Use of sublingual dexmedetomidine for the treatment of agitation

Abstract

To provide a composition or the like for treating agitation or signs of agitation.SOLUTION: The present invention discloses a method of treating agitation or signs of agitation in a subject comprising sublingual administration of an effective amount of an alpha-2 adrenergic agent, more particularly dexmedetomidine or a pharmaceutically acceptable salt thereof. The method is particularly suitable for the treatment of agitation associated with neurodegenerative diseases and / or neuropsychiatric diseases. The present invention also discloses sublingual administration of an alpha-2 adrenergic agent, more specifically dexmedetomidine or a pharmaceutically acceptable salt thereof, at a dose that is effective to treat agitation or the symptoms of agitation but does not cause significant sedation in the subject.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] The present invention discloses a method for treating agitation or symptoms of agitation in a subject, comprising sublingually administering an effective amount of an alpha-2 adrenergic agonist, more particularly dexmedetomidine or a pharmaceutically acceptable salt thereof. The present invention also discloses a sublingual composition for treating agitation or symptoms of agitation, comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers and / or excipients in conjunction with the formulation.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 441,164, filed December 31, 2016, U.S. Provisional Patent Application Serial No. 62 / 471,393, filed March 15, 2017, and U.S. Provisional Patent Application Serial No. 62 / 542,323, filed August 8, 2017, the disclosures of which are incorporated herein by reference in their entireties for all purposes. [Background technology]

[0003] Agitation is an umbrella term that can refer to a variety of behavioral abnormalities or disorders, including aggression, combativeness, hyperactivity, and disinhibition. Agitation is a nonspecific group of relatively unrelated behaviors typically seen in several different clinical settings with a fluctuating course. Agitation can be triggered by several different medical conditions and drug interactions, or by any situation that impairs a person's ability to think. Multiple underlying pathophysiological abnormalities involve dysregulation of the dopaminergic, serotonergic, noradrenergic, and GABAergic systems. Agitation is characterized by unproductive, pervasive, and excessive hyperactivity, both motor (akathisia) and cognitive, accompanied by unexpressed, unpleasant tension. The key to safety is early intervention and preventing agitation from progressing to aggression and violence.

[0004] Agitation can be associated with neurodegenerative disorders. One of the key symptoms of a long-term, progressive neurodegenerative process is clinically known as dementia. Dementia includes Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's dementia. Dementia in adults gradually destroys a person's memory and ability to learn, reason, make decisions, communicate information, and perform daily activities. In later stages, patients may experience changes in personality and behavior, such as anxiety, suspiciousness, agitation, and aggression.

[0005] Sebastiaan Engelborghs et al., in Neurochemistry International, 2007, November, 52(6):1052-60, disclosed that in frontotemporal dementia, high activity of dopaminergic neurotransmission and altered serotonergic regulation of dopaminergic neurotransmission are associated with agitated behavior and aggressive behavior, respectively. Pia Jul et al., in Journal of Alzheimer's disease, 2015, September, 49(3):783-95, disclosed that rTg4510 mice exhibit P301L-tau-dependent hyperactivity and that the agitation-like phenotype in these mice may be correlated with some of the behavioral abnormalities observed in progressive Alzheimer's disease (AD) and frontotemporal dementia (FTD). Nathan Hermannet et al., in Journal of Neuropsychiatry, 2004, Aug. 16(3):261-276, disclosed that compensatory increased activity within the noradrenergic system may contribute to the behavioral and psychiatric symptoms of agitation and aggression in Alzheimer's disease.

[0006] Agitation can also be associated with neuropsychiatric conditions such as schizophrenia, bipolar illnesses such as bipolar disorder or bipolar mania, depression, delirium, etc., or associated with alcohol or drug abuse withdrawal. Acute agitation, manifested by motor restlessness and accompanying mental tension, can be present in some psychiatric disorders, including schizophrenia and bipolar mania, and is a serious medical problem that can rapidly develop into aggressive behavior. Acute agitation is characterized by symptoms including pacing, hand clenching, hand clenching and unclenching, urgent talking, yelling, and threatening people with increased agitation.

[0007] To date, no single drug is considered the "standard of care" for treating agitation in patients with dementia or schizophrenia. Depending on the severity of agitation, three classes of drugs are generally most frequently used: first-generation antipsychotics, second-generation antipsychotics, and benzodiazepines, administered orally, intramuscularly, or intravenously. Intramuscular injections of typical antipsychotics and benzodiazepines, given alone or in combination, have been the treatment of choice for agitation over the past several decades. The currently favored treatment paradigm for acute agitation is the use of atypical antipsychotics administered with or without a complementary benzodiazepine.

[0008] More specifically, patients with agitation are commonly prescribed beta-blockers such as propranolol and pindolol, antianxiety medications such as buspirone, benzodiazepines such as lorazepam, anticonvulsants such as valproate and lamotrigine, antipsychotics such as haloperidol, droperidol, ziprasidone, and other high-potency dopamine blockers, and atypical antipsychotics such as olanzapine. However, buspirone, valproate, haloperidol, droperidol, and ziprasidone have potential adverse effects, and their optimal dosage and long-term effectiveness in managing chronic agitation in dementia are severely limited. Lorazepam is only effective in treating agitation in patients when used before medical treatment. Loxapine (an antipsychotic drug) is FDA-approved via inhalation to treat patients with agitation, but is associated with a black box warning about increased bronchospasm and mortality in elderly patients with dementia-related psychosis (FDA label, Loxapine or Adasve®). Its concomitant use with olanzapine, ziprasidone, or haloperidol has also been associated with QT prolongation, and extrapyramidal side effects should be monitored very carefully in the hospitalized setting. Reports of adverse events (including eight life-threatening events) associated with intramuscular olanzapine emphasize the need to follow strict prescribing guidelines and avoid concurrent use with other CNS antidepressants.

[0009] Expert consensus guidelines for the treatment of behavioral emergencies cite speed of onset as one of the most important factors in selecting a drug and its route of administration. However, antipsychotic drugs may require days to weeks before they have a robust antipsychotic effect. Nevertheless, they generally have a calming effect within minutes in agitated patients. For example, benzodiazepines or fast-acting sedatives rapidly calm severely agitated patients, but continued treatment with these drugs leads to tolerance.

[0010] Thus, the treatment of agitation in patients with neuropsychiatric conditions (e.g., schizophrenia or bipolar mania) and neurodegenerative diseases is still limited due to the potential for serious side effects associated with currently used medications, the route of administration (intravenous / intramuscular), and the resulting need for hospitalization to administer these medications. In an ideal situation, an anti-agitation medication for patients with schizophrenia or dementia should have a rapid onset of calming without sedation, be well tolerated, and be easy to administer with a high safety margin.

[0011] Alpha-2 adrenergic agonists are used therapeutically for a number of conditions, including hypertension, congestive heart failure, angina, spasticity, glaucoma, diarrhea, and for suppressing opiate withdrawal. Examples of alpha-2 adrenergic agonists include clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline, and thrombin. Examples of suitable alpha-2 adrenergic agonists include Zolin, talipexole, romifidine, propylhexedrine, norfenefrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, and 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione. The present inventors have unexpectedly discovered that sublingual administration of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof is a particularly effective and safe intervention for the treatment of agitation.

[0012] (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole (dexmedetomidine) is commercially available as an injectable formulation for sedation of initially intubated and mechanically ventilated patients during intensive care unit care, and for non-intubated patients prior to and / or during surgery and other procedures.

[0013] Dexmedetomidine has been reported to have antiagitation effects when administered intravenously or intrabuccally during surgical procedures and in intensive care units (ICUs). For example, Ibacache, et al., in Anesthesia & Analgesia, 2004, January; 98(1):60-3, discloses the administration of a single intravenous dose of dexmedetomidine to reduce agitation following sevoflurane anesthesia in children. Other intravenous administrations have been reported by Jeanne Boyer, et al., in Nursing Critical Care, 2010, January; 5(1):30-34; Yahya Shehabi, et al., in Anesthetic Intensive Care, 2010, January; 38(1):82-90; and Joseph D. Tobias, in Journal of Pediatric Pharmacology Therapeutic, January-March, 2010, 15(1):43-48. NCT02720705 (clinical trial identification number from clinicaltrials.gov) discloses the administration of transbuccal dexmedetomidine for the prevention of emergence agitation in preschool-aged children treated with sevoflurane in the intensive care unit setting.

[0014] The sublingual use of dexmedetomidine is disclosed in WO2016 / 061413. However, the focus of WO2016 / 061413 is the administration of dexmedetomidine sublingually at doses suitable for treating sleep disorders, inducing a pronounced state of sedation. We have now surprisingly found that sublingually administered dexmedetomidine or a pharmaceutically acceptable salt thereof can effectively treat agitation, including agitation associated with neurodegenerative diseases (e.g., Alzheimer's disease, frontotemporal dementia, and sundowning syndrome in Alzheimer's disease / dementia), agitation associated with neuropsychiatric conditions (e.g., bipolar disorder, schizophrenia, bipolar mania, delirium, and depression), agitation associated with alcohol and drug abuse withdrawal, or agitation associated with other conditions, such as treatment for OPD / IPD (e.g., MRI, CT, or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure). The dose administered sublingually may be selected to be effective to treat agitation, but insufficient to cause significant sedation. Summary of the Invention

[0015] The present invention provides a method for treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof, wherein the agitation is associated with a neurodegenerative disease such as dementia, Alzheimer's disease, frontotemporal dementia, or Parkinson's disease, or with a neuropsychiatric condition such as schizophrenia, bipolar disorder, bipolar mania, delirium, or depression, or with treatment of OPD / IPD (e.g., MRI, CT, or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure), or with alcohol and drug abuse withdrawal. In certain embodiments, agitation is suppressed without causing significant sedation.

[0016] In preferred embodiments, the present invention provides methods for treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In certain embodiments, agitation is suppressed without causing significant sedation.

[0017] Another aspect of the present invention provides a method of treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is associated with a neurodegenerative disease. In certain aspects, the agitation is reduced without causing significant sedation.

[0018] Yet another object of the present invention provides a method for treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is associated with dementia, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, or other neurodegenerative disorders. In certain embodiments, agitation is reduced without causing significant sedation.

[0019] Another object of the present invention is to provide a method of treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or another related neuropsychiatric condition. In certain embodiments, agitation is reduced without causing significant sedation.

[0020] A further object of the present invention provides a method for treating, preventing, or alleviating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is associated with sundowning syndrome in Alzheimer's disease / dementia. In certain embodiments, agitation is suppressed without causing significant sedation.

[0021] Yet another object of the present invention provides a method for treating agitation or agitation-related symptoms in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is associated with a procedure for OPD / IPD (e.g., an MRI, CT, or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure). In certain embodiments, agitation is suppressed without causing significant sedation.

[0022] Yet another object of the present invention is to provide a method for treating agitation or agitation-related symptoms in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is associated with alcohol and drug abuse withdrawal. In certain embodiments, the agitation is reduced without causing significant sedation.

[0023] A further aspect of the present invention provides a sublingual composition for treating agitation or symptoms of agitation in a subject in need thereof, wherein said agitation is associated with a neurodegenerative disease, and wherein said sublingual composition comprises an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients.

[0024] Another aspect of the present invention provides a sublingual composition for treating agitation or symptoms of agitation in a subject in need thereof, wherein said agitation is associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression or another related neuropsychiatric condition, said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients.

[0025] An additional aspect of the present invention provides a sublingual composition for treating agitation or symptoms of agitation in a subject in need thereof, wherein said agitation is associated with sundowning syndrome in Alzheimer's disease / dementia, said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients.

[0026] Yet another aspect of the present invention provides a sublingual composition for treating agitation or agitation-related symptoms in a subject in need thereof, wherein said agitation is associated with a treatment for OPD / IPD (e.g., an MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure), said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients.

[0027] Yet another aspect of the present invention provides a sublingual composition for treating agitation or agitation-related symptoms in a subject in need thereof, wherein said agitation is associated with alcohol and drug abuse withdrawal, said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients.

[0028] Another object of the present invention is to provide a sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients, said sublingual composition being selected from the group consisting of films, wafers, patches, lozenges, gels, sprays, tablets, liquid drops, and the like.

[0029] A further object of the present invention is to provide a method for treating agitation or symptoms of agitation by sublingually administering an effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the oral mucosa of a subject at a dosage that does not cause significant sedation.

[0030] In certain embodiments of the invention, the sublingually administered dose can conveniently range between about 3 micrograms and about 100 micrograms. Examples of suitable doses include about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 5 ...50 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 50 micrograms, about 5 micro The dosage may range from about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, or about 50 micrograms. The dosage may be administered one or more times per day. [Brief explanation of the drawings]

[0031] [Figure 1A] Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the cumulative duration of aggressive and agitated behaviors. Data presented as mean ± SEM. One-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 1B]Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the frequency of aggressive and agitated behavior. Data presented as mean ± SEM. One-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 1C] Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the cumulative duration of aggressive and agitated behavior. Data presented as mean ± SEM. One-way ANOVA followed by Dunnett's post-hoc test. **p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 1D] Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the frequency of aggressive and agitated behavior. Data presented as mean ± SEM. One-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 2A] Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​latency to challenge. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 2B] Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​latency to challenge. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3A]Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the cumulative duration of neutral behaviors such as grooming and exploration. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3B] Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the frequency of neutral behaviors such as grooming and exploration. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3C] Figure 1 shows the effect of sublingually administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​neutral behaviors such as immobility / calmness. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3D] Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the cumulative duration of neutral behaviors such as grooming and exploration. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3E]Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​the frequency of neutral behaviors such as grooming and exploration. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 3F] Figure 1 shows the effect of intravenously administered dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 μg / kg) on ​​neutral behaviors such as immobility / calmness. Data are presented as mean ± SEM. Statistical analysis was performed by one-way ANOVA followed by Dunnett's post-hoc test. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 versus vehicle control (Vehicle). [Figure 4A] 1 shows the mean plasma concentrations following sublingual (SL) administration of dexmedetomidine hydrochloride in rats. Data presented as mean ± SD. [Figure 4B] 1 shows the mean plasma concentrations of dexmedetomidine hydrochloride following intravenous (IV) administration in rats, with data expressed as mean ± SD. DETAILED DESCRIPTION OF THE INVENTION

[0032] I. Abbreviations The following abbreviations are used throughout this specification: AD: Alzheimer's disease AUC: Area under the curve BZDs: Benzodiazepines CNS: central nervous system CT / CAT scan: Computed tomography scan C max : The maximum (or peak) serum concentration achieved by a drug in a specified compartment EPS: extrapyramidal side effects FD&C: Federal Food, Drug, and Cosmetic FTD: Frontotemporal dementia GABA: gamma-aminobutyric acid 5-HT: 5-hydroxytryptamine ICU: intensive care unit IPD: Inpatient Department MRI: Magnetic Resonance Imaging Mg: milligram NE: norepinephrine OPD:Outpatient Department PTSD: Post-traumatic stress disorder RSS: Ramsay Sedation Score RIT: Rat Intruder Test SLOS: Smith-Lemli-Opitz syndrome T max :C max The time at which

[0033] II. Definition It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "a solvent" includes one or more such solvents, and the like.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although other methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

[0035] The terms "treating" and "treatment" as used herein refer to curative, prophylactic and / or preventative therapy and can be used interchangeably.

[0036] As used herein, unless otherwise indicated, the terms "pharmaceutical composition," "composition," "formulation," and "composition of the invention" are used interchangeably. Unless otherwise stated, the term is meant to encompass, but is not limited to, pharmaceutical compositions containing the active pharmaceutical ingredient, i.e., dexmedetomidine. The composition may also contain one or more "excipients," which are "inactive ingredients" or compounds lacking pharmaceutical activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affecting the structure or function of the human body.

[0037] As used herein, the term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect. An effective amount is sufficient to cause an improvement in a clinically significant condition in a subject.

[0038] As used herein, "pharmaceutically acceptable salts" refers to salts that are known to be non-toxic and are commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, etc. For example, salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids may also be used. The preferred salt is the hydrochloride salt.

[0039] As used herein, the term "subject" preferably refers to a human patient. In some embodiments, the subject can be any animal, including non-human mammals such as, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates.

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

[0041] The term "signs of agitation" includes excessive motor activity (examples include pacing, rocking, marking, pointing, restlessness, repetitive stereotypes), verbal aggression (e.g., yelling, speaking excessively loudly, using abusive language, screaming, shouting, threatening other people), and physical aggression (e.g., grabbing, shoving, pushing, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things, and destroying property).

[0042] The term "acute agitation" means agitation that occurs rapidly and is severe and sudden in onset. Acute agitation may be present particularly in neuropsychiatric conditions, but may also be associated with, for example, neurodegenerative diseases and neuropsychiatric conditions. If left untreated, acute agitation can lead to chronic agitation.

[0043] The term "chronic agitation" refers to agitation that develops over a longer period of time and is less severe than acute agitation. Chronic agitation may be present in particular in neurodegenerative diseases, but may also be associated with, for example, neurodegenerative diseases and neuropsychiatric conditions.

[0044] The term "neurodegenerative disease" includes, but is not limited to, Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia, dementia with Lewy bodies, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy or other related neurodegenerative diseases.

[0045] The term "neuropsychiatric condition" includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium or other related neuropsychiatric conditions.

[0046] "Sundowning syndrome" is a circadian evening symptom of increased confusion and restlessness that is common in patients with some forms of dementia. It appears to occur more often during the middle stages of Alzheimer's disease. It appears to subside as the patient's dementia progresses. Approximately 20-45% of patients with Alzheimer's disease will experience some form of evening confusion. The confusion and agitation worsen in the late afternoon and evening, or as the sun sets.

[0047] The term "perioperative agitation" refers to agitation before, during, or after a surgical procedure, or ICU agitation not associated with a neurodegenerative disease or neuropsychiatric condition.

[0048] The term "sublingual" literally means "under the tongue" and refers to a method of administering a substance via the mouth in such a way that the substance is rapidly absorbed through the blood vessels under the tongue rather than through the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, allowing the substance to directly access the blood circulation, thereby providing direct systemic administration independent of digestive influences and avoiding undesirable first-pass metabolism in the liver. Therefore, the total amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in the formulation may be reduced, thereby reducing the possibility of adverse side effects and providing cost benefits to manufacturers.

[0049] "Sedation," as used herein, means a state of reduced consciousness in which the patient or subject retains the ability to independently and continuously maintain a patent airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimuli and verbal commands. As used herein, "without causing significant sedation" means that the patient experiences a level of sedation below Level 3 on the Ramsay Sedation Scale, which means sedated but responsive to commands.

[0050] III. Method The present invention provides a method for treating agitation or symptoms of agitation in a subject, comprising sublingually administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof, wherein, in certain embodiments, agitation is suppressed without causing significant sedation.

[0051] In one embodiment, the alpha-2 adrenergic agonist includes clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline, talipexole , romifidine, propylhexedrine, norfenefrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, and 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, or a pharmaceutically acceptable salt thereof.

[0052] In a preferred embodiment, the present invention provides a method of treating agitation or symptoms of agitation in a subject, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein, in certain aspects, agitation is suppressed without causing significant sedation.

[0053] Agitation may be effectively treated with relatively low doses of dexmedetomidine or a pharmaceutically acceptable salt thereof via the sublingual route, such that in addition to providing relief from agitation without causing significant sedation, the treatment is effective with few or no side effects (e.g., cardiac or respiratory side effects).

[0054] In a further embodiment, the present invention is directed to a method of treating agitation or symptoms of agitation in a subject, comprising sublingually administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject to provide fast-acting relief without a substantial portion of the dexmedetomidine or pharmaceutically acceptable salt thereof entering the patient's liver.

[0055] In another embodiment, the present invention provides a method of treating agitation or symptoms of agitation in a subject, comprising administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof via a sublingual composition, wherein the sublingual composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, or liquid drop.

[0056] In a further embodiment, the present invention provides a method of treating agitation or symptoms of agitation in a subject in need thereof, comprising administering to the subject an effective amount of an alpha-2 adrenergic agonist together with one or more pharmaceutically acceptable carriers and / or excipients via a sublingual composition, wherein the sublingual composition is a sublingual film. In certain aspects, the agitation is associated with a neurodegenerative disease or a neuropsychiatric condition. In another particular aspect, the treatment is effective without causing significant sedation.

[0057] In a further embodiment, the present invention provides a method of treating agitation or symptoms of agitation in a subject in need thereof, comprising administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and / or excipients via a sublingual composition, wherein the sublingual composition is a sublingual film. In certain aspects, the agitation is associated with a neurodegenerative disease or a neuropsychiatric condition. In another particular aspect, the treatment is effective without causing significant sedation.

[0058] In yet another embodiment, the present invention provides a method for treating agitation or symptoms of agitation in a subject in need thereof, comprising administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedation. Suitable alpha-2 adrenergic agonists include clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline ...tetrahydrozoline, tetrahydrozoline, tramazoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetra Examples of alpha-2 adrenergic agonists include, but are not limited to, physidine, propylhexedrine, norfenefrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, and 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, or a pharmaceutically acceptable salt thereof. In certain embodiments of the present invention, the dosage of the alpha-2 adrenergic agonist used in the composition is from about 3 micrograms to about 100 micrograms.

[0059] In another embodiment, the present invention provides a method for treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedation. In certain aspects of the present invention, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof used in the sublingual composition is from about 3 micrograms to about 100 micrograms. Examples of suitable doses include from about 5 micrograms to about 100 micrograms, from about 5 micrograms to about 90 micrograms, from about 5 micrograms to about 85 micrograms, from about 5 micrograms to about 80 micrograms, from about 5 micrograms to about 75 micrograms, from about 5 micrograms to about 70 micrograms, from about 5 micrograms to about 65 micrograms, from about 5 micrograms to about 60 micrograms, from about 5 micrograms to about 55 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 45 micrograms, from about 5 micrograms to about 40 micrograms, and from about 5 micrograms to about 60 micrograms. The dosage may range from about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, or about 50 micrograms. The dosage may be administered one or more times per day.

[0060] In a further embodiment, the present invention provides a method of treating agitation or symptoms of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof at a dosage of from about 0.05 micrograms / kg to about 1.5 micrograms / kg of the subject's body weight. Examples of suitable dosages include from about 0.1 micrograms / kg to about 1 microgram / kg, from about 0.1 micrograms / kg to about 0.5 micrograms / kg, from about 0.1 micrograms / kg to about 0.4 micrograms / kg, from about 0.1 micrograms / kg to about 0.3 micrograms / kg, from about 0.1 micrograms / kg to about 0.2 micrograms / kg, about 0.07 micrograms / kg, about 0.05 micrograms / kg, about 0.1 micrograms / kg, and about 0.2 micrograms / kg. The dose may be administered one or more times daily.

[0061] In yet another embodiment, the present invention provides a method for treating agitation or symptoms of agitation associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedation. Suitable alpha-2 adrenergic agonists include clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline ...tetrahydrozoline, tetrahydrozoline, tramazoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, Examples of suitable alpha-2 adrenergic agonists include, but are not limited to, physidine, propylhexedrine, norfenefrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, and 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, or a pharmaceutically acceptable salt thereof. The dosage of the alpha-2 adrenergic agonist used in the composition is conveniently from about 3 micrograms to about 100 micrograms.

[0062] In yet a further embodiment, the present invention provides a method for treating agitation or symptoms of agitation associated with a neurodegenerative disease in a subject in need of treatment, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof at a dosage that does not cause unwanted (e.g., significant) sedation. The dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof used may conveniently be from about 3 micrograms to about 100 micrograms, e.g., from about 5 micrograms to about 100 micrograms, from about 5 micrograms to about 90 micrograms, from about 5 micrograms to about 85 micrograms, from about 5 micrograms to about 80 micrograms, from about 5 micrograms to about 75 micrograms, from about 5 micrograms to about 70 micrograms, from about 5 micrograms to about 65 micrograms, from about 5 micrograms to about 60 micrograms, from about 5 micrograms to about 55 micrograms, from about 5 micrograms to about 50 micrograms, or from about 5 micrograms to about 60 micrograms. The dose may be about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms, about 5 micrograms, about 6 micrograms, about 7 micrograms, about 8 micrograms, about 9 micrograms, about 10 micrograms, about 12 micrograms, about 14 micrograms, about 16 micrograms, or about 18 micrograms. The dose may be administered one or more times per day.

[0063] In yet another embodiment, the present invention provides a method for treating agitation or symptoms of agitation associated with a neuropsychiatric condition in a subject in need thereof, comprising administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedation. Suitable alpha-2 adrenergic agonists include clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline ...tetrahydrozoline, tetrahydrozoline, tramazoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, tetrahydrozoline, Examples of suitable alpha-2 adrenergic agonists include, but are not limited to, physidine, propylhexedrine, norfenefrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, and 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazole-2-thione, or a pharmaceutically acceptable salt thereof. The dosage of the alpha-2 adrenergic agonist used in the composition is conveniently from about 3 micrograms to about 100 micrograms.

[0064] In another embodiment, the present invention provides a method for treating agitation or symptoms of agitation associated with a neuropsychiatric condition in a subject in need thereof, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedation. The dose of dexmedetomidine or a pharmaceutically acceptable salt thereof used in the sublingual composition may conveniently be from about 3 micrograms to about 100 micrograms, e.g., from about 5 micrograms to about 100 micrograms, from about 5 micrograms to about 90 micrograms, from about 5 micrograms to about 85 micrograms, from about 5 micrograms to about 80 micrograms, from about 5 micrograms to about 75 micrograms, from about 5 micrograms to about 70 micrograms, from about 5 micrograms to about 65 micrograms, from about 5 micrograms to about 60 micrograms, from about 5 micrograms to about 55 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 45 micrograms, from about 5 micrograms to about 50 ...50 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 50 micrograms, from about 5 micrograms to about 50 micrograms, from The dose may be from about 5 micrograms to about 40 micrograms, from about 5 micrograms to about 35 micrograms, from about 5 micrograms to about 30 micrograms, from about 5 micrograms to about 25 micrograms, from about 5 micrograms to about 20 micrograms, from about 5 micrograms to about 15 micrograms, from about 5 micrograms to about 10 micrograms, less than 10 micrograms, about 5 micrograms, about 6 micrograms, about 7 micrograms, about 8 micrograms, about 9 micrograms, about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, or about 50 micrograms. The dose may be administered one or more times per day.

[0065] When treating a subject according to the methods of the present invention, the level of acceptable sedation is preferably at or below Level 3 according to the Ramsay Sedation Score (RSS) system. Accordingly, certain embodiments of the present invention provide a method of treating agitation or symptoms of agitation in a human subject in need thereof, comprising sublingually administering dexmedetomidine or a pharmaceutically acceptable salt thereof to said subject at a dose in the range of about 3 micrograms to about 100 micrograms, thereby achieving an RSS at or below Level 3 (e.g., Level 2 or Level 3).

[0066] IV. Pharmaceutical Compositions The present invention also provides a sublingual pharmaceutical composition comprising an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof, preferably dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0067] The sublingual pharmaceutical compositions of the present invention may also comprise a pharmaceutically acceptable carrier and / or excipient. Suitable pharmaceutically acceptable carriers include water, sodium chloride, binders, penetration enhancers, diluents, lubricants, flavoring agents, coloring agents, and the like.

[0068] The sublingual pharmaceutical compositions of the present invention may be administered to a subject alone or in combination with one or more other suitable active ingredients.

[0069] In one embodiment, the present invention provides a sublingual pharmaceutical composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof for the treatment of agitation in a subject, e.g., agitation associated with sundowning syndrome in neurodegenerative diseases, Alzheimer's disease, or dementia. In certain aspects, the sublingual pharmaceutical composition effectively treats agitation in a subject without causing significant sedation.

[0070] In another embodiment, the present invention provides a sublingual pharmaceutical composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof for the treatment of agitation in a subject associated with schizophrenia, bipolar disorder, bipolar mania, other bipolar illnesses, depression, delirium, or other related neuropsychiatric conditions in the subject. In certain aspects, the sublingual pharmaceutical composition effectively treats agitation in a subject without causing significant sedation.

[0071] The sublingual pharmaceutical composition of the present invention may be, for example, a film, wafer, patch, lozenge, gel, spray, tablet, liquid drop, or the like.

[0072] In one embodiment of the present invention, the sublingual pharmaceutical composition is in the form of a tablet or a filled powder.

[0073] In another embodiment of the present invention, the sublingual pharmaceutical composition is in the form of a patch or film (e.g., a thin film). The patch may have adhesive properties to prevent the patch from migrating or being swallowed. The patch may be ingestible in case of accidental swallowing, or may allow for easy disposal, or the patch may be removed from under the tongue after a prescribed time.

[0074] In yet another embodiment of the present invention, the sublingual pharmaceutical composition is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment can be adjusted to allow retention under the tongue.

[0075] In a further embodiment of the present invention, the sublingual pharmaceutical composition is a liquid (e.g., as a solution, suspension, or emulsion) and may be presented, for example, as a spray or drops. The solution includes the active ingredient together with a diluent, such as water, saline, sodium chloride solution, or other suitable solvent, such as propylene glycol, glycerol, ethyl alcohol, etc. The diluent for the solution may particularly be saline solution or water. The volume of the solution administered may conveniently be about 0.01 mL to about 1 mL (e.g., about 0.025 to 0.5 mL).

[0076] The non-solid compositions of the present invention may be conveniently administered by spraying, dripping, smearing or spraying the composition under the tongue.

[0077] In certain embodiments of the invention, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in liquid form, for example, in a flavored or unflavored saline solution. Liquid compositions may be conveniently administered sublingually as drops or as a spray.

[0078] Dexmedetomidine or a pharmaceutically acceptable salt thereof may conveniently represent from about 0.001% to 99.99% of the total composition, for example, from about 0.01% to about 90%, more particularly from about 0.01% to about 30%.

[0079] When the composition is a liquid or gel, a first unit dose is applied and held in place under the tongue for a predetermined period of time, for example, at least about 30 seconds, more particularly about 60 seconds or more. A second unit dose is then applied and held in place for a similar period of time. Surprisingly, this procedure significantly enhances the effectiveness of the composition of the present invention in treating agitation or symptoms of agitation.

[0080] In another embodiment, the sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard tablet or a compressed powder tablet. As disclosed in U.S. Patent No. 6,221,392 to Khankari et al., incorporated herein by reference, the tablet may conveniently be designed to dissolve under the tongue in about 30 to 120 seconds. In a specific embodiment, the sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard tablet having a low roughness component for an organoleptically pleasant mouthfeel. The tablet (or particles thereof containing an active ingredient that can be compressed to form a tablet) may also include a protective outer coating, such as a polymer conveniently used in the formation of microparticles, matrix-type microparticles, and microcapsules.

[0081] In a further embodiment, the sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt thereof is a hard, compressed, rapidly dissolving tablet. The tablet conveniently contains the active ingredient within a matrix. The matrix may be composed of, for example, at least one filler and a lubricant. Fillers include, for example, lactose or mannitol, and suitable lubricants include magnesium stearate, silicon dioxide, and talc. The matrix may also include one or more binders (e.g., povidone, sugar, or carboxymethylcellulose), disintegrants (e.g., croscarmellose sodium, crospovidone, or sodium starch glycolate), sweeteners (e.g., sucralose), and the like. The tablet conveniently has a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

[0082] Another aspect of the present invention provides a method for making packaged sublingual tablets. The method includes: (a) forming a mixture containing dexmedetomidine or a pharmaceutically acceptable salt thereof and a matrix containing at least a non-direct compression filler and a lubricant; (b) compressing the mixture to form a plurality of hard, compressed, rapidly disintegrating particles (e.g., beads) containing the active ingredient distributed in a matrix that can be dissolved sublingually; and (c) storing the product in bulk prior to packaging. In another embodiment, the dosage forms are then packaged in a lumen of a package so that there is more than one per package. Direct compression is the preferred method for forming the dosage form. Also provided herein is an openable and reclosable package containing a plurality of hard, compressed, rapidly dissolving tablets adapted for direct oral administration as described above.

[0083] In another embodiment, the present invention is a sublingual tablet comprising an effervescent agent. The effervescent agent may conveniently be present in an amount up to about 95% by weight, more particularly between about 30% and about 80% by weight, based on the weight of the finished tablet. When sufficient effervescent material is included in the tablet composition, the tablet will effervescently expand to about 5 cm when exposed to an aqueous environment. 3 More than 30cm 3Sublingual compositions containing effervescent agents are disclosed in U.S. Patent No. 6,200,604, which is incorporated herein by reference.

[0084] In one particular embodiment, the effervescent agent liberates carbon dioxide, for example, as a result of reaction of a soluble acid source with an alkaline carbonate or bicarbonate. The acid source may conveniently include food acids and acids such as citric acid, tartaric acid, amaric acid, fumaric acid, adipic acid, and succinic acid. Sources of carbonate and bicarbonate include, for example, anhydrous solid carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, and the like.

[0085] The spray compositions of the present invention for sublingual administration may contain one or more pharmaceutically acceptable liquids (e.g., present in an amount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, cosolvents, or nonsolvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, peppermint, etc.), and the like. The pharmaceutically acceptable liquid is selected to dissolve the active pharmaceutical ingredient and form a stable, homogeneous suspension or solution thereof, or to form a combination suspension or solution.

[0086] Additionally, the sublingual spray formulation of dexmedetomidine or a pharmaceutically acceptable salt thereof may contain one or more carriers and / or excipients. Examples of carriers / excipients may include viscosity modifiers (e.g., polymers, sugars, sugar alcohols, gums, clays, silica, etc.). One particular polymer that may be conveniently used is polyvinylpyrrolidone (PVP). The viscosity modifier may conveniently be present in an amount of about 0.01% to about 65% by weight of the spray formulation. Other examples of carriers / excipients include preservatives (e.g., ethanol, benzyl alcohol, propylparaben, and methylparaben). The preservative may conveniently be present in an amount of about 0.001% to about 10% by weight of the spray formulation. The carrier / excipient may be a flavoring agent, a sweetener (e.g., a sugar such as sucrose, glucose, dextrose, maltose, fructose, etc.), an artificial sweetener (e.g., saccharin, aspartame, acesulfame, sucralose, etc.), or a sugar alcohol (e.g., mannitol, xylitol, lactitol, maltitol syrup, etc.), conveniently present in an amount of about 0.001% to about 65% by weight of the spray formulation. Other examples of carriers / excipients include buffers and pH adjusters (e.g., sodium hydroxide, citrate, and citric acid), conveniently present in an amount of about 0.01% to about 5% by weight of the spray formulation. Colorants (e.g., present in an amount of about 0.001% to about 5% by weight of the spray formulation), fragrances (e.g., present in an amount of about 0.001% to about 1% by weight of the spray formulation), chelating agents such as EDTA (e.g., present in an amount of about 0.001% to about 1% by weight of the spray formulation), UV absorbers (e.g., present in an amount of about 0.001% to about 10% by weight of the spray formulation), and anti-foaming agents (e.g., low molecular weight alcohols, dimethicone), conveniently present in an amount of about 0.001% to about 5% by weight of the spray formulation, may also be included as suitable carriers / excipients in the spray formulations of the present invention.

[0087] One particular embodiment of the present invention provides a sublingual film comprising dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more carriers and / or excipients for the treatment of agitation.

[0088] Excipients that may be incorporated into the sublingual films of the present invention include one or more of the following: film-forming agents, mouthfeel modifiers, plasticizers, stabilizers, surfactants, preservatives, sweeteners, colorants, flavoring agents, emulsifiers, disintegrants, salivating agents, antioxidants, permeation enhancers, solvents, and the like.

[0089] Film-forming agents generally refer to agents that provide chemical structure to the films of the present invention. Effective amounts of film-forming agents range from about 10% to about 99% by weight of the composition, more preferably from about 50% to about 90% by weight. Film-forming agents that can be utilized as part of the film compositions of the present invention include, but are not limited to, cellulose ethers, modified starches, natural gums, food polymers, seaweed extracts, terrestrial plant extracts, pullulan, polyvinylpyrrolidone, derivatives thereof, and combinations thereof.

[0090] Examples of cellulose ethers include, but are not limited to, methylhydroxycellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, derivatives thereof, and combinations thereof.

[0091] Modified starches include, but are not limited to, acid and enzyme hydrolyzed corn starch and potato starch, derivatives thereof, and combinations thereof.

[0092] Examples of natural gums include, but are not limited to, gum arabic, guar gum, carob gum, carrageenan gum, acacia gum, karaya gum, ghatti gum, tragacanth agar, tamarind gum, xanthan gum, derivatives thereof, and combinations thereof.

[0093] Examples of edible polymers include, but are not limited to, microcrystalline cellulose, cellulose ethers, xanthan, derivatives thereof, and combinations thereof.

[0094] Examples of seaweed extracts include, but are not limited to, sodium alginate, carrageenan, derivatives thereof, and combinations thereof.

[0095] Terrestrial plant extracts include, but are not limited to, konjac, pectin, arabinogalactan, derivatives thereof, and combinations thereof.

[0096] Specific film-forming agents include pullulan, sodium alginate, polyvinylpyrrolidone, methylcellulose and methylhydroxycellulose (MHC).

[0097] The term "solvent" generally refers to a liquid that will dissolve a solute. Solvents may be used to dissolve film-forming agents and other excipients to prepare the film-forming compositions of the present invention. Solvents include, but are not limited to, demineralized / distilled water, ethyl alcohol, isopropyl alcohol, methyl ethyl ketone, propylene glycol, methyl ether acetate, dimethylacetamide, ethylene glycol monopropyl ether, and toluene. The sublingual films of the present invention may conveniently contain solvents in an amount of up to about 1% w / w.

[0098] The term "stabilizer" generally refers to an agent that will impart stability to a formulation over its shelf life. Stabilizers of the present invention can include, for example, oil / water emulsifiers and flavor fixatives. An effective amount of stabilizer in the compositions of the present invention can range, for example, from about 0% to about 45% by weight of the composition, more specifically, from about 4% to about 25% by weight. Examples of suitable stabilizers of the present invention include, but are not limited to, gum arabic, microcrystalline cellulose, carrageenan, xanthan gum, locust bean gum, derivatives thereof, and combinations thereof. Specific stabilizers of the present invention include gum arabic and microcrystalline cellulose.

[0099] Disintegrants aid in the dissolution of the edible film, allowing the effectiveness of the film to be realized more quickly. Disintegrants suitable for use in the edible films of the present invention include, but are not limited to, alginic acid, microcrystalline cellulose, and carboxymethylcellulose. Certain disintegrants, known as superdisintegrants, are also suitable for use in the edible films of the present invention. Superdisintegrants include cross-linked polymers (e.g., crospovidone), cross-linked starches (e.g., sodium starch glycolate), and cross-linked celluloses (e.g., modified carboxymethylcellulose such as croscarmellose). These superdisintegrants are insoluble in water and most other solvents, have rapid swelling properties, and have good water absorption with high capillary action, resulting in rapid disintegration. Their insolubility in many solvents means that they allow the sublingual compositions of the present invention to be manufactured in a single-step process, as opposed to a costly multi-step process.

[0100] The disintegrant or superdisintegrant is conveniently present in the sublingual compositions (e.g., edible films) of the present invention in an amount ranging from about 1% to about 10% by weight of the composition, more particularly from about 1% to about 5% by weight.

[0101] Suitable "emulsifiers" for use in the edible films of the present invention include, but are not limited to, gum arabic, carrageenan, triethanolamine stearate, quaternary ammonium compounds, acacia gum, gelatin, lecithin, bentonite, veegum, derivatives thereof, and combinations thereof. Emulsifiers can be used in the compositions of the present invention in amounts up to about 40% by weight of the composition, more specifically up to about 25% by weight. Emulsifiers can be stabilizers that create an oil / water emulsion that encapsulates volatile oils and flavoring agents, thereby essentially acting as a flavor fixative. A particular emulsifier for use in the edible films of the present invention is gum arabic.

[0102] A "plasticizer" or "plasticizer" may be utilized to improve the flexibility and reduce brittleness of the edible film compositions of the present invention. The plasticizer may conveniently comprise up to about 30% by weight of the composition, e.g., up to 15% by weight. Examples of suitable plasticizers include, but are not limited to, glycerin, sorbitol, triacetin, monoacetin, diacetin, polyethylene glycol, propylene glycol, hydrogenated starch hydrolysates, corn syrup, low molecular weight propylene glycol, phthalic acid derivatives such as dimethyl phthalate, diethyl phthalate, and dibutyl phthalate, citric acid derivatives such as tributyl citrate, triethyl citrate, and acetyl citrate, and their castor oil derivatives, and combinations thereof. Specific plasticizers of the present invention include sorbitol and glycerin.

[0103] The term "preservative" generally refers to an excipient used to kill, prevent, inhibit, or retard the growth and reproduction of microorganisms, and is included in products only in concentrations sufficient to prevent contamination or growth of inadvertently added microorganisms. Suitable preservatives include, but are not limited to, methylparaben, propylparaben, and sodium benzoate. The preservative may conveniently be present in the composition at about 0.001% w / w to about 10% w / w of the composition.

[0104] The term "sweetening agent" generally refers to an excipient used to impart a sweet taste to a pharmaceutical composition. Suitable sweetening agents for use in the compositions of the present invention include, but are not limited to, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, and sucrose. The sweetening agent may conveniently be present in the composition in an amount of about 5% w / w to about 20% w / w of the composition.

[0105] The term "colorant" or "coloring agent" generally refers to an excipient used to impart color to a pharmaceutical composition. Suitable coloring agents include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, other FD&C dyes, caramel, red iron oxide, and natural coloring agents such as grape skin extract, beet red flour, beta-carotene, annatto, carmine, turmeric, or paprika. The coloring agent may conveniently be present in the composition in an amount of about 0.001% to about 10% by weight of the composition.

[0106] The term "flavoring agent" or "flavoring agent" generally refers to an excipient used to impart a pleasant flavor (often an odor) to a pharmaceutical composition. Suitable flavoring agents include, but are not limited to, synthetic flavor oils, flavoring aromatics, natural oils, extracts from whole plants or parts of plants such as leaves, flowers, or fruits, or combinations thereof. Examples include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil. Other useful flavoring agents include vanilla, citrus fruit oils such as lemon, orange, grape, lime, or grapefruit, and fruit essential oils such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, or apricot essential oil. Specific flavors of interest for use in the compositions of the present invention include commercially available orange, grape, cherry, and bubble gum flavors, and mixtures thereof. The amount of flavoring agent used will depend on numerous factors, including the desired organoleptic effect. Specific flavors include grape and cherry flavors, as well as citrus flavors such as orange flavor. The flavoring agent may conveniently be present in the composition in an amount of about 0.001% w / w to about 10% w / w of the composition.

[0107] The term "salivation agent" refers to an agent that promotes the secretion of more saliva during use of the compositions of the present invention. This is an important feature if the composition is intended to be taken by the patient without the aid of water, which helps transport the composition to the patient's stomach. The salivation agent can be, for example, an emulsifier or food acid that initiates saliva production in the patient's mouth. Emulsifiers useful as salivation agents include alkylaryl sulfonates, alkyl sulfates, sulfonated amides and amines, sulfated and sulfonated esters and ethers, alkyl sulfonates, polyethoxylated esters, monoglycerides, diglycerides and triglycerides, diacetyltartaric acid esters of monoglycerides, polyglycerol esters, sorbitan esters and ethoxylates, lactylated esters, phospholipids such as lecithin, polyoxyethylene sorbitan esters, propylene glycol esters, sucrose esters, and mixtures thereof. The emulsifier may be saturated or unsaturated. It should be noted that some emulsifiers that are salivation agents may also function as binders. Examples of food acids useful as salivating agents include citric acid, malic acid, tartaric acid, food salts such as sodium chloride and salt substitutes, potassium chloride, and mixtures thereof. The amount of salivating agent present in the sublingual films of the present invention may conveniently be up to about 15% by weight of the final composition, for example, in the range of about 0.3% to about 0.4% by weight of the composition.

[0108] The term "antioxidant" generally refers to an excipient used to inhibit oxidation and thus prevent the degradation of an active agent by the oxidative process. Suitable antioxidants include, for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, citric acid, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, EDTA, and sodium edetate. The antioxidant may conveniently be present in the composition in an amount of about 0.001% w / w to about 2% w / w of the composition.

[0109] The term "permeation enhancer" generally refers to an excipient used to increase the penetration of an active agent through a cell membrane or to increase the local / systemic absorption of an active agent. Permeation enhancers that may be used in the present invention include, but are not limited to, solubilizing agents such as alcohols, polyethylene glycols, chelating agents (e.g., cyclodextrins), sucrose laurate, or sucrose oleate. The permeation enhancer may conveniently be present in the composition in an amount of about 0.1% w / w to about 5% w / w of the composition.

[0110] In one embodiment of the present invention, the sublingual pharmaceutical composition of the present invention comprises a mucosal permeation enhancer suitable for enhancing mucosal absorption of the composition.

[0111] Sublingual dexmedetomidine formulations (e.g., sprays, drops, etc.) may be made by mixing appropriate amounts of the aforementioned ingredients according to standard good manufacturing practice. The relative amounts of each ingredient should not interfere with the desired pharmacological and pharmacokinetic properties of the resulting formulation.

[0112] The sublingual dexmedetomidine films of the present invention may be conveniently prepared using PharmFilm® technology (owned by MonoSol) or technology owned by ARx LLC. Various patents and patent applications are incorporated herein in their entirety, including U.S. Patent or Patent Publication Nos. 9585961, 7470397, 7727466, 92481469545376, 2017-0087084, 96622979662301, 2017-0246108, 2017-0252294, 9441142, and MonoSol, all of which are assigned to ARx LLC. Rx-assigned U.S. patents or patent publication numbers include: 7425292, 7357891, 86636878685437, 7897080, 8241661, 8617589, 8936825, 9561191, 9303918, 9346601, 8282954, 7972618, 9073294.

[0113] To prepare the sublingual film of the present invention, an active agent, e.g., dexmedetomidine or a pharmaceutically acceptable salt thereof, a film-forming agent, and optionally one or more carriers and / or excipients selected from the group consisting of mouthfeel modifiers, plasticizers, stabilizers, surfactants, preservatives, sweeteners, colorants, flavorings, emulsifiers, disintegrants, salivating agents, antioxidants, and permeation enhancers, are dissolved in a compatible solvent to form a film-forming composition. Compatible solvents include water, alcohols such as ethanol, ethyl acetate, acetone, and mixtures thereof. The film-forming composition is cast onto a releasable carrier and dried to form a sheet / film. The carrier material must have a surface tension that allows the film solution to be uniformly spread across the intended carrier width upon immersion without forming destructive bonds between the film-carrier substrates. Examples of suitable carrier materials include glass, stainless steel, Teflon, and polyester-impregnated paper. Drying of the film may be carried out at elevated temperatures using a drying oven, drying terminal, vacuum dryer, or other suitable drying equipment that does not adversely affect the components that make up the film. The sublingual films of the present invention can also be prepared by other established methods, such as extrusion (e.g., hot melt extrusion, solid dispersion extrusion), casting (e.g., solid casting or semi-solid casting), calendering, etc.

[0114] V. Administration In an embodiment, the present invention provides a sublingual composition comprising an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat agitation. The amount of alpha-2 adrenergic agonist is sufficient to effectively treat agitation without causing significant sedation. The alpha-2 adrenergic agonist may conveniently be delivered to an animal (e.g., human) subject on an "as needed" basis in one dose, two or more doses per day. The composition may also be administered via a single dosage form or via multiple dosage forms.

[0115] In another embodiment, the present invention provides a sublingual composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat agitation. In certain embodiments, the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof used is sufficient to effectively treat agitation without causing significant sedation. Dexmedetomidine or a pharmaceutically acceptable salt thereof may be conveniently delivered to an animal (e.g., human) subject on an "as needed" basis in one, two, or more doses per day. The composition may also be administered via a single dosage form or via multiple dosage forms.

[0116] Following administration of a composition of the invention to a subject, the therapeutic (i.e., agitation-reducing) effect may begin within about 60 minutes (e.g., about 30, 20, 15, 10, 5, 3, 2, or 1 minute) after administration, or within about 30 seconds after administration. Symptoms of agitation may also be alleviated within about 1 to about 60 minutes, more typically within about 5 to about 30 minutes, after administration. If the symptoms of agitation are not alleviated within about 60 minutes, a second dose of a composition of the invention may be administered to the subject.

[0117] A treatment protocol may include one or more dosing intervals (e.g., two or more dosing intervals, five or more dosing intervals, or ten or more dosing intervals). Depending on the subject's physiology and the desired therapeutic effect, the duration of the dosing intervals and treatment protocols according to embodiments of the present invention may vary.

[0118] Dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered as a sublingual composition alone or in combination with one or more additional active agents to treat agitation or the symptoms of agitation. When used in combination, the active agents can be formulated as a single composition or as one or more separate compositions that can be administered simultaneously, sequentially, or separated by an appropriate time.

[0119] When dexmedetomidine or a pharmaceutically acceptable salt thereof is administered with a second active agent to treat agitation or the symptoms of agitation, the weight ratio of dexmedetomidine or a pharmaceutically acceptable salt thereof to the second active agent may generally range from about 1:2 to about 1:2.5, about 1:2.5 to about 1:3, about 1:3 to about 1:3.5, about 1:3.5 to about 1:4, about 1:4 to about 1:4.5, about 1:4.5 to about 1:5, about 1:5 to about 1:10, and about 1:10 to about 1:25, respectively. For example, the weight ratio may be between about 1:1 to about 1:5, about 1:5 to about 1:10, about 1:10 to about 1:15, or about 1:15 to about 1:25, among others. Alternatively, the weight ratio of each second active agent to dexmedetomidine or a pharmaceutically acceptable salt thereof may range from about 2:1 to about 2.5:1; about 2.5:1 to about 3:1; about 3:1 to about 3.5:1; about 3.5:1 to about 4:1; about 4:1 to about 4.5:1; about 4.5:1 to about 5:1; about 5:1 to about 10:1; and about 10:1 to about 25:1. For example, the weight ratio of each second active agent to dexmedetomidine or a pharmaceutically acceptable salt thereof may range from about 1:1 to about 5:1; about 5:1 to about 10:1; about 10:1 to about 15:1; or about 15:1 to about 25:1, among others. It should be understood that all ranges between the recited ranges are also contemplated herein and constitute further specific embodiments of the invention.

[0120] VI. Medication Regimen The dosage regimen employed may depend on several factors, such as the type of agitation being treated, the severity of the symptoms, and whether the agitation is due to an underlying medical disorder.

[0121] Dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered sublingually to an animal (e.g., a human) at a suitable dose. In certain embodiments, the human dose is from about 3 micrograms to about 100 micrograms (e.g., about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 5 ... The dose may be from about 5 micrograms to about 40 micrograms, from about 5 micrograms to about 35 micrograms, from about 5 micrograms to about 30 micrograms, from about 5 micrograms to about 25 micrograms, from about 5 micrograms to about 20 micrograms, from about 5 micrograms to about 15 micrograms, from about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, or about 50 micrograms). The dose may be administered one or more times per day.

[0122] Dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered sublingually to a human in an appropriate dosage. In some variations, the dosage for a human may be from about 0.05 micrograms / kg to about 1.5 micrograms / kg of the subject's body weight. Examples of suitable dosages include about 0.1 micrograms / kg to about 1 microgram / kg, about 0.1 micrograms / kg to about 0.5 micrograms / kg, about 0.1 micrograms / kg to about 0.4 micrograms / kg, about 0.1 micrograms / kg to about 0.3 micrograms / kg, about 0.1 micrograms / kg to about 0.2 micrograms / kg, about 0.07 micrograms / kg, about 0.05 micrograms / kg, about 0.1 micrograms / kg, and about 0.2 micrograms / kg. The dose may be administered one or more times daily.

[0123] VII. Specific Embodiments of the Invention Embodiment 1. A method of treating agitation or a symptom of agitation in a subject in need thereof, comprising sublingually administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 2. A method of treating agitation or a symptom of agitation in a subject in need thereof, comprising administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually at a dosage that treats agitation or a symptom of agitation without causing significant sedation.

[0125] Embodiment 3. The dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is from about 3 micrograms to about 100 micrograms (e.g., about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 50 ... 3. The method of claim 1 or 2, wherein the amount of hydroxybenzoate is in the range of about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms).

[0126] Embodiment 4. The method of embodiment 1, 2 or 3, wherein the subject is a mammal, preferably a human.

[0127] Embodiment 5. The method of any one of embodiments 1-4, wherein the agitation is associated with a neurodegenerative disease.

[0128] Embodiment 6. The method of embodiment 5, wherein the neurodegenerative disease is selected from Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0129] Embodiment 7. The method of any one of embodiments 1-4, wherein the agitation is associated with a neuropsychiatric condition.

[0130] Embodiment 8. The method of embodiment 7, wherein the neuropsychiatric condition is selected from schizophrenia, bipolar disorder (e.g., mania, disorder), delirium, and depression.

[0131] Embodiment 9. The method of embodiment 5, wherein the agitation is associated with sundowning syndrome in dementia or Alzheimer's disease.

[0132] Embodiment 10. A sublingual composition for use in treating agitation or symptoms of agitation in a subject in need thereof, wherein said agitation is not perioperative agitation, said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers / excipients.

[0133] Embodiment 11. A sublingual composition for use in treating agitation or symptoms of agitation in a subject in need thereof, wherein the agitation is associated with a neurodegenerative disease, the sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers / excipients.

[0134] Embodiment 12. A sublingual composition for use in treating agitation or symptoms of agitation in a subject in need thereof, wherein the agitation is associated with a neuropsychiatric condition, the sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers / excipients.

[0135] Embodiment 13. A sublingual composition for use in treating agitation or symptoms of agitation in a subject in need thereof, wherein said agitation is associated with dementia or sundowning syndrome in Alzheimer's disease, said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers / excipients.

[0136] Embodiment 14. The sublingual composition of embodiment 11, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0137] Embodiment 15. The sublingual composition of embodiment 14, wherein the neurodegenerative disease is selected from dementia, frontotemporal dementia, Alzheimer's disease, and Parkinson's disease.

[0138] Embodiment 16. The sublingual composition of embodiment 12, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar disorder (e.g., mania, disorder), delirium, and depression.

[0139] Embodiment 17. The sublingual composition of any one of embodiments 10-16, wherein the composition is selected from a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops, and the like.

[0140] Embodiment 18. The sublingual composition of embodiment 17, wherein the composition is a film.

[0141] Embodiment 19. A sublingual composition according to embodiment 18, wherein the film is mucoadhesive in nature and provides a rapid onset of action.

[0142] Embodiment 20. The sublingual composition of any one of embodiments 10-19, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dosage that treats agitation or symptoms of agitation without causing significant sedation.

[0143] Embodiment 21. The sublingual composition of embodiment 20, wherein the observed level of sedation does not exceed 3 on the Ramsay sedation scale.

[0144] Embodiment 22. Dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dose of from about 3 micrograms to about 100 micrograms (e.g., about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 40 micrograms, about 5 micrograms to about 5 22. The sublingual composition of any one of embodiments 10-21, wherein the sublingual composition is administered to the subject (e.g., a human) at a dosage in the range of: about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms).

[0145] Embodiment 23. A method of treating agitation or symptoms of agitation in a subject in need thereof, said method comprising sublingually administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said agitation is not perioperative agitation.

[0146] Embodiment 24. The method of embodiment 23, wherein the agitation is associated with a neurodegenerative disease and / or a neuropsychiatric condition.

[0147] Embodiment 25. The method of embodiment 24, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy, or other related neurodegenerative disorders.

[0148] Embodiment 26. The method of embodiment 24, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar illness (e.g., bipolar disorder or bipolar mania), delirium, and depression.

[0149] Embodiment 27. The method of any one of embodiments 23-26, wherein agitation or symptoms of agitation are effectively treated without causing significant sedation.

[0150] Embodiment 28. The method of any one of embodiments 23 to 27, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, wafer, patch, lozenge, gel, spray, tablet, liquid drops, or the like.

[0151] Embodiment 29. A method of treating agitation or a symptom of agitation in a subject in need thereof, wherein the agitation is associated with a treatment for OPD / IPD (e.g., an MRI, CT, or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedure), and the method comprises sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 30. A method of treating agitation or symptoms of agitation in a subject in need thereof, wherein the agitation is associated with alcohol and drug abuse withdrawal, the method comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 31. The method of embodiment 29 or 30, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually at a dosage that treats the agitation or symptoms of agitation without causing significant sedation.

[0154] Embodiment 32. The dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is from about 3 micrograms to about 100 micrograms (e.g., about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 5 32. The method of embodiment 31, wherein the amount of hydroxybenzoate is in the range of about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms).

[0155] Embodiment 33. The composition or method of any preceding embodiment, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once, twice, or three times daily, or "as needed."

[0156] Embodiment 34. The composition or method of any preceding embodiment, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a manner that produces a therapeutic effect in less than about 60 minutes, particularly within the range of about 30 seconds to about 30 minutes.

[0157] Embodiment 35. A method of treating agitation or a symptom of agitation in a subject in need thereof, comprising sublingually administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof.

[0158] Embodiment 36. A method of treating agitation or a symptom of agitation in a subject in need thereof, comprising administering to the subject an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof, wherein the alpha-2 adrenergic agonist is administered sublingually at a dosage that treats agitation or a symptom of agitation without causing significant sedation.

[0159] Embodiment 37. The dose of an alpha-2 adrenergic agonist is from about 3 micrograms to about 100 micrograms (e.g., about 5 micrograms to about 100 micrograms, about 5 micrograms to about 90 micrograms, about 5 micrograms to about 85 micrograms, about 5 micrograms to about 80 micrograms, about 5 micrograms to about 75 micrograms, about 5 micrograms to about 70 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 65 micrograms, about 5 micrograms to about 60 micrograms, about 5 micrograms to about 55 micrograms, about 5 micrograms to about 50 micrograms, about 5 micrograms to about 45 micrograms, about 5 micrograms to about 50 ... 37. The method of embodiment 35 or 36, wherein the amount of hydroxybenzoate is in the range of about 5 micrograms to about 40 micrograms, about 5 micrograms to about 35 micrograms, about 5 micrograms to about 30 micrograms, about 5 micrograms to about 25 micrograms, about 5 micrograms to about 20 micrograms, about 5 micrograms to about 15 micrograms, about 5 micrograms to about 10 micrograms, less than 10 micrograms (e.g., about 5, 6, 7, 8, or 9 micrograms), about 10 micrograms, about 12 micrograms, about 14 micrograms, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms).

[0160] Embodiment 38 The method of embodiment 35, 36 or 37, wherein the subject is a mammal, preferably a human.

[0161] Embodiment 39. The method of any one of embodiments 35-38, wherein the agitation is associated with a neurodegenerative disease.

[0162] Embodiment 40. The method of embodiment 39, wherein the neurodegenerative disease is selected from Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

[0163] Embodiment 41. The method of any one of embodiments 35-38, wherein the agitation is associated with a neuropsychiatric condition.

[0164] Embodiment 42. The method of embodiment 41, wherein the neuropsychiatric condition is selected from schizophrenia, bipolar disorder (e.g., mania, disorder), delirium, and depression.

[0165] Embodiment 43 The method of embodiment 39, wherein the agitation is associated with sundowning syndrome in dementia or Alzheimer's disease.

[0166] Embodiment 44. The method of any one of embodiments 35-38, wherein the agitation is associated with a treatment for OPD / IPD (e.g., an MRI, CT or CAT scan, a lumbar puncture, a bone marrow aspiration / biopsy, a tooth extraction or other dental procedure).

[0167] Embodiment 45. The method of any one of embodiments 35-38, wherein the agitation is associated with alcohol and drug abuse withdrawal.

[0168] Embodiment 46. The alpha-2 adrenergic agonist includes clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivazerol, azepexole, talipexole, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazoline, talipexole, romifidine, propionidine, thiazoline ... 39. The method of any one of embodiments 35-38, wherein the active ingredient in the medicament for treating rheumatoid arthritis includes, but is not limited to, cyclohex-3-enylmethyl ...

[0169] The above embodiments are not intended to be limiting, as alternative or additional embodiments may be provided in the practice of the invention. [Example]

[0170] VIII. Working Example: The following examples are intended to be illustrative and not limiting.

[0171] Example 1 Formulation 1: Sublingual tablet [Table 1] Manufacturing method Dexmedetomidine hydrochloride and excipients such as binders and sweeteners are dissolved / dispersed in a pharmaceutically acceptable solvent (preferably water), and this solution is used to granulate a sieved mixture of all other ingredients except lubricants and glidants in a suitable mixer / granulator. The granules are then dried in a fluid bed dryer or other suitable device, such as a tray dryer. The dried granules are then sized in a quadrocomill or multimill. The sized granules are then loaded into a suitable blender, such as a V-blender, lubricated with magnesium stearate and talc, and the final lubricated blend is then compressed into tablets of a specified diameter using suitable tooling.

[0172] Formulation 2: Sublingual film [Table 2] Manufacturing method Dexmedetomidine hydrochloride is dissolved / dispersed in a pharmaceutically acceptable solvent (preferably water) along with a film-forming polymer and other excipients, and the resulting solution is then coated (spread / cast) onto an inert backing layer. The polymer layer containing dexmedetomidine hydrochloride is further dried and cut to a suitable size using an appropriate mold / tool, and then packaged as required.

[0173] Formulation 3: Sublingual spray [Table 3] Manufacturing method Dexmedetomidine hydrochloride is mixed with all other excipients in the appropriate order. The resulting solutions / dispersions are then filled into spray containers using appropriate tooling. They are further processed through a metering nozzle so that the specified amount of dexmedetomidine is delivered with each actuation.

[0174] Formulation 4: Sublingual liquid drops [Table 4] Manufacturing method Dexmedetomidine hydrochloride (catalog no. SML0956) was dissolved in saline to obtain sublingual drops at a concentration of 1 mg / mL.

[0175] Example 2 To evaluate the effects of sublingual and intravenous administration of various doses of dexmedetomidine hydrochloride in a rat "resident-intruder" model of agitation or aggression.

[0176] The resident-intruder model is an established preclinical model of aggression and agitation that allows for the spontaneous and natural expression of both aggressive aggression / agitation and defensive behavior in laboratory rodents in a semi-natural laboratory setting. When rodents are exposed to a novel male in their cage environment, they perceive the novel male as an "intruder" and demonstrate a wide range of defensive behaviors, such as anal and genital sniffing, chasing, biting, and attacking (Nelson, et al., ILAR Journal, (2000), 41(3):153-162).

[0177] Materials and Methods Animals: Male Wistar rats, 12–13 weeks old and weighing 380–400 g, were used as resident males. Male rats, 7–8 weeks old and weighing 280–300 g, were used as "intruders." Resident rats were housed with female rats for 8 days to establish territories. Intruder rats were group-housed with three other male rats of similar age and weight. All animals were maintained in a controlled environment with a temperature of 22 ± 3°C, humidity of 50 ± 20%, a 12-hour light / dark cycle, and 15–20 fresh air exchanges per hour. Food and water were available ad libitum. All animal experiments were conducted in accordance with the guidelines of the Committee for Control of Animal Care and Use (CPCSEA), Government of India, and the Association for Accreditation of Laboratory Animal Facilities International (AAALAC).

[0178] Formulations investigated: The required amount of dexmedetomidine hydrochloride Formulation 4 was weighed and serial dilutions were made to obtain each dose as per Table 5. For the entire study, dilutions were prepared fresh daily prior to dosing from Formulation 4 with 0.9% saline.

[0179] Experimental Procedure: Following a 3-5 day acclimatization period, each resident male rat was housed with a female rat for 8 days. On day 8, basic aggression in the resident rats was assessed by exposing them to an "intruder rat" for 10 minutes. Only animals that demonstrated aggression in this basic aggression test were used for further testing. These animals were then randomized using a weight stratification method. Animal weight fluctuations did not exceed 20% of the group's mean weight at the time of randomization. Animals were housed with female rats for an additional day. On day 9, resident animals were paired with an intruder animal of the appropriate weight, ensuring that the resident always weighed more than the intruder. This encouraged dominant aggressive behavior in the resident animals. After randomization, animals were assigned permanent numbers. Cages were identified by cage cards detailing the study number, study code, group number, sex, dose, cage number, and animal number.

[0180] Resident male rats were administered various doses of dexmedetomidine hydrochloride (Dex) either sublingually or intravenously 15 minutes before behavioral testing (Table 5). For sublingual administration, the rat was held in one hand, and a blunt tongue depressor was used to move the tongue to one side of the mouth. Dexmedetomidine hydrochloride was then administered sublingually as liquid drops at specific concentrations using a micropipette and allowed to absorb for 50–60 seconds. Diazepam was used as the reference compound and was administered intraperitoneally. Vehicle controls were treated with 0.9% saline administered sublingually or intravenously. Normal controls (NC) received no treatment.

[0181] The behavior of resident rats was recorded for 15 min using an overhead video camera, and offline behavioral analysis was performed using Noldus Ethovision XT software. To distinguish resident rats from intruder rats in the video recordings, intruder rats were marked with a nontoxic paint. To analyze the potential effects of dexmedetomidine hydrochloride on agitation, we quantified various behavioral parameters, such as anal and genital sniffing, chasing, biting, aggression, and aggression latency, as well as neutral behavioral parameters, such as exploratory grooming and immobility. [Table 5]

[0182] statistical analysis Statistical analysis was performed using validated statistical software (GraphPad Prism 6). Data are expressed as mean ± SEM. One-way ANOVA (analysis of variance) followed by Dunnett's multiple comparison test with a 95% confidence interval was applied to compare groups. p < 0.05 was considered significant.

[0183] result This study was conducted to evaluate the effects of various doses of sublingually / intravenously administered dexmedetomidine hydrochloride on agitated behavior in a rat resident-intruder model of aggressive and agitated behavior.

[0184] Effects of sublingually / intravenously administered dexmedetomidine hydrochloride on aggressive / agitated behavior in a rat resident-intruder model: When rats are exposed to a novel male in their cage environment, they demonstrate a variety of defensive agitation behaviors, such as anal and genital sniffing, chasing, biting, and attacking (indicators of agitated and aggressive behaviors). The nonresident male is perceived as an intruder, and the resident male becomes agitated and attacks the intruder male, defending his territory. In this experiment, vehicle-treated rats demonstrated a variety of aggressive behaviors, and the intruder rats were subjected to anal and genital sniffing, attacking, chasing, and biting by resident or dominant rats.

[0185] Sublingually administered dexmedetomidine hydrochloride (Dex) dose-relatedly reduced the frequency and duration of these behaviors (Figures 1A and 1B). Significant reductions were observed in chasing and aggression compared to the vehicle control group. Similarly, intravenous administration of dexmedetomidine hydrochloride (Dex) reduced all indicators of aggressive and agitated behavior (Figures 1C and 1D). Significant reductions in anal and genital sniffing, biting, and aggression compared to the vehicle control were observed at doses above 0.5 μg / kg (Figures 1C and 1D). The reference compound, diazepam (3 mg / kg, i.p.), also produced significant reductions in all indicators of aggressive and agitated behavior assessed in this study (Figures 1A-1D).

[0186] Effect of sublingually / intravenously administered dexmedetomidine hydrochloride on latency to attack In addition to changes in the frequency and duration of aggression by resident males, we also evaluated the effect of dexmedetomidine hydrochloride (Dex) on the latency to attack an intruder rat. We observed a dose-related increase in the latency to attack an intruder rat following sublingual administration of dexmedetomidine hydrochloride (Dex), indicating a decrease in aggression and agitation (Figure 2A). When dexmedetomidine hydrochloride (Dex) was administered intravenously, a similar dose-related increase in the latency to attack an intruder rat occurred, which was significant compared to the vehicle control at a dose of 3 μg / kg (Figure 2B). Diazepam-treated animals showed a complete lack of aggressive behavior (Figures 2A and 2B).

[0187] Effects of sublingually / intravenously administered dexmedetomidine hydrochloride on neutral behavior Neutral behaviors, such as grooming, exploration, and immobility / calmness, were assessed following treatment with dexmedetomidine hydrochloride. Compared to vehicle control, no significant changes occurred in grooming or exploration following sublingual administration of dexmedetomidine hydrochloride, except for a decrease in exploration observed at doses of 1.5 μg / kg and 3 μg / kg (Figures 3A and 3B). Similarly, intravenously administered dexmedetomidine hydrochloride did not significantly affect grooming or exploration compared to vehicle control, except at the 3 μg / kg dose. For immobility / calmness, there was no significant effect of sublingually administered dexmedetomidine hydrochloride compared to vehicle control, whereas intravenously administered dexmedetomidine hydrochloride significantly increased immobility / calmness at the 3 μg / kg dose (Figures 3C and 3F). The reference compound, diazepam (3 mg / kg, ip), significantly reduced the frequency and duration of all neutral behaviors assessed in this test.

[0188] interpretation In this study, we investigated the potential of dexmedetomidine hydrochloride in reducing aggression and agitation in the rat resident-intruder model, an established preclinical model of aggression and agitation that allows for the spontaneous and natural expression of both aggressive aggression / agitation and defensive behavior in laboratory rodents in a semi-natural laboratory setting.

[0189] 1. Sublingual administration of dexmedetomidine hydrochloride produced dose-related reductions in several behavioral indices of aggression and agitation, such as anal and genital sniffing, chasing, aggression, and biting.

[0190] 2. A significant increase in the latency to attack the intruder rat was observed in a dose-related manner by pretreatment with dexmedetomidine hydrochloride when compared with the vehicle control group.

[0191] 3. No changes in the neutral behavior of the animals were observed, indicating a lack of obvious anxiety-like behavior in rodent rats treated with sublingually administered dexmedetomidine hydrochloride.

[0192] 4. Of the doses used in the study (0.5–3 μg / kg), doses of 1–1.5 μg / kg (administered sublingually or intravenously) effectively reduced behavioral indices of aggression and agitation without significantly affecting neutral behavior.

[0193] conclusion Dexmedetomidine hydrochloride effectively reduces various indices of agitation and aggression in a rat resident-intruder model. Doses of 1 to 1.5 μg / kg effectively reduced behavioral indices of aggression and agitation without significantly affecting neutral behavior. In this study, the efficacy of sublingually administered dexmedetomidine hydrochloride correlated with that of intravenously administered dexmedetomidine hydrochloride at these doses (Table 6). [Table 6] Table 6. When comparing the sublingual and intravenous routes of dexmedetomidine hydrochloride administration at doses of 1 μg / kg and 1.5 μg / kg, no significant differences were observed in the duration of behavioral indices of aggression and agitation (chasing, biting, attacking, anal and genital sniffing, and latency to attack) (i.e., similar effects via the sublingual and intravenous routes). Statistical analysis was performed using Student's t-test. * p<0.05, ** p<0.01, *** p<0.001 and **** p<0.0001. Sublingual versus intravenous route of administration.

[0194] Based on the effective dose in rats of 1-1.5 μg / kg, the equivalent sublingual doses in humans are calculated to be 0.161 μg / kg and 0.242 μg / kg. The equivalent total human doses for a 60 kg person would be 10 μg and 15 μg (https: / / www.fda.gov / downloads / drugs / guidances / ucm078932.pdf).

[0195] Example 3: Estimation of dexmedetomidine (0.5-3 μg / kg) in rat plasma samples by LC-MS / MS Objective: To estimate the levels of dexmedetomidine in plasma samples obtained after administration to animals via intravenous and sublingual routes at doses of 0.5, 1, 1.5 and 3 μg / kg.

[0196] Blood sampling: To determine the plasma concentration of dexmedetomidine, rats (n=3) were administered various doses of dexmedetomidine hydrochloride (0.5, 1, 1.5, and 3 μg / kg) sublingually or intravenously. Blood was collected from the retroorbital plexus under light isoflurane anesthesia at 0, 5, 15, 30, 60, and 120 minutes after administration. Plasma was separated and stored at -80°C until analysis of dexmedetomidine concentrations.

[0197] Materials and Methods Preparation of standard solutions A standard stock solution of dexmedetomidine hydrochloride was prepared by dissolving 1.358 mg of dexmedetomidine hydrochloride in 1358 µL of Milli-Q water to achieve a concentration of 829.071 mg / mL. Working solutions of various concentrations were prepared using diluent (methanol:water (50:50) % v / v).

[0198] Tolbutamide was used as an internal standard, and its stock solution was prepared by dissolving 25 mg of tolbutamide in 1000 μL of DMSO to achieve a concentration of 25 mg / mL. Working solutions of various concentrations were prepared by using diluent (acetonitrile:water (50:50) % v / v).

[0199] Preparation of solutions for SPE and chromatography: Mobile phase A (10 mM ammonium formate, pH 3.50): 0.6306 g of ammonium formate was weighed and transferred to a 1000 mL reagent bottle. To this, 1000 mL of Milli-Q water was added, and the pH of the resulting solution was adjusted to 3.5 with formic acid.

[0200] Mobile phase B: 100% acetonitrile

[0201] Diluent (methanol:water (50:50) % v / v): 50 mL of methanol was mixed with 50 mL of Milli-Q water. The resulting solution was used as the diluent.

[0202] Washing solution: 100 μL of ammonia was mixed with 100 mL of Milli-Q water. The resulting solution was used as the washing solution.

[0203] Elution solvent: 100 μL of formic acid was mixed with 100 mL of acetonitrile. The resulting solution was used as the elution solvent.

[0204] Analytical Method: Samples were analyzed using an Agilent 1290 Infinity II HPLC system coupled to an AB Sciex Triple Quad instrument (API-5000). Chromatographic separation was performed using an Agilent Zorbax Eclipse Plus C18 column (50 × 2.1 mm, 1.8 μm) in gradient mode. The mobile phase consisted of 10 mM ammonium formate (mobile phase A) at pH 3.5 and 100% acetonitrile (mobile phase B). The column temperature was 40 °C, and the flow rate was 0.35 mL / min. The MS instrument was operated in positive ion mode (ESI+). For analysis, 2 μL of sample was injected into the LC-MS / MS instrument. The autosampler temperature was 7 °C.

[0205] Quality control (QC) samples were prepared as follows, as shown in Table 7. [Table 7]

[0206] Sample preparation Sample preparation was performed using a WCX SPE 96-well plate. 50 μL of plasma sample was used for extraction. One set of linearity and two sets of quality control (QC) samples were also processed along with the test samples. Sample preparation: 10 μL of tolbutamide working solution was added to 50 μL of plasma (250 ng / mL tolbutamide). After mixing, 50 μL of buffer solution (10 mM ammonium formate, pH 3.5) was added. The contents were vortexed and loaded onto a pre-conditioned SPE plate.

[0207] LC-MS / MS analysis After placing the cartridges in a negative pressure SPE unit, they were conditioned by passing 200 μL of 100% methanol followed by 200 μL of water. The pretreated plasma samples were then loaded onto the preconditioned cartridges. After loading the pretreated plasma sample, the cartridge was washed with 100 μL of 0.1% ammonia solution. Finally, the bound analytes were eluted with 50 μL of 0.1% formic acid in acetonitrile. This step was repeated twice for complete elution. The final eluent volume was 100 μL. To 100 μL of eluent, 50 μL of 10 mM ammonium formate (pH 3.5) was added, and the sample was vortexed and transferred to a 96-well HPLC sample plate (Agilent) for LC-MS / MS analysis. For LC-MS / MS analysis, 2 μL of sample was injected. Calibration standards and QCs were treated in the same manner as the test samples. The mean plasma concentrations of dexmedetomidine in various rat plasma samples at various time points were determined by LC-MS / MS using Analyst 1.6.2 software (Table 8 and Figures 4A and 4B) with a calibration curve ranging from 0.011 to 53.061 ng / mL prepared in blank rat plasma matrix. The calibration curve was fitted by linear regression. The concentrations (pg / mL) in the QC and test samples were obtained from the Analyst software based on the calibration curve. The acceptance criteria for the calibration curve and QC were as follows: (1) At least 75% of the nonzero calibration standards must be included in the calibration curve with all back-calculated concentrations within ±20% deviation from the nominal concentration (excluding the low quantitation LLOQ, where ±20% deviation is acceptable); (2) The correlation coefficient (r) of the calibration curve must be 0.99 or greater; and (3) At least two-thirds (four out of six) of the QC samples must be within ±20% relative error (precision).

[0208] result [Table 8]

[0209] Interpretation and Conclusion Following sublingual administration of dexmedetomidine hydrochloride, a dose-related effect on plasma concentrations was observed at doses ranging from 0.5 to 3 μg / kg (Figure 4A, Table 8).

[0210] Following intravenous administration of dexmedetomidine hydrochloride, a dose-dependent effect on plasma concentrations was observed at doses ranging from 0.5 to 3 μg / kg (Figure 4B, Table 8).

[0211] Doses of 1 and 1.5 μg / kg effectively reduced various indices of agitation and aggression without significantly affecting neutral behavior. Plasma concentrations following administration of a 1 μg / kg dose (sublingual and intravenous routes) for 15 to 30 minutes (a time period corresponding to the duration of behavioral responses observed in efficacy studies; drug was administered 15 minutes before agitation behavior testing; animals were observed for 15 minutes) ranged from 43 ± 13.5 to 90 ± 12.1 pg / mL (Table 8). Similarly, plasma concentrations following administration of a 1.5 μg / kg dose (sublingual and intravenous routes) for 15 to 30 minutes ranged from 27 ± 7.1 to 114 ± 1.7 pg / mL (Table 8).

Claims

1. 1. A method of treating agitation or a symptom of agitation in a subject, comprising: The method comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof without causing significant sedation.

2. 1. A method of treating agitation or a symptom of agitation in a subject, comprising: administering sublingually to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The method, wherein the agitation is associated with a neurodegenerative disease.

3. 3. The method of claim 2, wherein the treatment is effective to suppress agitation or symptoms of agitation in a subject without causing significant sedation.

4. 4. The method of claim 2 or 3, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

5. 5. The method of claim 4, wherein the neurodegenerative disease is selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, and Parkinson's disease.

6. 1. A method of treating agitation or a symptom of agitation in a subject, comprising: administering sublingually to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; The method, wherein the agitation is associated with a neuropsychiatric disorder.

7. 7. The method of claim 6, wherein the treatment is effective in suppressing agitation or symptoms of agitation without causing significant sedation.

8. 8. The method of claim 6 or 7, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium and depression.

9. 10. The method of claim 1, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

10. 3. The method of claim 2, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

11. 7. The method of claim 6, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

12. 10. The method of claim 1, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually at a dose ranging from about 3 micrograms to about 100 micrograms.

13. 13. The method of claim 12, wherein the dose is from about 5 micrograms to about 30 micrograms.

14. 1. A sublingual composition for treating agitation or symptoms of agitation, comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers / excipients.

15. 15. The sublingual composition of claim 14, wherein the treatment is effective to suppress agitation or symptoms of agitation in a subject without causing significant sedation.

16. 15. The sublingual composition of claim 14, wherein the agitation is associated with a neurodegenerative disease.

17. 17. The sublingual composition of claim 16, wherein the treatment is effective to suppress agitation or symptoms of agitation in a subject without causing significant sedation.

18. 17. The sublingual composition of claim 16, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive dysfunction, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

19. 19. The sublingual composition of claim 18, wherein the neurodegenerative disease is selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, and Parkinson's disease.

20. 15. The sublingual composition of claim 14, wherein the agitation is associated with a neuropsychiatric disorder.

21. 21. The sublingual composition of claim 20, wherein the treatment is effective to suppress agitation or symptoms of agitation in a subject without causing significant sedation.

22. 21. The sublingual composition of claim 20, wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression.

23. 15. The sublingual composition of claim 14, wherein the dosage form is selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

24. 24. The sublingual composition of claim 23, wherein the dosage form is a thin film.

25. 25. A sublingual composition according to claim 23 or 24, wherein the film is mucoadhesive in nature and provides a rapid onset of action.

26. 17. The sublingual composition of claim 16, wherein the dosage form is selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

27. 27. The sublingual composition of claim 26, wherein the dosage form is a thin film.

28. 28. A sublingual composition according to claim 26 or 27, wherein the film is mucoadhesive in nature and provides a rapid onset of action.

29. 21. The sublingual composition of claim 20, wherein the dosage form is selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a liquid drop.

30. 30. The sublingual composition of claim 29, wherein the dosage form is a thin film.

31. 31. A sublingual composition according to claim 29 or 30, wherein the film is mucoadhesive in nature and provides a rapid onset of action.

32. 25. The sublingual composition of claim 23 or 24, wherein the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in a dosage range of about 3 micrograms to about 100 micrograms.

33. 33. The sublingual composition of claim 32, wherein the dosage is from about 5 micrograms to about 30 micrograms.

34. 28. The sublingual composition of claim 26 or 27, wherein the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in a dosage range of about 3 micrograms to about 100 micrograms.

35. 35. The sublingual composition of claim 34, wherein the dosage is from about 5 micrograms to about 30 micrograms.

36. 31. The sublingual composition of claim 29 or 30, wherein the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof in a dosage range of about 3 micrograms to about 100 micrograms.

37. 37. The sublingual composition of claim 36, wherein the dosage is from about 5 micrograms to about 30 micrograms.

38. 15. The sublingual composition of claim 14, which upon administration produces a therapeutic effect of suppressing agitation in about 30 seconds to about 30 minutes without causing significant sedation.

39. 1. A sublingual composition for treating agitation or symptoms of agitation in a subject, comprising: The sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is not perioperative agitation.

40. 1. A method of treating agitation or a symptom of agitation in a subject, comprising: The method, comprising sublingually administering to the subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is not perioperative agitation.

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