EA042166B1 - USE OF SUBLINGUAL DEXMEDETOMIDINE FOR THE TREATMENT OF AGITATION - Google Patents

Description

Technical field

The present invention provides a method for treating agitation or signs of agitation in a subject, comprising sublingual administration of an effective amount of an alpha-2 adrenergic agonist, more particularly dexmedetomidine or a pharmaceutically acceptable salt thereof. This invention also describes a sublingual composition for the treatment of agitation or signs of agitation, containing an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers and/or excipients, as well as its preparation.

Cross-reference to related applications

This application claims priority over U.S. Provisional Application Serial No. 62/441164 filed December 31, 2016, U.S. Provisional Application Serial No. 62/471393 filed March 15, 2017, and U.S. Provisional Application Serial No. 62/ 542323, filed August 8, 2017, the descriptions of which are incorporated herein by reference in their entirety for all purposes.

State of the art

Agitation is a general term that can refer to a range of behavioral disturbances or disorders, including aggression, belligerence, hyperactivity, and disinhibition. Agitation is a non-specific collection of relatively unrelated behavioral disorders that occur in several different clinical conditions and are usually characterized by a variable course. Agitation can be caused by several different pathological conditions and drug interactions, or any circumstance that impairs a person's ability to think. Multiple pathophysiological disorders are due to dysregulation of the dopaminergic, serotonergic, noradrenergic, and GABAergic systems. Agitation is characterized by unproductive, diffuse and excessive activity of both motor (akathisia) and cognitive functions, accompanied by internal unpleasant tension. The key to safety is early intervention to prevent agitation from developing into aggression and violence.

Agitation may be associated with neurodegenerative disorders. One of the important manifestations of a long-term progressive neurodegenerative process is such a clinically known condition as dementia. Dementias include dementia in Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (BTL), and Down's dementia.

Dementia in adults progressively destroys memory and a person's ability to learn, reason, make decisions, communicate, and perform daily activities. In later stages, patients may experience changes in personality and behavior such as anxiety, suspicion, agitation, and aggression.

Sebastiaan Engelborghs et al., in Neurochemistry International, 2007 Nov, 52(6):1052-60, described that in frontotemporal dementia, increased dopaminergic neurotransmission activity and altered serotonergic modulation of dopaminergic neurotransmission are associated with agitated and aggressive behavior, respectively. Pia Jul et al., in Journal of Alzheimer's disease, 2015 Sep, 49(3):783-95, described that rTg4510 mice exhibited P301L-tau-dependent hyperactivity, and the agitation-like phenotypes in these mice may correlate with some behavioral disorders seen in progressive Alzheimer's disease (AD) and frontotemporal dementia (FTD). Nathan Hermann et al., in Journal of Neuropsychiatry, 2004 Aug, 16(3):261-276, described that a compensatory increase in activity in the noradrenergic system may contribute to the behavioral and psychological symptoms of agitation and aggression in Alzheimer's disease.

Agitation may also be associated with neuropsychiatric conditions such as schizophrenia, bipolar illness such as bipolar disorder or mania, depression, delirium, etc., or agitation may be associated with alcohol and substance withdrawal symptoms. Acute agitation, manifested by a state of motor restlessness and accompanying mental stress, is a serious medical problem that can occur in some mental disorders, including schizophrenia and bipolar mania, and can quickly develop into aggressive behavior. Acute agitation is characterized by signs that include walking back and forth, wringing hands, clenching fists, yelling, yelling, and threatening behavior towards people when the agitation increases.

To date, there is no single drug considered as the standard of care for the treatment of agitation in patients with dementia or schizophrenia. Generally, three classes of drugs are most commonly used, depending on the degree of agitation, namely first-generation antipsychotics, second-generation antipsychotics, and oral, intramuscular, or intravenous benzodiazepines. For the past few decades, intramuscular administration of typical antipsychotics and benzodiazepines, administered alone or in combination, has been the treatment of choice for agitation. The current paradigm of choice for the treatment of acute agitation is the use of atypical

- 1 042166 antipsychotic drugs administered with or without additional benzodiazepines.

More specifically, patients with agitation are commonly prescribed beta blockers such as propranolol and pindolol, anti-anxiety medications such as buspirone, benzodiazepines such as lorazepam, anticonvulsants such as valproate and lamotrigine, antipsychotics such as haloperidol, droperidol, ziprasidone and other highly effective dopamine blocking agents, as well as atypical antipsychotics such as olanzapine. However, buspirone, valproate, haloperidol, droperidol, and ziprasidone have potential adverse effects, with optimal dose and long-term efficacy in the treatment of chronic agitation in dementia being very limited. Lorazepam is only effective for the treatment of agitation in patients when used prior to medical procedures. Loxapine (an antipsychotic) is FDA approved for the treatment of patients with agitation by inhalation, but is associated with a black box warning regarding bronchospasm and increased mortality in elderly patients with dementia-related psychosis (FDA label, loxapine or Adasuw®). Olanzapine, ziprasidone, or its combination with haloperidol is also associated with QT prolongation, and very careful monitoring of patients should be organized in the hospital setting for the possible development of extrapyramidal side effects. Reports of adverse effects (including eight deaths) associated with intramuscular administration of olanzapine emphasize the need to follow strict prescribing guidelines and avoid concomitant use with other CNS depressants.

The expert consensus guidelines for the treatment of emergency behavioral disorders indicate the rate of onset of the disorder as one of the most important factors in the choice of drug and route of administration. However, it may be necessary to take antipsychotic drugs from several days to several weeks before obtaining their persistent antipsychotic effect. At the same time, these drugs in most cases have a calming effect on patients with agitation within a few minutes. For example, benzodiazepines or fast-acting sedative drugs quickly calm a highly agitated patient, but chronic treatment with these drugs leads to addiction.

Therefore, the treatment of agitation in patients with neuropsychiatric conditions (such as schizophrenia or bipolar mania) and neurodegenerative diseases is still limited due to the potential for significant side effects associated with currently used drugs, their routes of administration (intravenous/intramuscular), and the subsequent need for hospitalization of the patient in medical institutions for the introduction of these drugs. In an ideal situation, a drug for the treatment of agitation in patients with schizophrenia or dementia should be characterized by the effect of quickly calming the patient without sedation, well tolerated and easy to administer with a high margin of safety.

Alpha-2 adrenergic agonists are used therapeutically for a number of pathological conditions, including hypertension, congestive heart failure, angina pectoris, spasticity, glaucoma, diarrhea, and to suppress withdrawal symptoms associated with opiate withdrawal. Examples of alpha-2 adrenergic agonists include clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadomidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, fazepsoline, miekerol , oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propylhexedrine, norfenephrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3- aminomethyl-cyclohex-3-enylmethyl)1,3-dihydroimidazole-2-thione, as well as 4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione. The present inventors have surprisingly found that sublingual administration of an alpha-2-adrenergic agonist, or a pharmaceutically acceptable salt thereof, is a particularly effective and safe method for treating agitation.

(S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole (dexmedetomidine) is a commercially available injectable formulation used to sedate initially intubated and mechanically ventilated patients during treatment in an intensive care unit setting. and non-intubated patients before and/or during surgical and other procedures.

Dexmedetomidine has been reported to have an anti-agitation effect when administered intravenously or buccally during surgical procedures and in the intensive care unit (ICU) setting. For example, Ibacache et al., in Anesthesia & Analgesia, 2004 Jan; 98(1):60-3, described the administration of a single intravenous dose of dexmedetomidine to reduce the level of agitation following sevoflurane anesthesia in children. Other IV administrations have been reported by Jeanne Boyer et al., in Nursing Critical Care, 2010 Jan, 5(1):30-34, Yahya Shehabi et al., in Anesthetic Intensive Care, 2010 Jan, 38(1):82-90 , and Joseph D. Tobias in Journal of Pediatric Pharmacology Therapeutic, Jan-Mar 2010, 15(1):43-48. NCT 02720705 (clinical trial identification number at Clinicaltrials.gov) describes the use of buccal dexmedetomidine to prevent agitation in

- 2,042,166 preschool children who received sevofuran in the intensive care unit.

Sublingual use of dexmedetomidine is described in WO 2016/061413. However, the focus of WO 2016/061413 is on sublingual administration of dexmedetomidine at doses suitable for treating sleep disorders and inducing significant sedation. In the course of this work, the authors unexpectedly found that dexmedetomidine or its pharmaceutically acceptable salt, administered sublingually, can effectively treat agitation, including agitation associated with neurodegenerative diseases (for example, Alzheimer's disease, frontotemporal dementia, and evening confusion syndrome in Alzheimer's disease/dementia). ), agitation associated with neuropsychiatric conditions (eg, bipolar disorder, schizophrenia, bipolar mania, delirium, and depression), agitation associated with alcohol and substance withdrawal symptoms, or agitation associated with other conditions such as AMB/STAC (outpatient/inpatient) procedures (eg, MRI, CT or CT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extractions, or other dental procedures). The dose selected for sublingual administration may be effective in treating agitation, but not sufficient to cause significant sedation.

The essence of the invention

The present invention provides a method for treating agitation or signs of agitation in a subject in need thereof, comprising administering an effective amount of an alpha-2-adrenergic agonist or a pharmaceutically acceptable salt thereof sublingually to the subject, said agitation being associated with neurodegenerative diseases such as Alzheimer's disease, frontal temporal dementia or parkinsonism? or said agitation is associated with neuropsychiatric conditions such as schizophrenia, bipolar disorder, bipolar mania, delirium, or depression, or said agitation is associated with AMB/STAS procedures (e.g., MRI, CT or CT scan, lumbar puncture, bone aspiration/biopsy brain, extraction of teeth, or other dental procedures), or said agitation is associated with withdrawal symptoms that occur when alcohol and psychoactive substances are withdrawn. In a specific aspect, agitation is suppressed without significant sedative effects.

In a preferred aspect of the present invention, there is provided a method for treating agitation or signs of agitation in a subject in need thereof, comprising sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In a specific aspect, agitation is suppressed without significant sedative effects.

In another aspect of the present invention, there is provided a method for treating agitation or signs of agitation in a subject in need thereof, comprising sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, said agitation being associated with a neurodegenerative disease. In a specific aspect, agitation is suppressed without significant sedative effects.

In yet another aspect of the present invention, there is provided a method for treating agitation or signs of agitation in a subject in need thereof, comprising sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, said agitation being associated with dementia, Alzheimer's disease, frontotemporal dementia , parkinsonism or other neurodegenerative diseases. In a specific aspect, agitation is suppressed without significant sedative effects.

In another aspect of the present invention, there is provided a method for treating agitation or signs of agitation in a subject in need thereof, comprising sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, said agitation being associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression or other related neuropsychiatric condition. In a specific aspect, agitation is suppressed without significant sedative effects.

In a further aspect of the present invention, there is provided a method for treating, preventing, or alleviating signs 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, said agitation being associated with Alzheimer's/Dementia Evening Confusion Syndrome. . In a specific aspect, agitation is suppressed without significant sedative effects.

In yet another aspect of the present invention, there is provided a method for treating agitation or signs of agitation in a subject in need thereof, comprising sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, said agitation being associated with AMB/STAS procedures (e.g., MRI, CT or CT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extractions, or other dental procedures). In a specific aspect, agitation is suppressed without significant sedative effects.

In yet another aspect of the present invention, a method is provided for treating agitation or signs

- 3 042166 agitation in a subject in need of this, including sublingual administration to said subject of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, while said agitation is associated with a withdrawal syndrome that occurs when alcohol and psychoactive substances are withdrawn. In a specific aspect, agitation is suppressed without significant sedative effects.

In a further aspect of the present invention, a sublingual composition is provided for the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with a neurodegenerative disease, and 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.

In another aspect of the present invention, a sublingual composition is provided for the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with schizophrenia, bipolar disorder, bipolar mania, delirium, depression, or other associated neuropsychiatric condition, and said sublingual the composition contains an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients.

In a further aspect of the present invention, a sublingual composition is provided for the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with Alzheimer's/Dementia Evening Confusion Syndrome, and 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.

In yet another aspect of the present invention, a sublingual composition is provided for the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with AMB/STAC procedures (e.g., MRI, CT or CT scan, lumbar puncture, aspiration/biopsy bone marrow, tooth extraction or other dental procedures), and said sublingual composition contains an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or excipients.

In yet another aspect of the present invention, a sublingual composition is provided for the treatment of agitation or signs associated with agitation in a subject in need thereof, wherein said agitation is associated with a withdrawal syndrome that occurs upon withdrawal of alcohol and psychoactive substances, and said sublingual composition contains an effective an amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers and/or excipients.

In another aspect of the present invention, a sublingual composition is provided 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 a film, a capsule, a patch, pastilles, gel, spray, tablet, liquid drops or the like.

In a further aspect of the present invention, there is provided a method for sublingually administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa of a subject for the treatment of agitation or signs of agitation at a dose that does not cause significant sedation.

In a particular aspect of the present invention, range from about from from from from about about about about about about 5 to to to to about about about about about about

100 mcg, mcg, mcg, mcg, mcg, from from from from to about about about about about about about to to to to up to sublingual dose,

100 mcg.

about about about about about

Examples of suitable dosages may generally include μg, μg, μg, μg, μg, from from from about about about about about to to about about about about about μg, μg, μg, μg, μg, to about 20 μg , about 5 to about 15 µg, about 5 to about 10 µg, less than 10 µg (e.g., about 5, 6, 7, 8, or 9 µg), about 10 µg, about 12 µg, about 14 µg, about 15 micrograms, about 16 micrograms, about 18 micrograms, about 20 micrograms, about 30 micrograms, about 50 micrograms. The specified dose can be administered one or more times a day.

Brief description of graphic materials

Fig. 1A. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on the combined duration of aggressive and agitated behavior. Data are expressed as mean ± SOS. One-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 vs.

- 4,042,166 control animals treated with vehicle (vehicle).

Fig. 1B. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on the incidence of aggressive and agitated behavior. Data are expressed as mean ± SOS. One-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 1C. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on the combined duration of aggressive and agitated behavior. Data are expressed as mean ± SOS. One-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 1D. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on the incidence of aggressive and agitated behavior. Data are expressed as mean ± SOS. One-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 2A. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on the pre-attack waiting period. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 2B. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on the pre-attack waiting period. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3A. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on the cumulative duration of neutral behaviors such as grooming and exploratory activity. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3b. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on the incidence of neutral behaviors such as grooming and exploratory activity. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3C. Effect of dexmedetomidine hydrochloride (Dex) administered sublingually at various doses (0.5-3 µg/kg) on neutral behavior such as periods of immobility/rest. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3D. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on the cumulative duration of neutral behaviors such as grooming and exploratory activity. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3E. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on the incidence of neutral behaviors such as grooming and exploratory activity. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

Fig. 3F. Effect of intravenous dexmedetomidine hydrochloride (Dex) at various doses (0.5-3 µg/kg) on neutral behavior such as periods of immobility/rest. Data are expressed as mean ± SOS. Statistical analysis was performed using one-way ANOVA followed by Dunnett's post hoc test. * p<0.05; ** p<0.01; *** p<0.001 and **** p<0.0001 compared to control animals treated with vehicle (vehicle).

- 5 042166

Fig. 4A. Mean plasma concentrations after sublingual (s/l) administration of dexmedetomidine hydrochloride to rats. Data are expressed as mean ± SD.

Fig. 4B. Mean plasma concentrations after intravenous (IV) administration of dexmedetomidine hydrochloride to rats. Data are expressed as mean ± SD.

Detailed description of the invention

I. List of abbreviations.

In this description, the following abbreviations apply:

AD - Alzheimer's disease,

AUC - area under the pharmacokinetic curve,

BZD - benzodiazepines,

CNS - central nervous system,

CT/CT-scan - computed tomography,

C _max is the maximum (or peak) serum concentration that the drug reaches in the specified compartment,

EPE - extrapyramidal side effects,

FD & C (Federal Food, Drug, and Cosmetic) - food, drugs and cosmetics,

FTD - frontotemporal dementia,

GABA - gamma amino acid,

5-HT - 5-hydroxytryptamine,

ICU - Intensive Care Unit,

STATS - inpatient department,

MRI - magnetic resonance imaging, mg - milligram,

NE - norepinephrine,

AMB - outpatient department,

PTSD - post-traumatic stress disorder,

RSS - Ramsey sedation scale,

RIT - Rat Intrusion Test,

SLOS - Smith-Lemli-Opitz syndrome,

T _max is the time at which C _max is observed.

II. Definitions.

It should be understood that the terminology used in this document is only intended to describe specific embodiments of the invention and is not limiting. When used in this description of the invention, the singular includes reference to the plural, unless the context clearly indicates otherwise. Thus, for example, reference to a solvent includes one or more such solvents, and the like.

Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings as generally accepted among specialists in the field of technology to which this invention pertains. While other methods and materials similar or equivalent to those described herein may be used in the practice of this invention, the preferred methods and materials are those described herein.

As used herein, the terms treatment and exposure refer to curative therapy, prophylactic therapy and/or preventive therapy and may be used interchangeably.

In this context, unless otherwise indicated, the terms pharmaceutical composition, composition, formulation and composition of the invention are used interchangeably. Unless otherwise indicated, these terms are intended to cover pharmaceutical compositions containing a drug substance, i.e. dexmedetomidine, and are not limited to. The composition may also contain one or more excipients, which are inactive ingredients or compounds devoid of pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease or in relation to the structure or any function of the human body.

In this context, the term effective amount is interchangeable with a therapeutically effective dose or a therapeutically effective amount and refers to an amount sufficient to achieve the desired effect. An effective amount is sufficient to cause an improvement in the clinically significant condition of the subject.

As used herein, the term pharmaceutically acceptable salt refers to a salt that is known to be non-toxic, which term is commonly used in the pharmaceutical literature. Typical inorganic acids used to form such a salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acids, and the like. Salts derived from organic acids such as alifati can also be used.

- 6 042166 mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxylacandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. The preferred salt is the hydrochloride salt.

In this context, the term subject preferably refers to a human patient. In some embodiments of this invention, the subject may be any animal, including non-human mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates.

In this context, the term agitation means irritability, emotional outburst, impaired thinking, or excessive motor and verbal activity, which may arise from dysfunction of certain areas of the brain, such as the frontal lobes, or due to dysfunction of neurotransmitter systems, such as the dopamine and norepinephrine systems. . In the present invention, agitation also includes aggression and hyperarousal in post-traumatic stress disorder. Agitation can be acute or chronic.

The term signs of agitation include excessive motor activity (examples include walking back and forth, stereotyped rocking movements, gesturing, finger pointing, restlessness, performing stereotyped and repetitive movements), verbal aggression (eg, yelling, speaking in too loud a voice, using profanity , yelling, yelling, threatening other people), physical aggression (eg, grabbing, pushing, shoving, fisting, resisting, hitting other people, kicking objects or people, scratching, biting, throwing objects, hitting themselves, slamming doors, tearing things and destroying property).

The term acute agitation means agitation that occurs quickly and is characterized by a strong and sudden onset. Acute agitation may be associated, for example, with neurodegenerative disease and neuropsychiatric conditions, although acute agitation may be particularly characteristic of neuropsychiatric conditions. Without appropriate treatment, acute agitation can progress to chronic agitation.

The term chronic agitation means that agitation develops over a long period of time and is less severe than acute agitation. Chronic agitation may be associated, for example, with neurodegenerative disease and neuropsychiatric conditions, although chronic agitation may be particularly characteristic of neurodegenerative diseases.

The term neurodegenerative disease includes, but is not limited to, Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia, Lewy body dementia, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy, or other associated neurodegenerative diseases.

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

Evening Confusion Syndrome is a circadian syndrome characterized by increased confusion and restlessness in the evening, commonly seen in patients with some forms of dementia. Apparently, this syndrome occurs more often in the middle stages of Alzheimer's disease. Apparently, the manifestations of this syndrome weaken with the progression of dementia in the patient. About 20-45% of Alzheimer's patients will experience some confusion in the evening. Confusion and agitation worse in afternoon and late afternoon or as the sun goes down.

The term perioperative agitation means agitation before, during, or after any surgical procedure, or agitation in the OPT that is not associated with a neurodegenerative disease or neuropsychiatric condition.

The term sublingual literally means under the tongue and refers to the way substances are administered through the mouth so that the substances are rapidly absorbed through the blood vessels under the tongue rather than in the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, whereby the substance has direct access to the circulation, thereby allowing direct systemic administration, bypassing the gastrointestinal tract and avoiding undesirable first-pass liver metabolism. Accordingly, the total amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in the formulation can be reduced, thereby reducing the chance of harmful side effects and providing an economic benefit to the manufacturer.

In this context, the term sedation means the achievement of a reduced level of consciousness in which the patient or subject retains the ability to maintain an independent and continuous airway and regular breathing, as well as the ability to adequately and rationally

- 7 042166 respond to physical stimulation and verbal commands. In this context, the term without significant sedation means that the patient's level of sedation does not exceed level 3 on the Ramsey Sedation Scale. Level 3 means the patient is sedated but responding to commands.

III. Ways.

The present invention describes a method for treating agitation or signs of agitation in a subject, comprising sublingual administration to said subject of an effective amount of an alpha-2 adrenergic agonist or a pharmaceutically acceptable salt thereof. In a specific aspect, agitation is suppressed without significant sedative effects.

In one embodiment of the present invention, alpha-2 adrenergic agonists include, but are not limited to, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivaserol, azepexol, talipexol, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propylhexedrine, norphenephrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91 52353, TCG-1000, 4-(3-Aminomethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2thione, and 4-(3-hydroxymethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione or their pharmaceutically acceptable salts.

In one preferred embodiment of the present invention, there is provided a method for treating agitation or signs of agitation in a subject, comprising sublingually administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In a specific aspect, agitation is suppressed without significant sedative effects.

Agitation can be effectively treated with sublingual administration of a relatively low dose of dexmedetomidine or a pharmaceutically acceptable salt thereof. Therefore, in a treatment that is effective in alleviating agitation, in addition to not causing significant sedation, there is a reduction or absence of side effects (eg, cardiac or respiratory side effects).

In a further embodiment, the present invention provides a method for treating agitation or signs of agitation in a subject, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to the subject to provide rapid relief without a substantial portion of the dexmedetomidine or pharmaceutically acceptable salt thereof entering the patient's liver.

In another embodiment, the present invention provides a method for treating agitation or signs of agitation in a subject in need thereof, comprising administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof via a sublingual composition to the subject, wherein the sublingual composition is selected from a film, capsule, patch, lozenge, gel , spray, tablet and liquid drops.

In a further embodiment, the present invention provides a method of treating agitation or signs 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 In this sublingual composition is a sublingual film. In a particular aspect, the agitation is associated with a neurodegenerative disease or neuropsychiatric condition. In another specific aspect, the treatment is effective without causing significant sedation.

In a further embodiment, the present invention provides a method for treating agitation or signs 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 In this sublingual composition is a sublingual film. In a particular aspect, the agitation is associated with a neurodegenerative disease or neuropsychiatric condition. In another specific aspect, the treatment is effective without causing significant sedation.

In yet another embodiment, the present invention provides a method of treating agitation or signs of agitation in a subject in need thereof, comprising administering to said 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. Useful alpha-2 adrenergic agonists include, but are not limited to, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitrazol, , talipexol, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propylhexedrine, norfenephrine, octopamine, moxonidine, lidamidine,

- 8 042166 tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethylcyclohex-3-enylmethyl)1,3-dihydroimidazole-2-thione, and also 4-( 3-hydroxymethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione or pharmaceutically acceptable salts thereof. In a specific aspect of this invention, the dosage of alpha-2-adrenergic agonist used in the composition is from about 3 to about 100 micrograms.

In another embodiment, the present invention provides a method of treating agitation or signs of agitation in a subject in need thereof, comprising administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, sublingually at a dose that does not cause significant sedation. In a specific aspect of the present invention, the dose of dexmedetomidine, or a pharmaceutically acceptable salt thereof, used in a sublingual composition is from about 3 to about 100 micrograms. Examples of suitable dosages include about 5 to about 100 µg, about 5 to about 90 µg, about 5 to about 85 µg, about 5 to about 80 µg, about 5 to about 75 µg, about 5 to about 70 µg, about 5 to about 65 µg, about 5 to about 60 µg, about 5 to about 55 µg, about 5 to about 50 µg, about 5 to about 45 µg, about 5 to about 40 µg, about 5 to about 35 µg, about 5 to about 30 µg, about 5 to about 25 µg, about 5 to about 20 µg, about 5 to about 15 µg, about 5 to about 10 µg, less than 10 micrograms (for example, 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 mcg. The specified dose can be administered one or more times a day.

In a further embodiment, the present invention provides a method for treating agitation or signs of agitation in a subject in need thereof, comprising administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, sublingually at a dose of about 0.05 to about 1.5 μg/kg of the subject's weight. . Examples of suitable dosages include about 0.1 to about 1 µg/kg, about 0.1 to about 0.5 µg/kg, about 0.1 to about 0.4 µg/kg, about 0.1 to about 0.3 µg/kg, about 0.1 to about 0.2 µg/kg, about 0.07 µg/kg, about 0.05 µg/kg, about 0.1 µg/kg, about 0.2 µg/kg, about 0.3 µg/kg, about 0.4 µg/kg, about 0.5 µg/kg, about 0.6 µg/kg, about 0.7 µg/kg, about 0.8 µg/ kg, about 0.9 µg/kg, about 1.0 µg/kg, about 1.1 µg/kg, about 1.2 µg/kg, about 1.3 µg/kg, about 1.4 µg/kg, about 1.5 µg/kg. The specified dose can be administered one or more times a day.

In yet another embodiment, the present invention provides a method of treating agitation or signs of agitation associated with a neurodegenerative disease in a subject in need thereof, comprising administering to said 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. effect. Useful alpha-2 adrenergic agonists include, but are not limited to, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitrazol, , talipexol, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propylhexedrine, norfenephrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141, ST-91, RWJ-52350, TCG-10 , 4-(3-Aminomethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione, as well as 4-(3-hydroxymethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione or pharmaceutically acceptable salts. The dose of alpha-2 adrenergic agonist used in the composition is conveniently from about 3 to about 100 micrograms.

In another further embodiment, the present invention provides a method for treating agitation or signs of agitation associated with a neurodegenerative disease in a subject in need thereof, comprising administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually at a dose that does not cause an undesirable (e.g. , significant) sedative effect. The dose of dexmedetomidine, or a pharmaceutically acceptable salt thereof, used may be from about 3 to about 100 micrograms, for example, from about to about 100 micrograms, for convenience, from about to about 90 from about from about from about from about from about about 5 to about up to about about about about about about about mcg, mcg, mcg, mcg, mcg, from from from to about 10 about about about about about to to about about about about about about about mcg, less than 10 mcg, about 5 mcg, mcg, mcg, mcg, mcg, mcg, ca. , mcg, mcg, about 9 mcg, about 10 mcg, about 12 mcg, about 14 mcg, about 16 mcg, about 18 mcg. The specified dose can be administered one or more times a day.

In yet another embodiment, the present invention provides a method for treating agitation or signs of agitation associated with a neuropsychiatric condition in a subject in need thereof, comprising administering to said subject an effective amount of an alpha-2-adrenergic agonist or a pharmaceutically acceptable salt thereof at a dose that does not cause significant sedative effect. Useful alpha-2 adrenergic agonists include, but are not limited to, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine, methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, mivaserolase, amitroraz , azepexol, talipexol, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propylhexedrine, norfenephrine, octopamine, moxonidine, lidamidine, tolonidine, UK14304, DJ-7141,

ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione, and 4-(3-hydroxymethylcyclohex-3-enylmethyl)-1 ,3-dihydroimidazole-2-thione or their pharmaceutically acceptable salts. The dose of alpha-2 adrenergic agonist used in the composition is conveniently from about 3 to about 100 micrograms.

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

The level of acceptable sedation in the treatment of a subject according to the method of this invention is preferably at or below level 3 according to the Ramsey Sedation Scoring System (RSS). Thus, in a particular embodiment, the present invention provides a method for treating agitation or signs of agitation in a human subject in need thereof, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof sublingually to said subject at a dose in the range of about 3 to 100 μg, thereby obtaining RSS at or below level 3 (for example, level 2 or level 3).

IV. pharmaceutical compositions.

The present invention also provides sublingual pharmaceutical compositions containing an effective amount of an alpha-2-adrenergic agonist or a pharmaceutically acceptable salt thereof, preferably dexmedetomidine or a pharmaceutically acceptable salt thereof.

The sublingual pharmaceutical compositions of this invention may also contain a pharmaceutically acceptable carrier and/or excipient. Suitable pharmaceutically acceptable carriers include water, sodium chloride, binders, penetration enhancers, diluents, lubricants, flavors, colorants, and the like.

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

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, such as agitation associated with a neurodegenerative disease, Alzheimer's evening confusion syndrome, or dementia. In a specific aspect, the sublingual pharmaceutical composition effectively treats agitation in a subject without producing significant sedation.

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 disorders, depression, delirium, or other associated neuropsychiatric condition. In a specific aspect, the sublingual pharmaceutical composition effectively treats agitation in a subject without producing significant sedation.

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

In one embodiment of the present invention, the sublingual pharmaceutical composition is in the form of a tablet or a packaged powder.

In another embodiment of the present invention, the sublingual pharmaceutical composition

- 10 042166 The position is presented in the form of a patch or film (eg thin film). The patch may have adhesive properties to prevent it from moving or being swallowed. The patch may be cleavable in case of accidental ingestion or to facilitate its disposal, or the patch may be removed from under the tongue after a set time.

In yet another embodiment of this 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 ensure retention under the tongue.

In a further embodiment of the present invention, the sublingual pharmaceutical composition is in the form of a liquid (eg, in the form of a solution, suspension or emulsion) and may be presented, for example, in the form of a spray or drops. Solutions include the active ingredient along with a diluent such as water, saline, sodium chloride solution, or any other suitable solvent such as propylene glycol, glycerin, ethyl alcohol, etc. The diluent for the solution may in particular be physiological saline or water. The amount of solution administered may conveniently be from about 0.01 to about 1 ml (eg, about 0.025-0.5 ml).

The non-solid compositions of the present invention may conveniently be administered by spraying, dripping, dyeing, or sublingual injection of the composition.

In a specific embodiment of the present invention, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in liquid form, for example in flavored or non-flavored physiological saline. The liquid composition may conveniently be administered sublingually in the form of drops or spray.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may conveniently comprise from about 0.001% to about 99.99% of the total composition, such as from about 0.01% to about 90%, more specifically from about 0.01% to about 30%.

When the composition is a liquid or gel, the first single dose is applied and held at the site of administration, under the tongue, for a predetermined time, such as at least about 30 seconds, or more specifically, about 60 seconds or more. A second single dose may then be administered and maintained for a similar period of time.

Of interest is the fact that this procedure markedly enhances the effect of the composition of this invention in the treatment of agitation or signs of agitation.

In another embodiment of the present invention, the sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt thereof is a solid or compressed powder tablet. Said tablet can be designed to dissolve under the tongue in about 30-120 seconds as described in US Pat. No. 6,221,392 to Khankari, et al, and incorporated herein by reference. In a particular embodiment of the present invention, the sublingual composition of dexmedetomidine or a pharmaceutically acceptable salt thereof is a solid tablet having a fine particle size component for an organoleptically pleasant mouthfeel. Said tablet (or particles thereof containing an active ingredient that can be compressed to form a tablet) may also contain a protective outer coating, for example any polymer commonly used to form microparticles, matrix-type microparticles and microcapsules.

In a further embodiment of the present invention, the sublingual composition of dexmedetomidine, or a pharmaceutically acceptable salt thereof, is a hard, compressed, instant tablet. The tablet for convenience includes the active ingredient in a matrix. The matrix may consist, for example, of 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 of the following: a binder (eg, povidone, sugar, or carboxymethylcellulose), a disintegrant (eg, croscarmellose sodium, crospovidone, or sodium starch glycolate), a sweetener (eg, sucralose), and the like. The tablet may have a friability of about 2% or less and a hardness of about 15 to about 50 N.

In another aspect of the present invention, a method for making a packaged sublingual tablet is provided. This method includes the following steps:

(a) forming a mixture containing dexmedetomidine or a pharmaceutically acceptable salt thereof and a matrix comprising at least an indirectly compressible excipient and a lubricant;

(b) compressing the mixture into a plurality of hard, compressed, rapidly disintegrating particles (eg, granules), including the active ingredient, dispersed in a sublingually soluble matrix; and (c) storage of the bulk product until packaging work is performed.

In another embodiment of the present invention, the dosage forms are then packaged within the package such that there is more than one per package. Direct pressing is

- 11 042166 the preferred method of forming dosage forms. Also provided is an openable and resealable pack containing a plurality of hard, compressed, fast dissolving tablets adapted for direct oral administration as described above.

In another embodiment, the present invention provides a sublingual tablet containing an effervescent agent. The effervescent agent may conveniently be present in an amount of up to about 95% by weight based on the weight of the finished tablet, and more particularly in an amount of from about 30% to about 80% by weight. Sufficient effervescent material is included in the tablet composition to generate more than about 5 cm ³ but less than about 30 cm ³ of gas when said tablet is exposed to an aqueous environment. Sublingual compositions containing effervescent agents are described in US Pat. No. 6,200,604, which is incorporated herein by reference.

In one particular embodiment of the present invention, the effervescent agent releases carbon dioxide, for example by reacting a soluble acid with an alkaline carbonate or bicarbonate. The acid source may conveniently include food acids and acids such as citric acid, tartaric acid, amalic, fumaric, adipic and succinic acids. Sources of carbonate and bicarbonate include dry solid carbonate and a bicarbonate salt such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, and the like.

Spray compositions of this invention for sublingual administration may include one or more pharmaceutically acceptable liquids (eg, present in an amount of from about 30% to about 99.99% by weight of said composition). Such liquids may be solvents, co-solvents or non-solvents for dexmedetomidine or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (eg, soybean, sunflower, peanut, peppermint, etc.), and the like. The pharmaceutically acceptable liquid is chosen either to dissolve the active pharmaceutical ingredient, or to obtain a stable, homogeneous suspension or solution, or to form any combination of suspension or solution.

In addition, sublingual nebulization formulations of dexmedetomidine or a pharmaceutically acceptable salt thereof may include one or more carriers and/or excipients. Examples of carriers/auxiliaries include viscosity modulating materials (eg, polymers, sugars, sugar alcohols, resins, clays, silicas, etc.). One particular polymer that can be conveniently used is polyvinylpyrrolidone (PVP). The viscosity modulating material may conveniently be present in an amount of from about 0.01% to about 65% by weight of the spray composition. Other examples of carriers/auxiliaries include preservatives (eg ethanol, benzyl alcohol, propylparaben and methylparaben). Preservatives may be present in an amount of from about 0.001% to about 10% by weight of the spray composition. Carriers/auxiliaries can also be flavors, sweeteners (e.g. sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g. saccharin, aspartame, acesulfame, sucralose, etc.). ) or sugar alcohols (eg, mannitol, xylitol, lactitol, maltitol syrup, etc.), which may conveniently be present in an amount of from about 0.001% to about 65% by weight of the spray composition. Other examples of carriers/auxiliaries include buffers and pH adjusters (eg, sodium hydroxide, citrate, and citric acid), which are conveniently present in an amount of from about 0.01% to about 5% by weight of the spray composition. Coloring agents (for example, present in an amount of from about 0.001 to about 5 wt.% of the spray composition), flavoring agents (for example, present in an amount of from about 0.001 to about 1 wt.% of the spray composition), chelating agents such as EDTA ( for example, present in an amount of from about 0.001 to about 1 wt.% of the spray composition), UV absorbers (for example, present in an amount of from about 0.001 to about 10 wt.% of the spray composition), and antifoam agents (for example, low molecular weight alcohols , dimethicone), for convenience present in an amount of from about 0.001 to about 5 wt.% of the spray composition, can also be included as appropriate carriers/auxiliaries in the spray formulations of this invention.

In one specific aspect of the present invention, a sublingual film is provided comprising dexmedetomidine, or a pharmaceutically acceptable salt thereof, together with one or more carriers and/or excipients, for the treatment of agitation.

Excipients that may be included in the sublingual films of this invention include one or more of the following: film forming agents, mouthfeel enhancers, plasticizers, stabilizers, surfactants, preservatives, sweeteners, colors, flavors, emulsifiers , disintegrants, salivary agents, antioxidants, penetration enhancers, solvents, and the like.

In most cases, film-forming agents means agents that provide the structure of the film according to this invention. The effective amount of film-forming agent is from about 10% to about 99% by weight, more preferably from about 50% to about 90% by weight of the composition.

- 12 042166

Film-forming agents that can be used as part of the film composition of this invention include, but are not limited to, cellulose ethers, modified starches, natural gums, food grade polymers, seaweed extracts, terrestrial plant extracts, pullulan, polyvinylpyrrolidone, their derivatives and their combinations.

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

Modified starches include, but are not limited to, acid and enzymatic hydrolysed corn and potato starches, their derivatives, and combinations thereof.

Examples of natural gums include, but are not limited to, gum arabic, guar gum, locust bean gum, carrageenan, gum arabic, karaya, gatti, tragacanth agar, tamarind gum, xanthan gum, derivatives thereof, and combinations thereof.

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

Examples of seaweed extracts include, but are not limited to, sodium alginate, carrageenans, derivatives thereof, and combinations thereof.

Land plant extracts include, but are not limited to, konjac, pectin, arabinoglactan, derivatives thereof, and combinations thereof.

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

The term solvent in most cases refers to liquids that dissolve solutes. The solvent can be used to dissolve the film-forming agents and other auxiliary substances for the preparation of film-forming compositions according to this 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. Sublingual film according to this invention may contain a solvent in an amount up to about 1 wt.%.

The term stabilizing agent generally refers to an agent that imparts stability to a composition over its shelf life. The stabilizing agents of this invention may include, for example, oil/water emulsifiers and flavors. An effective amount of a stabilizing agent in a composition of this invention may be, for example, in the range of from about 0 to about 45 wt.%, more specifically, from about 4 to about 25 wt.% of the composition. Examples of useful stabilizing agents of this invention include, but are not limited to, gum arabic, microcrystalline cellulose, carrageenan, xanthan gum, locust bean gum, derivatives thereof, and combinations thereof. Specific stabilizing agents of this invention include gum arabic and microcrystalline cellulose.

Disintegrants can help dissolve edible films, which ensures that the effect of said film is rapidly developed. Suitable disintegrants for use in the edible film of this invention include, but are not limited to, alginic acid, microcrystalline cellulose, and carboxymethyl cellulose. Special disintegrants, known as super disintegrants, are also suitable for use in the edible film of this invention. Superdisintegrants include crosslinked polymers (eg crospovidone), crosslinked starches (eg sodium starch glycolate) and crosslinked celluloses (eg modified carboxymethyl cellulose such as croscarmellose). These superdisintegrants are insoluble in water and most other solvents, have fast swelling properties and absorb water well with high capillary action resulting in rapid disintegration. Their insolubility in many solvents also means that they allow the sublingual compositions of this invention to be prepared in a one-step process as opposed to costly multi-step processes.

Disintegrators or superdisintegrants are conveniently present in the sublingual composition of this invention (eg, in an edible film) in an amount of from about 1 to about 10 wt.%, more specifically, from about 1 to about 5 wt.% of said composition.

Emulsifiers suitable for use in the edible film of this invention include, but are not limited to, gum arabic, carrageenan, triethanolamine stearate, quaternary ammonium compounds, gum arabic, gelatin, lecithin, bentonite, veegum, derivatives thereof, and combinations thereof. Emulsifiers can be used in the composition of this invention in an amount up to about 40 wt.%, more specifically, up to about 25 wt.% of the specified composition. The emulsifier may be a stabilizer, creating an oil/water emulsion that encapsulates volatile oils and flavors, thereby essentially acting as a flavor enhancer. A particular emulsifier for use in the edible film of this invention is gum arabic.

A plasticizing agent or plasticizer can be used to improve the flexibility and reduce the brittleness of the edible film composition of this invention. plasticizer

- 13 042166 agent can conveniently be up to about 30 wt.%, for example, up to about 15 wt.% of the specified composition. Examples of suitable plasticizers include, but are not limited to, glycerin, sorbitol, triacetin, monoacetin, diacetin, polyethylene glycol, propylene glycol, hydrogenated starch hydrolysates, corn syrups, low molecular weight propylene glycols, phthalate derivatives such as dimethyl, diethyl and dibutyl phthalate, citrate derivatives such as as tributyl, triethyl, acetyl citrate, castor oil and their derivatives, as well as combinations thereof. Specific plasticizers of this invention include sorbitol and glycerin.

In most cases, the term preservative refers to an excipient used to kill microorganisms or prevent, inhibit or retard their growth and reproduction, and is included in a product at a concentration sufficient only to prevent spoilage of the product or the growth of unintentionally added microorganisms. Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, and sodium benzoate. For convenience, the preservative may be present in the composition in an amount of from about 0.001% to about 10% by weight of said composition.

In most cases, the term sweetener refers to an excipient used to sweeten a pharmaceutical composition. Suitable sweeteners for use in the composition of this invention include, but are not limited to, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, and sucrose. For convenience, the sweetener may be present in the composition in an amount of from about 5% to about 20% by weight of said composition.

In most cases, the term coloring agent or dye refers to an excipient used to impart color to a pharmaceutical composition. Suitable dyes include, but are not limited to, FD&C Red #3, FD&C Red #20, FD&C Yellow #6, FD&C Blue #2, D&C Green #5, D&C Orange #5 , D&C Red No. 8, other F.D.&C colors, caramel, iron(III) oxide red, and natural colors such as grape skin extract, red beet powder, beta-carotene, annatto, carmine, turmeric, or paprika. For convenience, the coloring agent may be present in the composition in an amount of from about 0.001% to about 10% by weight of said composition.

In most cases, the term flavoring agent or flavoring agent refers to an excipient used to impart a pleasant taste (and often also a smell) to a pharmaceutical composition. Suitable flavoring agents include, but are not limited to, synthetic flavor oils, flavoring agents, natural oils, extracts of whole plants or parts thereof, such as leaves, flowers, fruits, or combinations thereof. Examples include cinnamon oil, wintergreen oil, 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 suitable flavorings include vanilla oil, citrus fruit oil such as lemon, orange, grape, lime or grapefruit oil, and fruit essences such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple or apricot essence. Flavors of particular interest for use in the composition of this invention include commercially available orange, grape, cherry, chewing gum flavors, and mixtures thereof. The amount of flavor used will depend on a number of factors, including the desired organoleptic effect. Specific flavors include grape and cherry flavors, as well as citrus fruit flavors such as orange flavor. For convenience, the flavorant may be present in the composition in an amount of from about 0.001% to about 10% by weight of said composition.

The term salivary agent is an agent that promotes more salivation during application of the composition of this invention. This can be an important feature if the composition is intended to be taken by a patient without the aid of water, to facilitate passage of said composition into the patient's stomach. The salivary inducing agent may be, for example, an emulsifier or a food acid which initiates salivation in the patient's mouth. Examples of emulsifiers useful as salivary agents include alkyl aryl sulfonates, alkyl sulfates, sulfated amides and amines, sulfated and sulfated esters and ethers, alkyl sulfonates, polyethoxylated esters, mono-, di- and triglycerides, monoglyceride and diacetyl-tartaric esters. acids, polyglycerol esters, sorbitan esters and ethoxylates, lactylated esters, phospholipids such as lecithin, polyoxyethylene sorbitan esters, proplyene glycol esters, sucrose esters, and mixtures thereof. Said emulsifier may be either saturated or unsaturated. It should be noted that some emulsifiers, which are salivary agents, may also function as binders. Examples of food acids useful as salivary agents include citric acid, malic acid, tartrate, food salts such as sodium chloride and salt substitutes, potassium chloride, and mixtures thereof. The amount of salivary agent present in the sublingual film of this invention may conveniently be up to about 15% by weight of the final composition, e.g.

- 14 042166 measures, in the range from about 0.3 to 0.4 wt.% of the specified composition.

In most cases, the term antioxidant refers to an excipient used to inhibit oxidation and thus prevent degradation of active agents by oxidative processes. Suitable antioxidants include, for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphoric acid, monothioglycerol, propyl gallate, sodium ascorbate, citric acid, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, EDHA, and sodium edetate. For convenience, the antioxidant may be present in the composition in an amount of from about 0.001% to about 2% by weight of said composition.

In most cases, the term penetration enhancer refers to an excipient used to enhance the penetration of the active agent into cell membranes or enhance local/systemic absorption of the active agent. Penetration enhancers that can be used in this invention include, but are not limited to, solubilizers such as alcohols, polyethylene glycols, chelating agents (eg, cyclodextrins), sucrose laurate, or sucrose oleate. For convenience, the penetration enhancer was present in an amount of from about 0.1% to about 5% by weight of said composition.

In one embodiment of the present invention, the sublingual pharmaceutical composition of the present invention comprises a mucosal permeation enhancer useful for enhancing mucosal absorption of said composition.

Sublingual formulations of dexmedetomidine (such as sprays, drops, and the like) can be prepared by mixing appropriate amounts of the above ingredients in accordance with standard good manufacturing practice principles. The relative amounts of each ingredient should not interfere with the desired pharmacological and pharmacokinetic properties of the resulting formulation.

The dexmedetomidine sublingual films of this invention can be conveniently prepared using PharmFilm® technology (proprietary of MonoSol) or technology owned by ARx LLC. Various patents and patent applications are incorporated herein in their entirety and include U.S. Patents or Publication Nos. 9585961, 7470397, 7727466, 9248146, 9545376, 2017-0087084, 9662297, 9662301, 2017-0246108, 20170252294, LLC assigned and 7425292, 7357891, 8663687, 8685437, 7897080, 8241661, 8617589, 8936825, 9561191, 9303918, 9346601, 8282954, 7972618, 9073294 assigned to Monosol.

In the manufacture of the sublingual film of this invention, the active agent, such as dexmedetomidine or a pharmaceutically acceptable salt thereof, film-forming agents, and optionally one or more carriers and/or excipients selected from the group consisting of a flavor enhancer, a plasticizer, a stabilizer, a surfactant, preservative, sweetener, coloring agent, flavoring agent, emulsifier, disintegrant, salivary agent, antioxidant, penetration enhancer, is 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 applied to a release carrier and dried to form a sheet/film. The carrier material must have a surface tension that allows the film solution to spread evenly across the intended carrier width without wicking to form a break bond between the film carrier substrates. Examples of suitable carrier materials include glass, stainless steel, Teflon, and polyethylene impregnated paper. Drying of the film can be carried out at high temperature using a drying oven, drying chamber, vacuum dryer, or any other suitable drying equipment that does not adversely affect the ingredients that make up the film. The sublingual film of this invention can also be prepared by other well-known methods, such as extrusion (eg, hot melt extrusion, solid dispersion extrusion), casting (eg, solid or semi-solid casting), rolling processes, and the like. .

V. Introduction.

In one aspect, 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 as needed to an animal subject (eg, human) in one, two or more doses per day. Said composition may also be administered as a single dosage form or multiple dosage forms.

In another aspect of the invention, there is provided a sublingual composition comprising dexmedetomidine, or a pharmaceutically acceptable salt thereof, administered to a subject in an amount sufficient to effectively treat agitation. In a particular aspect, the amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, administered is sufficient to effectively treat

- 15 042166 agitation without causing a significant sedative effect. Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may conveniently be delivered as needed to an animal subject (eg, human) in one, two, or more doses per day.

Said composition may also be administered as a single dosage form or multiple dosage forms.

Upon administration of a composition of this invention to a subject, a therapeutic (i.e., antiagitation) effect may begin within about 60 minutes (e.g., within about 30, 20, 15, 10, 5, 3, 2, or 1 minutes) after administration, or within for about 30 seconds after administration. Signs of agitation may also resolve within about 1 to about 60 minutes after administration, and more typically within about 5 to about 30 minutes. A second dose of a composition of this invention may be administered to a subject if signs of agitation do not subside within about 60 minutes.

Treatment protocols may include one or more dosing intervals (eg, two or more dosing intervals, five or more dosing intervals, or ten or more dosing intervals). Depending on the physiology of the subject and the desired therapeutic effect, the duration of dosing intervals and treatment protocols in accordance with embodiments of the present invention may vary.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may be administered as a sublingual composition for the treatment of agitation or signs of agitation, either as monotherapy or in combination with one or more other active agents. When used in combination, the active agents may be formulated either as a single composition or as two or more separate compositions, which may be administered simultaneously, sequentially, or over a period of time.

In cases where dexmedetomidine or a pharmaceutically acceptable salt thereof is administered with a second active agent for the treatment of agitation or signs of agitation, the weight ratio, respectively, 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; from about 1:5 to about 1:10; and from about 1:10 to about 1:25. For example, the weight ratio may specifically be from about 1:1 to about 1:5; from about 1:5 to about 1:10; about 1:10 to about 1:15; or from about 1:15 to about 1:25.

Alternatively, the weight ratio, respectively, of the 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 from about 10:1 to about 25:1. For example, the weight ratio, respectively, of the second active agent to dexmedetomidine or a pharmaceutically acceptable salt thereof may, in particular, range from about 1:1 to about 5:1; about 5:1 to about 10:1; about 10:1 to about 15:1; or from about 15:1 to about 25:1.

It should be understood that all ranges between these ranges are also covered in this document and constitute additional specific aspects of this invention.

VI. Dosing regimen.

The dosage regimen used 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 the underlying disease.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may be administered sublingually to an animal (eg, human) at any suitable dose. In certain embodiments of the present invention, the indicated human dose may be from about 3 to about 100 micrograms (e.g., from about 5 to about 100 micrograms, from about 5 to about 90 micrograms, from about 5 to about 85 micrograms, from about 5 to about 80 µg, about 5 to about 75 µg, about 5 to about 70 µg, about 5 to about 65 µg, about 5 to about 60 µg, about 5 to about 55 µg, about 5 to about 50 µg, about 5 to about 45 µg, about 5 to about 40 µg, about 5 to about 35 µg, about 5 to about 30 µg, about 5 to about 25 µg, about 5 to about 20 µg, about 5 to about 15 micrograms, about 5 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 mcg, about 16 mcg, about 18 mcg, about 20 mcg, about 30 mcg, about 50 mcg). The specified dose can be administered one or more times a day.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may be administered sublingually to a human at any suitable dose. In some embodiments, the human dose may be from about 0.05 to about 1.5 μg/kg of the subject's weight. Examples of suitable dosages include about 0.1 to about 1 µg/kg, about 0.1 to about 0.5 µg/kg, about 0.1 to about 0.4 µg/kg, about 0.1 to about 0.3 µg/kg, about 0.1 to about 0.2 µg/kg, about 0.07 µg/kg, about 0.05 µg/kg,

- 16 042166 about 0.1 µg/kg, about 0.2 µg/kg, about 0.3 µg/kg, about 0.4 µg/kg, about 0.5 µg/kg, about 0.6 µg/kg , about 0.7 µg/kg, about 0.8 µg/kg, about 0.9 µg/kg, about 1.0 µg/kg, about 1.1 µg/kg, about 1.2 µg/kg, about 1.3 mcg/kg, about 1.4 mcg/kg, about 1.5 mcg/kg. The specified dose can be administered one or more times a day.

VII. Embodiments of the present invention.

Embodiment of the Invention 1. A method of treating agitation or signs 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.

Embodiment 2. A method of treating agitation or signs of agitation in a subject in need thereof, comprising administering to said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually at a dose that is effective to treatment of agitation or signs of agitation without causing significant sedation.

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

Embodiment 4. The method of embodiments 1, 2 or 3, wherein said subject is a mammal, preferably a human.

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

An embodiment of the present invention 6. The method of embodiment 5, wherein said neurodegenerative disease is selected from Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (RTB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

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

Embodiment of the Invention 8. The method of Embodiment 7 wherein said neuropsychiatric condition is selected from schizophrenia, bipolar illness (such as mania, disorders), delirium and depression.

Embodiment of the Invention 9. The method of Embodiment 5 wherein the agitation is associated with evening confusion syndrome in dementia or Alzheimer's disease.

Embodiment 10. A sublingual composition for use in the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being non-perioperative agitation, and said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or a large number of pharmaceutically acceptable carriers/ excipients.

Embodiment 11. A sublingual composition for use in the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with a neurodegenerative disease and said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers/excipients.

Embodiment 12. A sublingual composition for use in the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with a neuropsychiatric condition, and said sublingual composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers/excipients.

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Embodiment 13. A sublingual composition for use in the treatment of agitation or signs of agitation in a subject in need thereof, said agitation being associated with evening confusion syndrome in dementia or Alzheimer's disease, and said sublingual composition comprising an effective amount of dexmedetomidine or its pharmaceutically acceptable salt together with one or more pharmaceutically acceptable carriers/auxiliaries.

An embodiment of the present invention 14. The sublingual composition of embodiment 11 wherein said neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (LTD), post-traumatic stress disorder , Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

Embodiment 15. The sublingual composition of Embodiment 14 wherein said neurodegenerative disease is selected from dementia, frontotemporal dementia, Alzheimer's disease and Parkinson's disease.

Embodiment 16. The sublingual composition of Embodiment 12 wherein said neuropsychiatric condition is selected from the group consisting of schizophrenia, bipolar disease (such as mania, disorder), delirium and depression.

An embodiment of the present invention 17. A sublingual composition according to any one of embodiments 10-16, wherein said composition is selected from a film, capsule, patch, lozenge, gel, spray, tablet, liquid drop or the like.

An embodiment of the present invention 18. Sublingual composition according to embodiment 17, characterized in that said composition is a film.

Embodiment of the Invention 19. The sublingual composition of Embodiment 18, wherein the film is mucoadhesive in nature and provides a rapid onset of action.

Embodiment 20. The sublingual composition of any one of embodiments 10-19, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered at a dose that is effective in treating agitation or signs of agitation without causing significant sedation.

An embodiment of the present invention 21. The sublingual composition of embodiment 20, wherein the observed level of sedation does not exceed 3 on the Ramsey sedation scale.

Embodiment 22. The sublingual composition of any one of embodiments 10-21, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to said subject (e.g., human) at a dose in the range of about 3 to about 100 μg (e.g., from about 5 to about 100 µg, about 5 to about 90 µg, about 5 to about 85 µg, about 5 to about 80 µg, about 5 to about 75 µg, about 5 to about 70 µg, about 5 up to about 65 µg, about 5 to about 60 µg, about 5 to about 55 µg, about 5 to about 50 µg, about 5 to about 45 µg, about 5 to about 40 µg, about 5 to about 35 mcg, about 5 to about 30 mcg, about 5 to about 25 mcg, about 5 to about 20 mcg, about 5 to about 15 mcg, about 5 to about 10 mcg, less than 10 mcg (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).

Embodiment 23. A method of treating agitation or signs 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 the agitation is not perioperative agitation.

An embodiment of the present invention 24. The method of embodiment 23 wherein the agitation is associated with a neurodegenerative disease and/or a neuropsychiatric condition.

An embodiment of the present invention 25. The method of embodiment 24 wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (LBD), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy and progressive supranuclear palsy, or other associated neurodegenerative disorders.

An embodiment of the present invention 26. The method of embodiment 24 wherein the neuropsychiatric condition is selected from the group consisting of schizophrenia, bipo

- 18 042166 mental illness (eg bipolar disorder or bipolar mania), delirium and depression.

An embodiment of the present invention 27. The method of any one of embodiments 23-26, wherein the agitation or signs of agitation are treatable without significant sedation.

Embodiment 28. The method of any one of embodiments 23-27, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a film, capsule, patch, lozenge, gel, spray, tablet, liquid drop, or the like.

An embodiment of the present invention 29. A method of treating agitation or signs 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, said agitation being associated with AMB/STAC procedures ( e.g. MRI, CT or CT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extractions, or other dental procedures).

Embodiment 30. A method of treating agitation or signs 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, said agitation being associated with a withdrawal syndrome occurring with the abolition of alcohol and psychoactive substances.

Embodiment 31. The method of embodiment 29 or 30 wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually at a dose that is effective to treat said agitation or signs of agitation without causing significant sedation.

Embodiment of the Invention 32. The method of Embodiment 31 wherein said dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is in the range of about 3 to about 100 µg (e.g., about 5 to about 100 µg, about 5 to about 90 µg, about 5 to about 85 µg, about 5 to about 80 µg, about 5 to about 75 µg, about 5 to about 70 µg, about 5 to about 65 µg, µg, about 5 to about 40 mcg, about 5 to about 35 mcg, about 5 to about 30 mcg, about 5 to about 25 mcg, about 5 to about 20 mcg, about 5 to about 15 mcg, about 5 to about 10 mcg , less than 10 micrograms (for example, 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 mcg, about 50 mcg).

An embodiment of the present invention 33. A composition or method according to any of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once, twice or three times a day or as needed.

Embodiment 34. A composition or method according to any of the preceding embodiments, wherein dexmedetomidine, or a pharmaceutically acceptable salt thereof, is administered in such a manner that it exerts therapeutic effect in less than about 60 minutes, especially within about 30 seconds to about 30 min.

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

Embodiment 36. A method of treating agitation or signs of agitation in a subject in need thereof, comprising administering to said subject an effective amount of an alpha-2-adrenergic agonist or a pharmaceutically acceptable salt thereof, wherein said alpha-2-adrenergic agonist is administered sublingually at a dose that is effective in treating agitation or signs of agitation without causing significant sedation.

An embodiment of the present invention 37. The method of embodiment 35 or 36, wherein said dose of the alpha-2-adrenergic agonist is in the range of about 3 to about 100 micrograms (e.g., about 5 to about 100 micrograms, about 5 to about 90 µg, about 5 to about 85 µg, about 5 to about 80 µg, about 5 to about 75 µg, about 5 to about 70 µg, about 5 to about 65 µg, about 5 to about 60 mcg, about 5 to about 55 mcg, about 5 to about 50 mcg, about 5 to about 45 mcg, about 5 to about 40 mcg, about 5 to about 35 mcg, about 5 to about 30 mcg , from about 5 to about 25 micrograms, from about 5 to about 20 micrograms, from about 5 to about 15 micrograms, from about 5 to about 10 micrograms, less than 10 micrograms (for example, about 5, 6, 7, 8 or 9 mcg), about 10 mcg, about 12 mcg, about 14 mcg, about 15 mcg, about 16 mcg, about 18 mcg, about 20 mcg, about 30 mcg, about 50 mcg).

An embodiment of the present invention 38. The method of embodiments 35, 36 or 37, wherein said subject is a mammal, preferably a human.

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An embodiment of the present invention 39. The method of any one of embodiments 35-38, wherein said agitation is associated with a neurodegenerative disease.

An embodiment of the present invention 40. The method of embodiment 39, wherein said neurodegenerative disease is selected from Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (LTD), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

An embodiment of the present invention 41. The method of any one of embodiments 35-38, wherein the agitation is associated with a neuropsychiatric condition.

An embodiment of the present invention 42. The method of embodiment 41 wherein said neuropsychiatric condition is selected from schizophrenia, bipolar illness (such as mania, disorders), delirium and depression.

Embodiment of the Invention 43. The method of Embodiment 39, wherein the agitation is associated with evening confusion syndrome in dementia or Alzheimer's disease.

An embodiment of the present invention 44. The method of any one of embodiments 35-38, wherein said agitation is an AMB/STAC associated procedure (e.g., MRI, CT or CT scan, lumbar puncture, bone marrow aspiration/biopsy, removal teeth or other dental procedures)

An embodiment of the present invention 45. A method according to any one of embodiments 35-38, wherein said agitation is associated with a withdrawal syndrome that occurs upon withdrawal of alcohol and psychoactive substances.

An embodiment of the present invention 46. The method of any one of embodiments 35-38, wherein said alpha-2 adrenergic agonists include, but are not limited to, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, dexmedetomidine , methyldopa, methylnorepinephrine, fadolmidine, iodoclonidine, apraclonidine, detomidine, lofexidine, amitraz, mivaserol, azepexol, talipexol, rilmenidine, naphazoline, oxymetazoline, xylometazoline, tetrahydrozoline, tramazolidinidine, tramazolin, talipexol, romifidine, propyloximonemidine, norphenoxamidine, norphenoxamidine, norphenimonemidine , tolonidine, UK14304, DJ-7141, ST-91, RWJ-52353, TCG-1000, 4-(3-aminomethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione, and also 4-(3 -hydroxymethylcyclohex-3-enylmethyl)-1,3-dihydroimidazole-2-thione or their pharmaceutically acceptable salts.

The embodiments above are not intended to be limiting, and alternative or additional embodiments of the invention may be envisaged in the practice of this invention.

VIII. Examples.

The following examples are intended to be illustrative and not limiting.

Example 1

Composition 1. Sublingual tablet.

Table 1

Composition for exemplary formulation of a sublingual tablet used for sublingual delivery

Ingredients Quantity Ranges Dexmedetomidine HC1 (base equivalent) 50 micrograms Povidone 5.0 mg 1.0-10.0% Croscarmellose sodium 7.0 mg 5 - 15% Sucralose 1.0 mg 0.05 - 3.0% magnesium stearate 0.75 mg 0.1-2.0% Talc 0.75 mg 0.1-2.0% Mannitol q. s 75.0 mg q. s. 100 % Water q. s

Manufacturing process.

Dexmedetomidine hydrochloride and excipients such as binder and sweetener are dissolved/dispersed in a pharmaceutically acceptable solvent (preferably water) and this solution is used to granulate the sieved mixture of all other ingredients except lubricant and glidant in a suitable mixer/ granulator. Behind

-20042166 The granules are then dried in a fluid bed dryer or other suitable dryer such as a tray dryer. The dried granules are then sorted by size in a quad crusher or a multi crusher. The sized granules are then loaded into a suitable blender, such as a V-blender, and lubricated with magnesium stearate and talc, after which the final lubricated mixture is used for compression into sized tablets using appropriate equipment.

Composition 2. Sublingual film.

Table 2 Composition for typical sublingual film formulation used for sublingual delivery

Ingredients Quantity Ranges Dexmedetomidine HC1 (base equivalent) 50 micrograms polyethylene oxide 5.0 mg 3 - 25% Polyethylene glycol 5.0 mg 3 - 25% Sucralose 0.2 mg 0.05 - 3.0% flavoring q. s. 0.01 - 1.0% Dye q. s. 0.01 - 1.0% Povidone q. s. 50 mg q. s. 100 %

Manufacturing process.

Dexmedetomidine hydrochloride, together with film-forming polymers and other excipients, is dissolved/dispersed in a pharmaceutically acceptable solvent (preferably water) and the resulting solution is then applied (spread/cast) onto an inert coating layer. The polymeric layer containing dexmedetomidine hydrochloride is then dried, separated and cut into appropriate sized pieces using appropriate dies/tools, and then packaged as required.

Composition 3. Sublingual spray.

Table 3

Composition for exemplary sublingual spray formulation _______________used for sublingual delivery _______________

Ingredients Quantity Ranges Dexmedetomidine HC1 (equivalent to base) 50 micrograms propylene glycol 10 µl 1.0-40.0% Alcohol 5 µl 1.0-40.0% Citric acid 0.2 mg 0.1 - 10% Peppermint 1 µl 0.05 - 3.0% Purified water q. s. 100 µl q. s. 100 %

Manufacturing process.

Dexmedetomidine hydrochloride, together with all other excipients, are mixed in the appropriate order. The resulting solution/dispersion is then filled into spray cans using appropriate equipment. The cans are then fitted with dispensing nozzles so that a certain amount of dexmedetomidine is delivered each time they are actuated.

Composition 4. Sublingual liquid drops.

Table 4

Composition for typical sublingual liquid drops used for sublingual delivery

Ingredients Quantity Dexmedetomidine HC1 (base equivalent) 10 mg Physiological saline solution (0.9% sodium chloride) q. s

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Manufacturing process.

Dexmedetomidine hydrochloride (catalog number SML0956) was dissolved in physiological saline to give a concentration of 1 mg/ml sublingual drops.

Example 2

Evaluation of the effect of sublingual and intravenous administration of dexmedetomidine hydrochloride in a resident alien rat model of agitation or aggression using various doses.

The alien-resident model is a well-known preclinical model of aggression and agitation and allows spontaneous and natural expression of both attack/agitation aggression and defensive behavior in laboratory rodents under semi-natural laboratory conditions. When rodents are exposed to a new male in their home cage environment, they perceive the new male as a foreigner and display defensive behaviors such as anogenital sniffing, stalking, biting and attacking (Nelson et al., ILAR Journal (2000), 41(3 ):153-162).

Materials and methods.

Animals: 12-13-week-old male Wistar rats weighing 380-400 g were used as male residents. Male rats of 7-8 weeks weighing from 280 to 300 g were used as strangers. Resident rats were kept with female rats for 8 days to establish territoriality. The alien rats were housed in groups of three with other male rats of similar age/body weight. All animals were kept in a controlled environment with temperature 22±3°C, humidity 50±20%, light/dark cycle of 12 h each and 15-20 changes of fresh air per hour and had free access to food and water. All animal experiments were conducted in accordance with the guidelines of the Committee for the Control and Supervision of Animal Experimentation (CPCSEA), the Federal Government of India's International Animal Laboratory Evaluation and Accreditation Association (AAALAC).

Analyzed composition: The required amount of composition 4 dexmedetomidine hydrochloride was weighed and serial dilutions were made to obtain the appropriate doses according to table. 5. Dilutions were prepared fresh each day prior to dosing using 0.9% physiological saline from Formulation 4 for the entire study.

Procedure for the experiment: After acclimatization for 3-5 days, each resident male was placed for 8 days with a female rat. On day 8, resident males were analyzed for basic aggression by exposing them to contact with an intruder rat for 10 min. Only those animals that showed aggression in this basic aggression test were used for the study. These animals were then randomized using the body weight stratification method. During randomization, the change in the weight of the animals did not exceed 20% of the average body weight in the group. The animals were housed with a female rat for an additional day. On day 9, the resident animal was mated with an intruder animal of the appropriate weight, so that the body weight of the resident was always greater than that of the intruder. This was supposed to promote dominant, aggressive behavior in resident animals. After randomization, animals were assigned a permanent number. Cells were identified by cards with study number, study code, group number, sex, dose, cell number, and animal number.

Male resident rats were administered various doses of dexmedetomidine hydrochloride (Dex) 15 min prior to behavioral analysis either sublingually or intravenously (Table 5). For sublingual administration, rats were held in one hand and the tongue moved to one side of the mouth with a blunt spatula. Dexmedetomidine hydrochloride was then administered sublingually in the form of liquid drops at a certain concentration using a micropipette and allowed to be absorbed for 50-60 seconds. Diazepam was used as a control compound and was administered intraperitoneally. For the vehicle control group, 0.9% physiological saline was administered sublingually or intravenously. The normal control (NC) group did not receive any treatment.

The behavior of resident rats was recorded with a hanging video camera for 15 min, and offline behavior analysis was performed using the Noldus Ethovision XT software. To distinguish the resident rat from the alien rat in the videotape, the alien rat was marked with a non-toxic paint. To analyze the potential effect of dexmedetomidine hydrochloride on agitation, the authors quantified various behavioral parameters such as anogenital sniffing, stalking, biting, attacking, and waiting time before attacking, as well as neutral behavioral parameters such as searching activity, grooming, and immobility.

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Table 5

Efficacy Study: Treatment Groups

Group No. Number of animals Cohort 1 (Sublingual Dosing Formulation 4 adjusted for the following doses) Cohort 2 (Intravenous dose of dexmedetomidine hydrochloride in water or saline) 1 8 Normal control 2 8 Vehicle as control Vehicle as control 3 8 Dexmedetomidine hydrochloride (0.5 mcg/kg) Dexmedetomidine hydrochloride (0.5 mcg/kg) 4 8 Dexmedetomidine hydrochloride (1.0 mcg/kg) Dexmedetomidine hydrochloride (1.0 mcg/kg) 5 8 Dexmedetomidine hydrochloride (1.5 mcg/kg) Dexmedetomidine hydrochloride (1.5 mcg/kg) 6 8 Dexmedetomidine hydrochloride (3.0 mcg/kg) Dexmedetomidine hydrochloride (3.0 mcg/kg) 7 8 Diazepam (3 mg/kg, i.p.)

Statistical analysis: Statistical analysis was performed using validated statistical software (GraphPad Prism 6). Data are presented as mean ± SOS. A one-way ANOVA (analysis of variance) analysis of variance followed by Dunnett's multiple comparison test with 95% confidence interval was used to compare the respective groups. p<0.05 was considered significant.

Results: This study was designed to evaluate the effect of sublingual/intravenous administration of various doses of dexmedetomidine hydrochloride on agitated behavior in a rat resident alien model of agitation or aggression.

Effect of sublingual/intravenous dexmedetomidine hydrochloride on aggressive/agitation behavior in a resident alien model in rats.

Rats exhibit various defensive agitated behaviors such as anogenital sniffing, stalking, biting, and attacking (indicators of agitated and aggressive behavior) when exposed to a new male in their home cage. The non-resident male is perceived as an outsider, and the resident male has signs of agitation and attacks the outsider male to defend his territory. In these experiments, vehicle-treated rats exhibited a wide range of aggressive behaviors, and the intruder rat was subjected to anogenital sniffing, attack, harassment, and biting by the resident or dominant rat.

Sublingually administered dexmedetomidine hydrochloride (Dex) reduced the frequency and duration of these behaviors in a dose-dependent manner (FIGS. 1A and 1B). Significant reductions were observed in stalking and assault rates compared to the vehicle-treated control group. Similarly, intravenous administration of dexmedetomidine hydrochloride (Dex) reduced all measures of aggressive and agitated behavior (FIGS. 1C and 1D). At doses above 0.5 μg/kg, there was a significant reduction in anogenital sniffing, biting, and assault compared to vehicle-treated control animals (FIGS. 1C and 1D). The reference compound diazepam (3 mg/kg, ip) also caused a significant reduction in all measures of aggressive and agitated behavior assessed in this study (Fig. Ία-ID).

Effect of sublingual/intravenous dexmedetomidine hydrochloride on the pre-attack waiting period.

In addition to changing the frequency and duration of attacks by a resident male, the authors also evaluated the effect of dexmedetomidine hydrochloride (Dex) on the waiting period before attacking an intruder rat. The authors observed an increase in the waiting period before attacking a stranger rat after sublingual administration of dexmedetomidine hydrochloride (Dex) in a dose-dependent manner, indicating a decrease in the level of aggression and agitation (Fig. 2A). When dexmedetomidine hydrochloride (Dex) was administered intravenously, a similar increase in waiting time before attacking an intruder rat occurred in a dose-dependent manner that was significant compared to vehicle controls at 3 μg/kg (Fig. 2B). Animals treated with diazepam showed a complete absence of attack behavior (FIGS. 2A and 2B).

Effect of sublingual/intravenous dexmedetomidine hydrochloride on neutral behavior.

Neutral behavior such as grooming, exploratory activity, and immobility/rest period were assessed after treatment with dexmedetomidine hydrochloride. After sublingual administration of dexmedetomidine hydrochloride, no significant changes were observed, with the exception of

- 23 042166 I eat a decrease in search activity observed at doses of 1.5 and 3 μg/kg (Fig. 3A and 3B), compared with control animals treated with the carrier. Similarly, intravenous administration of dexmedetomidine hydrochloride had no significant effect on body grooming and exploratory activity compared to vehicle-treated control animals, except at a dose of 3 μg/kg. With respect to the effect on immobility/rest period, no significant effect of sublingually administered dexmedetomidine hydrochloride compared to vehicle controls was noted, although intravenous dexmedetomidine hydrochloride significantly increased immobility period at 3 μg/kg (FIGS. 3C and 3F). The reference compound diazepam (3 mg/kg, ip) significantly reduced the frequency and duration of all neutral behaviors assessed in this study.

Interpretation.

In this study, the authors examined the potential of dexmedetomidine hydrochloride to reduce aggression and agitation in a resident-alien model in rats. The resident-alien model is a well-known preclinical aggression/agitation model and allows spontaneous and natural expression of both attack/agitation aggression and defensive behavior in laboratory rodents under semi-natural laboratory conditions.

1. Sublingual administration of dexmedetomidine hydrochloride resulted in a dose-dependent reduction in several behavioral indicators of aggression and agitation, such as anogenital sniffing, stalking, attacking, and biting.

2. A significant increase in waiting time before being attacked by an intruder rat was observed in a dose-dependent manner with prior treatment with dexmedetomidine hydrochloride compared to the vehicle control group.

3. No changes were observed in the neutral behavior of the animals, indicating no overt anxiety behavior in resident rats treated with sublingually administered dexmedetomidine hydrochloride.

4. Of the doses used in this study (0.5-3mcg/kg), doses of 1-1.5mcg/kg (sublingual or intravenous doses) effectively reduced behavioral measures of aggression and agitation without significant effect on neutral behavior .

Conclusion: Dexmedetomidine hydrochloride effectively reduces various measures of agitation and aggression in a resident-alien model in rats. A dose of 1-1.5 µg/kg effectively reduced behavioral indicators of aggression and agitation without significant effect on neutral behavior. In this study, the efficacy of sublingually administered dexmedetomidine hydrochloride correlated with intravenous dexmedetomidine hydrochloride at these doses (Table 6).

Table 6

Group p-values obtained after statistical comparison of the sublingual and intravenous route of administration using Student's t-test Duration (sec) The pursuit biting Assault/fight Anogenetic sniffing Waiting period before attack NK 1,000 1,000 1,000 1,000 1,000 Carrier 0.207 0.069 0.290 0.753 0.136 1 µg/kg 0.506 0.102 0.204 0.090 0.207 1.5 µg/kg 0.125 0.059 0.107 0.727 0.508

Compared between sublingual and intravenous administration of dexmedetomidine hydrochloride at doses of 1 and 1.5 mcg/kg, no significant differences (i.e., similar effects from sublingual versus intravenous administration) regarding the duration of behavioral indicators of aggression and agitation (chasing, biting , attack, anogenital sniffing, waiting period before attack) were not observed. Statistical analysis was performed using Student's t-test. *p<0.05, **p<0.01, ***p<0.001 and ****p<0.0001.

Comparison of sublingual and intravenous routes of administration.

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

Example 3 Quantification of dexmedetomidine (0.5-3 μg/kg) in rat plasma samples by LC-MS/MS.

Purpose: To evaluate the levels of dexmedetomidine in plasma samples from rats obtained after intravenous and sublingual administration of doses of 0.5, 1, 1.5 and 3 µg/kg to animals.

Blood sampling: To determine the concentration of dexmedetomidine in plasma, rats (n=3) were administered

- 24 042166 dexmedetomidine hydrochloride sublingually or intravenously in different doses (formulation 4 was adjusted to 0.5, 1, 1.5, 3 µg/kg). Blood was collected under light anesthesia with isoflurane from the retroorbital plexus at 0, 5, 15, 30, 60, and 120 minutes post-dose. Plasma was separated and stored at -80°C until analysis of the concentration of dexmedetomidine.

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 reach a concentration of 829.071 mg/ml. Working solutions of various concentrations were prepared using a diluent (methanol:water (50:50)% v/v).

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 reach a concentration of 25 mg/ml. Working solutions of various concentrations were prepared using a diluent (acetonitrile:water (50:50)% v/v).

Solution preparation for SPE and chromatography:

Mobile phase A (10 mM ammonium formate, pH 3.50): Weigh 0.6306 g of ammonium formate and transfer to a 1000 ml reagent bottle. To this was added 1000 ml of milli-Q water and the pH of the resulting solution was adjusted to 3.5 with formic acid.

Mobile phase B: 100% acetonitrile.

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 a diluent.

Wash solution: 100 µl of ammonia was mixed with 100 ml of milli-Q water. The resulting solution was used as a wash solution.

Elution solvent: 100 µl of formic acid was mixed with 100 ml of acetonitrile. The resulting solution was used as the elution solvent.

Analytical Methods: Samples were analyzed using an Agilent 1290 Infinity II HPLC system connected to an AB Sciex Triple Quad instrument (API-5000). Chromatographic separation was performed using an Agilent Zorbax Eclipse plus C18 column (50x2.1 mm, 1.8 µm) in gradient mode. The mobile phase consisted of 10 mM ammonium formate pH 3.5 (mobile phase A) 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 mode (ESI+). For analysis, 2 μl of sample was injected into the LC-MS/MS instrument. The autosampler temperature was 7°C.

Samples for quality control (QC) were prepared in accordance with table. 7.

Table 7

Dexmedetomidine conc (Solution A) (ng/ml) Volume of solution A (µl) Blank plasma pool (µl) Total volume (µl) Final calibration Conc (pg/ml) KKID 1.114 2 48 50 44.571 LQC 371.424 2 48 50 14856.962 MQC 928.560 2 48 50 37142.406 HQC

Sample preparation.

A 96-well WCX SPE plate was used for sample preparation. For extraction, 50 μl of a plasma sample was used. Along with the test samples, one linearity set and two quality control (QC) sets were also processed.

Pretreatment of samples: To 50 µl of plasma was added 10 µl of tolbutamide working solution (tolbutamide 250 ng/ml). After mixing, 50 μl of buffer solution (10 mM ammonium formate, pH 3.5) was added. The contents were swirled and loaded onto a pretreated SPE plate.

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 pre-treated plasma samples were then loaded into pre-conditioned cartridges.

After loading the pretreated plasma samples, the cartridges were washed with 100 µl of 0.1% ammonia solution. Finally, the bound analyte was eluted using 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 was added 50 µl of 10 mM ammonium formate (pH 3.5), the samples were vortexed and transferred to a 96-well HPLC plate (Agilent) and submitted for analysis by LC-MS/MS. For LC-MS/MS analysis, 2 μl of sample was injected. Calibration standards and QCs were processed in the same way as for the test samples.

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.

- 25 042166 (Table 8 and FIGS. 4A and 4B) with a calibration curve in the range of 0.011-53.061 ng/ml prepared in blank rat plasma. The calibration curve was fitted using linear regression. The concentrations in QC and test samples (pg/ml) 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 non-zero calibration standards must be included in the calibration curve with all reciprocal calculated concentrations within ±20% of nominal concentration (except for the lower quantitation level, LLOQ, where ±20% variation is acceptable);

2) the correlation coefficient (r) of the calibration curve must be greater than or equal to 0.99;

3) at least two-thirds (4 out of 6) of the QC samples must be within ±20% relative error (accuracy).

Results.

Table 8

Mean plasma concentrations in rats after sublingual or intravenous administration of dexmedetomidine hydrochloride at various doses

Groups with sublingual administration (I-IV) Mean concentration in pg/mL at various time points post-dose Groups with intravenous administration (V- νπΐ) Concentration in pg/ml at various time points after dosing. 0 min 5 minutes 15 minutes 30 min 60 min 120 min 0 min 5 minutes 15 minutes 30 min 60 min 120 min I - Dex. HC1 0.5 mcg/kg, s/l BLQ 48± 30.4 51 ± 29.1 87 ± 89.7 17±0.7 BLQ V - Dex. HC1 0.5 mcg/kg, i.v. BLQ 70ά 7.2 46 ± 14.2 35 ± 4.9 19 ά 3.5 BLQ II - Dex. HC1 1 mcg/kg, s/l BLQ 51 ά 44.7 47 ± 22.4 43 ± 13.5 13 ά 2.8 19 ± 7.07 VI - Dex. HC1 1 mcg/kg, i.v. BLQ 174 ά 12.5 90 ± 12.1 45± 1.7 63 d 58.0 BLQ III - Dex. HC1 1.5 mcg/kg, s/l BLQ 84 ± 37.7 27 ± 7.1 31 ± 5.5 37 ± 16.3 36 ± 6.36 VII - Dex. HC1 1.5 mcg/kg, i.v. BLQ 158 ά 56.1 114 ± 1.7 65±11.0 31 ά 10.3 21 ± 8.89 IV - Dex. HC1 3 µg/kg, s/l BLQ 71 ± 52.0 42 ± 13.0 160 ± 117.9 96 ά 21.5 93 ± 53.95 VIII - Dex. HC1 3 mcg/kg, i.v. BLQ 471 d 24.9 266 ± 31.6 139 ± 18.0 84 ± 17.4 34 ± 9.61

BLQ: below the lowest limit of quantification of the assay (LOQ: 0.05 ng/mL);

s/l: sublingually;

in / in: intravenously.

Data are expressed as mean ± SD.

Interpretation and conclusions.

After sublingual administration of dexmedetomidine hydrochloride, a dose-dependent effect on plasma concentrations was observed at doses in the range of 0.5-3 μg/kg (FIG. 4A, Table 8).

After intravenous administration of dexmedetomidine hydrochloride, a dose-dependent effect on plasma concentrations was observed at doses in the range of 0.5-3 μg/kg (FIG. 4B, Table 8).

Doses of 1 and 1.5 µg/kg effectively reduced various measures of agitation and aggression without significantly affecting neutral behavior. Plasma concentrations after a dose of 1 µg/kg (sublingual and intravenous) over the range of 15 to 30 minutes (time corresponding to the behavioral response time observed in the efficacy study; the drug was administered 15 minutes before behavioral analysis for agitation and the animal was observed within 15 min) ranged from 43±13.5 to 90±12.1 pg/ml (Table 8). Similarly, plasma concentrations after a dose of 1.5 μg/kg (sublingually and intravenously) in the range from 15 to 30 minutes vary from 27 ± 7.1 to 114 ± 1.7 pg / ml (Table 8).

Claims (11)

CLAIM 1. A method of treating agitation in an agitated subject, comprising administering to the oral mucosa of said subject an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof that does not cause a significant sedative effect for about 60 minutes after administration, while the agitation is associated with bipolar disorder. 2. The method according to claim 1, characterized in that said dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a dosage form selected from the group consisting of film, capsule, patch, lozenge, gel, spray, tablet and liquid drops. 3. The method according to claim 1 or 2, characterized in that said dexmedetomidine or its pharmaceutical - 26 042166 a ski acceptable salt is administered at a dose in the range of about 3 to about 100 micrograms. 4. The method of claim 3, wherein said dose is from about 5 to about 30 micrograms. 5. The method according to claims 1 to 4, characterized in that the agitation includes aggression. 6. Method according to claims 1 to 4, characterized in that the agitation is an acute agitation. 7. Method according to claims 1 to 4, characterized in that the agitation is chronic agitation. 8. The method according to claims 1 to 4, characterized in that the agitation is characterized by a severe course. 9. The method according to claims 1 to 8, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. 10. The method according to claims 1 to 8, characterized in that dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally. 11. The method according to claims 1 to 10, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.