, and combinations thereof. The amount of filler that can be conveniently added to the film formulation is typically up to about 25%, e.g., about 0.5% to about 20%, e.g., about 1% to about 15%, e.g., about 2% to about 10%, based on the weight of the film composition on a dry weight basis.

[0127] Surfactants / Nonionic Solubilizers The film typically incorporates at least one surfactant / nonionic solubilizer, including, but not limited to, poloxamer, polyoxyl hydrogenated castor oil, glyceryl oxystearate polyethylene glycol, fatty acid glyceryl polyglyceryl esters, polyglyceryl esters, and combinations thereof. The amount of surfactant(s) that can be added to the film composition is typically up to about 5%, e.g., about 0.5% to about 3%, e.g., about 1% to about 3%, based on the film composition weight on a dry weight basis.

[0128] Antifoaming ingredient Simethicone is one example of a useful antifoaming and / or defoaming agent, although other antifoaming and / or defoaming agents may also be suitable. The antifoaming and / or defoaming agent, such as simethicone, may be added to the film composition in an amount of from about 0.01% to about 5.0%, more preferably from about 0.05% to about 2.5%, and most preferably from about 0.1% to about 1.0%, based on the weight of the film composition on a dry weight basis.

[0129] coloring agent Color additives that can be included in the film composition include Food, Drug, and Cosmetic Colors (FD&C), Drug and Cosmetic Colors (D&C), or External Drug and Cosmetic Colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain naturally occurring colorants. Specific examples of color additives are inorganic pigments, such as iron oxide or titanium oxide, added at concentrations ranging from about 0.001% to about 10%, e.g., about 0.01% to about 3%, based on the weight of the film composition on a dry weight basis. In one embodiment, the color used in the dexmedetomidine composition (i.e., the deposition composition) is different from the color used in the film substrate (e.g., the placebo film). One of the colors of the monolith film and film substrate of the microdeposition film is emerald green, available as Fast Emerald Green Shade (06507). One of the colors of the dexmedetomidine composition (i.e., the deposition composition) is a color different from the color of the film substrate, e.g., blue (available as FD&C Blue 1). In some embodiments of the film embodiments of the present invention, for example, as described in the aspects and embodiments above, the film comprises about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, comprising two blue microdeposited specks of dexmedetomidine hydrochloride on a green film substrate.

[0130] In some embodiments of the film embodiments of the present invention, for example, as described in the aspects and embodiments above, the film comprises about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0131] In one embodiment (A), there is provided a self-supporting dissolvable film, (i) about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide, and optionally, (iv) one or more pharmaceutically acceptable carriers.

[0132] In another embodiment (B), there is provided a self-supporting dissolvable film, (i) about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide, and optionally, (iv) one or more pharmaceutically acceptable carriers.

[0133] In certain embodiments, the one or more water-soluble polymers (ii) of the immediately preceding embodiment (A) or (B) above comprise a low molecular weight water-soluble polymer and two high molecular weight water-soluble polymers, e.g., the low molecular weight water-soluble polymer has a molecular weight of about 5,000 daltons to about 49,000 daltons (e.g., about 40,000 daltons), and the high molecular weight water-soluble polymers each have a molecular weight greater than about 60,000 daltons (e.g., one of the two high molecular weight water-soluble polymers has a molecular weight of about 140,000 daltons and the other high molecular weight water-soluble polymer has a molecular weight of about 370,000 daltons). Each of the water-soluble polymers is, in some embodiments, hydroxypropyl cellulose. The polyethylene oxide, in some embodiments, has a molecular weight of about 600,000 daltons.

[0134] In certain embodiments, a pharmaceutical film composition is provided comprising, or consisting essentially of, a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more excipients selected from polyethylene oxide, hydroxypropyl cellulose, sucralose, peppermint oil, emerald green colorant, and FD&C blue colorant.

[0135] In another embodiment (C), there is provided a self-supporting dissolvable film, (i) about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt); (ii) a low molecular weight water-soluble polymer having a molecular weight of about 40,000 daltons; (iii) a high molecular weight water-soluble polymer having a molecular weight from about 140,000 daltons; (iv) a high molecular weight water-soluble polymer having a molecular weight from about 370,000 daltons; (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 daltons.

[0136] In another embodiment (D), there is provided a self-supporting dissolvable film, (i) about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride); (ii) a low molecular weight water-soluble polymer having a molecular weight of about 40,000 daltons; (iii) a high molecular weight water-soluble polymer having a molecular weight from about 140,000 daltons; (iv) a high molecular weight water-soluble polymer having a molecular weight from about 370,000 daltons; (v) a water-soluble polyethylene oxide having a molecular weight of about 600,000 daltons.

[0137] In certain embodiments of the films of embodiments (C) and (D) just mentioned, the film components, excluding dexmedetomidine or a pharmaceutically acceptable salt thereof, form a monolayer film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate (e.g., in a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight water-soluble polymer having a molecular weight of about 40,000 daltons, and a high molecular weight water-soluble polymer having a molecular weight of about 140,000 daltons). Each of the water-soluble polymers, in some embodiments, is hydroxypropyl cellulose.

[0138] In another embodiment (E), there is provided a self-supporting dissolvable film, (a) a composition comprising: (i) about 180 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided in which the composition of part (a) resides on the surface of the film substrate (b).

[0139] In another embodiment (F), there is provided a self-supporting dissolvable film, (a) a composition comprising: (i) about 120 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided in which the composition of part (a) resides on the surface of the film substrate (b).

[0140] In particular embodiments of the films of embodiments (E) and (F) just mentioned, dexmedetomidine hydrochloride is present at about 0.1 w / w% to about 2 w / w% of the total film weight, hydroxypropyl cellulose (40,000 MW) is present at about 4 w / w% to about 8 w / w% of the total film weight, hydroxypropyl cellulose (140,000 MW) is present at about 4 w / w% to about 8 w / w% of the total film weight, hydroxypropyl cellulose (370,000 MW) is present at about 25 w / w% to about 30 w / w% of the total film weight, and polyethylene oxide (600,000 MW) is present at about 50 w / w% to about 60 w / w% of the total film weight.

[0141] In some embodiments, the pharmaceutical compositions of the present disclosure provide a detectable human plasma dexmedetomidine concentration, C, following single and multiple dose administration of the pharmaceutical composition of the present disclosure. max In some embodiments, the pharmaceutical composition of the present disclosure has a time to reach a dexmedetomidine plasma concentration in humans, T max In some embodiments, the pharmaceutical compositions of the present disclosure provide a detectable area under the curve (AUC) of dexmedetomidine and its metabolite concentrations in human plasma after single dose administration or multiple dose administration. In some embodiments, the AUC of dexmedetomidine (or its metabolite) is measured from time 0 (time of administration) to time 0 through 12 hours, and the AUC 0-12h In some embodiments, the AUC of dexmedetomidine (or its metabolite) is measured from time 0 (time of administration) to 24 hours from time 0, and is expressed as AUC 0-24h In some embodiments, the AUC of dexmedetomidine (or its metabolite) is measured from time 0 to the last measurable concentration, and is expressed as AUC 0-last In some embodiments, the AUC of dexmedetomidine (or its metabolite) is measured from time 0 (the time of administration) to a time extrapolated to infinity, and expressed as AUC 0-Inf In some embodiments, the AUC of dexmedetomidine (or its metabolite) 0-last and AUC0-Inf The range and value of AUC of dexmedetomidine (or its metabolites) 0-6h Thus, in some embodiments, the AUC 0-6h The range and value of AUC 0-last and AUC 0-inf It can also serve as a range and value of

[0142] In some embodiments, oral mucosal (e.g., sublingual or buccal) administration of a film (E) containing about 180 μg of dexmedetomidine hydrochloride to a subject with schizophrenia results in a C of about 100 ng / L to about 800 ng / L. max , T of about 1 hour to about 8 hours max , and AUC of approximately 500 h·ng / L to approximately 8900 h·ng / L last In some embodiments, the pharmacokinetic parameters were about 80% to about 125% of those of the C max is about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 300n g / L, about 325ng / L, about 350ng / L, about 375ng / L, about 400ng / L, about 425ng / L, about 450ng / L, and 475ng / L, about 500ng / L, about 525ng / L, about 5 In some embodiments, the T is 50 ng / L, about 575 ng / L, about 600 ng / L, about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L. maxis approximately 0.8 hours, approximately 0.9 hours, approximately 1 hour, approximately 1.25 hours, approximately 1.5 hours, approximately 1.75 hours, approximately 2.0 hours, approximately 2.25 hours, approximately 2.5 hours, approximately 2.75 hours, approximately 3.0 hours, approximately 3.25 hours, approximately 3.5 hours, approximately 3.75 hours, approximately 4.0 hours, approximately 4.25 hours, approximately 4.5 hours, approximately 4.75 hours, approximately 5.0 hours, approximately 5.25 hours , about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours, or about 10 hours. In some embodiments, the AUC lastis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, Approximately 2750 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 425 0 hours ng / L, approximately 4500 hours ng / L, approximately 4750 hours ng / L, approximately 5000 hours ng / L, approximately 5250 hours ng / L, approximately 5500 hours ng / L, approximately 5750 hours ng / L g / L, approximately 6000 hours ng / L, approximately 6250 hours ng / L, approximately 6500 hours ng / L, approximately 6750 hours ng / L, approximately 7000 hours ng / L, approximately 7250 hours ng / L, Approximately 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L, approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 h·ng / L, about 9250 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L, or about 11875 h·ng / L. In some embodiments, the film is administered sublingually.

[0143] In some embodiments, oral mucosal (e.g., sublingual or buccal) administration of a film (F) containing about 120 μg of dexmedetomidine hydrochloride to a subject with schizophrenia results in a C of about 110 ng / L to about 400 ng / L. max , about 1 hour to about 4 hours T max , and AUC of approximately 500 h·ng / L to approximately 4200 h·ng / L last In some embodiments, the pharmacokinetic parameters were about 80% to about 125% of those of the C maxis about 80 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, and 475 ng / L, or about 500 ng / L. max is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, or about 5.0 hours. In some embodiments, AUC last is approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, about 2750 h·ng / L, about 3000 h·ng / L, about 3250 h·ng / L, about 3500 h·ng / L, about 3750 h·ng / L, about 4000 h·ng / L, about 4250 h·ng / L, about 4500 h·ng / L, about 4750 h·ng / L, about 5000 h·ng / L, about 5250 h·ng / L, or about 5500 h·ng / L. In a specific embodiment, the film is administered sublingually.

[0144] In some embodiments, the present disclosure provides a pharmaceutical buccal composition comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive polymers, and optional excipients selected from one or more of a plasticizer, a penetration enhancer, a colorant, a sweetener, a flavoring agent, a taste-masking agent, or a saliva stimulator. The mucoadhesive polymer may be selected from hydrophilic polymers and hydrogels. Examples of hydrophilic polymers include polyvinyl alcohol (PVA), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, and hydroxypropylcellulose (HPC). Examples of hydrogels include cationic polymers such as carbopol, polyacrylates, and chitosan, and nonionic polymers such as Eudragit analogs.

[0145] Spray, drops, or gel In some embodiments, the present disclosure provides pharmaceutical spray or drop compositions suitable for sublingual or buccal administration, comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable liquids (about 1% to about 99.995% by weight). Such liquids can be solvents, cosolvents, or nonsolvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerin, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.), and the like. The pharmaceutically acceptable liquid is selected to dissolve dexmedetomidine or a pharmaceutically acceptable salt thereof, to produce a stable, homogeneous suspension thereof, or to form any combination of a suspension or solution. In addition to these ingredients, spray or drop formulations of dexmedetomidine or a pharmaceutically acceptable salt thereof may contain one or more excipients, such as viscosity-adjusting materials (e.g., polymers, sugars, sugar alcohols, gums, clays, silicas, etc., e.g., polyvinylpyrrolidone (PVP)), preservatives (e.g., ethanol, benzyl alcohol, propylparaben, and methylparaben), flavorings (e.g., peppermint oil), sweeteners (sugars, e.g., sucrose, glucose, dextrose, maltose, fructose, etc.), 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), colorants, fragrances, chelating agents (e.g., EDTA), ultraviolet absorbers, and antifoaming agents (e.g., low molecular weight alcohols, dimethicone).In addition to one or more of the aforementioned ingredients suitable for sublingual or buccal sprays or drops, gel formulations of dexmedetomidine or a pharmaceutically acceptable salt thereof may include one or more excipients, for example, viscosity-adjusting materials (e.g., water-soluble or water-swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, etc.).

[0146] Sprays, drops, and gels can be made by mixing appropriate amounts of the aforementioned ingredients according to standard good manufacturing practices. Such excipients can be included in the formulation to improve patient or subject taste acceptance, improve bioavailability, extend shelf life, reduce manufacturing and packaging costs, comply with government regulatory agency requirements, and for other purposes. The relative amounts of each ingredient should not interfere with the desired pharmacological and pharmacokinetic properties of the resulting formulation.

[0147] In some embodiments, an oromucosal spray composition is provided that comprises or consists essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0148] In one embodiment, patients may be treated by sublingual or buccal administration with one to two actuations from a spray pump. The advantage of spray delivery is the ability to easily titrate one or two doses to the patient as needed with a single actuation.

[0149] Pump-action sprayers are characterized by the need for the application of external pressure, e.g., external manual, mechanical, or electrically initiated, to actuate, in contrast to pressurized systems, e.g., propellant-driven aerosol sprayers, where actuation is typically achieved by the controlled release of pressure, e.g., by the controlled opening of a valve.

[0150] Various sublingual spray formulations containing dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and the excipients listed in Table 1. [Table 1]

[0151] Various sublingual drop compositions containing dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and excipients as listed in Table 2. [Table 2]

[0152] Various sublingual gel compositions comprising dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and excipients as listed in Table 3. [Table 3]

[0153] tablet In some embodiments, the present disclosure provides tablet formulations suitable for oral mucosal administration (e.g., sublingual or buccal administration) comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine 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 vehicles. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerin, N-methylpyrrolidone, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, etc.), and the like. Taste-masking agents include, for example, Amberlite, Opadry® AMB TAN, polymethacrylates (especially Eudragit® L100), sodium starch glycolate (Primojel), Carbopol polymer, PEG-5M, sodium acetate, ethylcellulose, and betacyclodextrin. Flavoring agents can be, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, and saccharin. Disintegrants include, for example, sodium starch glycolate, low-substituted hydroxypropyl cellulose, alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, guar gum, methylcellulose, polacrilin potassium, poloxamer, and sodium alginate. Diluents can be, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, or maltitol. Binders can be, for example, alginic acid, carbomer, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, methyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, or sodium alginate. At least one lubricant can be advantageously incorporated into the formulation to prevent powder from adhering to the tablet punch during the compression procedure.Lubricants can be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate. Glidants are used to promote powder flow by reducing interparticle friction and cohesion. Because they do not have the ability to reduce die wall friction, they are used in combination with lubricants. Glidants can be, for example, colloidal silicon dioxide, calcium silicate, and tribasic calcium phosphate.

[0154] Various buccal tablet formulations containing dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and the excipients listed in Table 4. [Table 4]

[0155] Various sublingual tablet compositions comprising dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 60 μg, 90 μg, 120 μg, and 180 μg and the excipients listed in Table 5. [Table 5]

[0156] Intranasal preparations The compositions of the present disclosure can be administered to the nasal cavity in any suitable form, for example, they can be administered to the nasal cavity in the form of a spray emulsion, suspension, or solution, as drops, or as a powder.

[0157] Powder blends according to the present disclosure can be prepared by mixing dexmedetomidine or a pharmaceutically acceptable salt thereof with inactive ingredients standard in the art. Such inactive ingredients include, but are not limited to, diluents such as calcium phosphate, lactose, sugars such as dextrose and sucrose, polyols such as mannitol and sorbitol, and microcrystalline cellulose, glidants such as colloidal silica, and lubricants such as magnesium stearate and hydrogenated vegetable oils, as well as surfactants such as polysorbates and polyethylene glycol. While a pestle and mortar and / or sieve may be suitable for small-scale preparation of a uniform powder blend, a mechanical mixer is required for larger-scale production. Many types of mixers are available, and these are extensively described in the literature, for example, in Chapter 37, Remington: The Science and Practice of Pharmacy, 20th Edition, Lipincott, Williams and Wilkins, Baltimore, 2000.

[0158] When the powder composition of the present disclosure comprises granules, these granules can be manufactured by techniques well known to those skilled in the art, such as wet granulation, dry granulation (slugging), extrusion / spheronization, fluidized bed granulation, and spray congealing. Further details about granulation processes can be found in the literature, for example, Chapter 6, Pharmaceutical Principles of Solid Dosage Forms, JT Carstensen, Technomic, Lancaster, PA, 1993.

[0159] In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, other ingredients may be incorporated into the granules. Such other ingredients include, but are not limited to, diluents such as calcium phosphate, lactose, dextrose, mannitol, and microcrystalline cellulose; binders such as povidone (polyvinylpyrrolidone), methylcellulose, polyethylene glycol, gelatin, and acacia; disintegrants such as starch, croscarmellose, and crospovidone; glidants such as colloidal silica; and lubricants such as magnesium stearate and hydrogenated vegetable oil. Methods for preparing microspheres are well known to those skilled in the art, and include, but are not limited to, spray drying, interfacial polymerization, coacervation / phase separation, and solvent evaporation. Methods for producing microspheres are described, for example, in the Physicochemical Principles of Microspheres (2002). of Pharmacy, 3rd Edition, pages 357 to 360, AT Florence and D Attwood, Macmillan, London, 1998, and Physical Pharmacy, 4th Edition, pages 516 to 519, A Martin, Wilkins and Wilkins, Baltimore, 1993. Alternatively, microspheres may be produced using the methods described in WO98 / 30207 and documents cited therein.

[0160] The powder compositions of the present disclosure may be administered to a subject in aerosolized form, whereby energy from the patient's inhalation (sniffing) is used to aerosolize the powder into the nasal cavity, or the device itself provides the aerosolization energy, such as with compressed air. An example of the former device is that manufactured by Pfeiffer, and an example of the latter is the "Monopowder" manufactured by Valois. The present invention also provides a nasal drug delivery device or dose cartridge for use with the nasal delivery device loaded with the above-described composition.

[0161] In one embodiment, the compositions of the present disclosure also disclose a process for preparing a solution of the present disclosure, comprising mixing the ingredients in a suitable solvent such as water, ethanol, propylene glycol, polyethylene glycol, glycofurol, benzyl benzoate, and polyoxyethylene castor oil derivatives. The compositions can be prepared using methods known in the art.

[0162] The solutions of the present disclosure may also contain other pharmaceutically acceptable ingredients known in the art, including, but not limited to, celluloses (e.g., hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and microcrystalline cellulose), carbomers, polyethylene oxides, poloxamers, or polyethylene glycols, antioxidants (e.g., sodium metabisulfite), chelating agents (such as edetic acid or one of its salts), preservatives (potassium sorbate, parabens, phenylethyl alcohol, or benzalkonium chloride), flavorings, sweeteners, thickeners, adhesives, or gelling agents (including, but not limited to, celluloses (e.g., hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxyl cellulose, and microcrystalline cellulose, poloxamers, polyethylene glycols, carbomers, or polyethylene oxides).

[0163] The solutions of the present disclosure may contain preservatives and / or be sterile. If preservatives are omitted from the compositions, microorganisms can be removed using any suitable method known in the art, for example, by rendering the compositions aseptic or by terminally sterilizing them. In some embodiments, the compositions of the present invention are non-pyrogenic.

[0164] In one embodiment, the intranasal composition of the present disclosure comprises an aqueous suspension, solution, or emulsion containing material in addition to the active ingredient, for example, suitable dispersing and / or wetting agents, such as propylene glycol or polyethylene glycol, emulsifying agents, suspending agents, surfactants, solubilizing agents, vehicles, and the like.

[0165] The pharmaceutical compositions may also be formulated as liposomes, microcapsules, or centrosomes together with one or more suitable pharmaceutically acceptable carriers.

[0166] In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, the microspheres used in the present disclosure may contain components known in the art to be suitable for inclusion in microspheres, such as, but not limited to, starch, dextran, gelatin, albumin, collagen, hyaluronic acid, chitosan, lactose, sucrose, dextrose, mannitol, methacrylate copolymers such as Eudragit® polymers (Degussa, Germany), celluloses such as methylcellulose, and polyesters such as poly(lactide-co-glycolide).

[0167] Any device suitable for intranasal administration can be used. In some embodiments, the device is a metered dose device. The metered dose device can deliver a specific dosage of the composition. The metered dose device can be a unit-dose, double-dose, or multi-dose device. The pharmaceutically effective amount that can be administered using the metered dose device can be a unit-dose device. In some embodiments, the metered dose can be a device capable of intranasally delivering the pharmaceutical composition. Examples of metered dose devices include, but are not limited to, pump devices, mechanical devices, pressurized devices, and / or electromechanical devices. Examples of metered dose devices include, but are not limited to, spray pumps, pre-compressed nasal spray pumps, metering valve devices, actuated spray devices, side-actuated spray devices, syringe nasal spray devices (e.g., syringes with atomizers for delivering the spray to the nasal cavity), mucosal spray devices, electromechanical pump devices (with or without counters), and the like. Examples of metered dose devices also include, but are not limited to, commercially available devices manufactured by Aptar Pharma (Congers, NY). Examples of metered dose devices include UDS (Aptar Pharma), BDS (Aptar Pharma), eDevices (Aptar Pharma), Equadel (Aptar Pharma), Latitude (Aptar Pharma), DF30 (Aptar Pharma), VP7 (Aptar Pharma), Classic Nasal Device (Aptar Pharma), and MAD Other examples include, but are not limited to, Nasal Drug Device (Wolf Tory Medical, Inc.), BD Accuspray SCF™ (Becton Dickinson), etc. Another example includes, but is not limited to, the Aptar Unitdose Intranasal System.

[0168] Parenteral formulations: Liquid pharmaceutical compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion can include, but are not limited to, intravenous, intraperitoneal, intramuscular, intrathecal, and subcutaneous. In some embodiments, parenteral formulations can include pre-filled syringes, vials, powders for injection for reconstitution, concentrates for injection (ready to be diluted) that are diluted before delivery, or solutions (ready to be used).

[0169] Injectable pharmaceutical compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.

[0170] The pharmaceutical compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances.

[0171] In certain embodiments, the pharmaceutical compositions of the present disclosure include biodegradable subcutaneous implants, osmotic control devices, subcutaneous implants, subcutaneous sustained-release injections, lipid nanoparticles, liposomes, etc. Liquid preparations may include, but are not limited to, solutions, suspensions, and emulsions. Such preparations are exemplified by water or water / propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration.

[0172] For intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient(s) are usually used, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solute(s) should be controlled to render the preparation isotonic.

[0173] The liquid vehicle used to prepare intramuscular injections can be, for example, water, saline solution, another aqueous liquid (aqueous solvent), or a non-aqueous liquid (non-aqueous solvent). Non-aqueous solvents can include organic solvents such as ethanol, isopropyl alcohol, diethylene glycol monoethyl ether, or other alkyl derivatives, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), or oily vehicles such as castor oil, arachis oil, sesame oil, or other solvents such as carboxymethylcellulose, polysorbates, and mixtures thereof. These aqueous and non-aqueous solvents can also function as cosolvents to increase the solubility of the drug or reduce the viscosity of the oily vehicle.

[0174] The formulation may contain excipients. Pharmaceutically acceptable excipients that may be included in the formulation include buffers such as citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer; amino acids; urea; alcohol; ascorbic acid; phospholipids; proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA and sodium chloride; liposomes; polyvinylpyrrolidone; sugars such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine; lipids; preservatives; suspending agents; stabilizers; and dyes. As used herein, the term "stabilizer" refers to a compound optionally used in the pharmaceutical composition of the present invention to avoid the need for sulfites and extend shelf life. Non-limiting examples of stabilizers include antioxidants. Buffer systems for use with the present formulation include citrate buffer, acetate buffer, bicarbonate buffer, and phosphate buffer.

[0175] The formulation may also include a non-ionic detergent, examples of which include, but are not limited to, Polysorbate 20, Polysorbate 80, Triton® X-100, Triton® X-114, Nonidet P-40, Octyl α-glucoside, Octyl β-glucoside, Brij 35, Pluronic, and Tween® 20.

[0176] The parenteral formulations of the present disclosure can be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacteria-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heat.

[0177] Administration of the above-described parenteral formulations can be by periodic injection of a bolus of the preparation, or by intravenous or intraperitoneal administration from an external reservoir (e.g., an intravenous solution bag) or an internal reservoir (e.g., a bioerodible implant, bioartificial, or organ). See, e.g., U.S. Pat. Nos. 4,407,957 and 5,798,113, each of which is incorporated herein by reference in its entirety. Pulmonary delivery methods and devices are described, for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and 5,814,607, each of which is incorporated herein by reference in its entirety. Other useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposome delivery, needle-delivered injections, needle-free injections, nebulizers, aerosolizers, electroporation, and transdermal patches. Needleless injector devices are described in U.S. Patent Nos. 5,879,327, 5,520,639, 5,846,233, and 5,704,911, the specifications of which are incorporated herein by reference in their entireties. Any of the formulations described herein can be administered using these methods. Additional injectable dexmedetomidine formulations are described in U.S. Patent Nos. 8,242,158, 9,649,296, Japanese Patent No. 5,921,928, Japanese Patent Application No. 2016154598, Chinese Patent Application No. 103284945, Chinese Patent Application No. 104161760, Chinese Patent Application No. 105168122, and Chinese Patent Application No. 105534891. No. 20170128421, Chinese Patent Application No. 107028880, Chinese Patent Application No. 107412152, Chinese Patent Application No. 108498469, European Patent No. 2252290, Japanese Patent Application No. 2019048091, and US Patent Application No. 20190183729.

[0178] In certain non-limiting embodiments, the dexmedetomidine intramuscular composition of the present disclosure comprises about 0.05 μg / mL to about 15 μg / mL of dexmedetomidine or a pharmaceutically acceptable salt thereof, sodium chloride at a concentration of about 0.01 to about 2.0 weight percent, and a pH within the range of about 1 to about 10.

[0179] Oral formulation: The present disclosure includes oral formulations that can be used to deliver dexmedetomidine. Examples of oral formulations include tablets, orally disintegrating tablets, orally dissolving tablets, wafers, solutions, suspensions, emulsions, and capsules.

[0180] The present disclosure encompasses orally disintegrating tablets comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one orally disintegrating carrier, wherein the orally disintegrating tablet disintegrates in about 0.5 to about 120 seconds and / or a therapeutically effective amount of dexmedetomidine is absorbed into the bloodstream within about 1 to about 5 minutes. In some embodiments, a therapeutically effective amount of dexmedetomidine is absorbed into the bloodstream within about 3 minutes.

[0181] In some embodiments, at least one orally disintegrating carrier is selected from the group consisting of water-soluble sugars or sugar alcohols, crospovidone, (low-substituted) hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate, microcrystalline cellulose, and combinations thereof. The water-soluble sugar or sugar alcohol is selected from the group consisting of sucrose, sorbitol, mannitol, xylitol, erythritol, isomalt, and fructose. In some embodiments, the orally disintegrating carriers together constitute at least 50% by weight, e.g., at least 80% by weight, or at least 85% by weight, of the orally disintegrating carrier. The aforementioned carriers are typically in the form of particles having a volume-weighted average particle size of 50 to 300 micrometers, e.g., 70 to 200 micrometers. F-Melt® (Fuji Chemical Industry Co.) is an example of a commercially available particulate material comprising a disintegrant dispersed in a matrix containing C4-C6 sugar alcohols (mannitol and xylitol). Ludiflash® (BASF) is another example of a commercially available particulate material that contains a disintegrant dispersed in a matrix of a C4-C6 sugar alcohol (mannitol).

[0182] The orally disintegrating tablets used herein can be prepared by mixing dexmedetomidine with a water-soluble diluent and compressed into a tablet. A suspension containing dexmedetomidine can be prepared using appropriate excipients, and the dexmedetomidine suspension can be dispensed into blister packs and freeze-dried. An exemplary freeze-drying preparation platform that can be used for dexmedetomidine ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. Specifically, excipients including water are blended, and dexmedetomidine is separately milled to a particle size and mixed with the excipients. The suspension is then freeze-dried by flash freezing and freeze-drying. Other methods of preparing ODT may be used, without limitation, and detailed descriptions of these general methods are found in, for example, U.S. Pat. Nos. 5,631,023, 5,837,287, 6,149,938, 6,212,791, 6,284,270, 6,316,029, 6,465,010, 6,471,992, 6,509, 040, 6,814,978, 6,908,626, 6,908,626, 6,982,251, 7,282,217, 7,425,341, 7,939,105, 7,993,674, 8,048,449, 8,127,516, 8,158,152, 8,221,480, 8,256,233, and 8,313,768.

[0183] The liquid pharmaceutical suspension of the present disclosure for oral administration comprises at least one particulate drug as an active ingredient, which is dexmedetomidine or a pharmaceutically acceptable salt thereof. While the particulate dexmedetomidine may be partially dissolved in the liquid phase, it should preferably be greater than about 50 percent particulate. The suspension of the present disclosure comprises at least one suspension polymer exhibiting plastic flow that provides a yield value of about 0.2 to about 15 Pa, preferably about 0.5 to about 10 Pa, with polymers exhibiting Bingham plastic flow and shear-thinning plastic flow being preferred. Polymers exhibiting thixotropic plastic flow can be used only if the lag time to recover 50% of the yield value is rapid, i.e., less than about 1 hour, preferably less than about 5 minutes, and most preferably less than about 1 minute. The polymer exhibiting plastic flow may be selected from, but is not limited to, xanthan gum, carbomer, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and combinations thereof. The final yield value of the suspension should be less than about 15 Pa, preferably less than about 10 Pa, to ensure that the product can be poured without shaking.

[0184] In addition to the yield value, the rheology of the final suspension should have an apparent viscosity of at least about 50 cps, preferably at least about 100 cps, and most preferably at least about 200 cps, at a shear rate of 100 s-1 to retard particle motion when the shear rate exceeds the yield value, such as during shaking or pouring. For thixotropic plastic flow, high viscosity retards particle motion, while the yield value is restored after shear is applied. If the suspension polymer(s) added to impart the yield value are insufficient to achieve the desired apparent viscosity of at least about 50 cps at a shear rate of 100 s-1, a viscosity-building agent without a yield value can be added. These viscosity-building agents may be selected from, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, guar gum, locust bean gum, and combinations thereof.

[0185] The liquid suspensions of the present disclosure may contain additional ingredients used in the pharmaceutical industry, referred to herein as excipients, including, but not limited to, well-known ingredients, flavorings, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH adjusters, acidifying agents, preservatives, cosolvents, and mixtures thereof.

[0186] The present disclosure also relates to a homogenous, stable pharmaceutical dexmedetomidine solution suitable for oral administration to a mammal.

[0187] The oral liquid pharmaceutical solution of the present disclosure comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from the group consisting of co-solvents, solvents, antioxidants, microbial preservatives, buffers, flavoring agents, sweeteners, and diluents.

[0188] Co-solvents and solvents may include, but are not limited to, glycerin, alcohol, propylene glycol, polyethylene glycol, benzyl alcohol, water, ethanol, isopropyl alcohol, or mixtures thereof.

[0189] Suitable antioxidants may include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycerol, cysteine, sodium thioglycolate, acetone sodium bisulfite, ascorbate (sodium / acid), sodium bisulfite, cysteine / cysteic acid HCl, sodium dithionite (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, monosodium glutamate, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, monothioglycerol (thioglycerol), propyl gallate, sodium sulfite, alpha-tocopherol, sodium thioglycolate, calcium and sodium EDTA compounds, or mixtures thereof.

[0190] Buffering agents may include, but are not limited to, ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate dehydrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, calcium carbonate phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide, or mixtures thereof.

[0191] Diluents may include, but are not limited to, maltitol solution, glucose syrup, glycerin, sorbitol and mannitol solution, sucrose, sorbitol, xylitol, dextrose, fructose, potassium saccharin, aspartame, saccharin sodium, spray dried or anhydrous lactose, mannitol, starch, or mixtures thereof.

[0192] Sweeteners may include, but are not limited to, sucralose, aspartame, acesulfame potassium, thaumatin, mogrosides, saccharin and their salts, sodium cyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol, lactitol, xylitol, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoammonium glycyrrhizinate, isomalt, glycerin, dextrose, or mixtures thereof.

[0193] Fragrances may include, but are not limited to, fruit fragrances such as orange, banana, strawberry, cherry, wild cherry, lemon, and other fragrances such as cardamom, anise, mint, menthol, vanillin, or mixtures thereof.

[0194] Microbial preservatives may include, but are not limited to, sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acid and its alkyl esters, methyl and propyl paraben, or mixtures thereof.

[0195] In one embodiment, the present disclosure relates to an oral solid pharmaceutical composition (e.g., in the form of a tablet) comprising a pharmacologically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The composition of the present disclosure includes additives conventional to the dosage form in question. Tableting aids commonly used in tablet formulations can be used; see the extensive literature on this subject, in particular Fiedler's "Lexikon der Hilfsstoffe" (4th ed., ECV Aulendorf, 1996), which is incorporated herein by reference. These include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, fillers or diluents, surfactants, and the like.

[0196] Disintegrants suitable for the compositions of the present disclosure include, among others, cross-linked PVP, crospovidone, guar gum, alginic acid, sodium alginate, cross-linked CMC, and Ac-Di-Sol®. In some embodiments, the disintegrant is crospovidone.

[0197] Suitable binders for the compositions of the present disclosure include, inter alia, starches, for example, potato starch, wheat starch, corn starch, celluloses such as microcrystalline cellulose, for example, products known under the trade names Avicel®, Filtrak®, Heweten®, or Pharmacel®, 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.

[0198] Suitable glidants for the compositions of the present disclosure can include colloidal silica, such as Aerosil®, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate, among others.

[0199] Suitable fillers or diluents for the compositions of the present invention include, inter alia, powdered sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, particularly those having a density of about 0.45 g / cm, e.g., Avicel®, or powdered cellulose, and talc.

[0200] A preferred filler may be Avicel®.

[0201] Suitable lubricants for the compositions of the present disclosure include magnesium stearate, aluminum stearate, or calcium stearate, polyethylene glycol (PEG) having a molecular weight of 4,000 to 8,000, and talc, among others.

[0202] One or more of these additives can be selected and used by those skilled in the art by routine experimentation and without any undue burden, taking into account the particular desired properties of the solid oral dosage form. The amount of each type of additive used, e.g., glidant, binder, disintegrant, filler or diluent, and lubricant, may vary within ranges conventional in the art. For example, the amount of glidant may vary within the range of 0.1 to 10% by weight, particularly 0.1 to 5% by weight, for example 0.1 to 0.5% by weight, the amount of binder may vary within the range of about 10 to 65.3% by weight, for example 10 to 45% by weight, for example 20 to 30% by weight, the amount of disintegrant may vary within the range of 5 to 60% by weight, for example 13 to 50% by weight, for example 15 to 40% by weight, for example 20 to 30% by weight, for example 25% by weight, the amount of filler or diluent may vary within the range of 15 to 65% by weight, for example 20 to 50%, for example 25 to 40% by weight, for example 30% by weight, and the amount of lubricant may vary within the range of 0.1 to 5.0% by weight.

[0203] IV. Methods and Administration In some embodiments (A), the present disclosure provides a method of treating a condition (e.g., agitation) in a human subject, comprising administering to the subject at least about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In some embodiments, the treatment is effective without causing significant sedation. In some embodiments, the condition is agitation or symptoms of agitation. In some embodiments, the agitation or symptoms of agitation are associated with schizophrenia. In some embodiments, the agitation or symptoms of agitation are associated with a bipolar disorder, such as bipolar disorder type I. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

[0204] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 μg to about 405 μg, e.g., a dose of about 120 μg to about 270 μg, or a dose of about 180 μg to about 405 μg, e.g., a dose of about 180 μg to about 270 μg (including an administered dose of about 120 μg or about 180 μg).

[0205] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 μg to about 405 μg, e.g., a dose of about 120 μg to about 270 μg, or a dose of about 180 μg to about 405 μg, e.g., a dose of about 180 μg to about 270 μg (including an administered dose of about 120 μg or about 180 μg), to treat agitation or symptoms of agitation in a human subject.

[0206] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 μg to about 405 μg, e.g., a dose of about 120 μg to about 270 μg, or a dose of about 180 μg to about 405 μg, e.g., a dose of about 180 μg to about 270 μg (including an administered dose of about 120 μg or about 180 μg), to treat agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation.

[0207] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 120 μg to about 405 μg, e.g., a dose of about 120 μg to about 270 μg, or a dose of about 180 μg to about 405 μg, e.g., a dose of about 180 μg to about 270 μg (including an administered dose of about 120 μg or about 180 μg), to treat agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation or causing clinically significant cardiovascular effects.

[0208] In some embodiments (B), the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering about 120 μg or about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) thereof as a single dose. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

[0209] In some embodiments, the present disclosure provides methods for treating acute agitation associated with schizophrenia and bipolar disorder (e.g., bipolar disorder type I) in a human subject, comprising oromucosal administration of a film composition comprising 120 μg or 180 μg of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) as a single dose. In some embodiments, an additional dose (e.g., 90 μg or 60 μg) can be taken after a suitable period (e.g., 2 hours) in case of persistent or recurrent agitation (e.g., by cutting the 180 μg or 120 μg film in half).

[0210] In some embodiments, the present disclosure provides a method for treating acute agitation associated with schizophrenia and bipolar disorder (e.g., bipolar disorder type I) in a human subject, comprising oromucosal administration of a film composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride), wherein the subject is being concomitantly treated with an antipsychotic. Suitable antipsychotics contemplated within the scope of the present disclosure include, but are not limited to, aripiprazole, benperidol, flupenthixol, amisulpride, chlorpromazine, asenapine, risperidone, ziprasidone, lurasidone, clozapine, cariprazine, olanzapine, and quetiapine. In some embodiments, the antipsychotic is aripiprazole.

[0211] In certain embodiments (C), the present disclosure provides a method for treating agitation or symptoms of agitation in a human subject with dementia without inducing significant sedation, comprising administering about 30 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, 30 μg, 60 μg, or 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single daily dose. In some embodiments, an additional dose (e.g., 30 μg) may be taken after a suitable period (e.g., 2, 4, 6, 8, or 12 hours) in the event of persistent or recurrent agitation. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally 1 to 6 times daily as a unit dose containing about 30 μg to about 90 μg. For example, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally one, two, three, four, five, or six times every two hours, four, six, eight, ten, or twelve hours. In some embodiments, unit doses containing about 30 μg to 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken one to six times daily at two-hour intervals, provided that a maximum of three doses are taken within 12 hours of the first dose. In some embodiments, unit doses containing about 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken one to four times daily at two-hour intervals, provided that a maximum of two doses are taken within 12 hours of the first dose. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally (e.g., sublingually or bucally) as a film. In some embodiments, administration may be accomplished by cutting the film in half to deliver half the dose (e.g., a 60 μg dose may be administered along with half (30 μg) of a second 60 μg dose to make a 90 μg dose).

[0212] In certain embodiments (D), the present disclosure also provides a method for managing or treating agitation in a delirious subject without inducing significant sedation, comprising administering about 20 μg to about 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is hospitalized. In some embodiments, the subject is hospitalized in an intensive care unit. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) is administered oromucosally in a unit dose containing about 20 μg or about 60 μg as a single dose. In some embodiments, each unit dose can be administered 1 to 4 times at appropriate intervals (e.g., every 0.5 hours, 1 hour, 2 hours, or 3 hours) within 6 hours of the first dose to produce the desired effect, e.g., 20 μg units administered four times at 0.5-hour intervals within 6 hours of the first dose to produce the effect of an 80 μg dose, or 60 μg units administered four times at 0.5-hour intervals within 6 hours of the first dose to produce the effect of a 240 μg dose. In some embodiments, treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g., sublingually or bucally) as a film as described herein.

[0213] In certain embodiments (E), the present disclosure provides a method for shortening opioid withdrawal in a human subject in need thereof, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily to the subject, wherein the withdrawal period is up to 14 days. In some embodiments, the withdrawal period can be 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days. In some embodiments, the human subject is an adult (i.e., at least 18 years of age), suffers from opioid use disorder, and is physically dependent on opioids. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually, buccally, orally, intranasally, or parenterally. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) is administered sublingually as a film. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is oromucosally administered in a single dose ranging from about 30 μg to about 200 μg. In some embodiments, dexmedetomidine is administered twice daily at doses of about 30 μg, about 60 μg, about 90 μg, about 120 μg, or about 180 μg, approximately 12 hours apart for a period of at least 3 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days). In further embodiments, each unit may be administered with an appropriate dosing interval (e.g., about 12 hours between doses) or simultaneously; for example, two 30 μg doses may be administered simultaneously to produce the effect of a 60 μg dose, or three 60 μg doses may be administered simultaneously to produce the effect of a 180 μg dose. In one embodiment, withdrawal symptoms following treatment are assessed (eg, over a 10 day period) using the Clinical Opiate Withdrawal Scale and / or the Gossop Short-Term Opiate Withdrawal Scale.In some embodiments, the opioid may be selected from the group consisting of, but not limited to, fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil, carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil, butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene), thebaine, sufentanil, or pentazocine. In some embodiments, the opioid was administered for a longer period prior to withdrawal than neonatal treatment. It has been unexpectedly discovered that dexmedetomidine is effective in shortening the duration of opioid withdrawal in adult subjects. This is surprising because opioids (e.g., fentanyl) are localized in body fat over time and released intermittently, causing unpredictable effects on patients during the withdrawal process. Clinicians did not anticipate that repeated doses of dexmedetomidine would be an effective therapy because of the opioid's variable and intermittent release.

[0214] In some embodiments, the present disclosure provides a method of promoting stage 3 non-rapid eye movement (NREM) sleep in a human subject, the method comprising sublingually administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof as a single dose. In some embodiments, the human subject is admitted to an intensive care unit suffering from hyperactive delirium.

[0215] In some embodiments, the present disclosure provides methods for treating cocaine toxicity and / or symptoms associated with cocaine toxicity, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as an oromucosal film in a dose range of about 30 μg to about 200 μg in a single dose therapy or a multiple dose therapy.

[0216] In another embodiment (F), the present disclosure provides a method for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) thereof, resulting in a mean total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, of about 3800 ng·h / L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, is about 80% to about 125% of 3800 ng·h / L. For example, the AUC is about 3024 ng·h / L, about 3100 ng·h / L, about 3200 ng·h / L, about 3300 ng·h / L, about 3400 ng·h / L, about 3500 ng·h / L, about 3600 ng·h / L, about 3700 ng·h / L, about 3800 ng·h / L, about 3900 ng·h / L, about 4000 ng·h / L, about 4100 ng·h / L, about 4200 ng·h / L, about 4300 ng·h / L, about 4400 ng·h / L, about 4500 ng·h / L, about 4600 ng·h / L, or about 4725 ng·h / L.

[0217] In another embodiment (G), the present disclosure provides a method for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) thereof, resulting in a mean total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, of about 1800 ng·h / L. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the mean total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, is about 80% to about 125% of 1800 ng·h / L. For example, the AUC is about 1440 ng·h / L, 1500 ng·h / L, about 1600 ng·h / L, about 1700 ng·h / L, about 1800 ng·h / L, about 1900 ng·h / L, about 2000 ng·h / L, about 2100 ng·h / L, about 2200 ng·h / L, or about 2250 ng·h / L.

[0218] In a further embodiment (H), the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the plasma AUC The mean total dexmedetomidine exposure, as measured by T0-T∞, was approximately 470 h·ng / L, approximately 500 h·ng / L, approximately 600 h·ng / L, approximately 700 h·ng / L, approximately 800 h·ng / L, approximately 900 h·ng / L, approximately 1000 h·ng / L, approximately 1250 h·ng / L, approximately 1500 h·ng / L, approximately 1750 h·ng / L, approximately 2000 h·ng / L, approximately 2250 h·ng / L, approximately 3000 h·ng / L, approximately 4000 h·ng / L, approximately 5000 h·ng / L, approximately 6000 h·ng / L, approximately 7000 h·ng / L, approximately 8000 h·ng / L, approximately 90 ... ng / L, approx. 2500 hours ng / L, approx. 2750 hours ng / L, approx. 3000 hours ng / L, approx. 3250 hours ng / L, approx. 3500 hours ng / L, approx. 3750 hours ng / L, approx. 40 00 hours ng / L, approximately 4250 hours ng / L, approximately 4500 hours ng / L, approximately 4750 hours ng / L, approximately 5000 hours ng / L, approximately 5250 hours ng / L to approximately 5500 hours ng / L, Approximately 5750 hours ng / L, approximately 6000 hours ng / L, approximately 6250 hours ng / L to approximately 6500 hours ng / L, approximately 6750 hours ng / L, approximately 7000 hours ng / L, approximately 7250 hours ng / L g / L ~ approx. 7500 hours ng / L, approx. 7750 hours ng / L, approx. 8000 hours ng / L, approx. 8250 hours ng / L ~ approx. 8500 hours ng / L, approx. 8750 hours ng / L, approx. 9000 hours about 80% to about 125% of about 9250 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L, or about 11875 h·ng / L.

[0219] In a further embodiment (I), the present disclosure provides a method of treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising administering an appropriate amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞. In some embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the plasma AUC The mean total dexmedetomidine exposure, as measured by T0-T∞, was approximately 470 h·ng / L, approximately 500 h·ng / L, approximately 600 h·ng / L, approximately 700 h·ng / L, approximately 800 h·ng / L, approximately 900 h·ng / L, approximately 1000 h·ng / L, approximately 1250 h·ng / L, approximately 1500 h·ng / L, approximately 1750 h·ng / L, approximately 2000 h·ng / L, approximately 2250 h·ng / L, approximately 2300 h·ng / L, approximately 2400 h·ng / L, approximately 2500 h·ng / L, approximately 2600 h·ng / L, approximately 2700 h·ng / L, approximately 2800 h·ng / L, approximately 2900 h·ng / L, approximately 3000 h·ng / L, approximately 3100 h·ng / L, approximately 3200 h·ng / L, approximately 3300 h·ng / L, approximately 3400 h·ng / L, approximately 3500 h·ng / L, approximately 3600 h·ng / L, approximately 3700 h·ng / L, approximately 3800 h·ng / L, approximately 3900 h·ng / L, approximately 4000 h·ng / L, approximately 4100 h·ng / L, approximately 4200 h·ng / L, approximately 4300 h·ng / L, approximately 4400 h·ng / L, approximately 4500 h·ng / L, approximately 4600 h·ng / L, approximately 4700 h·ng / L, approximately 4800 h·ng / L, approximately 4900 h·ng / L, approximately 5000 h·ng / L, approximately 5100 h·ng / L, approximately 52 about 80% to about 125% of 500 h·ng / L, about 2750 h·ng / L, about 3000 h·ng / L, about 3250 h·ng / L, about 3500 h·ng / L, about 3750 h·ng / L, about 4000 h·ng / L, about 4250 h·ng / L, about 4500 h·ng / L, about 4750 h·ng / L, about 5000 h·ng / L, about 5250 h·ng / L, or about 5500 h·ng / L.

[0220] In some embodiments of each of Embodiments (A) through (I), dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered orally, oromucosally (e.g., sublingually, bucally), intravenously, intramuscularly, subcutaneously, topically, transdermally, intratracheally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally.

[0221] In some embodiments of each of Embodiments (A) through (I), dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject by a sublingual, buccal, oral, intranasal, or parenteral route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by a sublingual or buccal route. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel, or drop, particularly a film. In some embodiments, a film is placed under the tongue near the base of the left or right tongue. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered bucally in the form of a film, patch, or tablet, particularly a film. In some embodiments, a film is placed inside the lip or cheek near the jawline. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in the form of an intramuscular injection. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject by oral administration. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is orally administered in the form of a tablet, an orally disintegrating tablet (ODT), an effervescent tablet, a capsule, a pellet, a pill, a lozenge or troche, a powder, a dispersible granule, a cachet, an aqueous solution, a syrup, an emulsion, a suspension, a solution, a soft gel, a dispersion, or the like. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is orally administered to a subject in the form of an orally disintegrating tablet.

[0222] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually to a subject as a single dose comprising about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, and agitation or symptoms of agitation are treated without inducing clinically significant cardiovascular effects, hi some embodiments, agitation or symptoms of agitation are treated without a diastolic blood pressure falling below about 60 mmHg and / or a heart rate falling below about 50 beats / minute.

[0223] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is sublingually administered to a subject as a single dose comprising about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, and agitation or symptoms of agitation are treated without inducing clinically significant cardiovascular effects. In some embodiments, agitation or symptoms of agitation are treated without a systolic blood pressure falling below about 80 mmHg and / or a diastolic blood pressure falling below about 60 mmHg and / or a heart rate falling below about 50 beats per minute.

[0224] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 8 hours. In some embodiments, the dexmedetomidine is administered as a single dose. In some embodiments, the total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, is about 80% to about 125% of the total dexmedetomidine exposure of about 600 to about 9500 ng·h / L. For example, approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L L, approx. 2750 hours ng / L, approx. 3000 hours ng / L, approx. 3250 hours ng / L, approx. 3500 hours ng / L, approx. 3750 hours ng / L, approx. 4000 hours ng / L, approx. 42 50 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 6000 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L ~ approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 900 0 h·ng / L, approximately 9250 h·ng / L, approximately 9500 h·ng / L, approximately 9750 h·ng / L, approximately 10000 h·ng / L, approximately 10250 h·ng / L, approximately 10500 h·ng / L, approximately 10750 h·ng / L, approximately 11000 h·ng / L, approximately 11250 h·ng / L, approximately 11500 h·ng / L, or approximately 11875 h·ng / L.In some embodiments, the plasma Tmax (T0-T∞) is about 80% to about 125% of about 1 to about 8 hours, e.g., about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, or about 5.25 hours. about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours, or about 10 hours.

[0225] In certain embodiments, methods are provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 4 hours. In some embodiments, dexmedetomidine is administered as a single dose. In some embodiments, the plasma AUC Total dexmedetomidine exposure, as measured by T0-T∞, was approximately 470 h·ng / L, approximately 500 h·ng / L, approximately 600 h·ng / L, approximately 700 h·ng / L, approximately 800 h·ng / L, approximately 900 h·ng / L, approximately 1000 h·ng / L, approximately 1250 h·ng / L, approximately 1500 h·ng / L, approximately 1750 h·ng / L, approximately 2000 h·ng / L, approximately 2250 h·ng / L, approximately 25 In some embodiments, the plasma T is about 80% to about 125% of about 00 h·ng / L, about 2750 h·ng / L, about 3000 h·ng / L, about 3250 h·ng / L, about 3500 h·ng / L, about 3750 h·ng / L, about 4000 h·ng / L, about 4250 h·ng / L, about 4500 h·ng / L, about 4750 h·ng / L, about 5000 h·ng / L, about 5250 h·ng / L, or about 5500 h·ng / L. max TO-T∞ is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, or about 5.0 hours.

[0226] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 180 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: a Cmax of about 300 ng / L to about 500 ng / L (e.g., about 400 ng / L) and an AUC T0-T∞ of about 2300 ng·h / L to about 3600 ng·h / L (e.g., about 2900 ng·h / L). For example, the Cmax is about 240 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, and 475 ng / L, about 500 ng / L, about 600 ng / L, or about 625 ng / L, and the AUC 0-inf is approximately 1840 h·ng / L, approximately 2000 h·ng / L, approximately 2250 h·ng / L, approximately 2500 h·ng / L, approximately 2750 h·ng / L, approximately 3000 h·ng / L, approximately 3250 h·ng / L, approximately 3500 h·ng / L, approximately 3750 h·ng / L, approximately 4000 h·ng / L, approximately 4250 h·ng / L, or approximately 4500 h·ng / L.

[0227] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 150 ng / L to about 350 ng / L (e.g., about 220 ng / L) and AUC T0-T∞ of about 1100 ng·h / L to about 1800 ng·h / L (e.g., about 1410 ng·h / L). For example, the Cmax is about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, or about 425 ng / L, and the AUC is about 900 hr·ng / L, about 1000 hr·ng / L, about 1250 hr·ng / L, about 1500 hr·ng / L, about 1750 hr·ng / L, about 2000 hr·ng / L, or about 2250 hr·ng / L.

[0228] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3800 ng·h / L, as measured by plasma AUC T0-T∞, and a mean plasma Cmax of about 400 ng / L. In some embodiments, the plasma AUC T0-T∞ is between 80% and 125% of about 3800 ng·h / L, and the mean plasma Cmax is between 80% and 125% of about 400 ng / L.

[0229] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L and a mean plasma Cmax of about 200 ng / L, as measured by plasma AUC T0-T∞. In some embodiments, the plasma AUC T0-T∞ is between 80% and 125% of about 1800 ng·h / L, and the mean plasma Cmax is between 80% and 125% of about 200 ng / L.

[0230] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3800 ng·h / L, as measured by plasma AUC T0-T∞, with a median plasma Tmax of about 2 hours. In some embodiments, the plasma AUC T0-T∞ is between 80% and 125% of about 3800 ng·h / L, and the median plasma Tmax is between 80% and 125% of about 2 hours.

[0231] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L, as measured by plasma AUC T0-T∞, with a median plasma Tmax of about 2 hours. In some embodiments, the plasma AUC T0-T∞ is between 80% and 125% of about 1800 ng·h / L, and the median plasma Tmax is between 80% and 125% of about 2 hours.

[0232] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3800 ng·h / L, a mean plasma Cmax of about 400 ng / L, and a median plasma Tmax of about 2 hours, as measured by plasma AUC T0-T∞. In some embodiments, the plasma AUC T0-T∞ is between 80% and 125% of about 3800 ng·h / L, the mean plasma Cmax is between 80% and 125% of about 400 ng / L, and the median plasma Tmax is between 80% and 125% of about 2 hours.

[0233] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering to the subject a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L, a mean plasma Cmax of about 200 ng / L, and a median plasma Tmax of about 2 hours, as measured by plasma AUC T0-T∞. In some embodiments, the plasma AUC T0-T∞ is 80% to about 125% of about 1800 ng·h / L, the mean plasma Cmax is about 80% to about 125% of about 200 ng / L, and the median plasma Tmax is about 80% to about 125% of about 2 hours.

[0234] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Cmax of about 100 ng / L to about 800 ng / L. In some embodiments, the plasma AUC T0-T∞ is 80% to about 125% of about 600 ng·h / L to about 9500 ng·h / L, and the mean plasma Cmax is about 80% to about 125% of about 100 ng / L to about 800 ng / L.

[0235] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Cmax of about 110 ng / L to about 400 ng / L. In some embodiments, the plasma AUC T0-T∞ is 80% to about 125% of about 590 ng·h / L to about 4400 ng·h / L, and the mean plasma Cmax is about 80% to about 125% of about 110 ng / L to about 400 ng / L.

[0236] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a 180 μg dose of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 8 hours. In some embodiments, the plasma AUC T0-T∞ is 80% to about 125% of about 600 ng·h / L to about 9500 ng·h / L, and the plasma Tmax is about 80% to about 125% of about 1 to about 8 hours.

[0237] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising sublingually administering a 120 μg dose of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 4 hours. In some embodiments, the plasma AUC T0-T∞ is 80% to about 125% of about 5900 ng·h / L to about 4400 ng·h / L, and the plasma Tmax is about 80% to about 125% of about 1 to about 4 hours.

[0238] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 180 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, resulting in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L.

[0239] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 120 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, resulting in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L.

[0240] In certain embodiments, provided is a method of treating a condition (e.g., agitation) in a human subject in need thereof without inducing significant sedation, the method comprising administering to the subject a unit dose of 180 μg or 120 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, which results in rapid absorption with peak concentrations achieved, on average, within about 2.5 hours after administration.

[0241] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L. In some embodiments, the plasma Tmax is about 1 hour to about 8 hours.

[0242] In some embodiments, a method of treating a condition (e.g., agitation) in a human subject is provided, comprising sublingually administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L. In some embodiments, the plasma Tmax is about 1 hour to about 4 hours.

[0243] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels with the following values: C of about 300 ng / L to about 500 ng / L (e.g., about 400 ng / L) and about 80% to about 125% of AUC T-T of about 2300 ng h / L to about 3600 ng h / L (e.g., about 2900 ng h / L). In some embodiments, the plasma T is about 2 hours.

[0244] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising sublingually administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels with the following values: C of about 150 ng / L to about 300 ng / L (e.g., about 220 ng / L) and about 80% to about 125% of AUC T-T of about 1100 ng h / L to about 1800 ng h / L (e.g., about 1400 ng h / L). In some embodiments, the plasma T is about 2 hours.

[0245] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, the method comprising buccal administration of a dose of 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 8 hours.

[0246] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of a dose of 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 4 hours.

[0247] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 300 ng / L to about 500 ng / L (e.g., about 400 ng / L) and AUC T0-T∞ of about 2300 ng·h / L to about 3600 ng·h / L (e.g., about 2900 ng·h / L).

[0248] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 150 ng / L to about 300 ng / L (e.g., about 220 ng / L) and AUC T0-T∞ of about 1100 ng·h / L to about 1800 ng·h / L (e.g., about 1400 ng·h / L).

[0249] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3800 ng·h / L and a mean plasma Cmax of about 400 ng / L, as measured by plasma AUC T0-T∞.

[0250] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L and a mean plasma Cmax of about 200 ng / L, as measured by plasma AUC T0-T∞.

[0251] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3780 ng·h / L, as measured by plasma AUC T0-T∞, with a median plasma Tmax of about 2 hours.

[0252] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L, as measured by plasma AUC T0-T∞, with a median plasma Tmax of about 2 hours.

[0253] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 3800 ng·h / L, as measured by plasma AUC T0-T∞, with a mean plasma Cmax of about 400 ng / L and a median plasma Tmax of about 2 hours.

[0254] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration to the subject of a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a mean total dexmedetomidine exposure of about 1800 ng·h / L, as measured by plasma AUC T0-T∞, with a mean plasma Cmax of about 200 ng / L and a median plasma Tmax of about 2 hours.

[0255] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L with a plasma Cmax of about 100 ng / L to about 800 ng / L, as measured by plasma AUC T0-T∞.

[0256] In some embodiments, provided is a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising buccal administration of a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, with a plasma Cmax of about 110 ng / L to about 400 ng / L, as measured by plasma AUC T0-T∞.

[0257] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject with schizophrenia or bipolar disorder without inducing significant sedation, the method comprising buccal administration of a dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 8 hours.

[0258] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, the method comprising buccal administration of a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 590 to about 4400 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 to about 4 hours.

[0259] In some embodiments, methods are provided for treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 180 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, resulting in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L.

[0260] In some embodiments, methods of treating a condition in a human subject are provided, comprising buccally administering to the subject about 120 μg of dexmedetomidine, or a pharmaceutically acceptable salt thereof, resulting in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L.

[0261] In some embodiments, provided is a method of treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L, and having a plasma Tmax of about 1 hour to about 8 hours.

[0262] In some embodiments, a method of treating a condition (e.g., agitation) in a human subject is provided, comprising buccally administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 hr·ng / L to about 4400 hr·ng / L, and having a plasma Tmax of about 1 hour to about 4 hours.

[0263] In some embodiments, provided is a method of treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: a Cmax of about 300 ng / L to about 500 ng / L (e.g., about 400 ng / L) and an AUC T0-T∞ of about 2300 ng·h / L to about 3600 ng·h / L (e.g., about 2900 ng·h / L), and wherein the plasma Tmax is about 2 hours.

[0264] In some embodiments, provided is a method of treating a condition (e.g., agitation) in a human subject, comprising buccally administering to the subject about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: a Cmax of about 150 ng / L to about 300 ng / L (e.g., about 200 ng / L) and an AUC T0-T∞ of about 1100 ng·h / L to about 1800 ng·h / L (e.g., about 1400 ng·h / L), and wherein the plasma Tmax is about 2 hours.

[0265] In certain embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is parenterally administered to a subject in the form of an intramuscular injection, and the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 140 μg to about 190 μg.

[0266] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscularly administering a dose of about 120 μg to about 190 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 9500 ng·h / L, with a plasma Tmax of about 5 minutes to about 4 hours, as measured by plasma AUC T0-T∞.

[0267] In some embodiments, provided is a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscularly administering a dose of about 120 μg to about 190 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in a total dexmedetomidine exposure of about 600 to about 12,600 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 5 minutes to about 4 hours.

[0268] In some embodiments, provided is a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscularly administering a dose of about 120 μg to about 190 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 12,600 ng·h / L and a plasma Cmax of about 200 to about 800 ng / L, as measured by plasma AUC T0-T∞.

[0269] In some embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising intramuscularly administering a dose of about 120 μg to about 190 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 12,600 ng·h / L, as measured by plasma AUC T0-T∞, with a median Tmax of about 2 hours.

[0270] In some embodiments, provided is a method for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising intravenously administering a dose of about 120 μg to about 190 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, which results in a total dexmedetomidine exposure of about 600 to about 12,600 ng·h / L, as measured by plasma AUC T0-T∞, and a plasma Tmax of about 5 minutes to about 15 minutes.

[0271] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is orally administered to the subject, and the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of about 900 μg to about 1200 μg.

[0272] In certain embodiments, provided is a method of treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising orally administering a dose of about 900 μg to about 1200 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 12600 ng·h / L, as measured by plasma AUC T0-T∞, with a plasma Tmax of about 1 hour to about 8 hours.

[0273] In certain embodiments, a method is provided for treating agitation or symptoms of agitation in a human subject having schizophrenia or bipolar disorder without inducing significant sedation, comprising orally administering a dose of about 900 μg to about 1200 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, resulting in a total dexmedetomidine exposure of about 600 to about 12600 ng·h / L, as measured by plasma AUC T0-T∞, with a median Tmax of about 2 hours.

[0274] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose (eg, a single unit dose or multiple unit doses administered simultaneously).

[0275] Another embodiment of the present disclosure provides a self-supporting dissolving film comprising about 180 μg of dexmedetomidine hydrochloride, wherein sublingual application of the film to a subject with schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L.

[0276] Another embodiment of the present disclosure provides a self-supporting dissolving film comprising about 120 μg of dexmedetomidine hydrochloride, wherein sublingual application of the film to a subject with schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L.

[0277] Another embodiment of the present disclosure provides a self-supporting dissolving film comprising about 180 μg of dexmedetomidine hydrochloride, wherein sublingual application of the film to a subject with schizophrenia or bipolar disorder results in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 300 ng / L to about 500 ng / L (e.g., about 400 ng / L) and AUC T0-T∞ of about 2300 ng h / L to about 3600 ng h / L (e.g., about 2900 ng h / L), with a plasma Tmax of about 2 hours.

[0278] Another embodiment of the present disclosure provides a self-supporting dissolving film comprising about 120 μg of dexmedetomidine hydrochloride, wherein sublingual application of the film to a subject with schizophrenia or bipolar disorder results in mean plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 150 ng / L to about 300 ng / L (e.g., about 200 ng / L) and AUC T0-T∞ of about 1100 ng h / L to about 1800 ng h / L (e.g., about 1400 ng h / L), with a plasma Tmax of about 2 hours.

[0279] Another embodiment of the present disclosure provides a self-supporting dissolving film comprising about 180 μg to about 240 μg of dexmedetomidine hydrochloride, wherein sublingual application of the film to a subject with schizophrenia or bipolar disorder results in a total dexmedetomidine exposure, as measured by plasma AUC T0-T∞, of about 600 to about 12,600 ng·h / L, with a plasma Tmax of about 1 to about 8 hours.

[0280] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 180 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), wherein the composition of portion (a) is present on a surface of the film substrate (b), wherein sublingual application of the film to a subject having schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 hr·ng / L to about 9500 hr·ng / L. For example, Cmax is approximately 80ng / L, approximately 100ng / L, approximately 125ng / L, approximately 150ng / L, approximately 175ng / L, approximately 200ng / L, approximately 225ng / L, approximately 250ng / L, approximately 275ng / L. , about 300ng / L, about 325ng / L, about 350ng / L, about 375ng / L, about 400ng / L, about 425ng / L, about 450ng / L, and 475ng / L, about 500ng / L, about 525ng / L, approximately 550ng / L, approximately 575ng / L, approximately 600ng / L, approximately 625ng / L, approximately 650ng / L, approximately 675ng / L, approximately 700ng / L, approximately 725ng / L, approximately 750ng / L, approximately 775ng / L, about 800ng / L, about 825ng / L, about 850ng / L, about 875ng / L, about 900ng / L, about 925ng / L, about 950ng / L, about 975ng / L to about 1000ng / L, and AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L , approx. 2750 hours ng / L, approx. 3000 hours ng / L, approx. 3250 hours ng / L, approx. 3500 hours ng / L, approx. 3750 hours ng / L, approx. 4000 hours ng / L, approx. 42 50 hours ng / L, approximately 4500 hours ng / L, approximately 4750 hours ng / L, approximately 5000 hours ng / L, approximately 5250 hours ng / L, approximately 5500 hours ng / L, approximately 5750 hours ng / L, approximately 6000 hours ng / L, approximately 6250 hours ng / L, approximately 6500 hours ng / L, approximately 6750 hours ng / L, approximately 7000 hours ng / L, approximately 7250 hours ng / L, approximately 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L, approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9 000 h·ng / L, about 9250 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L. In some embodiments, Tmax is from about 1 to about 8 hours. For example, Tmax may be about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours to about 10 hours.

[0281] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 120 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided, in which the composition of portion (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L. For example, Cmax is about 80 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, and 475 ng / L to about 500 ng / L, and AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, about 2750 h·ng / L, about 3000 h·ng / L, about 3250 h·ng / L, about 3500 h·ng / L, about 3750 h·ng / L, about 4000 h·ng / L, about 4250 h·ng / L, about 4500 h·ng / L, about 4750 h·ng / L, about 5000 h·ng / L, about 5250 h·ng / L to about 5500 h·ng / L. In some embodiments, T is from about 1 to about 4 hours. For example, Tmax is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours to about 5.0 hours.

[0282] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 180 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided, in which the composition of part (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 100 ng / L to about 800 ng / L and AUC T0-T∞ of about 600 h·ng / L to about 9500 h·ng / L, and a plasma Tmax of about 1 hour to about 8 hours. For example, Cmax is approximately 80ng / L, approximately 100ng / L, approximately 125ng / L, approximately 150ng / L, approximately 175ng / L, approximately 200ng / L, approximately 225ng / L, approximately 250ng / L, approximately 2 75ng / L, about 300ng / L, about 325ng / L, about 350ng / L, about 375ng / L, about 400ng / L, about 425ng / L, about 450ng / L, and 475ng / L, about 50 0ng / L, approximately 600ng / L, approximately 625ng / L, approximately 650ng / L, approximately 675ng / L, approximately 700ng / L, approximately 725ng / L, approximately 750ng / L, approximately 775ng / L, approximately 800n g / L, about 825ng / L, about 850ng / L, about 875ng / L, about 900ng / L, about 925ng / L, about 950ng / L, about 975ng / L to about 1000ng / L, and AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 2750 hours·ng / L, approximately 3000 hours·ng / L, approximately 3250 hours·ng / L, approximately 3500 hours·ng / L, approximately 3750 hours·ng / L, approximately 4000 hours·ng / L ng / L, approximately 4250 hours ng / L, approximately 4500 hours ng / L, approximately 4750 hours ng / L, approximately 5000 hours ng / L, approximately 5250 hours ng / L ~ approximately 5500 hours ng / L, approximately 5750 hours ng / L, approximately 6000 hours ng / L, approximately 6250 hours ng / L / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approx. 7750 hours ng / L, approx. 8000 hours ng / L, approx. 8250 hours ng / L ~ approx. 8500 hours ng / L, The Tmax values ​​are approximately 8750 h·ng / L, approximately 9000 h·ng / L, approximately 9250 h·ng / L, approximately 9500 h·ng / L, approximately 9750 h·ng / L, approximately 10000 h·ng / L, approximately 10250 h·ng / L, approximately 10500 h·ng / L, approximately 10750 h·ng / L, approximately 11000 h·ng / L, approximately 11250 h·ng / L, approximately 11500 h·ng / L to approximately 11875 h·ng / L, and the Tmax values ​​are approximately 0.8 hours, approximately 0.9 hours, approximately 1 hour, approximately 1.25 hours, approximately 1.5 hours, approximately 1.75 hours, approximately 2.0 hours, and approximately 2.0 hours. 25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours to about 10 hours.

[0283] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 120 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided, in which the composition of part (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in plasma dexmedetomidine absorption levels of about 80% to about 125% of the following values: Cmax of about 110 ng / L to about 400 ng / L and AUC T0-T∞ of about 590 h·ng / L to about 4400 h·ng / L, with a plasma Tmax of about 1 hour to about 4 hours. For example, Cmax is about 80 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, and 475 ng / L to about 500 ng / L, and AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 2750 hours·ng / L, approximately 3000 hours·ng / L, approximately 3250 hours·ng / L, approximately 3500 hours·ng / L, approximately 3750 hours·ng / L, approximately 4000 hours·ng / L and the Tmax is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, and about 4.75 hours to about 5.0 hours.

[0284] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 180 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided in which the composition of portion (a) is present on the surface of a film substrate (b). Sublingual application of the film to a subject with schizophrenia or bipolar disorder results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 300 ng / L to about 474 ng / L (e.g., about 400 ng / L) and AUC T0-T∞ of about 2300 ng h / L to about 3600 ng h / L (e.g., about 2900 ng h / L), with a plasma Tmax of about 2 hours. For example, the Cmax is about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, or about 450 ng / L to about 475 ng / L, and the AUC 0-inf is about 2250 h·ng / L, about 2500 h·ng / L, about 2750 h·ng / L, about 3000 h·ng / L, about 3250 h·ng / L, about 3500 h·ng / L, or about 3750 h·ng / L. In some embodiments, T is about 1 to about 4 hours. For example, T is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, or about 5.0 hours.

[0285] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 120 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided in which the composition of portion (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in a mean plasma dexmedetomidine absorption level of about 80% to about 125% of the following values: Cmax of about 150 ng / L to about 300 ng / L (e.g., about 200 ng / L) and AUC T0-T∞ of about 1100 ng h / L to about 1800 ng h / L (e.g., about 1400 ng h / L), with a plasma Tmax of about 2 hours. For example, the Cmax is about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, or about 300 ng / L, and the AUC 0-inf is about 1100 h·ng / L, about 1250 h·ng / L, about 1500 h·ng / L, about 1750 h·ng / L to about 1800 h·ng / L. In some embodiments, T is about 1 to about 4 hours. For example, T is about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours to about 5.0 hours.

[0286] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 180 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided, in which the composition of portion (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in a total dexmedetomidine exposure of about 600 to about 12,600 ng·h / L, as measured by plasma AUC T0-T∞, and a plasma T max AUC is about 1 to about 8 hours. 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 2750 hours·ng / L, approximately 3000 hours·ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approximately 4500 hours ng / L, approximately 4750 hours ng / L, Approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 6000 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 675 0 hours ng / L, approximately 7000 hours ng / L, approximately 7250 hours ng / L ~ approximately 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L ~ approximately 8500 hours ·ng / L, approx. 8750 hours ·ng / L, approx. 9000 hours ·ng / L, approx. 9250 hours ·ng / L, approx. 9500 hours ·ng / L, approx. 9750 hours ·ng / L, approx. 10000 hours ·ng / L, approx. 10250 hours · ng / L, about 10,500 h·ng / L, about 10,750 h·ng / L, about 11,000 h·ng / L, about 11,250 h·ng / L, about 11,500 h·ng / L, about 11,750 h·ng / L, about 12,000 h·ng / L, about 12,250 h·ng / L, or about 12,600 h·ng / L, and the Tmax is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours.

[0287] Another embodiment of the present disclosure is a self-supporting dissolvable film comprising: (a) a composition comprising: (i) about 120 μg of dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose (40,000 MW), and (iii) a composition consisting essentially of hydroxypropyl cellulose (140,000 MW); (b) a film substrate, (i) Hydroxypropyl cellulose (40,000 MW), (ii) hydroxypropyl cellulose (140,000 MW); (iii) hydroxypropyl cellulose (370,000 MW), and (iv) a film substrate consisting essentially of polyethylene oxide (600,000 MW), A self-supporting dissolvable film is provided, in which the composition of portion (a) is present on the surface of a film substrate (b), and sublingual application of the film to a subject with schizophrenia or bipolar disorder results in a total dexmedetomidine exposure of about 590 to about 8750 ng·h / L, as measured by plasma AUC T0-T∞, and a plasma T max AUC is about 1 to about 4 hours. 0-inf is approximately 590 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 2750 hours·ng / L, approximately 3000 hours·ng / L, approximately 3250 hours·ng / L, approximately 3500 hours·ng / L, approximately 3750 hours·ng / L, approximately 4000 hours·ng / L, approximately 4250 hours·ng / L, approximately 4500 hours·ng / L, approximately The Tmax is 4750 h·ng / L, about 5000 h·ng / L, about 5250 h·ng / L to about 5500 h·ng / L, about 5750 h·ng / L, about 6000 h·ng / L, about 6250 h·ng / L to about 6500 h·ng / L, about 6750 h·ng / L, about 7000 h·ng / L, about 7250 h·ng / L to about 7500 h·ng / L, about 7750 h·ng / L, about 8000 h·ng / L, about 8250 h·ng / L, about 8500 h·ng / L, or about 8750 h·ng / L, and the Tmax is about 1 hour, about 2 hours, about 3 hours, or about 4 hours.

[0288] In some embodiments, agitation or symptoms of agitation in a patient with schizophrenia or bipolar disorder are significantly alleviated within 60 minutes after administration of a single 120 μg or 180 μg dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), as measured by relative PEC scores immediately before and 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the relative PEC scores differ by at least 6 points. In other embodiments, the relative PEC scores differ by at least 8 points. In yet other embodiments, the difference in relative PEC scores is maintained for at least 6 hours. In certain embodiments, a difference of at least 8 points is maintained for up to about 24 hours following administration of a single 180 μg dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

[0290] In some embodiments, the PEC score reduction at 2 hours after administration of 180 μg of dexmedetomidine hydrochloride is -10.8 compared to placebo (-4.5), as measured by change from baseline in PEC total score. In some embodiments, the PEC score reduction at 2 hours after administration of 180 μg of dexmedetomidine hydrochloride is greater (-10.8) compared to administration of 120 μg (-9.2) or 80 μg (-7.3) of dexmedetomidine hydrochloride. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately before or after the onset of agitation or symptoms of agitation in a human subject.

[0291] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 10 minutes after the onset of agitation or symptoms of agitation in a human subject. In some embodiments, a booster dose of 90 μg or 60 μg may be taken a suitable period (e.g., 2 hours) after the initial administration.

[0292] In some embodiments, after administration of about 30 μg, about 60 μg, about 90 μg, about 120 μg, or about 180 μg unit doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject experiencing opioid withdrawal symptoms (e.g., agitation or signs of agitation), the withdrawal symptoms are significantly alleviated as measured by relative COWS and / or SOWS-Gossop scores immediately before and 2 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In certain embodiments, the units can each be administered twice daily for an appropriate withdrawal period (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).

[0293] In certain embodiments, after administration of about 20 μg to about 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to an agitated human subject with delirium who is hospitalized (e.g., in an intensive care unit), agitation or signs of agitation and delirium severity are significantly reduced as measured by RASS and DRS-R-98, respectively. For example, agitation or signs of agitation and delirium severity are significantly reduced as measured by RASS and DRS-R-98 immediately before administration of dexmedetomidine and every 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after administration. In some embodiments, dexmedetomidine can be administered oromucosally (e.g., sublingually or bucally) one to four times daily at appropriate dosing intervals (e.g., every 30 minutes) within six hours of the first dose to produce the desired effect, for example, four 20 μg unit doses administered within six hours of the first dose at 30-hour dosing intervals to produce an 80 μg dose effect, or four 60 μg unit doses administered within six hours of the first dose at 30-minute dosing intervals to produce a 240 μg effect.

[0294] In some embodiments, after administration of about 30 μg to about 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to an agitated human subject with dementia, agitation or symptoms of agitation are significantly reduced as measured by PAS and PEC. For example, agitation or symptoms of agitation are significantly reduced as measured by PAS and PEC immediately before administration of dexmedetomidine or a pharmaceutically acceptable salt thereof and every 2 hours for up to at least 24 hours thereafter. In one embodiment, dexmedetomidine is administered oromucosally (e.g., sublingually or bucally). In some embodiments, each unit dose contains about 30 μg to 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a dose of dexmedetomidine can be taken 1, 2, 3, 4, 5, or 6 times daily every 2 hours, provided that a maximum of 3 doses are taken within 12 hours of the first dose. In some embodiments, unit doses containing about 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof can each be taken 1, 2, 3, or 4 times daily every 2 hours, provided that a maximum of 2 doses are taken within 12 hours of the first dose.

[0295] In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g., sublingually or bucally) as a film. In some embodiments, administration may be accomplished by cutting the film in half to deliver a half dose (e.g., a 60 μg dose may be administered along with half of the 60 μg dose (30 μg) to make a 90 μg dose).

[0296] In some embodiments, the disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder I), and in some embodiments, the patient has both schizophrenia and a bipolar disorder (e.g., bipolar disorder I).

[0297] According to some embodiments of the method for treating agitation, comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, the composition may be administered by various means. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, bucally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or bucally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drop. In some embodiments, the composition is administered bucally in the form of a film, patch, or tablet.

[0298] According to some embodiments of a method for treating agitation comprising administering a unit dose composition containing about 120 μg of dexmedetomidine, the method may further comprise administering a second dose of dexmedetomidine after a period ranging from about 30 minutes to about 12 hours. For example, this period may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered about 2 hours later. In some embodiments, the second dose is in the range of about 10 μg to about 180 μg. For example, the booster dose can be about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170, or about 180 μg. In some embodiments, the booster dose is about 60 μg or 90 μg.

[0299] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, the unit dose composition can be administered to a patient in a fasted state. In some embodiments, the unit dose composition is administered in a fed state.

[0300] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Negative Syndrome Scale Excited Component (PEC) score compared to baseline. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences a 40% or greater reduction in the PEC score from baseline. For example, patients experience about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150% or more from baseline. Therapeutic efficacy may also be compared by comparing the PEC score with a placebo. In some embodiments, the PEC score is 30% or more lower than the placebo (e.g., the placebo group has a mean change from baseline in the PEC total score of -3, and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient's PEC score is 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%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200% or more lower. In some embodiments, the patient experiences a mean PEC score change of more than about -4 (i.e., a decrease of 4 points or more) compared to baseline within 2 hours after administration of the composition. For example, at the 2 hour time point, a patient may experience a mean PEC score change of about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or greater than about -12.In some embodiments, the PEC score decrease (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -6 or less (e.g., -7, -8, etc.). In some embodiments, the PEC score decrease (e.g., greater than about -4) is substantially maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -4, about -5, or about -6 or less (e.g., -7, -8, etc.). In some embodiments, the mean PEC score change is -8 or greater and is maintained from 2 hours after administration of the composition up to at least about 6 hours after administration.

[0301] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0302] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of the single dose results in a mean Cmax within the range of about 80% to about 125% of about 110 ng / L to about 400 ng / L. max For example, a single dose may result in a mean C of about 88 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, about 475 ng / L, or about 500 ng / L (including all integers and ranges therebetween). max In some embodiments, the average C maxis about 100 ng / L to about 500 ng / L, about 150 ng / L to about 450 ng / L, about 150 ng / L to about 400 ng / L, about 200 ng / L to about 350 ng / L, about 200 ng / L to about 300 ng / L, about 200 ng / L to about 250 ng / L, or about 210 ng / L to about 240 ng / L. max is within the range of about 80% to about 125% of about 238 ng / L. max is within the range of about 80% to about 125% of about 238 ng / L. max is approximately 238 ng / L.

[0303] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in a mean AUC 100 / 1000 serotonin concentration within the range of about 80% to about 125% of about 590 h·ng / L to about 4400 h·ng / L. 0-inf For example, a single dose may result in a mean AUC of about 475 h·ng / L, about 500 h·ng / L, about 1000 h·ng / L, about 1500 h·ng / L, about 2000 h·ng / L, about 2500 h·ng / L, about 3000 h·ng / L, about 3500 h·ng / L, about 4000 h·ng / L, about 4500 h·ng / L, about 5000 h·ng / L, or about 5500 h·ng / L (including all integers and ranges therebetween). 0-inf In some embodiments, the mean AUC 0-inf is about 500 hours·ng / L to about 5000 hours·ng / L, about 500 hours·ng / L to about 4000 hours·ng / L, about 500 hours·ng / L to about 3000 hours·ng / L, about 1000 hours·ng / L to about 3000 hours·ng / L, about 1000 hours·ng / L to about 2500 hours·ng / L, about 1000 hours·ng / L to about 2000 hours·ng / L, about 1000 hours·ng / L to about 1500 hours·ng / L, or about 1500 hours·ng / L to about 2000 hours·ng / L. In some embodiments, the mean AUC 0-inf is within the range of about 80% to about 125% of about 1800 ng·h / L.0-inf is approximately 1800 ng·h / L.

[0304] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of the single dose results in a mean T within a range of about 80% to about 125% for about 1 hour to about 4 hours. max For example, a single dose may result in a mean T of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours to about 5.0 hours. max In some embodiments, Tmax is about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0305] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in a geometric mean C value within the range of about 80% to about 125% of about 110 ng / L to about 400 ng / L. max For example, a single dose may result in a geometric mean C of about 88 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, about 475 ng / L, or about 500 ng / L (including all integers and ranges therebetween). max In some embodiments, the geometric mean C maxis about 100 ng / L to about 500 ng / L, about 150 ng / L to about 450 ng / L, about 150 ng / L to about 400 ng / L, about 200 ng / L to about 350 ng / L, about 200 ng / L to about 300 ng / L, about 200 ng / L to about 250 ng / L, or about 210 ng / L to about 240 ng / L. max is in the range of about 80% to about 125% of about 220 ng / L. max is about 220 ng / L. max The median value is approximately 238 ng / L.

[0306] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in a geometric mean AUC within the range of about 80% to about 125% of about 590 h·ng / L to about 4400 h·ng / L. 0-inf For example, a single dose may result in a geometric mean AUC of about 475 h·ng / L, about 500 h·ng / L, about 1000 h·ng / L, about 1500 h·ng / L, about 2000 h·ng / L, about 2500 h·ng / L, about 3000 h·ng / L, about 3500 h·ng / L, about 4000 h·ng / L, about 4500 h·ng / L, about 5000 h·ng / L, or about 5500 h·ng / L (including all integers and ranges therebetween). 0-inf In some embodiments, the geometric mean AUC 0-inf is about 500 hours·ng / L to about 5000 hours·ng / L, about 500 hours·ng / L to about 4000 hours·ng / L, about 500 hours·ng / L to about 3000 hours·ng / L, about 1000 hours·ng / L to about 3000 hours·ng / L, about 1000 hours·ng / L to about 2500 hours·ng / L, about 1000 hours·ng / L to about 2000 hours·ng / L, about 1000 hours·ng / L to about 1500 hours·ng / L, or about 1500 hours·ng / L to about 2000 hours·ng / L. 0-inf is within the range of about 80% to about 125% of about 1410 ng·h / L.0-inf is approximately 1410 ng·h / L.

[0307] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of the single dose results in a geometric mean T within the range of about 80% to about 125% of the T value at about 1 hour to about 4 hours. max For example, a single dose results in a geometric mean T of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours to about 5.0 hours. max In some embodiments, the geometric mean Tmax is about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, the T max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0308] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in a C in the range of about 80% to about 125%, of about 110 ng / L to about 400 ng / L. max For example, a single dose results in a C of about 88 ng / L, about 100 ng / L, about 125 ng / L, about 150 ng / L, about 175 ng / L, about 200 ng / L, about 225 ng / L, about 250 ng / L, about 275 ng / L, about 300 ng / L, about 325 ng / L, about 350 ng / L, about 375 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, about 475 ng / L, or about 500 ng / L (including all integers and ranges therebetween). max The median is provided. In some embodiments, the mean C maxThe median value is about 100 ng / L to about 500 ng / L, about 150 ng / L to about 450 ng / L, about 150 ng / L to about 400 ng / L, about 200 ng / L to about 350 ng / L, about 200 ng / L to about 300 ng / L, about 200 ng / L to about 250 ng / L, or about 210 ng / L to about 240 ng / L. max The median value is within the range of about 80% to about 125% of about 230 ng / L. max The median value is approximately 230 ng / L.

[0309] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in an AUC within the range of about 80% to about 125% of about 590 h·ng / L to about 4400 h·ng / L. 0-inf For example, a single dose may result in an AUC of about 475 h·ng / L, about 500 h·ng / L, about 1000 h·ng / L, about 1500 h·ng / L, about 2000 h·ng / L, about 2500 h·ng / L, about 3000 h·ng / L, about 3500 h·ng / L, about 4000 h·ng / L, about 4500 h·ng / L, about 5000 h·ng / L, or about 5500 h·ng / L (including all integers and ranges therebetween). 0-inf The median is taken. In some embodiments, the AUC 0-infThe median values ​​were approximately 500 hours·ng / L to approximately 5000 hours·ng / L, approximately 500 hours·ng / L to approximately 4000 hours·ng / L, approximately 500 hours·ng / L to approximately 3000 hours·ng / L, approximately 1000 hours·ng / L to approximately 3000 hours·ng / L, approximately 1000 hours·ng / L to approximately 2500 hours·ng / L, approximately 1000 hours·ng / L to approximately 2000 hours·ng / L, approximately 1000 hours·ng / L to approximately 1500 hours·ng / L, and approximately 1 In some embodiments, the AUC is between 500 hours·ng / L and about 2000 hours·ng / L, between about 1000 hours·ng / L and about 1500 hours·ng / L, between about 1500 hours·ng / L and about 2000 hours·ng / L, between about 1000 hours·ng / L and about 1250 hours·ng / L, between about 1000 hours·ng / L and about 1200 hours·ng / L, between about 1100 hours·ng / L and about 1200 hours·ng / L, or between about 1150 hours·ng / L and about 1250 hours·ng / L. 0-inf The median is within the range of about 80% to about 125% of about 1180 ng·h / L. 0-inf The median value is approximately 1180 ng·h / L.

[0310] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, administration of a single dose results in a T range of about 80% to about 125% for about 1 hour to about 4 hours. max For example, a single dose results in a T of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours to about 5.0 hours. max In some embodiments, the median Tmax is about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, the T max The median value is within the range of about 80% to about 125% of about 2 hours. max The median time is approximately 2 hours.

[0311] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 120 μg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0312] In some embodiments, the disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 180 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder I), and in some embodiments, the patient has both schizophrenia and a bipolar disorder (e.g., bipolar disorder I).

[0313] According to some embodiments of the method for treating agitation, comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, the composition may be administered by various means. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, bucally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or bucally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drop. In some embodiments, the composition is administered bucally in the form of a film, patch, or tablet.

[0314] According to some embodiments of a method for treating agitation comprising administering a unit dose composition containing about 180 μg of dexmedetomidine, the method may further comprise administering a second dose of dexmedetomidine after a period ranging from about 30 minutes to about 12 hours. For example, this period may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered about 2 hours later. In some embodiments, the second dose ranges from about 10 μg to about 180 μg. For example, the booster dose can be about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170, or about 180 μg. In some embodiments, the booster dose is about 60 μg or 90 μg.

[0315] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, the unit dose composition can be administered to a patient in a fasted state. In some embodiments, the unit dose composition is administered in a fed state.

[0316] According to some embodiments of a method for treating agitation comprising administering about 180 μg of a unit dose composition containing dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale Agitation Item (PEC) score compared to baseline. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences a 40% or greater reduction in PEC score from baseline. For example, patients experience about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150% or more from baseline. Therapeutic efficacy may also be compared by comparing the PEC score with a placebo. In some embodiments, the PEC score is 30% or more lower than the placebo (e.g., the placebo group has a mean change from baseline in the PEC total score of -3, and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient's PEC score is 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%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200% or more lower. In some embodiments, the patient experiences a mean PEC score change of more than about -4 (i.e., a decrease of 4 points or more) compared to baseline within 2 hours after administration of the composition. For example, at the 2 hour time point, a patient may experience a mean PEC score change of about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or greater than about -12.In some embodiments, the PEC score decrease (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -6 or less (e.g., -7, -8, etc.). In some embodiments, the PEC score decrease (e.g., greater than about -4) is substantially maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -4, about -5, or about -6 or less (e.g., -7, -8, etc.). In some embodiments, the mean PEC score change is -8 or greater and is maintained from 2 hours after administration of the composition up to at least about 24 hours after administration.

[0317] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0318] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of the single dose results in a mean Cmax within the range of about 80% to about 125% of about 100 ng / L to about 800 ng / L. max For example, C maxis about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 30 0ng / L, approximately 325ng / L, approximately 350ng / L, approximately 375ng / L, approximately 400ng / L, approximately 425ng / L, approximately 450ng / L, approximately 475ng / L, approximately 500ng / L, approximately 600ng / L , about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L (including all integers and ranges therebetween). max is about 100 ng / L to about 1000 ng / L, about 100 ng / L to about 800 ng / L, about 200 ng / L to about 600 ng / L, about 300 ng / L to about 600 ng / L, about 300 ng / L to about 500 ng / L, about 350 ng / L to about 500 ng / L, about 300 ng / L to about 450 ng / L, about 400 ng / L to about 500 ng / L, or about 400 ng / L to about 450 ng / L. In some embodiments, the average C max is within the range of about 80% to about 125% of about 440 ng / L. max is approximately 440 ng / L.

[0319] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of a single dose results in a mean AUC 180 μg / mL within the range of about 80% to about 125% of about 600 h·ng / L to about 9500 h·ng / L. 0-inf For example, AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 275 0 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 600 0 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L to approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 hours ng / L, approximately 925 0 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L (including all integers and ranges therebetween). 0-infis approximately 500 hours·ng / L to approximately 10,000 hours·ng / L, approximately 1,000 hours·ng / L to approximately 7,500 hours·ng / L, approximately 1,000 hours·ng / L to approximately 6,000 hours·ng / L, approximately 1,500 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 4 000 h·ng / L, about 2000 h·ng / L to about 3000 h·ng / L, about 2500 h·ng / L to about 4000 h·ng / L, about 3000 h·ng / L to about 4000 h·ng / L, about 3500 h·ng / L to about 4000 h·ng / L, or about 2500 h·ng / L to about 3000 h·ng / L. 0-inf is within the range of about 80% to about 125% of about 3800 ng·h / L. 0-inf is approximately 3800 ng·h / L.

[0320] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of the single dose results in a mean T within a range of about 80% to about 125% for about 1 hour to about 8 hours. max For example, a single dose can provide a therapeutic effect of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, Average T of approximately 5.25 hours, approximately 5.5 hours, approximately 5.75 hours, approximately 6.0 hours, approximately 6.25 hours, approximately 6.5 hours, approximately 6.75 hours, approximately 7.0 hours, approximately 7.25 hours, approximately 7.5 hours, approximately 7.75 hours, approximately 8.0 hours, approximately 8.25 hours, approximately 8.5 hours, approximately 8.75 hours, approximately 9.0 hours, approximately 9.25 hours, approximately 9.5 hours, approximately 9.75 hours to approximately 10 hours max In some embodiments, T maxis about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, T max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0321] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of the single dose results in a geometric mean C value within the range of about 80% to about 125% of about 100 ng / L to about 800 ng / L. max For example, C max is about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 30 0ng / L, approximately 325ng / L, approximately 350ng / L, approximately 375ng / L, approximately 400ng / L, approximately 425ng / L, approximately 450ng / L, approximately 475ng / L, approximately 500ng / L, approximately 600ng / L , about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L (including all integers and ranges therebetween). max is about 100 ng / L to about 1000 ng / L, about 100 ng / L to about 800 ng / L, about 200 ng / L to about 600 ng / L, about 300 ng / L to about 600 ng / L, about 300 ng / L to about 500 ng / L, about 350 ng / L to about 500 ng / L, about 300 ng / L to about 450 ng / L, about 400 ng / L to about 500 ng / L, about 400 ng / L to about 450 ng / L, about 350 ng / L to about 450 ng / L, or about 350 ng / L to about 400 ng / L. maxis in the range of about 80% to about 125% of about 380 ng / L. max is approximately 380 ng / L.

[0322] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of a single dose results in a geometric mean AUC within the range of about 80% to about 125% of about 600 h·ng / L to about 9500 h·ng / L. 0-inf For example, AUC 0-inf is approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 275 0 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 600 0 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L to approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 hours ng / L, approximately 925 0 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L (including all integers and ranges therebetween). 0-infis approximately 500 hours·ng / L to approximately 10,000 hours·ng / L, approximately 1,000 hours·ng / L to approximately 7,500 hours·ng / L, approximately 1,000 hours·ng / L to approximately 6,000 hours·ng / L, approximately 1,500 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 4 000 h·ng / L, about 2000 h·ng / L to about 3000 h·ng / L, about 2500 h·ng / L to about 4000 h·ng / L, about 3000 h·ng / L to about 4000 h·ng / L, about 3500 h·ng / L to about 4000 h·ng / L, or about 2500 h·ng / L to about 3000 h·ng / L. 0-inf is within the range of about 80% to about 125% of about 2880 ng·h / L. 0-inf is approximately 2880 ng·h / L.

[0323] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of the single dose results in a geometric mean T within the range of about 80% to about 125% of the T value at about 1 hour to about 8 hours. max For example, a single dose can provide a response of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about Geometric mean T of 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours to about 10 hours max In some embodiments, T maxis about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, the geometric mean T max is in the range of about 80% to about 125% of about 2 hours. In some embodiments, the geometric mean T max is about 2 hours.

[0324] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of a single dose results in a C in the range of about 80% to about 125%, of about 100 ng / L to about 800 ng / L. max The median is obtained. For example, C max is about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 30 0ng / L, approximately 325ng / L, approximately 350ng / L, approximately 375ng / L, approximately 400ng / L, approximately 425ng / L, approximately 450ng / L, approximately 475ng / L, approximately 500ng / L, approximately 600ng / L , about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L (including all integers and ranges therebetween). max The median value is about 100 ng / L to about 1000 ng / L, about 100 ng / L to about 800 ng / L, about 200 ng / L to about 600 ng / L, about 300 ng / L to about 600 ng / L, about 300 ng / L to about 500 ng / L, about 350 ng / L to about 500 ng / L, about 300 ng / L to about 450 ng / L, about 400 ng / L to about 500 ng / L, about 400 ng / L to about 450 ng / L, about 450 ng / L to about 500 ng / L, and about 470 ng / L to about 490 ng / L. maxThe median value is within the range of about 80% to about 125% of about 485 ng / L. max The median value is approximately 485 ng / L.

[0325] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of a single dose results in an AUC within the range of about 80% to about 125% of about 600 h·ng / L to about 9500 h·ng / L. 0-inf The median value is given, e.g., AUC 0-inf is approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 275 0 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 600 0 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L to approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 hours ng / L, approximately 925 0 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L (including all integers and ranges therebetween). 0-infis approximately 500 hours·ng / L to approximately 10,000 hours·ng / L, approximately 1,000 hours·ng / L to approximately 7,500 hours·ng / L, approximately 1,000 hours·ng / L to approximately 6,000 hours·ng / L, approximately 1,500 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 4 000 hours·ng / L, about 2000 hours·ng / L to about 3000 hours·ng / L, about 2500 hours·ng / L to about 4000 hours·ng / L, about 3000 hours·ng / L to about 4000 hours·ng / L, about 3500 hours·ng / L to about 4000 hours·ng / L, or about 2500 hours·ng / L to about 3000 hours·ng / L. 0-inf The median is within the range of about 80% to about 125% of about 2900 ng·h / L. 0-inf The median value is approximately 2900 ng·h / L.

[0326] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, administration of a single dose results in a T range of about 80% to about 125% for about 1 hour to about 8 hours. max For example, a single dose provides a median of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours , about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours, about 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours to about 10 hours T max In some embodiments, the median is given. maxis about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, T max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0327] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 180 μg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0328] In some embodiments, the disclosure provides a method of treating agitation associated with schizophrenia or bipolar disorder, comprising administering to a human patient a unit dose composition comprising about 120 to about 180 μg of dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the patient has schizophrenia, in some embodiments, the patient has bipolar disorder (e.g., bipolar disorder type I), and in some embodiments, the patient has both schizophrenia and bipolar disorder (e.g., bipolar disorder type I).

[0329] According to some embodiments of the method for treating agitation, comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, the composition may be administered by various means. For example, in some embodiments, a composition comprising dexmedetomidine (e.g., dexmedetomidine hydrochloride) or a pharmaceutically acceptable salt is administered sublingually, bucally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually or bucally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drop. In some embodiments, the composition is administered bucally in the form of a film, patch, or tablet.

[0330] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, the method may further comprise administering a second dose of dexmedetomidine after a period ranging from about 30 minutes to about 12 hours. For example, this period may be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, or about 23 hours. In some embodiments, the second dose is administered about 2 hours later. In some embodiments, the second dose is in the range of about 10 μg to about 180 μg. For example, the booster dose can be about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170, or about 180 μg. In some embodiments, the booster dose is about 60 μg or 90 μg.

[0331] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, the unit dose composition can be administered to a patient in a fasted state. In some embodiments, the unit dose composition is administered in a fed state.

[0332] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Syndrome Scale Agitation Item (PEC) score compared to baseline. In some embodiments, agitation is significantly reduced within about 45 minutes to about 1 hour. In some embodiments, agitation is significantly reduced in less than 45 minutes (e.g., about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes). In some embodiments, the patient experiences a 40% or greater reduction in PEC score from baseline. For example, patients experience about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150% or more from baseline. Therapeutic efficacy may also be compared by comparing the PEC score with a placebo. In some embodiments, the PEC score is 30% or more lower than the placebo (e.g., the placebo group has a mean change from baseline in the PEC total score of -3, and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient's PEC score is 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%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200% or more lower. In some embodiments, the patient experiences a mean PEC score change of more than about -4 (i.e., a decrease of 4 points or more) compared to baseline within 2 hours after administration of the composition. For example, at the 2 hour time point, a patient may experience a mean PEC score change of about -4, about -5, about -6, about -7, about -8, about -9, about -10, about -11, or greater than about -12.In some embodiments, the PEC score decrease (e.g., greater than about -4) is maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -6 or less (e.g., -7, -8, etc.). In some embodiments, the PEC score decrease (e.g., greater than about -4) is substantially maintained for at least 6 hours after administration of the composition. For example, if patients experience a mean change from baseline in PEC total score (e.g., of -6) at 2 hours, the mean PEC score change for patients at 6 hours is about -4, about -5, or about -6 or less (e.g., -7, -8, etc.). In some embodiments, the mean PEC score change is -8 or greater and is maintained from 2 hours after administration of the composition up to at least about 24 hours after administration.

[0333] According to some embodiments of a method for treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, the subject is treated without experiencing significant sedation. In some embodiments, the subject is treated without experiencing clinically significant cardiovascular effects.

[0334] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, administration of a single dose results in a mean Cmax within the range of about 80% to about 125% of about 100 ng / L to about 800 ng / L. max For example, C maxis about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 30 0ng / L, approximately 325ng / L, approximately 350ng / L, approximately 375ng / L, approximately 400ng / L, approximately 425ng / L, approximately 450ng / L, approximately 475ng / L, approximately 500ng / L, approximately 600ng / L , about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L (including all integers and ranges therebetween). max is about 100ng / L to about 1000ng / L, about 100ng / L to about 800ng / L, about 200ng / L to about 600ng / L, about 300ng / L to about 600ng / L, about 300ng / L to about 500ng / L, about 350ng / L to about 500ng / L, about 300ng / L to about 450ng / L, about 400ng / L to about 500ng / L, or In some embodiments, the average C is about 400 ng / L to about 450 ng / L, about 100 ng / L to about 500 ng / L, about 150 ng / L to about 450 ng / L, about 150 ng / L to about 400 ng / L, about 200 ng / L to about 350 ng / L, about 200 ng / L to about 300 ng / L, about 200 ng / L to about 250 ng / L, or about 210 ng / L to about 240 ng / L. max is in the range of about 80% to about 125% of 200 ng / L to about 500 ng / L. max is approximately 230 ng / L to approximately 440 ng / L.

[0335] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, administration of a single dose results in a mean AUC 100 / 1000 ng / L in the range of about 80% to about 125% of about 600 hr·ng / L to about 9500 hr·ng / L. 0-inf For example, AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 275 0 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 600 0 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L to approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 hours ng / L, approximately 925 0 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L (including all integers and ranges therebetween). 0-infis approximately 500 hours·ng / L to approximately 10,000 hours·ng / L, approximately 1,000 hours·ng / L to approximately 7,500 hours·ng / L, approximately 1,000 hours·ng / L to approximately 6,000 hours·ng / L, approximately 1,500 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 4,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 3,000 hours·ng / L, approximately 2,500 hours·ng / L to approximately 4,000 hours·ng / L, approximately 3,000 hours·ng / L to approximately 4,000 hours·ng / L, approximately 500 hours·ng / L to approximately 50 00 h·ng / L, about 500 h·ng / L to about 4000 h·ng / L, about 500 h·ng / L to about 3000 h·ng / L, about 1000 h·ng / L to about 3000 h·ng / L, about 1000 h·ng / L to about 2500 h·ng / L, about 1000 h·ng / L to about 2000 h·ng / L, about 1000 h·ng / L to about 1500 h·ng / L, or about 1500 h·ng / L to about 2000 h·ng / L, about 3500 h·ng / L to about 4000 h·ng / L, or about 2500 h·ng / L to about 3000 h·ng / L. 0-inf is in the range of about 80% to about 125% of 1400 ng·h / L to about 4000 ng·h / L. 0-inf is about 3800 ng·h / L. 0-inf is within the range of about 80% to about 125% of 1800 ng·h / L to about 3800 ng·h / L.

[0336] According to some embodiments of a method of treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, administration of the single dose results in a mean T within a range of about 80% to about 125% for about 1 hour to about 8 hours. maxFor example, a single dose can provide a therapeutic effect of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, Average T of approximately 5.25 hours, approximately 5.5 hours, approximately 5.75 hours, approximately 6.0 hours, approximately 6.25 hours, approximately 6.5 hours, approximately 6.75 hours, approximately 7.0 hours, approximately 7.25 hours, approximately 7.5 hours, approximately 7.75 hours, approximately 8.0 hours, approximately 8.25 hours, approximately 8.5 hours, approximately 8.75 hours, approximately 9.0 hours, approximately 9.25 hours, approximately 9.5 hours, approximately 9.75 hours to approximately 10 hours max In some embodiments, T max is about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, T max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0337] According to some embodiments of the method of treating agitation comprising administering a unit dose composition comprising about 120 μg to about 180 μg of dexmedetomidine, the aforementioned pharmacokinetic parameters are non-steady state.

[0338] In some embodiments, the present disclosure provides a method for treating or ameliorating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a human patient in need thereof, wherein the patient is at least 18 years of age and the withdrawal period is up to 14 days. "Opioid withdrawal" refers to a variety of symptoms and complaints that appear with the sudden removal or rapid reduction of a normal opioid dosage. Physical symptoms may include sweating, nausea, yawning, chills, diarrhea, nipple swelling, piloerection, tachycardia, elevated blood pressure, hyperalgesia, stomach cramps, and muscle spasms. Observed psychological symptoms of opioid withdrawal may include agitation, dysphoria, restlessness, irritability, anxiety, and depression. In some embodiments, the opioid withdrawal symptom is agitation. Onset often begins within 6 to 24 hours of the last opioid use. In some embodiments, treatment or amelioration of opioid withdrawal refers to treatment or alleviation of one or more of the aforementioned symptoms. Treatment or amelioration may be measured by various means known in the art, including, but not limited to, Clinical Opiate Withdrawal Scale (COWS) and / or Gossop's Short Term Opiate Withdrawal Scale (SOWS-Gossop) scores.

[0339] Thus, in some embodiments, the present disclosure provides methods for treating or ameliorating agitation associated with opioid withdrawal. In some embodiments, the treatment or amelioration comprises shortening the opioid withdrawal period. For example, a patient treated according to embodiments of the present disclosure may experience an opioid withdrawal period of about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days, whereas a similar patient not treated according to embodiments of the present disclosure would have a longer opioid withdrawal treatment period.

[0340] In some embodiments, the composition is administered twice daily. In some embodiments, the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in a dose range of about 30 μg to about 200 μg. For example, the composition comprises a unit dose of about 30 μg, about 60 μg, about 90 μg, about 120 μg, or 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In some embodiments, a single dose of a composition comprising about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for up to at least about 24 hours. In some embodiments, the composition is administered twice daily for 7 days.

[0341] In some embodiments, the patient is suffering from opioid withdrawal, and the opioid is one of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil, carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil, butorphanol, meperidine, methadone, dextropropoxyphene (propoxyphene), thebaine, sufentanil, and pentazocine. In some embodiments, the opioid is fentanyl. In some embodiments, the opioid was administered for a period of time longer than neonatal treatment prior to withdrawal.

[0342] In some embodiments, the composition is administered sublingually, bucally, orally, intranasally, or parenterally. In some embodiments, the composition is administered sublingually in the form of a tablet, film, spray, gel, or drop. In some embodiments, the composition is administered sublingually in the form of a film. In some embodiments, the composition is administered bucally in the form of a film, patch, or tablet. In some embodiments, the composition is administered bucally in the form of a film. In some embodiments, the patient is treated without inducing clinically significant cardiovascular effects.

[0343] In some embodiments, the present disclosure provides pharmaceutical compositions comprising about 20 μg to about 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In some embodiments, the dose of dexmedetomidine is about 120 μg. In some embodiments, the dose of dexmedetomidine is about 180 μg.

[0344] In some embodiments, the composition is formulated for sublingual or buccal administration. In some embodiments, the composition is formulated for sublingual administration in the form of a tablet, film, spray, gel, or drop. In some embodiments, the composition is formulated for buccal administration in the form of a film, patch, or tablet.

[0345] In some embodiments, a pharmaceutical composition comprising about 20 μg to about 240 μg of dexmedetomidine is administered to a patient with agitation associated with schizophrenia or bipolar disorder, and the agitation is significantly reduced within about 2 hours after administration of the composition, as measured by the mean change in the Positive and Negative Symptoms Scale Agitation Item (PEC) score compared to baseline. For example, the agitation is significantly reduced at 30 minutes, 45 minutes, 1 hour, 90 minutes, or about 2 hours. In some embodiments, the patient experiences a 40% or greater reduction in the PEC score from baseline. For example, patients experience about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150% or more from baseline. Therapeutic efficacy may also be compared by comparing the PEC score with a placebo. In some embodiments, the PEC score is 30% or more lower than the placebo (e.g., the placebo group has a mean change from baseline in the PEC total score of -3, and the dexmedetomidine-containing composition has a score of -3.9). For example, compared to placebo, the patient's PEC score is 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%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, or about 200% or more lower. In some embodiments, the patient experiences a mean PEC score change of more than about -4 (i.e., a decrease of 4 points or more) compared to baseline within 2 hours after administration of the composition. For example, at 2 hours, patients may experience a mean PEC score change of about −4, about −5, about −6, about −7, about −8, about −9, about −10, about −11, or greater than about −12. In some embodiments, the PEC score decrease (e.g., greater than about −4) is maintained for at least 6 hours after administration of the composition.For example, if a patient experiences a mean change from baseline in PEC total score at 2 hours (e.g., -6), then at 6 hours, the patient's mean PEC score change is about -6 or less (e.g., -7, -8, etc.). In some embodiments, the mean PEC score change is -8 or greater and is maintained from 2 hours after administration of the composition up to at least about 24 hours after administration.

[0346] According to some embodiments of pharmaceutical compositions comprising about 20 μg to about 240 μg of dexmedetomidine, subjects are treated without experiencing significant sedation. In some embodiments, subjects are treated without experiencing clinically significant cardiovascular effects.

[0347] Administration of a single dose of a pharmaceutical composition containing about 20 μg to about 240 μg of dexmedetomidine results in a mean C value within the range of about 80% to about 125% of about 100 ng / L to about 800 ng / L. max For example, C max is about 80ng / L, about 100ng / L, about 125ng / L, about 150ng / L, about 175ng / L, about 200ng / L, about 225ng / L, about 250ng / L, about 275ng / L, about 30 0ng / L, approximately 325ng / L, approximately 350ng / L, approximately 375ng / L, approximately 400ng / L, approximately 425ng / L, approximately 450ng / L, approximately 475ng / L, approximately 500ng / L, approximately 600ng / L , about 625 ng / L, about 650 ng / L, about 675 ng / L, about 700 ng / L, about 725 ng / L, about 750 ng / L, about 775 ng / L, about 800 ng / L, about 825 ng / L, about 850 ng / L, about 875 ng / L, about 900 ng / L, about 925 ng / L, about 950 ng / L, about 975 ng / L, or about 1000 ng / L (including all integers and ranges therebetween). maxis about 100ng / L to about 1000ng / L, about 100ng / L to about 800ng / L, about 200ng / L to about 600ng / L, about 300ng / L to about 600ng / L, about 300ng / L to about 500ng / L, about 350ng / L to about 500ng / L, about 300ng / L to about 450ng / L, about 400ng / L to about 500ng / L, or In some embodiments, the average C is about 400 ng / L to about 450 ng / L, about 100 ng / L to about 500 ng / L, about 150 ng / L to about 450 ng / L, about 150 ng / L to about 400 ng / L, about 200 ng / L to about 350 ng / L, about 200 ng / L to about 300 ng / L, about 200 ng / L to about 250 ng / L, or about 210 ng / L to about 240 ng / L. max is in the range of about 80% to about 125% of 200 ng / L to about 500 ng / L. max is approximately 230 ng / L to approximately 440 ng / L.

[0348] Administration of a single dose of a pharmaceutical composition containing about 20 μg to about 240 μg of dexmedetomidine results in a mean AUC within the range of about 80% to about 125% of about 600 h·ng / L to about 9500 h·ng / L. 0-inf For example, AUC 0-infis approximately 470 hours·ng / L, approximately 500 hours·ng / L, approximately 600 hours·ng / L, approximately 700 hours·ng / L, approximately 800 hours·ng / L, approximately 900 hours·ng / L, approximately 1000 hours·ng / L, approximately 1250 hours·ng / L, approximately 1500 hours·ng / L, approximately 1750 hours·ng / L, approximately 2000 hours·ng / L, approximately 2250 hours·ng / L, approximately 2500 hours·ng / L, approximately 275 0 hours ng / L, approximately 3000 hours ng / L, approximately 3250 hours ng / L, approximately 3500 hours ng / L, approximately 3750 hours ng / L, approximately 4000 hours ng / L, approximately 4250 hours ng / L, approx. 4500 hours ng / L, approx. 4750 hours ng / L, approx. 5000 hours ng / L, approx. 5250 hours ng / L ~ approx. 5500 hours ng / L, approx. 5750 hours ng / L, approx. 600 0 hours ng / L, approx. 6250 hours ng / L ~ approx. 6500 hours ng / L, approx. 6750 hours ng / L, approx. 7000 hours ng / L, approx. 7250 hours ng / L ~ approx. 7500 hours ng / L, approximately 7750 hours ng / L, approximately 8000 hours ng / L, approximately 8250 hours ng / L to approximately 8500 hours ng / L, approximately 8750 hours ng / L, approximately 9000 hours ng / L, approximately 925 0 h·ng / L, about 9500 h·ng / L, about 9750 h·ng / L, about 10000 h·ng / L, about 10250 h·ng / L, about 10500 h·ng / L, about 10750 h·ng / L, about 11000 h·ng / L, about 11250 h·ng / L, about 11500 h·ng / L to about 11875 h·ng / L (including all integers and ranges therebetween). 0-infis approximately 500 hours·ng / L to approximately 10,000 hours·ng / L, approximately 1,000 hours·ng / L to approximately 7,500 hours·ng / L, approximately 1,000 hours·ng / L to approximately 6,000 hours·ng / L, approximately 1,500 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 5,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 4,000 hours·ng / L, approximately 2,000 hours·ng / L to approximately 3,000 hours·ng / L, approximately 2,500 hours·ng / L to approximately 4,000 hours·ng / L, approximately 3,000 hours·ng / L to approximately 4,000 hours·ng / L, approximately 500 hours·ng / L to approximately 50 00 h·ng / L, about 500 h·ng / L to about 4000 h·ng / L, about 500 h·ng / L to about 3000 h·ng / L, about 1000 h·ng / L to about 3000 h·ng / L, about 1000 h·ng / L to about 2500 h·ng / L, about 1000 h·ng / L to about 2000 h·ng / L, about 1000 h·ng / L to about 1500 h·ng / L, or about 1500 h·ng / L to about 2000 h·ng / L, about 3500 h·ng / L to about 4000 h·ng / L, or about 2500 h·ng / L to about 3000 h·ng / L. 0-inf is in the range of about 80% to about 125% of 1400 ng·h / L to about 4000 ng·h / L. 0-inf is about 3800 ng·h / L. 0-inf is within the range of about 80% to about 125% of 1800 ng·h / L to about 3800 ng·h / L.

[0349] Administration of a single dose of a pharmaceutical composition containing about 20 μg to about 240 μg of dexmedetomidine results in a mean T within a range of about 80% to about 125% of that of about 1 hour to about 8 hours. maxFor example, a single dose can provide a therapeutic effect of about 0.8 hours, about 0.9 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, Average T of approximately 5.25 hours, approximately 5.5 hours, approximately 5.75 hours, approximately 6.0 hours, approximately 6.25 hours, approximately 6.5 hours, approximately 6.75 hours, approximately 7.0 hours, approximately 7.25 hours, approximately 7.5 hours, approximately 7.75 hours, approximately 8.0 hours, approximately 8.25 hours, approximately 8.5 hours, approximately 8.75 hours, approximately 9.0 hours, approximately 9.25 hours, approximately 9.5 hours, approximately 9.75 hours to approximately 10 hours max In some embodiments, T max is about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1.5 hours to about 3 hours, about 1.75 hours to about 2.5 hours, or about 1.75 hours to about 2.25 hours. In some embodiments, T max is in the range of about 80% to about 125% of about 2 hours. max is about 2 hours.

[0350] In some embodiments, the aforementioned pharmacokinetic parameters are non-steady state.

[0351] In some embodiments, the present disclosure provides methods for reducing agitation to 1 (very improved) or 2 (much improved) within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), as measured by the Clinical Global Impression-Improvement Scale. In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is maintained for more than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0352] In some embodiments, the present disclosure provides methods for reducing agitation to a rating of 3 (mild agitation) or 4 (normal behavior) within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the Agitation Calmness Scale (ACES). In some embodiments, the agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, the reduction in agitation is reduced to a rating of 4 (normal behavior). In some embodiments, the reduction in agitation is maintained for more than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0353] In some embodiments, the present disclosure provides methods of achieving a 40% or greater reduction in agitation within 2 hours after administration of a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by the PEC scale. In some embodiments, agitation is reduced within about 30 minutes to about 1 hour. In some embodiments, a reduction in agitation is 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, 90% or greater, or 100% or greater. In some embodiments, a reduction in agitation is maintained for more than about 2 hours. For example, the reduction in agitation is maintained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the composition comprises about 120 μg of dexmedetomidine. In some embodiments, the composition comprises about 180 μg of dexmedetomidine. In some embodiments, the patient has schizophrenia. In some embodiments, the patient has bipolar disorder.

[0354] In some embodiments, the present disclosure provides a method for achieving a sustained PEC score reduction in agitation in a subject with bipolar disorder or schizophrenia, comprising administering to the subject a pharmaceutical composi...

Claims

[Claim 1] The invention described in the specification.

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