Dexmedetomidine treatment regimen

Abstract

This specification discloses a method for administering dexmedetomidine or a pharmaceutically acceptable salt thereof to human subjects. The disclosed method is particularly suitable for the treatment of agitation associated with neurodegenerative diseases and / or neuropsychiatric disorders or disorders (e.g., Alzheimer's disease).

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority under 35 U.S. SC 119(e) to U.S. Provisional Patent Application No. 63 / 510,101 filed on 23 June 2023 and U.S. Provisional Patent Application No. 63 / 523,098 filed on 25 June 2023, the disclosures of which are incorporated herein by whole reference. This application also incorporates the subject matter of PCT Patent Application Publication No. WO2022 / 147537 filed on 4 January 2022, by whole reference. [Background technology]

[0002] On December 17, 1999, the U.S. Food and Drug Administration approved the dexmedetomidine product, PRECEDEX® (formulated as an intravenous solution for continuous infusion, indicated as a sedative for patients who are initially intubated and placed on mechanical ventilation during procedures in the intensive care unit). PRECEDEX® was later approved as a sedative for non-intubated patients before and / or during surgical and other procedures.

[0003] Dexmedetomidine is often administered intravenously and via other routes to treat a variety of conditions (e.g., pain, anxiety, delirium, withdrawal symptoms, sleep disturbances, and agitation) before or after surgery. However, administering dexmedetomidine in an appropriate dosage form that provides effective and rapid relief without causing significant sedation is a challenging task. The use of dexmedetomidine is also limited in clinical practice due to common side effects (e.g., hypotension and bradycardia). For example, serious cardiovascular side effects have occurred at therapeutic doses after administration of dexmedetomidine hydrochloride as a sublingual spray, tablet, or intravenously. Therefore, there is a continuing and unmet need for an effective dexmedetomidine product that is effective without causing significant sedation and, preferably, without serious adverse effects (cardiovascular events). The unmet need for an independent medicine that can effectively treat agitation and signs of agitation without causing the aforementioned adverse effects or sedation is particularly serious. [Overview of the Initiative]

[0004] The inventors of this application have, surprisingly, found that relatively low doses of dexmedetomidine or a pharmaceutically acceptable salt thereof are effective in treating agitation or signs of agitation in patients with dementia. For example, when dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to patients with dementia, C is more effective compared to the same dose administered to patients with schizophrenia and bipolar disorder. max The pharmacokinetic effect is approximately 38% higher, and the AUC is approximately 55% higher. Surprisingly, the inventors also found that the pharmacokinetic effects after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof differ in the treatment of agitation in patients with different underlying conditions. For example, sublingual or buccal administration of approximately 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to patients with dementia yields a pharmacokinetic effect similar to that of sublingual or buccal administration of approximately 90 μg of dexmedetomidine hydrochloride to patients with schizophrenia or bipolar disorder.

[0005] In other embodiments, the Disclosure provides a method for treating agitation or signs of agitation in human subjects suffering from dementia without inducing significant sedation, the method comprising administering about 30 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0006] In embodiments, the present disclosure provides a method for treating agitation or signs of agitation in elderly dementia patients (e.g., 65 years of age or older), the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at a concentration of approximately 50 ng / L to approximately 300 ng / L of dexmedetomidine C max The method includes administering a dose sufficient to obtain the desired result, with the route of administration being the oral mucosa, preferably sublingual, buccal, or gingival. In embodiments, the patient is an elderly patient (e.g., about 65 years of age or older).

[0007] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to patients in a distressed state suffering from dementia in doses of approximately 30 μg to approximately 90 μg. In the embodiment, a unit dose containing approximately 30 μg to approximately 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered 1 to 6 times a day at intervals of at least 2 hours (e.g., approximately 2, 4, 6, 8, 10, or 12 hours) if there is persistent or recurrent distress. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in doses of approximately 30 μg, approximately 40 μg, approximately 50 μg, approximately 60 μg, approximately 70 μg, approximately 80 μg, or approximately 90 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in doses of approximately 30 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 40 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 50 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 60 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 70 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 80 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 90 μg.

[0008] In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a patient in an agitated state suffering from dementia at a dose of approximately 30 to 90 μg, and the patient has not received treatment for hypertension prior to the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiments, the patient has not received treatment for hypertension within approximately 10 hours, approximately 1 day, or approximately 1 week prior to the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiments, the patient is not sedated after the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiments, the route of administration is oral mucosa, and oral mucosal administration includes sublingual, buccal, or gingival administration. In the embodiments, AUC 0-8The range is approximately 200hr × ng / L to approximately 1500hr × ng / L. In the embodiment, AUC 0-inf The range is approximately 200hr × ng / L to approximately 2200hr × ng / L. In the embodiment, agitation is acute agitation. In the embodiment, agitation is chronic agitation. In the embodiment, AUC value and C max The values ​​are in the range of approximately 80% to approximately 125% of the given values. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) is administered as a film to the oral mucosa (e.g., sublingual or buccal). In embodiments, the patient achieves a mean change in PEC score of less than -2 relative to baseline within 2 hours of administration of the composition. In embodiments, the patient achieves a mean change in PAS score of less than -2 relative to baseline within 2 hours of administration of the composition. In embodiments, the patient achieves a mean change in Mod-CMAI score of less than -7 relative to baseline 2 hours after administration of the composition. In embodiments, the patient achieves an improvement of approximately 1 (very improved) or approximately 2 (significantly improved) in the CGI-I score. In embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior), as measured on the Agitation and Sedation Rating Scale (ACES), within approximately 2 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In this embodiment, the elderly patient is approximately 70 years of age or older. In this embodiment, the elderly patient is approximately 75 to 80 years of age. In this embodiment, the elderly patient is approximately 80 years of age or older.

[0009] In embodiments, the Disclosure provides a method for treating acute agitation or signs of agitation in human subjects suffering from dementia, the method comprising administering about 40 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof is done "as needed".

[0010] In embodiments, the Disclosure provides a method for treating acute agitation or signs of agitation in human subjects suffering from dementia, the method comprising administering about 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof is performed "as needed" (or PRN).

[0011] In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the subject. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered sublingually. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered orally.

[0012] In embodiments, the present disclosure provides a method for treating an acute agitated episode in a patient with Alzheimer's disease, the method comprising administering 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the patient, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient, the agitation is moderate to severe, and the patient is at least 65 years old, optionally at least 75 years old.

[0013] In the embodiments, agitation is not due to pain, infection, concomitant medications, environmental conditions, or mental states other than dementia.

[0014] In this embodiment, the patient does not exhibit delirium.

[0015] In this embodiment, the patient receives sublingual administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the patient is orally administered dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0017] In this embodiment, the patient is determined to have a total score of 14 or higher on the Positive / Negative Symptom Rating Scale (PANSS) - Agitation Item (PEC) scale before administration.

[0018] In this embodiment, the PEC score decreases by approximately 4 to 6 points within 2 hours after administration.

[0019] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, a spray, or a cachet. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

[0020] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as needed (or PRN).

[0021] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times daily.

[0022] In the embodiment, the subjects had not previously received treatment with antipsychotic drugs.

[0023] In this embodiment, the subject has previously received treatment with antipsychotic drugs.

[0024] In this embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once daily.

[0025] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for at least 24 hours, 48 ​​hours, 1 week, 2 weeks, 4 weeks, or 6 weeks. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for 12 weeks. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered up to 28 times within a 12-week period. In the embodiment, the subject is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 doses of dexmedetomidine or a pharmaceutically acceptable salt thereof within a 12-week period.

[0026] In this embodiment, the agitation is psychomotor agitation.

[0027] In the embodiments, the route of administration is the oral mucosa (e.g., sublingual, buccal, or gingival). In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a film to the oral mucosa. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a sublingual film. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as an intraoral film. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a gingival film.

[0028] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt is administered orally via the mucosa for at least 1, 2, 6, or 12 weeks. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt is administered orally via the mucosa for approximately 15, 18, 21, or 24 weeks or more. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt is administered orally via the mucosa for as long as necessary until the underlying disease is resolved.

[0029] In the embodiments, the subjects are diagnosed with Alzheimer's disease based on the 2018 NIA-AA criteria. In the embodiments, the subjects suffer from both dementia and Alzheimer's disease.

[0030] In the embodiment, the target MMSE score is 15-23. In the embodiment, the target MMSE score is 16. In the embodiment, the target MMSE score is 17. In the embodiment, the target MMSE score is 18. In the embodiment, the target MMSE score is 19. In the embodiment, the target MMSE score is 20. In the embodiment, the target MMSE score is 21. In the embodiment, the target MMSE score is 22.

[0031] In this embodiment, the subjects have a total score of 14 or higher on the PEC scale prior to administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0032] In the embodiment, subjects have a total score of 8 or higher on four items, including the Pittsburgh Agitation Scale (PAS), which comprises abnormal vocalizations, motor agitation, aggression, and resistance to care, prior to administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0033] In this embodiment, the subject has suffered from dementia for approximately 2 years. In this embodiment, the subject has suffered from dementia for approximately 3 years. In this embodiment, the subject has suffered from dementia for approximately 4 years. In this embodiment, the subject has suffered from dementia for approximately 5 years or more.

[0034] In this embodiment, the subject is an elderly patient. In this embodiment, the elderly patient is 65 years of age or older. In this embodiment, the elderly patient is 80 years of age. In this embodiment, the elderly patient is over 80 years of age.

[0035] In some embodiments, agitation is chronic. In some embodiments, agitation is moderate to severe. In some embodiments, agitation is mild.

[0036] In the embodiment, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in only mild to moderate adverse effects.

[0037] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in the total PEC score compared to the baseline score (i.e., before administration). In the embodiments, a mean change in PEC score below -2 relative to baseline is achieved within 2 hours of administration.

[0038] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in PAS scores compared to baseline scores (i.e., pre-administration scores). In the embodiments, a mean change in PAS scores below -2 compared to baseline is achieved within 2 hours after administration.

[0039] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in ACES scores compared to baseline scores (i.e., pre-administration). In the embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior), as measured by the Agitation and Sedation Rating Scale (ACES), within approximately two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0040] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in the CGI-I score compared to the baseline score (i.e., before administration). In the embodiments, an improvement of approximately 1 (very improved) or approximately 2 (significantly improved) in the CGI-I score is observed.

[0041] In the embodiments, improvement in scores is observed as early as 30 minutes after administration. In the embodiments, improvement in scores is observed as early as 1 hour after administration. In the embodiments, improvement in scores is observed as early as 2 hours after administration.

[0042] In other embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering to the subject about 30 μg to about 600 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (e.g., sublingual, buccal, or gingival). In embodiments, the withdrawal period is up to about 14 days. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa twice daily in unit doses containing about 30 μg, about 60 μg, about 90 μg, about 120 μg, about 150 μg, about 180 μg, about 240 μg, or about 300 μg. In embodiments, the withdrawal period may 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 other embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering to the subject about 30 μg to about 600 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (e.g., sublingual, buccal, or gingival). In embodiments, the withdrawal period is up to about 60 days. In this embodiment, the withdrawal period may be 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 days. In the embodiments, the human subjects are adults (e.g., 18 years of age or older). In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered via the oral mucosa (e.g., sublingual, buccal, gingival), orally, intranasally, or parenterally. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) is administered sublingually as a film. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g., dexmedetomidine hydrochloride) is administered buccally or sublingually as a film.In embodiments, opioid withdrawal is withdrawal from the use of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil, carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil, butorphanol, meperidine, methadone, dextropropoxifen (propoxifen), thebaine, sufentanil, or pentazocine, or a combination thereof.

[0043] In embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt (e.g., dexmedetomidine hydrochloride) to the oral mucosa (i.e., sublingual, buccal, or gingival) of the subject in an amount of about 30 μg to about 600 μg. In embodiments, the mean plasma concentration is in the range of about 40 ng / L to about 500 ng / L two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., dexmedetomidine hydrochloride). In embodiments, the mean plasma concentration is in the range of about 20 ng / L to about 150 ng / L twelve hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride). In the embodiment, the mean plasma concentration is in the range of approximately 50 ng / L to approximately 500 ng / L two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride). In the embodiment, the mean plasma concentration is in the range of approximately 10 ng / L to 150 ng / L twelve hours after administration of dexmedetomidine or a pharmaceutically acceptable salt.

[0044] In other embodiments, the present disclosure provides a method of treating agitation in patients with agitation-related dementia who need it. The method includes administering to the patient a mucoadhesive oral mucosa (e.g., sublingual, buccal, or gingival) composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof in an amount of about 30 μg to about 120 μg. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the mucosa once or twice a day in unit doses containing 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, or about 120 μg. In embodiments, the patient has Alzheimer's disease. In embodiments, the patient is 65 to 80 years old. In embodiments, the dose is about 30 mcg, and administration to the oral mucosa results in C max being about 36 ng / L to about 147 ng / L, and AUC 0-inf being about 200 hr×ng / L to about 1500 hr×ng / L. In embodiments, the dose is about 40 mcg, and administration to the oral mucosa results in C max being about 50 ng / L to about 300 ng / L, and AUC 0-inf being about 200 hr×ng / L to about 1500 hr×ng / L.

[0045] The present invention also provides a method for managing or treating agitation in a delirious subject, the method comprising administering to the subject about 20 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiment, the subject is hospitalized. In the embodiment, the subject is hospitalized in the intensive care unit. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally via the mucous membrane (e.g., sublingual, buccal, or gingival) in doses of about 20 μg, about 30 μg, about 60 μg, about 80 μg, about 90 μg, about 100 μg, about 120 μg, about 150 μg, about 180 μg, about 210 μg, about 240 μg, about 270 μg, or about 300 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered 1 to 6 times a day. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily. To achieve the desired dose, dexmedetomidine can be administered orally via the mucosa as a single dose, multiple doses, or one or more unit doses (e.g., half a dose), or in combination thereof. For example, to administer 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, the subject may be administered, for example, a single unit dose of 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, two doses of 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, or three doses of 40 mg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film. Therefore, half doses can be achieved by cutting the film in half (for example, cutting a 120 μg or 180 μg film in half) to obtain doses of 60 μg and 90 μg, respectively. In embodiments, multiple doses (e.g., 1 to 4 times) can be administered at appropriate intervals (e.g., every 0.5 hours) to obtain the desired effect; for example, a 20 μg unit dose or a 60 μg unit dose can be administered four times at 0.5-hour intervals within 6 hours of the first dose to obtain the effects of doses of 80 μg and 240 μg, respectively.In the embodiment, each drug unit may be administered 1 to 2 times at appropriate dosing intervals (every 12 hours) to obtain the desired effect; for example, 120 μg units may be administered twice a day at 12-hour intervals to obtain the effect of a 240 μg dose. In the embodiment, each drug unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., every 1 to 6 hours) to obtain the desired effect; for example, a 120 μg dose (starting dose) may be administered, followed by 7 more doses at intervals of approximately 1 to 6 hours to obtain a maximum cumulative dose of 960 μg. In the embodiment, each drug unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., every 1 to 6 hours) to obtain the desired effect; for example, a 180 μg dose (starting dose) may be administered, followed by 120 μg 6 times a day at intervals of approximately 1 to 6 hours to obtain a maximum cumulative dose of 900 μg. In the embodiments, each dosing unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., at least 1 to 6 hours) to obtain the desired effect; for example, a dose of 240 μg (starting dose) is administered, followed by an additional 120 μg six times a day at intervals of approximately 1 to approximately 6 hours to obtain a maximum cumulative dose of 960 μg. In the embodiments, each dosing unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., at least 1 to 6 hours) to obtain the desired effect; for example, a dose of 300 μg (starting dose) is administered, followed by an additional 120 μg five times a day at intervals of approximately 1 to 6 hours to obtain a maximum cumulative dose of 900 μg. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film to the oral mucosa (e.g., sublingual or buccal). In the embodiments, the subjects are 18 to 64 years old. In the embodiments, the subjects are over 65 years old. In the embodiment, dexmedetomidine is administered 1 to 6 times daily at doses of approximately 60 μg, 90 μg, 120 μg, and 150 μg (for example, in patients 65 years of age or older). In the embodiment, dexmedetomidine is administered 1 to 6 times daily at doses of approximately 120 μg, 180 μg, 240 μg, and 300 μg (for example, in patients under 65 years of age). In the embodiment, subjects are treated without experiencing clinically significant cardiovascular effects.

[0046] In embodiments, the Disclosure provides a method for managing or treating agitation or signs of agitation in delirium subjects, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof in doses of approximately 20 μg, approximately 40 μg, approximately 60 μg, approximately 90 μg, approximately 120 μg, or approximately 150 μg, when the subject is 65 years of age or older. In embodiments, the doses may be administered 1 to 10 times at appropriate intervals (e.g., 1 to 6 hours) to obtain the desired effect; for example, a dose of approximately 60 μg, 90 μg, 120 μg, or 150 μg (starting dose) is administered, followed by an additional 60 μg 5 to 7 times a day at intervals of approximately 1 to approximately 6 hours to obtain a maximum cumulative dose of 480 μg.

[0047] The present invention also provides pharmaceutical compositions comprising about 20 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In one embodiment, the dose of dexmedetomidine is about 30 μg. In another embodiment, the dose of dexmedetomidine is about 40 μg. In yet another embodiment, the dose of dexmedetomidine is about 60 μg. In yet another embodiment, the dose of dexmedetomidine is about 90 μg. In yet another embodiment, the dose of dexmedetomidine is about 120 μg. In yet another embodiment, the dose of dexmedetomidine is about 150 μg. In yet another embodiment, the dose of dexmedetomidine is about 180 μg. In yet another embodiment, the dose of dexmedetomidine is about 240 μg. In yet another embodiment, the dose of dexmedetomidine is about 300 μg. In this embodiment, the dosage can be taken 1 to 10 times a day. [Brief explanation of the drawing]

[0048] [Figure 1] This shows the change in PEC score from baseline up to 8 hours after administration of 30 μg and 60 μg of dexmedetomidine oral mucosal thin film in elderly dementia patients, compared to placebo. [Figure 2]This shows the change in PAS scores from baseline up to 8 hours after administration of 30 μg and 60 μg of dexmedetomidine oral mucosal thin film in elderly dementia patients, compared to placebo. [Figure 3] This shows the change in Mod-CMAI scores from baseline 2 hours after administration of 30 μg and 60 μg of dexmedetomidine oral mucosal thin film in elderly dementia patients, compared to placebo. [Figure 4] The response rates (%) in elderly dementia patients, measured by Clinical Global Impression-I (CGI-I), are shown at 1, 2, 4, and 8 hours after administration of oral mucosal films containing 30 μg (center bar) and 60 μg (right bar), compared to placebo (left bar). [Figure 5] The image shows improved sedation (measured using the Accelerated Agitation and Sedation Scale (ACES)) in elderly dementia patients two hours after administration of oral mucosal films containing 30 μg (center bar) and 60 μg (right bar) compared to placebo (left bar). [Figure 6] The dose-dependent relationship between Cmax (top) and AUC0-8 (bottom) in elderly dementia patients is shown. [Figure 7] This shows score simulations for placebo and SL-dosing regimens. [Figure 8] This shows a simulation of the percentage change in PEC from baseline for placebo and SL-administered regimens. [Figure 9] This shows PAS score simulations for placebo and SL-dosing regimens. [Figure 10] This shows a simulation of the percentage change in PAS from baseline for placebo and SL-administered regimens. [Figure 11] This shows CMAI score simulations for placebo and SL-dosing regimens. [Figure 12] This shows the simulation of the change in CMAI (percentage) from baseline for placebo and SL-administered regimens. [Figure 13] This shows the change in total PEC score from baseline over time, within 4 hours of the first dose (FAS population). [Figure 14] Significant changes in the total PANSS excitatory component (PEC) score from baseline were observed for the initial dose and all subsequent doses, and the response to all treatment episodes in Example 5 was demonstrated by PEC. [Figure 15] Significant response rates were observed 1 and 2 hours after the initial 60mcg dose, and clinically significant improvement was confirmed by CGI-I according to Example 5. [Figure 16] The clinically meaningful improvements observed in all treatment-induced episodes, as shown in CGI-I according to Example 5, are demonstrated. [Figure 17] The results from the initial administration in Example 5 demonstrate a significant sedative effect, as evidenced by the Agitation and Sedation Assessment Scale (ACES) score. [Modes for carrying out the invention]

[0049] Abbreviation ACES: A scale for evaluating agitation and sedation.

[0050] AD: Alzheimer's disease

[0051] AE: Adverse event

[0052] AUC: Area under the curve

[0053] AUC 0-8 Area under the plasma concentration-time curve from administration to 8 hours later

[0054] AUC 0-inf Area under the plasma concentration-time curve from administration to infinity

[0055] AUD: Alcohol Use Disorder

[0056] BAC / BrAC: Exhaled alcohol concentration

[0057] BAES: Biphasic Alcohol Efficacy Scale

[0058] BID: Twice a day

[0059] BMI: Body Mass Index

[0060] CAPS-5: Clinical Diagnostic Interview Scale for PTSD (DSM-5 compliant)

[0061] CGI-I: Clinical General Impression - Improvement

[0062] CGI-S: Clinical General Impression - Severity

[0063] CIWA-AR: Clinical Alcohol Withdrawal Assessment Scale

[0064] CLIA: Clinical Laboratory Improvement Method

[0065] C max :Maximum plasma concentration

[0066] COWS: Clinical Opioid Withdrawal Scale

[0067] CMAI: Cohen-Mansfield Intensity Rating Scale

[0068] CMC: Carboxymethylcellulose

[0069] C-SSRS: Columbia Suicide Severity Scale

[0070] CT: Computed Tomography

[0071] DBP: Diastolic blood pressure

[0072] DEQ: Drug Effects Questionnaire

[0073] DES-R: Differential Emotion Scale

[0074] Dex or DEX: Dexmedetomidine

[0075] DSM: Diagnostic and Statistical Manual of Mental Disorders

[0076] DSMB: Drug Safety Monitoring Board

[0077] DT: Collapse Time

[0078] ECG: Electrocardiogram

[0079] FTD: Frontotemporal lobe disease

[0080] HPC: Hydroxypropylcellulose

[0081] HPMC: Hydroxypropylmethylcellulose

[0082] HR: Heart rate

[0083] HVLT-R: Hopkins Language Learning Test

[0084] ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

[0085] ICU-Intensive Care Unit

[0086] IUD: Intrauterine contraceptive device

[0087] ITT: Treatment Intention Group

[0088] LAR: Legally Recognized Representative

[0089] LEC-5: Life Event Checklist (DSM-5 Compatible)

[0090] LS: Least Squares Method

[0091] MedDRA: International Glossary of Medical Terms

[0092] MINI-5: Mini International Neuropsychiatric Interview (DSM-5 compliant)

[0093] MMRM: Mixed Model Repeating Index

[0094] MMSE: Mini-Mental State Examination

[0095] MW: molecular weight

[0096] mm: millimeters

[0097] mcg: microgram

[0098] mg: milligrams

[0099] μg: microgram

[0100] ml: milliliter

[0101] mmHg: millimeters of mercury

[0102] msec: milliseconds

[0103] NDS: Alcohol Consumption Scale

[0104] ng: nanogram

[0105] PANSS: Positive and Negative Syndrome Scale

[0106] PAS: Pittsburgh Intensity Scale

[0107] PCL-5: DSM-5 PTSD Checklist

[0108] PCRS: Placebo-controlled reminder script

[0109] PEC:PANSS excitement ingredient

[0110] PEO: Polyethylene oxide

[0111] PD: Pharmacodynamic

[0112] PK: Pharmacokinetics

[0113] PTSD: Post-Traumatic Stress Disorder

[0114] PVA: Polyvinyl alcohol

[0115] QTcF: QT interval corrected for heart rate using the Fridericia formula.

[0116] QID: 4 times a day

[0117] RASS: Richmond Agitation and Sedation Scale

[0118] RVIP: Rapid Information Processing Challenges

[0119] SAE: Serious Adverse Event

[0120] SOWS-Gossop: Gossop's Simplified Opioid Withdrawal Scale

[0121] SAP: Statistical Analysis Plan

[0122] SBP: Systolic blood pressure

[0123] SD: standard deviation

[0124] SE: standard error

[0125] SL: sublingual

[0126] STAI: State Trait Anxiety Scale

[0127] T 1 / 2 : Half-life of excretion

[0128] TEAE: Adverse events that occur as a result of treatment

[0129] TLFB: Timeline Follow Back

[0130] Tmax: Time to maximum plasma concentration

[0131] Wt%: Percentage by weight

[0132] ULN: upper limit of normality

[0133] VAS: Visual Analog Scale

[0134] YCS: Yale Craving Scale

[0135] YMRS: Young Mania Rating Scale

[0136] definition Throughout this specification, numerical ranges are provided for specific quantities. It should be understood that these ranges include all subranges within them. Therefore, the range "50 to 80" includes all possible ranges within it (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 can be endpoints of the range it encompasses (e.g., the range 50 to 80 includes ranges with endpoints such as 55 to 80, 50 to 75, etc.).

[0137] The terms "a" or "an" refer to one or more of the entities. Therefore, in this specification, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably. In addition, references to "drugs" with the indefinite article "a" or "an" do not preclude the possibility of two or more drugs being present unless the context clearly requires the presence of only one or just one of the drugs.

[0138] As used herein, "approximately" means plus or minus 10% of the indicated value.

[0139] As used herein, the term “agitation” means irritability, emotional outbursts, thought disturbances, or excessive motor and verbal activity that may result from dysfunction of a specific brain region (e.g., the frontal lobe) or a neurotransmitter system (e.g., dopamine and norepinephrine). In this disclosure, agitation also includes aggression and hyperarousal in post-traumatic stress disorder. Agitation may be acute or chronic.

[0140] The term "buccal" refers to the administration of a dosage form into the gums and the inside of the lips or cheeks.

[0141] As used herein, the term “comprise” and its conjugations as used herein and in the claims are used in a non-restrictive sense to mean that the items following the word are included, but not excluded, except for items not specifically mentioned. This disclosure may appropriately “comprise,” “consist of,” or “consist essentially of” the steps, elements, and / or reagents described in the claims.

[0142] In this specification, the term “clinically significant cardiovascular effect” means a decrease in blood pressure (hypotension) and / or heart rate (bradycardia) to such an extent that medical intervention is required to address cardiovascular side effects, and the term “medical intervention” means an intervention more serious than the administration of liquids such as energy drinks.

[0143] As used herein, the phrase “deposited on the surface of a polymer matrix” means that dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a liquid composition separately from the preparation of a solid polymer matrix and deposited, for example, as one or more microdeposits on the solid polymer, which then dries. Hereinafter, the dried product is sometimes referred to as a “microdeposited matrix film.” Liquid formulations of the drug may be in any form (including liquids, emulsions, suspensions, or dispersions).

[0144] As used herein, the expression "placed within a polymer matrix" means that dexmedetomidine or a pharmaceutically acceptable salt thereof is directly incorporated into the polymer solution before the formation of a solid polymer matrix film composition.

[0145] The term "soluble" means that the films herein disintegrate readily after being administered to the oral mucosa, for example, within at least about 20 minutes. Disintegration is achieved by saliva and / or other aqueous substances on the mucosal surface.

[0146] The term "effective dose" is interchangeable with "therapeutic effective dose" or "therapeutic effective amount" and refers to a quantity sufficient to produce the desired effect. An effective dose is sufficient to improve the condition in question (e.g., agitation).

[0147] As used herein, the term “film” includes thin films of any shape (including rectangular, square, or other desired shapes). The film may be of any desired thickness and size so as to be conveniently positioned on the patient’s oral mucosa. For example, the film may be a relatively thin film with a thickness of about 20 to 200 micrometers, or a slightly thicker film with a thickness of about 20 to 1000 micrometers. In embodiments, the film may be even thicker, for example, having a thickness of more than about 30 millimeters.

[0148] The terms “formulation” and “composition” shall be used interchangeably unless they are intended to have clearly different meanings.

[0149] The term "intranasal administration" refers to the administration of a drug via the nasal route, where the drug is inhaled through the nose. Administration can be either topical or systemic, meaning that a drug delivered topically may exert either a purely topical or systemic effect.

[0150] In this specification, the term "mucosal attachment" is used to refer to attachment to mucous membranes (e.g., the mucous membranes of the oral cavity).

[0151] The term "mucosal adhesion" refers to the property of adhering to the surface of mucosal tissue in vivo. Such adhesion requires the formulation to adhere to and localize on the mucosa, and then force is applied to separate the mucosal adhesive material from the mucosa.

[0152] "Opioid or alcohol or substance withdrawal" refers to a range of signs and symptoms that appear as a result of abruptly discontinuing or rapidly reducing the regular use of opioids, alcohol, or other substances. Physical symptoms may include sweating, nausea, yawning, chills, diarrhea, nipple dilation, piloerection, tachycardia, increased blood pressure, hypersensitivity to pain, stomach cramps, and muscle spasms. Opioid or alcohol or substance withdrawal is a set of symptoms (syndrome) resulting from the abrupt discontinuation or reduction of opioid alcohol or other substances, especially if previous use was heavy and prolonged. Signs and symptoms of withdrawal may include drug cravings, anxiety, restless legs, nausea, vomiting, diarrhea, sweating, and increased heart rate. Psychological symptoms of opioid withdrawal may include agitation, dysphoria, lack of sedation, irritability, anxiety, and depression. In embodiments, opioid withdrawal symptoms are agitation. In the embodiments, treatment or improvement of opioid withdrawal means treating or alleviating one or more of the symptoms described above.

[0153] The term "oral mucosa" means administration to the oral mucosa, specifically the oral cavity and / or pharynx. Oral mucosal administration includes administration via the sublingual, buccal, or gingival route.

[0154] The term "parenteral" refers to the administration of a drug by injection beneath one or more layers of the skin or mucous membrane, and may include, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular injection.

[0155] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inert substance intended to be used as a carrier. Where used herein, the terms "carrier" and "excipient" are interchangeable unless explicitly intended to have distinct meanings.

[0156] The term "pharmaceutically acceptable salt" refers to a salt that is known to be non-toxic and is 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, and hypophosphorous acid. Salts derived from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanonic acids, hydroxyalkanoic and hydroxylalkanedionic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, may also be used. Hydrochloride salts are preferred.

[0157] The term "self-supporting" means that the films described herein maintain structural integrity during handling without requiring a backing layer. Some degree of flexibility is considered in the films, and this may be desirable.

[0158] The term “signs of agitation” includes excessive motor activity (e.g., pacing, rocking, gesturing, pointing, restlessness, repetitive gestures), verbal aggression (e.g., shouting, speaking excessively loudly, using abusive language, yelling, shouting, threatening others), physical aggression (e.g., grabbing, pushing violently, shoving, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, self-inflicted harm, slamming doors, tearing objects), and property destruction.

[0159] As used herein, the terms “subject” or “patient” preferably refer to a human subject or patient. However, in embodiments, the subject may be any animal (e.g., a non-human mammal, e.g., a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, or primate).

[0160] The term "significantly reduced" refers to a reduction level of at least 10%, preferably 20%, more preferably 40%, even more preferably 60%, even more preferably 80%, and 90% or more compared to a control. For example, those skilled in the art will readily understand that the reduction can be determined in relation to agitation using well-known agitation measures (e.g., PEC score and CGI-I). For example, when agitation is significantly reduced in a patient, the reduction may be interpreted as a patient achieving a reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more in the total PEC score from baseline (e.g., determined 2 hours after administration). In embodiments, significantly reduced agitation refers to a reduction of at least 40% in the total PEC score from baseline. Similarly, a significant reduction in agitation can be determined using the CGI-I scale, which may refer to patients with a score of 1 or 2 on the CGI-I scale (e.g., determined 1, 2, or 4 hours after administration) or the Agitation-Sedation Rating Scale (ACES), or, for example, patients with a score of 3 or higher.

[0161] "Sublingual" means "below the tongue" and refers to a method of administering substances through the blood vessels beneath the tongue. Sublingual absorption occurs through the vascularized sublingual mucosa, which allows the substance to reach the bloodstream directly, thereby providing direct systemic delivery with no gastrointestinal effects and avoiding undesirable first-pass hepatic metabolism.

[0162] As used herein, “treatment” refers to procedures and / or prevention, as the context may indicate.

[0163] As used herein, the terms “to treat,” “to treat,” and “treatment” refer to a specific disease or disorder, which includes the reduction, improvement, mitigation, or elimination of the symptoms and / or condition of the disease or disorder.

[0164] The term "prevention" means preventing the onset of a disease or condition or related symptoms, or, for example, preventing its recurrence after a period of improvement.

[0165] The terms “unit dose,” “unit dosage,” or “unit dosage form” refer to a physically distinct unit containing a predetermined amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0166] As used herein, the term “water-soluble polymer” means (i) a polymer that is at least partially soluble in water, preferably completely or largely soluble in water, and / or (ii) a polymer that absorbs water. A polymer that absorbs water is referred to herein as a water-swellable polymer.

[0167] Terms such as "no significant sedation" mean that the patient experiences a level of sedation of 3 or less on the Ramsay Sedation Scale. Level 3 means being sedated but responsive to instructions. In embodiments, dexmedetomidine may be administered to result in a Richmond Agitation Sedation Scale (RASS) score of -1 ("mild sedation").

[0168] AUC 0-inf The term AUC represents the total amount of exposure to a drug over an entire period of time. 0-inf AUC last and AUC ext It is calculated as the sum of AUC. last AUC is calculated by integrating the concentration-time data using the trapezoidal rule up to the last quantifiable concentration. ext This is calculated by dividing the last quantifiable concentration by the discharge rate constant.

[0169] The terms "PRN" or "as needed" refer to the fact that the prescribed medication (dexmedetomidine sublingual film as used herein) is not scheduled for administration, but rather administered as needed.

[0170] Active ingredients The IUPAC name for dexmedetomidine is (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As monohydrochloride, it is primarily used as a therapeutic agent to sedate patients during procedures in an intensive care setting, or as a sedative to patients before and / or during surgical and other procedures. Such pharmaceuticals are currently marketed under the registered trademark name "PRECEDEX®".

[0171] Pharmacopoecitable salts of dexmedetomidine that may be included herein generally include any suitable salts that are approved or may be approved for human administration by the U.S. FDA or other appropriate foreign or national agency. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphate, dihydrophosphate, sulfuric acid, hydrosulfic acid, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, such as 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 acidic salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine forate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, and dexmedetomidine ascorbate. Embodiments may include deuterated forms of dexmedetomidine or pharmaceutically acceptable salts thereof.

[0172] Method and administration In embodiments, the disclosure includes a method for treating agitation or signs of agitation in a subject, the method comprising oral mucosal administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to a subject in an agitated state. In embodiments, the disclosure includes a method for treating agitation or signs of agitation in a subject with dementia, the method comprising oral mucosal administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to a subject in an agitated state. In embodiments, the disclosure provides a method for treating agitation in elderly patients with dementia, the method comprising oral mucosal administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state. In embodiments, the disclosure provides a method for managing or treating agitation in a delirious subject, the method comprising oral mucosal administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state. In embodiments, the disclosure also provides a method for treating or improving opioid withdrawal or related symptoms, the method comprising orally administering dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a patient in need. In embodiments, the disclosure provides a method for treating cocaine toxicity and / or symptoms related to cocaine toxicity, the method comprising orally administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the disclosure provides a method for treating agitation or signs of agitation in pediatric subjects, the method comprising orally administering dexmedetomidine or a pharmaceutically acceptable salt thereof to subjects in an agitated state. In embodiments, agitation is acute agitation. In embodiments, agitation is chronic agitation. In embodiments, the present invention is a method for treating agitation without inducing significant sedation. In embodiments, the treatment is effective without causing clinically significant cardiovascular effects.

[0173] In the various methods of the present invention, exemplary doses of dexmedetomidine or a pharmaceutically acceptable salt to be administered to a particular patient depend on the type and severity of symptoms, the overall health status of the particular patient, the specific form of dexmedetomidine or a pharmaceutically acceptable salt to be administered, and the specific formulation used to treat the patient. In embodiments, one or more units (e.g., a film composition) are administered to deliver the dose. In embodiments, the dose may be administered in combination of two or more dose units, for example, 60 μg (30 μg units + 30 μg units), 90 μg (30 μg units + 60 μg units), 120 μg (60 μg units + 60 μg units), 150 μg (half of 120 μg units + half of 180 μg units), 240 μg (180 μg units + half of 120 μg units), 300 μg (120 μg units + 180 μg units), and so on. The dosage may be administered once or more times a day (including two, three, four, five, or six times a day).

[0174] In the embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt administered is about 0.5 μg to about 1200 μg. Examples of preferred dosages include, for example, 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.

[0175] In the embodiment, the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is approximately 10 μg to approximately 300 μg, for example, approximately 10 μg, approximately 15 μg, approximately 20 μg, approximately 25 μg, approximately 30 μg, approximately 35 μg, approximately 40 μg, approximately 45 μg, approximately 50 μg, approximately 55 μg, approximately 60 μg, approximately 65 μg, approximately 70 μg, approximately 75 μg, approximately 80 μg, approximately 85 μg, approximately 90 μg, approximately 95 μg, approximately 100 μg, approximately 105 μg, approximately 110 μg, approximately 115 μg, approximately 120 μg, approximately 125 μg, approximately 130 μg, approximately 135 μg, approximately 140 μg, approximately 145 μg, approximately 150 μg, approximately It may be administered in doses of 155 μg, approximately 160 μg, approximately 165 μg, approximately 170 μg, approximately 175 μg, approximately 180 μg, approximately 185 μg, approximately 190 μg, approximately 195 μg, approximately 200 μg, approximately 205 μg, approximately 210 μg, approximately 215 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 235 μg, approximately 240 μg, approximately 245 μg, approximately 250 μg, approximately 255 μg, approximately 260 μg, approximately 265 μg, approximately 270 μg, approximately 275 μg, approximately 280 μg, approximately 285 μg, approximately 290 μg, approximately 295 μg, and approximately 300 μg (including all values ​​and ranges in between).

[0176] In the embodiment, the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 120 μg to about 405 μg, for example, about 120 μg, about 125 μg, about 130 μg, about 135 μg, about 140 μg, about 145 μg, about 150 μg, about 155 μg, about 160 μg, about 165 μg, about 170 μg, about 175 μg, about 180 μg, about 185 μg, about 190 μg, about 195 μg, about 200 μg, about 205 μg, about 210 μg, about 215 μg, about 220 μg, about 225 μg, about 230 μg, about 235 μg, about 240 μg, about 245 μg, about 250 μg, about 255 μg It may be administered in doses of approximately μg, approximately 260 μg, approximately 265 μg, approximately 270 μg, approximately 275 μg, approximately 280 μg, approximately 285 μg, approximately 290 μg, approximately 295 μg, approximately 300 μg, approximately 305 μg, approximately 310 μg, approximately 315 μg, approximately 320 μg, approximately 325 μg, approximately 330 μg, approximately 335 μg, approximately 340 μg, approximately 345 μg, approximately 350 μg, approximately 355 μg, approximately 360 μg, approximately 365 μg, approximately 370 μg, approximately 375 μg, approximately 380 μg, approximately 385 μg, approximately 390 μg, approximately 395 μg, approximately 400 μg, or approximately 405 μg (including all values ​​and ranges in between). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered in doses of about 120 μg to about 405 μg, for example, about 120 μg to about 270 μg, about 120 μg, and about 180 μg.

[0177] In the embodiment, the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is approximately 10 μg to approximately 300 μg, for example, approximately 10 μg, approximately 15 μg, approximately 20 μg, approximately 25 μg, approximately 30 μg, approximately 35 μg, approximately 40 μg, approximately 45 μg, approximately 50 μg, approximately 55 μg, approximately 60 μg, approximately 65 μg, approximately 70 μg, approximately 75 μg, approximately 80 μg, approximately 85 μg, approximately 90 μg, approximately 95 μg, approximately 100 μg, approximately 105 μg, approximately 110 μg, approximately 115 μg, approximately 120 μg, approximately 125 μg, approximately 130 μg, approximately 135 μg, approximately 140 μg, approximately 145 μg, approximately 150 μg, approximately 155 μg, approximately 16 It can be administered via oral mucosa (e.g., sublingually or buccally) in doses of 0 μg, approximately 165 μg, approximately 170 μg, approximately 175 μg, approximately 180 μg, approximately 185 μg, approximately 190 μg, approximately 195 μg, approximately 200 μg, approximately 205 μg, approximately 210 μg, approximately 215 μg, approximately 220 μg, approximately 225 μg, approximately 230 μg, approximately 235 μg, approximately 240 μg, approximately 245 μg, approximately 250 μg, approximately 255 μg, approximately 260 μg, approximately 265 μg, approximately 270 μg, approximately 275 μg, approximately 280 μg, approximately 285 μg, approximately 290 μg, approximately 295 μg, and approximately 300 μg (including all values ​​and ranges in between). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered via the oral mucosa (e.g., sublingually or buccally) in doses of about 10 μg to about 300 μg, for example, 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.

[0178] In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 300 μg. In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 270 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 240 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 210 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 180 μg. In one embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 150 μg. In another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 120 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 90 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 60 μg. In yet another embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 40 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered orally via the mucosa in an amount of approximately 30 μg. In the embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in doses of approximately 30 μg to approximately 180 μg (e.g., 30 μg, 40 μg, 45 μg, 60 μg, 90 μg, 120 μg, or 180 μg). In the embodiment, one or more units are administered to deliver the dose.

[0179] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered intramuscularly in doses of approximately 100 μg to approximately 200 μg, for example, approximately 100 μg, approximately 105 μg, approximately 110 μg, approximately 115 μg, approximately 120 μg, approximately 125 μg, approximately 130 μg, approximately 135 μg, approximately 140 μg, approximately 145 μg, approximately 150 μg, approximately 155 μg, approximately 160 μg, approximately 165 μg, approximately 170 μg, approximately 175 μg, approximately 180 μg, approximately 185 μg, approximately 190 μg, approximately 195 μg, or approximately 200 μg (including all values ​​and ranges in between). In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered intramuscularly in doses of about 100 μg to about 200 μg, for example, about 120 μg to about 190 μg.

[0180] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 500 μg to about 1500 μg based on the total weight of the oral composition, for example, about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about 550 μg, about 560 μg, about 570 μg, about 580 μg, about 590 μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 680 μg, about 690 μg, about 700 μg, about 710μg, about 720μg, about 730μg, about 740μg, about 750μg, about 760μg, about 770μg, about 780μg, about 790μg, about 800μg, about 810μg, about 820μg, about 830μg, about 840μg, about 850μg, about 86 0μg, about 870μg, about 880μg, about 890μg, about 900μg, about 910μg, about 920μg, about 930μg, about 940μg, about 950μg, about 960μg, about 970μg, about 980μg, about 990μg, about 1000μg, about 101 0μg, about 1020μg, about 1030μg, about 1040μg, about 1050μg, about 1060μg, about 1070μg, about 1080μg, about 1090μg, about 1100μg, about 1110μg, about 1120μg, about 1130μg, about 1140μg , about 1150μg, about 1160μg, about 1170μg, about 1180μg, about 1190μg, about 1200μg, about 1210μg, about 1220μg, about 1230μg, about 1240μg, about 1250μg, about 1260μg, about 1270μg, about 1 It can be administered orally in doses of 280 μg, approximately 1290 μg, approximately 1300 μg, approximately 1310 μg, approximately 1320 μg, approximately 1330 μg, approximately 1340 μg, approximately 1350 μg, approximately 1360 μg, approximately 1370 μg, approximately 1380 μg, approximately 1390 μg, approximately 1400 μg, approximately 1410 μg, approximately 1420 μg, approximately 1430 μg, approximately 1440 μg, approximately 1450 μg, approximately 1460 μg, approximately 1470 μg, approximately 1480 μg, approximately 1490 μg, or approximately 1500 μg (including all values ​​and ranges in between).

[0181] In this embodiment, the dose is approximately 30 μg, and the AUC 0-8The range is approximately 200hr×ng / L to approximately 600hr×ng / L, for example, approximately 200hr×ng / L to approximately 400hr×ng / L, approximately 300hr×ng / L to approximately 600hr×ng / L, approximately 300hr×ng / L to approximately 500hr×ng / L, and approximately 350hr×ng / L to approximately 450hr×ng / L.

[0182] In this embodiment, the dose is approximately 30 μg, and the AUC 0-infThis ranges from approximately 200 hours × ng / L to approximately 1700 hours × ng / L, for example, approximately 200 hr × ng / L, approximately 225 ng × hr / mL, approximately 250 ng × hr / mL, approximately 275 ng × hr / mL, approximately 300 ng × hr / mL, approximately 325 ng × hr / mL, approximately 350 ng × hr / mL, approximately 375 ng × hr / mL, approximately 400 ng × hr / mL, approximately 425 ng × hr / mL, approximately 450 ng × hr / mL, approximately 475 ng × hr / mL, approximately 500 ng × hr / mL, approximately 525 ng × hr / mL, approximately 550 ng × hr / mL, approximately 575ng×hr / mL, approximately 600ng×hr / mL, approximately 625ng×hr / mL, approximately 650ng×hr / mL, approximately 675ng×hr / mL, approximately 700ng×hr / mL, approximately 725ng×hr / mL, approximately 750ng×hr / mL , about 775ng×hr / mL, about 800ng×hr / mL, about 825ng×hr / mL, about 850ng×hr / mL, about 875ng×hr / mL, about 900ng×hr / mL, about 925ng×hr / mL, about 950ng×hr / mL, about 975n g × hr / mL, approximately 1000ng × hr / mL, approximately 1025ng × hr / mL, approximately 1050ng × hr / mL, approximately 1075ng × hr / mL, approximately 1100ng × hr / mL, approximately 1125ng × hr / mL, approximately 1150ng × hr / mL, approximately 11 75ng×hr / mL, approx. 1200ng×hr / mL, approx. 1225ng×hr / mL, approx. 1250ng×hr / mL, approx. 1275ng×hr / mL, approx. 1300ng×hr / mL, approx. 1325ng×hr / mL, approx. 1350ng×hr / mL, approx. These values ​​are 1375 ng × hr / mL, approximately 1400 ng × hr / mL, approximately 1425 ng × hr / mL, approximately 1450 ng × hr / mL, approximately 1475 ng × hr / mL, approximately 1500 ng × hr / mL, approximately 1525 ng × hr / mL, approximately 1550 ng × hr / mL, approximately 1575 ng × hr / mL, approximately 1600 ng × hr / mL, approximately 1625 ng × hr / mL, approximately 1650 ng × hr / mL, approximately 1675 ng × hr / mL, or approximately 1700 ng × hr / mL (including all values ​​and ranges in between).

[0183] In this embodiment, the dose is approximately 30 μg, and the AUC 0-8 The range is approximately 80% to 125% of approximately 200 hours × ng / L to approximately 600 hours × ng / L, and the AUC0-inf The range is approximately 80% to 125% of the range between approximately 200 hours × ng / L and approximately 1700 hours × ng / L.

[0184] In this embodiment, the dose is approximately 40 μg, and the AUC 0-inf The range is approximately 300hr×ng / L to 2200hr×ng / L, 500hr×ng / L to 1500hr×ng / L, 500hr×ng / L to 1400hr×ng / L, 500hr×ng / L to 1000hr×ng / L, 600hr×ng / L to 1400hr×ng / L, 600hr×ng / L to 1200hr×ng / L, 600hr×ng / L to 1000hr×ng / L, 800hr×ng / L to 1400hr×ng / L, or approximately 80% to 125% of 800hr×ng / L to 1000hr×ng / L.

[0185] In this embodiment, the dose is approximately 40 μg, and the AUC 0-infThis ranges from approximately 300 hr × ng / L to approximately 2200 hr × ng / L, for example, approximately 300 hr × ng / L, approximately 325 ng × hr / mL, approximately 350 ng × hr / mL, approximately 375 ng × hr / mL, approximately 400 ng × hr / mL, approximately 425 ng × hr / mL, approximately 450 ng × hr / mL, approximately 475 ng × hr / mL, approximately 500 ng × hr / mL, approximately 525 ng × hr / mL, approximately 550 ng × hr / mL, approximately 575 ng × hr / mL, approximately 600 ng × hr / mL, approximately 625 ng × hr / mL, approximately 650 ng × hr / mL, approximately 675 ng × hr / mL, and approximately 700 ng × hr / mL. L, approximately 725ng×hr / mL, approximately 750ng×hr / mL, approximately 775ng×hr / mL, approximately 800ng×hr / mL, approximately 825ng×hr / mL, approximately 850ng×hr / mL, approximately 875ng×hr / mL, approximately 900ng×hr / mL, approximately 925ng×hr / mL, approximately 950n g×hr / mL, approximately 975ng×hr / mL, approximately 1000ng×hr / mL, approximately 1025ng×hr / mL, approximately 1050ng×hr / mL, approximately 1075ng×hr / mL, approximately 1100ng×hr / mL, approximately 1125ng×hr / mL, approximately 1150ng×hr / mL, approximately 1175n g × hr / mL, approximately 1200ng × hr / mL, approximately 1225ng × hr / mL, approximately 1250ng × hr / mL, approximately 1275ng × hr / mL, approximately 1300ng × hr / mL, approximately 1325ng × hr / mL, approximately 1350ng × hr / mL, approximately 1375ng × hr / mL, approximately 140 0ng x hr / mL, approx. 1425ng x hr / mL, approx. 1450ng x hr / mL, approx. 1475ng x hr / mL, approx. 1500ng x hr / mL, approx. 1525ng x hr / mL, approx. 25ng×hr / mL, approximately 1650ng×hr / mL, approximately 1675ng×hr / mL, approximately 1700ng×hr / mL, approximately 1725ng×hr / mL, approximately 1750ng×hr / mL, approximately 1775ng×hr / mL, approximately 1800ng×hr / mL, approximately 1825ng×hr / mL, approximately 1850ng×hr / mL, approximately 1875ng×hr / mL, approximately 1900ng×hr / mL, approximately 1925ng×hr / mL, approximately 1950ng×hr / mL, approximately 1975ng×hr / mL, approximately 2000ng×hr / mL, approximately 2025ng×hr / mL, approximately 2050ng×hr / mL,The values ​​are approximately 2075 ng × hr / mL, approximately 2100 ng × hr / mL, approximately 2125 ng × hr / mL, approximately 2150 ng × hr / mL, approximately 2175 ng × hr / mL, or approximately 2200 ng × hr / mL (including all values ​​and ranges in between). In the embodiment, the dose is approximately 40 μg, and the AUC is 0-inf The range is approximately 300hr×ng / L to approximately 2200hr×ng / L, for example, approximately 400hr×ng / L to approximately 2000hr×ng / L, approximately 400hr×ng / L to approximately 1800hr×ng / L, approximately 500hr×ng / L to approximately 1500hr×ng / L, for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L.

[0186] In this embodiment, the dose is approximately 45 μg, and the AUC 0-8 The range is approximately 80% to 125% of the following ranges: approximately 500hr×ng / L to approximately 900hr×ng / L, approximately 500hr×ng / L to approximately 800hr×ng / L, approximately 600hr×ng / L to approximately 900hr×ng / L, approximately 600hr×ng / L to approximately 800hr×ng / L, and approximately 650hr×ng / L to approximately 750hr×ng / L.

[0187] In this embodiment, the dose is approximately 45 μg, and the AUC 0-8 The range is approximately 500hr×ng / L to approximately 900hr×ng / L, for example, approximately 500hr×ng / L to approximately 800hr×ng / L, approximately 600hr×ng / L to approximately 900hr×ng / L, approximately 600hr×ng / L to approximately 800hr×ng / L, and approximately 650hr×ng / L to approximately 750hr×ng / L.

[0188] In this embodiment, the dose is approximately 60 μg, and the AUC 0-8 The range is approximately 80% to 125% of approximately 500 hours × ng / L to approximately 1500 hours × ng / L, and the AUC 0-infThe range is approximately 80% to 125% of the range between approximately 500 hours × ng / L and approximately 2000 hours × ng / L.

[0189] In this embodiment, the dose is approximately 60 μg, and the AUC 0-infThis ranges from approximately 500 hours × ng / L to approximately 3500 hours × ng / L, for example, approximately 500 hr × ng / L, approximately 550 ng × hr / mL, approximately 600 ng × hr / mL, approximately 650 ng × hr / mL, approximately 700 ng × hr / mL, approximately 750 ng × hr / mL, approximately 800 ng × hr / mL, approximately 850 ng × hr / mL, approximately 900 ng × hr / mL, approximately 950 ng × hr / mL, approximately 1000 ng × hr / mL, approximately 1050 ng × hr / mL, approximately 1100 ng × hr / mL, approximately 1150 ng × hr / mL, approximately 1200 ng × hr / mL, approximately 1250ng×hr / mL, approximately 1300ng×hr / mL, approximately 1350ng×hr / mL, approximately 1400ng×hr / mL, approximately 1450ng×hr / mL, approximately 1500ng×hr / mL, approximately 1550ng×hr / mL, approximately 1600ng× hr / mL, approximately 1650ng×hr / mL, approximately 1700ng×hr / mL, approximately 1750ng×hr / mL, approximately 1800ng×hr / mL, approximately 1850ng×hr / mL, approximately 1900ng×hr / mL, approximately 1950ng×hr / mL, approximately 2000ng×h r / mL, approximately 2050ng×hr / mL, approximately 2100ng×hr / mL, approximately 2150ng×hr / mL, approximately 2200ng×hr / mL, approximately 2250ng×hr / mL, approximately 2300ng×hr / mL, approximately 2350ng×hr / mL, approximately 2400ng×h r / mL, approximately 2450ng×hr / mL, approximately 2500ng×hr / mL, approximately 2550ng×hr / mL, approximately 2600ng×hr / mL, approximately 2650ng×hr / mL, approximately 2700ng×hr / mL, approximately 2750ng×hr / mL, approximately 2800ng×h The values ​​are r / mL, approximately 2850 ng×hr / mL, approximately 2900 ng×hr / mL, approximately 2950 ng×hr / mL, approximately 3000 ng×hr / mL, approximately 3050 ng×hr / mL, approximately 3100 ng×hr / mL, approximately 3150 ng×hr / mL, approximately 3200 ng×hr / mL, approximately 3250 ng×hr / mL, approximately 3300 ng×hr / mL, approximately 3350 ng×hr / mL, approximately 3400 ng×hr / mL, approximately 3450 ng×hr / mL, or approximately 3500 ng×hr / mL (including all values ​​and ranges in between). In the embodiment, the dose is approximately 60 μg, and the AUC 0-infThe range is approximately 500hr×ng / L to 3500hr×ng / L, approximately 500hr×ng / L to 3000hr×ng / L, approximately 500hr×ng / L to 2500hr×ng / L, approximately 500hr×ng / L to 2000hr×ng / L, for example, approximately 600hr×ng / L to 1900hr×ng / L, approximately 700hr×ng / L to 1800hr×ng / L, approximately 700hr×ng / L to 1700hr×ng / L, approximately 700hr×ng / L to 1600hr×ng / L, approximately 700hr×ng / L to approximately 1500hr×ng / L, approximately 800hr×ng / L to approximately 1500hr×ng / L, approximately 900hr×ng / L to approximately 1500, approximately 1000hr×ng / L to approximately 1500hr×ng / L, approximately 1100hr×ng / L to approximately 1500hr×ng / L, approximately 1200hr×ng / L to approximately 1500hr×ng / L, approximately 1300hr×ng / L to approximately 1500hr×ng / L, or approximately 1400hr×ng / L to approximately 1500hr×ng / L.

[0190] In this embodiment, the dose is approximately 60 μg, and the AUC 0-8 The range is approximately 500hr×ng / L to approximately 1500hr×ng / L, for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L.

[0191] In this embodiment, the dose is approximately 90 μg, and the AUC 0-8 The range is approximately 500hr×ng / L to 1500hr×ng / L, approximately 500hr×ng / L to 1400hr×ng / L, approximately 500hr×ng / L to 1000hr×ng / L, approximately 600hr×ng / L to 1400hr×ng / L, approximately 600hr×ng / L to 1200hr×ng / L, approximately 600hr×ng / L to 1000hr×ng / L, approximately 800hr×ng / L to 1400hr×ng / L, or 80% to 125% of approximately 800hr×ng / L to 1000hr×ng / L.

[0192] In this embodiment, the dose is approximately 90 μg, and the AUC 0-infThis ranges from approximately 500 hr × ng / L to approximately 5000 hr × ng / L, for example, approximately 500 hr × ng / L, approximately 550 ng × hr / mL, approximately 600 ng × hr / mL, approximately 650 ng × hr / mL, approximately 700 ng × hr / mL, approximately 750 ng × hr / mL, approximately 800 ng × hr / mL, approximately 850 ng × hr / mL, approximately 900 ng × hr / mL, approximately 950 ng × hr / mL, approximately 1000 ng × hr / mL, approximately 1050 ng × hr / mL, approximately 1100 ng × hr / mL, approximately 1150 ng × hr / mL, approximately 1200 ng × hr / mL, approximately 1250 ng × hr / mL, approximately 1300 ng×hr / mL, approximately 1350ng×hr / mL, approximately 1400ng×hr / mL, approximately 1450ng×hr / mL, approximately 1500ng×hr / mL, approximately 1550ng×hr / mL, approximately 1600ng×hr / mL, approximately 1650ng×hr / mL, approximately 1700ng×hr / mL, approximately 175 22 00ng×hr / mL, approximately 2250ng×hr / mL, approximately 2300ng×hr / mL, approximately 2350ng×hr / mL, approximately 2400ng×hr / mL, approximately 2450ng×hr / mL, approximately 2500ng×hr / mL, approximately 2550ng×hr / mL, approximately 2600ng×hr / mL, approximately 2 650ng×hr / mL, approximately 2700ng×hr / mL, approximately 2750ng×hr / mL, approximately 2800ng×hr / mL, approximately 2850ng×hr / mL, approximately 2900ng×hr / mL, approximately 2950ng×hr / mL, approximately 3000ng×hr / mL, approximately 3050ng×hr / mL, approximately 3100ng×hr / mL, approx. 3150ng×hr / mL, approx. 3200ng×hr / mL, approx. 3250ng×hr / mL, approx. 3300ng×hr / mL, approx. 3350ng×hr / mL, approx. 3400ng×hr / mL, approx. 3450ng×hr / mL, approx. 3500ng×hr / mL, Approximately 3550ng×hr / mL, approximately 3600ng×hr / mL, approximately 3650ng×hr / mL, approximately 3700ng×hr / mL, approximately 3750ng×hr / mL, approximately 3800ng×hr / mL, approximately 3850ng×hr / mL, approximately 3900ng×hr / mL, approximately 3950ng×hr / mL,These values ​​are approximately 4000 ng × hr / mL, 4050 ng × hr / mL, 4100 ng × hr / mL, 4150 ng × hr / mL, 4200 ng × hr / mL, 4250 ng × hr / mL, 4300 ng × hr / mL, 4350 ng × hr / mL, 4400 ng × hr / mL, 4450 ng × hr / mL, 4500 ng × hr / mL, 4550 ng × hr / mL, 4600 ng × hr / mL, 4650 ng × hr / mL, 4700 ng × hr / mL, 4750 ng × hr / mL, 4800 ng × hr / mL, 4850 ng × hr / mL, 4900 ng × hr / mL, 4950 ng × hr / mL, or approximately 5000 ng × hr / mL (including all values ​​and ranges in between). In this embodiment, the dose is approximately 90 μg, and the AUC is 0-inf The range is approximately 500hr×ng / L to approximately 5000hr×ng / L, for example, approximately 500hr×ng / L to approximately 4500hr×ng / L, approximately 500hr×ng / L to approximately 4000hr×ng / L, approximately 500hr×ng / L to approximately 3500hr×ng / L, approximately 500hr×ng / L to approximately 3000hr×ng / L, approximately 500hr×ng / L to approximately 2500hr×ng / L, approximately 500hr×ng / L to approximately 2000hr×ng / L is approximately 500hr × ng / L to approximately 1400hr × ng / L, approximately 500hr × ng / L to approximately 1000hr × ng / L, approximately 600hr × ng / L to approximately 1400hr × ng / L, approximately 600hr × ng / L to approximately 1200hr × ng / L, approximately 600hr × ng / L to approximately 1000hr × ng / L, approximately 800hr × ng / L to approximately 1400hr × ng / L, or approximately 800hr × ng / L to approximately 1000hr × ng / L.

[0193] In this embodiment, the dose is approximately 90 μg, and the AUC 0-8The range is approximately 500hr×ng / L to approximately 1500hr×ng / L, for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L.

[0194] Advantageously, the dosage is in the range of approximately 50 ng / L to approximately 500 ng / L, for example, approximately 50 ng / L to approximately 400 ng / L, preferably approximately 50 ng / L to approximately 300 ng / L. max Present.

[0195] Advantageously, the dosage is in the range of about 50 ng / L to about 500 ng / L (for example, about 50 ng / L to about 400 ng / L, preferably about 50 ng / L to about 300 ng / L) C max The following is presented. Advantageously, the dosage is approximately 200hr × ng / L to approximately 1500hr × ng / L, for example, approximately 200hr × ng / L to approximately 1250hr × ng / L, approximately 200hr × ng / L to approximately 1000hr × ng / L, approximately 200hr × ng / L to approximately 750hr × ng / L, approximately 200hr × ng / L to approximately 500hr × ng / L, approximately 500hr × ng / L to approximately 1500hr × ng / L, approximately 500hr × ng / L~Approx. 1250hr×ng / L, Approx. 500hr×ng / L~Approx. 1000hr×ng / L, Approx. 500hr×ng / L~Approx. 750hr×ng / L, Approx. 750hr×ng / L~Approx. 1500hr×n g / L, AUC in the range of approximately 750hr×ng / L to approximately 1250hr×ng / L, approximately 750hr×ng / L to approximately 1000hr×ng / L, approximately 1000hr×ng / L to approximately 1500hr×ng / L 0-8The following is presented. In the embodiment, the dose is approximately 200hr×ng / L, approximately 300hr×ng / L, approximately 400hr×ng / L, approximately 500hr×ng / L, approximately 600hr×ng / L, approximately 700hr×ng / L, approximately 800hr×ng / L, approximately 900hr×ng / L, approximately 1000hr×ng / L, approximately 1100hr×ng / L, approximately 1200hr×ng / L, approximately 1300hr×ng / L, approximately 1400hr×ng / L, or approximately 1500hr×ng / L AUC 0-8 The following is presented. Advantageously, this dose offers an AUC in the range of approximately 200hr×ng / L to approximately 2200hr×ng / L, approximately 200hr×ng / L to approximately 2000hr×ng / L, for example, approximately 300hr×ng / L to approximately 1900hr×ng / L, approximately 400hr×ng / L to approximately 1800hr×ng / L, approximately 500hr×ng / L to approximately 1700hr×ng / L, approximately 500hr×ng / L to approximately 1600hr×ng / L, approximately 500hr×ng / L to approximately 1500hr×ng / L, approximately 600hr×ng / L to approximately 1500hr×ng / L, and approximately 700hr×ng / L to approximately 1500hr×ng / L. 0-inf The following is presented. In this embodiment, the dosage is approximately 200hr×ng / L, approximately 300hr×ng / L, approximately 400hr×ng / L, approximately 500hr×ng / L, approximately 600hr×ng / L, approximately 700hr×ng / L, approximately 750hr×ng / L, approximately 800hr×ng / L, approximately 850hr×ng / L, approximately 900hr×ng / L, approximately 950hr×ng / L, approximately 1000hr×ng / L, approximately 1050hr×ng / L, approximately 1100hr×ng / L, approximately 1150hr×ng / L, approximately 1200hr×ng / L, approximately 1250hr×ng / L, approximately 1300hr×ng / L, approximately 1350hr×ng / L, approximately 1400hr×ng / L, approximately 1450hr×ng / L, or approximately 1500hr×ng / L AUC 0-inf The following is presented. In the embodiment, Cmax and AUC 0-inf and AUC 0-8 Preferably, these ranges and values ​​are 80% to 125%.

[0196] In this embodiment, the dose is approximately 30 μg, C maxThis ranges from approximately 30 ng / L to approximately 150 ng / L, for example, approximately 30 ng / L, approximately 35 ng / L, approximately 40 ng / L, approximately 45 ng / L, approximately 50 ng / L, approximately 55 ng / L, approximately 60 ng / L, approximately 65 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 80 ng / L, approximately 85 ng / L, approximately 90 ng / L, approximately 95 ng / L, approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, or approximately 150 ng / L (including all values ​​and ranges in between).

[0197] In this embodiment, the dose is approximately 30 μg, C max The range is approximately 80% to 125% of the following levels: approximately 50 ng / L to 150 ng / L, approximately 50 ng / L to 125 ng / L, approximately 50 ng / L to 100 ng / L, approximately 50 ng / L to 85 ng / L, approximately 75 ng / L to 150 ng / L, approximately 75 ng / L to 125 ng / L, approximately 75 ng / L to 100 ng / L, and approximately 100 ng / L to 150 ng / L.

[0198] In this embodiment, the dose is approximately 30 μg, C max The range is approximately 50 ng / L to approximately 150 ng / L, for example, approximately 50 ng / L to approximately 125 ng / L, approximately 50 ng / L to approximately 100 ng / L, approximately 50 ng / L to approximately 75 ng / L, approximately 75 ng / L to approximately 150 ng / L, approximately 75 ng / L to approximately 125 ng / L, approximately 75 ng / L to approximately 100 ng / L, and approximately 100 ng / L to approximately 150 ng / L. In the embodiment, C max and AUC 0-8 Preferably, this range is 80% to 125% of these ranges.

[0199] In this embodiment, the dose is approximately 30 μg, C maxThe range is approximately 50 ng / L to approximately 150 ng / L, for example, approximately 50 ng / L to approximately 125 ng / L, approximately 50 ng / L to approximately 100 ng / L, approximately 50 ng / L to approximately 85 ng / L, approximately 75 ng / L to approximately 150 ng / L, approximately 75 ng / L to approximately 125 ng / L, approximately 75 ng / L to approximately 100 ng / L, and approximately 100 ng / L to approximately 150 ng / L. In the embodiment, C max and AUC 0-inf Preferably, this range is 80% to 125% of these ranges.

[0200] In this embodiment, the dose is approximately 40 μg, C max is about 40ng / L to about 200ng / L, for example, about 40ng / L, about 45ng / L, about 50ng / L, about 55ng / L, about 60ng / L, about 65ng / L, about 70ng / L, about 75 ng / L, approximately 80ng / L, approximately 85ng / L, approximately 90ng / L, approximately 95ng / L, approximately 100ng / L, approximately 105ng / L, approximately 110ng / L, approximately 115ng / L, approximately 120ng / L, approximately These values ​​are approximately 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, 150 ng / L, 155 ng / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, 195 ng / L, or 200 ng / L (including all values ​​and ranges in between).

[0201] In this embodiment, the dose is approximately 40 μg, C max The range is approximately 50 ng / L to 250 ng / L, for example, approximately 80% to 125% of the following ranges: approximately 50 ng / L to 225 ng / L, approximately 50 ng / L to 200 ng / L, approximately 100 ng / L to 180 ng / L, approximately 100 ng / L to 150 ng / L, and approximately 150 ng / L to 200 ng / L.

[0202] In this embodiment, the dose is approximately 40 μg, C maxThe range is approximately 50 ng / L to approximately 250 ng / L, for example, approximately 50 ng / L to approximately 225 ng / L, approximately 50 ng / L to approximately 200 ng / L, approximately 100 ng / L to approximately 180 ng / L, approximately 100 ng / L to approximately 150 ng / L, and approximately 150 ng / L to approximately 200 ng / L. In the embodiment, C max and AUC 0-inf Preferably, these ranges and values ​​are 80% to 125%.

[0203] In this embodiment, the dose is approximately 45 μg, C max The range is approximately 80% to 125% of the following levels: approximately 75 ng / L to 175 ng / L, approximately 75 ng / L to 150 ng / L, approximately 75 ng / L to 125 ng / L, approximately 75 ng / L to 100 ng / L, and approximately 100 ng / L to 150 ng / L.

[0204] In this embodiment, the dose is approximately 45 μg, C max The range is approximately 75 ng / L to approximately 175 ng / L, for example, approximately 75 ng / L to approximately 150 ng / L, approximately 75 ng / L to approximately 125 ng / L, approximately 75 ng / L to approximately 100 ng / L, and approximately 100 ng / L to approximately 150 ng / L. In the embodiment, C max and AUC 0-8 Preferably, these ranges and values ​​are 80% to 125%.

[0205] In this embodiment, the dose is approximately 60 μg, C maxis about 70ng / L to about 300ng / L, for example, about 70ng / L, about 75ng / L, about 80ng / L, about 85ng / L, about 90ng / L, about 95ng / L, about 100ng / L, about 105ng / L, about 110ng / L, about 115ng / L, about 120ng / L, Approximately 125ng / L, approximately 130ng / L, approximately 135ng / L, approximately 140ng / L, approximately 145ng / L, approximately 150ng / L, approximately 155ng / L, approximately 160ng / L, approximately 165ng / L, approximately 170ng / L, approximately 175ng / L, approximately 180ng / L, approximately 185ng / L These values ​​are approximately 190 ng / L, 195 ng / L, 200 ng / L, 205 ng / L, 210 ng / L, 215 ng / L, 220 ng / L, 225 ng / L, 230 ng / L, 235 ng / L, 240 ng / L, 245 ng / L, 250 ng / L, 255 ng / L, 260 ng / L, 265 ng / L, 270 ng / L, 275 ng / L, 280 ng / L, 285 ng / L, 290 ng / L, 295 ng / L, or 300 ng / L (including all values ​​and ranges in between).

[0206] In this embodiment, the dose is approximately 60 μg, C max The range is approximately 80% to 125% of the following levels: approximately 100 ng / L to 300 ng / L, approximately 100 ng / L to 250 ng / L, approximately 100 ng / L to 225 ng / L, approximately 100 ng / L to 200 ng / L, approximately 100 ng / L to 150 ng / L, approximately 150 ng / L to 250 ng / L, and approximately 150 ng / L to 200 ng / L.

[0207] In this embodiment, the dose is approximately 60 μg, C max The range is approximately 100 ng / L to approximately 250 ng / L, for example, approximately 100 ng / L to approximately 225 ng / L, approximately 100 ng / L to approximately 200 ng / L, approximately 150 ng / L to approximately 250 ng / L, and approximately 150 ng / L to approximately 200 ng / L. In the embodiment, C max and AUC 0-8 Preferably, these ranges and values ​​are 80% to 125%.

[0208] In this embodiment, the dose is approximately 60 μg, C maxThe range is approximately 100 ng / L to approximately 300 ng / L, for example, approximately 100 ng / L to approximately 250 ng / L, approximately 100 ng / L to approximately 225 ng / L, approximately 100 ng / L to approximately 200 ng / L, approximately 100 ng / L to approximately 150 ng / L, approximately 150 ng / L to approximately 250 ng / L, and approximately 150 ng / L to approximately 200 ng / L. In the embodiment, C max and AUC 0-inf Preferably, these ranges and values ​​are 80% to 125%.

[0209] In this embodiment, the dose is approximately 90 μg, C max The range is approximately 80% to 125% of the following levels: approximately 100 ng / L to approximately 400 ng / L, 100 ng / L to approximately 350 ng / L, approximately 100 ng / L to approximately 300 ng / L, approximately 200 ng / L to approximately 400 ng / L, and approximately 200 ng / L to approximately 350 ng / L.

[0210] In this embodiment, the dose is approximately 90 μg, C max The range is approximately 100 ng / L to approximately 400 ng / L, for example, approximately 100 ng / L to approximately 350 ng / L, approximately 100 ng / L to approximately 300 ng / L, approximately 200 ng / L to approximately 400 ng / L, and approximately 200 ng / L to approximately 350 ng / L. In the embodiment, C max and AUC 0-8 Preferably, these ranges and values ​​are 80% to 125%.

[0211] In the embodiment, when the dose is 30 μg, the mean plasma concentration is in the range of approximately 20 ng / L to approximately 50 ng / L (e.g., approximately 25 ng / L, approximately 30 ng / L, approximately 35 ng / L, approximately 40 ng / L, and approximately 45 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 6. In the embodiment, C max The values ​​are preferably within these ranges and 80% to 125% of the values.

[0212] In the embodiment, when the dose is 60 μg, the mean plasma concentration is in the range of about 25 ng / L to about 150 ng / L (e.g., about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6.

[0213] In this embodiment, the dose is approximately 90 μg, C maxis from about 100 ng / L to about 500 ng / L, such as about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L, about 150 ng / L, about 155 ng / L, about 160 ng / L, about 165 ng / L, about 170 ng / L, about 175 ng / L, about 180 ng / L, about 185 ng / L, about 190 ng / L, about 195 ng / L, about 200 ng / L, about 205 ng / L, about 210 ng / L, about 215 ng / L, about 220 ng / L, about 225 ng / L, about 230 ng / L, about 235 ng / L, about 240 ng / L, about 245 ng / L, about 250 ng / L, about 255 ng / L, about 260 ng / L, about 265 ng / L, about 270 ng / L, about 275 ng / L, about 280 ng / L, about 285 ng / L, about 290 ng / L, about 295 ng / L, about 300 ng / L, about 305 ng / L, about 310 ng / L, about 315 ng / L, about 320 ng / L, about 325 ng / L, about 330 ng / L, about 335 ng / L, about 340 ng / L, about 345 ng / L, about 350 ng / L, about 355 ng / L, about 360 ng / L, about 365 ng / L, about 370 ng / L, about 375 ng / L, about 380 ng / L, about 385 ng / L, about 390 ng / L, about 395 ng / L, about 400 ng / L, about 405 ng / L, about 410 ng / L, about 415 ng / L, about 420 ng / L, about 425 ng / L, about 430 ng / L, about 435 ng / L, about 440 ng / L, about 445 ng / L, about 450 ng / L, about 455 ng / L, about 460 ng / L, about 465 ng / L, about 470 ng / L, about 475 ng / L, about 480 ng / L, about 485 ng / L, about 490 ng / L, about 495 ng / L, or about 500 ng / L (including all values and ranges therebetween).

[0214] In the embodiment, when the dose is 90 μg, the mean plasma concentration is in the range of about 30 ng / L to about 150 ng / L (e.g., about 30 ng / L, 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L, or about 145 ng / L, including all values ​​and ranges in between) after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 6. max The values ​​are preferably within these ranges and 80% to 125% of the values.

[0215] In the embodiment, when the dose is 120 μg, the mean plasma concentration is in the range of about 50 ng / L to about 200 ng / L (e.g., about 50 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt on about 6 days. These values ​​are approximately 120 ng / L, 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, 150 ng / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, 195 ng / L, or 200 ng / L (including all values ​​and ranges in between). In embodiments, the mean plasma concentration is preferably 80% to 125% of these ranges and values.

[0216] In the embodiment, when the dose is 180 μg, the mean plasma concentration is in the range of approximately 100 ng / L to approximately 450 ng / L (e.g., approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L, approximately 16 (This includes 0 ng / L, approximately 165 ng / L, approximately 170 ng / L, approximately 175 ng / L, approximately 180 ng / L, approximately 185 ng / L, approximately 190 ng / L, approximately 195 ng / L, approximately 200 ng / L, approximately 225 ng / L, approximately 250 ng / L, approximately 275 ng / L, approximately 300 ng / L, approximately 325 ng / L, approximately 350 ng / L, approximately 375 ng / L, approximately 400 ng / L, approximately 425 ng / L, or approximately 450 ng / L, including all values ​​and ranges in between). max The values ​​are preferably within these ranges and 80% to 125% of the values.

[0217] In the embodiment, when the dose is 240 μg, the mean plasma concentration is in the range of approximately 100 ng / L to approximately 400 ng / L (e.g., approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6. L, approximately 160 ng / L, approximately 165 ng / L, approximately 170 ng / L, approximately 175 ng / L, approximately 180 ng / L, approximately 185 ng / L, approximately 190 ng / L, approximately 195 ng / L, approximately 200 ng / L, approximately 225 ng / L, approximately 250 ng / L, approximately 275 ng / L, approximately 300 ng / L, approximately 325 ng / L, approximately 350 ng / L, approximately 375 ng / L, approximately 395 ng / L, approximately 400 ng / L (including all values ​​and ranges in between). In the embodiment, C max The values ​​are preferably within these ranges and 80% to 125% of the values.

[0218] In the embodiment, when the dose is 30 μg, the mean plasma concentration is in the range of about 10 ng / L to about 100 ng / L (e.g., about 10 ng / L, about 15 ng / L, about 20 ng / L, about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 80 ng / L, about 90 ng / L, about 95 ng / L, or about 95 ng / L (including all values ​​and ranges in between)) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12.

[0219] In the embodiment, when the dose is 60 μg, the mean plasma concentration is in the range of about 10 ng / L to about 150 ng / L (e.g., about 10 ng / L, about 15 ng / L, about 20 ng / L, about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt on about 12 days. These values ​​are approximately 55 ng / L, 60 ng / L, 70 ng / L, 75 ng / L, 90 ng / L, 100 ng / L, 105 ng / L, 110 ng / L, 115 ng / L, 120 ng / L, 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, or 150 ng / L (including all values ​​and ranges in between).

[0220] In the embodiment, when the dose is 90 μg, the mean plasma concentration is in the range of about 25 ng / L to about 150 ng / L (e.g., about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 μg / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L, or about 150 ng / L (including all values ​​and ranges in between)) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on about 12 days.

[0221] In the embodiment, when the dose is 120 μg, the mean plasma concentration is in the range of about 50 ng / L to about 200 ng / L (e.g., about 55 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt on about 12 days. These values ​​are approximately 120 μg / L, 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, 150 ng / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, and 195 ng / L, or 200 ng / L (including all values ​​and ranges in between).

[0222] In the embodiment, when the dose is 180 μg, the mean plasma concentration is in the range of about 100 ng / L to about 400 ng / L (e.g., about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L, about 1) after administration of dexmedetomidine or a pharmaceutically acceptable salt on about 12 days. These values ​​are approximately 5 μg / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, 195 ng / L, 200 ng / L, 225 ng / L, 250 ng / L, 275 ng / L, 300 ng / L, 325 ng / L, 350 ng / L, and 375 ng / L, or 400 ng / L (including all values ​​and ranges in between).

[0223] In the embodiment, when the dose is 240 μg, the mean plasma concentration is in the range of approximately 50 ng / L to approximately 500 ng / L (e.g., approximately 55 ng / L, approximately 60 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 80 ng / L, approximately 90 ng / L, approximately 95 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L, approximately 160 ng / L, approximately 165 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 12. , approximately 170 ng / L, approximately 175 ng / L, approximately 180 ng / L, approximately 185 ng / L, approximately 190 ng / L, approximately 195 ng / L, approximately 200 ng / L, approximately 225 ng / L, approximately 250 ng / L, approximately 275 ng / L, approximately 300 ng / L, approximately 325 ng / L, approximately 350 ng / L, approximately 375 ng / L, approximately 395 ng / L, approximately 400 ng / L, approximately 425 ng / L, approximately 450 ng / L, approximately 460 ng / L, approximately 465 ng / L, approximately 475 ng / L, approximately 480 ng / L, approximately 485 ng / L, approximately 490 ng / L, approximately 495 ng / L, or approximately 500 (including all values ​​and ranges in between).

[0224] In this embodiment, the target age range is approximately 1 to 100 years old, for example, approximately 1 year old, approximately 2 years old, approximately 3 years old, approximately 4 years old, approximately 5 years old, approximately 6 years old, approximately 7 years old, approximately 8 years old, approximately 9 years old, approximately 10 years old, approximately 11 years old, approximately 12 years old, approximately 13 years old, approximately 14 years old, approximately 15 years old, approximately 16 years old, approximately 17 years old, approximately 18 years old, approximately 19 years old, approximately 20 years old, approximately 25 years old, approximately 30 years old, approximately 35 years old, approximately 40 years old, approximately 45 years old, approximately 50 years old, approximately 55 years old, approximately 60 years old, approximately 65 years old, approximately 70 years old, approximately 75 years old, approximately 80 years old, approximately 85 years old, approximately 90 years old, approximately 95 years old, and approximately 100 years old (including all values ​​and ranges in between).

[0225] In this embodiment, the target age range is approximately 1 to 18 years old, for example, approximately 1 year old, approximately 2 years old, approximately 3 years old, approximately 4 years old, approximately 5 years old, approximately 6 years old, approximately 7 years old, approximately 8 years old, approximately 9 years old, approximately 10 years old, approximately 11 years old, approximately 12 years old, approximately 13 years old, approximately 14 years old, approximately 15 years old, approximately 16 years old, approximately 17 years old, and approximately 18 years old (including all values ​​and ranges in between).

[0226] In this embodiment, the target age range is approximately 10 to 17 years old, for example, approximately 10, 11, 12, 13, 14, 15, 16, and 17 years old (including all values ​​and ranges in between).

[0227] In this embodiment, the target age range is approximately 13 to 17 years old, for example, approximately 13, 14, 15, 16, and 17 years old (including all values ​​and ranges in between).

[0228] In this embodiment, the target age range is approximately 18 to 64 years old, for example, approximately 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 years old. These are approximately 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, and 64 years old (including all values ​​and ranges in between).

[0229] In this embodiment, the target age range is approximately 21 to 50 years old, for example, approximately 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 years old (including all values ​​and ranges in between).

[0230] In the embodiment, the target is over 64 years old. In the embodiment, the target is approximately 65 to approximately 80 years old, for example, approximately 65, approximately 66, approximately 67, approximately 68, approximately 69, approximately 70, approximately 71, approximately 72, approximately 73, approximately 74, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, and approximately 80 years old (including all values ​​and ranges in between). In the embodiment, the target is approximately 75 to approximately 80 years old, for example, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, and approximately 80 years old (including all values ​​and ranges in between). In this embodiment, the target age group is over 80 years old, for example, approximately 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 years old (including all values ​​and ranges in between).

[0231] To achieve a desired dose, dexmedetomidine can be administered orally via the mucosa as a single dose, multiple doses, or one or more unit doses (e.g., half a dose), or in combination thereof. For example, to administer 120 μg of dexmedetomidine, a patient may be administered a single dose of 120 μg of dexmedetomidine, two doses of 60 μg of dexmedetomidine, or a half dose of 240 μg of dexmedetomidine. In embodiments, dexmedetomidine is administered as a film. Therefore, a half dose can be achieved by cutting the film in half (e.g., cutting a 120 μg or 180 μg film in half) to obtain doses of 60 μg and 90 μg.

[0232] In the embodiment, the drug may be administered multiple times (e.g., 1 to 4 times) at appropriate dosing intervals (e.g., every 0.5 hours) to obtain the desired effect; for example, a 20 μg unit dose or a 60 μg unit dose may be administered four times at 0.5-hour intervals within 6 hours of the initial dose to obtain the effects of 80 μg and 240 μg doses, respectively. In the embodiment, each drug unit may be administered 1 to 2 times at appropriate dosing intervals (every 12 hours) to obtain the desired effect; for example, a 120 μg unit may be administered twice a day at 12-hour intervals to obtain the effect of 240 μg dose. In the embodiment, each drug unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., every 1 to 6 hours) to obtain the desired effect; for example, a 120 μg dose (starting dose) may be administered, followed by seven more doses at intervals of approximately 1 to 6 hours to obtain a maximum cumulative dose of 960 μg. In the embodiment, each drug unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., every 1 to 6 hours) to obtain the desired effect; for example, a dose of 180 μg (starting dose) may be administered, followed by an additional 120 μg six times a day at intervals of approximately 1 to approximately 6 hours to obtain a maximum cumulative dose of 900 μg. In the embodiment, each drug unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., at least 1 to 6 hours) to obtain the desired effect; for example, a dose of 240 μg (starting dose) may be administered, followed by an additional 120 μg six times a day at intervals of approximately 1 to approximately 6 hours to obtain a maximum cumulative dose of 960 μg. In the embodiment, each dosing unit may be administered 1 to 10 times at appropriate dosing intervals (e.g., at least 1 to 6 hours) to obtain the desired effect; for example, a 300 μg dose (starting dose) is administered, followed by a further 120 μg dose five times a day at intervals of approximately 1 to 6 hours to obtain a maximum cumulative dose of 900 μg. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film to the oral mucosa (e.g., sublingual or buccal).

[0233] In the embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered 1 to 6 times per day.

[0234] In an embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered 1 to 4 times a day. In an embodiment, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered 2 times a day.

[0235] In an embodiment, for dexmedetomidine to achieve a desired effect, it is administered 1 to 10 times a day to the oral mucosa (e.g., sublingually or buccally) at an appropriate dosing interval (e.g., every 30 minutes) within 6 hours from the first dose; for example, a unit dose of 20 μg is administered 4 times at a dosing interval of every 30 minutes within 6 hours from the first dose to obtain the effect of an 80 μg dose; or, a 60 μg unit dose is administered 4 times at a dosing interval of every 30 minutes within 6 hours from the first dose to obtain the effect of 240 μg. In an embodiment, each dosing unit can be administered 1 to 2 times at an appropriate dosing interval (e.g., at least 12 hours apart) to achieve a desired effect; for example, a 120 μg unit is administered 2 times a day at an interval of 12 hours. In an embodiment, each dosing unit can be administered 1 to 10 times at an appropriate dosing interval (e.g., at least 1 hour to 6 hours) to achieve a desired effect; for example, a 120 μg dose (starting dose) is administered 7 more times a day at an interval of about 1 to about 6 hours to obtain a maximum cumulative dose of 960 μg. In an embodiment, each dosing unit can be administered 1 to 10 times at an appropriate dosing interval (e.g., at least 1 to 6 hours) to achieve a desired effect; for example, a 180 μg dose (starting dose) is administered, and then 120 μg is administered 6 more times a day at an interval of about 1 to about 6 hours to obtain a maximum cumulative dose of 900 μg. In an embodiment, each dosing unit can be administered 1 to 10 times at an appropriate dosing interval (e.g., at least 1 to 6 hours) to achieve a desired effect; for example, a 240 μg dose (starting dose) is administered, and then 120 μg doses are administered 6 more times a day at an interval of about 1 to about 6 hours to obtain a maximum cumulative dose of 960 μg. In an embodiment, each dosing unit can be administered 1 to 10 times at an appropriate dosing interval (e.g., at least 1 to 6 hours) to achieve a desired effect; for example, a 300 μg dose (starting dose) is administered, and then 120 μg doses are administered 5 more times a day at an interval of about 1 to about 6 hours to obtain a maximum cumulative dose of 900 μg.

[0236] In an embodiment, a lower dosage (e.g., about 10 μg to about 60 μg) is administered in the morning, and a higher dosage (e.g., a dosage exceeding 60 μg) is administered in the evening or at night.

[0237] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered orally, via the oral mucosa (e.g., sublingually, buccally), intravenously, intramuscularly, subcutaneously, topically, transdermally, intratracheally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intraventricularly, or intranasally.

[0238] In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject via the sublingual, buccal, oral, intranasal, or parenteral route. In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered via the sublingual or oral route.

[0239] In an embodiment, the present disclosure is a method of treating agitation or signs of agitation in a human subject with dementia. In an embodiment, the present disclosure is a method of treating agitation or signs of agitation in a subject with dementia without inducing significant sedation.

[0240] In embodiments, the present disclosure provides a method for treating agitation or signs of agitation in human subjects 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 embodiments, the subjects with dementia are suffering from Alzheimer's disease. In embodiments, 30 μg, 40 μg, 60 μg, or 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once daily. In embodiments, in cases of persistent or recurrent agitation, an additional dose (e.g., 10 μg, 20 μg, 30 μg, or 40 μg) is administered after a preferred period (e.g., 2, 4, 6, 8, or 12 hours). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally mucosally 1 to 6 times daily in unit doses containing about 30 μg to about 90 μg. For example, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally mucosally 1, 2, 3, 4, 5, or 6 times every 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours. In embodiments, a unit dose containing approximately 30 μg to 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered 1 to 6 times a day at 2-hour intervals, provided that up to 3 doses are administered within 12 hours of the initial dose. In embodiments, each unit dose containing approximately 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof may be taken 1 to 4 times a day at 2-hour intervals, provided that up to 2 doses are administered within 12 hours of the initial dose. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film orally mucosally (e.g., sublingual or buccal). In embodiments, a dose is achieved by cutting the film in half to deliver a half dose. For example, a 60 μg dose can be administered together with half of a second 60 μg dose (30 μg) to create a 90 μg dose.

[0241] In embodiments herein, a method is provided for treating agitation associated with dementia in patients in need thereof, the method comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the patient at least twice, including an initial dose and repeated doses, wherein the agitation is reduced for the first time by the initial dose, and the agitation is repeatedly reduced by the repeated doses, with the repeated reduction of agitation being similar to the initial reduction of agitation.

[0242] In the embodiments, the reduction of the first and second stress levels is measured by the total PEC score. In the embodiments, the reduction of the first and second stress levels is determined by the PAS score. In the embodiments, the reduction of the first and second stress levels is measured by CGI-I.

[0243] In the embodiment, similar intensification reductions are defined as changes in the total PEC score that are within 0.1, 0.2, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 of each other.

[0244] In the embodiment, a similar surge reduction is defined as a PAS score change of 0.1, 0.2, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 relative to each other.

[0245] In the embodiment, similar surge reductions are defined as CGI-I score changes of 0.1, 0.2, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 relative to each other.

[0246] In the embodiment, similar exacerbation reductions are defined as percentage response rates determined by PEC total scores within 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%, 15%, 20%, or 30% of each other.

[0247] In the embodiment, similar exacerbation reductions are defined as percentage response rates determined by PEC scores within 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%, 15%, 20%, or 30% of each other.

[0248] In the embodiment, similar reductions in exacerbations are defined as percentage response rates determined by CGI-I scores of 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%, 15%, 20%, or 30% relative to each other.

[0249] In some embodiments, repeated dosing cannot be performed until at least two hours have elapsed since the initial dose, and until the evaluation of the initial dose at two hours later has been completed. In some embodiments, repeated dosing must be performed within 12 hours of the initial dose and must be based on a PEC change of less than 40% from baseline. In some embodiments, the maximum number of repeated dosing per subject is one.

[0250] In embodiments, the present disclosure provides a method for treating agitation or signs of agitation in human subjects 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, wherein the agitation is acute agitation. In embodiments, the present disclosure provides a method for treating agitation or signs of agitation in human subjects 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, wherein the agitation is chronic agitation.

[0251] The present invention provides a method for treating agitation in elderly dementia patients, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state.

[0252] Data have shown that doses exceeding approximately 90 μg have adverse effects on elderly dementia patients and should not be used. For example, high doses can interact with antihypertensive drugs to cause unacceptable hypotension, bradycardia, and dizziness; in severe cases, syncope may occur. However, in certain circumstances, doses exceeding approximately 90 μg may be used in elderly dementia patients in agitated states, provided that the patient is not at risk of hypotension as a side effect. Therefore, this disclosure provides that doses exceeding approximately 90 μg be administered to patients who have not received treatment for hypertension for at least 10 hours, at least 24 hours, at least 48 hours, or at least 1 week prior to the administration of dexmedetomidine. Such high doses may be approximately 100 μg to approximately 130 μg, for example, approximately 100 μg, approximately 110 μg, approximately 120 μg, or approximately 130 μg. Advantageously, dexmedetomidine can be used as an alternative to antihypertensive drugs while treating both agitation and hypertension.

[0253] In embodiments, dexmedetomidine may be administered to elderly dementia patients in an agitated state via pathways that avoid first-pass metabolism (e.g., intravenous, intramuscular, subcutaneous, or transdermal). Preferably, delivery is via the oral mucosa (e.g., buccal or sublingual). In embodiments, the dosage form is a film. A preferred film is described below: U.S. Patent No. 10,792,246 (in whole, incorporated herein by reference for all purposes). In this embodiment, the elderly patient is 55 years of age or older, for example, approximately 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 years of age. In the embodiment, the elderly patient is approximately 65 years of age or older. In the embodiment, the elderly patient is approximately 70 years of age or older. In the embodiment, the elderly patient is approximately 75 to 80 years of age. In the embodiment, the elderly patient is approximately 80 years of age or older. In the embodiment, the elderly patient suffers from both dementia and Alzheimer's disease.

[0254] In the embodiment, agitation is acute agitation. In the embodiment, agitation is chronic agitation.

[0255] In embodiments, the present disclosure provides a method for treating agitation in elderly dementia patients, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state, wherein the dose of dexmedetomidine is about 30 μg to about 90 μg (e.g., 40 μg); maxHowever, the concentration is approximately 50 ng / L to approximately 300 ng / L; the route of administration is oral mucosa, intravenous, intramuscular, subcutaneous, or transdermal; and the elderly patient is 65 years of age or older. For example, the dose may be approximately 30 μg to approximately 90 μg, for example, approximately 30 μg to approximately 60 μg, approximately 60 μg to approximately 90 μg, approximately 30 μg to approximately 45 μg, or approximately 30 μg to approximately 40 μg. In embodiments, the dose may be approximately 30 μg, approximately 40 μg, approximately 45 μg, approximately 50 μg, approximately 60 μg, approximately 75 μg, approximately 80 μg, or approximately 90 μg.

[0256] In the embodiment, the dosage is approximately 200hr × ng / L to approximately 1500hr × ng / L; for example, approximately 200hr × ng / L to approximately 1250hr × ng / L, approximately 200hr × ng / L to approximately 1000hr × ng / L, approximately 200hr × ng / L to approximately 750hr × ng / L, approximately 200hr × ng / L to approximately 500hr × ng / L, approximately 500hr × ng / L to approximately 1500hr × ng / L, approximately 500hr × ng / AUC in the range of L to approximately 1250hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 500hr×ng / L to approximately 750hr×ng / L, approximately 750hr×ng / L to approximately 1500hr×ng / L, approximately 750hr×ng / L to approximately 1250hr×ng / L, approximately 750hr×ng / L to approximately 1000hr×ng / L, or approximately 1000hr×ng / L to approximately 1500hr×ng / L 0-8 The present invention provides a dose with an AUC of approximately 200hr×ng / L, approximately 300hr×ng / L, approximately 400hr×ng / L, approximately 500hr×ng / L, approximately 600hr×ng / L, approximately 700hr×ng / L, approximately 800hr×ng / L, approximately 900hr×ng / L, approximately 1000hr×ng / L, approximately 1100hr×ng / L, approximately 1200hr×ng / L, approximately 1300hr×ng / L, approximately 1400hr×ng / L, or approximately 1500hr×ng / L. 0-8 To provide.

[0257] In the embodiment, the dose is in the range of approximately 200hr×ng / L to approximately 5000hr×ng / L, approximately 200hr×ng / L to approximately 3500hr×ng / L, approximately 200hr×ng / L to approximately 2200hr×ng / L, approximately 200hr×ng / L to approximately 2000hr×ng / L; for example, approximately 300hr×ng / L to approximately 1900hr×ng / L, approximately 400hr×ng / L to approximately 1800hr×ng / L, approximately 500hr×ng / L to approximately 1700hr×ng / L, approximately 500hr×ng / L to approximately 1600hr×ng / L, approximately 500hr×ng / L to approximately 1500hr×ng / L, approximately 600hr×ng / L to approximately 1500hr×ng / L, and approximately 700hr×ng / L to approximately 1500hr×ng / L with an AUC in the range of approximately 1500hr×ng / L. 0-infThe following dosages are provided. In the embodiment, the dosages are approximately 200hr × ng / L, approximately 300hr × ng / L, approximately 400hr × ng / L, approximately 500hr × ng / L, approximately 600hr × ng / L, approximately 700hr × ng / L, approximately 750hr × ng / L, approximately 800hr × ng / L, approximately 850hr × ng / L, approximately 900hr × ng / L, approximately 950hr × ng / L, approximately 1000hr × ng / L, approximately 1050hr × ng / L, approximately 1100hr × ng / L, and approximately 1150hr × ng / L. , approximately 1200hr×ng / L, approximately 1250hr×ng / L, approximately 1300hr×ng / L, approximately 1350hr×ng / L, approximately 1400hr×ng / L, approximately 1450hr×ng / L, approximately 1500hr×ng / L, approximately 1600 hr×ng / L, approx. 1700hr×ng / L, approx. 1800hr×ng / L, approx. 1900hr×ng / L, approx. 2000hr×ng / L, approx. 2100hr×ng / L, approx. 2200hr×ng / L, approx. 2300hr×ng / L , about 2400hr×ng / L, about 2500hr×ng / L, about 2600hr×ng / L, about 2700hr×ng / L, about 2800hr×ng / L, about 2900hr×ng / L, about 3000hr×ng / L, about 3100 hr×ng / L, approx. 3200hr×ng / L, approx. 3300hr×ng / L, approx. 3400hr×ng / L, approx. 3500hr×ng / L, approx. 2200hr×ng / L, approx. 3600hr×ng / L, approx. 3700hr×ng / AUC for L, approximately 3800hr×ng / L, approximately 3900hr×ng / L, approximately 4000hr×ng / L, approximately 4100hr×ng / L, approximately 4200hr×ng / L, approximately 4300hr×ng / L, approximately 4400hr×ng / L, approximately 4500hr×ng / L, approximately 4600hr×ng / L, approximately 4700hr×ng / L, approximately 4800hr×ng / L, approximately 4900hr×ng / L, or approximately 5000hr×ng / L (including all values ​​and ranges in between). 0-inf Provides C max and AUC 0-8 Preferably, these ranges and values ​​are 80% to 125%. In the embodiment, C max and AUC 0-infis preferably 80% to 125% of these ranges and values. The ranges obtained using these dexmedetomidine dosages were not predicted based on previous trials. In fact, compared to schizophrenic patients, C max data is approximately 38% higher and AUC data is approximately 55% higher.

[0258] In embodiments, the present disclosure provides a method of treating an acute agitation episode in an elderly dementia patient, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at a dosage sufficient for the dexmedetomidine AUC 0-8 to be in the range of about 200 hour×ng / L to about 1500 hour×ng / L, C max is from about 50 ng / L to about 300 ng / L, the patient is 65 years of age or older; and the route of administration is selected from buccal mucosa, intravenous, intramuscular, subcutaneous, and transdermal. In embodiments, the present disclosure provides a method of treating an acute agitation episode in an elderly dementia patient, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at a dosage sufficient for the dexmedetomidine AUC 0-inf to be in the range of about 200 hour×ng / L to about 2200 hour×ng / L, C maxis from about 50 ng / L to about 300 ng / L, the patient is 65 years of age or older; and the route of administration is selected from buccal mucosa, intravenous, intramuscular, subcutaneous, and transdermal. In embodiments, a method of treating an acute agitation episode in an elderly dementia patient comprises administering to the patient from about 30 μg to about 90 μg (such as about 30 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 75 μg, about 80 μg, or about 90 μg) of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, a method of treating an acute agitation episode in an elderly dementia patient comprises administering to the patient about 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, a method of treating an acute agitation episode in an elderly dementia patient comprises administering to the patient about 40 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, a method of treating an acute agitation episode in an elderly dementia patient comprises administering to the patient about 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the patient is not significantly sedated within about 60 minutes after administration.

[0259] In embodiments, the present disclosure provides a method of treating chronic agitation in an elderly dementia patient, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at a dose sufficient for the dexmedetomidine AUC 0-8 to be in the range of about 200 hour×ng / L to about 1500 hour×ng / L, and C max is from about 50 ng / L to about 300 ng / L, the patient is 65 years of age or older, and the route of administration is selected from buccal mucosa, intravenous, intramuscular, subcutaneous, and transdermal. In embodiments, the present disclosure provides a method of treating chronic agitation in an elderly dementia patient, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at a dose sufficient for the dexmedetomidine AUC 0-inf to be in the range of about 200 hour×ng / L to about 2200 hour×ng / L, and C maxHowever, the concentration is approximately 50 ng / L to approximately 300 ng / L, the patient is 65 years of age or older, and the route of administration is selected from oral mucosa, intravenous, intramuscular, subcutaneous, and transdermal. In embodiments, a method for treating chronic agitation in elderly dementia patients includes administering to the patient approximately 30 μg to approximately 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., approximately 30 μg, approximately 40 μg, approximately 45 μg, approximately 50 μg, approximately 60 μg, approximately 75 μg, approximately 80 μg, or approximately 90 μg). In embodiments, a method for treating chronic agitation in elderly dementia patients includes administering to the patient approximately 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the patient is not significantly sedated within approximately 60 minutes after administration.

[0260] In embodiments, the present disclosure provides a method for treating chronic agitation in elderly dementia patients, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state, dexmedetomidine AUC 0-inf This includes administering a dose sufficient to result in a range of approximately 200 hours × ng / L to approximately 3500 hours × ng / L, C max However, the concentration is approximately 50 ng / L to approximately 300 ng / L, the patient is 65 years of age or older, and the route of administration is selected from oral mucosa, intravenous, intramuscular, subcutaneous, and transdermal. In embodiments, this disclosure provides a method for treating chronic agitation in elderly dementia patients, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state, dexmedetomidine AUC 0-inf This includes administering a dose sufficient to bring the total dose to a range of approximately 200 hours × ng / L to approximately 5000 hours × ng / L, C max However, the concentration is approximately 50 ng / L to 500 ng / L, the patient is 65 years of age or older, and the route of administration is selected from oral mucosa, intravenous, intramuscular, subcutaneous, and transdermal.

[0261] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in doses of approximately 30 μg to approximately 130 μg, and the patient has not received treatment for hypertension within approximately 10 hours prior to the administration of dexmedetomidine. In embodiments, the present disclosure provides a method for treating an acute agitated episode in a patient with Alzheimer's disease, the method comprising administering 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the patient, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient, the agitation is moderate to severe, and the patient is at least 65 years old, optionally at least 75 years old.

[0262] In the embodiments, agitation is not due to pain, infection, concomitant medications, environmental conditions, or mental states other than dementia.

[0263] In this embodiment, the patient does not exhibit delirium.

[0264] In this embodiment, the patient receives sublingual administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, the patient is orally administered dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0266] In this embodiment, the patient is determined to have a total score of 14 or higher on the Positive / Negative Symptom Rating Scale (PANSS) - Agitation Item (PEC) scale before administration.

[0267] In this embodiment, the PEC score decreases by approximately 4 to 6 points within 2 hours after administration.

[0268] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, a spray, or a cachet. In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

[0269] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as needed.

[0270] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times daily.

[0271] In embodiments, the Disclosure provides a method for treating acute agitation or signs of agitation in human subjects suffering from dementia, the method comprising administering about 40 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof is performed "as needed" (or PRN).

[0272] In embodiments, the Disclosure provides a method for treating acute agitation or signs of agitation in human subjects suffering from dementia, the method comprising administering about 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof is performed "as needed" (or PRN).

[0273] In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the subject. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered sublingually, and in the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered buccally.

[0274] In the embodiment, the subjects had not previously received treatment with antipsychotic drugs.

[0275] In this embodiment, the subject has previously received treatment with antipsychotic drugs.

[0276] In this embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once daily.

[0277] In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered up to 28 times over a 12-week period. In the embodiment, the subject is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 doses of dexmedetomidine or a pharmaceutically acceptable salt thereof over a 12-week period.

[0278] In this embodiment, the agitation is psychomotor agitation.

[0279] In the embodiments, the route of administration is the oral mucosa (e.g., sublingual, buccal, or gingival). In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a film to the oral mucosa. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a sublingual film. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as an intraoral film. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered as a gingival film.

[0280] In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered for at least 24 hours, 48 ​​hours, 1 week, or 2 weeks. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally via the mucosa for at least 12 weeks.

[0281] In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered orally via the mucosa for approximately 15 weeks, 18 weeks, 21 weeks, or 24 weeks or longer. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered orally via the mucosa to the subject for the period necessary until the underlying disease is resolved.

[0282] In the embodiments, the subjects are diagnosed with Alzheimer's disease based on the 2018 NIA-AA criteria. In the embodiments, the subjects suffer from both dementia and Alzheimer's disease.

[0283] In the embodiment, the target MMSE score is 15-23. In the embodiment, the target MMSE score is 16. In the embodiment, the target MMSE score is 17. In the embodiment, the target MMSE score is 18. In the embodiment, the target MMSE score is 19. In the embodiment, the target MMSE score is 20. In the embodiment, the target MMSE score is 21. In the embodiment, the target MMSE score is 22.

[0284] In this embodiment, the subjects have a total score of 14 or higher on the PEC scale prior to administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0285] In the embodiment, subjects have a total score of 8 or higher on four items, including the Pittsburgh Agitation Scale (PAS), which comprises abnormal vocalizations, motor agitation, aggression, and resistance to care, prior to administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0286] In this embodiment, the subject has suffered from dementia for approximately 2 years. In this embodiment, the subject has suffered from dementia for approximately 3 years. In this embodiment, the subject has suffered from dementia for approximately 4 years. In this embodiment, the subject has suffered from dementia for approximately 5 years or more.

[0287] In some embodiments, the subjects are elderly patients. In some embodiments, the patients are at least 65 years old. In some embodiments, the elderly patients are 65 years of age or older. In some embodiments, the elderly patients are 80 years old. In some embodiments, the aggravation is chronic.

[0288] In the embodiment, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in only mild to moderate adverse effects.

[0289] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in the total PEC score compared to the baseline score (i.e., before administration). In the embodiments, a mean change in PEC score below -2 relative to baseline is achieved within 2 hours of administration.

[0290] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in PAS scores compared to baseline scores (i.e., pre-administration scores). In the embodiments, a mean change in PAS scores below -2 compared to baseline is achieved within 2 hours after administration.

[0291] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in ACES scores compared to baseline scores (i.e., pre-administration). In the embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior), as measured by the Agitation and Sedation Rating Scale (ACES), within approximately two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0292] In the embodiments, administration of dexmedetomidine or a pharmaceutically acceptable salt thereof to agitated human subjects results in a significant improvement in the CGI-I score compared to the baseline score (i.e., before administration). In the embodiments, an improvement of approximately 1 (very improved) or approximately 2 (significantly improved) in the CGI-I score is observed.

[0293] In the embodiments, improvement in scores is observed as early as 30 minutes after administration. In the embodiments, improvement in scores is observed as early as 1 hour after administration. In the embodiments, improvement in scores is observed as early as 2 hours after administration.

[0294] In embodiments, the present invention also provides a method for managing or treating agitation in a delirious subject, the method comprising administering about 20 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the subject is hospitalized. In embodiments, the subject is hospitalized in the intensive care unit. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally via the mucosa in doses of 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 120 μg, about 150 μg, about 180 μg, about 210 μg, about 240 μg, about 270 μg, or about 300 μg.

[0295] In embodiments, the present disclosure provides a method for managing or treating agitation in a subject with delirium, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof in doses of about 40 μg, about 60 μg, about 90 μg, about 120 μg, or about 150 μg, the subject being over 64 years of age. In embodiments, 1 to 10 doses may be administered at appropriate intervals (e.g., 1 to 6 hours) to obtain the desired effect; for example, a dose of about 60 μg, about 90 μg, about 120 μg, or about 150 μg (starting dose) may be administered, followed by further doses of about 60 μg 5 to 7 times a day at intervals of about 1 to about 6 hours to obtain a maximum cumulative dose of about 480 μg.

[0296] In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising oral mucosal administration of about 10 μg to about 90 μg (e.g., about 10 μg, about 15 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, or about 90 μg) of dexmedetomidine or a pharmaceutically acceptable salt thereof, when the agitation is associated with schizophrenia. In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising oral mucosal administration of a single dose containing about 20 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof when the agitation is associated with schizophrenia. In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising oral mucosal administration of a single dose containing about 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof when the agitation is associated with schizophrenia. In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising oral mucosal administration of a single dose containing about 80 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof when the agitation is associated with schizophrenia. In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising administering a single dose containing about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof orally via the mucosa when the agitation is associated with schizophrenia. In embodiments, the Disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising administering a single dose containing about 80 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof orally via the mucosa when the agitation is associated with bipolar disorder.In embodiments, the disclosure provides a method for treating agitation or signs of agitation in pediatric subjects without inducing significant sedation, the method comprising oral mucosal administration of a single dose containing about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, when the agitation is associated with bipolar disorder. In embodiments, subjects are about 13–17 years of age. In embodiments, subjects are about 10–17 years of age. In embodiments, the agitation is acute. In embodiments, subjects are diagnosed with diminished psychosis syndrome DSM-5 298.8(F28). In embodiments, subjects have a score of 4 or higher on at least one of the five PEC items at baseline. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a film. In embodiments, reduction of agitation or signs of agitation is measured by the relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiment, clinical improvement in agitation is measured using the PANSS, ACES, and / or CGI-I scales.

[0297] In this embodiment, the target children are approximately 1 to 18 years old, for example, approximately 1 year old, approximately 2 years old, approximately 3 years old, approximately 4 years old, approximately 5 years old, approximately 6 years old, approximately 7 years old, approximately 8 years old, approximately 9 years old, approximately 10 years old, approximately 11 years old, approximately 12 years old, approximately 13 years old, approximately 14 years old, approximately 15 years old, approximately 16 years old, approximately 17 years old, and approximately 18 years old (including all values ​​and ranges in between).

[0298] In this embodiment, the target children are approximately 10 to 17 years old, for example, approximately 10, 11, 12, 13, 14, 15, 16, and 17 years old (including all values ​​and ranges in between).

[0299] In this embodiment, the target children are approximately 13 to 17 years old, for example, approximately 13, 14, 15, 16, and 17 years old (including all values ​​and ranges in between).

[0300] In embodiments, the disclosure also provides a method for treating or alleviating opioid withdrawal symptoms, the method comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a human patient in need. In embodiments, the onset of opioid withdrawal begins within 6 to 24 hours of the last opioid use.

[0301] In embodiments, the present disclosure provides a method for treating or alleviating opioid withdrawal symptoms, the method 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 amount of dexmedetomidine or a pharmaceutically acceptable salt thereof ranges from about 20 μg to about 600 μg, for example, 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 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg , about 230μg, about 240μg, about 250μg, about 260μg, about 270μg, about 280μg, about 290μg, about 300μg, about 310μg, about 320μg, about 33 0μg, about 340μg, about 350μg, about 360μg, about 370μg, about 380μg, about 390μg, about 400μg, about 410μg, about 420μg, about 430μg, It is administered in doses of approximately 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, or 600 μg (including all values ​​and ranges in between). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily (at 12-hour intervals) in doses of approximately 240 μg. In embodiments, the patient is at least 18 years of age. In embodiments, the withdrawal period is up to 14 days. In embodiments, the withdrawal period is up to 12 days. In embodiments, the withdrawal period is up to 10 days. In embodiments, the withdrawal period is up to 6 days.

[0302] It was unexpectedly discovered that dexmedetomidine is effective in shortening opioid withdrawal periods in patients. This is surprising because opioids (e.g., fentanyl) localize in body fat over time and are released intermittently, causing unpredictable effects on patients during the withdrawal process. Because opioid release is highly variable and intermittent, clinicians had not anticipated that repeated doses of dexmedetomidine would be an effective treatment.

[0303] In embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject once daily. In embodiments, the withdrawal period is 1 to 14 days, for example, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days (including all values ​​and ranges in between).

[0304] In embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject in need thereof, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject twice daily. In embodiments, the withdrawal period is 1 to 14 days, for example, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days (including all values ​​and ranges in between).

[0305] In other embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject twice daily. In embodiments, the withdrawal period is up to about 60 days. In this embodiment, the withdrawal period may be 59 days, 58 days, 57 days, 56 days, 55 days, 54 days, 53 days, 52 days, 51 days, 50 days, 49 days, 48 ​​days, 47 days, 46 days, 45 days, 44 days, 43 days, 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days (including all values ​​and ranges in between).

[0306] In embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject twice daily, with a withdrawal period of up to 14 days. In embodiments, the withdrawal period is up to 12 days. In other embodiments, the Disclosure provides a method for shortening the opioid withdrawal period in a human subject requiring it, the method comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject twice daily, with a withdrawal period of up to 60 days. In embodiments, the human subject is an adult (e.g., at least 18 years of age) suffering from opioid use disorder in which the subject is physically dependent on opioids. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt is administered sublingually, buccally, orally, intranasally, or parenterally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) is administered sublingually as a film. In the embodiment, the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 μg to about 600 μg, for example, 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 μg, about 180 μg, about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, It is administered orally via the mucosa in doses of approximately 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, or 600 μg (including all values ​​and ranges in between). In the embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally via the mucosa in a single dose range of approximately 30 μg to approximately 600 μg.In the embodiment, dexmedetomidine is administered in doses of approximately 30 μg, 60 μg, 90 μg, 120 μg, 180 μg, 240 μg, or 300 μg for at least 3 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days), twice daily at intervals of approximately 12 hours. In the embodiment, each unit may be administered at an appropriate interval (e.g., an interval of approximately 12 hours) or simultaneously. For example, two 30 μg units may be administered simultaneously to produce the effect of a 60 μg dose, or three 60 μg units may be administered simultaneously to produce the effect of a 180 μg dose.

[0307] In embodiments, the opioid may be selected from the group consisting of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil, carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil, butorphanol, meperidine, methadone, dextropropoxifen (propoxifen), thebaine, sufentanil, or pentazocine, but is not limited thereto. In embodiments, the opioid was administered for a longer period than neonatal treatment prior to withdrawal.

[0308] In embodiments, the dose range of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 μg to about 600 μg. For example, the composition contains a unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof of about 30 μg, about 60 μg, about 90 μg, about 120 μg, 150 μg, 180 μg, 240 μg, or 300 μg. In embodiments, a single dose of about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective for at least about 24 hours. In embodiments, the dose is administered twice daily. In embodiments, the composition is administered twice daily for 7 days.

[0309] In the embodiment, two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) on day 6, the mean plasma concentration required to achieve reduction of opioid withdrawal symptoms is in the range of approximately 40 ng / L to approximately 500 ng / L (e.g., approximately 40 ng / L to approximately 450 ng / L, approximately 40 ng / L to approximately 400 ng / L, approximately 40 ng / L to approximately 350 ng / L, approximately 40 ng / L). L ~ about 300ng / L, about 40ng / L - about 250ng / L, about 40ng / mL - about 200ng / L, about 50ng / L - about 150ng / L, about 60ng / L - about 150ng / L, about 7 0ng / L to about 100ng / L, for example, about 75ng / L, about 80ng / L, about 90ng / L, about 95ng / L, about 105ng / L, about 115ng / L, about 120ng / L).

[0310] In the embodiment, the mean plasma concentration required to achieve reduction of opioid withdrawal symptoms 6 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) on day 6 is in the range of approximately 20 ng / L to approximately 200 ng / L (e.g., approximately 20 ng / L to approximately 180 ng / L, approximately 20 ng / L to approximately 175 ng / L, approximately 30 ng / L to approximately 170 ng / L, approximately 35 ng / L to approximately 165 ng / L, approximately 40 ng / mL to approximately 160 ng / L, approximately 50 ng / L to approximately 150 ng / L, approximately 65 ng / L to approximately 125 ng / L, approximately 60 ng / L to approximately 100 ng / L, e.g., approximately 70 ng / L, approximately 75 ng / L, approximately 80 ng / L, approximately 85 ng / L, approximately 90 ng / L, approximately 95 ng / L).

[0311] In the embodiment, the mean plasma concentration required to achieve reduction of opioid withdrawal symptoms 12 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) on day 6 is in the range of approximately 20 ng / L to approximately 150 ng / L (e.g., approximately 20 ng / L to approximately 125 ng / L, approximately 20 ng / L to approximately 100 ng / L, approximately 30 ng / L to approximately 90 ng / L, approximately 30 ng / L to approximately 75 ng / L).

[0312] In the embodiment, the mean plasma concentrations required to achieve reduction of opioid withdrawal symptoms two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) on day 12 are approximately 50 ng / L to approximately 500 ng / L, for example, approximately 50 ng / L to approximately 450 ng / L, approximately 50 ng / L to approximately 400 ng / L, approximately 75 ng / L to approximately 350 ng / L, approximately 75 ng / L to approximately 300 ng / L, approximately 90 ng / L to approximately 250 ng / L, approximately 90 ng / L to approximately 200 ng / L, and approximately 100 ng / L to approximately 150 ng / L (including approximately 140 ng / L, approximately 130 ng / L, approximately 125 ng / L, approximately 120 ng / L, and approximately 110 ng / L).

[0313] In the embodiment, the mean plasma concentration required to achieve reduction of opioid withdrawal symptoms 6 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt (e.g., hydrochloride) on day 12 is in the range of approximately 20 ng / L to approximately 250 ng / L, for example, approximately 20 ng / L to approximately 225 ng / L, approximately 20 ng / L to approximately 200 ng / L, approximately 20 ng / L to approximately 180 ng / L, and approximately 20 ng / L. ~175ng / L, approx. 30ng / L~170ng / mL, approx. 35ng / L~165ng / L, approx. 40ng / L~160ng / L, approx. 50ng / L~150ng / L, approx. 65ng / L to about 125ng / L; about 60ng / L to about 100ng / L (including about 70ng / L, about 75ng / L, about 80ng / L, about 85ng / L, about 90ng / L, and about 95ng / L).

[0314] In the embodiment, the mean plasma concentration required to achieve reduction of opioid withdrawal symptoms 12 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 12 is in the range of approximately 10 ng / L to 150 ng / L (e.g., approximately 10 ng / L to 140 ng / L, approximately 20 ng / L to approximately 130 ng / L, approximately 30 ng / L to approximately 120 ng / L, approximately 40 ng / L to approximately 100 ng / L, approximately 50 ng / L to approximately 90 ng / L, approximately 75 ng / L to approximately 90 ng / L).

[0315] In the embodiment, the mean plasma concentration value is preferably 80% to 125% of these ranges and values.

[0316] In embodiments, the Disclosure provides a method for treating cocaine toxicity and / or symptoms associated with cocaine toxicity, the method comprising oral mucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as an oral mucosal film in a dose range of about 30 μg to about 400 μg as a single-dose or multi-dose therapy. In embodiments, the Disclosure provides a pharmaceutical composition comprising about 20 μg to about 600 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In embodiments, the dose of dexmedetomidine is about 120 μg. In embodiments, the dose of dexmedetomidine is about 180 μg. In embodiments, the dose of dexmedetomidine is about 150 μg. In embodiments, the dose of dexmedetomidine is about 240 μg. In this embodiment, the dose of dexmedetomidine is approximately 300 μg.

[0317] Clinical evaluation items The reduction of agitation in elderly dementia patients can be assessed using various measures: PEC, PAS, ACES, Mod-CMAI, and / or CGI-I.

[0318] In the embodiment, the patient achieves a mean change in PEC score below -2, -3, -4, -5, -6, -7, -8, -9, or -10 relative to baseline within 2 hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 30 μg, and the patient achieves a mean change in PEC score below -4 relative to baseline within 2 hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 40 μg, and the patient achieves a mean change in PEC score below -5 relative to baseline within 2 hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 60 μg, and the patient achieves a mean change in PEC score below -7 relative to baseline within 2 hours of administration of the composition. In the embodiment, the reduction in PEC score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration of the composition.

[0319] In the embodiment, the patient achieves a mean change in PAS score below -2, -3, -4, -5, -6, -7, -8, -9, or -10 relative to baseline within 2 hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 30 μg, and the patient achieves a mean change in PAS score below -3 relative to baseline within 2 hours of administration of the composition.

[0320] In one embodiment, the dose of dexmedetomidine is 40 μg, and the patient achieves a mean change in PAS score of less than -4 from baseline within 2 hours of administration of the composition. In another embodiment, the dose of dexmedetomidine is 60 μg, and the patient achieves a mean change in PEC score of less than -5 from baseline within 2 hours of administration of the composition. In yet another embodiment, the reduction in PAS score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration of the composition.

[0321] In the embodiment, the patient achieves a mean change in Mod-CMAI score below -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, or -18 relative to baseline two hours after administration of the composition. In the embodiment, the dose of dexmedetomidine is 30 μg, and the patient achieves a mean change in Mod-CMAI score below -7 relative to baseline within two hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 40 μg, and the patient achieves a mean change in Mod-CMAI score below -10 relative to baseline within two hours of administration of the composition. In the embodiment, the dose of dexmedetomidine is 60 μg, and the patient achieves a mean change in Mod-CMAI score below -13 relative to baseline within two hours of administration of the composition. In the embodiment, the reduction in Mod-CMAI score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration of the composition.

[0322] In the embodiment, the patient achieves an improvement of approximately 1 (very good improvement) or approximately 2 (significant improvement) in the CGI-I score. In the embodiment, the score improvement is maintained for approximately 2 to 6 hours. In the embodiment, the dose of dexmedetomidine is 30 μg. In the embodiment, the dose of dexmedetomidine is 40 μg. In the embodiment, the dose of dexmedetomidine is 60 μg. In the embodiment, the score is maintained for approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or approximately 12 hours.

[0323] In the embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) as measured on the Agitation and Sedation Rating Scale (ACES) 2 hours after administration of the composition. In the embodiments, the dose of dexmedetomidine is 60 μg. In the embodiments, the dose of dexmedetomidine is 40 μg. In the embodiments, agitation is reduced to 3 (mild agitation).

[0324] In the embodiment, approximately 20 μg to approximately 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered to an agitated human subject hospitalized with delirium (e.g., in the ICU), and then agitation or signs of agitation and the severity of delirium are measured using RASS and DRS-R-98, respectively, and are significantly reduced. For example, agitation or signs of agitation and the severity of delirium are measured using RASS and DRS-R-98 immediately before administration of dexmedetomidine and at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after administration, and are significantly reduced. In the embodiment, the subject experiences a decrease of 2 points or more in RASS 2 hours after administration of approximately 20 μg to approximately 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiment, subjects experienced a decrease of 2 points or more in their RASS score two hours after administration of approximately 30 μg, 60 μg, 90 μg, 120 μg, 180 μg, 240 μg, or 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In the embodiment, subjects experienced a decrease of 2 points or more in their RASS score two hours after administration of approximately 20 μg to 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, and their initial RASS score was not -3 or lower.

[0325] Treatment or relief of opioid withdrawal symptoms may be measured by various means known in the art, including, but not limited to, the Clinical Opioid Withdrawal Scale (COWS) and / or Gossop's Short-Term Opioid Withdrawal Scale (SOWS-Gossop) score.

[0326] In the embodiment, post-treatment withdrawal symptoms are assessed using the Clinical Opioid Withdrawal Scale and / or Gossop's Short-Term Opiate Withdrawal Scale (e.g., over 10 days).

[0327] In the embodiments, a unit dose of dexmedetomidine or a pharmaceutically acceptable salt of approximately 30 μg, 60 μg, 90 μg, 120 μg, 180 μg, 240 μg, or 300 μg is administered to human subjects experiencing opioid withdrawal symptoms (e.g., agitation or signs of agitation), followed by a significant reduction in withdrawal symptoms as measured by relative COWS and / or SOWS-Gossop scores immediately before and 2 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt of the salt. In the embodiments, each unit may be administered twice daily over an appropriate withdrawal period (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).

[0328] Pharmaceutical composition Dosage form / method of administration In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally via the mucosa in the form of tablets, films, sprays, gels, or drops, particularly in the form of films. In some embodiments, the film is placed sublingually, near the base of the tongue, on the left or right side. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of films, patches, or tablets, particularly in the form of films. In some embodiments, the film is placed against the inside of the lip or cheek, near the jawline. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered parenterally to the subject in the form of intramuscular injection. In some embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject via the oral route. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets, orally disintegrating tablets (ODTs), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, cachets, aqueous solutions, syrups, emulsions, suspensions, liquids, softgels, dispersions, etc. In the embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the subject in the form of orally disintegrating tablets.

[0329] According to the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof can be administered to human subjects via various routes, including oral mucosal (e.g., sublingual, buccal), oral, and parenteral. Formulations suitable for use in accordance with this disclosure are outlined below. Additional formulations suitable for use in accordance with this disclosure are described in US2020 / 0000717 (which is incorporated herein by reference in its entirety for all purposes).

[0330] Oral mucosal preparations (sublingual and / or intraoral preparations) Dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated in accordance with this disclosure into dosage forms suitable for oral mucosal administration (e.g., sublingual or buccal). Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, and suspensions. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.

[0331] Suitable carriers for inclusion in oral mucosal (e.g., sublingual or buccal) formulations include, but are not limited to, sugars, starches, cellulose and their derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, isotonic salines, pyrogen-free water, and combinations thereof. Carriers that dissolve readily in saliva may be preferred.

[0332] Oral mucosal (e.g., sublingual or buccal) formulations may also contain other pharmaceutically acceptable carriers and / or excipients (e.g., binders, lubricants, diluents, coatings, disintegrants, barrier layer components, flow enhancers, colorants, dissolution enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, and mixtures thereof). Specific excipients that can be used in accordance with this disclosure are, for example, described below: Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill.

[0333] film A film suitable for sublingual or buccal administration (i.e., oral mucosal administration) according to this disclosure comprises (i) a dexmedetomidine or a pharmaceutically acceptable salt thereof, which is either placed within a polymer matrix or (ii) deposited on the surface of a polymer matrix (e.g., the surface of a “placebo” film).

[0334] polymer components of the film The polymer component comprises one or more water-soluble polymers within the film matrix and / or as part of drug-containing deposits (e.g., one or more droplets) on the polymer surface. In embodiments of this disclosure, the polymer component consists of a single water-soluble polymer. In embodiments, the polymer component consists of two or more water-soluble polymers, each containing two or more identical water-soluble polymers having different molecular weights.

[0335] The polymer components in the film matrix are of a suitable composition and are present in sufficient quantities to ensure the rapid disintegration of the film matrix in the oral mucosa. For example, the presence of polymer components can allow the film matrix to completely disintegrate in the oral mucosa in about 15 to 180 seconds, for example, about 30 to 180 seconds (including about 120 seconds). The polymer components in the film matrix also provide sufficient strength to the film (i.e., the film is self-supporting).

[0336] The polymer component, when present in one or more droplets of the dexmedetomidine composition deposited on the surface of the polymer matrix / substrate, may consist of, for example, a water-soluble polymer such as hydroxypropylcellulose, but different water-soluble polymers are also intended as described in the following definitions of “first water-soluble polymer” and “second water-soluble polymer” herein. For example, the polymer component may consist of one, two, or three hydroxypropylcelluloses having different molecular weights. Conveniently, the molecular weights of the different hydroxypropylcelluloses may be in the range of (i) less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), (ii) about 90,000 daltons to about 200,000 daltons, and (iii) about 200,000 daltons to about 500,000 daltons. Two or more hydroxypropylcelluloses may be mixed in any preferred ratio to achieve the desired droplet viscosity. The viscosity of a solution or suspension of a dexmedetomidine composition can be measured at a temperature of 25°C using a Brookfield viscometer with a small sample adapter and may range from about 5 cps to about 3700 cps. For 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. In some embodiments of this disclosure, the viscosity of a solution or suspension of a dexmedetomidine composition is about 6 cps to about 20 cps at 25°C and a shear rate of about 7 (1 / sec).

[0337] When present in a monolithic (i.e., placebo or drug-containing) film, the polymer component consists of, for example, one water-soluble polymer or two different water-soluble polymers. If two different water-soluble polymers are present, one of the water-soluble polymers may be present in the polymer component as a combination of the same polymer but with different molecular weights. For example, the polymer component may consist of one, two, or three hydroxypropylcelluloses with different molecular weights, but the different water-soluble polymers are also intended to be as described below, under the definitions of “first water-soluble polymer” and “second water-soluble polymer” (e.g., polyethylene oxide). Conveniently, the molecular weights of the different hydroxypropylcelluloses may be in the range of (i) less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons), (ii) about 90,000 daltons to about 200,000 daltons, and (iii) about 200,000 daltons to about 500,000 daltons (e.g., about 300,000 daltons to about 450,000 daltons). Two or more hydroxypropylcelluloses (e.g., low molecular weight and high molecular weight hydroxypropylcellulose) can be mixed in any preferred ratio to achieve the desired film properties. When present in a monolithic (i.e., placebo or drug-containing) film or microdeposition film matrix composition, the polymer component may conveniently consist of one or more water-soluble polymers with molecular weights 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). Structurally different water-soluble polymers, if present, may conveniently have higher molecular weights, e.g., above about 500,000 daltons.

[0338] In embodiments, the present disclosure provides a pharmaceutical film composition 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., 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.

[0339] In embodiments, the present disclosure provides a pharmaceutical film composition 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., 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.

[0340] In embodiments, the present disclosure provides a pharmaceutical film composition 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., 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.

[0341] In the embodiments, one or more first water-soluble polymers are selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methylcellulose, and mixtures thereof (including mixtures of the same polymer having different molecular weights).

[0342] In embodiments, one or more second water-soluble polymers are selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof (including mixtures of the same polymer having different molecular weights). Polyethylene oxide (PEO) may also be present herein as a second water-soluble polymer, or may be described separately below as an example of a pharmaceutically acceptable carrier in the pharmaceutical film composition (more specifically, as a mucosal adhesive).

[0343] In the embodiment, the weight ratio of the first water-soluble polymer to the second water-soluble polymer (or more) (including PEO if present in the film) in the entire film composition is about 2:1 to about 1:50, for example, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, These are approximately 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, and 1:40 (including all values ​​and ranges in between).

[0344] In the embodiment, the weight ratio of the first water-soluble polymer to the second water-soluble polymer (or more) (including PEO if present in the film) in the entire film composition is about 1:10 to about 1:30, about 1:15 to about 1:25, or about 1:15 to about 1:20. In the embodiment, a ratio of about 1:15 to about 1:20 yields beneficial functional effects.

[0345] In embodiments, other water-soluble polymers may be included in the film together with the first water-soluble polymer / second water-soluble polymer, or may replace such polymer(s). In embodiments, other water-soluble polymers include povidone (polyvinylpyrrolidone), copovidone (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 components (including water-soluble polymer carriers, if present) conveniently constitute about 40% to about 99.8%, about 50% to about 99.7%, and about 60% to about 99.6% of the film composition, based on the weight of the film on a dry weight basis.

[0346] In embodiments, the polymer component of the film composition includes a first water-soluble polymer present in an amount of about 2% to about 15% (e.g., about 3% w / w to about 8% w / w of the total film weight) on a dry weight basis of the polymer component. This water-soluble polymer may conveniently have a molecular weight of about 5,000 daltons to about 49,000 daltons. Examples of such suitable water-soluble polymers include those selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, and mixtures thereof.

[0347] In the embodiment, low molecular weight hydroxypropyl cellulose may be present in the film at a concentration of about 3% to about 8% w / w of the total film weight.

[0348] In the embodiments, one or more second water-soluble polymers (e.g., polyethylene oxide) are present in an amount of about 50 to about 98 weight percent on a dry weight basis of the polymer components. In the embodiments, one or more second water-soluble polymers each have a molecular weight of more than 60,000 daltons (e.g., about 90,000 daltons to about 1,500,000 daltons), in particular when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

[0349] In the embodiment, one or more second water-soluble polymers are present in the film at a concentration of about 25% w / w to about 40% w / w of the total film weight, the molecular weight of each of the one or more second water-soluble polymers is about 90,000 daltons to about 200,000 daltons and / or about 200,000 daltons to about 500,000 daltons, and the polymers are selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

[0350] In this embodiment, polyethylene oxide is present in the film at a concentration of approximately 50% to 60% w / w of the total film weight.

[0351] In embodiments, the polymer component of the film composition comprises a low molecular weight water-soluble polymer (e.g., molecular weight less than about 60,000 daltons) and one or more high molecular weight polymers (e.g., molecular weight greater than about 60,000, 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 provides particular advantages in the tensile strength and pharmacokinetics of the film composition, especially when the polymer is a combination of hydroxypropyl cellulose and polyethylene oxide.

[0352] In embodiments, the present disclosure provides a film composition comprising: a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; a polymer component comprising a water-soluble polymer; and a pharmaceutically acceptable carrier.

[0353] In embodiments, the present disclosure provides a film composition comprising: a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; a polymer component comprising: (a) a first water-soluble polymer having a molecular weight of about 5,000 daltons to about 49,000 daltons, in about 2 to about 15 weight percent of the total polymer component on a dry weight basis (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof); and (b) a second water-soluble polymer having a molecular weight exceeding 60,000 daltons (e.g., exceeding 100,000 daltons), in about 50 to about 98 weight percent of the total polymer component on a dry weight basis (e.g., polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof); and a pharmaceutically acceptable carrier.

[0354] The molecular weight of hydroxypropylcellulose may vary when present in the film of this disclosure and may exist as both a low molecular weight water-soluble polymer and one or more high molecular weight water-soluble polymers. In embodiments, the molecular weight is less than about 60,000 daltons (e.g., about 5,000 daltons to about 49,000 daltons). In embodiments, the molecular weight of hydroxypropylcellulose is about 90,000 daltons to about 200,000 daltons. In embodiments, the molecular weight of hydroxypropylcellulose is about 200,000 daltons to about 500,000 daltons.

[0355] In embodiments, the composition contains hydroxypropyl cellulose in the range of about 10% to about 90% (e.g., about 20% to about 80%, for example, about 20% to about 50%, for example, about 25% to about 45%) on a dry weight basis of the polymer component.

[0356] The molecular weight of the polyethylene oxide in the film of this disclosure may also vary. In embodiments, the composition includes a water-soluble high molecular weight polyethylene oxide to enhance the film's mucosal adhesion. In embodiments, the molecular weight of the polyethylene oxide is about 100,000 daltons to about 1,500,000 daltons (e.g., about 100,000 daltons, about 200,000 daltons, about 300,000 daltons, about 600,000 daltons, about 900,000 daltons, or 1,000,000 daltons). In embodiments, the composition includes, as a polymer component, a combination of polyethylene oxide with a molecular weight of about 600,000 daltons to about 900,000 daltons and polyethylene oxide with a molecular weight of about 100,000 daltons to about 300,000 daltons.

[0357] In the embodiment, the composition contains about 30% to about 90% by weight of polyethylene oxide (for example, about 40% to about 85% by weight and about 55% to about 80% by weight of polyethylene oxide) on a dry weight basis of the total polymer components.

[0358] Such film compositions may contain a drug dispersed within the film or a drug deposited in trace amounts on the surface of the film. When deposited in trace amounts on the surface of a "placebo" film, the drug may conveniently and optionally be added as part of the dexmedetomidine composition as one or more droplets in a liquid carrier (e.g., a solvent, e.g., an alcohol, e.g., ethanol) together with one or more (e.g., two) water-soluble polymers and / or pharmaceutically acceptable carriers. Suitable water-soluble polymers include: (1) low molecular weight water-soluble polymers (e.g., low molecular weight water-soluble polymers with a molecular weight of less than approximately 60,000 daltons (e.g., molecular weight of approximately 5,000 daltons to approximately 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 with a molecular weight exceeding approximately 60,000 daltons (e.g., molecular weight of approximately 60,000 daltons to approximately 150,000 daltons) (e.g., hydroxypropylcellulose (77,000 MW), hydroxypropylcellulose (80,000 MW), hydroxypropylcellulose (90,000 MW), or hydroxypropylcellulose (140,000 MW)), and / or high molecular weight water-soluble polymers with a molecular weight exceeding approximately 60,000 daltons (e.g., molecular weights of approximately 200,000 daltons to approximately 900,000 daltons) (e.g., hydroxypropyl cellulose (approximately 340,000 MW), hydroxypropyl cellulose (approximately 370,000 MW), polyethylene oxide (approximately 200,000 MW), or polyethylene oxide (approximately 600,000 MW)). Each water-soluble polymer may be independently selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide, and methylcellulose (e.g., hydroxypropyl cellulose and / or polyethylene oxide).

[0359] In the embodiment, the composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer which is hydroxypropyl cellulose, and one or two high molecular weight polymers which are hydroxypropyl cellulose, in an ethanol solvent.

[0360] In the embodiment, the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), hydroxypropyl cellulose (about 40,000 MW), and one or both of hydroxypropyl cellulose (about 140,000 MW) and hydroxypropyl cellulose (about 370,000 MW).

[0361] In the embodiment, the composition comprises only dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) and two hydroxypropyl celluloses (i.e., hydroxypropyl cellulose (about 40,000 MW) and hydroxypropyl cellulose (about 140,000 MW)).

[0362] In embodiments, the deposition composition may be in any form (e.g., liquid, emulsion, suspension, or dispersion). For example, the dexmedetomidine composition may be added as one or more droplets to an ethanol-based solution containing a pH neutralizer (e.g., sodium hydroxide) as needed. In embodiments, the surface of the film substrate contains two or more microdeposition spots of dexmedetomidine hydrochloride in the polymer matrix (e.g., two microdeposition spots). The viscosity of the deposition solution / suspension may range from about 6 cps to about 3700 cps when measured at 25°C using a Brookfield viscometer with a small sample adapter. For 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.

[0363] In embodiments of this 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 / sec).

[0364] After drying to remove the solvent, the film contains the aforementioned dexmedetomidine composition (e.g., placebo), but no solvent is deposited (e.g., microdeposits) on the surface of the film substrate. The dried composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) may cover the entire surface of the film substrate or only a portion of the surface of the film substrate.

[0365] In the embodiment, the dried dexmedetomidine composition appears on the surface of the film substrate as one or more individual drug-containing droplets. Alternatively, a stencil may be used to represent one or more defined individual areas of the drug-containing composition on the surface of the film substrate.

[0366] In embodiments, the Disclosure provides a dry film product comprising a film substrate having one or more distinct drug-containing droplets on the surface of the film substrate, each of which comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and two molecular weights of hydroxypropylcellulose: hydroxypropylcellulose (40,000 MW) available as HPC-SSL and hydroxypropylcellulose (140,000 MW) sold under the trademark Klucel® Type JF NF, and the film substrate comprises three molecular weights of hydroxypropylcellulose: hydroxypropylcellulose (40,000 MW), hydroxypropylcellulose (140,000 MW), and hydroxypropylcellulose (370,000 MW) sold under the trademark Klucel® Type GF NF. In some embodiments, the film substrate also comprises polyethylene oxide (600,000 MW) available under the name Sentry Polyox WSR 205 LEO NF.

[0367] In embodiments, the dried film product comprises a deposition composition (also referred to herein as the "dexmedetomidine composition") comprising: (i) dexmedetomidine hydrochloride present in 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 in about 5% to about 85% w / w of the deposition composition; (iii) hydroxypropyl cellulose (140,000 MW) present in about 5% to about 85% w / w of the deposition composition; and (iv) hydroxypropyl cellulose (370,000 MW) present in about 0% to about 65% w / w of the deposition composition. The film also includes a polymer matrix, which comprises: (i) hydroxypropyl cellulose (40,000 MW) present at approximately 3% to 40% w / w of the polymer matrix; (ii) hydroxypropyl cellulose (140,000 MW) present at approximately 3% to 40% w / w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 MW) present at approximately 0% to 30% w / w of the polymer matrix; and (iv) polyethylene oxide (600,000 MW) present at approximately 55% to 75% w / w of the polymer matrix.

[0368] In embodiments, the dry film product (e.g., microdeposition film product) comprises: (i) dexmedetomidine hydrochloride present in about 1% to about 50% w / w of the total film weight; (ii) hydroxypropyl cellulose (40,000 MW) present in about 2% to about 30% w / w of the total film weight; (iii) hydroxypropyl cellulose (140,000 MW) present in about 2% to about 30% w / w of the total film weight; (iv) hydroxypropyl cellulose (370,000 MW) present in about 10% to about 50% w / w of the total film weight; (v) polyethylene oxide (600,000 MW) present in about 40% to about 75% w / w of the total film weight; and (vi) optionally, other pharmaceutically acceptable carriers.

[0369] In embodiments, the films disclosed herein combine several types of hydroxypropyl cellulose (HPC) to provide films with advantageous properties. For example, a film composition may contain a combination of two or three of hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000 MW), and hydroxypropyl cellulose (370,000 MW). In some embodiments, polyethylene oxide (600,000 MW) is included in these types of HPC when it is part of a monolithic film.

[0370] In certain film compositions of this disclosure, low molecular weight hydroxypropyl cellulose (e.g., 40,000 MW) is present in an amount of about 3% to about 8% (e.g., about 5%) w / w of the total film weight, high molecular weight hydroxypropyl cellulose (e.g., 140,000 MW) is present in an amount of about 3% to about 8% (e.g., about 5%) w / w of the total film weight, high molecular weight hydroxypropyl cellulose (e.g., 370,000 MW) is present in an amount of about 20% to about 40% w / w of the total film weight, and polyethylene oxide (e.g., 600,000 MW) is present in an amount of about 40% to about 70% (e.g., about 50% to about 60%) w / w of the total film weight. In some embodiments, two high molecular weight water-soluble polymers are present together in an amount of about 25% to about 40% w / w of the total film weight.

[0371] The selection and ratio of water-soluble polymers can be controlled so that the film composition is completely dissolved in oral mucosal fluid within a few seconds to a few minutes (e.g., within about 0.25 minutes to about 15 minutes), thereby ensuring that a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is delivered via the oral mucosa. For example, the film composition may be present in the sublingual or buccal region of the mouth for up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes (e.g., including periods of about 30 seconds to about 15 minutes, about 1 minute to about 10 minutes, or about 1 minute to about 5 minutes).

[0372] Standard basket or paddle apparatuses described in any pharmacopoeia can be used for in vitro dissolution tests. The choice of dissolution medium will essentially depend on the sink conditions and the maximum dose of the drug. The temperature of the eluate should be maintained at 37 ± 0.5°C, and the rpm should be maintained at 50 (see below: Bala et al., in Int J Pharm Investigation, vol.3(2), pages 67-76).

[0373] The films disclosed herein have several functional advantages that promote the rapid onset of drug effects. In some embodiments, the disintegration time (DT) of the thin film compositions disclosed herein, when applied sublingually or buccally, is approximately 15 to 180 seconds, 15 to 160 seconds, 25 to 150 seconds, 15 to 140 seconds, 15 to 120 seconds, 40 to 120 seconds, 50 to 120 seconds, for example, approximately 120 seconds. The disintegration time within this time frame allows for the optimal onset of drug effects.

[0374] In embodiments, the thin film composition of the present invention has mucosal adhesion properties that localize the film to the oral mucosa (e.g., buccal or sublingual), providing the practical advantage of reducing or preventing effective removal before dissolution. This property is particularly advantageous in clinical settings where there are subjects in agitated conditions. Accordingly, in embodiments, the thin film composition has a mucosal adhesion force (mucosal adhesion strength or shear strength) of about 50 g or more, about 100 g or more, about 200 g or more, about 300 g or more, about 400 g or more, about 500 g or more, about 600 g or more, about 700 g or more, about 800 g or more, about 900 g or more, or about 1000 g or more. In embodiments, the mucosal adhesion force is in 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.

[0375] The bursting strength of the film also contributes to drug delivery. The specific thin film compositions of the present invention have bursting strengths of approximately 50g, 100g, 200g, 300g, 400g, 500g, 600g, 700g, 800g, 900g, 1000g, 1100g, 1200g, 1300g, 1400g, 1500g, 1600g, 1700g, 1800g, 1900g, and 2 The burst strength may be in the range of approximately 200g to 15,000g, approximately 300g to 10,000g, or approximately 400g to 5,000g.

[0376] Pharmacologically acceptable carriers The film composition may further contain one or more pharmaceutically acceptable carriers (including, but not limited to, liquid carriers, fragrances, sweeteners, cooling agents, antioxidants, pH adjusters, penetration enhancers, mucosal adhesives, plasticizers, bulking agents, surfactants / nonionic solubilizers, stabilizers, defoamers, colorants, etc.). In embodiments, the film composition is substantially free of acidic buffers or other acidic agents.

[0377] liquid carrier According to the embodiments, the pharmaceutically acceptable carrier comprises a liquid carrier. The liquid carrier comprises a polymer matrix (drug-containing or placebo) and one or more solvents useful for preparing the deposition composition onto the polymer matrix. In embodiments, the solvent may be water. In embodiments, the solvent may be a polar organic solvent (not limited to, but including ethanol, isopropanol, acetone, butanol, benzyl alcohol, and mixtures thereof). In embodiments, the solvent may be a non-polar organic solvent (e.g., methylene chloride, toluene, ethyl acetate, and mixtures thereof). Specific solvents are alcohols, particularly ethanol, water, and mixtures thereof. Preferably, the solvent content in the wet polymer matrix is ​​at least about 30% by weight of the total wet weight of the entire film composition before drying. The subsequently dried film composition preferably contains less than about 10% by weight of the solvent, more preferably less than about 8% by weight of the solvent, even more preferably less than about 6% by weight of the solvent, and most preferably less than about 2% by weight of the solvent.

[0378] Flavoring / Sweetener / Cooling agent To improve the taste of the film composition of the present invention, it may be beneficial to add sweeteners, flavoring agents, cooling agents, taste masking agents, or combinations thereof to the film composition. Flavors can be selected from natural and synthetic flavoring liquids. An exemplary list of such substances includes volatile oils, synthetic flavoring oils, flavoring agents, oils, liquids, oleoresins, or extracts obtained from plants, leaves, flowers, fruits, stems, and combinations thereof. Non-limited flavoring oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitter almond oil. In some embodiments, the flavor is peppermint oil, peppermint oil flavor available as NF.

[0379] The amount may vary to obtain the desired result in the final product. Such changes are within the scope of those skilled in the art and do not require excessive experimentation. Generally, the films of the present invention may use amounts from about 0.1% to about 30% by weight to impart flavor. Suitable sweeteners include both natural and artificial sweeteners. Examples of suitable sweeteners include, for example, water-soluble sweeteners such as monosaccharides, disaccharides, and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levrose), 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 dihydrochalcone; water-soluble artificial sweeteners such as soluble saccharin salts (i.e., saccharin sodium or saccharin calcium salt), cyclamate salts, and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners such as chlorinated derivatives of the common sugar (sucrose) known as sucralose. In some embodiments, the sweetener is sucralose.

[0380] Flavorings, sweeteners, and cooling agents can be added in conventional amounts, generally up to a total amount of approximately 0.01% to approximately 10% of the film weight on a dry weight basis, for example, up to approximately 0.1% to approximately 7% of the film weight on a dry weight basis, for example, up to approximately 0.1% to approximately 5% of the film weight on a dry weight basis.

[0381] Other taste masking agents include, for example, polymers, oils, or waxes. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is coated with a taste masking agent before the formulation of the film composition. In embodiments, 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, when used to coat the active ingredient. In embodiments, the taste masking agent may be present in an amount of about 25% to about 35% by weight of the particles or granules containing the active ingredient.

[0382] Antioxidant Examples of oxygen scavengers or antioxidants that significantly improve the long-term stability of film compositions against oxidative degradation include sulfites such as sodium sulfite, sodium bisulfite, and sodium metabisulfite, as well as potassium and calcium analogs. A suitable amount of sulfite (e.g., sodium sulfite) is up to about 5% on a dry weight basis relative to the weight of the film composition, for example, about 0.001% to about 2%.

[0383] pH adjuster / pH neutralizer The absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa may be increased in an alkaline microenvironment. For example, this can be achieved when the film composition maintains a pH greater than 6, about 6 to about 9, or about 6.5 to about 8. In embodiments, the film may contain an alkaline substance that raises 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, etc. Alkaline buffers (e.g., glycine) are an example of pH neutralizers. A suitable amount of pH adjuster / pH neutralizer present in the film composition is, for example, up to about 10% (e.g., about 1% to about 5%) based on the weight of the film composition on a dry weight basis.

[0384] Penetration enhancer Certain effective osmotic enhancers that promote the absorption of dexmedetomidine or its pharmaceutically acceptable salts via the oral mucosa include alcohols. Alcohol osmotic enhancers (e.g., butanol) can be conveniently added to the film composition in amounts up to about 10% (e.g., about 0.1% to about 5%, or about 1% to about 3%) based on the weight of the film composition on a dry weight basis.

[0385] Mucosal adhesive Examples of mucosal adhesives that can be added to film compositions include, but are not limited to, sodium alginate, sodium carboxymethylcellulose, guar gum, polyethylene oxide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, karaya gum, methylcellulose, letene, and tragacanth. One mucosal adhesive is polyethylene oxide, which can be conveniently added to a film composition in an amount of about 20% to about 90% (e.g., about 40% to about 70%) based on the total weight of the film composition on a dry weight basis.

[0386] plasticizer Plasticizers that can be effectively used herein include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate, and glycerol. Depending on the selected film-forming polymer(s) and other components of the film formulation, the preferred amount of plasticizer in the film composition may typically be up to about 10% (e.g., about 0.1% to about 5%, e.g., about 0.5% to about 5%) based on the weight of the film on a dry weight basis. For specific applications, high molecular weight polyethylene glycol (including polyethylene oxide) may be used.

[0387] Filler Suitable fillers that can be added to the film composition include starch, calcium salts (e.g., calcium carbonate), and sugars (e.g., 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 of the present invention is typically up to about 25% of the film composition's weight on a dry weight basis, for example, about 0.5% to about 20%, for example, about 1% to about 15%, for example, about 2% to about 10%.

[0388] Surfactants / Nonionic Solubilizers The film typically incorporates at least one surfactant / nonionic solubilizer (e.g., but not limited to poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearate, 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 about 5% or less (e.g., about 0.5% to about 3%, or about 1% to about 3%) based on the dry weight of the film composition.

[0389] Antifoaming ingredient Simethicone is one example of a useful defoaming agent and / or defoaming agent, but other defoaming agents and / or defoaming agents may also be used appropriately. A defoaming agent and / or defoaming agent (e.g., simethicone) may be added to the film composition in an amount of about 0.01% to about 5.0%, more preferably about 0.05% to about 2.5%, and most preferably about 0.1% to about 1.0%, based on the weight of the film composition on a dry weight basis.

[0390] Coloring agents Coloring additives that may be included in the film composition include food, pharmaceutical and cosmetic colorants (FD&C), pharmaceutical and cosmetic colorants (D&C), or topical pharmaceutical and cosmetic colorants (Ext. D&C). These colors are dyes, corresponding lakes, and certain natural and derived colorants. Specific examples of coloring additives are inorganic pigments (e.g., iron or titanium oxides), which are 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 embodiments, the color used in the dexmedetomidine composition (i.e., the deposition composition) is different from the color used in the film substrate (e.g., placebo film). One color for the film substrate of monolithic films and microdeposition films is emerald green, which is available as Fast Emerald Green Shade (06507). One color of the dexmedetomidine composition (i.e., the deposition composition) is a color different from the color of the film substrate, for example, blue (available as FD&C Blue No. 1). In embodiments of the film of the present disclosure, for example, embodiments of the film of the present disclosure, such as those described in the above aspects and embodiments, are films containing about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, with two blue microdeposition spots of dexmedetomidine hydrochloride on a green film substrate.

[0391] Embodiments of the film of the present disclosure are, for example, films comprising about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof, as described in the above embodiments and models.

[0392] In one embodiment (A), a self-supporting soluble film is provided, comprising the following: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 180 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0393] In another embodiment (B), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 120 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0394] In another embodiment (C), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 90 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0395] Another embodiment (D) provides a self-supporting soluble film comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 80 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0396] In another embodiment (E), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 60 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0397] In another embodiment (F), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 40 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0398] In another embodiment (G), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 20 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0399] In another embodiment (H), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 10 μg, (ii) One or more water-soluble polymers, (iii) Polyethylene oxide, and optionally, (iv) One or more pharmaceutically acceptable carriers.

[0400] In certain embodiments, one or more water-soluble polymers (ii) of embodiments (A) to (H) above comprises one low molecular weight water-soluble polymer and two high molecular weight water-soluble polymers, for example, the molecular weight of the low molecular weight water-soluble polymer being about 5,000 daltons to about 49,000 daltons (e.g., about 40,000 daltons), and the molecular weight of each high molecular weight water-soluble polymer being greater than about 60,000 daltons (e.g., the molecular weight of one of the two high molecular weight water-soluble polymers is about 140,000 daltons, and the other high molecular weight water-soluble polymer is about 370,000 daltons). In some embodiments, each water-soluble polymer is hydroxypropyl cellulose. In some embodiments, the molecular weight of polyethylene oxide is about 600,000 daltons.

[0401] In certain embodiments, a pharmaceutical film composition is provided comprising, or essentially comprising, 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 colorants, and FD&C blue colorants.

[0402] In another embodiment (I), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 180 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0403] In another embodiment (J), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 120 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0404] In another embodiment (K), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 90 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0405] In another embodiment (L), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 80 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0406] In another embodiment (M), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 60 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0407] In another embodiment (N), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 40 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0408] In another embodiment (O), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 20 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0409] In another embodiment (P), a self-supporting soluble film is provided, comprising: (i) Dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) about 10 μg, (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0410] In certain embodiments of the films described in Embodiments (I) and (P), the film is formed from a single layer of film substrate, with the film components, excluding dexmedetomidine or a pharmaceutically acceptable salt thereof, forming a single layer of film substrate, and the dexmedetomidine or a pharmaceutically acceptable salt thereof present on the surface of the film substrate (for example, in a composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof, a low molecular weight water-soluble polymer with a molecular weight of about 40,000 daltons and a high molecular weight water-soluble polymer with a molecular weight of about 140,000 daltons). In some embodiments, each water-soluble polymer is hydroxypropyl cellulose.

[0411] Embodiment (Q) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 180 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0412] Embodiment (R) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 120 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0413] Embodiment (S) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 90 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0414] Embodiment (T) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 80 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0415] Embodiment (U) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 60 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0416] Embodiment (V) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 40 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0417] Embodiment (W) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 20 μg (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0418] Embodiment (X) provides a self-supporting soluble film comprising: (a) A composition consisting essentially of the following: (i) Dexmedetomidine hydrochloride, approximately 10 μg, (ii) Hydroxypropyl cellulose (40,000 MW), and (iii) Hydroxypropyl cellulose (140,000 MW), and (b) A film substrate consisting essentially of the following: (i) Hydroxypropyl cellulose (40,000 MW), (ii) Hydroxypropyl cellulose (140,000 MW), (iii) Hydroxypropyl cellulose (370,000 MW), and (iv) Polyethylene oxide (600,000 MW), (The composition of part (a) is present on the surface of the film substrate (b)).

[0419] In the specific embodiments of the films described above in embodiments (Q) and (X), dexmedetomidine hydrochloride is present at approximately 0.1% to approximately 2% w / w of the total film weight, hydroxypropyl cellulose (40,000 MW) is present at approximately 4% to approximately 8% w / w of the total film weight, hydroxypropyl cellulose (140,000 MW) is present at approximately 4% to approximately 8% w / w of the total film weight, hydroxypropyl cellulose (370,000 MW) is present at approximately 25% to approximately 30% w / w of the total film weight, and polyethylene oxide (600,000 MW) is present at approximately 50% to approximately 60% w / w of the total film weight.

[0420] In embodiments, the pharmaceutical composition of the present disclosure is measured in human plasma concentrations of dexmedetomidine at a detectable C concentration after single and multiple doses of the pharmaceutical composition of the present disclosure. max The present invention provides the following: In embodiments, the pharmaceutical composition of the present invention provides the T of dexmedetomidine in human plasma concentrations after a single or multiple administration of the pharmaceutical composition of the present invention. max The present disclosure provides, in embodiments, the pharmaceutical compositions of this disclosure provide the detectable area under the curve (AUC) of dexmedetomidine and its metabolites at human plasma concentrations after a single or multiple dose. In some embodiments, the AUC of dexmedetomidine (or its metabolites) is measured from time 0 (time of administration) to 24 hours (referenced to time 0), and the AUC is measured from time 0 (time of administration) to 24 hours (referenced to time 0). 0-24h It is expressed as follows. In the embodiment, the AUC of dexmedetomidine (or its metabolite) is measured from time 0 (administration time) to a time extrapolated to infinity, and the AUC 0-Inf It is expressed as follows. In the embodiment, the AUC of dexmedetomidine (or its metabolite) 0-last and AUC 0-Inf The range and value are the AUC of dexmedetomidine (or its metabolites). 0-6hThe range and values ​​are similar to those of the above. In embodiments, the present disclosure provides a pharmaceutical buccal film composition comprising, or essentially comprising, a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucosal adhesive polymers, and any excipient selected from one or more plasticizers, penetration enhancers, colorants, sweeteners, flavoring agents, tasters, or salivary secretion enhancers. The mucosal adhesive polymer may be selected from hydrophilic polymers and hydrogels. Examples of hydrophilic polymers include polyvinyl alcohol [PVA], sodium carboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], hydroxyethylcellulose, and hydroxypropylcellulose [HPC]. Examples of hydrogels include anionic polymers (e.g., carbopol, polyacrylate), cationic polymers (e.g., chitosan), and nonionic polymers (e.g., Eudragit analogs).

[0421] Spray, drop, gel formulations In embodiments, the present disclosure provides a pharmaceutically acceptable spray or drop composition suitable for sublingual or buccal administration, comprising, or essentially comprising, 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 may be solvents, co-solvents, or non-solvents of 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, and pharmaceutically acceptable oils (e.g., soybean oil, sunflower oil, peanut oil, etc.). The pharmaceutically acceptable liquids are selected to dissolve dexmedetomidine or a pharmaceutically acceptable salt thereof, to produce a stable and homogeneous suspension thereof, or to form any combination of suspension and solution. In addition to these components, spray or drop formulations of dexmedetomidine or a pharmaceutically acceptable salt thereof may contain one or more excipients, e.g., viscosity modifiers (e.g., polymers, sugars, sugar alcohols, gums, clays, silica, polyvinylpyrrolidone (PVP)); preservatives (e.g., ethanol, benzyl alcohol, propylparaben, and methylparaben); flavorings (e.g., peppermint oil); sweeteners (e.g., 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); UV absorbers, and antifoaming agents (e.g., low molecular weight alcohols, dimethicone).In addition to one or more of the above-mentioned components suitable for sublingual or buccal spray or drop formulations, a gel formulation of dexmedetomidine or a pharmaceutically acceptable salt thereof may contain one or more excipients (e.g., water-soluble or water-swellable polymers, e.g., Carbopol, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose).

[0422] Sprays, drops, and gels may be prepared by mixing appropriate amounts of the above-mentioned components in accordance with good manufacturing practices. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf life, to reduce manufacturing and packaging costs, to meet the requirements of government regulatory bodies, and for other purposes. The relative amounts of each component shall not interfere with the desirable pharmacological and pharmacokinetic properties of the resulting formulation.

[0423] In one embodiment, an oral mucosal spray composition is provided comprising, or essentially comprising, a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0424] In the embodiment, the patient is treated by sublingual or buccal administration with one or two sprays from a spray pump. The advantage of spray delivery is that the patient can easily adjust the dosage as needed, in one or two doses, with a single spray.

[0425] Pump-operated sprays are characterized in that they require the application of external pressure, for example, pressure induced manually, mechanically, or electrically from an external source, for operation. This is in contrast to pressurized systems (e.g., high-pressure gas-driven aerosol sprays), where operation is usually achieved by controlling and releasing pressure (e.g., by controlling the opening of a valve).

[0426] Various oral mucosal spray formulations containing dexmedetomidine hydrochloride in doses of approximately 10 mg, 20 μg, 30 μg, 40 μg, 60 μg, 80 μg, 90 μg, 120 μg, 180 μg, and 240 μg, along with the excipients listed in Table 1.

[0427] [Table 1]

[0428] Various oral mucosal drop-type compositions comprising dexmedetomidine hydrochloride in doses of approximately 10 μg, 20 μg, 30 μg, 40 μg, 60 μg, 90 μg, 120 μg, 180 μg, and 240 μg, along with the excipients listed in Table 2.

[0429] [Table 2]

[0430] Various oral mucosal gel compositions comprising dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 40 μg, 60 μg, 90 μg, 120 μg, 180 μg, and 240 μg, and the excipients listed in Table 3.

[0431] [Table 3]

[0432] tablet In embodiments, the present disclosure provides a tablet formulation suitable for oral mucosal administration (e.g., sublingual or buccal administration) comprising, or essentially consisting 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 include taste masking agents, diluents, disintegrants, binders, lubricants, flow enhancers, flavoring agents, or liquid solvents. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, glycerin, N-methylpyrrolidone, and pharmaceutically acceptable oils (e.g., soybean oil, sunflower oil, peanut oil, etc.). Examples of flavor masking agents include amber light, Opadry® AMB TAN, polymethacrylate (especially Eudragit® L100), sodium starch glycolate (Primojel), carbopole polymer, PEG-5M, sodium acetate, ethylcellulose, and beta-dextrin. Flavorings may include, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, and saccharin. Disintegrants include, for example, sodium starch glycolate, low-substituted hydroxypropylcellulose, alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, guar gum, methylcellulose, poloxamer, and sodium alginate. The diluent may be, for example, microcrystalline cellulose, dextrose, dextrose, fructose, mannitol, sucralose, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, or maltitol. The binder may be, for example, alginic acid, carbomer, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, methylcellulose, polydextrose, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, or sodium alginate.Conveniently, at least one lubricant may be incorporated into the formulation to prevent the powder from adhering to the tableting punch during the compression process. The lubricant may be, for example, talc, magnesium stearate, calcium stearate, glyceryl behenate, hydrogenated castor oil, stearic acid, or sodium lauryl sulfate. A glidant is used to promote powder flow by reducing friction and aggregation between particles. Since the glidant does not have the function of reducing die wall friction, it is used in combination with a lubricant. The flow promoter may be, for example, colloidal silicon dioxide, calcium silicate, or tricalcium phosphate.

[0433] Various oral tablet formulations containing dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 40 μg, 60 μg, 90 μg, 120 μg, 180 μg, and 240 μg, along with the excipients listed in Table 4.

[0434] [Table 4]

[0435] Various oral mucosal tablet compositions comprising dexmedetomidine hydrochloride in doses of 20 μg, 30 μg, 40 μg, 60 μg, 90 μg, 120 μg, 180 μg, and 240 μg, and the excipients listed in Table 5.

[0436] [Table 5]

[0437] Intranasal preparations The compositions of this disclosure may be administered into the nasal cavity in any preferred form. For example, the compositions may be administered into the nasal cavity in the form of a spray emulsion, suspension, or liquid, or as drops or powder.

[0438] The powder blends according to this disclosure may be prepared by mixing dexmedetomidine or a pharmaceutically acceptable salt thereof with a standard inert component in the art. Such inert components include, but are not limited to, diluents (e.g., calcium phosphate, lactose), sugars (e.g., dextrose and sucrose), polyols (e.g., mannitol and sorbitol), as well as microcrystalline cellulose, flow promoters (e.g., colloidal silica), lubricants (e.g., magnesium stearate and hydrogenated vegetable oil), and surfactants (e.g., polysorbate and polyethylene glycol). For small-scale preparation of homogeneous powder blends, a mortar and pestle and / or sieve are suitable, but for large-scale production, a mechanical mixer is required. Various types of mixers are available and are widely described in the literature (e.g., Chapter 37, Remington: The Science and Practice of Pharmacy, 20th Edition, Lipincott, Williams and Wilkins, Baltimore, 2000).

[0439] If the powder compositions of this disclosure contain granules, these granules may be produced by methods well known to those skilled in the art (e.g., wet granulation, dry granulation (slugging), extrusion / spheroidization, fluidized bed granulation, and spray coagulation). Further details of the granulation process can be found in the literature (e.g., Chapter 6, Pharmaceutical Principles of Solid Dosage Forms, JTCarstensen, Technomic, Lancaster, PA, 1993).

[0440] In addition to dexmedetomidine or its pharmaceutically acceptable salts, other components may be incorporated into the granules. Such other components include, but are not limited to, diluents (e.g., calcium phosphate, lactose, dextrose, mannitol, and microcrystalline cellulose), binders (e.g., povidone (polyvinylpyrrolidone), methylcellulose, polyethylene glycol, gelatin, and acacia), disintegrants (e.g., starch, croscarmellose, and crospovidone), flow enhancers (e.g., colloidal silica), and lubricants (e.g., 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 manufacturing microspheres are described, for example, in: Physicochemical Principles of Pharmacy, 3rd Edition, pages 357 to 360, A.T. Florence and D. Attwood, Macmillan, London, 1998 and Physical Pharmacy, 4th Edition, pages 516 to 519, A.M. Martin, Wilkins and Wilkins, Baltimore, 1993. Alternatively, microspheres may be manufactured using the methods described in W098 / 30207 and the documents cited therein.

[0441] The powder compositions of this disclosure can be administered to a subject in aerosol form, thereby using energy from the patient's inhalation (smelling) to aerosolize the powder into the nasal cavity, or the device itself provides aerosolizing energy, for example, via compressed air. An example of the former device is 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 filled with the compositions defined above, or a dose cartridge used in a nasal delivery device.

[0442] In embodiments, the compositions of the present disclosure also disclose a process for preparing the solutions of the present disclosure, the process comprising mixing the components in a suitable solvent (e.g., water, ethanol, propylene glycol, polyethylene glycol, glycoflore, benzyl benzoate, and polyoxyethylene castor oil derivatives). The compositions may be prepared using methods known in the art.

[0443] The solutions of this disclosure may contain other pharmaceutically acceptable components well known in the art. Such components include, but are not limited to, thickeners, adhesives, or gelling agents (e.g., cellulose (e.g., hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, and microcrystalline cellulose), carbomers, polyethylene oxide, poloxamers, or polyethylene glycol), antioxidants (e.g., sodium metabisulfite), chelating agents (e.g., EDTA or its salts), preservatives (e.g., potassium sorbate, parabens, phenylethyl alcohol, or benzalkonium chloride), fragrances, sweeteners, thickeners, adhesives, or gelling agents (e.g., cellulose (e.g., hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxycellulose, and microcrystalline cellulose), poloxamers, polyethylene glycol, carbomers, or polyethylene oxide).

[0444] The solutions of this disclosure may contain preservatives and / or be sterilized. If preservatives are omitted from the composition, microorganisms can be removed using any suitable method known in the art (e.g., by aseptically preparing the composition or by finally sterilizing the composition). In some embodiments, the compositions of the present invention are non-pyrogenic.

[0445] In embodiments, the intranasal compositions of the present disclosure include, in addition to the active ingredient, an aqueous suspension, solution, or emulsion containing materials (e.g., suitable dispersants and / or wetting agents, e.g., propylene glycol or polyethylene glycol, emulsifiers, suspending agents, surfactants, solubilizers, vehicles, etc.).

[0446] The pharmaceutical composition may also be formulated as liposomes, microcapsules, or centrosomes together with one or more suitable pharmaceutically acceptable carriers.

[0447] In addition to dexmedetomidine or a pharmaceutically acceptable salt thereof, the microspheres used in this disclosure may also include components known in the art to be suitable for inclusion in starch, dextran, gelatin, albumin, collagen, hyaluronic acid, chitosan, lactose, sucrose, dextrose, mannitol, methacrylate copolymers (e.g., Eudragit® polymer (Degsa, Germany), cellulose (e.g., methylcellulose), and polyesters (e.g., poly(lactide-co-glycolide))).

[0448] Any device suitable for intranasal administration can be used. In embodiments, the device is a metered-dose device. Examples of metered-dose devices include, but are not limited to, spray pumps, pre-compressed nasal spray pumps, metered-dose valve devices, actuated spray devices, lateral actuated spray devices, syringe nasal spray devices (e.g., syringes with a spray for delivering spray into the nasal cavity), mucosal spray devices, and electromechanical pump devices (with and without counters). Examples of metered-dose devices include, but are not limited to, devices manufactured by Aptar Pharma (Congers, New York), which are commercially available. Examples of metering and dispensing devices include, but are not limited to, 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), MAD Nasal Drug Device (Wolf Tory Medical, Inc.), and BD Accuspray SCF (trademark) (Becton Dickinson). Another example is, but is not limited to, the Aptar Unitdose Intranasal System.

[0449] 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 may include, but are not limited to, intravenous, intraperitoneal, intramuscular, subarachnoid, and subcutaneous routes. In embodiments, parenteral formulations may include pre-filled syringes, vials, powders to be reconstituted at infusion, infusion concentrates (readily dilutable) to be diluted before delivery, or solutions (readily usable).

[0450] Pharmaceutical compositions for injection may be aqueous isotonic solutions or suspensions, and suppositories may be prepared from lipid emulsions or suspensions.

[0451] The pharmaceutical composition may be sterile and / or may contain auxiliary agents, such as preservatives, stabilizers, wetting agents, or emulsifiers, dissolution accelerators, salts for adjusting osmotic pressure, and / or buffers. Furthermore, they may also contain other therapeutically valuable substances.

[0452] In embodiments, the pharmaceutical compositions of this disclosure include biodegradable subcutaneous implants, osmotic pressure control devices, subcutaneous implants, subcutaneous sustained-release injectables, lipid nanoparticles, liposomes, and the like. Liquid preparations include, but are not limited to, solutions, suspensions, and emulsions. Examples of such preparations include water or water / propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration.

[0453] When used intramuscularly, intraperitoneally, subcutaneously, or intravenously, a sterile solution of the active ingredient(s) is typically used, and the pH of the solution must be appropriately adjusted and buffered. For intravenous use, the total concentration of the solute(s) must be controlled to make the preparation isotonic.

[0454] The liquid vehicle used in the preparation of the intramuscular injection may be, for example, water, saline solution, another aqueous liquid (aqueous solvent), or a non-aqueous liquid (non-aqueous solvent).

[0455] The parenteral formulations of this disclosure can be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of a sterilizing agent, irradiation, and heating.

[0456] The parenteral formulations described above may be administered by periodic injection of bolus of the preparation, or by intravenous or intraperitoneal administration from an external (e.g., intravenous bag) or internal (e.g., biodegradable implant, bioprosthetic organ, or organ) reservoir. See, for example, U.S. Patent Nos. 4,407,957 and 5,798,113 (each incorporated herein by reference in whole). Methods and apparatus for intrapulmonary delivery are described, for example, U.S. Patents Nos. 5,654,007, 5,780,014 and 5,814,607 (each incorporated herein by reference in whole). Other useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposome delivery, needle delivery injection, needleless injection, nebulizers, aerozoizers, electroporation, and transdermal patches. Needleless syringe devices are described in U.S. Patent Nos. 5,879,327, 5,520,639, 5,846,233, and 5,704,911, which are incorporated herein by reference in their entirety. Any of the formulations described herein can be administered by these methods. Further injectable formulations of dexmedetomidine are described below: U.S. Patent No. 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, Chinese Patent Application No. Patent No. 105534891, Chinese Patent Application No. 106038538, US Patent Application 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.

[0457] This disclosure includes intramuscular compositions comprising dexmedetomidine or a pharmaceutically acceptable salt thereof in a concentration of about 0.05 μg / ml to about 15 μg / ml, sodium chloride in a concentration of about 0.01% to about 2.0% by weight, and a pH in the range of about 1 to about 10.

[0458] Oral preparations This disclosure includes oral formulations that can be used to deliver dexmedetomidine. Examples of oral formulations include tablets, orally disintegrating tablets, orally soluble tablets, wafers, solutions, suspensions, emulsions, and capsules.

[0459] This disclosure encompasses orally disintegrating tablets comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one orally disintegrating carrier, wherein the orally disintegrating tablets disintegrate in about 0.5 to about 120 seconds, and / or a therapeutically effective dose of dexmedetomidine is absorbed into the bloodstream within about 1 to about 5 minutes. In embodiments, a therapeutically effective dose of dexmedetomidine is absorbed into the bloodstream within about 3 minutes.

[0460] In the embodiment, at least one orally disintegrating carrier is selected from the group consisting of water-soluble sugars or sugar alcohols, crospovidone, (low-substituted) hydroxypropylcellulose, croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch, sodium starch glycolate, sodium lauryl sulfate, crystalline cellulose, and combinations thereof. The water-soluble sugars or sugar alcohols are selected from the group consisting of sucrose, sorbitol, mannitol, xylitol, erythritol, isomalt, and fructose. In the embodiment, the orally disintegrating carriers together constitute at least 50% by weight, for example, at least 80% by weight or at least 85% by weight of the orally disintegrating carriers. The carriers described above are in the form of particles and typically have a volume-weighted average particle size of 50 to 300 micrometers, for example, 70 to 200 micrometers. F-Melt® (Fuji Chemical Industry Co., Ltd.) is an example of a commercially available granular material containing a disintegrant dispersed in a matrix containing C4-C6 sugar alcohols (mannitol and xylitol). Ludiflash® (BASF) is another example of a commercially available granular material containing a disintegrant dispersed in a matrix of C4-C6 sugar alcohols (mannitol).

[0461] Orally disintegrating tablets as used herein may be prepared by mixing dexmedetomidine with a water-soluble diluent and compressing it into tablets. A suspension containing dexmedetomidine may be prepared with appropriate excipients, and the dexmedetomidine suspension may be filled into blister packs and lyophilized. An exemplary lyophilized preparation platform that can be used for dexmedetomidine ODT is the ZYDIS® (Catalent, Somerset, New Jersey, USA) formulation. In particular, an excipient containing water is blended, and dexmedetomidine is separately ground according to size and mixed with the excipient. The suspension is then lyophilized by rapid freezing and lyophilization. Other methods for preparing ODT may be used, but are not limited to these. A detailed description of the general method is disclosed, for example, in the following U.S. Patent 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; 6,471,992; 6,509,040; 6,814,978; and 6,908,626. ; Nos. 6,908,626; Nos. 6,982,251; Nos. 7,282,217; Nos. 7,425,341; Nos. 7,939,105; Nos. 7,993,674; Nos. 8,048,449; Nos. 8,127,516; Nos. 8,158,152; Nos. 8,221,480; Nos. 8,256,233; and Nos. 8,313,768 (each of these is incorporated herein by reference in whole).

[0462] Specific Embodiments Embodiment 1. A method for treating an acute agitated episode in a patient with Alzheimer's disease, comprising administering 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the patient, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient, the agitation is moderate to severe, and the patient is at least 65 years old, optionally at least 75 years old.

[0463] Embodiment 2. The method according to Embodiment 1, wherein the agitation is not due to pain, infection, concomitant medication, environmental conditions, or a mental illness other than dementia.

[0464] Embodiment 3. The method according to Embodiment 1, wherein the patient does not exhibit delirium.

[0465] Embodiment 4. The method according to Embodiment 1, wherein the patient is administered dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually.

[0466] Embodiment 5. The method according to Embodiment 1, wherein the patient is orally administered dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0467] Embodiment 6. The method according to Embodiment 1, wherein the patient is determined to have a total score of 14 or higher on the Positive / Negative Symptom Rating Scale (PANSS) - Agitation Item (PEC) scale before administration.

[0468] Embodiment 7. The method according to Embodiment 6, wherein the PEC score decreases by approximately 4 to 6 points within 2 hours after administration.

[0469] Embodiment 8. The method according to Embodiment 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, a spray, or a cachet.

[0470] Embodiment 9. The method according to Embodiment 8, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film.

[0471] Embodiment 10. The method according to Embodiment 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as needed.

[0472] Embodiment 11. The method according to Embodiment 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or more times daily.

[0473] Embodiment 12. The method according to Embodiment 1, wherein the patient has previously been treated with any antipsychotic drug.

[0474] Embodiment 13. The method according to Embodiment 1, wherein the patient has not been previously treated with any antipsychotic drug.

[0475] Embodiment 14. The method according to Embodiment 7, wherein improvement in the score is observed as early as 30 minutes after administration.

[0476] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0477] Embodiment 16. A method for treating agitation or signs of agitation in elderly dementia patients, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state in a concentration of approximately 80% to 125% of approximately 50 ng / L to approximately 500 ng / L. max The method involves administering a dose sufficient to obtain the desired result, provided the patient is 65 years of age or older.

[0478] Embodiment 17. A method for treating an acute agitation episode in an elderly dementia patient, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at an AUC in the range of approximately 80% to approximately 125% of approximately 200 hr × ng / L to approximately 2200 hr × ng / L. 0-inf This includes administering a dose sufficient to obtain C max However, the range is approximately 80% to 125% of the range of approximately 50 ng / L to approximately 300 ng / L, and the patient is 65 years of age or older.

[0479] Embodiment 18. A method for treating an acute agitation episode in an elderly dementia patient, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at an AUC in the range of approximately 80% to approximately 125% of approximately 200 hr × ng / L to approximately 1500 hr × ng / L. 0-8 This includes administering a dose sufficient to obtain C maxHowever, the range is approximately 80% to 125% of the range of approximately 50 ng / L to approximately 300 ng / L, and the patient is 65 years of age or older.

[0480] Embodiment 19. The method according to any of Embodiments 16 to 18, wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 μg to about 90 μg (e.g., about 30 μg to about 60 μg, 60 μg to about 90 μg, or 30 μg to about 45 μg).

[0481] Embodiment 20. The method according to Embodiment 19, wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 75 μg, about 80 μg, or about 90 μg.

[0482] Embodiment 21. The method according to any one of Embodiments 16 to 18, wherein the administration route is an oral mucosal route, and the oral mucosal route includes a sublingual, buccal, or gingival route.

[0483] Embodiment 22. The method according to any one of Embodiments 16 to 21, comprising administering approximately 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa once to six times a day with at least two-hour intervals between doses.

[0484] Embodiment 23. The method according to any one of Embodiments 16 to 21, comprising administering approximately 40 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa once to six times a day with at least two-hour intervals between doses.

[0485] Embodiment 24. The method according to any one of Embodiments 16 to 21, comprising administering approximately 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa once to six times a day with at least two-hour intervals between doses.

[0486] Embodiment 25. The method according to any one of Embodiments 16 to 21, comprising administering approximately 90 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa once to four times a day with at least two-hour intervals between doses.

[0487] Embodiment 26. The method according to any one of Embodiments 16 to 21, comprising administering a single dose of about 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa, followed by a dose of 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof 2 hours later.

[0488] Embodiment 27. The method according to any one of Embodiments 16 to 21, comprising administering a single dose of about 30 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa, followed by a dose of 60 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof 6 hours later.

[0489] Embodiment 28. The method according to Embodiments 16-18, wherein the elderly patient is approximately 75 to approximately 80 years old.

[0490] Embodiment 29. The method according to Embodiments 16-18, wherein the elderly patient is approximately 80 years of age or older.

[0491] Embodiment 30. A method for treating an acute agitation episode in an elderly dementia patient, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to a patient in an agitated state at an AUC in the range of approximately 80% to approximately 125% of approximately 200 hr × ng / L to approximately 2200 hr × ng / L. 0-inf This includes administering a dose sufficient to obtain C max However, the concentration is in the range of approximately 80% to 125% of approximately 50 ng / L to approximately 300 ng / L, and the route of administration is selected from oral mucosa, intravenous, intramuscular, subcutaneous, and transdermal.

[0492] Embodiment 31. The method according to Embodiment 30, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of about 30 μg to about 130 μg.

[0493] Embodiment 32. AUC 0-8However, 200hr x ng / L to about 1500hr x ng / L (for example, about 200hr x ng / L to about 1250hr x ng / L, about 200hr x ng / L to about 1000hr x ng / L, about 200hr x ng / L ~ approx. 750hr x ng / L, approx. 200hr x ng / L ~ approx. 500hr x ng / L, approx. 500hr x ng / L ~ approx. 1500hr x ng / L, approx. 500hr x ng / L ~ approx. 1250hr x ng The method according to embodiment 30 or 31, wherein the values ​​are approximately 500hr × ng / L to approximately 1000hr × ng / L, approximately 500hr × ng / L to approximately 750hr × ng / L, approximately 750hr × ng / L to approximately 1500hr × ng / L, approximately 750hr × ng / L to approximately 1250hr × ng / L, approximately 750hr × ng / L to approximately 1000hr × ng / L, and approximately 1000hr × ng / L to approximately 1500hr × ng / L.

[0494] Embodiment 33. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 30 μg, C max However, it is approximately 50 ng / L to approximately 150 ng / L, and AUC 0-8 The method according to any one of embodiments 30 to 32, wherein the range is approximately 200hr × ng / L to approximately 600hr × ng / L (for example, approximately 200hr × ng / L to approximately 400hr ng / L, approximately 300hr × ng / L to approximately 600hr × ng / L, approximately 300hr × ng / L to approximately 500hr × ng / L, approximately 350hr × ng / L to approximately 450hr × ng / L).

[0495] Embodiment 34. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 40 μg, C max However, it is approximately 50 ng / L to approximately 250 ng / L, and AUC 0-8 The method according to any one of embodiments 30 to 32, wherein the range is approximately 200hr × ng / L to approximately 600hr × ng / L (for example, approximately 200hr × ng / L to approximately 400hr ng / L, approximately 300hr × ng / L to approximately 600hr × ng / L, approximately 300hr × ng / L to approximately 500hr × ng / L, approximately 350hr × ng / L to approximately 450hr × ng / L).

[0496] Embodiment 35. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 45 μg, C max However, the AUC is approximately 75 ng / L to 175 ng / L. 0-8 The method according to embodiments 30 to 32, wherein the range is approximately 500hr × ng / L to approximately 900hr × ng / L (for example, approximately 500hr × ng / L to approximately 800hr ng / L, approximately 600hr × ng / L to approximately 900hr × ng / L, approximately 600hr × ng / L to approximately 800hr × ng / L, and approximately 650hr × ng / L to approximately 750hr × ng / L).

[0497] Embodiment 36. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 60 μg, C max However, it is approximately 100 ng / L to approximately 250 ng / L, and AUC 0-8 The method according to Embodiments 30 to 32, wherein the range is approximately 500hr×ng / L to approximately 1500hr×ng / L (for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L).

[0498] Embodiment 37. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 90 μg, C max However, it is approximately 100 ng / L to 400 ng / L, and AUC 0-8 The method according to Embodiments 30 to 32, wherein the range is approximately 500hr×ng / L to approximately 1500hr×ng / L (for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L).

[0499] Embodiment 38. Administration of dexmedetomidine or a pharmaceutically acceptable salt thereof reduces AUC 0-inf The method according to embodiment 33, wherein the range is approximately 80% to approximately 125% of approximately 200 hours × ng / L to approximately 1000 hours × ng / L (for example, approximately 200 hours × ng / L to approximately 900 hours × ng / L, approximately 300 hours × ng / L to approximately 800 hours × ng / L, approximately 300 hours × ng / L to approximately 750 hours × ng / L, approximately 350 hours × ng / L to approximately 750 hours × ng / L).

[0500] Embodiment 39. Administration of dexmedetomidine or a pharmaceutically acceptable salt thereof reduces AUC 0-inf The range is approximately 300hr×ng / L to approximately 2200hr×ng / L (for example, approximately 400hr×ng / L to approximately 2000hr×ng / L, approximately 400hr×ng / L to approximately 1800hr×ng / L, approximately 500hr×ng / L to approximately 1500hr×ng / L, for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng The method according to embodiment 34, wherein the amount is approximately 80% to approximately 125% of (approximately 600hr × ng / L to approximately 1400hr × ng / L, approximately 600hr × ng / L to approximately 1200hr × ng / L, approximately 600hr × ng / L to approximately 1000hr × ng / L, approximately 800hr × ng / L to approximately 1400hr × ng / L, or approximately 800hr × ng / L to approximately 1000hr × ng / L).

[0501] Embodiment 40. Administration of dexmedetomidine or a pharmaceutically acceptable salt thereof reduces AUC 0-inf The method according to embodiment 35, wherein the range is approximately 80% to approximately 125% of approximately 500hr×ng / L to approximately 1500hr×ng / L (for example, approximately 500hr×ng / L to approximately 1400hr×ng / L, approximately 500hr×ng / L to approximately 1000hr×ng / L, approximately 600hr×ng / L to approximately 1400hr×ng / L, approximately 600hr×ng / L to approximately 1200hr×ng / L, approximately 600hr×ng / L to approximately 1000hr×ng / L, approximately 800hr×ng / L to approximately 1400hr×ng / L, or approximately 800hr×ng / L to approximately 1000hr×ng / L).

[0502] Embodiment 41. Administration of dexmedetomidine or a pharmaceutically acceptable salt thereof reduces AUC 0-inf The range is approximately 500hr×ng / L to approximately 2000hr×ng / L (for example, approximately 600hr×ng / L to approximately 1900hr×ng / L, approximately 700hr×ng / L to approximately 1800hr×ng / L, approximately 700hr×ng / L to approximately 1700hr×ng / L, approximately 700hr×ng / L to approximately 1600hr×ng / L, approximately 700hr×ng / L to approximately 1500hr×ng / L, approximately 800hr×ng / L to approximately 1500hr×ng / The method according to Embodiment 36, wherein L is approximately 80% to approximately 125% of (approximately 900hr × ng / L to approximately 1500, approximately 1000hr × ng / L to approximately 1500hr × ng / L, approximately 1100hr × ng / L to approximately 1500hr × ng / L, approximately 1200hr × ng / L to approximately 1500hr × ng / L, approximately 1300hr × ng / L to approximately 1500hr × ng / L, or approximately 1400hr × ng / L to approximately 1500hr × ng / L).

[0503] Embodiment 42.C max The method according to embodiment 33, wherein the values ​​are approximately 80% to 125% of the following ranges: approximately 50 ng / L to approximately 150 ng / L, approximately 50 ng / L to approximately 125 ng / L, approximately 50 ng / L to approximately 100 ng / L, approximately 50 ng / L to approximately 75 ng / L, approximately 75 ng / L to approximately 150 ng / L, approximately 75 ng / L to approximately 125 ng / L, approximately 75 ng / L to approximately 100 ng / L, and approximately 100 ng / L to approximately 150 ng / L.

[0504] Embodiment 43.C max The method according to embodiment 34, wherein the glycemic index is approximately 50 ng / L to approximately 250 ng / L, for example, approximately 50 ng / L to approximately 225 ng / L, approximately 50 ng / L to approximately 200 ng / L, approximately 100 ng / L to approximately 180 ng / L, approximately 100 ng / L to approximately 150 ng / L, and approximately 150 ng / L to approximately 200 ng / L, which is approximately 80% to approximately 125% of these ranges.

[0505] Embodiment 44.C maxThe method according to Embodiment 35, wherein the values ​​are approximately 80% to 125% of the following ranges: approximately 75 ng / L to approximately 150 ng / L, approximately 75 ng / L to approximately 125 ng / L, approximately 75 ng / L to approximately 100 ng / L, and approximately 100 ng / L to approximately 150 ng / L.

[0506] Embodiment 45.C max The method according to embodiment 36, wherein the glycemic index is approximately 80% to 125% of the following ranges: approximately 100 ng / L to approximately 250 ng / L, approximately 100 ng / L to approximately 225 ng / L, approximately 100 ng / L to approximately 200 ng / L, approximately 150 ng / L to approximately 250 ng / L, and approximately 150 ng / L to approximately 200 ng / L.

[0507] Embodiment 46.C max The method according to embodiment 37, wherein the values ​​are approximately 80% to 125% of the following ranges: approximately 100 ng / L to approximately 400 ng / L, approximately 100 ng / L to approximately 350 ng / L, approximately 100 ng / L to approximately 300 ng / L, approximately 200 ng / L to approximately 400 ng / L, and approximately 200 ng / L to approximately 350 ng / L.

[0508] Embodiment 47. The method according to Embodiment 30, wherein the elderly patient suffers from both dementia and Alzheimer's disease.

[0509] Embodiment 48. The patient is not significantly sedated within 60 minutes after administration of a pharmaceutically acceptable salt of dexmedetomidine. The method according to any one of Embodiments 1 to 47.

[0510] Embodiment 49.C max The method according to any one of Embodiments 1 to 47, wherein the values ​​and ranges are at least 30% higher than those obtained in patients with schizophrenia and bipolar disorder.

[0511] Embodiment 50.C max The method according to any one of Embodiments 1 to 47, wherein the value is approximately 35% higher than that obtained in patients with schizophrenia and bipolar disorder.

[0512] Embodiment 51. The method according to any one of Embodiments 1 to 47, wherein the AUC value and range are at least 50% higher than those obtained in patients with schizophrenia and bipolar disorder.

[0513] Embodiment 52. The method according to any one of Embodiments 1 to 47, wherein the AUC value and range are approximately 55% higher than those obtained in patients with schizophrenia and bipolar disorder.

[0514] Embodiment 53.C max AUC 0-∞ and AUC 0-8 The method according to any one of Embodiments 1 to 47, wherein the range and values ​​are approximately 40% and 60% higher than those obtained in patients with schizophrenia and bipolar disorder.

[0515] Embodiment 54. The method according to any one of Embodiments 1 to 53, wherein the reduction of agitation in elderly dementia patients is evaluated using PEC, PAS, ACES, Mod-CMAI, and / or CGI-I.

[0516] Embodiment 55. The method according to any one of Embodiments 1 to 54, wherein agitation or signs of agitation are significantly reduced within 60 minutes after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0517] Embodiment 56. The method according to Embodiment 55, wherein the reduction in intensity 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.

[0518] Embodiment 57. The method according to any one of Embodiments 1 to 53, wherein the patient achieves a mean change in PAS score of less than -2 from baseline within 2 hours of administration of dexmedetomidine.

[0519] Embodiment 58. The method according to any one of Embodiments 1 to 57, wherein the patient achieves a mean change in PEC score of less than -2 from baseline within 2 hours of administration of dexmedetomidine.

[0520] Embodiment 59. The method according to Embodiment 58, wherein the reduction in the PEC score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration of dexmedetomidine.

[0521] Embodiment 60. The method according to any one of Embodiments 1 to 56, wherein the patient achieves a mean change in mod-CMAI score of less than -7 relative to baseline two hours after administration of dexmedetomidine.

[0522] Embodiment 61. The method according to Embodiment 60, wherein the reduction in the mod-CMAI score is maintained for at least 2 hours (e.g., including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours) after administration of dexmedetomidine.

[0523] Embodiment 62. The method according to any one of Embodiments 1 to 56, wherein the patient achieves an improvement of approximately 1 (very good improvement) or approximately 2 (much improvement) in the CGI-I score.

[0524] Embodiment 63. The method according to Embodiment 62, wherein the score improvement is maintained for approximately 2 to 6 hours.

[0525] Embodiment 64. The method according to Embodiment 62, wherein the score improvement is maintained for approximately 12 hours.

[0526] Embodiment 65. The method according to any one of Embodiments 1 to 56, wherein agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) as measured on the Agitation and Sedation Rating Scale (ACES) two hours after administration of the composition.

[0527] Embodiment 66. The method according to Embodiment 65, which reduces the intensity to 3 (mild intensity).

[0528] Embodiment 68. The method according to Embodiment 31, wherein the patient has not received treatment for hypertension within at least 10 hours prior to the administration of dexmedetomidine.

[0529] Embodiment 69. The agitation is acute agitation. The method according to any one of Embodiments 1 to 68.

[0530] Embodiment 70. The method according to any one of Embodiments 1 to 68, wherein the agitation is chronic agitation.

[0531] Embodiment 71. A method for administering dexmedetomidine or a pharmaceutically acceptable salt thereof in a dose greater than approximately 90 μg to treat agitation in elderly dementia patients who have not received hypertensive treatment for at least 10 hours, at least 24 hours, at least 48 hours, or at least 1 week prior to the administration of dexmedetomidine.

[0532] Embodiment 72. The method according to any one of Embodiments 1 to 71, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally.

[0533] Embodiment 73. The method according to Embodiment 72, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel, or drops.

[0534] Embodiment 74. The method according to Embodiment 73, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

[0535] Embodiment 75. The method according to any one of Embodiments 1 to 74, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally.

[0536] Embodiment 76. The method according to Embodiment 75, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet, film, spray, gel, or drops.

[0537] Embodiment 77. The method according to Embodiment 76, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of a film.

[0538] Embodiment 78. The method according to any of the prior embodiments, wherein the patient is treated without causing any clinically significant cardiovascular effects.

[0539] Embodiment 79. The method according to any of the prior embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0540] Embodiment 80. A method for treating agitation or signs of agitation in a delirious human patient hospitalized in an ICU without inducing significant sedation, comprising administering approximately 20 μg of dexmedetomidine or a pharmaceutically acceptable salt orally mucosally 1 to 4 times within 6 hours after the initial dose, at intervals of at least 30 minutes.

[0541] Embodiment 81. A method for treating agitation or signs of agitation in a delirious human patient hospitalized in an ICU without inducing significant sedation, comprising administering approximately 20 μg of dexmedetomidine or a pharmaceutically acceptable salt orally mucosally 1 to 4 times within 6 hours after the initial dose, at intervals of at least 30 minutes.

[0542] Embodiment 82. A method for treating agitation or signs of agitation in a delirious human subject hospitalized in an ICU without inducing significant sedation, comprising administering approximately 40 μg of dexmedetomidine or a pharmaceutically acceptable salt orally mucosally 1 to 4 times within 6 hours after the initial dose, at intervals of at least 30 minutes.

[0543] Embodiment 83. A method for treating agitation or signs of agitation in a delirious human patient hospitalized in an ICU without inducing significant sedation, comprising administering approximately 60 μg of dexmedetomidine or an acceptable salt thereof orally mucosally 1 to 4 times within 6 hours after the initial dose, at intervals of at least 30 minutes.

[0544] Embodiment 84. A method for treating agitation or signs of agitation in a delirious human subject hospitalized in an ICU without inducing significant sedation, comprising administering about 20 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt via the oral mucosa (e.g., sublingually or buccally).

[0545] Embodiment 85. The method according to Embodiment 84, wherein agitation or signs of agitation and the severity of delirium are significantly reduced as measured by RASS and DRS-R-98, respectively.

[0546] Embodiment 86. The method according to Embodiment 84, wherein the subject achieves a decrease of 2 points or more in RASS in 2 hours.

[0547] Embodiment 87. The method according to Embodiment 84, wherein dexmedetomidine or a pharmaceutically acceptable salt is administered in doses of about 20 μg, 60 μg, 80 μg, 90 μg, 100 μg, 120 μg, 150 μg, 180 μg, 210 μg, 240 μg, 270 μg, or 300 μg.

[0548] Embodiment 88. The method according to Embodiment 84, wherein dexmedetomidine or a pharmaceutically acceptable salt is administered in a dose of approximately 270 μg.

[0549] Embodiment 89. The method according to Embodiment 84, wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt is about 300 μg.

[0550] Embodiment 90. The method according to Embodiment 84, wherein the initial RASS of the target is not -3 or less.

[0551] Embodiment 91. The method according to Embodiment 84, wherein dexmedetomidine or a pharmaceutically acceptable salt is administered as a single unit dose or a multi-unit dose.

[0552] Embodiment 92. The method according to Embodiment 84, wherein dexmedetomidine or a pharmaceutically acceptable salt is administered 1 to 10 times a day at intervals of approximately 1 to 6 hours from the first dose to obtain the desired effect.

[0553] Embodiment 93. The method according to Embodiment 84, wherein dexmedetomidine or a pharmaceutically acceptable salt is administered twice daily.

[0554] Embodiment 94. The method according to Embodiment 84, wherein a dose of approximately 120 μg of dexmedetomidine or a pharmaceutically acceptable salt is administered twice daily at 12-hour intervals.

[0555] Embodiment 95. The method according to Embodiment 84, wherein a dose of about 120 μg of dexmedetomidine or a pharmaceutically acceptable salt is administered seven times a day at intervals of about 1 to 6 hours to obtain a maximum cumulative dose of 960 μg.

[0556] Embodiment 96. The method according to Embodiment 84, wherein a dose of approximately 180 μg of dexmedetomidine or a pharmaceutically acceptable salt is administered, followed by six additional doses of 120 μg at intervals of approximately 1 to 6 hours.

[0557] Embodiment 97. The method according to Embodiment 84, wherein a dose of approximately 240 μg of dexmedetomidine or a pharmaceutically acceptable salt is administered, followed by an additional 120 μg six times a day at intervals of approximately 1 to approximately 6 hours to obtain a maximum cumulative dose of 960 μg.

[0558] Embodiment 98. The method according to Embodiment 84, wherein a dose of about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt is administered, followed by an additional 120 μg five times a day at intervals of about 1 to about 6 hours to obtain a maximum cumulative dose of 900 μg.

[0559] Embodiment 99. The method according to any one of Embodiments 80 to 98, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel, or drops.

[0560] Embodiment 100. The method according to Embodiment 99, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually as a film.

[0561] Embodiment 101. The method according to any one of Embodiments 80 to 98, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet, film, spray, gel, or drops.

[0562] Embodiment 102. The method according to Embodiment 101, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally as a film.

[0563] Embodiment 103. The method according to any one of Embodiments 80 to 98, wherein the subject is between 18 and 64 years of age.

[0564] Embodiment 104. The method according to any one of Embodiments 80 to 98, wherein the subject is over 64 years of age.

[0565] Embodiment 105. A method for shortening the opioid withdrawal period by administering dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) twice daily to a human subject at least 18 years of age in need thereof, wherein the withdrawal period is up to 14 days.

[0566] Embodiment 106. A method for treating or alleviating opioid withdrawal symptoms, comprising administering a composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof 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.

[0567] Embodiment 107. The method according to Embodiment 106, wherein the treatment includes shortening the opioid withdrawal period.

[0568] Embodiment 108. The method according to Embodiment 107, wherein the opioid withdrawal symptoms are severe.

[0569] Embodiment 109. The method according to Embodiment 106, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose range of 30 μg to about 600 μg.

[0570] Embodiment 110. The method according to Embodiment 109, wherein the composition is a dose range of 30 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0571] Embodiment 111. The method according to Embodiment 109 or 110, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered twice daily in unit doses of about 30 μg, 60 μg, 90 μg, 120 μg, 150 μg, 180 μg, 240 μg, 270 μg, or 300 μg.

[0572] Embodiment 112. The method according to Embodiment 109 or 110, wherein the withdrawal period is 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or up to 3 days.

[0573] Embodiment 113. The method according to Embodiment 109 or 110, wherein the composition is administered twice daily for seven days.

[0574] Embodiment 114. The method according to Embodiment 109 or 110, wherein the opioid is selected from the group consisting of fentanyl, morphine, codeine, heroin, oxycodone, hydrocodone, alfentanil, carfentanil, tramadol, hydromorphone, buprenorphine, naloxone, naltrexone, remifentanil, butorphanol, meperidine, methadone, dextropropoxifen (propoxifen), thebaine, sufentanil, or pentazocine.

[0575] Embodiment 115. The method according to Embodiment 109 or 110, wherein the opioid was administered for a longer period than neonatal treatment prior to withdrawal.

[0576] Embodiment 116. The method according to Embodiment 109 or 110, wherein improvement in the subject is assessed after treatment using the Clinical Opioid Withdrawal Scale (COWS) and / or Gossop's Short-Term Opiate Withdrawal Scale (SOWS) (e.g., over 10 days).

[0577] Embodiment 117. The method according to Embodiment 109 or 110, wherein improvement in opioid withdrawal is measured in terms of retention (number of days) and percentage of subjects who withdraw from opioids after discontinuation of opioids.

[0578] Embodiment 118. The method according to Embodiment 109 or 110, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose of approximately 240 μg twice daily (at 12-hour intervals).

[0579] Embodiment 119. The method according to Embodiment 114, wherein the opioid is fentanyl.

[0580] Embodiment 120. The method according to Embodiment 109 or 110, wherein the patient is between 18 and 64 years of age.

[0581] Embodiment 121. The method according to any of Embodiments 106 to 120, wherein a retention rate of at least about 40% was observed on day 6 after treatment with a dose of 120 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0582] Embodiment 122. The method according to any of Embodiments 106 to 120, wherein a retention rate of at least about 50% was observed on day 6 after treatment with a dose of 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0583] Embodiment 123. The method according to any one of Embodiments 106 to 120, wherein a significant reduction in subjective assessment of insomnia (measured on the SOWS scale) is obtained on day 7 after administration of a dose of approximately 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily.

[0584] Embodiment 124. The method according to any of Embodiments 106 to 120, wherein a significant reduction in anxiety or irritability (measured on the COWS scale) is obtained on day 8 after administering a dose of approximately 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof twice daily.

[0585] Embodiment 125. The method according to Embodiment 108, wherein agitation is reduced to 3 (mild agitation) or 4 (normal behavior) and 5 (mild sedation) on the Agitation and Sedation Rating Scale (ACES) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0586] Embodiment 126. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of approximately 40 ng / L to approximately 500 ng / L six hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on the second day.

[0587] Embodiment 127. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of approximately 20 ng / L to approximately 200 ng / L six hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) on day 6.

[0588] Embodiment 128. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of about 20 ng / L to about 150 ng / L 12 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) on day 6.

[0589] Embodiment 129. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of approximately 50 ng / L to approximately 500 ng / L two hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) on day 12.

[0590] Embodiment 130. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of about 20 ng / L to about 250 ng / L 6 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) on day 12.

[0591] Embodiment 131. The method according to any one of Embodiments 106 to 125, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof yields an average plasma concentration in the range of approximately 10 ng / L to 150 ng / L 12 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12.

[0592] Embodiment 132. The method according to any one of Embodiments 106 to 125, wherein the mean plasma concentration is preferably 80% to 125% of these ranges and values.

[0593] Embodiment 133. The method according to either Embodiment 106 or 107, wherein, when the dose is 30 μg, the mean plasma concentration is in the range of about 20 ng / L to about 50 ng / L (e.g., about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, and about 45 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6.

[0594] Embodiment 134. The method according to either Embodiment 106 or 107, wherein, when the dose is 60 μg, the mean plasma concentration is in the range of about 25 ng / L to about 150 ng / L (e.g., about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6.

[0595] Embodiment 135. The method according to either Embodiment 106 or 107, wherein, when the dose is 90 μg, the mean plasma concentration is in the range of about 30 ng / L to about 150 ng / L (e.g., about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 μg / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, 145 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6.

[0596] Embodiment 136. When the dose is 120 μg, the mean plasma concentration is in the range of approximately 50 ng / L to approximately 200 ng / L (e.g., approximately 55 ng / L, approximately 60 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 90 ng / L, approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 6. The method according to either embodiment 106 or 107, wherein the glucose levels are approximately 120 ng / L, 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, 150 ng / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, and 195 ng / L.

[0597] Embodiment 137. When the dose is 180 μg, the mean plasma concentration is in the range of approximately 100 ng / L to approximately 450 ng / L after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 6 (e.g., approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L, approximately 160 ng / L, approximately 1 The method according to either embodiment 106 or 107, wherein the glycemic index is 65 ng / L, approximately 170 ng / L, approximately 175 ng / L, approximately 180 ng / L, approximately 185 ng / L, approximately 190 ng / L, approximately 195 ng / L, approximately 200 ng / L, approximately 225 ng / L, approximately 250 ng / L, approximately 275 ng / L, approximately 300 ng / L, approximately 325 ng / L, approximately 350 ng / L, approximately 375 ng / L, approximately 400 ng / L, approximately 425 ng / L, and approximately 450 ng / L.

[0598] Embodiment 138. When the dose is 240 μg, the mean plasma concentration is in the range of approximately 100 ng / L to approximately 400 ng / L (e.g., approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on approximately day 6. The method according to either embodiment 106 or 107, wherein the glycemic levels are approximately 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, 195 ng / L, 200 ng / L, 225 ng / L, 250 ng / L, 275 ng / L, 300 ng / L, 325 ng / L, 350 ng / L, 375 ng / L, and 395 ng / L.

[0599] Embodiment 139. The method according to either Embodiment 106 or 107, wherein, when the dose is 30 μg, the mean plasma concentration after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12 is in the range of about 10 ng / L to about 100 ng / L (e.g., about 15 ng / L, about 20 ng / L, about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 80 ng / L, about 90 ng / L, about 95 ng / L).

[0600] Embodiment 140. The method according to either Embodiment 106 or 107, wherein, when the dose is 60 μg, the mean plasma concentration is in the range of about 10 ng / L to about 150 ng / L (e.g., 15 ng / L, about 20 ng / L, about 25 ng / L, about 30 ng / L, about 35 ng / L, about 40 ng / L, about 45 ng / L, about 50 ng / L, about 55 ng / L, about 60 ng / L, about 70 ng / L, about 75 ng / L, about 90 ng / L, about 100 ng / L, about 105 ng / L, about 110 ng / L, about 115 ng / L, about 120 ng / L, about 125 ng / L, about 130 ng / L, about 135 ng / L, about 140 ng / L, about 145 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12.

[0601] Embodiment 141. The method according to either Embodiment 106 or 107, wherein, when the dose is 90 μg, the mean plasma concentration is in the range of approximately 25 ng / L to approximately 150 ng / L (e.g., approximately 30 ng / L, approximately 35 ng / L, approximately 40 ng / L, approximately 45 ng / L, approximately 50 ng / L, approximately 55 ng / L, approximately 60 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 90 ng / L, approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12.

[0602] Embodiment 142. When the dose is 120 μg, the mean plasma concentration is in the range of approximately 50 ng / L to approximately 200 ng / L (e.g., approximately 55 ng / L, approximately 60 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 90 ng / L, approximately 100 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on day 12. The method according to either embodiment 106 or 107, wherein the glucose levels are approximately 120 ng / L, 125 ng / L, 130 ng / L, 135 ng / L, 140 ng / L, 145 ng / L, 150 ng / L, 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, and 195 ng / L.

[0603] Embodiment 143. When the dose is 180 μg, the mean plasma concentration is in the range of approximately 100 ng / L to approximately 400 ng / L (e.g., approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L) after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof on approximately day 12. The method according to either embodiment 106 or 107, wherein the glycemic loads are approximately 160 ng / L, 165 ng / L, 170 ng / L, 175 ng / L, 180 ng / L, 185 ng / L, 190 ng / L, 195 ng / L, 200 ng / L, 225 ng / L, 250 ng / L, 275 ng / L, 300 ng / L, 325 ng / L, 350 ng / L, 375 ng / L, and 400 ng / L.

[0604] Embodiment 144. When the dose is 240 μg, the mean plasma concentration after administration of dexmedetomidine or a pharmaceutically acceptable salt on day 12 is approximately 50 ng / L to approximately 500 ng / L, for example, approximately 55 ng / L, approximately 60 ng / L, approximately 70 ng / L, approximately 75 ng / L, approximately 80 ng / L, approximately 90 ng / L, approximately 95 ng / L, approximately 105 ng / L, approximately 110 ng / L, approximately 115 ng / L, approximately 120 ng / L, approximately 125 ng / L, approximately 130 ng / L, approximately 135 ng / L, approximately 140 ng / L, approximately 145 ng / L, approximately 150 ng / L, approximately 160 ng / L, approximately 165 ng / L, approximately 1 The method according to either embodiment 106 or 107, in the range of 70 ng / L, about 175 ng / L, about 180 ng / L, about 185 ng / L, about 190 ng / L, about 195 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 395 ng / L, about 400 ng / L, about 425 ng / L, about 450 ng / L, about 460 ng / L, about 465 ng / L, about 475 ng / L, about 480 ng / L, about 485 ng / L, about 490 ng / L, and about 495 ng / L.

[0605] Embodiment 145. The method according to any one of Embodiments 133 to 144, wherein the mean plasma concentration is 80% to 125% of these ranges and values.

[0606] Embodiment 146. The method according to any one of Embodiments 105 to 145, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the oral mucosa (e.g., sublingually or buccally) in the form of a tablet, film, spray, gel, or drop.

[0607] Embodiment 147. The method according to Embodiment 146, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a tablet, film, spray, gel, or drops.

[0608] Embodiment 148. The method according to Embodiment 147, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.

[0609] Embodiment 149. The method according to Embodiment 148, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of a film, patch, or tablet.

[0610] Embodiment 150. The method according to Embodiment 146, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of a film.

[0611] Embodiment 151. The method according to any of the prior embodiments, wherein the patient is treated without causing any clinically significant cardiovascular effects.

[0612] Embodiment 152. The method according to any one of Embodiments 105 to 145, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally, intranasally, or parenterally.

[0613] Embodiment 153. The method according to any of the relevant prior embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film, and the film is a self-supporting soluble film comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof (ii) One or more water-soluble polymers, and optionally, (iii) One or more pharmaceutically acceptable carriers.

[0614] Embodiment 154(ii) is the method according to Embodiment 153, wherein Embodiment 154(ii) comprises one low molecular weight water-soluble polymer and two high molecular weight water-soluble polymers.

[0615] Embodiment 155. The method according to Embodiment 154, wherein the molecular weight of the low molecular weight water-soluble polymer is about 5,000 daltons to about 49,000 daltons, and the molecular weight of each high molecular weight water-soluble polymer is greater than about 60,000 daltons.

[0616] Embodiment 156. The method according to Embodiment 154, wherein the molecular weight of the low molecular weight water-soluble polymer is about 40,000 daltons, 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.

[0617] Embodiment 157. The method according to any one of Embodiments 154 to 156, wherein each water-soluble polymer is hydroxypropyl cellulose.

[0618] Embodiment 158. The method according to any one of Embodiments 154 to 156, wherein the film also includes polyethylene oxide.

[0619] Embodiment 159. The method according to Embodiment 158, wherein the molecular weight of polyethylene oxide is approximately 600,000 daltons.

[0620] Embodiment 160. The method according to any of the relevant prior embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a film, and the film is a self-supporting soluble film comprising: (i) dexmedetomidine or a pharmaceutically acceptable salt thereof (ii) A low molecular weight water-soluble polymer with a molecular weight of approximately 40,000 daltons, (iii) High molecular weight water-soluble polymers with a molecular weight of approximately 140,000 daltons or more. (iv) High molecular weight water-soluble polymers with a molecular weight of approximately 370,000 daltons or more. (v) A water-soluble polyethylene oxide with a molecular weight of approximately 600,000 daltons.

[0621] Embodiment 161. The method according to Embodiment 160, wherein the film components, excluding dexmedetomidine or a pharmaceutically acceptable salt thereof, form a single layer of film substrate, and dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate.

[0622] Embodiment 162. The method according to Embodiment 161, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of a film substrate in a composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof, the molecular weight of the low molecular weight water-soluble polymer is about 40,000 daltons, and the molecular weight of the high molecular weight water-soluble p...

Claims

1. A method for treating an acute agitated episode in a patient with Alzheimer's disease, comprising administering 60 mcg of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of the patient, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient, the agitation is moderate to severe, and the patient is at least 65 years old, optionally at least 75 years old.

2. The method according to claim 1, wherein the agitation is not due to pain, infection, concomitant medication, environmental conditions, or a mental illness other than dementia.

3. The method according to claim 1, wherein the patient does not exhibit delirium.

4. The method according to claim 1, wherein the patient administers the dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually.

5. The method according to claim 1, wherein the patient is orally administered dexmedetomidine or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the patient is determined to have a total score of 14 or higher on the Positive / Negative Symptom Rating Scale (PANSS) - Excitation Item (PEC) scale before administration.

7. The method according to claim 6, wherein the PEC score decreases by approximately 4 to approximately 6 points within 2 hours after administration.

8. The method according to claim 1, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, a spray, or a cachet.

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

10. The method according to claim 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as needed (or pre-registered).

11. The method according to claim 1, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or more times daily.

12. The method according to claim 1, wherein the patient has previously received treatment with some kind of antipsychotic drug.

13. The method according to claim 1, wherein the patient had not previously received any treatment with antipsychotic drugs.

14. The method according to claim 7, wherein the improvement in the score is observed as early as 30 minutes after administration.

15. The method according to any one of claims 1 to 14, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

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